Fresenius Kabi Usa, Llc

Fresenius Kabi Usa, Llc Drugs

• Polymyxin B
  

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  Polymyxin B

  

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  ParenteralIntravenous

  Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral  5% Dextrose Injection for continuous drip.Adults and children: 15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function. This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment. Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day.Infants: Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects. Intramuscular Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 Polymyxin B units in 2 mL Sterile Water for Injection or 0.9% Sodium Chloride Injection or Procaine Hydrochloride Injection 1%.Adults and children: 25,000 to 30,000 units/kg/day. This should be reduced in the presence of renal impairment. The dosage may be divided and given at either 4 or 6 hour intervals.Infants: Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.Note: Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by Ps aeruginosa. Intrathecal A treatment of choice for Ps aeruginosa meningitis. Dissolve 500,000 polymyxin B units in 10 mL 0.9% Sodium Chloride Injection, USP for 50,000 units per mL dosage unit.Adults and children over 2 years of age: Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.Children under 2 years of age: 20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day. Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal. IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS.Topical Ophthalmic:

  Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection, USP for a 10,000 to 25,000 units per mL concentration. For the treatment of Ps aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates.Subconjunctival injection of up to 100,000 units/day may be used for the treatment of Ps aeruginosa infections of the cornea and conjunctiva. Note: Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

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• Glucagon
  

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  Glucagon

  

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  2.1 Recommended Dose

  Determine the dose based on the type of diagnostic procedure, the route of administration and expected procedure duration [see Clinical Pharmacology (12.2)]. 

  The usual dose to inhibit movement of the:

  Stomach and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. Colon is 0.5 mg to 0.75 mg given intravenously or 1 mg to 2 mg given intramuscularly.  

  Bolus doses above 1 mg administered intravenously have caused nausea and vomiting and are not recommended [see Adverse Reactions (6)].

  2.2 Reconstitution of the Lyophilized Powder

  Glucagon for Injection is a lyophilized powder, which requires reconstitution with Sterile Water for Injection prior to intravenous or intramuscular use.

  Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial containing Glucagon for Injection lyophilized powder. Shake the vial gently until the powder is completely dissolved and no particles remain in the reconstituted solution.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.  The reconstituted solution should be clear and of water-like consistency.  Discard the reconstituted solution if there are signs of gel formation or particles. The reconstituted solution has a concentration of approximately 1 mg of glucagon per mL. Use the reconstituted glucagon immediately after reconstitution. 

  2.3 Important Administration Instructions

  Glucagon for Injection must be administered by medical personnel. The timing of administration of Glucagon for Injection depends upon the organ under examination and route of administration [see Clinical Pharmacology (12.2)]. If given intravenously, administer Glucagon for Injection as a bolus over a time period of 1 minute. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure.

  2.1 Recommended Dose

  Determine the dose based on the type of diagnostic procedure, the route of administration and expected procedure duration [see Clinical Pharmacology (12.2)]. 

  The usual dose to inhibit movement of the:

  Stomach and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. Colon is 0.5 mg to 0.75 mg given intravenously or 1 mg to 2 mg given intramuscularly.  

  Bolus doses above 1 mg administered intravenously have caused nausea and vomiting and are not recommended [see Adverse Reactions (6)].

  2.2 Reconstitution of the Lyophilized Powder

  Glucagon for Injection is a lyophilized powder, which requires reconstitution with Sterile Water for Injection prior to intravenous or intramuscular use.

  Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial containing Glucagon for Injection lyophilized powder. Shake the vial gently until the powder is completely dissolved and no particles remain in the reconstituted solution.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.  The reconstituted solution should be clear and of water-like consistency.  Discard the reconstituted solution if there are signs of gel formation or particles. The reconstituted solution has a concentration of approximately 1 mg of glucagon per mL. Use the reconstituted glucagon immediately after reconstitution. 

  2.3 Important Administration Instructions

  Glucagon for Injection must be administered by medical personnel. The timing of administration of Glucagon for Injection depends upon the organ under examination and route of administration [see Clinical Pharmacology (12.2)]. If given intravenously, administer Glucagon for Injection as a bolus over a time period of 1 minute. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure.

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• Dexamethasone Sodium Ph...
  

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  Dexamethasone Sodium Phosphate

  

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  Dexamethasone sodium phosphate injection, 4 mg/mL– For intravenous, intramuscular, intra-articular, intralesional, and soft tissue injection.

  Dexamethasone sodium phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

  Solutions used for intravenous administration or further dilution of this product should be preservative free when used in the neonate, especially the premature infant.

  When it is mixed with an infusion solution, sterile precautions should be observed.  Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

  DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

  Intravenous and Intramuscular Injection:

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily.

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author  Dosage Cavanagh1 3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg Dietzman2 2 to 6 mg/kg of body weight as a single intravenous injection Frank3 40 mg initially followed by repeatintravenous injection every 4 to 6 hours while shock persists Oaks4 40 mg initially followed by repeatintravenous injection every 2 to 6 hours while shock persists Schumer5 1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days.  For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with two mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, 4 mg/mL: first day, 1 or 2 mL (4 or 8 mg), intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Intra-articular, Intralesional and Soft Tissue Injection:

  Intra-articular, intralesional, and soft tissue injections are generally employed when the affected joints or areas are limited to one or two sites.  Dosage and frequency of injection varies depending on the condition and the site of injection.  The usual dose is from 0.2 to 6 mg.  The frequency usually ranges from once every three to five days to once every two to three weeks.  Frequent intra-articular injection may result in damage to joint tissues.

  Some of the usual single doses are:

   Site of Injection Amount of Dexamethasone Phosphate (mg) Large Joints(e.g., Knee) 2 to 4 Small Joints(e.g., Interphalangeal,Temporomandibular) 0.8 to 1 Bursae 2 to 3 Tendon Sheaths  0.4 to 1 Soft Tissue Infiltration 2 to 6 Ganglia  1 to 2

  Dexamethasone sodium phosphate injection is particularly recommended for use in conjunction with one of the less soluble, longer-acting steroids for intra-articular and soft tissue injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

  Intra-articular, Intralesional and Soft Tissue Injection:

  Intra-articular, intralesional, and soft tissue injections are generally employed when the affected joints or areas are limited to one or two sites.  Dosage and frequency of injection varies depending on the condition and the site of injection.  The usual dose is from 0.2 to 6 mg.  The frequency usually ranges from once every three to five days to once every two to three weeks.  Frequent intra-articular injection may result in damage to joint tissues.

  Some of the usual single doses are:

   Site of Injection Amount of Dexamethasone Phosphate (mg) Large Joints(e.g., Knee) 2 to 4 Small Joints(e.g., Interphalangeal,Temporomandibular) 0.8 to 1 Bursae 2 to 3 Tendon Sheaths  0.4 to 1 Soft Tissue Infiltration 2 to 6 Ganglia  1 to 2

  Dexamethasone sodium phosphate injection is particularly recommended for use in conjunction with one of the less soluble, longer-acting steroids for intra-articular and soft tissue injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate Injection, USP may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high-dose therapy.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.

  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area. The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area:

   AGE (years)    DOSE (mg)       < 1         6    1   8    2   10   3 or older   12 

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity.  Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.            

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions. Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued.  Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases.  Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis fungoides (cutaneous T cell lymphoma) 

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.   Dose reduction or cessation is guided by patient response and hematologic monitoring. Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion. _ _ _ Doxorubicin† as a single drug 30 mg/m2/day IV x 3 days 8,17 Doxorubicin† Cisplatin† 50 mg/m2 IV100 mg/m2 IV 20,23,33,3620,23,33,36 Bleomycin† Cyclophosphamide† Dactinomycin† 15 units/m2 IV x 2 days 600 mg/m2 IV x 2 days 0.6 mg/m2 IV x  2 days 2,13,26,39,42 2,13,26,39,42 2,13,26,39,42

   *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606.

  †See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity.

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

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• Dexmedetomidine Hydroch...
  

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  Dexmedetomidine Hydrochloride

  

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  2.1 Dosing Guidelines

  Dexmedetomidine Hydrochloride Injection dosing should be individualized and titrated to desired clinical response. Dexmedetomidine Hydrochloride Injection is not indicated for infusions lasting longer than 24 hours. Dexmedetomidine Hydrochloride Injection should be administered using a controlled infusion device.

  2.2 Dosage Information

   Table 1: Dosage Information

   INDICATION    DOSAGE AND ADMINISTRATION    Initiation of Procedural Sedation    For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.  For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes. For patients over 65 years of age:  a loading infusion of 0.5 mcg/kg over 10 minutes [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].  Maintenance of Procedural Sedation    For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour.  The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.  For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.3 Dosage Adjustment

  Due to possible pharmacodynamic interactions, a reduction in dosage of Dexmedetomidine Hydrochloride Injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug Interactions (7.1)].

  Dosage reductions may need to be considered for adult patients with hepatic impairment and geriatric patients [see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.4 Preparation of Solution

  Strict aseptic technique must always be maintained during handling of Dexmedetomidine Hydrochloride Injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL) must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration.  Preparation of solutions is the same, whether for the loading dose or maintenance infusion.

  To prepare the infusion, withdraw 2 mL of Dexmedetomidine Hydrochloride Injection, and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL.  Shake gently to mix well.

  2.5 Administration with Other Fluids

  Dexmedetomidine Hydrochloride Injection infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

  Dexmedetomidine Hydrochloride Injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.

  Dexmedetomidine Hydrochloride Injection has been shown to be compatible when administered with the following intravenous fluids:

  0.9% sodium chloride in water 5% dextrose in water 20% mannitol Lactated Ringer’s solution 100 mg/mL magnesium sulfate solution 0.3% potassium chloride solution

  2.6 Compatibility with Natural Rubber

  Compatibility studies have demonstrated the potential for absorption of Dexmedetomidine Hydrochloride Injection to some types of natural rubber.  Although Dexmedetomidine Hydrochloride Injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

  2.1 Dosing Guidelines

  Dexmedetomidine Hydrochloride Injection dosing should be individualized and titrated to desired clinical response. Dexmedetomidine Hydrochloride Injection is not indicated for infusions lasting longer than 24 hours. Dexmedetomidine Hydrochloride Injection should be administered using a controlled infusion device.

  2.2 Dosage Information

   Table 1: Dosage Information

   INDICATION    DOSAGE AND ADMINISTRATION    Initiation of Procedural Sedation    For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.  For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes. For patients over 65 years of age:  a loading infusion of 0.5 mcg/kg over 10 minutes [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].  Maintenance of Procedural Sedation    For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour.  The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.  For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured. For patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)]. For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.3 Dosage Adjustment

  Due to possible pharmacodynamic interactions, a reduction in dosage of Dexmedetomidine Hydrochloride Injection or other concomitant anesthetics, sedatives, hypnotics or opioids may be required when co-administered [see Drug Interactions (7.1)].

  Dosage reductions may need to be considered for adult patients with hepatic impairment and geriatric patients [see Warnings and Precautions (5.7), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

  2.4 Preparation of Solution

  Strict aseptic technique must always be maintained during handling of Dexmedetomidine Hydrochloride Injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL) must be diluted with 0.9% sodium chloride injection to achieve required concentration (4 mcg/mL) prior to administration.  Preparation of solutions is the same, whether for the loading dose or maintenance infusion.

  To prepare the infusion, withdraw 2 mL of Dexmedetomidine Hydrochloride Injection, and add to 48 mL of 0.9% sodium chloride injection to a total of 50 mL.  Shake gently to mix well.

  2.5 Administration with Other Fluids

  Dexmedetomidine Hydrochloride Injection infusion should not be co-administered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

  Dexmedetomidine Hydrochloride Injection has been shown to be incompatible when administered with the following drugs: amphotericin B, diazepam.

  Dexmedetomidine Hydrochloride Injection has been shown to be compatible when administered with the following intravenous fluids:

  0.9% sodium chloride in water 5% dextrose in water 20% mannitol Lactated Ringer’s solution 100 mg/mL magnesium sulfate solution 0.3% potassium chloride solution

  2.6 Compatibility with Natural Rubber

  Compatibility studies have demonstrated the potential for absorption of Dexmedetomidine Hydrochloride Injection to some types of natural rubber.  Although Dexmedetomidine Hydrochloride Injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.

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• Neuralgia Hp
  

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  Neuralgia Hp

  

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  Adults

  The dosage recommendations for imipenem and cilastatin for injection (I.V.) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

  The total daily dosage for imipenem and cilastatin for injection (I.V.) should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Adult patients with impaired renal function, as judged by creatinine clearance ≤ 70 mL/min/1.73 m2, require adjustment of dosage as described in the succeeding section of these guidelines.

  Intravenous Dosage Schedule for Adults with Normal Renal Function and Body Weight ≥ 70 kg

  Doses cited in Table 3 are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of ≥ 71 mL/min/1.73 m2 and a body weight of ≥ 70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤ 70 mL/min/1.73 m2 and/or a body weight less than 70 kg. (see Tables 4 and 5).

  Dosage regimens in column A of Table 3 are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table 3 are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of P. aeruginosa.

  TABLE 3

  INTRAVENOUS DOSAGE SCHEDULE FOR ADULTS WITH NORMAL RENAL FUNCTION AND BODY WEIGHT ≥ 70 kg

  Type orSeverityof Infection AFully susceptible organisms includinggram-positive and gram-negativeaerobes and anaerobes BModerately susceptible organisms, primarily some strains of P. aeruginosa Mild 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) 500 mg q 6 h(TOTAL DAILY DOSE = 2 g) Moderate 500 mg q 8 h(TOTAL DAILY DOSE = 1.5 g)or500 mg q 6 h(TOTAL DAILY DOSE = 2 g)  500 mg q 6 h(TOTAL DAILY DOSE = 2 g)or1 g q 8 h(TOTAL DAILY DOSE = 3 g) Severe, life threatening only 500 mg q 6 h(TOTAL DAILY DOSE = 2 g) 1 g q 8 h(TOTAL DAILY DOSE = 3 g)or1 g q 6 h(TOTAL DAILY DOSE = 4 g)  Uncomplicated urinary tract infection 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) Complicated urinary tract infection  500 mg q 6 h(TOTAL DAILY DOSE = 2 g) 500 mg q 6 h(TOTAL DAILY DOSE = 2 g)

  Due to the high antimicrobial activity of imipenem and cilastatin for injection (I.V.), it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4 g/day, whichever is lower. There is no evidence that higher doses provide greater efficacy. However, patients over twelve years of age with cystic fibrosis and normal renal function have been treated with imipenem and cilastatin for injection (I.V.) at doses up to 90 mg/kg/day in divided doses, not exceeding 4 g/day.

  Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg

  Patients with creatinine clearance of ≤ 70 mL/min/1.73 m2 and/or body weight less than 70 kg require dosage reduction of imipenem and cilastatin for injection (I.V.) as indicated in the tables below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

  To determine the dose for adults with impaired renal function and/or reduced body weight:

  Choose a total daily dose from Table 3 based on infection characteristics. a) If the total daily dose is 1 g, 1.5 g, or 2 g, use the appropriate subsection of Table 4 and continue with step 3. b) If the total daily dose is 3 g or 4 g, use the appropriate subsection of Table 5 and continue with step 3. From Table 4 or 5:a) Select the body weight on the far left which is closest to the patient's body weight (kg).b) Select the patient's creatinine clearance category.c) Where the row and column intersect is the reduced dosage regimen.   

   

  TABLE 4 REDUCED INTRAVENOUS DOSAGE OF IMIPENEM AND CILASTATIN FOR INJECTION (I.V.) IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg  

  If TOTAL DAILY DOSE from TABLE 3 is: And Body Weight (kg) is: 1 g/ day 1.5 g/day 2 g/day and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: ≥ 70 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 500 q 8 h 250 q 6 h 250 q 8 h 250 q 12 h 500 q 6 h 500 q 8 h 250 q 6 h 250 q 12 h 60 250 q 8 h 125 q 6 h 250 q 12 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 8 h 250 q 12 h 500 q 8 h 250 q 6 h 250 q 8 h 250 q 12 h 50 125 q 6 h 125 q 6 h 125 q 8 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 250 q 6 h 250 q 6 h 250 q 8 h 250 q 12 h 40 125 q 6 h 125 q 8 h 125 q 12 h 125 q 12 h 250 q 8 h 125 q 6 h 125 q 8 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 30 125 q 8 h 125 q 8 h 125 q 12 h 125 q 12 h 125 q 6 h 125 q 8 h 125 q 8 h 125 q 12 h 250 q 8 h 125 q 6 h 125 q 8 h 125 q 12 h

  TABLE 5 REDUCED INTRAVENOUS DOSAGE OF IMIPENEM AND CILASTATIN FOR INJECTION (I.V.) IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg

  If TOTAL DAILY DOSE from TABLE 3 is: And Body Weight(kg)is: 3 g/ day 4 g/day and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: ≥ 70 1000q 8 h 500q 6 h 500q 8 h 500q 12 h 1000q 6 h 750q 8 h 500q 6 h 500q 12 h 60 750q 8 h 500q 8 h 500q 8 h 500q 12 h 1000q 8 h 750q 8 h 500q 8 h 500q 12 h 50 500q 6 h 500q 8 h 250q 6 h 250q 12 h 750q 8 h 500q 6 h 500q 8 h 500q 12 h 40 500q 8 h 250q 6 h 250q 8 h 250q 12 h 500q 6 h 500q 8 h 250q 6 h 250q 12 h 30 250q 6 h 250q 8 h 250q 8 h 250q 12 h 500q 8 h 250q 6 h 250q 8 h 250q 12 h

  Patients with creatinine clearances of 6 to 20 mL/min/1.73 m2 should be treated with imipenem and cilastatin for injection (I.V.) 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.

  Patients with creatinine clearance ≤ 5 mL/min/1.73 m2 should not receive imipenem and cilastatin for injection (I.V.) unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of imipenem and cilastatin for injection (I.V.) for patients undergoing peritoneal dialysis. Hemodialysis

  When treating patients with creatinine clearances of ≤ 5 mL/min/1.73 m2who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6 to 20 mL/min/1.73 m2. (See Reduced Intravenous Dosage Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg.) Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive imipenem and cilastatin for injection (I.V.) after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session.  Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, imipenem and cilastatin for injection (I.V.) is recommended only when the benefit outweighs the potential risk of seizures. (see PRECAUTIONS).

  Pediatric Patients

  See PRECAUTIONS, Pediatric Patients.

  For pediatric patients ≥ 3 months of age, the recommended dose for non-CNS infections is 15 to 25 mg/kg/dose administered every six hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.

  For pediatric patients ≤ 3 months of age (weighing ≥ 1,500 g), the following dosage schedule is recommended for non-CNS infections:

        < 1 wk of age: 25 mg/kg every 12 hrs       1 to 4 wks of age: 25 mg/kg every 8 hrs       4 wks to 3 mos. of age: 25 mg/kg every 6 hrs.

  Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes. Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes.

  Imipenem and cilastatin for injection (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures.

  Imipenem and cilastatin for injection (I.V.) is not recommended in pediatric patients < 30 kg with impaired renal function, as no data are available.

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• Dexamethasone Sodium Ph...
  

  ×

  Dexamethasone Sodium Phosphate

  

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  Dexamethasone sodium phosphate injection, 10 mg/mL– For intravenous and intramuscular injection only.

  Dexamethasone sodium phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

  Solutions used for intravenous administration or further dilution of this product should be preservative free when used in the neonate, especially the premature infant.

  When it is mixed with an infusion solution, sterile precautions should be observed.  Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

  DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

  Intravenous and Intramuscular Injection

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily. 

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author Dosage Cavanagh1 3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg Dietzman2 2 to 6 mg/kg of body weight as a single intravenous injection Frank3 40 mg initially followed by repeat intravenous injection every 4 to 6 hours while shock persists Oaks4 40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists Schumer5 1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with 2 mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, first day, 4 or 8 mg intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

  Intravenous and Intramuscular Injection

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily. 

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author Dosage Cavanagh1 3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg Dietzman2 2 to 6 mg/kg of body weight as a single intravenous injection Frank3 40 mg initially followed by repeat intravenous injection every 4 to 6 hours while shock persists Oaks4 40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists Schumer5 1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with 2 mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, first day, 4 or 8 mg intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

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• Vancomycin Hydrochlorid...
  

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  Vancomycin Hydrochloride

  

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  Infusion-related events are related to both the concentration and the rate of administration of vancomycin.  Concentrations of no more than 5 mg/mL and rates of no more than 10 mg/min are recommended in adults (see also age-specific recommendations).  In selected patients in need of fluid restriction, a concentration up to 10 mg/mL may be used; use of such higher concentrations may increase the risk of infusion-related events.  Infusion-related events may occur, however, at any rate or concentration.

  Patients with Normal Renal Function

  Adults

  The usual daily dose is 2 g divided either as 500 mg every six hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min, or over a period of at least 60 minutes, whichever is longer.  Other patients factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

  Children

  The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours.  Each dose should be administered over a period of at least 60 minutes.  

  Infants and Neonates

  In neonates and young infants, the total daily IV dosage may be lower.  In both neonates and infants, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the first week of life and every eight hours thereafter up to the age of one month.  Each dose should be administered over 60 minutes.  Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

  Patients with Impaired Renal Function and Elderly Patients

  Dosage adjustment must be made in patients with impaired renal function.  In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function.  Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay or high-pressure liquid chromatography.  

  If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table.  The dosage of vancomycin per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table).

  DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION

                                              (Adapted from Moellering et al.3)

  Creatinine Clearance                                                                        Vancomycin Dose

          mL/min                                                                                                 mg/24 hr

               100                                                                                                       1545

                90                                                                                                        1390

                80                                                                                                        1235

                70                                                                                                        1080

                60                                                                                                         925

                50                                                                                                         770

                40                                                                                                         620

                30                                                                                                         465

                20                                                                                                         310

                10                                                                                                         155

  The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency.  

  The table is not valid for functionally anephric patients.  For such patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 hr.  In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1000 mg once every several days rather than administering the drug on a daily basis.  In anuria, a dose of 1000 mg every 7 to 10 days has been recommended.

  When only serum creatinine is known, the following formula (based on sex, weight and age of the patient) may be used to calculate creatinine clearance.  Calculated creatinine clearances (mL/min) are only estimates.  The creatinine clearance should be measured promptly.

  Men:                                        Weight (kg) x (140–age in years)        

                                          72 x serum creatinine concentration (mg/dL)

   Women:                           0.85 x above value

  The serum creatinine must represent a steady state of renal function or the estimated value for creatinine clearance will not be valid.  Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by decreasing renal function, such as shock, severe heart failure or oliguria; (2) in which a normal relationship between muscle mass and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition or inactivity.  

  The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) route have not been assessed.

  Intermittent infusion is the recommended method of administration.

  Compatibility with Other Drugs and IV Fluids

  The following diluents are physically and chemically compatible (with 4 g/L vancomycin hydrochloride):

     5% Dextrose Injection, USP

     5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP

     Lactated Ringer’s Injection, USP

     5% Dextrose and Lactated Ringer’s Injection

     Normosol®-M and 5% Dextrose

     0.9% Sodium Chloride Injection, USP

     Isolyte® E

  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Vancomycin solution has a low pH and may cause physical instability of other compounds.

  Patients with Normal Renal Function

  Adults

  The usual daily dose is 2 g divided either as 500 mg every six hours or 1 g every 12 hours. Each dose should be administered at no more than 10 mg/min, or over a period of at least 60 minutes, whichever is longer.  Other patients factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

  Children

  The usual intravenous dosage of vancomycin is 10 mg/kg per dose given every 6 hours.  Each dose should be administered over a period of at least 60 minutes.  

  Infants and Neonates

  In neonates and young infants, the total daily IV dosage may be lower.  In both neonates and infants, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the first week of life and every eight hours thereafter up to the age of one month.  Each dose should be administered over 60 minutes.  Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

  Patients with Impaired Renal Function and Elderly Patients

  Dosage adjustment must be made in patients with impaired renal function.  In premature infants and the elderly, greater dosage reductions than expected may be necessary because of decreased renal function. Measurement of vancomycin serum concentrations can be helpful in optimizing therapy, especially in seriously ill patients with changing renal function.  Vancomycin serum concentrations can be determined by use of microbiologic assay, radioimmunoassay, fluorescence polarization immunoassay, fluorescence immunoassay or high-pressure liquid chromatography.  

  If creatinine clearance can be measured or estimated accurately, the dosage for most patients with renal impairment can be calculated using the following table.  The dosage of vancomycin per day in mg is about 15 times the glomerular filtration rate in mL/min (see following table).

  DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION

                                              (Adapted from Moellering et al.3)

  Creatinine Clearance                                                                        Vancomycin Dose

          mL/min                                                                                                 mg/24 hr

               100                                                                                                       1545

                90                                                                                                        1390

                80                                                                                                        1235

                70                                                                                                        1080

                60                                                                                                         925

                50                                                                                                         770

                40                                                                                                         620

                30                                                                                                         465

                20                                                                                                         310

                10                                                                                                         155

  The initial dose should be no less than 15 mg/kg, even in patients with mild to moderate renal insufficiency.  

  The table is not valid for functionally anephric patients.  For such patients, an initial dose of 15 mg/kg of body weight should be given to achieve prompt therapeutic serum concentrations. The dose required to maintain stable concentrations is 1.9 mg/kg/24 hr.  In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1000 mg once every several days rather than administering the drug on a daily basis.  In anuria, a dose of 1000 mg every 7 to 10 days has been recommended.

  When only serum creatinine is known, the following formula (based on sex, weight and age of the patient) may be used to calculate creatinine clearance.  Calculated creatinine clearances (mL/min) are only estimates.  The creatinine clearance should be measured promptly.

  Men:                                        Weight (kg) x (140–age in years)        

                                          72 x serum creatinine concentration (mg/dL)

   Women:                           0.85 x above value

  The serum creatinine must represent a steady state of renal function or the estimated value for creatinine clearance will not be valid.  Such a calculated clearance is an overestimate of actual clearance in patients with conditions: (1) characterized by decreasing renal function, such as shock, severe heart failure or oliguria; (2) in which a normal relationship between muscle mass and total body weight is not present, such as in obese patients or those with liver disease, edema, or ascites; and (3) accompanied by debilitation, malnutrition or inactivity.  

  The safety and efficacy of vancomycin administration by the intrathecal (intralumbar or intraventricular) route have not been assessed.

  Intermittent infusion is the recommended method of administration.

  Compatibility with Other Drugs and IV Fluids

  The following diluents are physically and chemically compatible (with 4 g/L vancomycin hydrochloride):

     5% Dextrose Injection, USP

     5% Dextrose Injection and 0.9% Sodium Chloride Injection, USP

     Lactated Ringer’s Injection, USP

     5% Dextrose and Lactated Ringer’s Injection

     Normosol®-M and 5% Dextrose

     0.9% Sodium Chloride Injection, USP

     Isolyte® E

  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Vancomycin solution has a low pH and may cause physical instability of other compounds.

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• Moxifloxacin
  

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  Moxifloxacin

  

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  2.1 Dosage in Adult Patients

  The dose of moxifloxacin injection is 400 mg intravenously once every 24 hours.  The duration of therapy depends on the type of infection as described in Table 1.   

                     Table 1: Dosage and Duration of Therapy in Adult Patients 

    Type of Infectiona Dose Every 24 hours Durationb (days) Acute Bacterial Sinusitis (1.1) 400 mg 10 Acute Bacterial Exacerbation of Chronic Bronchitis (1.2) 400 mg 5 Community Acquired Pneumonia 400 mg 7 to 14 Uncomplicated Skin and Skin Structure Infections (SSSI) (1.4) 400 mg 7 Complicated SSSI (1.5) 400 mg 7 to 21 Complicated Intra-Abdominal Infections (1.6) 400 mg 5 to 14

  a Due to the designated pathogens [see Indications and Usage (1), for IV use, see Use in Specific Populations (8.5)]. 

  b Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

  When switching from intravenous to oral formulation, no dosage adjustment is necessary [see Clinical Pharmacology (12.4)].  Patients whose therapy is started with moxifloxacin injection may be switched to moxifloxacin tablets when clinically indicated at the discretion of the physician.

  2.2 Administration Instructions

  Moxifloxacin Injection Solution for Infusion

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Moxifloxacin injection should be administered by intravenous infusion only.  It is not intended for intra-arterial, intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

  Moxifloxacin injection should be administered by intravenous infusion over a period of 60 minutes by direct infusion or through a Y-type intravenous infusion set which may already be in place.  Caution: rapid or bolus intravenous infusion must be avoided.

  Because only limited data are available on the compatibility of moxifloxacin intravenous injection with other intravenous substances, additives or other medications should not be added to moxifloxacin injection or infused simultaneously through the same intravenous line.  If the same intravenous line or a Y-type line is used for sequential infusion of other drugs, or if the “piggyback” method of administration is used, the line should be flushed before and after infusion of moxifloxacin injection with an infusion solution compatible with moxifloxacin injection as well as with other drug(s) administered via this common line.

  Moxifloxacin Injection is compatible with the following intravenous solutions at ratios from 1:10 to 10:1

  0.9% Sodium Chloride Injection, USP                            Sterile Water for Injection, USP

  1 molar Sodium Chloride Injection                                   10% Dextrose for Injection, USP

  5% Dextrose Injection, USP                                             Lactated Ringer’s for Injection

  2.3 Preparation for Administration of Moxifloxacin Injection

  To prepare moxifloxacin injection premix in flexible plastic containers:

  1.  Close flow control clamp of administration set.

  2.  Remove cover from port at bottom of container.

  3.  Insert piercing pin from an appropriate transfer set (for example, one that does not require excessive force, such as ISO compatible administration set) into port with a gentle twisting motion until pin is firmly seated.

  NOTE: Refer to complete directions that have been provided with the administration set.

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• Piperacillin And Tazoba...
  

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  Piperacillin And Tazobactam

  

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  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.1     Adult Patients

  The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).  The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.2     Nosocomial Pneumonia

  Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).  The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days.  Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

  2.3     Renal Impairment

  In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of actual renal function impairment.  The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows:

  Table 1:  Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam)

  Renal Function

        

  (creatinine clearance,

  All Indications

  Nosocomial

  mL/min)

  (except nosocomial pneumonia)

  Pneumonia

  >40 mL/min

  3.375 q6h

  4.5 q6h

  20-40 mL/min*

  2.25 q6h

  3.375 q6h

  <20 mL/min*

  2.25 q8h

  2.25 q6h

  Hemodialysis**

  2.25 q12h

  2.25 q8h

  CAPD

  2.25 q12h

  2.25 q8h

  *Creatinine clearance for patients not receiving hemodialysis**0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days

  For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.  Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.  No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients.

  2.4     Pediatric Patients

  For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.  For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].  Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.  It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

  2.5     Reconstitution and Dilution of Powder Formulations

  Single Dose Vials

  Reconstitute piperacillin and tazobactam for injection vials with a compatible reconstitution diluent from the list provided below.

  2.25 g, 3.375 g, and 4.5 g piperacillin and tazobactam for injection should be reconstituted with 10 mL, 15 mL, and 20 mL, respectively.  Swirl until dissolved.

  Compatible Reconstitution Diluents for Single Dose Vials 0.9% Sodium chloride for injectionSterile water for injection‡ Dextrose 5%Bacteriostatic saline/parabensBacteriostatic water/parabensBacteriostatic saline/benzyl alcoholBacteriostatic water/benzyl alcohol

  Reconstituted piperacillin and tazobactam for injection solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.  Administer by infusion over a period of at least 30 minutes.  During the infusion it is desirable to discontinue the primary infusion solution.

  Compatible Intravenous Solutions for Single Dose Vials 0.9% Sodium chloride for injectionSterile water for injection‡ Dextran 6% in salineDextrose 5%

  LACTATED RINGER’S SOLUTION IS NOT COMPATIBILE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION. ‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

  Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

  Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

  Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates.

  Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.

  Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following Reconstitution

  Piperacillin and tazobactam for injection reconstituted from single vials is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.  Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Single dose vials should be used immediately after reconstitution.  Discard any unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F), or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).  Vials should not be frozen after reconstitution.

  Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.  Piperacillin and tazobactam for injection contains no preservatives.  Appropriate consideration of aseptic technique should be used.

  Piperacillin and tazobactam for injection reconstituted from single vials can be used in ambulatory intravenous infusion pumps.  Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.  Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.  One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge).  The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions.  Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump.

  2.6     Compatibility with Aminoglycosides

  Due to the in vitro inactivation of aminoglycosides by piperacillin, Piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration.  Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)].

  In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam for injection is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions:

  Table 2: Compatibility with Aminoglycosides

  Aminoglycoside

  Piperacillin and Tazobactam Dose (grams)

  Piperacillin and Tazobactam Diluent Volume (mL)

  Aminoglycoside Concentration Range a (mg/mL)

  Acceptable Diluents

  Amikacin

  2.25, 3.375, 4.5

  50, 100, 150

  1.75 – 7.5

  0.9% sodium chloride or 5% dextrose

  Gentamicin

  2.25, 3.375, 4.5

  50, 100 150

  0.7 – 3.32

  0.9% sodium chloride or 5% dextrose

  aThe concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin).  Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam has not been evaluated.  See package insert for each aminoglycoside for complete Dosage and Administration instructions.

  Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for coadministration via Y-site infusion.  Simultaneous coadministration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam for injection.

  Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion.  Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Piperacillin And Tazoba...
  

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  Piperacillin And Tazobactam

  

  ---

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.1 Adult Patients

  The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).  The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.2 Nosocomial Pneumonia

  Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).  The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days.  Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

  2.3 Renal Impairment

  In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of actual renal function impairment.  The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows:

  Table 1:  Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam)

  Renal Function

     

       

  (creatinine clearance,

  All Indications

  Nosocomial

  mL/min)

  (except nosocomial pneumonia)

  Pneumonia

  >40 mL/min

  3.375 q6h

  4.5 q6h

  20-40 mL/min*

  2.25 q6h

  3.375 q6h

  <20 mL/min*

  2.25 q8h

  2.25 q6h

  Hemodialysis**

  2.25 q12h

  2.25 q8h

  CAPD

  2.25 q12h

  2.25 q8h

  *Creatinine clearance for patients not receiving hemodialysis **0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days

  For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.  Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.  No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients.

  2.4 Pediatric Patients

  For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.  For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].  Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.  It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

  2.5 Reconstitution and Dilution of Powder Formulations

  Pharmacy Bulk Package Bottles

  Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

  The pharmacy bulk package bottle is for use in a hospital pharmacy admixture service only under a laminar flow hood.  After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique.  Use entire contents of pharmacy bulk package bottle promptly.  Discard unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F), or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Reconstitute the pharmacy bulk package bottle with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.  Shake well until dissolved.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.

  Compatible Reconstitution Diluents for Pharmacy Bulk Bottles 0.9% Sodium chloride for injectionSterile water for injection‡ Dextrose 5%Bacteriostatic saline/parabensBacteriostatic water/parabensBacteriostatic saline/benzyl alcoholBacteriostatic water/benzyl alcohol

  Reconstituted piperacillin and tazobactam for injection solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.  Administer by infusion over a period of at least 30 minutes.  During the infusion it is desirable to discontinue the primary infusion solution.

  Compatible Intravenous Solutions for Pharmacy Bulk Package Bottles and Single Dose Vials 0.9% Sodium chloride for injectionSterile water for injection‡ Dextran 6% in salineDextrose 5%

  LACTATED RINGER’S SOLUTION IS NOT COMPATIBILE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION.

  ‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

  Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

  Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

  Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates.

  Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.

  Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following Reconstitution

  Piperacillin and tazobactam for injection reconstituted from pharmacy bulk package bottles is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.  The pharmacy bulk package bottle should NOT be frozen after reconstitution.  Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Pharmacy bulk package bottles should be used immediately after reconstitution.  Discard any unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F),  or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).  Pharmacy bulk package bottles should not be frozen after reconstitution.

  Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.  Piperacillin and tazobactam for injection contains no preservatives.  Appropriate consideration of aseptic technique should be used.

  Piperacillin and tazobactam for injection reconstituted from bulk package bottles can be used in ambulatory intravenous infusion pumps.  Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.  Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.  One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge).  The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions.  Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump.

  2.6 Compatibility with Aminoglycosides

  Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration.  Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)].

  In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions:

  Table 2: Compatibility with Aminoglycosides

  Aminoglycoside

  Piperacillin and Tazobactam Dose (grams)

  Piperacillin and Tazobactam Diluent Volume (mL)

  Aminoglycoside Concentration Rangea (mg/mL)

  Acceptable Diluents

  Amikacin

  2.25, 3.375, 4.5

  50, 100, 150

  1.75 – 7.5

  0.9% sodium chloride or 5% dextrose

  Gentamicin

  2.25, 3.375, 4.5

  50, 100 150

  0.7 – 3.32

  0.9% sodium chloride or 5% dextrose

  aThe concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin).  Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam has not been evaluated.  See package insert for each aminoglycoside for complete Dosage and Administration instructions.

  Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for coadministration via Y-site infusion.  Simultaneous coadministration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam.

  Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion.  Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Piperacillin And Tazoba...
  

  ×

  Piperacillin And Tazobactam

  

  ---

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.1 Adult Patients

  The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).  The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.2 Nosocomial Pneumonia

  Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).  The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days.  Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

  2.3 Renal Impairment

  In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of actual renal function impairment.  The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows:

  Table 1:  Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam)

  Renal Function

     

       

  (creatinine clearance,

  All Indications

  Nosocomial

  mL/min)

  (except nosocomial pneumonia)

  Pneumonia

  >40 mL/min

  3.375 q6h

  4.5 q6h

  20-40 mL/min*

  2.25 q6h

  3.375 q6h

  <20 mL/min*

  2.25 q8h

  2.25 q6h

  Hemodialysis**

  2.25 q12h

  2.25 q8h

  CAPD

  2.25 q12h

  2.25 q8h

  *Creatinine clearance for patients not receiving hemodialysis **0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days

  For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.  Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.  No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients.

  2.4 Pediatric Patients

  For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.  For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].  Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.  It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

  2.5 Reconstitution and Dilution of Powder Formulations

  Pharmacy Bulk Package Bottles

  Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

  The pharmacy bulk package bottle is for use in a hospital pharmacy admixture service only under a laminar flow hood.  After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique.  Use entire contents of pharmacy bulk package bottle promptly.  Discard unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F), or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Reconstitute the pharmacy bulk package bottle with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.  Shake well until dissolved.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.

  Compatible Reconstitution Diluents for Pharmacy Bulk Bottles 0.9% Sodium chloride for injectionSterile water for injection‡ Dextrose 5%Bacteriostatic saline/parabensBacteriostatic water/parabensBacteriostatic saline/benzyl alcoholBacteriostatic water/benzyl alcohol

  Reconstituted piperacillin and tazobactam for injection solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.  Administer by infusion over a period of at least 30 minutes.  During the infusion it is desirable to discontinue the primary infusion solution.

  Compatible Intravenous Solutions for Pharmacy Bulk Package Bottles and Single Dose Vials 0.9% Sodium chloride for injectionSterile water for injection‡ Dextran 6% in salineDextrose 5%

  LACTATED RINGER’S SOLUTION IS NOT COMPATIBILE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION.

  ‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

  Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

  Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

  Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates.

  Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.

  Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following Reconstitution

  Piperacillin and tazobactam for injection reconstituted from pharmacy bulk package bottles is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.  The pharmacy bulk package bottle should NOT be frozen after reconstitution.  Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Pharmacy bulk package bottles should be used immediately after reconstitution.  Discard any unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F),  or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).  Pharmacy bulk package bottles should not be frozen after reconstitution.

  Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.  Piperacillin and tazobactam for injection contains no preservatives.  Appropriate consideration of aseptic technique should be used.

  Piperacillin and tazobactam for injection reconstituted from bulk package bottles can be used in ambulatory intravenous infusion pumps.  Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.  Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.  One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge).  The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions.  Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump.

  2.6 Compatibility with Aminoglycosides

  Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration.  Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)].

  In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions:

  Table 2: Compatibility with Aminoglycosides

  Aminoglycoside

  Piperacillin and Tazobactam Dose (grams)

  Piperacillin and Tazobactam Diluent Volume (mL)

  Aminoglycoside Concentration Rangea (mg/mL)

  Acceptable Diluents

  Amikacin

  2.25, 3.375, 4.5

  50, 100, 150

  1.75 – 7.5

  0.9% sodium chloride or 5% dextrose

  Gentamicin

  2.25, 3.375, 4.5

  50, 100 150

  0.7 – 3.32

  0.9% sodium chloride or 5% dextrose

  aThe concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin).  Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam has not been evaluated.  See package insert for each aminoglycoside for complete Dosage and Administration instructions.

  Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for coadministration via Y-site infusion.  Simultaneous coadministration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam.

  Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion.  Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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  Bone Collector

  

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  2.1 Recommended Dose

  Determine the dose based on the type of diagnostic procedure, the route of administration and expected procedure duration [see Clinical Pharmacology (12.2)]. 

  The usual dose to inhibit movement of the:

  Stomach and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. Colon is 0.5 mg to 0.75 mg given intravenously or 1 mg to 2 mg given intramuscularly.  

  Bolus doses above 1 mg administered intravenously have caused nausea and vomiting and are not recommended [see Adverse Reactions (6)].

  2.2 Reconstitution of the Lyophilized Powder

  Glucagon for Injection is a lyophilized powder, which requires reconstitution with Sterile Water for Injection prior to intravenous or intramuscular use.

  Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial containing Glucagon for Injection lyophilized powder. Shake the vial gently until the powder is completely dissolved and no particles remain in the reconstituted solution.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.  The reconstituted solution should be clear and of water-like consistency.  Discard the reconstituted solution if there are signs of gel formation or particles. The reconstituted solution has a concentration of approximately 1 mg of glucagon per mL. Use the reconstituted glucagon immediately after reconstitution. 

  2.3 Important Administration Instructions

  Glucagon for Injection must be administered by medical personnel. The timing of administration of Glucagon for Injection depends upon the organ under examination and route of administration [see Clinical Pharmacology (12.2)]. If given intravenously, administer Glucagon for Injection as a bolus over a time period of 1 minute. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure.

  2.1 Recommended Dose

  Determine the dose based on the type of diagnostic procedure, the route of administration and expected procedure duration [see Clinical Pharmacology (12.2)]. 

  The usual dose to inhibit movement of the:

  Stomach and small bowel is 0.2 mg to 0.5 mg given intravenously or 1 mg given intramuscularly. Colon is 0.5 mg to 0.75 mg given intravenously or 1 mg to 2 mg given intramuscularly.  

  Bolus doses above 1 mg administered intravenously have caused nausea and vomiting and are not recommended [see Adverse Reactions (6)].

  2.2 Reconstitution of the Lyophilized Powder

  Glucagon for Injection is a lyophilized powder, which requires reconstitution with Sterile Water for Injection prior to intravenous or intramuscular use.

  Using a syringe, withdraw 1 mL of Sterile Water for Injection and inject into the vial containing Glucagon for Injection lyophilized powder. Shake the vial gently until the powder is completely dissolved and no particles remain in the reconstituted solution.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to administration.  The reconstituted solution should be clear and of water-like consistency.  Discard the reconstituted solution if there are signs of gel formation or particles. The reconstituted solution has a concentration of approximately 1 mg of glucagon per mL. Use the reconstituted glucagon immediately after reconstitution. 

  2.3 Important Administration Instructions

  Glucagon for Injection must be administered by medical personnel. The timing of administration of Glucagon for Injection depends upon the organ under examination and route of administration [see Clinical Pharmacology (12.2)]. If given intravenously, administer Glucagon for Injection as a bolus over a time period of 1 minute. Discard any unused portion. After the end of the diagnostic procedure, give oral carbohydrates to patients who have been fasting, if this is compatible with the diagnostic procedure.

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• Aztreonam
  

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  Aztreonam

  

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  Dosage in Adult Patients

  Aztreonam for injection may be administered intravenously or by intramuscular injection.  Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.

                                                                 Table 4:  Aztreonam for Injection Dosage Guidelines for Adults*

   Type of Infection    Dose    Frequency  (hours) Urinary tract infections  500 mg or 1 g   8 or 12  Moderately severe systemic infections  1 g or 2 g   8 or 12  Severe systemic or life-threatening infections  2 g   6 or 8 

  * Maximum recommended dose is 8 g per day.

  Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

  The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (e.g., intra-abdominal abscess), peritonitis or other severe systemic or life-threatening infections.

  The duration of therapy depends on the severity of infection.  Generally, aztreonam for injection should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.  Persistent infections may require treatment for several weeks.  Doses smaller than those indicated should not be used.

  Renal Impairment in Adult Patients

  Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency.  Therefore, the dosage of aztreonam for injection should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

  When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr).  The serum creatinine should represent a steady state of renal function.

  Males: Clcr =       weight (kg) x (140 – age)

                         72 x serum creatinine (mg/dL)

                    

                      Females: 0.85 x above value

                       

  In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g or 2 g should be given initially.  The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8 or 12 hours.  For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

  Dosage in the Elderly

  Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function.  Serum creatinine may not be an accurate determinant of renal status.  Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

  Dosage in Pediatric Patients

  Aztreonam for injection should be administered intravenously to pediatric patients with normal renal function.  There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment (see PRECAUTIONS, Pediatric Use). 

                                                                Table 5: Aztreonam for Injection Dosage Guidelines for Pediatric Patients* 

   Type of Infection    Dose    Frequency  (hours)  Mild to moderate infections   30 mg/kg   8   Moderate to severe infections   30 mg/kg   6 or 8 

  *Maximum recommended dose is 120 mg/kg/day.

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• Vancomycin Hydrochlorid...
  

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  Vancomycin Hydrochloride

  

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  2.1 Adults

  Vancomycin hydrochloride capsules are used in treating C. difficile-associated diarrhea and staphylococcal enterocolitis.

  C. difficile-associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days. Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days.

  2.2 Pediatric Patients

  The usual daily dosage is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days.  The total daily dosage should not exceed 2 g.

  2.1 Adults

  Vancomycin hydrochloride capsules are used in treating C. difficile-associated diarrhea and staphylococcal enterocolitis.

  C. difficile-associated diarrhea: The recommended dose is 125 mg administered orally 4 times daily for 10 days. Staphylococcal enterocolitis: Total daily dosage is 500 mg to 2 g administered orally in 3 or 4 divided doses for 7 to 10 days.

  2.2 Pediatric Patients

  The usual daily dosage is 40 mg/kg in 3 or 4 divided doses for 7 to 10 days.  The total daily dosage should not exceed 2 g.

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• Up And Up Omeprazole
  

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  Up And Up Omeprazole

  

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  Argatroban injection 250 mg per 2.5 mL (100 mg per mL) must be diluted prior to infusion.  If the solution is cloudy, or if an insoluble precipitate is noted, the vial should be discarded.  Argatroban injection should not be mixed with other drugs prior to dilution.

  2.1 Preparation for Intravenous Administration

  Prior to administration, argatroban injection should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final concentration of 1 mg/mL.  The contents of each 2.5 mL vial should be diluted 100-fold by mixing with 250 mL of diluent.  Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.

  The diluted solution must be mixed by inversion of the diluent bag for 1 minute.  Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing.  The final diluted solution must be clear before use. Use of diluted solution at room temperature is recommended.  The pH of the intravenous solution prepared as recommended is 3.2 to 7.5.   

  Solutions prepared are physically, chemically, and microbiologically stable when stored as directed below in Table 1 and protected from light:

                               Table 1

    Recommended Storage Conditions of Diluted Solution

  Diluent Storage Limit Storage Temperature 0.9% Sodium Chloride Injection 96 hours 20 to 25°C (68 to 77°F) 96 hours 2 to 8°C (36 to 46°F) 5% Dextrose Injection or Lactated Ringer’s Injection 4 hours 20 to 25°C (68 to 77°F) 4 hours 2 to 8°C (36 to 46°F)

  Discard unused final product at the completion of these post dilution storage periods. Prepared solutions should not be exposed to direct sunlight.  No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  2.2 Dosing in Patients with Heparin-Induced Thrombocytopenia

  Initial Dosage:

  Before administering argatroban injection, discontinue heparin therapy and obtain a baseline aPTT.  The recommended initial dose of argatroban injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 2).

                                                                                                                                                                                      Table 2Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban Injection for Patients with HIT* and Without Hepatic Impairment (1 mg/mL Final Concentration)

   Body Weight (kg) Dose (mcg/min) Infusion Rate (mL/hr) 50 100 6 60 120 7  70 140 8  80  160 10  90  180 11 100  200 12  110  220 13  120  240 14  130  260 16  140  280 17

  *with or without thrombosis

  Monitoring Therapy:For use in HIT, therapy with argatroban injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds).  Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of argatroban injection.  Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

  Dosage Adjustment:After the initiation of argatroban injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies (14.1)].

  2.3 Dosing in Patients Undergoing Percutaneous Coronary Intervention

  Initial Dosage:Initiate an infusion of argatroban injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes (see Table 3).  Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed.  The PCI procedure may proceed if the ACT is greater than 300 seconds.

  Dosage Adjustment:If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 3).

  If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (see Table 4).

  Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

  In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min.  Check the ACT after each additional bolus or change in the rate of infusion.

                                                                                                                                          Table 3Recommended Starting and Maintenance Doses (Within the Target ACT Range) of Argatroban Injection in Patients Undergoing PCI Without Hepatic Impairment                                                                                                                     (1 mg/mL Final Concentration) 

    Body   Weight (kg)   Starting Bolus Dose   (350 mcg/kg) Starting and Maintenance Continuous Infusion Dosing For ACT 300 to 450 seconds   25 mcg/kg/min Bolus   Dose (mcg)  Bolus Volume (mL) Continuous Infusion Dose (mg/min)  Continuous Infusion   Rate (mL/hr) 50 17,500 18 1,250 75  60  21,000  21 1,500 90  70  24,500  25 1,750 105  80  28,000  28 2,000 120  90  31,500  32 2,250  135  100  35,000  35 2,500  150  110  38,500  39  2,750 165  120 42,000  42  3,000 180  130  45,500  46 3,250 195  140   49,000  49 3,500 210

  NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs

                                                            Table 4 Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment                                         (1 mg/mL Final Concentration) 

   Body  Weight (kg) If ACT Less than 300 seconds Dosage Adjustment† 30 mcg/kg/min If ACT Greater than  450 seconds Dosage Adjustment* 15 mcg/kg/min  Additional Bolus  Dose (mcg)  Bolus Volume  (mL)  Continuous Infusion  Dose (mcg/min)  Continuous Infusion  Rate (mL/hr)  Continuous Infusion  Dose (mcg/min) Continuous Infusion  Rate (mL/hr)  50  7,500  8 1,500 90 750 45  60  9,000  9  1,800  108  900 54  70  10,500  11  2,100 126  1,050 63  80   12,000  12  2,400 144  1,200 72  90 13,500  14  2,700  162  1,350 81  100  15,000  15  3,000 180  1,500 90  110  16,500 17  3,300 198  1,650 99  120  18,000 18  3,600  216  1,800  108  130  19,500  20  3,900 234  1,950 117 140  21,000 21  4,200  252  2,100  126

  NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs

  † Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds.

  * No bolus dose is given if ACT greater than 450 seconds

  Monitoring Therapy: For use in PCI, therapy with argatroban injection is monitored using ACT.  Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure.  Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

  Continued Anticoagulation after PCI:If a patient requires anticoagulation after the procedure, argatroban injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range [see  Dosage and Administration (2.1)].                                                                                               

  2.4 Dosing in Patients with Hepatic Impairment

  Initial Dosage:

  For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in argatroban injection clearance relative to those with normal hepatic function.  Monitor the aPTT closely, and adjust the dosage as clinically indicated.

  Monitoring Therapy:

  Achievement of steady-state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

  For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved.  Use of argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)]. 

  2.5 Dosing in Pediatric Patients with Heparin-Induced Thrombocytopenia/Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

  Initial Dosage:

  Initial argatroban injection infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations (8.4)].

  Monitoring Therapy:

  In general, therapy with argatroban injection is monitored using the aPTT.  Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of argatroban injection in patients without hepatic impairment [see Warnings and Precautions  (5.2)].   Dose adjustment may be required to attain the target aPTT.  Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

  Dosage Adjustment:

  [see Use in Specific Populations (8.4)].

  2.6 Conversion to Oral Anticoagulant Therapy

  Initiating Oral Anticoagulant Therapy:

  When converting patients from argatroban injection to oral anticoagulant therapy, consider the potential for combined effects on INR with co-administration of argatroban and warfarin.  A loading dose of warfarin should not be used.  Initiate therapy using the expected daily dose of warfarin.  To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that argatroban and warfarin therapy be overlapped.  There are insufficient data available to recommend the duration of the overlap.

  Co-Administration of Warfarin and Argatroban Injection at Doses up to 2 mcg/kg/min:

  Measure INR daily while argatroban injection and warfarin are co-administered. In general, with doses of argatroban injection up to 2 mcg/kg/min, argatroban injection can be discontinued when the INR is greater than 4 on combined therapy. After argatroban injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

  Co-Administration of Warfarin and Argatroban Injection at Doses Greater than 2 mcg/kg/min:

  For doses of argatroban injection greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban injection is less predictable.  In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of argatroban injection to a dose of 2 mcg/kg/min.  Repeat the INR on argatroban injection and warfarin 4 to 6 hours after reduction of the argatroban injection dose and follow the process outlined above for administering argatroban injection at doses up to 2 mcg/kg/min.

  2.1 Preparation for Intravenous Administration

  Prior to administration, argatroban injection should be diluted in 0.9% Sodium Chloride Injection, 5% Dextrose Injection, or Lactated Ringer’s Injection to a final concentration of 1 mg/mL.  The contents of each 2.5 mL vial should be diluted 100-fold by mixing with 250 mL of diluent.  Use 250 mg (2.5 mL) per 250 mL of diluent or 500 mg (5 mL) per 500 mL of diluent.

  The diluted solution must be mixed by inversion of the diluent bag for 1 minute.  Upon preparation, the solution may show slight but brief haziness due to the formation of microprecipitates that rapidly dissolve upon mixing.  The final diluted solution must be clear before use. Use of diluted solution at room temperature is recommended.  The pH of the intravenous solution prepared as recommended is 3.2 to 7.5.   

  Solutions prepared are physically, chemically, and microbiologically stable when stored as directed below in Table 1 and protected from light:

                               Table 1

    Recommended Storage Conditions of Diluted Solution

  Diluent Storage Limit Storage Temperature 0.9% Sodium Chloride Injection 96 hours 20 to 25°C (68 to 77°F) 96 hours 2 to 8°C (36 to 46°F) 5% Dextrose Injection or Lactated Ringer’s Injection 4 hours 20 to 25°C (68 to 77°F) 4 hours 2 to 8°C (36 to 46°F)

  Discard unused final product at the completion of these post dilution storage periods. Prepared solutions should not be exposed to direct sunlight.  No significant potency losses have been noted following simulated delivery of the solution through intravenous tubing.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  2.2 Dosing in Patients with Heparin-Induced Thrombocytopenia

  Initial Dosage:

  Before administering argatroban injection, discontinue heparin therapy and obtain a baseline aPTT.  The recommended initial dose of argatroban injection for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion (see Table 2).

                                                                                                                                                                                      Table 2Recommended Doses and Infusion Rates for 2 mcg/kg/min Dose of Argatroban Injection for Patients with HIT* and Without Hepatic Impairment (1 mg/mL Final Concentration)

   Body Weight (kg) Dose (mcg/min) Infusion Rate (mL/hr) 50 100 6 60 120 7  70 140 8  80  160 10  90  180 11 100  200 12  110  220 13  120  240 14  130  260 16  140  280 17

  *with or without thrombosis

  Monitoring Therapy:For use in HIT, therapy with argatroban injection is monitored using the aPTT with a target range of 1.5 to 3 times the initial baseline value (not to exceed 100 seconds).  Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within 1 to 3 hours following initiation of argatroban injection.  Check the aPTT 2 hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

  Dosage Adjustment:After the initiation of argatroban injection, adjust the dose (not to exceed 10 mcg/kg/min) as necessary to obtain a steady-state aPTT in the target range [see Clinical Studies (14.1)].

  2.3 Dosing in Patients Undergoing Percutaneous Coronary Intervention

  Initial Dosage:Initiate an infusion of argatroban injection at 25 mcg/kg/min and administer a bolus of 350 mcg/kg via a large bore intravenous line over 3 to 5 minutes (see Table 3).  Check an activated clotting time (ACT) 5 to 10 minutes after the bolus dose is completed.  The PCI procedure may proceed if the ACT is greater than 300 seconds.

  Dosage Adjustment:If the ACT is less than 300 seconds, an additional intravenous bolus dose of 150 mcg/kg should be administered, the infusion dose increased to 30 mcg/kg/min, and the ACT checked 5 to 10 minutes later (see Table 3).

  If the ACT is greater than 450 seconds, decrease the infusion rate to 15 mcg/kg/min, and check the ACT 5 to 10 minutes later (see Table 4).

  Continue titrating the dose until a therapeutic ACT (between 300 and 450 seconds) has been achieved; continue the same infusion rate for the duration of the PCI procedure.

  In case of dissection, impending abrupt closure, thrombus formation during the procedure, or inability to achieve or maintain an ACT over 300 seconds, additional bolus doses of 150 mcg/kg may be administered and the infusion dose increased to 40 mcg/kg/min.  Check the ACT after each additional bolus or change in the rate of infusion.

                                                                                                                                          Table 3Recommended Starting and Maintenance Doses (Within the Target ACT Range) of Argatroban Injection in Patients Undergoing PCI Without Hepatic Impairment                                                                                                                     (1 mg/mL Final Concentration) 

    Body   Weight (kg)   Starting Bolus Dose   (350 mcg/kg) Starting and Maintenance Continuous Infusion Dosing For ACT 300 to 450 seconds   25 mcg/kg/min Bolus   Dose (mcg)  Bolus Volume (mL) Continuous Infusion Dose (mg/min)  Continuous Infusion   Rate (mL/hr) 50 17,500 18 1,250 75  60  21,000  21 1,500 90  70  24,500  25 1,750 105  80  28,000  28 2,000 120  90  31,500  32 2,250  135  100  35,000  35 2,500  150  110  38,500  39  2,750 165  120 42,000  42  3,000 180  130  45,500  46 3,250 195  140   49,000  49 3,500 210

  NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs

                                                            Table 4 Recommended Dose Adjustments of Argatroban Injection for Patients Outside of ACT Target Range Undergoing PCI Without Hepatic Impairment                                         (1 mg/mL Final Concentration) 

   Body  Weight (kg) If ACT Less than 300 seconds Dosage Adjustment† 30 mcg/kg/min If ACT Greater than  450 seconds Dosage Adjustment* 15 mcg/kg/min  Additional Bolus  Dose (mcg)  Bolus Volume  (mL)  Continuous Infusion  Dose (mcg/min)  Continuous Infusion  Rate (mL/hr)  Continuous Infusion  Dose (mcg/min) Continuous Infusion  Rate (mL/hr)  50  7,500  8 1,500 90 750 45  60  9,000  9  1,800  108  900 54  70  10,500  11  2,100 126  1,050 63  80   12,000  12  2,400 144  1,200 72  90 13,500  14  2,700  162  1,350 81  100  15,000  15  3,000 180  1,500 90  110  16,500 17  3,300 198  1,650 99  120  18,000 18  3,600  216  1,800  108  130  19,500  20  3,900 234  1,950 117 140  21,000 21  4,200  252  2,100  126

  NOTE: 1 mg = 1,000 mcg; 1 kg = 2.2 lbs

  † Additional intravenous bolus dose of 150 mcg/kg should be administered if ACT less than 300 seconds.

  * No bolus dose is given if ACT greater than 450 seconds

  Monitoring Therapy: For use in PCI, therapy with argatroban injection is monitored using ACT.  Obtain ACTs before dosing, 5 to 10 minutes after bolus dosing, following adjustments in the infusion rate, and at the end of the PCI procedure.  Obtain additional ACTs every 20 to 30 minutes during a prolonged procedure.

  Continued Anticoagulation after PCI:If a patient requires anticoagulation after the procedure, argatroban injection may be continued, but at a rate of 2 mcg/kg/min and adjusted as needed to maintain the aPTT in the desired range [see  Dosage and Administration (2.1)].                                                                                               

  2.4 Dosing in Patients with Hepatic Impairment

  Initial Dosage:

  For adult patients with HIT and moderate or severe hepatic impairment (based on Child-Pugh classification), an initial dose of 0.5 mcg/kg/min is recommended, based on the approximately 4-fold decrease in argatroban injection clearance relative to those with normal hepatic function.  Monitor the aPTT closely, and adjust the dosage as clinically indicated.

  Monitoring Therapy:

  Achievement of steady-state aPTT levels may take longer and require more dose adjustments in patients with hepatic impairment compared to patients with normal hepatic function.

  For patients with hepatic impairment undergoing PCI and who have HIT or are at risk for HIT, carefully titrate argatroban until the desired level of anticoagulation is achieved.  Use of argatroban in PCI patients with clinically significant hepatic disease or AST/ALT levels greater than or equal to 3 times the upper limit of normal should be avoided [see Warnings and Precautions (5.2)]. 

  2.5 Dosing in Pediatric Patients with Heparin-Induced Thrombocytopenia/Heparin-Induced Thrombocytopenia and Thrombosis Syndrome

  Initial Dosage:

  Initial argatroban injection infusion doses are lower for seriously ill pediatric patients compared to adults with normal hepatic function [see Use in Specific Populations (8.4)].

  Monitoring Therapy:

  In general, therapy with argatroban injection is monitored using the aPTT.  Tests of anticoagulant effects (including the aPTT) typically attain steady-state levels within one to three hours following initiation of argatroban injection in patients without hepatic impairment [see Warnings and Precautions  (5.2)].   Dose adjustment may be required to attain the target aPTT.  Check the aPTT two hours after initiation of therapy and after any dose change to confirm that the patient has attained the desired therapeutic range.

  Dosage Adjustment:

  [see Use in Specific Populations (8.4)].

  2.6 Conversion to Oral Anticoagulant Therapy

  Initiating Oral Anticoagulant Therapy:

  When converting patients from argatroban injection to oral anticoagulant therapy, consider the potential for combined effects on INR with co-administration of argatroban and warfarin.  A loading dose of warfarin should not be used.  Initiate therapy using the expected daily dose of warfarin.  To avoid prothrombotic effects and to ensure continuous anticoagulation when initiating warfarin, it is suggested that argatroban and warfarin therapy be overlapped.  There are insufficient data available to recommend the duration of the overlap.

  Co-Administration of Warfarin and Argatroban Injection at Doses up to 2 mcg/kg/min:

  Measure INR daily while argatroban injection and warfarin are co-administered. In general, with doses of argatroban injection up to 2 mcg/kg/min, argatroban injection can be discontinued when the INR is greater than 4 on combined therapy. After argatroban injection is discontinued, repeat the INR measurement in 4 to 6 hours. If the repeat INR is below the desired therapeutic range, resume the infusion of argatroban injection and repeat the procedure daily until the desired therapeutic range on warfarin alone is reached.

  Co-Administration of Warfarin and Argatroban Injection at Doses Greater than 2 mcg/kg/min:

  For doses of argatroban injection greater than 2 mcg/kg/min, the relationship of INR between warfarin alone to the INR on warfarin plus argatroban injection is less predictable.  In this case, in order to predict the INR on warfarin alone, temporarily reduce the dose of argatroban injection to a dose of 2 mcg/kg/min.  Repeat the INR on argatroban injection and warfarin 4 to 6 hours after reduction of the argatroban injection dose and follow the process outlined above for administering argatroban injection at doses up to 2 mcg/kg/min.

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• Enoxaparin Sodium
  

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  Enoxaparin Sodium

  

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  All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring enoxaparin activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].

  For subcutaneous use, enoxaparin sodium should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

  Enoxaparin sodium is not intended for intramuscular administration.

  2.1 Adult Dosage

  Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

  Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with enoxaparin sodium 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

  Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of enoxaparin sodium has been administered in the controlled clinical trial.

  Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of enoxaparin sodium). Enoxaparin sodium should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of enoxaparin sodium administration has been administered in controlled clinical trials.

  Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of enoxaparin sodium is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with enoxaparin sodium should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of enoxaparin sodium has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].

  Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-segment elevation myocardial infarction, the recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the enoxaparin sodium treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

  For patients managed with percutaneous coronary intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last enoxaparin sodium SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium should be administered [see Warnings and Precautions (5.2)].

  2.2 Renal Impairment

  Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

  The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  Table 1 Dosage Regimens for Patients with Severe Renal Impairment(creatinine clearance <30mL/minute) Indication Dosage Regimen Prophylaxis in abdominal surgery 30 mg administered SC once daily Prophylaxis in hip or knee replacement surgery 30 mg administered SC once daily Prophylaxis in medical patients during acute illness 30 mg administered SC once daily Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin 1 mg/kg administered SC once daily Treatment of acute ST-segment elevation myocardial infarction in patients <75 years of age, when administered in conjunction with aspirin 30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily. Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, when administered in conjunction with aspirin 1 mg/kg administered SC once daily (no initial bolus)

  2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction

  For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

  No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].

  2.4 Administration

  Enoxaparin sodium injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

  The use of a tuberculin syringe or equivalent is recommended when using enoxaparin sodium multiple-dose vials to assure withdrawal of the appropriate volume of drug.

  Enoxaparin sodium must not be administered by intramuscular injection. Enoxaparin sodium is intended for use under the guidance of a physician.

  For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.

  Subcutaneous Injection Technique: Patients should be lying down and enoxaparin sodium administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

  Enoxaparin sodium prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.

  Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe.

  Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.Figure A

  Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).Figure B

  Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).Figure C

  Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D).Figure D

  Immediately dispose of the syringe in the nearest sharps container (see Figure E).Figure E

  NOTE:

  The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient's skin. Do not replace the needle shield after injection. The safety system should not be sterilized.

  Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.

  Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should be used. Enoxaparin sodium should be administered through an intravenous line. Enoxaparin sodium should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of drug. Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

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• Calcium Gluconate
  

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  Calcium Gluconate

  

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  The dose is dependent on the requirements of the individual patient.  Intravenous calcium gluconate injection must be administered slowly.

  Usual Dosage

  Adults—500 mg to 2 g (5 to 20 mL)

  Pediatric patients—200 to 500 mg (2 to 5 mL)

  Infants— Not more than 200 mg (not more than 2 mL)

  Usual Dosage

  Adults—500 mg to 2 g (5 to 20 mL)

  Pediatric patients—200 to 500 mg (2 to 5 mL)

  Infants— Not more than 200 mg (not more than 2 mL)

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• Calcium Gluconate
  

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  Calcium Gluconate

  

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  The dose is dependent on the requirements of the individual patient.  Intravenous calcium gluconate injection must be administered slowly.

  Usual Dosage

  Adults—500 mg to 2 g (5 to 20 mL)

  Pediatric patients—200 to 500 mg (2 to 5 mL)

  Infants—Not more than 200 mg (not more than 2 mL)

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Usual Dosage

  Adults—500 mg to 2 g (5 to 20 mL)

  Pediatric patients—200 to 500 mg (2 to 5 mL)

  Infants—Not more than 200 mg (not more than 2 mL)

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Doxycycline Hyclate
  

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  Doxycycline Hyclate

  

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  NOTE: After mixing as directed, methylprednisolone contains benzyl alcohol (see DESCRIPTION, WARNINGS  and  PRECAUTIONS, Pediatric Use).

  Because of possible physical incompatibilities, methylprednisolone should not be diluted or mixed with other solutions.

  Use only Bacteriostatic Water for Injection with Benzyl Alcohol when reconstituting methylprednisolone sodium succinate for injection, USP (see DESCRIPTION).  Use within 48 hours after mixing.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  This preparation may be administered by intravenous injection, by intravenous infusion, or by intramuscular injection, the preferred method for initial emergency use being intravenous injection.  Following the initial emergency period, consideration should be given to employing a longer acting injectable preparation or an oral preparation.

  There are reports of cardiac arrhythmias and/or cardiac arrest following the rapid administration of large IV doses of methylprednisolone (greater than 0.5 gram administered over a period of less than 10 minutes).  Bradycardia has been reported during or after the administration of large doses of methylprednisolone sodium succinate, and may be unrelated to the speed or duration of infusion.  When high dose therapy is desired, the recommended dose of Methylprednisolone Sodium Succinate for Injection, USP sterile powder is 30 mg/kg administered intravenously over at least 30 minutes.  This dose may be repeated every 4 to 6 hours for 48 hours.

  In general, high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized; usually not beyond 48 to 72 hours.

  In other indications, initial dosage will vary from 10 to 40 mg of methylprednisolone depending on the specific disease entity being treated.  However, in certain overwhelming, acute, life-threatening situations, administrations in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  It Should Be Emphasized that Dosage Requirements are Variable and Must Be Individualized on the Basis of the Disease Under Treatment and the Response of the Patient.  After a favorable response is noted, the proper maintenance dosage should be determined by decreasing the initial drug dosage in small decrements at appropriate time intervals until the lowest dosage which will maintain an adequate clinical response is reached.  Situations which may make dosage adjustments necessary are changes in clinical status secondary to remissions or exacerbations in the disease process, the patient’s individual drug responsiveness, and the effect of patient exposure to stressful situations not directly related to the disease entity under treatment.  In this latter situation, it may be necessary to increase the dosage of the corticosteroid for a period of time consistent with the patient’s condition.  If after long-term therapy the drug is to be stopped, it is recommended that it be withdrawn gradually rather than abruptly.

  Methylprednisolone sodium succinate may be administered by intravenous or intramuscular injection or by intravenous infusion, the preferred method for initial emergency use being intravenous injection.  To administer by intravenous (or intramuscular) injection, prepare solution as directed.  The desired dose may be administered intravenously over a period of several minutes.

  To prepare solutions for intravenous infusion, first prepare the solution for injection as directed.  This solution may then be added to indicated amounts of 5% dextrose in water, isotonic saline solution, or 5% dextrose in isotonic saline solution.

  In pediatric patients, the initial dose of methylprednisolone may vary depending on the specific disease entity being treated.  The range of initial doses is 0.11 to 1.6 mg/kg/day in three or four divided doses (3.2 to 48 mg/m2 bsa/day).

  The National Heart, Lung, and Blood Institute (NHLBI) recommended dosing for systemic prednisone, prednisolone, or methylprednisolone in pediatric patients whose asthma is uncontrolled by inhaled corticosteroids and long-acting bronchodilators is 1 to 2 mg/kg/day in single or divided doses.  It is further recommended that short course, or “burst” therapy, be continued until the patient achieves a peak expiratory flow rate of 80% of his or her personal best or until symptoms resolve.  This usually requires 3 to 10 days of treatment, although it can take longer.  There is no evidence that tapering the dose after improvement will prevent a relapse.

  Dosage may be reduced for infants and children but should be governed more by the severity of the condition and response of the patient than by age or size.  It should not be less than 0.5 mg per kg every 24 hours.

  Dosage must be decreased or discontinued gradually when the drug has been administered for more than a few days.  If a period of spontaneous remission occurs in a chronic condition, treatment should be discontinued.  Routine laboratory studies, such as urinalysis, two-hour postprandial blood sugar, determination of blood pressure and body weight, and a chest X-ray should be made at regular intervals during prolonged therapy.  Upper GI X-rays are desirable in patients with an ulcer history or significant dyspepsia.

  In treatment of acute exacerbations of multiple sclerosis, daily doses of 160 mg of methylprednisolone for a week followed by 64 mg every other day for 1 month have been shown to be effective (see PRECAUTIONS, Neurologic-Psychiatric).

  For the purpose of comparison, the following is the equivalent milligram dosage of the various glucocorticoids:

   Cortisone, 25  Triamcinolone, 4  Hydrocortisone, 20  Paramethasone, 2  Prednisolone, 5  Betamethasone, 0.75  Prednisone, 5  Dexamethasone, 0.75  Methylprednisolone, 4

  These dose relationships apply only to oral or intravenous administration of these compounds.  When these substances or their derivatives are injected intramuscularly or into joint spaces, their relative properties may be greatly altered.

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• Neostigmine Methylsulfa...
  

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  Neostigmine Methylsulfate

  

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  2.1 Important Dosage and Administration Instructions

  Neostigmine should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Prior to Neostigmine Methylsulfate Injection administration and up until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Use a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulus to evaluate the extent of recovery of neuromuscular function, and to determine the time of the first dose and the need for additional doses of Neostigmine Methylsulfate Injection. Prior to the administration of Neostigmine Methylsulfate Injection, there must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level (i.e., the response prior to NMBA administration). Dose selection should be based on the extent of spontaneous recovery at time of injection, half-life of the neuromuscular blocking agent (NMBA) to be reversed, and need for rapid NMBA reversal. Patients should continue to be monitored for adequacy of reversal of the effect of NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used. Neostigmine Methylsulfate Injection is administered by intravenous bolus injection.  Additional, carefully adjusted bolus doses are administered according to the patient’s response. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection [see Dosage and Administration (2.4), Warnings and Precautions (5.5)]. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade.  Satisfactory recovery should be judged by the patient’s ability to maintain a patent airway, adequacy of ventilation, and skeletal muscle tone.

  2.2 Recommended Dosage in Adults

  The recommended dose range of Neostigmine Methylsulfate Injection is 0.03 mg/kg to 0.07 mg/kg administered as an intravenous bolus.  A dose less than 0.04 mg/kg is recommended for reversal of the effect of NMBAs with shorter half-lives (e.g., rocuronium), or when the first twitch response to the TOF stimulus is substantially greater than 10% of baseline, or when a second twitch is present.  A dose of 0.07 mg/kg is recommended for the reversal of the effect of NMBAs with longer half-lives (e.g., vecuronium or pancuronium), or when first twitch response is not substantially greater than 10% of baseline, or if there is need for more rapid recovery. Additional doses may be required. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.

  2.3 Recommended Dosage in Pediatric Patients including Neonates

  Adult guidelines should be followed when Neostigmine Methylsulfate Injection is administered to pediatric patients.  Pediatric patients require Neostigmine Methylsulfate Injection doses similar to those for adult patients.

  2.4 Concomitant or Pre-Administration of Anticholinergic Agents

  An anticholinergic agent (e.g., atropine sulfate or glycopyrrolate) should be administered intravenously several minutes prior to or with Neostigmine Methylsulfate Injection administration using separate syringes.  For bradycardic patients, the anticholinergic agent should be administered prior to Neostigmine Methylsulfate Injection.

  2.1 Important Dosage and Administration Instructions

  Neostigmine should be administered by trained healthcare providers familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents (NMBA) and neuromuscular block reversal agents. Prior to Neostigmine Methylsulfate Injection administration and up until complete recovery of normal ventilation, the patient should be well ventilated and a patent airway maintained. Use a peripheral nerve stimulator capable of delivering a train-of-four (TOF) stimulus to evaluate the extent of recovery of neuromuscular function, and to determine the time of the first dose and the need for additional doses of Neostigmine Methylsulfate Injection. Prior to the administration of Neostigmine Methylsulfate Injection, there must be a twitch response to the first stimulus in the TOF of at least 10% of its baseline level (i.e., the response prior to NMBA administration). Dose selection should be based on the extent of spontaneous recovery at time of injection, half-life of the neuromuscular blocking agent (NMBA) to be reversed, and need for rapid NMBA reversal. Patients should continue to be monitored for adequacy of reversal of the effect of NMBAs for a period of time that would assure full recovery based on the patient’s medical condition and the pharmacokinetics of neostigmine and the NMBA used. Neostigmine Methylsulfate Injection is administered by intravenous bolus injection.  Additional, carefully adjusted bolus doses are administered according to the patient’s response. An anticholinergic agent (e.g., atropine or glycopyrrolate) should be administered prior to or concomitantly with Neostigmine Methylsulfate Injection [see Dosage and Administration (2.4), Warnings and Precautions (5.5)]. TOF monitoring alone should not be relied upon to determine the adequacy of reversal of neuromuscular blockade.  Satisfactory recovery should be judged by the patient’s ability to maintain a patent airway, adequacy of ventilation, and skeletal muscle tone.

  2.2 Recommended Dosage in Adults

  The recommended dose range of Neostigmine Methylsulfate Injection is 0.03 mg/kg to 0.07 mg/kg administered as an intravenous bolus.  A dose less than 0.04 mg/kg is recommended for reversal of the effect of NMBAs with shorter half-lives (e.g., rocuronium), or when the first twitch response to the TOF stimulus is substantially greater than 10% of baseline, or when a second twitch is present.  A dose of 0.07 mg/kg is recommended for the reversal of the effect of NMBAs with longer half-lives (e.g., vecuronium or pancuronium), or when first twitch response is not substantially greater than 10% of baseline, or if there is need for more rapid recovery. Additional doses may be required. The recommended maximum total dose is 0.07 mg/kg or up to a total of 5 mg, whichever is less.

  2.3 Recommended Dosage in Pediatric Patients including Neonates

  Adult guidelines should be followed when Neostigmine Methylsulfate Injection is administered to pediatric patients.  Pediatric patients require Neostigmine Methylsulfate Injection doses similar to those for adult patients.

  2.4 Concomitant or Pre-Administration of Anticholinergic Agents

  An anticholinergic agent (e.g., atropine sulfate or glycopyrrolate) should be administered intravenously several minutes prior to or with Neostigmine Methylsulfate Injection administration using separate syringes.  For bradycardic patients, the anticholinergic agent should be administered prior to Neostigmine Methylsulfate Injection.

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• Restil 40 Number 9
  

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  Restil 40 Number 9

  

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  2.1 Dosing for Partial Onset Seizures

  Adults 16 Years and Older

  Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg.  There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

  Pediatric Patients

  1 Month to < 6 Months

  Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).  In the clinical trial, the mean daily dose was 35 mg/kg in this age group.  The effectiveness of lower doses has not been studied.

  6 Months to < 4 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

  4 Years to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 44 mg/kg.  The maximum daily dose was 3,000 mg/day.

  2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase the dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been studied.

  2.3 Dosing for Primary Generalized Tonic-Clonic Seizures

  Adults 16 Years and Older

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

  Pediatric Patients Ages 6 to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

  2.4 Switching from Oral Dosing

  When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

  2.5 Switching to Oral Dosing

  At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

  2.6 Preparation and Administration Instructions

  Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration.  If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.  Consideration should also be given to the total daily fluid intake of the patient.  Levetiracetam injection should be administered as a 15-minute IV infusion.  One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Product with particulate matter or discoloration should not be used.

  Any unused portion of the levetiracetam injection vial contents should be discarded.

  Adults

  See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1,000 mg, or 1,500 mg.

  Table 1:  Preparation and Administration of Levetiracetam Injection for Adults

  Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg 5 mL (5 mL vial) 100 mL 15 minutes 1,000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1,500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

  For example, to prepare a 1,000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

  Pediatric Patients

  When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).  

  The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

  Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 100 mg/mL

  2.7 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam injection dosing must be individualized according to the patient’s renal function status.  Recommended dosage adjustments for adults with renal impairment are shown in Table 2.  Information is unavailable for dosage adjustments in pediatric patients with renal impairment.  In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.  To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

  CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients) 72 x serum creatinine (mg/dL)

  Then CLcr is adjusted for body surface area (BSA) as follows:

  CLcr (mL/min/1.73 m2) = CLcr (mL/min) x 1.73 BSA subject (m2)

  Table 2:  Dosage Adjustment Regimen for Adult Patients with Renal Impairment

  Group Creatinine Clearance (mL/min/1.73 m2) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ------­ 500 to 1,0001 Every 24 hours1

  1    Following dialysis, a 250 to 500 mg supplemental dose is recommended.

  2.8 Compatibility and Stability

  Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

  Diluents

  Sodium chloride (0.9%) injection, USP

  Lactated Ringer’s injection

  Dextrose 5% injection, USP

  Other Antiepileptic Drugs

  Lorazepam

  Diazepam

  Valproate sodium

  There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

  2.1 Dosing for Partial Onset Seizures

  Adults 16 Years and Older

  Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg.  There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

  Pediatric Patients

  1 Month to < 6 Months

  Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).  In the clinical trial, the mean daily dose was 35 mg/kg in this age group.  The effectiveness of lower doses has not been studied.

  6 Months to < 4 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

  4 Years to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 44 mg/kg.  The maximum daily dose was 3,000 mg/day.

  2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase the dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been studied.

  2.4 Switching from Oral Dosing

  When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

  2.5 Switching to Oral Dosing

  At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

  2.6 Preparation and Administration Instructions

  Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration.  If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.  Consideration should also be given to the total daily fluid intake of the patient.  Levetiracetam injection should be administered as a 15-minute IV infusion.  One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Product with particulate matter or discoloration should not be used.

  Any unused portion of the levetiracetam injection vial contents should be discarded.

  Adults

  See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1,000 mg, or 1,500 mg.

  Table 1:  Preparation and Administration of Levetiracetam Injection for Adults

  Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg 5 mL (5 mL vial) 100 mL 15 minutes 1,000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1,500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

  For example, to prepare a 1,000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

  Pediatric Patients

  When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).  

  The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

  Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 100 mg/mL

  2.7 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam injection dosing must be individualized according to the patient’s renal function status.  Recommended dosage adjustments for adults with renal impairment are shown in Table 2.  Information is unavailable for dosage adjustments in pediatric patients with renal impairment.  In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.  To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

  CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients) 72 x serum creatinine (mg/dL)

  Then CLcr is adjusted for body surface area (BSA) as follows:

  CLcr (mL/min/1.73 m2) = CLcr (mL/min) x 1.73 BSA subject (m2)

  Table 2:  Dosage Adjustment Regimen for Adult Patients with Renal Impairment

  Group Creatinine Clearance (mL/min/1.73 m2) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ------­ 500 to 1,0001 Every 24 hours1

  1    Following dialysis, a 250 to 500 mg supplemental dose is recommended.

  2.8 Compatibility and Stability

  Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

  Diluents

  Sodium chloride (0.9%) injection, USP

  Lactated Ringer’s injection

  Dextrose 5% injection, USP

  Other Antiepileptic Drugs

  Lorazepam

  Diazepam

  Valproate sodium

  There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

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• Ketorolac Tromethamine
  

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  Ketorolac Tromethamine

  

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  IN ADULTS, THE COMBINED DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND KETOROLAC TROMETHAMINE TABLETS IS NOT TO EXCEED 5 DAYS.  IN ADULTS, THE USE OF KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS CONTINUATION THERAPY TO KETOROLAC TROMETHAMINE INJECTION.

  Ketorolac Tromethamine Injection

  Adult Patients

  Ketorolac tromethamine injection may be used as a single or multiple dose on a regular or “prn” schedule for the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting.  Hypovolemia should be corrected prior to the administration of ketorolac tromethamine (see WARNINGS, Renal Effects).  Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

  When administering ketorolac tromethamine injection, the IV bolus must be given over no less than 15 seconds.  The IM administration should be given slowly and deeply into the muscle.  The analgesic effect begins in ~30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM.  Duration of analgesic effect is usually 4 to 6 hours.

  Single-Dose Treatment: The Following Regimen Should Be Limited To Single Administration Use Only

  Adult Patients

  IM Dosing:

  Patients < 65 years of age: One dose of 60 mg. Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.

  IV Dosing:

  Patients < 65 years of age: One dose of 30 mg. Patients ≥ 65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg.

  Pediatric Patients (2 to 16 years of age): The pediatric population should receive only a single dose of ketorolac tromethamine injection as follows:

  IM Dosing:

  One dose of 1 mg/kg up to a maximum of 30 mg.

  IV Dosing:

  One dose of 0.5 mg/kg up to a maximum of 15 mg.

  Multiple-Dose Treatment (IV or IM) In Adults:

  Patients < 65 years of age: The recommended dose is 30 mg ketorolac tromethamine injection every 6 hours.  The maximum daily dose should not exceed 120 mg. For Patients ≥ 65 years of age, renally impaired patients (see WARNINGS) and patients less than 50 kg (110 lbs):  The recommended dose is 15 mg ketorolac tromethamine injection every 6 hours.  The maximum daily dose for these populations should not exceed 60 mg.

  For breakthrough pain do not increase the dose or the frequency of ketorolac tromethamine.  Consideration should be given to supplementing these regimens with low doses of opioids prn unless otherwise contraindicated.

  Pharmaceutical Information for Ketorolac Tromethamine Injection

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Ketorolac tromethamine injection should not be mixed in a small volume (e.g., in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution.

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• Cefoxitin
  

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  Cefoxitin

  

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  Treatment

  Adults

  The usual adult dosage range is 1 gram to 2 grams every six to eight hours. Dosage should be determined by susceptibility of the causative organisms, severity of infection, and the condition of the patient (see Table 3 for dosage guidelines).

  If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefoxitin sodium has no activity against this organism.

  CEFOXITIN FOR INJECTION may be used in patients with reduced renal function with the following dosage adjustments:

  In adults with renal insufficiency, an initial loading dose of 1 gram to 2 grams may be given. After a loading dose, the recommendations for maintenance dosage (Table 4) may be used as a guide.

  When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

  Males:                 Weight (kg) x (140-age)          

                    72 x serum creatinine (mg/100 mL) 

  Females: 0.85 x above value

  In patients undergoing hemodialysis, the loading dose of 1 to 2 grams should be given after each hemodialysis, and the maintenance dose should be given as indicated in Table 4.

  Antibiotic therapy for group A beta-hemolytic streptococcal infections should be maintained for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

  Pediatric Patients

  The recommended dosage in pediatric patients three months of age and older is 80 to 160 mg/kg of body weight per day divided into four to six equal doses. The higher dosages should be used for more severe or serious infections. The total daily dosage should not exceed 12 grams. At this time no recommendation is made for pediatric patients from birth to three months of age (see PRECAUTIONS).

  In pediatric patients with renal insufficiency, the dosage and frequency of dosage should be modified consistent with the recommendations for adults (see Table 4).

  Prevention

  Effective prophylactic use depends on the time of administration. CEFOXITIN FOR INJECTION usually should be given one-half to one hour before the operation, which is sufficient time to achieve effective levels in the wound during the procedure. Prophylactic administration should usually be stopped within 24 hours since continuing administration of any antibiotic increases the possibility of adverse reactions but, in the majority of surgical procedures, does not reduce the incidence of subsequent infection.

  For prophylactic use in uncontaminated gastrointestinal surgery, vaginal hysterectomy, or abdominal hysterectomy, the following doses are recommended:

  Adults:

  2 grams administered intravenously just prior to surgery (approximately one-half to one hour before the initial incision) followed by 2 grams every 6 hours after the first dose for no more than 24 hours.

  Pediatric Patients (3 months and older):

  30 to 40 mg/kg doses may be given at the times designated above.

  Cesarean section patients:

  For patients undergoing cesarean section, either a single 2 gram dose administered intravenously as soon as the umbilical cord is clamped OR a 3-dose regimen consisting of 2 grams given intravenously as soon as the umbilical cord is clamped followed by 2 grams 4 and 8 hours after the initial dose is recommended. (SeeCLINICAL STUDIES)

  Table 3 - Guidelines for Dosage of CEFOXITIN FOR INJECTION

  Type of Infection Daily Dosage Frequency and Route Uncomplicated forms* of infections such as pneumonia, urinary tract infection, cutaneous infection 3 to 4 grams 1 gram every 6-8 hours IV Moderately severe or severe infections 6 to 8 grams 1 gram every4 hoursor 2 grams every 6-8 hours IV Infections commonly needing antibiotics in higher dosage (e.g., gas gangrene) 12 grams 2 grams every 4 hours or 3 grams every 6 hours IV

  * Including patients in whom bacteremia is absent or unlikely.

  Table 4 - Maintenance Dosage of CEFOXITIN FOR INJECTION in Adults with Reduced Renal Function

  Renal Function  Creatinine Clearance(mL/min)  Dose (grams) Frequency  Mild impairmentModerate impairmentSevere impairmentEssentially no function  50 to 3029 to 109 to 5< 5  1 to 21 to 20.5 to 10.5 to 1  every 8-12 hoursevery 12-24 hoursevery 12-24 hoursevery 24-48 hours

    

  Table 5 - Preparation of Solution for Intravenous Administration

  Strength Amount of Diluent to be Added (mL)** ApproximateWithdrawableVolume (mL)  Approximate AverageConcentration(mg/mL)  1 gram Vial 2 gram Vial  10 10 or 20  10.5 11.1 or 21  95 180 or 95

  ** Shake to dissolve and let stand until clear.

  Preparation of Solution

  Table 5 is provided for convenience in constituting CEFOXITIN FOR INJECTION for intravenous administration.

  For Vials

  One gram should be constituted with at least 10 mL, and 2 grams with 10 or 20 mL, of Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection. These primary solutions may be further diluted in 50 to 1000 mL of the diluents listed under the Vials  portion of the COMPATIBILITY AND STABILITYsection.

  Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, in whom use of CEFOXITIN FOR INJECTION may be indicated, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluent containing benzyl alcohol should not be used when CEFOXITIN FOR INJECTION is constituted for administration to pediatric patients in this age range.

  Administration

  CEFOXITIN FOR INJECTION may be administered intravenously after constitution.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Intravenous Administration

  The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending. For intermittent intravenous administration, a solution containing 1 gram or 2 grams in 10 mL of Sterile Water for Injection can be injected over a period of three to five minutes. Using an infusion system, it may also be given over a longer period of time through the tubing system by which the patient may be receiving other intravenous solutions. However, during infusion of the solution containing CEFOXITIN FOR INJECTION, it is advisable to temporarily discontinue administration of any other solutions at the same site.

  For the administration of higher doses by continuous intravenous infusion, a solution of CEFOXITIN FOR INJECTION may be added to an intravenous bottle containing 5 percent Dextrose Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose and 0.9 percent Sodium Chloride Injection. BUTTERFLY®†† or scalp vein-type needles are preferred for this type of infusion.

  Solutions of CEFOXITIN FOR INJECTION, like those of most beta-lactam antibiotics, should not be added to aminoglycoside solutions (e.g., gentamicin sulfate, tobramycin sulfate, amikacin sulfate) because of potential interaction. However, CEFOXITIN FOR INJECTION and aminoglycosides may be administered separately to the same patient.

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• Ibuprofen
  

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  Ibuprofen

  

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  NOTE: CONTAINS BENZYL ALCOHOL (see WARNINGS and PRECAUTIONS,  Pediatric Use).

  CISATRACURIUM BESYLATE INJECTION SHOULD ONLY BE ADMINISTERED INTRAVENOUSLY.

  The dosage information provided below is intended as a guide only.  Doses of Cisatracurium should be individualized (see CLINICAL PHARMACOLOGY, Individualization of Dosages). The use of a peripheral nerve stimulator will permit the most advantageous use of cisatracurium, minimize the possibility of overdosage or underdosage, and assist in the evaluation of recovery.

  Adults

  Initial Doses

  One of two intubating doses of cisatracurium may be chosen, based on the desired time to tracheal intubation and the anticipated length of surgery.  In addition to the dose of neuromuscular blocking agent, the presence of co-induction agents (e.g., fentanyl and midazolam) and the depth of anesthesia are factors that can influence intubation conditions.  Doses of 0.15 (3 x ED95) and 0.2 (4 x ED95) mg/kg cisatracurium, as components of a propofol/nitrous oxide/oxygen induction-intubation technique, may produce generally GOOD or EXCELLENT conditions for intubation in 2 and 1.5 minutes, respectively.  Similar intubation conditions may be expected when these doses of cisatracurium are administered as components of a thiopental/nitrous oxide/oxygen induction-intubation technique.  In two intubation studies using thiopental or propofol and midazolam and fentanyl as co-induction agents, EXCELLENT intubation conditions were most frequently achieved with the 0.2 mg/kg compared to 0.15 mg/kg dose of cisatracurium.  The clinically effective durations of action for 0.15 and 0.2 mg/kg cisatracurium during propofol anesthesia are 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively.  Lower doses may result in a longer time for the development of satisfactory intubation conditions.  Doses up to 8 x ED95 cisatracurium have been safely administered to healthy adult patients and patients with serious cardiovascular disease.  These larger doses are associated with longer clinically effective durations of action (see CLINICAL PHARMACOLOGY).

  Because slower times to onset of complete neuromuscular block were observed in elderly patients and patients with renal dysfunction, extending the interval between administration of cisatracurium and the intubation attempt for these patients may be required to achieve adequate intubation conditions.

  A dose of 0.03 mg/kg cisatracurium is recommended for maintenance of neuromuscular block during prolonged surgical procedures.  Maintenance doses of 0.03 mg/kg each sustain neuromuscular block for approximately 20 minutes.  Maintenance dosing is generally required 40 to 50 minutes following an initial dose of 0.15 mg/kg cisatracurium and 50 to 60 minutes following an initial dose of 0.2 mg/kg cisatracurium, but the need for maintenance doses should be determined by clinical criteria.  For shorter or longer durations of action, smaller or larger maintenance doses may be administered.

  Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum Alveolar Concentration) may prolong the clinically effective duration of action of initial and maintenance doses.  The magnitude of these effects may depend on the duration of administration of the volatile agents.  Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of cisatracurium and therefore, no adjustment to the initial dose should be necessary when cisatracurium is administered shortly after initiation of volatile agents.  In long surgical procedures during enflurane or isoflurane anesthesia, less frequent maintenance dosing or lower maintenance doses of cisatracurium may be necessary.  No adjustments to the initial dose of cisatracurium are required when used in patients receiving propofol anesthesia.

  Children

  Initial Doses

  The recommended dose of cisatracurium for children 2 to 12 years of age is 0.1 to 0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg cisatracurium produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) and clinically effective block for 28 minutes (range: 21 to 38 minutes).  When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium produces maximum neuromuscular block in about 3 minutes (range: 1.5 to 8 minutes) and clinically effective block (time to 25% recovery) for 36 minutes (range: 29 to 46 minutes).

  Infants

  Initial Doses

  The recommended dose of cisatracurium for intubation of infants 1 month to 23 months is 0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia.  When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium produces maximum neuromuscular block in about 2 minutes (range: 1.3 to 3.4 minutes) and clinically effective block (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes).

  Use by Continuous Infusion

  Infusion in the Operating Room (OR)   

  After administration of an initial bolus dose of cisatracurium, a diluted solution of cisatracurium can be administered by continuous infusion to adults and children aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures.  Infusion of cisatracurium should be individualized for each patient.  The rate of administration should be adjusted according to the patient's response as determined by peripheral nerve stimulation.  Accurate dosing is best achieved using a precision infusion device.

  Infusion of cisatracurium should be initiated only after early evidence of spontaneous recovery from the initial bolus dose.  An initial infusion rate of 3 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function.  Thereafter, a rate of 1 to 2 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under opioid/nitrous oxide/oxygen anesthesia.

  Reduction of the infusion rate by up to 30% to 40% should be considered when cisatracurium is administered during stable isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen at the 1.25 MAC level).  Greater reductions in the infusion rate of cisatracurium may be required with longer durations of administration of isoflurane or enflurane.

  The rate of infusion of atracurium required to maintain adequate surgical relaxation in patients undergoing coronary artery bypass surgery with induced hypothermia (25° to 28°C) is approximately half the rate required during normothermia.  Based on the structural similarity between cisatracurium and atracurium, a similar effect on the infusion rate of cisatracurium may be expected.

  Spontaneous recovery from neuromuscular block following discontinuation of infusion of cisatracurium may be expected to proceed at a rate comparable to that following administration of a single bolus dose.

  Infusion in the Intensive Care Unit (ICU)

  The principles for infusion of cisatracurium in the OR are also applicable to use in the ICU.  An infusion rate of approximately 3 mcg/kg/min (range: 0.5 to 10.2 mcg/kg/min) should provide adequate neuromuscular block in adult patients in the ICU.  There may be wide interpatient variability in dosage requirements and these may increase or decrease with time (see PRECAUTIONS, Long-Term Use in the Intensive Care Unit [ICU]).  Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly re-establish neuromuscular block prior to reinstitution of the infusion.

  Infusion Rate Tables

  The amount of infusion solution required per minute will depend upon the concentration of cisatracurium in the infusion solution, the desired dose of cisatracurium, and the patient's weight.  The contribution of the infusion solution to the fluid requirements of the patient also must be considered. Tables 10 and 11 provide guidelines for delivery, in mL/hr (equivalent to microdrops/minute when 60 microdrops = 1 mL), of cisatracurium solutions in concentrations of 0.1 mg/mL (10 mg/100 mL) or 0.4 mg/mL (40 mg/100 mL).

  Table 10. Infusion Rates of Cisatracurium for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.1 mg/mL

   Drug Delivery Rate (mcg/kg/min)      1    1.5    2    3    5    Patient Weight (kg)    Infusion Delivery Rate (mL/hr)    10   6   9   12   18   30   45   27   41   54   81   135   70   42   63   84   126   210   100   60   90   120   180   300 

  Table 11. Infusion Rates of Cisatracurium for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.4 mg/mL

   Drug Delivery Rate (mcg/kg/min)      1    1.5    2    3    5    Patient Weight (kg)    Infusion Delivery Rate (mL/hr)    10   1.5   2.3   3   4.5   7.5   45   6.8   10.1   13.5   20.3   33.8   70   10.5   15.8   21   31.5   52.5   100   15   22.5   30   45   75 

  Cisatracurium Besylate Injection Compatibility and Admixtures

  Y-site Administration

  Cisatracurium Besylate Injection is acidic (pH = 3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions).

  Studies have shown that Cisatracurium Besylate Injection is compatible with:

  5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP SUFENTA® (sufentanil citrate) Injection, diluted as directed ALFENTA® (alfentanil hydrochloride) Injection, diluted as directed SUBLIMAZE® (fentanyl citrate) Injection, diluted as directed VERSED® (midazolam hydrochloride) Injection, diluted as directed Droperidol Injection, diluted as directed

  Cisatracurium Besylate Injection is not compatible with DIPRIVAN® (propofol) Injection or TORADOL® (ketorolac) Injection for Y-site administration.  Studies of other parenteral products have not been conducted.

  Dilution Stability

  Cisatracurium Besylate Injection diluted in 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or 5% Dextrose and 0.9% Sodium Chloride Injection, USP to 0.1 mg/mL may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency.  Dilutions to 0.1 mg/mL or 0.2 mg/mL in 5% Dextrose and Lactated Ringer's Injection may be stored under refrigeration for 24 hours.

  Cisatracurium Besylate Injection should not be diluted in Lactated Ringer's Injection, USP due to chemical instability.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Solutions which are not clear, or contain visible particulates, should not be used.  Cisatracurium Besylate Injection is a colorless to slightly yellow or greenish-yellow solution.

  Adults

  Initial Doses

  One of two intubating doses of cisatracurium may be chosen, based on the desired time to tracheal intubation and the anticipated length of surgery.  In addition to the dose of neuromuscular blocking agent, the presence of co-induction agents (e.g., fentanyl and midazolam) and the depth of anesthesia are factors that can influence intubation conditions.  Doses of 0.15 (3 x ED95) and 0.2 (4 x ED95) mg/kg cisatracurium, as components of a propofol/nitrous oxide/oxygen induction-intubation technique, may produce generally GOOD or EXCELLENT conditions for intubation in 2 and 1.5 minutes, respectively.  Similar intubation conditions may be expected when these doses of cisatracurium are administered as components of a thiopental/nitrous oxide/oxygen induction-intubation technique.  In two intubation studies using thiopental or propofol and midazolam and fentanyl as co-induction agents, EXCELLENT intubation conditions were most frequently achieved with the 0.2 mg/kg compared to 0.15 mg/kg dose of cisatracurium.  The clinically effective durations of action for 0.15 and 0.2 mg/kg cisatracurium during propofol anesthesia are 55 minutes (range: 44 to 74 minutes) and 61 minutes (range: 41 to 81 minutes), respectively.  Lower doses may result in a longer time for the development of satisfactory intubation conditions.  Doses up to 8 x ED95 cisatracurium have been safely administered to healthy adult patients and patients with serious cardiovascular disease.  These larger doses are associated with longer clinically effective durations of action (see CLINICAL PHARMACOLOGY).

  Because slower times to onset of complete neuromuscular block were observed in elderly patients and patients with renal dysfunction, extending the interval between administration of cisatracurium and the intubation attempt for these patients may be required to achieve adequate intubation conditions.

  A dose of 0.03 mg/kg cisatracurium is recommended for maintenance of neuromuscular block during prolonged surgical procedures.  Maintenance doses of 0.03 mg/kg each sustain neuromuscular block for approximately 20 minutes.  Maintenance dosing is generally required 40 to 50 minutes following an initial dose of 0.15 mg/kg cisatracurium and 50 to 60 minutes following an initial dose of 0.2 mg/kg cisatracurium, but the need for maintenance doses should be determined by clinical criteria.  For shorter or longer durations of action, smaller or larger maintenance doses may be administered.

  Isoflurane or enflurane administered with nitrous oxide/oxygen to achieve 1.25 MAC (Minimum Alveolar Concentration) may prolong the clinically effective duration of action of initial and maintenance doses.  The magnitude of these effects may depend on the duration of administration of the volatile agents.  Fifteen to 30 minutes of exposure to 1.25 MAC isoflurane or enflurane had minimal effects on the duration of action of initial doses of cisatracurium and therefore, no adjustment to the initial dose should be necessary when cisatracurium is administered shortly after initiation of volatile agents.  In long surgical procedures during enflurane or isoflurane anesthesia, less frequent maintenance dosing or lower maintenance doses of cisatracurium may be necessary.  No adjustments to the initial dose of cisatracurium are required when used in patients receiving propofol anesthesia.

  Children

  Initial Doses

  The recommended dose of cisatracurium for children 2 to 12 years of age is 0.1 to 0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia. When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.1 mg/kg cisatracurium produces maximum neuromuscular block in an average of 2.8 minutes (range: 1.8 to 6.7 minutes) and clinically effective block for 28 minutes (range: 21 to 38 minutes).  When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium produces maximum neuromuscular block in about 3 minutes (range: 1.5 to 8 minutes) and clinically effective block (time to 25% recovery) for 36 minutes (range: 29 to 46 minutes).

  Infants

  Initial Doses

  The recommended dose of cisatracurium for intubation of infants 1 month to 23 months is 0.15 mg/kg administered over 5 to 10 seconds during either halothane or opioid anesthesia.  When administered during stable opioid/nitrous oxide/oxygen anesthesia, 0.15 mg/kg cisatracurium produces maximum neuromuscular block in about 2 minutes (range: 1.3 to 3.4 minutes) and clinically effective block (time to 25% recovery) for about 43 minutes (range: 34 to 58 minutes).

  Use by Continuous Infusion

  Infusion in the Operating Room (OR)   

  After administration of an initial bolus dose of cisatracurium, a diluted solution of cisatracurium can be administered by continuous infusion to adults and children aged 2 or more years for maintenance of neuromuscular block during extended surgical procedures.  Infusion of cisatracurium should be individualized for each patient.  The rate of administration should be adjusted according to the patient's response as determined by peripheral nerve stimulation.  Accurate dosing is best achieved using a precision infusion device.

  Infusion of cisatracurium should be initiated only after early evidence of spontaneous recovery from the initial bolus dose.  An initial infusion rate of 3 mcg/kg/min may be required to rapidly counteract the spontaneous recovery of neuromuscular function.  Thereafter, a rate of 1 to 2 mcg/kg/min should be adequate to maintain continuous neuromuscular block in the range of 89% to 99% in most pediatric and adult patients under opioid/nitrous oxide/oxygen anesthesia.

  Reduction of the infusion rate by up to 30% to 40% should be considered when cisatracurium is administered during stable isoflurane or enflurane anesthesia (administered with nitrous oxide/oxygen at the 1.25 MAC level).  Greater reductions in the infusion rate of cisatracurium may be required with longer durations of administration of isoflurane or enflurane.

  The rate of infusion of atracurium required to maintain adequate surgical relaxation in patients undergoing coronary artery bypass surgery with induced hypothermia (25° to 28°C) is approximately half the rate required during normothermia.  Based on the structural similarity between cisatracurium and atracurium, a similar effect on the infusion rate of cisatracurium may be expected.

  Spontaneous recovery from neuromuscular block following discontinuation of infusion of cisatracurium may be expected to proceed at a rate comparable to that following administration of a single bolus dose.

  Infusion in the Intensive Care Unit (ICU)

  The principles for infusion of cisatracurium in the OR are also applicable to use in the ICU.  An infusion rate of approximately 3 mcg/kg/min (range: 0.5 to 10.2 mcg/kg/min) should provide adequate neuromuscular block in adult patients in the ICU.  There may be wide interpatient variability in dosage requirements and these may increase or decrease with time (see PRECAUTIONS, Long-Term Use in the Intensive Care Unit [ICU]).  Following recovery from neuromuscular block, readministration of a bolus dose may be necessary to quickly re-establish neuromuscular block prior to reinstitution of the infusion.

  Infusion Rate Tables

  The amount of infusion solution required per minute will depend upon the concentration of cisatracurium in the infusion solution, the desired dose of cisatracurium, and the patient's weight.  The contribution of the infusion solution to the fluid requirements of the patient also must be considered. Tables 10 and 11 provide guidelines for delivery, in mL/hr (equivalent to microdrops/minute when 60 microdrops = 1 mL), of cisatracurium solutions in concentrations of 0.1 mg/mL (10 mg/100 mL) or 0.4 mg/mL (40 mg/100 mL).

  Table 10. Infusion Rates of Cisatracurium for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.1 mg/mL

   Drug Delivery Rate (mcg/kg/min)      1    1.5    2    3    5    Patient Weight (kg)    Infusion Delivery Rate (mL/hr)    10   6   9   12   18   30   45   27   41   54   81   135   70   42   63   84   126   210   100   60   90   120   180   300 

  Table 11. Infusion Rates of Cisatracurium for Maintenance of Neuromuscular Block During Opioid/Nitrous Oxide/Oxygen Anesthesia for a Concentration of 0.4 mg/mL

   Drug Delivery Rate (mcg/kg/min)      1    1.5    2    3    5    Patient Weight (kg)    Infusion Delivery Rate (mL/hr)    10   1.5   2.3   3   4.5   7.5   45   6.8   10.1   13.5   20.3   33.8   70   10.5   15.8   21   31.5   52.5   100   15   22.5   30   45   75 

  Cisatracurium Besylate Injection Compatibility and Admixtures

  Y-site Administration

  Cisatracurium Besylate Injection is acidic (pH = 3.25 to 3.65) and may not be compatible with alkaline solution having a pH greater than 8.5 (e.g., barbiturate solutions).

  Studies have shown that Cisatracurium Besylate Injection is compatible with:

  5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 5% Dextrose and 0.9% Sodium Chloride Injection, USP SUFENTA® (sufentanil citrate) Injection, diluted as directed ALFENTA® (alfentanil hydrochloride) Injection, diluted as directed SUBLIMAZE® (fentanyl citrate) Injection, diluted as directed VERSED® (midazolam hydrochloride) Injection, diluted as directed Droperidol Injection, diluted as directed

  Cisatracurium Besylate Injection is not compatible with DIPRIVAN® (propofol) Injection or TORADOL® (ketorolac) Injection for Y-site administration.  Studies of other parenteral products have not been conducted.

  Dilution Stability

  Cisatracurium Besylate Injection diluted in 5% Dextrose Injection, USP; 0.9% Sodium Chloride Injection, USP; or 5% Dextrose and 0.9% Sodium Chloride Injection, USP to 0.1 mg/mL may be stored either under refrigeration or at room temperature for 24 hours without significant loss of potency.  Dilutions to 0.1 mg/mL or 0.2 mg/mL in 5% Dextrose and Lactated Ringer's Injection may be stored under refrigeration for 24 hours.

  Cisatracurium Besylate Injection should not be diluted in Lactated Ringer's Injection, USP due to chemical instability.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Solutions which are not clear, or contain visible particulates, should not be used.  Cisatracurium Besylate Injection is a colorless to slightly yellow or greenish-yellow solution.

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• Doxy 100
  

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  Doxy 100

  

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  NOTE:  Rapid administration is to be avoided.  Parenteral therapy is indicated only when oral therapy is not indicated.  Oral therapy should be instituted as soon as possible.  If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

  THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE FOR INJECTION (100 to 200 MG/DAY) DIFFERS FROM THAT OF THE OTHER TETRACYCLINES (1 to 2 G/DAY).  EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

  Studies to date have indicated that doxycycline hyclate at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS , Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS , Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

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• Bacteriostatic Water
  

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  Bacteriostatic Water

  

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  The volume of the preparation to be used for diluting or dissolving any drug for injection, is dependent on the vehicle concentration, dose and route of administration as recommended by the manufacturer.

  Use aseptic technique for single or multiple entry and withdrawal from all containers.  When diluting or dissolving drugs, mix thoroughly and use promptly.

  Do not store reconstituted solutions of drugs for injection unless otherwise directed by the manufacturer of the solute.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Rohto Ice
  

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  Rohto Ice

  

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  Dexamethasone sodium phosphate injection, 10 mg/mL– For intravenous and intramuscular injection only.

  Dexamethasone sodium phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

  Solutions used for intravenous administration or further dilution of this product should be preservative free when used in the neonate, especially the premature infant.

  When it is mixed with an infusion solution, sterile precautions should be observed.  Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

  DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

  Intravenous and Intramuscular Injection

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily. 

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author

  Dosage

  Cavanagh1

  3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg

  Dietzman2

  2 to 6 mg/kg of body weight as a single intravenous injection

  Frank3

  40 mg initially followed by repeat intravenous injection every 4 to 6 hours while shock persists

  Oaks4

  40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists

  Schumer5

  1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with 2 mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, first day, 4 or 8 mg intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

  Intravenous and Intramuscular Injection

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily. 

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author

  Dosage

  Cavanagh1

  3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg

  Dietzman2

  2 to 6 mg/kg of body weight as a single intravenous injection

  Frank3

  40 mg initially followed by repeat intravenous injection every 4 to 6 hours while shock persists

  Oaks4

  40 mg initially followed by repeat intravenous injection every 2 to 6 hours while shock persists

  Schumer5

  1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short-term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days. For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with 2 mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, first day, 4 or 8 mg intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

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• Phazyme
  

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  Phazyme

  

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  Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of Tranexamic Acid Injection intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight three to four times daily, may be used for 2 to 8 days.

  Note: For patients with moderate to severe impaired renal function, the following dosages are recommended:

  Serum Creatinine (μmol/L)

  Tranexamic Acid I.V. Dosage

  120 to 250 (1.36 to 2.83 mg/dL)

  10 mg/kg BID

  250 to 500 (2.83 to 5.66 mg/dL)

  10 mg/kg daily

  10 mg/kg every 48 hours

  >500 (>5.66 mg/dL)

  or

  5 mg/kg every 24 hours

  For intravenous infusion, Tranexamic Acid Injection may be mixed with most solutions for infusion such as electrolyte solutions, carbohydrate solutions, amino acid solutions, and Dextran solutions. The mixture should be prepared the same day the solution is to be used. Heparin may be added to Tranexamic Acid Injection. Tranexamic Acid Injection should NOT be mixed with blood. The drug is a synthetic amino acid, and should NOT be mixed with solutions containing penicillin.

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• Pyridoxine Hydrochlorid...
  

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  Pyridoxine Hydrochloride

  

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  Pyridoxine Hydrochloride Injection may be administered intramuscularly or intravenously.  In cases of dietary deficiency, the dosage is 10 to 20 mg daily for 3 weeks.  Follow-up treatment is recommended daily for several weeks with an oral therapeutic multivitamin preparation containing 2 to 5 mg pyridoxine.  Poor dietary habits should be corrected, and an adequate, well balanced diet should be prescribed.

  The vitamin B6 dependency syndrome may require a therapeutic dosage of as much as 600 mg a day and a daily intake of 30 mg for life.

  In deficiencies due to INH, the dosage is 100 mg daily for 3 weeks followed by a 30 mg maintenance dose daily.

  In poisoning caused by ingestion of more than 10 g of INH, an equal amount of pyridoxine should be given — 4 g intravenously followed by 1 g intramuscularly every 30 minutes.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Promethazine Hydrochlor...
  

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  Promethazine Hydrochloride And Phenylephrine Hydrochloride

  

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  Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Xylocaine Injection for various types of anesthetic procedures.  The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions.  When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Xylocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures.  The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient.  In all cases the lowest concentration and smallest dose that will produce the desired result should be given.  Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease.

  The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (i.e., total dose) of local anesthetic used.  Thus, an increase in volume and concentration of Xylocaine Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia.  However, increasing the volume and concentration of Xylocaine Injection may result in a more profound fall in blood pressure when used in epidural anesthesia.  Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

  For intravenous regional anesthesia, only the 50 mL single dose vial containing Xylocaine (lidocaine HCl) 0.5% Injection should be used.

  Epidural Anesthesia

  For epidural anesthesia, only the following dosage forms of Xylocaine Injection are recommended:

  1% without epinephrine                        10 mL Plastic Ampule

  1% without epinephrine                        30 mL single dose solutions

  1% with epinephrine  1:200,000           30 mL single dose solutions

  1.5% without epinephrine                     10 mL Plastic Ampule

  1.5% without epinephrine                     20 mL Plastic Ampule

  1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

  2% without epinephrine                        10 mL Plastic Ampule

  2% with epinephrine  1:200,000           20 mL ampules, 20 mL single dose solutions

  Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

  In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

  Caudal and Lumbar Epidural Block

  As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient“epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

  In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

  Epidural Anesthesia

  For epidural anesthesia, only the following dosage forms of Xylocaine Injection are recommended:

  1% without epinephrine                        10 mL Plastic Ampule

  1% without epinephrine                        30 mL single dose solutions

  1% with epinephrine  1:200,000           30 mL single dose solutions

  1.5% without epinephrine                     10 mL Plastic Ampule

  1.5% without epinephrine                     20 mL Plastic Ampule

  1.5% with epinephrine  1:200,000         30 mL ampules, 30 mL single dose solutions

  2% without epinephrine                        10 mL Plastic Ampule

  2% with epinephrine  1:200,000           20 mL ampules, 20 mL single dose solutions

  Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

  In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

  Caudal and Lumbar Epidural Block

  As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter. Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient“epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

  In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

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• Cefoxitin
  

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  Cefoxitin

  

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  The intent of this pharmacy bulk package is for the preparation of solutions for intravenous infusion only.

  Treatment

  Adults

  The usual adult dosage range is 1 gram to 2 grams every six to eight hours. Dosage should be determined by susceptibility of the causative organisms, severity of infection, and the condition of the patient (see Table 3 for dosage guidelines).

  If C. trachomatis is a suspected pathogen, appropriate anti-chlamydial coverage should be added, because cefoxitin sodium has no activity against this organism.

  CEFOXITIN FOR INJECTION may be used in patients with reduced renal function with the following dosage adjustments:

  In adults with renal insufficiency, an initial loading dose of 1 gram to 2 grams may be given. After a loading dose, the recommendations for maintenance dosage (Table 4) may be used as a guide.

  When only the serum creatinine level is available, the following formula (based on sex, weight, and age of the patient) may be used to convert this value into creatinine clearance. The serum creatinine should represent a steady state of renal function.

  Males:                 Weight (kg) x (140-age)          

                       72 x serum creatinine (mg/100 mL)

  Females:         0.85 x above value

  In patients undergoing hemodialysis, the loading dose of 1 to 2 grams should be given after each hemodialysis, and the maintenance dose should be given as indicated in Table 4.

  Antibiotic therapy for group A beta-hemolytic streptococcal infections should be maintained for at least 10 days to guard against the risk of rheumatic fever or glomerulonephritis.

  In staphylococcal and other infections involving a collection of pus, surgical drainage should be

  carried out where indicated.

  Pediatric Patients

  The recommended dosage in pediatric patients three months of age and older is 80 to 160 mg/kg of body weight per day divided into four to six equal doses. The higher dosages should be used for more severe or serious infections. The total daily dosage should not exceed 12 grams.

  At this time no recommendation is made for pediatric patients from birth to three months of age (see PRECAUTIONS).

  In pediatric patients with renal insufficiency, the dosage and frequency of dosage should be modified consistent with the recommendations for adults (see Table 4).

  PREVENTION

  Effective prophylactic use depends on the time of administration. CEFOXITIN FOR INJECTION usually should be given one-half to one hour before the operation, which is sufficient time to achieve effective levels in the wound during the procedure. Prophylactic administration should usually be stopped within 24 hours since continuing administration of any antibiotic increases the possibility of adverse reactions but, in the majority of surgical procedures, does not reduce the incidence of subsequent infection.

  For prophylactic use in uncontaminated gastrointestinal surgery, vaginal hysterectomy, or abdominal hysterectomy, the following doses are recommended:

  Adults:

  2 grams administered intravenously just prior to surgery (approximately one-half to one hour before the initial incision) followed by 2 grams every 6 hours after the first dose for no more than 24 hours.

  Pediatric Patients (3 months and older):

  30 to 40 mg/kg doses may be given at the times designated above.

  Cesarean section patients:

  For patients undergoing cesarean section, either a single 2 gram dose administered intravenously as soon as the umbilical cord is clamped OR a 3-dose regimen consisting of 2 grams given intravenously as soon as the umbilical cord is clamped followed by 2 grams 4 and 8 hours after the initial dose is recommended. (See CLINICAL STUDIES)

  Table 3 - Guidelines for Dosage of CEFOXITIN FOR INJECTION

  Type of Infection Daily Dosage Frequency andRoute Uncomplicated forms* of infections such as pneumonia, urinary tract infection, cutaneous infection 3 to 4 grams 1 gram every 6-8 hours IV Moderately severe or severe infections 6 to 8 grams 1 gram every 4 hoursor 2 grams every 6-8 hours IV Infections commonly needing antibiotics in higher dosage (e.g., gas gangrene) 12 grams 2 grams every 4 hoursor 3 grams every 6 hours IV

  * Including patients in whom bacteremia is absent or unlikely.

  Table 4 - Maintenance Dosage of CEFOXITIN FOR INJECTION in Adults with Reduced Renal Function

  Renal Function CreatinineClearance(mL/min)  Dose(Grams) Frequency Mild impairment 50 to 30  1 to 2  every 8-12 hours  Moderate impairment 29 to 10  1 to 2  every 12-24 hours  Severe impairment 9 to 5  0.5 to 1  every 12-24 hours  Essentially no function < 5 0.5 to 1 every 24-48 hours

  Table 5 - Preparation of Solution for Intravenous Administration

  Strength Amount of Diluent to be Added (mL)** ApproximateWithdrawableVolume (mL) ApproximateAverageConcentration(mg/mL) Pharmacy BulkPackage – 10 grams 43 or 93 49 or 98.5 200 or 100

  ** Shake to dissolve and let stand until clear.

  PREPARATION OF SOLUTION

  Table 5 is provided for convenience in constituting CEFOXITIN FOR INJECTION for intravenous administration.

  The 10 gram pharmacy bulk package bottle should be constituted with 43 or 93 mL of Sterile Water for Injection, Bacteriostatic Water for Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection. CAUTION: THE 10 GRAM BULK STOCK SOLUTION IS NOT FOR DIRECT INFUSION. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION. These primary solutions may be further diluted in 50 to 1000 mL of the diluents listed under the Bulk Packages portion of the COMPATIBILITY AND STABILITY section.

  Benzyl alcohol as a preservative has been associated with toxicity in neonates. While toxicity has not been demonstrated in pediatric patients greater than three months of age, in whom use of CEFOXITIN FOR INJECTION may be indicated, small pediatric patients in this age range may also be at risk for benzyl alcohol toxicity. Therefore, diluent containing benzyl alcohol should not be used when CEFOXITIN FOR INJECTION is constituted for administration to pediatric patients in this age range.

  ADMINISTRATION

  CEFOXITIN FOR INJECTION may be administered intravenously after constitution.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Intravenous Administration

  The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

  For intermittent intravenous administration: using an infusion system, a solution containing 1 gram or 2 grams may be given over a period of time through the tubing system by which the patient may be receiving other intravenous solutions. However, during infusion of the solution containing CEFOXITIN FOR INJECTION, it is advisable to temporarily discontinue administration of any other solutions at the same site.

  For the administration of higher doses by continuous intravenous infusion, a solution of CEFOXITIN FOR INJECTION may be added to an intravenous bottle containing 5 percent Dextrose Injection, 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose and 0.9 percent Sodium Chloride Injection. BUTTERFLY®†† or scalp vein-type needles are preferred for this type of infusion.

  Solutions of CEFOXITIN FOR INJECTION, like those of most beta-lactam antibiotics, should not be added to aminoglycoside solutions (e.g., gentamicin sulfate, tobramycin sulfate, amikacin sulfate) because of potential interaction. However, CEFOXITIN FOR INJECTION and aminoglycosides may be administered separately to the same patient.

  Directions for Proper Use of Pharmacy Bulk Package bottle:

  Pharmacy Bulk Package Not for Direct Infusion

  RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION

  The Pharmacy Bulk Package bottle is for use in a pharmacy admixture service under a laminar flow hood. Penetration into the Pharmacy Bulk Package bottle should be made only one time after reconstitution with a sterile transfer set or other sterile dispensing device, which allows measured distribution of the contents. Dispense the contents in aliquots using aseptic technique. The use of a syringe with a needle is not recommended as it may cause leakage. AFTER INITIAL ENTRY USE ENTIRE CONTENTS OF THE PHARMACY BULK PACKAGE PROMPTLY. A maximum time of 4 HOURS from initial entry is permitted to complete fluid transfer operations. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 4 HOURS. This time limit should begin with the introducing of solvent or diluent into the Pharmacy Bulk Package bottle. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION.

  COMPATIBILITY AND STABILITY

  Pharmacy Bulk Package

  CEFOXITIN FOR INJECTION as supplied in pharmacy bulk package bottles and constituted to 1 gram/10 mL with Sterile Water for Injection, Bacteriostatic Water for Injection, (see PREPARATION OF SOLUTION), 0.9 percent Sodium Chloride Injection, or 5 percent Dextrose Injection should be DISCARDED 4 HOURS AFTER INITIAL ENTRY. FURTHER DILUTION IS REQUIRED BEFORE USE. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION. RECONSTITUTED STOCK SOLUTION MUST BE TRANSFERRED AND FURTHER DILUTED FOR I.V. INFUSION.

  These primary solutions may be further diluted in 50 to 1000 mL of the following diluents and maintain potency for an additional 18 hours at room temperature or an additional 48 hours under refrigeration:

  0.9 percent Sodium Chloride Injection

  5 percent or 10 percent Dextrose Injection

  5 percent Dextrose and 0.9 percent Sodium Chloride Injection

  5 percent Dextrose Injection with 0.2 percent or 0.45 percent saline solution

  Lactated Ringer's Injection

  5 percent Dextrose in Lactated Ringer's Injection

  5 percent Sodium Bicarbonate Injection

  M/6 sodium lactate solution

  Mannitol 5% and 10%

  After the periods mentioned above, any unused solutions should be discarded.

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• Healthy Accents Miconaz...
  

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  Healthy Accents Miconazole 3

  

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  Advanced Colorectal Cancer

  Either of the following two regimens is recommended:

   Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

  5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days.  This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.  The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

  Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.  However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens.

  Leucovorin Rescue After High-Dose Methotrexate Therapy

  The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).4  Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.  In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

  GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

  DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

   Clinical Situation    Laboratory Findings    Leucovorin Dosage and Duration    Normal Methotrexate Elimination   Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.   15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).   Delayed Late Methotrexate Elimination   Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.   Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.  Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

  Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.  In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

  Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above.  These abnormalities may or may not be associated with significant clinical toxicity.  If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.  The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  Impaired Methotrexate Elimination or Inadvertent Overdosage

  Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS).  Leucovorin 10 mg/m2 should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at 24 hour intervals.  If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

  Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly.  The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

  Megaloblastic Anemia Due to Folic Acid Deficiency

  Up to 1 mg daily.  There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

  Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

  Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see WARNINGS).

  Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

  Advanced Colorectal Cancer

  Either of the following two regimens is recommended:

   Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

  5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days.  This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.  The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

  Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.  However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens.

  Leucovorin Rescue After High-Dose Methotrexate Therapy

  The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).4  Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.  In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

  GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

  DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

   Clinical Situation    Laboratory Findings    Leucovorin Dosage and Duration    Normal Methotrexate Elimination   Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.   15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).   Delayed Late Methotrexate Elimination   Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.   Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.  Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

  Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.  In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

  Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above.  These abnormalities may or may not be associated with significant clinical toxicity.  If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.  The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  Impaired Methotrexate Elimination or Inadvertent Overdosage

  Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS).  Leucovorin 10 mg/m2 should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at 24 hour intervals.  If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

  Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly.  The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

  Megaloblastic Anemia Due to Folic Acid Deficiency

  Up to 1 mg daily.  There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

  Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

  Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see WARNINGS).

  Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

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• Ropinirole
  

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  Ropinirole

  

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  When there is urgent need, therapy in the hospitalized patient may be initiated intramuscularly or as a rapid intravenous bolus injection directly into the vein.  Hydralazine Hydrochloride Injection should be used only when the drug cannot be given orally.  The usual dose is 20 to 40 mg, repeated as necessary.

  Certain patients (especially those with marked renal damage) may require a lower dose.   Blood pressure should be checked frequently.  It may begin to fall within a few minutes after injection, with the average maximal decrease occurring in 10 to 80 minutes.  In cases where there has been increased intracranial pressure, lowering the blood pressure may increase cerebral ischemia.  Most patients can be transferred to oral hydralazine hydrochloride within 24 to 48 hours.

  The product should be used immediately after the vial is opened.  The product should not be added to infusion solutions.  Hydralazine Hydrochloride Injection may discolor upon contact with metal; discolored solutions should be discarded. 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Sensorcaine Mpf
  

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  Sensorcaine Mpf

  

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  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be administered.  Dosages of Sensorcaine-MPF Spinal Injection should be reduced for elderly and debilitated patients and patients with cardiac and/or liver disease.

  For specific techniques and procedures, refer to standard textbooks.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Sensorcaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  The extent and degree of spinal anesthesia depend upon several factors including dosage, specific gravity of the anesthetic solution, volume of solution used, force of injection, level of puncture, and position of the patient during and immediately after injection.

  Seven and one-half mg (7.5 mg or 1 mL) Sensorcaine-MPF Spinal Injection has generally proven satisfactory for spinal anesthesia for lower extremity and perineal procedures including TURP and vaginal hysterectomy.  Twelve mg (12 mg or 1.6 mL) has been used for lower abdominal procedures such as abdominal hysterectomy, tubal ligation, and appendectomy.  These doses are recommended as a guide for use in the average adult and may be reduced for the elderly or debilitated patients. Because experience with Sensorcaine-MPF Spinal Injection is limited in patients below the age of 18 years, dosage recommendations in this age group cannot be made.

  Obstetrical Use

  Doses as low as 6 mg of bupivacaine hydrochloride have been used for vaginal delivery under spinal anesthesia.  The dose range of 7.5 mg to 10.5 mg (1 mL to 1.4 mL) bupivacaine hydrochloride has been used for Cesarean section under spinal anesthesia.

  In recommended doses, Sensorcaine-MPF Spinal Injection produces complete motor and sensory block.

  Unused portions of solutions should be discarded following initial use.

  Sensorcaine-MPF Spinal Injection should be inspected visually for discoloration and particulate matter prior to administration; solutions which are discolored or which contain particulate matter should not be administered.

  Obstetrical Use

  Doses as low as 6 mg of bupivacaine hydrochloride have been used for vaginal delivery under spinal anesthesia.  The dose range of 7.5 mg to 10.5 mg (1 mL to 1.4 mL) bupivacaine hydrochloride has been used for Cesarean section under spinal anesthesia.

  In recommended doses, Sensorcaine-MPF Spinal Injection produces complete motor and sensory block.

  Unused portions of solutions should be discarded following initial use.

  Sensorcaine-MPF Spinal Injection should be inspected visually for discoloration and particulate matter prior to administration; solutions which are discolored or which contain particulate matter should not be administered.

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• Good Sense Pain Relief ...
  

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  Good Sense Pain Relief Pm

  

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  Parenteral

  Intravenous

  Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip.

  Adults and children:  15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function.  This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment.  Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day.

  Infants:  Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

  Intramuscular

  Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%.

  Adults and children:  25,000 to 30,000 units/kg/day.  This should be reduced in the presence of renal impairment.  The dosage may be divided and given at either 4 or 6 hour intervals.

  Infants:  Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

  Note:  Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by P aeruginosa.

  Intrathecal

  A treatment of choice for P. aeruginosa meningitis.  Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit.

  Adults and children over 2 years of age:  Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

  Children under 2 years of age:  20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day.  Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

  IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS.

  Topical

  Ophthalmic:  Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration.

  For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates.

  Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva.

  Note:  Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

  Parenteral

  Intravenous

  Dissolve 500,000 polymyxin B units in 300 to 500 mL solutions for parenteral dextrose injection 5% for continuous drip.

  Adults and children:  15,000 to 25,000 units/kg body weight/day in individuals with normal kidney function.  This amount should be reduced from 15,000 units/kg downward for individuals with kidney impairment.  Infusions may be given every 12 hours; however, the total daily dose must not exceed 25,000 units/kg/day.

  Infants:  Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

  Intramuscular

  Not recommended routinely because of severe pain at injection sites, particularly in infants and children. Dissolve 500,000 polymyxin B units in 2 mL sterile water for injection or sodium chloride injection or procaine hydrochloride injection 1%.

  Adults and children:  25,000 to 30,000 units/kg/day.  This should be reduced in the presence of renal impairment.  The dosage may be divided and given at either 4 or 6 hour intervals.

  Infants:  Infants with normal kidney function may receive up to 40,000 units/kg/day without adverse effects.

  Note:  Doses as high as 45,000 units/kg/day have been used in limited clinical studies in treating prematures and newborn infants for sepsis caused by P aeruginosa.

  Intrathecal

  A treatment of choice for P. aeruginosa meningitis.  Dissolve 500,000 polymyxin B units in 10 mL sodium chloride injection, USP for 50,000 units per mL dosage unit.

  Adults and children over 2 years of age:  Dosage is 50,000 units once daily intrathecally for 3 to 4 days, then 50,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

  Children under 2 years of age:  20,000 units once daily, intrathecally for 3 to 4 days or 25,000 units once every other day.  Continue with a dose of 25,000 units once every other day for at least 2 weeks after cultures of the cerebrospinal fluid are negative and sugar content has returned to normal.

  IN THE INTEREST OF SAFETY, SOLUTIONS OF PARENTERAL USE SHOULD BE STORED UNDER REFRIGERATION, AND ANY UNUSED PORTIONS SHOULD BE DISCARDED AFTER 72 HOURS.

  Topical

  Ophthalmic:  Dissolve 500,000 polymyxin B units in 20 to 50 mL sterile water for injection or sodium chloride injection USP for a 10,000 to 25,000 units per mL concentration.

  For the treatment of P. aeruginosa infections of the eye, a concentration of 0.1 percent to 0.25 percent (10,000 units to 25,000 units per mL) is administered 1 to 3 drops every hour, increasing the intervals as response indicates.

  Subconjunctival injection of up to 100,000 units/day may be used for the treatment of P. aeruginosa infections of the cornea and conjunctiva.

  Note:  Avoid total systemic and ophthalmic instillation over 25,000 units/kg/day.

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• Milrinone Lactate
  

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  Milrinone Lactate

  

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  Milrinone should be administered with a loading dose followed by a continuous infusion (maintenance dose) according to the following guidelines:

                          LOADING DOSE

  50 mcg/kg: Administer slowly over 10 minutes

  The table below shows the loading dose in milliliters (mL) of milrinone (1 mg/mL) by patient body weight (kg).

                    Loading Dose (mL) Using 1 mg/mL Concentration

   Patient Body Weight (kg)    kg      30        40         50         60         70         80         90         100        110        120        mL      1.5   2   2.5   3   3.5   4   4.5   5   5.5   6 

  The loading dose may be given undiluted, but diluting to a rounded total volume of 10 or 20 mL (see Maintenance Dose for diluents) may simplify the visualization of the injection rate.

                                               MAINTENANCE DOSE

     Infusion Rate Total Daily Dose (24 Hours)   MinimumStandardMaximum    0.375 mcg/kg/min0.50 mcg/kg/min0.75 mcg/kg/min       0.59 mg/kg0.77 mg/kg1.13 mg/kg  Administer as a continuous intravenous infusion. 

  Milrinone drawn from vials should be diluted prior to maintenance dose administration.  The diluents that may be used are 0.45% Sodium Chloride Injection USP, 0.9% Sodium Chloride Injection USP, or 5% Dextrose Injection USP.  The table below shows the volume of diluent in milliliters (mL) that must be used to achieve 200 mcg/mL concentration for infusion, and the resultant total volumes.

   Desired Infusion Concentration  mcg/mL  Milrinone  1 mg/mL (mL)     Diluent (mL)     Total Volume (mL)  200  10  40  50  200  20  80  100

  The infusion rate should be adjusted according to hemodynamic and clinical response.  Patients should be closely monitored.  In controlled clinical studies, most patients showed an improvement in hemodynamic status as evidenced by increases in cardiac output and reductions in pulmonary capillary wedge pressure.

  Note: SeeDosage Adjustment in Renally Impaired Patients.  Dosage may be titrated to the maximum hemodynamic effect and should not exceed 1.13 mg/kg/day.  Duration of therapy should depend upon patient responsiveness.

  The maintenance dose in mL/hr by patient body weight (kg) may be determined by reference to the following table.

  Milrinone Infusion Rate (mL/hr) Using 200 mcg/mL Concentration

   Maintenance  Dose (mcg/kg/min)          Patient Body Weight (kg)      30    40    50    60    70  0.375   3.4   4.5   5.6   6.8   7.9   0.400   3.6   4.8   6   7.2   8.4   0.500   4.5   6   7.5   9   10.5   0.600   5.4   7.2        9   10.8   12.6   0.700   6.3   8.4   10.5   12.6   14.7   0.750      6.8       9        11.3           13.5           15.8       Maintenance  Dose (mcg/kg/min)  Patient Body Weight (kg)      80    90    100    110    120  0.375   9   10.1   11.3   12.4   13.5   0.400   9.6   10.8   12   13.2   14.4   0.500   12   13.5   15   16.5   18   0.600   14.4   16.2   18   19.8   21.6   0.700       16.8           18.9       21        23.1           25.2       0.750   18   20.3       22.5       24.8   27 

  When administering milrinone lactate by continuous infusion, it is advisable to use a calibrated electronic infusion device.

  Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present.

  Dosage Adjustment in Renally Impaired Patients

  Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone.  Reductions in infusion rate may be necessary in patients with renal impairment.  For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:

   Creatinine Clearance  (mL/min/1.73 m2)  Infusion Rate  (mcg/kg/min)  5   0.20   10   0.23   20   0.28   30   0.33   40   0.38   50   0.43 

  Dosage Adjustment in Renally Impaired Patients

  Data obtained from patients with severe renal impairment (creatinine clearance = 0 to 30 mL/min) but without congestive heart failure have demonstrated that the presence of renal impairment significantly increases the terminal elimination half-life of milrinone.  Reductions in infusion rate may be necessary in patients with renal impairment.  For patients with clinical evidence of renal impairment, the recommended infusion rate can be obtained from the following table:

   Creatinine Clearance  (mL/min/1.73 m2)  Infusion Rate  (mcg/kg/min)  5   0.20   10   0.23   20   0.28   30   0.33   40   0.38   50   0.43 

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• Calcitriol
  

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  Calcitriol

  

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  The optimal dose of calcitriol injection must be carefully determined for each patient.

  The effectiveness of calcitriol injection therapy is predicated on the assumption that each patient is receiving an adequate and appropriate daily intake of calcium.  The RDA for calcium in adults is 800 mg.  To ensure that each patient receives an adequate daily intake of calcium, the physician should either prescribe a calcium supplement or instruct the patient in proper dietary measures.

  The recommended initial dose of calcitriol injection, depending on the severity of the hypocalcemia and/or secondary hyperparathyroidism, is 1 mcg (0.02 mcg/kg) to 2 mcg administered three times weekly, approximately every other day.  Doses as small as 0.5 mcg and as large as 4 mcg three times weekly have been used as an initial dose.  If a satisfactory response is not observed, the dose may be increased by 0.5 to 1 mcg at two to four week intervals.  During this titration period, serum calcium and phosphorus levels should be obtained at least twice weekly.  If hypercalcemia or a serum calcium times phosphate product greater than 70 is noted, the drug should be immediately discontinued until these parameters are appropriate.  Then, the calcitriol injection dose should be reinitiated at a lower dose.  Doses may need to be reduced as the PTH levels decrease in response to the therapy.  Thus, incremental dosing must be individualized and commensurate with PTH, serum calcium and phosphorus levels.  The following is a suggested approach to dose titration:

  PTH Levels

  Calcitriol Injection Dose      

  the same or increasing

  increase

  decreasing by <30%

  increase

  decreasing by >30%, <60%

  maintain

  decreasing by >60%

  decrease

  one and one-half to three times the upper limit of normal     

  maintain

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Discard unused portion.

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• Mannitol
  

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  Mannitol

  

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  For Intravenous Injection

  General Recommendations–Give mannitol injection only intravenously.  The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output.  Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours.  The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr). 

  Test Dose–In marked oliguria or inadequate renal function a test dose of mannitol should be given.  The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr).  If urine flow does not increase within two or three hours a second test dose may be given.  If there is an inadequate response the patient should be reevaluated. 

  Prevention of Acute Renal Failure (Oliguria)–When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given.  The concentration and amount will depend upon the fluid requirements of the patient.  Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis.  If diuresis does not occur the 20 g dose may be repeated.  If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. 

  Treatment of Oliguria–The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. 

  Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure–A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity.  When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes.  Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate.  Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol.  Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. 

  Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection. 

  Urinary Excretion of Toxic Substances–Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high.  The concentration will depend upon the fluid requirement and urinary output.  Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air.  If benefits are not observed after 200 g of mannitol are given, discontinue it. 

  For Urologic Irrigation

  A 2.5% solution is used.  The use of 2.5% mannitol solution minimizes the hemolytic effect of water alone, the entrance of hemolyzed blood into the circulation, and the resulting hemoglobinemia which is considered a major factor in producing serious renal complications. 

  For Intravenous Injection

  General Recommendations–Give mannitol injection only intravenously.  The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output.  Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours.  The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr). 

  Test Dose–In marked oliguria or inadequate renal function a test dose of mannitol should be given.  The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr).  If urine flow does not increase within two or three hours a second test dose may be given.  If there is an inadequate response the patient should be reevaluated. 

  Prevention of Acute Renal Failure (Oliguria)–When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given.  The concentration and amount will depend upon the fluid requirements of the patient.  Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis.  If diuresis does not occur the 20 g dose may be repeated.  If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. 

  Treatment of Oliguria–The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. 

  Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure–A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity.  When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes.  Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate.  Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol.  Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. 

  Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection. 

  Urinary Excretion of Toxic Substances–Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high.  The concentration will depend upon the fluid requirement and urinary output.  Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air.  If benefits are not observed after 200 g of mannitol are given, discontinue it. 

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• Octreotide
  

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  Octreotide

  

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  Octreotide Acetate Injection may be administered subcutaneously or intravenously.  Subcutaneous injection is the usual route of administration of Octreotide Acetate Injection for control of symptoms.  Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose.  Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.  Do not use if particulates and/or discoloration are observed.  Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination.  Octreotide Acetate Injection is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

  Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours.  It may be diluted in volumes of 50 to 200 mL and infused intravenously over 15 to 30 minutes or administered by IV push over 3 minutes.  In emergency situations (e.g.: carcinoid crisis) it may be given by rapid bolus.

  The initial dosage is usually 50 mcg administered twice or three times daily.  Upward dose titration is frequently required.  Dosage information for patients with specific tumors follows.

  Acromegaly

  Dosage may be initiated at 50 mcg t.i.d.  Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses.  IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration.  Alternatively, multiple growth hormone levels at 0 to 8 hours after Octreotide Acetate Injection administration permit more rapid titration of dose.  The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females.  The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness.  Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced.  IGF-I (somatomedin C) or growth hormone levels should be re-evaluated at 6 month intervals.

  Octreotide Acetate Injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity.  If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, Octreotide Acetate Injection therapy may be resumed.

  Carcinoid Tumors

  The suggested daily dosage of Octreotide Acetate Injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg).  In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day.  However, experience with doses above 750 mcg/day is limited.

  VIPomas

  Daily dosages of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range 150 to 750 mcg) to control symptoms of the disease.  On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.

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• Neostigmine Methylsulfa...
  

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  Neostigmine Methylsulfate

  

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  Symptomatic Control of Myasthenia Gravis

  Symptomatic Control of Myasthenia Gravis One mL of the1:2000 solution (0.5 mg) IM or SC.  Subsequent doses should be based on the individual patient’s response.

  Prevention of Postoperative Distention and Urinary Retention

  One mL of the 1:4000 solution (0.25 mg) IM or SC as soon as possible after operation; repeat every four to six hours for two or three days.

  Treatment of Postoperative Distention

  One mL of the 1:2000 solution (0.5 mg) IM or SC, as required.

  Treatment of Urinary Retention

  One mL of the 1:2000 solution (0.5 mg) IM or SC.  If urination does not occur within an hour, the patient should be catheterized. After the patient has voided, or the bladder has been emptied, continue the 0.5 mg injections every three hours for at least five injections.

  Reversal of Effects of Nondepolarizing Neuromuscular Blocking Agents

  When neostigmine methylsulfate is administered IV, it is recommended that atropine sulfate (0.6 to 1.2 mg) also be given IV using separate syringes.  Some authorities have recommended that the atropine be injected several minutes before the neostigmine methylsulfate rather than concomitantly.  The usual dose is 0.5 to 2 mg neostigmine methylsulfate given by slow IV injection, repeated as required. Only in exceptional cases should the total dose of neostigmine methylsulfate exceed 5 mg.  It is recommended that the patient be well ventilated and a patent airway maintained until complete recovery of normal respiration is assured.  The optimum time for administration of the drug is during hyperventilation when the carbon dioxide level of the blood is low.  It should never be administered in the presence of high concentrations of halothane or cyclopropane.  In cardiac cases and severely ill patients, it is advisable to titrate the exact dose of neostigmine methylsulfate required, using a peripheral nerve stimulator device.  In the presence of bradycardia, the pulse rate should be increased to about 80/min with atropine before administering neostigmine methylsulfate. 

  Parenteral drug products should beinspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Symptomatic Control of Myasthenia Gravis

  Symptomatic Control of Myasthenia Gravis One mL of the1:2000 solution (0.5 mg) IM or SC.  Subsequent doses should be based on the individual patient’s response.

  Prevention of Postoperative Distention and Urinary Retention

  One mL of the 1:4000 solution (0.25 mg) IM or SC as soon as possible after operation; repeat every four to six hours for two or three days.

  Treatment of Postoperative Distention

  One mL of the 1:2000 solution (0.5 mg) IM or SC, as required.

  Treatment of Urinary Retention

  One mL of the 1:2000 solution (0.5 mg) IM or SC.  If urination does not occur within an hour, the patient should be catheterized. After the patient has voided, or the bladder has been emptied, continue the 0.5 mg injections every three hours for at least five injections.

  Reversal of Effects of Nondepolarizing Neuromuscular Blocking Agents

  When neostigmine methylsulfate is administered IV, it is recommended that atropine sulfate (0.6 to 1.2 mg) also be given IV using separate syringes.  Some authorities have recommended that the atropine be injected several minutes before the neostigmine methylsulfate rather than concomitantly.  The usual dose is 0.5 to 2 mg neostigmine methylsulfate given by slow IV injection, repeated as required. Only in exceptional cases should the total dose of neostigmine methylsulfate exceed 5 mg.  It is recommended that the patient be well ventilated and a patent airway maintained until complete recovery of normal respiration is assured.  The optimum time for administration of the drug is during hyperventilation when the carbon dioxide level of the blood is low.  It should never be administered in the presence of high concentrations of halothane or cyclopropane.  In cardiac cases and severely ill patients, it is advisable to titrate the exact dose of neostigmine methylsulfate required, using a peripheral nerve stimulator device.  In the presence of bradycardia, the pulse rate should be increased to about 80/min with atropine before administering neostigmine methylsulfate. 

  Parenteral drug products should beinspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Ketorolac Tromethamine
  

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  Ketorolac Tromethamine

  

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  IN ADULTS, THE COMBINED DURATION OF USE OF KETOROLAC TROMETHAMINE INJECTION AND KETOROLAC TROMETHAMINE TABLETS IS NOT TO EXCEED 5 DAYS.  IN ADULTS, THE USE OF KETOROLAC TROMETHAMINE TABLETS IS ONLY INDICATED AS CONTINUATION THERAPY TO KETOROLAC TROMETHAMINE INJECTION.

  Ketorolac Tromethamine Injection

  Adult Patients

  Ketorolac tromethamine injection may be used as a single or multiple dose on a regular or “prn” schedule for the management of moderately severe acute pain that requires analgesia at the opioid level, usually in a postoperative setting.  Hypovolemia should be corrected prior to the administration of ketorolac tromethamine (see WARNINGS: Renal Effects).  Patients should be switched to alternative analgesics as soon as possible, but ketorolac tromethamine therapy is not to exceed 5 days.

  When administering ketorolac tromethamine injection, the IV bolus must be given over no less than 15 seconds.  The IM administration should be given slowly and deeply into the muscle.  The analgesic effect begins in~30 minutes with maximum effect in 1 to 2 hours after dosing IV or IM.  Duration of analgesic effect is usually 4 to 6 hours.

  Single-Dose Treatment: The Following Regimen Should Be Limited To Single Administration Use Only

  Adult Patients

  IM Dosing:

  ·        Patients <65 years of age: One dose of 60 mg.

  ·        Patients ≥65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 30 mg.

  IV Dosing:

  ·        Patients <65 years of age: One dose of 30 mg.

  ·        Patients ≥65 years of age, renally impaired and/or less than 50 kg (110 lbs) of body weight: One dose of 15 mg.

  Pediatric Patients (2 to 16 years of age): The pediatric population should receive only a single dose of ketorolac tromethamine injection as follows:

  IM Dosing:

  ·        One dose of 1 mg/kg up to a maximum of 30 mg.

  IV Dosing:

  ·        One dose of 0.5 mg/kg up to a maximum of 15 mg.

  Multiple-Dose Treatment (IV or IM) In Adults:

  ·        Patients <65 years of age: The recommended dose is 30 mg ketorolac tromethamine injection every 6 hours.  The maximum daily dose should not exceed 120 mg.

  ·        For Patients ≥65 years of age, renally impaired patients (see WARNINGS) and patients less than 50 kg (110 lbs):  The recommended dose is 15 mg ketorolac tromethamine injection every 6 hours.  The maximum daily dose for these populations should not exceed 60 mg.

  For breakthrough pain do not increase the dose or the frequency of ketorolac tromethamine.  Consideration should be given to supplementing these regimens with low doses of opioids prn unless otherwise contraindicated.

  Pharmaceutical Information for Ketorolac Tromethamine Injection

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Ketorolac tromethamine injection should not be mixed in a small volume (eg, in a syringe) with morphine sulfate, meperidine hydrochloride, promethazine hydrochloride or hydroxyzine hydrochloride; this will result in precipitation of ketorolac from solution.

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• Panadol
  

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  Panadol

  

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  2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

  Ondansetron injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

  Adults:

  The recommended adult intravenous dosage of ondansetron is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)].  The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy.  Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron.

  Pediatrics:

  For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1) and Clinical Pharmacology (12.2, 12.3)].  The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy.  Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron.  The drug should be infused intravenously over 15 minutes.

  2.2 Prevention of Postoperative Nausea and Vomiting

  Ondansetron injection should not be mixed with solutions for which physical and chemical compatibility have not been established.  In particular, this applies to alkaline solutions as a precipitate may form.

  Adults:

  The recommended adult intravenous dosage of ondansetron is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery.  Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults.  While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied.  In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

  Pediatrics:

  For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1 mg/kg dose for patients weighing 40 kg or less, or a single 4 mg dose for patients weighing more than 40 kg.  The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery.  Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ondansetron.

  2.3 Stability and Handling

  After dilution, do not use beyond 24 hours.  Although ondansetron injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

  Ondansetron injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

  Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright.  Potency and safety are not affected.  If a precipitate is observed, resolubilize by shaking the vial vigorously.

  2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

  In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.  There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].

  2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

  Ondansetron injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

  Adults:

  The recommended adult intravenous dosage of ondansetron is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)].  The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy.  Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron.

  Pediatrics:

  For pediatric patients 6 months through 18 years of age, the intravenous dosage of ondansetron is three 0.15 mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1) and Clinical Pharmacology (12.2, 12.3)].  The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy.  Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of ondansetron.  The drug should be infused intravenously over 15 minutes.

  2.2 Prevention of Postoperative Nausea and Vomiting

  Ondansetron injection should not be mixed with solutions for which physical and chemical compatibility have not been established.  In particular, this applies to alkaline solutions as a precipitate may form.

  Adults:

  The recommended adult intravenous dosage of ondansetron is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery.  Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults.  While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied.  In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

  Pediatrics:

  For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1 mg/kg dose for patients weighing 40 kg or less, or a single 4 mg dose for patients weighing more than 40 kg.  The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery.  Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic ondansetron.

  2.3 Stability and Handling

  After dilution, do not use beyond 24 hours.  Although ondansetron injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

  Ondansetron injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

  Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright.  Potency and safety are not affected.  If a precipitate is observed, resolubilize by shaking the vial vigorously.

  2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

  In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended.  There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].

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• Enviro I
  

  ×

  Enviro I

  

  ---

  Gentamicin Injection may be given intramuscularly or intravenously.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  DOSAGE FOR PATIENTS WITH NORMAL RENAL FUNCTION

  Children: 6 to 7.5 mg/kg/day. (2 to 2.5 mg/kg administered every 8 hours.)

  It is desirable to measure periodically both peak and trough serum concentrations of gentamicin when feasible during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after intramuscular injection) is expected to be in the range of 3 to 5 mcg/mL.  When monitoring peak concentrations after intramuscular or intravenous administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  The usual duration of treatment is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary. In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  For Intravenous Administration

  The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass.

  For intermittent intravenous administration, a single dose of Gentamicin Injection may be diluted in 0.9% Sodium Chloride Injection or in 5% Dextrose Injection.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for intravenous and intramuscular administration is identical.

  Gentamicin Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

  DOSAGE FOR PATIENTS WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate but not excessive, blood levels.  Whenever possible, serum concentrations of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses. In adults, the interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8. For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).  These guidelines may be considered when treating children with serious renal impairment.

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.

  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage. After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 3).  For example, after an initial dose of 20 mg (2 mg/kg), a child weighing 10 kg with a serum creatinine level of 2 mg/100 mL could be given 10 mg every eight hours (20 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process. It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

   TABLE 3  DOSAGE ADJUSTMENT GUIDE FOR PATIENTS WITH RENAL IMPAIRMENT (Dosage at Eight-Hour Intervals After the Usual Initial Dose)  Serum Creatinine(mg %)  Approximate CreatinineClearance Rate(mL/min/1.73 m2)  Percent of Usual DosesShown Above  ≤1   >100   100   1.1 to 1.3   70 to 100   80   1.4 to 1.6   55 to 70   65   1.7 to 1.9   45 to 55   55   2 to 2.2   40 to 45   50   2.3 to 2.5   35 to 40   40   2.6 to 3   30 to 35   35   3.1 to 3.5   25 to 30   30   3.6 to 4   20 to 25   25   4.1 to 5.1   15 to 20   20   5.2 to 6.6   10 to 15   15   6.7 to 8   <10   10 

  In patients with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  In children, the recommended dose at the end of each dialysis period is 2 to 2.5 mg/kg depending upon the severity of the infection.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Tobramycin
  

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  Tobramycin

  

  ---

  Tobramycin may be given intramuscularly or intravenously.  Recommended dosages are the same for both routes.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS).

  Administration for Patients with Normal Renal Function

  Adults with Serious Infections:  3 mg/kg/day in 3 equal doses every 8 hours (see Table 1).

  Adults With Life-Threatening Infections:  Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 1).  The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).

  Table 1 

  DOSAGE SCHEDULE GUIDE FOR ADULTS WITH

  NORMAL RENAL FUNCTION

  (Dosage at 8-Hour Intervals)

  For

  Patient

  Weighing 

  Usual Dose for

  Serious Infections

  1 mg/kg q8h

  (Total, 3 mg/kg/day)

    kg   lb   mg/dose   mL/dose*

  q8h

  120

  264

  120 mg

  3 mL

  115

  253

  115 mg

  2.9 mL

  110

  242

  110 mg

  2.75 mL

  105

  231

  105 mg

  2.6 mL

  100

  220

  100 mg

  2.5 mL

  95

  209

  95 mg

  2.4 mL

  90

  198

  90 mg

  2.25 mL

  85

  187

  85 mg

  2.1 mL

  80

  176

  80 mg

  2 mL

  75

  165

  75 mg

  1.9 mL

  70

  154

  70 mg

  1.75 mL

  65

  143

  65 mg

  1.6 mL

  60

  132

  60 mg

  1.5 mL

  55

  121

  55 mg

  1.4 mL

  50

  110

  50 mg

  1.25 mL

  45

  99

  45 mg

  1.1 mL

  40

  88

  40 mg

  1 mL

  For

  Patient

  Weighing

  Maximum Dose for Life-

  Threatening Infections

  (Reduce as soon as possible)

  1.66 mg/kg q8h

  (Total, 5 mg/kg/day) 

   kg   lb mg/dose  mL/dose* 

  q8h

  120

  264

  200 mg

  5 mL

  115

  253

  191 mg

  4.75 mL

  110

  242

  183 mg

  4.5 mL

  105

  231

  175 mg

  4.4 mL

  100

  220

  166 mg

  4.2 mL

  95

  209

  158 mg

  4 mL

  90

  198

  150 mg

  3.75 mL

  85

  187

  141 mg

  3.5 mL

  80

  176

  133 mg

  3.3 mL

  75

  165

  125 mg

  3.1 mL

  70

  154

  116 mg

  2.9 mL

  65

  143

  108 mg

  2.7 mL

  60

  132

  100 mg

  2.5 mL

  55

  121

  91 mg

  2.25 mL

  50

  110

  83 mg

  2.1 mL

  45

  99

  75 mg

  1.9 mL

  40

  88

  66 mg

  1.6 mL

  *Applicable to all product forms except the tobramycin pediatric injection (see HOW SUPPLIED).

   

  Pediatric Patients (greater than 1 week of age):  6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

  Premature or Full-Term Neonates 1 Week of Age or Less:  Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

  It is desirable to limit treatment to a short term.  The usual duration of treatment is 7 to 10 days.  A longer course of therapy may be necessary in difficult and complicated infections.  In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

  Dosage in Patients with Cystic Fibrosis

  In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose.  In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended.  This dosing regimen is suggested only as a guide.  The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

  Administration for Patients with Impaired Renal Function

  Whenever possible, serum tobramycin concentrations should be monitored during therapy.

  Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals.  Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly.  They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin.  The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.  Neither method should be used when dialysis is being performed.

  Reduced dosage at 8-hour intervals:  When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 1 by the percent of normal dose from the accompanying nomogram.

   

   

  * Scales have been adjusted to facilitate dosage calculations.

  An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

  Normal dosage at prolonged intervals:  If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage frequency in hours for the dosage given in Table 1 can be determined by multiplying the patient’s serum creatinine by 6.

  Dosage in Obese Patients

  The appropriate dose may be calculated by using the patient’s estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

  Intramuscular Administration

  Tobramycin may be administered by withdrawing the approriate dose directly from a vial.

  Intravenous Administration

  For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses.  For pediatric patients, the volume of diluent should be proportionately less than that for adults.  The diluted solution usually should be infused over a period of 20 to 60 minutes.  Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

  Tobramycin injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

  Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

  Administration for Patients with Normal Renal Function

  Adults with Serious Infections:  3 mg/kg/day in 3 equal doses every 8 hours (see Table 1).

  Adults With Life-Threatening Infections:  Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 1).  The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).

  Table 1 

  DOSAGE SCHEDULE GUIDE FOR ADULTS WITH

  NORMAL RENAL FUNCTION

  (Dosage at 8-Hour Intervals)

  For

  Patient

  Weighing 

  Usual Dose for

  Serious Infections

  1 mg/kg q8h

  (Total, 3 mg/kg/day)

    kg   lb   mg/dose   mL/dose*

  q8h

  120

  264

  120 mg

  3 mL

  115

  253

  115 mg

  2.9 mL

  110

  242

  110 mg

  2.75 mL

  105

  231

  105 mg

  2.6 mL

  100

  220

  100 mg

  2.5 mL

  95

  209

  95 mg

  2.4 mL

  90

  198

  90 mg

  2.25 mL

  85

  187

  85 mg

  2.1 mL

  80

  176

  80 mg

  2 mL

  75

  165

  75 mg

  1.9 mL

  70

  154

  70 mg

  1.75 mL

  65

  143

  65 mg

  1.6 mL

  60

  132

  60 mg

  1.5 mL

  55

  121

  55 mg

  1.4 mL

  50

  110

  50 mg

  1.25 mL

  45

  99

  45 mg

  1.1 mL

  40

  88

  40 mg

  1 mL

  For

  Patient

  Weighing

  Maximum Dose for Life-

  Threatening Infections

  (Reduce as soon as possible)

  1.66 mg/kg q8h

  (Total, 5 mg/kg/day) 

   kg   lb mg/dose  mL/dose* 

  q8h

  120

  264

  200 mg

  5 mL

  115

  253

  191 mg

  4.75 mL

  110

  242

  183 mg

  4.5 mL

  105

  231

  175 mg

  4.4 mL

  100

  220

  166 mg

  4.2 mL

  95

  209

  158 mg

  4 mL

  90

  198

  150 mg

  3.75 mL

  85

  187

  141 mg

  3.5 mL

  80

  176

  133 mg

  3.3 mL

  75

  165

  125 mg

  3.1 mL

  70

  154

  116 mg

  2.9 mL

  65

  143

  108 mg

  2.7 mL

  60

  132

  100 mg

  2.5 mL

  55

  121

  91 mg

  2.25 mL

  50

  110

  83 mg

  2.1 mL

  45

  99

  75 mg

  1.9 mL

  40

  88

  66 mg

  1.6 mL

  *Applicable to all product forms except the tobramycin pediatric injection (see HOW SUPPLIED).

   

  Pediatric Patients (greater than 1 week of age):  6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

  Premature or Full-Term Neonates 1 Week of Age or Less:  Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

  It is desirable to limit treatment to a short term.  The usual duration of treatment is 7 to 10 days.  A longer course of therapy may be necessary in difficult and complicated infections.  In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

  Dosage in Patients with Cystic Fibrosis

  In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose.  In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended.  This dosing regimen is suggested only as a guide.  The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

  Administration for Patients with Impaired Renal Function

  Whenever possible, serum tobramycin concentrations should be monitored during therapy.

  Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals.  Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly.  They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin.  The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.  Neither method should be used when dialysis is being performed.

  Reduced dosage at 8-hour intervals:  When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 1 by the percent of normal dose from the accompanying nomogram.

   

   

  * Scales have been adjusted to facilitate dosage calculations.

  An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

  Normal dosage at prolonged intervals:  If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage frequency in hours for the dosage given in Table 1 can be determined by multiplying the patient’s serum creatinine by 6.

  Dosage in Obese Patients

  The appropriate dose may be calculated by using the patient’s estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

  Intramuscular Administration

  Tobramycin may be administered by withdrawing the approriate dose directly from a vial.

  Intravenous Administration

  For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses.  For pediatric patients, the volume of diluent should be proportionately less than that for adults.  The diluted solution usually should be infused over a period of 20 to 60 minutes.  Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

  Tobramycin injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

  Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

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• Medicated Apricot Scrub...
  

  ×

  Medicated Apricot Scrub

  

  ---

  Gentamicin Injection may be given intramuscularly or intravenously.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  DOSAGE FOR PATIENTS

  WITH NORMAL RENAL FUNCTION

  Children: 6 to 7.5 mg/kg/day. (2 to 2.5 mg/kg administered every 8 hours.)

  Infants and Neonates: 7.5 mg/kg/day. (2.5 mg/kg administered every 8 hours.)

  Premature or Full-term Neonates One Week of Age or Less: 5 mg/kg/day. (2.5 mg/kg administered every 12 hours.)

  It is desirable to measure periodically both peak and trough serum concentrations of gentamicin when feasible during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after intramuscular injection) is expected to be in the range of 3 to 5 mcg/mL.  When monitoring peak concentrations after intramuscular or intravenous administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  The usual duration of treatment is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  For Intravenous Administration

  The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass.

  For intermittent intravenous administration, a single dose of Gentamicin Injection may be diluted in 0.9% Sodium Chloride Injection or in 5% Dextrose Injection.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for intravenous and intramuscular administration is identical.

  Gentamicin Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

  DOSAGE FOR PATIENTS

  WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate but not excessive, blood levels.  Whenever possible, serum concentrations of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  In adults, the interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).  These guidelines may be considered when treating infants and children with serious renal impairment.

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.

  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 3).  For example, after an initial dose of 20 mg (2 mg/kg), a child weighing 10 kg with a serum creatinine level of 2 mg/100 mL could be given 10 mg every eight hours (20 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

  TABLE 3  DOSAGE ADJUSTMENT GUIDE FOR PATIENTS WITH RENAL IMPAIRMENT (Dosage at Eight-Hour Intervals After the Usual Initial Dose) Serum Creatinine(mg %) Approximate CreatinineClearance Rate(mL/min/1.73m2) Percent of Usual DosesShown Above ≤1 >100 100 1.1 to 1.3 70 to 100 80 1.4 to 1.6 55 to 70 65 1.7 to 1.9 45 to 55 55 2 to 2.2 40 to 45 50 2.3 to 2.5 35 to 40 40 2.6 to 3 30 to 35 35 3.1 to 3.5 25 to 30 30 3.6 to 4 20 to 25 25 4.1 to 5.1 15 to 20 20 5.2 to 6.6 10 to 15 15 6.7 to 8 <10 10

  In patients with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  In children, the recommended dose at the end of each dialysis period is 2 to 2.5 mg/kg depending upon the severity of the infection.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Benztropine Mesylate
  

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  Benztropine Mesylate

  

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  Since there is no significant difference in onset of effect after intravenous or intramuscular injection, usually there is no need to use the intravenous route. The drug is quickly effective after either route, with improvement sometimes noticeable a few minutes after injection.  In emergency situations, when the condition of the patient is alarming, 1 to 2 mL of the injection normally will provide quick relief. If the parkinsonian effect begins to return, the dose can be repeated.

  Because of cumulative action, therapy should be initiated with a low dose which is increased gradually at five or six-day intervals to the smallest amount necessary for optimal relief. Increases should be made in increments of 0.5 mg, to a maximum of 6 mg, or until optimal results are obtained without excessive adverse reactions.

  Postencephalitic and Idiopathic Parkinsonism

  The usual daily dose is 1 to 2 mg, with a range of 0.5 to 6 mg parenterally.

  As with any agent used in parkinsonism, dosage must be individualized according to age and weight, and the type of parkinsonism being treated.  Generally, older patients, and thin patients cannot tolerate large doses.  Most patients with postencephalitic parkinsonism need fairly large doses and tolerate them well.  Patients with a poor mental outlook are usually poor candidates for therapy.

  In idiopathic parkinsonism, therapy may be initiated with a single daily dose of 0.5 to 1 mg at bedtime.  In some patients, this will be adequate; in others 4 to 6 mg a day may be required.

  In postencephalitic parkinsonism, therapy may be initiated in most patients with 2 mg a day in one or more doses.  In highly sensitive patients, therapy may be initiated with 0.5 mg at bedtime, and increased as necessary.

  Some patients experience greatest relief by taking the entire dose at bedtime; others react more favorably to divided doses, two to four times a day.  Frequently, one dose a day is sufficient, and divided doses may be unnecessary or undesirable.

  The long duration of action of this drug makes it particularly suitable for bedtime medication when its effects may last throughout the night, enabling patients to turn in bed during the night more easily, and to rise in the morning.

  When benztropine mesylate is started, do not terminate therapy with other antiparkinsonian agents abruptly.  If the other agents are to be reduced or discontinued, it must be done gradually.  Many patients obtain greatest relief with combination therapy.

  Benztropine mesylate may be used concomitantly with SINEMET® (Carbidopa-Levodopa), or with levodopa, in which case periodic dosage adjustment may be required in order to maintain optimum response.

  Drug-Induced Extrapyramidal Disorders

  In treating extrapyramidal disorders due to neuroleptic drugs (e.g., phenothiazines), the recommended dosage is 1 to 4 mg once or twice a day parenterally.  Dosage must be individualized according to the need of the patient.  Some patients require more than recommended; others do not need as much.

  In acute dystonic reactions, 1 to 2 mL of the injection usually relieves the condition quickly.

  When extrapyramidal disorders develop soon after initiation of treatment with neuroleptic drugs (e.g., phenothiazines), they are likely to be transient.  One to 2 mg of benztropine mesylate two or three times a day usually provides relief within one or two days.  After one or two weeks, the drug should be withdrawn to determine the continued need for it.  If such disorders recur, benztropine mesylate can be reinstituted.

  Certain drug-induced extrapyramidal disorders that develop slowly may not respond to benztropine mesylate.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

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• Childrens Chewable Pain...
  

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  Childrens Chewable Pain Reliever

  

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  2.1 Epilepsy

  Valproate sodium injection is for intravenous use only.

  Use of valproate sodium injection for periods of more than 14 days has not been studied.  Patients should be switched to oral valproate products as soon as it is clinically feasible.

  Valproate sodium injection should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.

  In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of valproate sodium injection (up to 15 mg/kg and mean dose of 1,184 mg) over 5 to 10 minutes (1.5 to 3 mg/kg/min).  Patients generally tolerated the more rapid infusions well [see Adverse Reactions (6.1)].  This study was not designed to assess the effectiveness of these regimens.  For pharmacokinetics with rapid infusions, see Clinical Pharmacology (12.3).

  Initial Exposure to Valproate

  The following dosage recommendations were obtained from studies utilizing oral divalproex sodium products.

  Complex Partial Seizures

  For adults and children 10 years of age or older.

  Monotherapy (Initial Therapy)

  Valproate sodium injection has not been systematically studied as initial therapy.  Patients should initiate therapy at 10 to 15 mg/kg/day.  The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.  Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.  If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).  No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

  The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males.  The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

  Conversion to Monotherapy

  Patients should initiate therapy at 10 to 15 mg/kg/day.  The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.  Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.  If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).  No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.  Concomitant anti-epilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.  This reduction may be started at initiation of valproate sodium injection therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction.  The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency.

  Adjunctive Therapy

  Valproate sodium injection may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day.  The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response.  Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.  If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).  No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.  If the total daily dose exceeds 250 mg, it should be given in divided doses.

  In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin dosage was needed [see Clinical Studies (14)]. However, since valproate may interact with these or other concurrently administered AEDs as well as other drugs, periodic plasma concentration determinations of concomitant AEDs are recommended during the early course of therapy [see Drug Interactions (7)].

  Simple and Complex Absence Seizures

  The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizures are controlled or side effects preclude further increases.  The maximum recommended dosage is 60 mg/kg/day.  If the total daily dose exceeds 250 mg, it should be given in divided doses.

  A good correlation has not been established between daily dose, serum concentrations, and therapeutic effect.  However, therapeutic valproate serum concentration for most patients with absence seizures is considered to range from 50 to 100 mcg/mL.  Some patients may be controlled with lower or higher serum concentrations [see Clinical Pharmacology (12.3)].

  As the valproate sodium injection dosage is titrated upward, blood concentrations of phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

  Anti-epilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

  Replacement Therapy

  When switching from oral valproate products, the total daily dose of valproate sodium injection should be equivalent to the total daily dose of the oral valproate product [see Clinical Pharmacology (12)], and should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary.  Patients receiving doses near the maximum recommended daily dose of 60 mg/kg/day, particularly those not receiving enzyme-inducing drugs, should be monitored more closely.  If the total daily dose exceeds 250 mg, it should be given in a divided regimen.  There is no experience with more rapid infusions in patients receiving valproate sodium injection as replacement therapy.  However, the equivalence shown between valproate sodium injection and oral valproate products (divalproex sodium) at steady state was only evaluated in an every 6 hour regimen.  Whether, when valproate sodium injection is given less frequently (i.e., twice or three times a day), trough levels fall below those that result from an oral dosage form given via the same regimen, is unknown.  For this reason, when valproate sodium injection is given twice or three times a day, close monitoring of trough plasma levels may be needed.

  2.2 General Dosing Advice

  Dosing in Elderly Patients

  Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients.  Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.  Dose reductions or discontinuation of valproate should be considered in patients with decreased food or fluid intake and in patients with excessive somnolence.  The ultimate therapeutic dose should be achieved on the basis of both tolerability and clinical response [see Warnings and Precautions (5.13), Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

  Dose-Related Adverse Reactions

  The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose-related.  The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions (5.7)].  The benefit of improved therapeutic effect with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.

  Administration

  Rapid infusion of valproate sodium injection has been associated with an increase in adverse reactions.  There is limited experience with infusion times of less than 60 minutes or rates of infusion > 20 mg/min in patients with epilepsy [see Adverse Reactions (6)].

  Valproate sodium injection should be administered intravenously as a 60 minute infusion, as noted above.  It should be diluted with at least 50 mL of a compatible diluent.  Any unused portion of the vial contents should be discarded.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Compatibility and Stability

  Valproate sodium injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F).  

   • dextrose (5%) injection, USP

   • sodium chloride (0.9%) injection, USP

   • lactated ringer's injection, USP

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• Chlorothiazide
  

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  Chlorothiazide

  

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  Chlorothiazide sodium for injection should be reserved for patients unable to take oral medication or for emergency situations.

  Therapy should be individualized according to patient response.  Use the smallest dosage necessary to achieve the required response.

  Intravenous use in infants and children has been limited and is not generally recommended.

  When medication can be taken orally, therapy with chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, using the same dosage schedule as for the parenteral route.

  Chlorothiazide sodium for injection may be given slowly by direct intravenous injection or by intravenous infusion.

  Extravasation must be rigidly avoided.  Do not give subcutaneously or intramuscularly.

  The usual adult dosage is 500 mg to 1 g once or twice a day.  Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week.  With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

  Directions for Reconstitution

  Use aseptic technique.  Because chlorothiazide sodium for injection contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

  Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection.  Never add less than 18 mL.  When reconstituted with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium is 28 mg/mL.  The reconstituted solution is clear and essentially free from visible particles.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.  The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion.  Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

  Directions for Reconstitution

  Use aseptic technique.  Because chlorothiazide sodium for injection contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

  Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection.  Never add less than 18 mL.  When reconstituted with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium is 28 mg/mL.  The reconstituted solution is clear and essentially free from visible particles.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.  The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion.  Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

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• Chlorothiazide
  

  ×

  Chlorothiazide

  

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  Chlorothiazide sodium for injection should be reserved for patients unable to take oral medication or for emergency situations.

  Therapy should be individualized according to patient response.  Use the smallest dosage necessary to achieve the required response.

  Intravenous use in infants and children has been limited and is not generally recommended.

  When medication can be taken orally, therapy with chlorothiazide tablets or oral suspension may be substituted for intravenous therapy, using the same dosage schedule as for the parenteral route.

  Chlorothiazide sodium for injection may be given slowly by direct intravenous injection or by intravenous infusion.

  Extravasation must be rigidly avoided.  Do not give subcutaneously or intramuscularly.

  The usual adult dosage is 500 mg to 1 g once or twice a day.  Many patients with edema respond to intermittent therapy, i.e., administration on alternate days or on three to five days each week.  With an intermittent schedule, excessive response and the resulting undesirable electrolyte imbalance are less likely to occur.

  Directions for Reconstitution

  Use aseptic technique.  Because chlorothiazide sodium for injection contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

  Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection.  Never add less than 18 mL.  When reconstituted with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium is 28 mg/mL.  The reconstituted solution is clear and essentially free from visible particles.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.  The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion.  Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

  Directions for Reconstitution

  Use aseptic technique.  Because chlorothiazide sodium for injection contains no preservative, a fresh solution should be prepared immediately prior to each administration, and the unused portion should be discarded.

  Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection.  Never add less than 18 mL.  When reconstituted with 18 mL of Sterile Water, the final concentration of intravenous chlorothiazide sodium is 28 mg/mL.  The reconstituted solution is clear and essentially free from visible particles.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to use whenever solution and container permit.  The solution is compatible with dextrose or sodium chloride solutions for intravenous infusion.  Avoid simultaneous administration of solutions of chlorothiazide with whole blood or its derivatives.

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• Anti-diarrheal
  

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  Anti-diarrheal

  

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  Table 1 (Recommended Dosages) summarizes the recommended volumes and concentrations of Xylocaine Injection for various types of anesthetic procedures.  The dosages suggested in this table are for normal healthy adults and refer to the use of epinephrine-free solutions.  When larger volumes are required, only solutions containing epinephrine should be used except in those cases where vasopressor drugs may be contraindicated.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Xylocaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  These recommended doses serve only as a guide to the amount of anesthetic required for most routine procedures.  The actual volumes and concentrations to be used depend on a number of factors such as type and extent of surgical procedure, depth of anesthesia and degree of muscular relaxation required, duration of anesthesia required, and the physical condition of the patient.  In all cases the lowest concentration and smallest dose that will produce the desired result should be given.  Dosages should be reduced for children and for the elderly and debilitated patients and patients with cardiac and/or liver disease.

  The onset of anesthesia, the duration of anesthesia and the degree of muscular relaxation are proportional to the volume and concentration (ie, total dose) of local anesthetic used.  Thus, an increase in volume and concentration of Xylocaine Injection will decrease the onset of anesthesia, prolong the duration of anesthesia, provide a greater degree of muscular relaxation and increase the segmental spread of anesthesia.  However, increasing the volume and concentration of Xylocaine Injection may result in a more profound fall in blood pressure when used in epidural anesthesia.  Although the incidence of side effects with lidocaine HCl is quite low, caution should be exercised when employing large volumes and concentrations, since the incidence of side effects is directly proportional to the total dose of local anesthetic agent injected.

  For intravenous regional anesthesia, only the 50 mL single dose vial containing Xylocaine (lidocaine HCl) 0.5% Injection should be used.

  Epidural Anesthesia

  For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

  1% without epinephrine                         10 mL Plastic Ampule

  1% without epinephrine                         30 mL single dose solutions

  1% with epinephrine   1:200,000           30 mL single dose solutions

  1.5% without epinephrine                      10 mL Plastic Ampule

  1.5% without epinephrine                      20 mL Plastic Ampule

  1.5% with epinephrine  1:200,000          30 mL ampules, 30 mL single dose solutions

  2% without epinephrine                         10 mL Plastic Ampule

  2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

  Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

  In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

  Caudal and Lumbar Epidural Block

  As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

  In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

  Epidural Anesthesia

  For epidural anesthesia, only the following dosage forms Xylocaine Injection are recommended:

  1% without epinephrine                         10 mL Plastic Ampule

  1% without epinephrine                         30 mL single dose solutions

  1% with epinephrine   1:200,000           30 mL single dose solutions

  1.5% without epinephrine                      10 mL Plastic Ampule

  1.5% without epinephrine                      20 mL Plastic Ampule

  1.5% with epinephrine  1:200,000          30 mL ampules, 30 mL single dose solutions

  2% without epinephrine                         10 mL Plastic Ampule

  2% with epinephrine   1:200,000           20 mL ampules, 20 mL single dose solutions

  Although these solutions are intended specifically for epidural anesthesia, they may also be used for infiltration and peripheral nerve block, provided they are employed as single dose units.  These solutions contain no bacteriostatic agent. 

  In epidural anesthesia, the dosage varies with the number of dermatomes to be anesthetized (generally 2 to 3 mL of the indicated concentration per dermatome).

  Caudal and Lumbar Epidural Block

  As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine HCl should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block.  The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.  Epinephrine, if contained in the test dose (10 to 15 mcg have been suggested), may serve as a warning of unintentional intravascular injection.  If injected into a blood vessel, this amount of epinephrine is likely to produce a transient “epinephrine response” within 45 seconds, consisting of an increase in heart rate and systolic blood pressure, circumoral pallor, palpitations and nervousness in the unsedated patient.  The sedated patient may exhibit only a pulse rate increase of 20 or more beats per minute for 15 or more seconds.  Patients on beta blockers may not manifest changes in heart rate, but blood pressure monitoring can detect an evanescent rise in systolic blood pressure.  Adequate time should be allowed for onset of anesthesia after administration of each test dose.  The rapid injection of a large volume of Xylocaine Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

  In the event of the known injection of a large volume of local anesthetic solution into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

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• Topotecan Hydrochloride...
  

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  Topotecan Hydrochloride

  

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  Prior to administration of the first course of topotecan hydrochloride, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

  2.1 Small Cell Lung Cancer

  Recommended Dosage 

  The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed.  The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

  Dosage Modification Guidelines

  In the event of severe neutropenia (defined as <500 cells/ mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.

  2.2 Cervical Cancer

  Recommended Dosage

  The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

  Dosage Modification Guidelines

  Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug.  See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

  In the event of severe febrile neutropenia (defined as <1,000 cells/mm3 with temperature of 38°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.6 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.6 mg/m2 for subsequent courses.

  2.3 Dosage Adjustment in Specific Populations

  Renal Impairment

  No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min).  Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min).  Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

  Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL.  In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL.  Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

  2.4 Instructions for Handling, Preparation and Intravenous Administration

  Handling

  Topotecan hydrochloride is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing.  If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water.  If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

  Use procedures for proper handling and disposal of anticancer drugs.  Several guidelines on this subject have been published.1-4

  Preparation and Administration

  Each 4 mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection.  Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

  Stability

  Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] and protected from light in the original package.  Because the vials contain no preservative, contents should be used immediately after reconstitution.

  Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

  2.1 Small Cell Lung Cancer

  Recommended Dosage 

  The recommended dose of topotecan hydrochloride is 1.5 mg/m2 by intravenous infusion over 30 minutes daily for 5 consecutive days, starting on day 1 of a 21-day course. In the absence of tumor progression, a minimum of 4 courses is recommended because tumor response may be delayed.  The median time to response in 4 small cell lung cancer trials was 5 to 7 weeks.

  Dosage Modification Guidelines

  In the event of severe neutropenia (defined as <500 cells/ mm3) during any course, reduce the dose by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses. Alternatively, in the event of severe neutropenia, administer G-CSF (granulocyte-colony stimulating factor) following the subsequent course (before resorting to dose reduction) starting from day 6 of the course (24 hours after completion of topotecan administration). In the event the platelet count falls below 25,000 cells/mm3, reduce doses by 0.25 mg/m2 (to 1.25 mg/m2) for subsequent courses.

  2.2 Cervical Cancer

  Recommended Dosage

  The recommended dose of topotecan hydrochloride is 0.75 mg/m2 by intravenous infusion over 30 minutes daily on days 1, 2, and 3; followed by cisplatin 50 mg/m2 by intravenous infusion on day 1 repeated every 21 days (a 21-day course).

  Dosage Modification Guidelines

  Dosage adjustments for subsequent courses of topotecan hydrochloride in combination with cisplatin are specific for each drug.  See manufacturer’s prescribing information for cisplatin administration and hydration guidelines and for cisplatin dosage adjustment in the event of hematologic toxicity.

  In the event of severe febrile neutropenia (defined as <1,000 cells/mm3 with temperature of 38°C or 100.4°F), reduce the dose of topotecan hydrochloride to 0.6 mg/m2 for subsequent courses. Alternatively, in the event of severe febrile neutropenia, administer G-CSF following the subsequent course (before resorting to dose reduction) starting from day 4 of the course (24 hours after completion of administration of topotecan hydrochloride). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of topotecan hydrochloride to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.6 mg/m2 for subsequent courses.

  2.3 Dosage Adjustment in Specific Populations

  Renal Impairment

  No dosage adjustment of topotecan hydrochloride appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min).  Dosage adjustment of topotecan hydrochloride to 0.75 mg/m2 is recommended for patients with moderate renal impairment (20 to 39 mL/min).  Insufficient data are available in patients with severe renal impairment to provide a dosage recommendation for topotecan hydrochloride [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

  Topotecan hydrochloride in combination with cisplatin for the treatment of cervical cancer should only be initiated in patients with serum creatinine ≤1.5 mg/dL.  In the clinical trial, cisplatin was discontinued for a serum creatinine >1.5 mg/dL.  Insufficient data are available regarding continuing monotherapy with topotecan hydrochloride after cisplatin discontinuation in patients with cervical cancer.

  2.4 Instructions for Handling, Preparation and Intravenous Administration

  Handling

  Topotecan hydrochloride is a cytotoxic anticancer drug.  Prepare topotecan hydrochloride under a vertical laminar flow hood while wearing gloves and protective clothing.  If topotecan hydrochloride solution contacts the skin, wash the skin immediately and thoroughly with soap and water.  If topotecan hydrochloride contacts mucous membranes, flush thoroughly with water.

  Use procedures for proper handling and disposal of anticancer drugs.  Several guidelines on this subject have been published.1-4

  Preparation and Administration

  Each 4 mg vial of topotecan hydrochloride is reconstituted with 4 mL Sterile Water for Injection.  Then the appropriate volume of the reconstituted solution is diluted in either 0.9% Sodium Chloride Intravenous Infusion or 5% Dextrose Intravenous Infusion prior to administration.

  Stability

  Unopened vials of topotecan hydrochloride are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP Controlled Room Temperature] and protected from light in the original package.  Because the vials contain no preservative, contents should be used immediately after reconstitution.

  Reconstituted vials of topotecan hydrochloride diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.

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• Prednisone
  

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  Prednisone

  

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  The volume of the preparation to be used for diluting or dissolving any drug for injection, is dependent on the vehicle concentration, dose and route of administration as recommended by the manufacturer.

  Use aseptic technique for single entry and withdrawal from all containers.  Single dose vials should be entered just once.

  When diluting or dissolving drugs, mix thoroughly and use promptly.

  Do not store reconstituted solutions of drugs for injection unless otherwise directed by the manufacturer of the solute.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Gentamicin
  

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  Gentamicin

  

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  Gentamicin Injection may be given intramuscularly or intravenously.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  DOSAGE FOR PATIENTS

  WITH NORMAL RENAL FUNCTION

  Children: 6 to 7.5 mg/kg/day. (2 to 2.5 mg/kg administered every 8 hours.)

  Infants and Neonates: 7.5 mg/kg/day. (2.5 mg/kg administered every 8 hours.)

  Premature or Full-term Neonates One Week of Age or Less: 5 mg/kg/day. (2.5 mg/kg administered every 12 hours.)

  It is desirable to measure periodically both peak and trough serum concentrations of gentamicin when feasible during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after intramuscular injection) is expected to be in the range of 3 to 5 mcg/mL.  When monitoring peak concentrations after intramuscular or intravenous administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  The usual duration of treatment is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  For Intravenous Administration

  The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass.

  For intermittent intravenous administration, a single dose of Gentamicin Injection may be diluted in 0.9% Sodium Chloride Injection or in 5% Dextrose Injection.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for intravenous and intramuscular administration is identical.

  Gentamicin Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

  DOSAGE FOR PATIENTS

  WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate but not excessive, blood levels.  Whenever possible, serum concentrations of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  In adults, the interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).  These guidelines may be considered when treating infants and children with serious renal impairment.

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.

  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 1).  For example, after an initial dose of 20 mg (2 mg/kg), a child weighing 10 kg with a serum creatinine level of 2 mg/100 mL could be given 10 mg every eight hours (20 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

  TABLE 1

  DOSAGE ADJUSTMENT GUIDE

  FOR PATIENTS WITH RENAL IMPAIRMENT

  (Dosage at Eight-Hour Intervals

  After the Usual Initial Dose)

  Serum

  Creatinine

  (mg %)

  Approximate

  Creatinine

  Clearance Rate

  (mL/min/1.73m2)

  Percent of

  Usual Doses

  Shown Above

    ≤1

            >100

  100

  1.1 to 1.3

  70 to 100

  80

  1.4 to 1.6

  55 to 70

  65

  1.7 to 1.9

  45 to 55

  55

  2 to 2.2

  40 to 45

  50

  2.3 to 2.5

  35 to 40

  40

      2.6 to 3

  30 to 35

  35

  3.1 to 3.5

  25 to 30

  30

      3.6 to 4

  20 to 25

  25

  4.1 to 5.1

  15 to 20

  20

  5.2 to 6.6

  10 to 15

  15

      6.7 to 8

           <10

  10

  In patients with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  In children, the recommended dose at the end of each dialysis period is 2 to 2.5 mg/kg depending upon the severity of the infection.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Cladribine
  

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  Cladribine

  

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  Usual Dosage

  The recommended dose and schedule of cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven consecutive days at a dose of 0.09 mg/kg/day.  Deviations from this dosage regimen are not advised.  If the patient does not respond to the initial course of cladribine injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional courses.  Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see WARNINGS).

  Specific risk factors predisposing to increased toxicity from cladribine injection have not been defined.  In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology.  Patients should be monitored closely for hematologic and non-hematologic toxicity (see WARNINGS and PRECAUTIONS).

  Preparation and Administration of Intravenous Solutions

  Cladribine injection must be diluted with the designated diluent prior to administration.  Since the drug product does not contain any antimicrobial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of cladribine injection solutions.

  To prepare a single daily dose

  Cladribine injection should be passed through a sterile 0.22 μm disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion.  Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine injection through the sterile filter to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP.  Infuse continuously over 24 hours.  Repeat daily for a total of seven consecutive days.The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.  Admixtures of cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex® PVC infusion containers.  Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.

   Dose of Cladribine Injection  Recommended Diluent  Quantity of Diluent 24-hourinfusionmethod  1 (day) x 0.09 mg/kg   0.9% Sodium ChlorideInjection, USP  500 mL 

  To prepare a 7-day infusion

  The seven-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved).  In order to minimize the risk of microbial contamination, both cladribine injection and the diluent should be passed through a sterile 0.22μm disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir.  First add the calculated dose of cladribine injection (7 days x 0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter. 

  Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL.  After completing solution preparation, clamp off the line, disconnect and discard the filter.  Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly.  Reclamp the line and discard the syringe and filter assembly.  Infuse continuously over seven days.  Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative.  Admixtures for the seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTE™ Reservoir.

   Dose of Cladribine  Injection   Recommended Diluent   Quantity of Diluent  7-day infusion method (use sterile 0.22μm filter when preparing infusion solution  7 (days) x 0.09 mg/kg   Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol)   q.s. to 100 mL 

  Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.  Solutions containing cladribine injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.  Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS).

  Care must be taken to assure the sterility of prepared solutions.  Once diluted, solutions of cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than eight hours prior to start of administration.  Vials of cladribine injection are for single-use only.  Any unused portion should be discarded in an appropriate manner (see Handling and Disposal).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  A precipitate may occur during the exposure of cladribine injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously.  DO NOT HEAT OR MICROWAVE.

  Chemical Stability of Vials

  When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of cladribine injection are stable until the expiration date indicated on the package.  Freezing does not adversely affect the solution.  If freezing occurs, thaw naturally to room temperature.  DO NOT heat or microwave.  Once thawed, the vial of cladribine injection is stable until expiry if refrigerated.  DO NOT refreeze.  Once diluted, solutions containing cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.

  Handling and Disposal

  The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering cladribine injection.  The use of disposable gloves and protective garments is recommended.  If cladribine injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.  Several guidelines on this subject have been published.(2-8)  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.  Refer to your Institution’s guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

  Usual Dosage

  The recommended dose and schedule of cladribine injection for active Hairy Cell Leukemia is as a single course given by continuous infusion for seven consecutive days at a dose of 0.09 mg/kg/day.  Deviations from this dosage regimen are not advised.  If the patient does not respond to the initial course of cladribine injection for Hairy Cell Leukemia, it is unlikely that they will benefit from additional courses.  Physicians should consider delaying or discontinuing the drug if neurotoxicity or renal toxicity occurs (see WARNINGS).

  Specific risk factors predisposing to increased toxicity from cladribine injection have not been defined.  In view of the known toxicities of agents of this class, it would be prudent to proceed carefully in patients with known or suspected renal insufficiency or severe bone marrow impairment of any etiology.  Patients should be monitored closely for hematologic and non-hematologic toxicity (see WARNINGS and PRECAUTIONS).

  Preparation and Administration of Intravenous Solutions

  Cladribine injection must be diluted with the designated diluent prior to administration.  Since the drug product does not contain any antimicrobial preservative or bacteriostatic agent, aseptic technique and proper environmental precautions must be observed in preparation of cladribine injection solutions.

  To prepare a single daily dose

  Cladribine injection should be passed through a sterile 0.22 μm disposable hydrophilic syringe filter prior to introduction into the infusion bag, prior to each daily infusion.  Add the calculated dose (0.09 mg/kg or 0.09 mL/kg) of cladribine injection through the sterile filter to an infusion bag containing 500 mL of 0.9% Sodium Chloride Injection, USP.  Infuse continuously over 24 hours.  Repeat daily for a total of seven consecutive days.The use of 5% dextrose as a diluent is not recommended because of increased degradation of cladribine.  Admixtures of cladribine injection are chemically and physically stable for at least 24 hours at room temperature under normal room fluorescent light in Baxter Viaflex® PVC infusion containers.  Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.

   Dose of Cladribine Injection  Recommended Diluent  Quantity of Diluent 24-hourinfusionmethod  1 (day) x 0.09 mg/kg   0.9% Sodium ChlorideInjection, USP  500 mL 

  To prepare a 7-day infusion

  The seven-day infusion solution should only be prepared with Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved).  In order to minimize the risk of microbial contamination, both cladribine injection and the diluent should be passed through a sterile 0.22μm disposable hydrophilic syringe filter as each solution is being introduced into the infusion reservoir.  First add the calculated dose of cladribine injection (7 days x 0.09 mg/kg or mL/kg) to the infusion reservoir through the sterile filter. 

  Then add a calculated amount of Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol preserved) also through the filter to bring the total volume of the solution to 100 mL.  After completing solution preparation, clamp off the line, disconnect and discard the filter.  Aseptically aspirate air bubbles from the reservoir as necessary using the syringe and a dry second sterile filter or a sterile vent filter assembly.  Reclamp the line and discard the syringe and filter assembly.  Infuse continuously over seven days.  Solutions prepared with Bacteriostatic Sodium Chloride Injection for individuals weighing more than 85 kg may have reduced preservative effectiveness due to greater dilution of the benzyl alcohol preservative.  Admixtures for the seven-day infusion have demonstrated acceptable chemical and physical stability for at least seven days in the SIMS Deltec MEDICATION CASSETTE™ Reservoir.

   Dose of Cladribine  Injection   Recommended Diluent   Quantity of Diluent  7-day infusion method (use sterile 0.22μm filter when preparing infusion solution  7 (days) x 0.09 mg/kg   Bacteriostatic 0.9% Sodium Chloride Injection, USP (0.9% benzyl alcohol)   q.s. to 100 mL 

  Since limited compatibility data are available, adherence to the recommended diluents and infusion systems is advised.  Solutions containing cladribine injection should not be mixed with other intravenous drugs or additives or infused simultaneously via a common intravenous line, since compatibility testing has not been performed.  Preparations containing benzyl alcohol should not be used in neonates (see WARNINGS).

  Care must be taken to assure the sterility of prepared solutions.  Once diluted, solutions of cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than eight hours prior to start of administration.  Vials of cladribine injection are for single-use only.  Any unused portion should be discarded in an appropriate manner (see Handling and Disposal).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  A precipitate may occur during the exposure of cladribine injection to low temperatures; it may be resolubilized by allowing the solution to warm naturally to room temperature and by shaking vigorously.  DO NOT HEAT OR MICROWAVE.

  Chemical Stability of Vials

  When stored in refrigerated conditions between 2° to 8°C (36° to 46°F) and protected from light, unopened vials of cladribine injection are stable until the expiration date indicated on the package.  Freezing does not adversely affect the solution.  If freezing occurs, thaw naturally to room temperature.  DO NOT heat or microwave.  Once thawed, the vial of cladribine injection is stable until expiry if refrigerated.  DO NOT refreeze.  Once diluted, solutions containing cladribine injection should be administered promptly or stored in the refrigerator (2° to 8°C) for no more than 8 hours prior to administration.

  Handling and Disposal

  The potential hazards associated with cytotoxic agents are well established and proper precautions should be taken when handling, preparing, and administering cladribine injection.  The use of disposable gloves and protective garments is recommended.  If cladribine injection contacts the skin or mucous membranes, wash the involved surface immediately with copious amounts of water.  Several guidelines on this subject have been published.(2-8)  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.  Refer to your Institution’s guidelines and all applicable state/local regulations for disposal of cytotoxic waste.

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• Doxy 100
  

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  Doxy 100

  

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  NOTE:  Rapid administration is to be avoided.  Parenteral therapy is indicated only when oral therapy is not indicated.  Oral therapy should be instituted as soon as possible.  If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

  THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE FOR INJECTION (100 to 200 MG/DAY) DIFFERS FROM THAT OF THE OTHER TETRACYCLINES (1 to 2 G/DAY).  EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

  Studies to date have indicated that doxycycline hyclate at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS, Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS, Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

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• Propofol
  

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  Propofol

  

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  Propofol blood concentrations at steady state are generally proportional to infusion rates, especially in individual patients.  Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.  An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

  Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

  When administering Propofol Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing Propofol Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

  Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of Propofol Injectable Emulsion. 

  For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate Propofol Injectable Emulsion infusion to provide satisfactory anesthesia.  With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of Propofol Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

  Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of Propofol Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of Propofol Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, Propofol Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Propofol Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of Propofol Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of Propofol Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of Propofol Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative‑hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Propofol Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering Propofol Injectable Emulsion to pediatric patients.  Boluses of Propofol Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of Propofol Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  Propofol Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, Propofol Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with Propofol Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, Propofol Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system. 

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary Propofol Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non‑narcotic (lorazepam) premedication.  The rate of Propofol Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses. 

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when Propofol Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, Propofol Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of Propofol Injectable Emulsion will reduce the opioid requirements (see Table 4).  When Propofol Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                        Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  Propofol Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  Propofol Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl      =   5 mcg of alfentanil (for bolus)

                                    =   10 mcg of alfentanil (for maintenance)

                                        or

                                    =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  Adult Patients

  In adults, anesthesia can be maintained by administering Propofol Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  Propofol Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of Propofol Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol. 

  Intermittent Bolus

  Increments of Propofol Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  Propofol Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of Propofol Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  Propofol Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Propofol Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When Propofol Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of Propofol Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing Propofol Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When Propofol Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of Propofol Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of Propofol Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of Propofol Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of Propofol Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Propofol Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When Propofol Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of Propofol Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of Propofol Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of Propofol Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION). 

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  Propofol Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of Propofol Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  Conversely, the Propofol Injectable Emulsion dosage requirement may be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of cns function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES: 

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg)

  Pediatric Patients – healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary Propofol Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min

  Low-Dose Propofol Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h)

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of Propofol Injectable Emulsion required for sedation.

  The tubing and any unused portions of Propofol Injectable Emulsion

  should be discarded after 12 hours because Propofol Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of Propofol, it is recommended that it be administered prior to Propofol administration or that it be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol.

  Compatibility and Stability

  Propofol Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  Propofol Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).  

  Administration with Other Fluids

  Compatibility of Propofol Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, Propofol Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and Propofol Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  Propofol Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of Propofol Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of Propofol Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  Propofol Injectable Emulsion is a single-use parenteral product which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, Propofol Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Accordingly, strict aseptic technique must still be adhered to.  Do not use if contamination is suspected.  Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION,  Handling Procedures).  There have been reports in which failure to use aseptic technique when handling Propofol Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  Propofol, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  Propofol Injectable Emulsion should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial syringe rubber stopper should be disinfected using 70% isopropyl alcohol.  Propofol Injectable Emulsion should be drawn into sterile syringes immediately after vials are opened.  When withdrawing Propofol Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe(s) should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vials have been opened.

  Propofol Injectable Emulsion should be prepared for single-patient use only.  Any unused portions of Propofol Injectable Emulsion, reservoirs, dedicated administration tubing and/or solutions containing Propofol Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual Propofol Injectable Emulsion.

   

  Guidelines for Aseptic Technique for ICU Sedation

  Propofol Injectable Emulsion should be prepared for single-patient use only.  When Propofol Injectable Emulsion is administered directly from the vial, strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of Propofol Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused portions of Propofol Injectable Emulsion must be discarded after 12 hours.

  If Propofol Injectable Emulsion is transferred to a syringe or other container prior to administration, the handling procedures for General anesthesia/MAC sedation should be followed, and the product should be discarded and administration lines changed after 12 hours.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of Propofol Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, Propofol Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Propofol Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of Propofol Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of Propofol Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of Propofol Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative‑hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of Propofol Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering Propofol Injectable Emulsion to pediatric patients.  Boluses of Propofol Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of Propofol Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  Propofol Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, Propofol Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with Propofol Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, Propofol Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system. 

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary Propofol Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non‑narcotic (lorazepam) premedication.  The rate of Propofol Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses. 

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when Propofol Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, Propofol Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of Propofol Injectable Emulsion will reduce the opioid requirements (see Table 4).  When Propofol Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                        Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  Propofol Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  Propofol Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl      =   5 mcg of alfentanil (for bolus)

                                    =   10 mcg of alfentanil (for maintenance)

                                        or

                                    =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  Adult Patients

  In adults, anesthesia can be maintained by administering Propofol Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  Propofol Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of Propofol Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol. 

  Intermittent Bolus

  Increments of Propofol Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  Propofol Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of Propofol Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  Propofol Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Propofol Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When Propofol Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of Propofol Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing Propofol Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When Propofol Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of Propofol Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of Propofol Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of Propofol Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of Propofol Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Propofol Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When Propofol Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of Propofol Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of Propofol Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of Propofol Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION). 

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  Propofol Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of Propofol Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  Conversely, the Propofol Injectable Emulsion dosage requirement may be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of cns function should be carried out daily throughout maintenance to determine the minimum dose of PROPOFOL required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES: 

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg)

  Pediatric Patients – healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary Propofol Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min

  Low-Dose Propofol Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h)

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of Propofol Injectable Emulsion required for sedation.

  The tubing and any unused portions of Propofol Injectable Emulsion

  should be discarded after 12 hours because Propofol Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of Propofol, it is recommended that it be administered prior to Propofol administration or that it be added to Propofol immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg Propofol.

  Compatibility and Stability

  Propofol Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  Propofol Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).  

  Administration with Other Fluids

  Compatibility of Propofol Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, Propofol Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and Propofol Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  Propofol Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of Propofol Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of Propofol Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  Propofol Injectable Emulsion is a single-use parenteral product which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, Propofol Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Accordingly, strict aseptic technique must still be adhered to.  Do not use if contamination is suspected.  Discard unused portions as directed within the required time limits (see DOSAGE AND ADMINISTRATION,  Handling Procedures).  There have been reports in which failure to use aseptic technique when handling Propofol Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  Propofol, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  Propofol Injectable Emulsion should be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial syringe rubber stopper should be disinfected using 70% isopropyl alcohol.  Propofol Injectable Emulsion should be drawn into sterile syringes immediately after vials are opened.  When withdrawing Propofol Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe(s) should be labeled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vials have been opened.

  Propofol Injectable Emulsion should be prepared for single-patient use only.  Any unused portions of Propofol Injectable Emulsion, reservoirs, dedicated administration tubing and/or solutions containing Propofol Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual Propofol Injectable Emulsion.

   

  Guidelines for Aseptic Technique for ICU Sedation

  Propofol Injectable Emulsion should be prepared for single-patient use only.  When Propofol Injectable Emulsion is administered directly from the vial, strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of Propofol Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused portions of Propofol Injectable Emulsion must be discarded after 12 hours.

  If Propofol Injectable Emulsion is transferred to a syringe or other container prior to administration, the handling procedures for General anesthesia/MAC sedation should be followed, and the product should be discarded and administration lines changed after 12 hours.

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• Adenosine
  

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  Adenosine

  

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  For rapid bolus intravenous use only.

   

  Adenosine Injection, USP should be given as a rapid bolus by the peripheral intravenous route.  To be certain the solution reaches the systemic circulation, it should be administered either directly into a vein or, if given into an IV line, it should be given as close to the patient as possible and followed by a rapid saline flush.

  Adult Patients

  The dose recommendation is based on clinical studies with peripheral venous bolus dosing.  Central venous (CVP or other) administration of Adenosine Injection, USP has not been systematically studied.

  The recommended intravenous doses for adults are as follows:

      Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period).

      Repeat administration:  If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus.

      This 12 mg dose may be repeated a second time if required.

  Pediatric Patients

  The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

  Pediatric Patients with a Body Weight < 50 kg:

      Initial dose: give 0.05 to 0.1 mg/kg as a rapid IV bolus either centrally or peripherally.  A saline flush should follow.

      Repeat administration:  If conversion of PSVT does not occur within 1 to 2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg.  Follow each bolus with a saline flush.  This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

  Pediatric Patients with a Body Weight > 50 kg:

      Administer the adult dose.

      Doses greater than 12 mg are not recommended for adult and pediatric patients.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Adult Patients

  The dose recommendation is based on clinical studies with peripheral venous bolus dosing.  Central venous (CVP or other) administration of Adenosine Injection, USP has not been systematically studied.

  The recommended intravenous doses for adults are as follows:

      Initial dose: 6 mg given as a rapid intravenous bolus (administered over a 1 to 2 second period).

      Repeat administration:  If the first dose does not result in elimination of the supraventricular tachycardia within 1 to 2 minutes, 12 mg should be given as a rapid intravenous bolus.

      This 12 mg dose may be repeated a second time if required.

  Pediatric Patients

  The dosages used in neonates, infants, children and adolescents were equivalent to those administered to adults on a weight basis.

  Pediatric Patients with a Body Weight < 50 kg:

      Initial dose: give 0.05 to 0.1 mg/kg as a rapid IV bolus either centrally or peripherally.  A saline flush should follow.

      Repeat administration:  If conversion of PSVT does not occur within 1 to 2 minutes, additional bolus injections of adenosine can be administered at incrementally higher doses, increasing the amount given by 0.05 to 0.1 mg/kg.  Follow each bolus with a saline flush.  This process should continue until sinus rhythm is established or a maximum single dose of 0.3 mg/kg is used.

  Pediatric Patients with a Body Weight > 50 kg:

      Administer the adult dose.

      Doses greater than 12 mg are not recommended for adult and pediatric patients.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

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• Arranon
  

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  Arranon

  

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  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used.  The smallest dose and concentration required to produce the desired result should be administered.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Naropin is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  Patients in poor general condition due to aging or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients.  To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly.

  Use an adequate test dose (3 to 5 mL of a short-acting local anesthetic solution containing epinephrine) prior to induction of complete block.  This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.  Allow adequate time for onset of anesthesia following administration of each test dose.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Solutions which are discolored or which contain particulate matter should not be administered.

                                                                                                           Table 7  Dosage Recommendations

   Conc.   Volume   Dose   Onset   Duration   mg/mL   (%)   mL   mg   min   hours   SURGICAL ANESTHESIA    Lumbar Epidural    5   (0.5%)   15 to 30   75 to 150   15 to 30   2 to 4   Administration    7.5   (0.75%)   15 to 25   113 to 188   10 to 20   3 to 5   Surgery   10   (1%)   15 to 20   150 to 200   10 to 20   4 to 6   Lumbar Epidural    5   (0.5%)   20 to 30   100 to 150   15 to 25   2 to 4   Administration    7.5   (0.75%)   15 to 20   113 to 150   10 to 20   3 to 5   Cesarean Section   Thoracic Epidural    5   (0.5%)   5 to 15   25 to 75   10 to 20   n/a*   Administration    7.5   (0.75%)   5 to 15   38 to 113   10 to 20   n/a*   Surgery   Major Nerve Block†    5   (0.5%)   35 to 50   175 to 250   15 to 30   5 to 8   (eg, brachial plexus block)   7.5   (0.75%)   10 to 40   75 to 300   10 to 25   6 to 10   Field Block    5   (0.5%)   1 to 40   5 to 200   1 to 15   2 to 6   (eg, minor nerve blocks and infiltration)   LABOR PAIN MANAGEMENT    Lumbar Epidural Administration    Initial Dose   2   (0.2%)   10 to 20   20 to 40   10 to 15   0.5 to 1.5   Continuous infusion‡    2   (0.2%)   6 to 14 mL/h  12 to 28 mg/h  n/a*   n/a*   Incremental injections (top-up)‡  2   (0.2%)   10 to 15 mL/h  20 to 30 mg/h  n/a*   n/a*   POSTOPERATIVE PAIN MANAGEMENT    Lumbar Epidural Administration    Continuous infusion§    2   (0.2%)   6 to 14 mL/h  12 to 28 mg/h  n/a*   n/a*   Thoracic Epidural  Administration  2   (0.2%)   6 to 14 mL/h  12 to 28 mg/h  n/a*   n/a*   Continuous infusion§    Infiltration    2   (0.2%)   1 to 100   2 to 200   1 to 5   2 to 6   (eg, minor nerve block)   5   (0.5%)   1 to 40   5 to 200   1 to 5   2 to 6 

  *  =  Not Applicable

  †  =  The dose for a major nerve block must be adjusted according to site of administration and patient status.  Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see PRECAUTIONS).

  ‡  =   Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.

  §  =  Cumulative doses up to 770 mg of Naropin over 24 hours (intraoperative block plus postoperative infusion);  Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, ie, 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.

  The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults.  Individual variations in onset and duration occur.  The figures reflect the expected average dose range needed.  For other local anesthetic techniques standard current textbooks should be consulted.

  When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered.  Experience to date indicates that a cumulative dose of up to 770 mg Naropin administered over 24 hours is well tolerated in adults when used for postoperative pain management: ie, 2016 mg.  Caution should be exercised when administering Naropin for prolonged periods of time, eg, > 70 hours in debilitated patients.

  For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL Naropin is induced via an epidural catheter.  Analgesia is maintained with an infusion of Naropin, 2 mg/mL (0.2%).  Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block.  With this technique a significant reduction in the need for opioids was demonstrated.  Clinical experience supports the use of Naropin epidural infusions for up to 72 hours.

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• Methotrexate
  

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  Methotrexate

  

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  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate for Injection, USP may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area: 

  Age (years)

  Dose (mg)

      < 1

        6

         1

        8

         2

       10

  3 or older

       12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity.  Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity.  Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued.  Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases.  Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis Fungoides (cutaneous T cell lymphoma)

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.  

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion(starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

   

  Doxorubicin† 

  as a single drug

  30 mg/m2/day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin† 

  Cyclophosphamide†

   Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

   *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

  †See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

   When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate for Injection, USP may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area: 

  Age (years)

  Dose (mg)

      < 1

        6

         1

        8

         2

       10

  3 or older

       12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity.  Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity.  Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued.  Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases.  Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis Fungoides (cutaneous T cell lymphoma)

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.  

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion(starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

   

  Doxorubicin† 

  as a single drug

  30 mg/m2/day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin† 

  Cyclophosphamide†

   Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

   *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

  †See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

   When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

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• Atomy Bb Broad Spectrum...
  

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  Atomy Bb Broad Spectrum Spf30

  

  ---

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.1 Adult Patients

  The usual total daily dose of piperacillin and tazobactam for injection for adults is 3.375 g every six hours totaling 13.5 g (12.0 g piperacillin/1.5 g tazobactam).  The usual duration of piperacillin and tazobactam for injection treatment is from 7 to 10 days.

  Piperacillin and tazobactam for injection should be administered by intravenous infusion over 30 minutes.

  2.2 Nosocomial Pneumonia

  Initial presumptive treatment of patients with nosocomial pneumonia should start with piperacillin and tazobactam for injection at a dosage of 4.5 g every six hours plus an aminoglycoside, totaling 18.0 g (16.0 g piperacillin/2.0 g tazobactam).  The recommended duration of piperacillin and tazobactam for injection treatment for nosocomial pneumonia is 7 to 14 days.  Treatment with the aminoglycoside should be continued in patients from whom P. aeruginosa is isolated.

  2.3 Renal Impairment

  In patients with renal impairment (creatinine clearance ≤ 40 mL/min) and dialysis patients (hemodialysis and CAPD), the intravenous dose of piperacillin and tazobactam for injection should be reduced to the degree of actual renal function impairment.  The recommended daily doses of piperacillin and tazobactam for injection for patients with renal impairment are as follows:

  Table 1:  Recommended Dosing of Piperacillin and Tazobactam for Injection in Patients with Normal Renal Function and Renal Impairment (As total grams piperacillin/tazobactam)

  Renal Function

     

       

  (creatinine clearance,

  All Indications

  Nosocomial

  mL/min)

  (except nosocomial pneumonia)

  Pneumonia

  >40 mL/min

  3.375 q6h

  4.5 q6h

  20-40 mL/min*

  2.25 q6h

  3.375 q6h

  <20 mL/min*

  2.25 q8h

  2.25 q6h

  Hemodialysis**

  2.25 q12h

  2.25 q8h

  CAPD

  2.25 q12h

  2.25 q8h

  *Creatinine clearance for patients not receiving hemodialysis **0.75 g (0.67 g piperacillin/0.08 g tazobactam) should be administered following each hemodialysis session on hemodialysis days

  For patients on hemodialysis, the maximum dose is 2.25 g every twelve hours for all indications other than nosocomial pneumonia and 2.25 g every eight hours for nosocomial pneumonia.  Since hemodialysis removes 30% to 40% of the administered dose, an additional dose of 0.75 g piperacillin and tazobactam for injection (0.67 g piperacillin/0.08 g tazobactam) should be administered following each dialysis period on hemodialysis days.  No additional dosage of piperacillin and tazobactam for injection is necessary for CAPD patients.

  2.4 Pediatric Patients

  For children with appendicitis and/or peritonitis 9 months of age or older, weighing up to 40 kg, and with normal renal function, the recommended piperacillin and tazobactam for injection dosage is 100 mg piperacillin/12.5 mg tazobactam per kilogram of body weight, every 8 hours.  For pediatric patients between 2 months and 9 months of age, the recommended piperacillin and tazobactam for injection dosage based on pharmacokinetic modeling, is 80 mg piperacillin/10 mg tazobactam per kilogram of body weight, every 8 hours [see Use in Specific Populations (8.4) and Clinical Pharmacology (12.3)].  Pediatric patients weighing over 40 kg and with normal renal function should receive the adult dose.  It has not been determined how to adjust piperacillin and tazobactam for injection dosage in pediatric patients with renal impairment.

  2.5 Reconstitution and Dilution of Powder Formulations

  Pharmacy Bulk Package Bottles

  Reconstituted stock solution must be transferred and further diluted for intravenous infusion.

  The pharmacy bulk package bottle is for use in a hospital pharmacy admixture service only under a laminar flow hood.  After reconstitution, entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and contents should be dispensed as aliquots into intravenous solution using aseptic technique.  Use entire contents of pharmacy bulk package bottle promptly.  Discard unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F), or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Reconstitute the pharmacy bulk package bottle with exactly 152 mL of a compatible reconstitution diluent, listed below, to a concentration of 200 mg/mL of piperacillin and 25 mg/mL of tazobactam.  Shake well until dissolved.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to and during administration whenever solution and container permit.

  Compatible Reconstitution Diluents for Pharmacy Bulk Bottles 0.9% Sodium chloride for injectionSterile water for injection‡ Dextrose 5%Bacteriostatic saline/parabensBacteriostatic water/parabensBacteriostatic saline/benzyl alcoholBacteriostatic water/benzyl alcohol

  Reconstituted piperacillin and tazobactam for injection solution should be further diluted (recommended volume per dose of 50 mL to 150 mL) in a compatible intravenous solution listed below.  Administer by infusion over a period of at least 30 minutes.  During the infusion it is desirable to discontinue the primary infusion solution.

  Compatible Intravenous Solutions for Pharmacy Bulk Package Bottles and Single Dose Vials 0.9% Sodium chloride for injectionSterile water for injection‡ Dextran 6% in salineDextrose 5%

  LACTATED RINGER’S SOLUTION IS NOT COMPATIBILE WITH PIPERACILLIN AND TAZOBACTAM FOR INJECTION.

  ‡ Maximum recommended volume per dose of sterile water for injection is 50 mL.

  Piperacillin and tazobactam for injection should not be mixed with other drugs in a syringe or infusion bottle since compatibility has not been established.

  Piperacillin and tazobactam for injection is not chemically stable in solutions that contain only sodium bicarbonate and solutions that significantly alter the pH.

  Piperacillin and tazobactam for injection should not be added to blood products or albumin hydrolysates.

  Parenteral drug products should be inspected visually for particulate matter or discoloration prior to administration, whenever solution and container permit.

  Stability of Piperacillin and Tazobactam for Injection Powder Formulations Following Reconstitution

  Piperacillin and tazobactam for injection reconstituted from pharmacy bulk package bottles is stable in glass and plastic containers (plastic syringes, I.V. bags and tubing) when used with compatible diluents.  The pharmacy bulk package bottle should NOT be frozen after reconstitution.  Discard unused portions after storage for 24 hours at room temperature or after storage for 48 hours at refrigerated temperature 2°C to 8°C (36°F to 46°F).

  Pharmacy bulk package bottles should be used immediately after reconstitution.  Discard any unused portion after 24 hours if stored at room temperature 20°C to 25°C (68°F to 77°F),  or after 48 hours if stored at refrigerated temperature 2°C to 8°C (36°F to 46°F).  Pharmacy bulk package bottles should not be frozen after reconstitution.

  Stability studies in the I.V. bags have demonstrated chemical stability (potency, pH of reconstituted solution and clarity of solution) for up to 24 hours at room temperature and up to one week at refrigerated temperature.  Piperacillin and tazobactam for injection contains no preservatives.  Appropriate consideration of aseptic technique should be used.

  Piperacillin and tazobactam for injection reconstituted from bulk package bottles can be used in ambulatory intravenous infusion pumps.  Stability of piperacillin and tazobactam for injection in an ambulatory intravenous infusion pump has been demonstrated for a period of 12 hours at room temperature.  Each dose was reconstituted and diluted to a volume of 37.5 mL or 25 mL.  One-day supplies of dosing solution were aseptically transferred into the medication reservoir (I.V. bags or cartridge).  The reservoir was fitted to a preprogrammed ambulatory intravenous infusion pump per the manufacturer's instructions.  Stability of piperacillin and tazobactam for injection is not affected when administered using an ambulatory intravenous infusion pump.

  2.6 Compatibility with Aminoglycosides

  Due to the in vitro inactivation of aminoglycosides by piperacillin, piperacillin and tazobactam for injection and aminoglycosides are recommended for separate administration.  Piperacillin and tazobactam for injection and aminoglycosides should be reconstituted, diluted, and administered separately when concomitant therapy with aminoglycosides is indicated [see Drug Interactions (7.1)].

  In circumstances where co-administration via Y-site is necessary, piperacillin and tazobactam is compatible for simultaneous coadministration via Y-site infusion only with the following aminoglycosides under the following conditions:

  Table 2: Compatibility with Aminoglycosides

  Aminoglycoside

  Piperacillin and Tazobactam Dose (grams)

  Piperacillin and Tazobactam Diluent Volume (mL)

  Aminoglycoside Concentration Rangea (mg/mL)

  Acceptable Diluents

  Amikacin

  2.25, 3.375, 4.5

  50, 100, 150

  1.75 – 7.5

  0.9% sodium chloride or 5% dextrose

  Gentamicin

  2.25, 3.375, 4.5

  50, 100 150

  0.7 – 3.32

  0.9% sodium chloride or 5% dextrose

  aThe concentration ranges in Table 2 are based on administration of the aminoglycoside in divided doses (10-15 mg/kg/day in two daily doses for amikacin and 3-5 mg/kg/day in three daily doses for gentamicin).  Administration of amikacin or gentamicin in a single daily dose or in doses exceeding those stated above via Y-site with piperacillin and tazobactam has not been evaluated.  See package insert for each aminoglycoside for complete Dosage and Administration instructions.

  Only the concentration and diluents for amikacin or gentamicin with the dosages of piperacillin and tazobactam for injection listed above have been established as compatible for coadministration via Y-site infusion.  Simultaneous coadministration via Y-site infusion in any manner other than listed above may result in inactivation of the aminoglycoside by piperacillin and tazobactam.

  Piperacillin and tazobactam for injection is not compatible with tobramycin for simultaneous coadministration via Y-site infusion.  Compatibility of piperacillin and tazobactam with other aminoglycosides has not been established.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Methotrexate
  

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  Methotrexate

  

  ---

  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate Injection, USP may be given by the intramuscular, intravenous or the intra-arterial route.  The preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high-dose therapy.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area:

  AGE (years)

  DOSE (mg)

          <  1

         6

              1

         8

              2

        10

        3 or older

        12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity.  Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.          

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity. Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced or discontinued.  Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases.  Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis fungoides (cutaneous T cell lymphoma)

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion (starting dose)

  4,5,6,7,11,12,15, 16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

  _ _ _

  Doxorubicin† as a

  single drug

  30 mg/m2/day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin†

  Cyclophosphamide†

  Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x  2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

  *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

  †See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

  When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

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• Esmolol Hydrochloride
  

  ×

  Esmolol Hydrochloride

  

  ---

  2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia

  Esmolol hydrochloride is administered by continuous intravenous infusion with or without a loading dose.  Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response.

                    Table 1: Step-Wise Dosing

  Step

  Action

  1

  Optional loading dose (500 mcg per kg over 1 minute), then

  50 mcg per kg per min for 4 min

  2

  Optional loading dose if necessary, then 100 mcg per kg

  per min for 4 min

  3

  Optional loading dose if necessary, then 150 mcg per kg

  per min for 4 min

  4

  If necessary increase dose to 200 mcg per kg per min

  In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.

  The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate.  Dosages greater than 200 mcg per kg per minute provide little added heart-rate lowering effect, and the rate of adverse reactions increases.

  Maintenance infusions may be continued for up to 48 hours.

  2.2 Intraoperative and Postoperative Tachycardia and Hypertension

  In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control.

  Immediate Control

  Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary. Adjust the infusion rate as required to maintain desired heart rate and blood pressure.  Refer to Maximum Recommended Doses below.

  Gradual Control

  Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes. Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia.  Refer to Maximum Recommended Doses below.

  Maximum Recommended Doses

  For the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases. For the treatment of hypertension, higher maintenance infusion dosages (250 to 300 mcg per kg per min) may be required.  The safety of doses above 300 mcg per kg per minute has not been studied.

  2.3 Transition from Esmolol Hydrochloride Injection Therapy to Alternative Drugs

  After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished.

  When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows:

  Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%). After administration of the second dose of the alternative agent, monitor the patient’s response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion.

  2.4 Directions for Use

  Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Esmolol hydrochloride injection is recommended for intravenous administration.  It may be used to administer the appropriate loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2)].

  Compatibility with Commonly Used Intravenous Fluids

  Esmolol hydrochloride injection was tested for compatibility with 10 commonly used intravenous fluids at a final concentration of 10 mg esmolol hydrochloride per mL.  Esmolol hydrochloride injection was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:

  Dextrose (5%) Injection, USP Dextrose (5%) in Lactated Ringer’s Injection Dextrose (5%) in Ringer’s Injection Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP Lactated Ringer’s Injection, USP Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP Sodium Chloride (0.45%) Injection, USP Sodium Chloride (0.9%) Injection, USP

  2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia

  Esmolol hydrochloride is administered by continuous intravenous infusion with or without a loading dose.  Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response.

                    Table 1: Step-Wise Dosing

  Step

  Action

  1

  Optional loading dose (500 mcg per kg over 1 minute), then

  50 mcg per kg per min for 4 min

  2

  Optional loading dose if necessary, then 100 mcg per kg

  per min for 4 min

  3

  Optional loading dose if necessary, then 150 mcg per kg

  per min for 4 min

  4

  If necessary increase dose to 200 mcg per kg per min

  In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.

  The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate.  Dosages greater than 200 mcg per kg per minute provide little added heart-rate lowering effect, and the rate of adverse reactions increases.

  Maintenance infusions may be continued for up to 48 hours.

  2.2 Intraoperative and Postoperative Tachycardia and Hypertension

  In this setting it is not always advisable to slowly titrate to a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control.

  Immediate Control

  Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary. Adjust the infusion rate as required to maintain desired heart rate and blood pressure.  Refer to Maximum Recommended Doses below.

  Gradual Control

  Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes. Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia.  Refer to Maximum Recommended Doses below.

  Maximum Recommended Doses

  For the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases. For the treatment of hypertension, higher maintenance infusion dosages (250 to 300 mcg per kg per min) may be required.  The safety of doses above 300 mcg per kg per minute has not been studied.

  2.3 Transition from Esmolol Hydrochloride Injection Therapy to Alternative Drugs

  After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished.

  When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows:

  Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%). After administration of the second dose of the alternative agent, monitor the patient’s response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion.

  2.4 Directions for Use

  Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Esmolol hydrochloride injection is recommended for intravenous administration.  It may be used to administer the appropriate loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2)].

  Compatibility with Commonly Used Intravenous Fluids

  Esmolol hydrochloride injection was tested for compatibility with 10 commonly used intravenous fluids at a final concentration of 10 mg esmolol hydrochloride per mL.  Esmolol hydrochloride injection was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:

  Dextrose (5%) Injection, USP Dextrose (5%) in Lactated Ringer’s Injection Dextrose (5%) in Ringer’s Injection Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP Lactated Ringer’s Injection, USP Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP Sodium Chloride (0.45%) Injection, USP Sodium Chloride (0.9%) Injection, USP

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• Indomethacin
  

  ×

  Indomethacin

  

  ---

  For intravenous administration only.

  Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy.  A course of therapy is defined as three intravenous doses of Indomethacin for Injection given at 12 to 24 hour intervals, with careful attention to urinary output.  If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Indomethacin for Injection, do not give additional doses until laboratory studies indicate that renal function has returned to normal [see Warnings and Precautions (5.7)].

  Dosage according to age is as follows:

  AGE at 1stdose

  DOSAGE (mg/kg)

   

  Less than 48 hours

  1st

  0.2

  2nd

  0.1

  3rd

  0.1

  2 to 7 days

  0.2

  0.2

  0.2

  Over 7 days

  0.2

  0.25

  0.25

  If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course of Indomethacin for Injection, no further doses are necessary.  If the ductus arteriosus re-opens, a second course of 1 to 3 doses may be given, each dose separated by a 12 to 24 hour interval as described above.

  If the neonate remains unresponsive to therapy with Indomethacin for Injection after 2 courses, surgery may be necessary for closure of the ductus arteriosus.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

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• Potassium Phosphates
  

  ×

  Potassium Phosphates

  

  ---

  Potassium phosphates is administered intravenously only after dilution in a larger volume of fluid.  The dose and rate of administration are dependent upon the individual needs of the patient.  Serum potassium, inorganic phosphorus and calcium levels should be monitored as a guide to dosage.

  Withdraw the calculated volume aseptically and transfer to appropriate intravenous fluid to provide the desired number of millimoles (mmol) of phosphate and milliequivalent (mEq) of Potassium (K+).

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• Sodium Phosphates
  

  ×

  Sodium Phosphates

  

  ---

  Sodium Phosphates Injection is administered intravenously only after dilution and thorough mixing in a larger volume of fluid.  The dose and rate of administration are dependent upon the individual needs of the patient.  Serum sodium, inorganic phosphorus and calcium levels should be monitored as a guide to dosage.  Using aseptic technique, all or part of the contents of one or more vials may be added to other intravenous fluids to provide any desired number of millimoles of phosphate and milli-equivalents of sodium.

  In patients on TPN, approximately 10 to 15 mmol of phosphorus (equivalent to 310 to 465 mg elemental phosphorus) per liter bottle of TPN solution is usually adequate to maintain normal serum phosphate, though larger amounts may be required in hypermetabolic states.  The amount of sodium which accompanies the addition of phosphate also should be kept in mind, and if necessary, serum sodium levels should be monitored.

  The suggested dose of phosphorus for infants receiving TPN is 1.5 to 2 mmol/kg/day.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Gentamicin
  

  ×

  Gentamicin

  

  ---

  Gentamicin injection may be given IM or IV.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  PATIENTS WITH NORMAL RENAL FUNCTION

  Adults

  The recommended dosage of gentamicin injection for patients with serious infections and normal renal function is 3 mg/kg/day, administered in three equal doses every eight hours (Table I).

  For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses.  This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table I).

  It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage.  When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after IM injection) is expected to be in the range of 4 to 6 mcg/mL.  When monitoring peak concentrations after IM or IV administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  TABLE I

  DOSAGE SCHEDULE GUIDE

  FOR ADULTS WITH NORMAL

  RENAL FUNCTION

  (Dosage at Eight-Hour Intervals)

  40 mg per mL

  Patient’s

  Weight*

  Usual Dose for

  Serious

  Infections

  1 mg/kg q8h

  (3 mg/kg/day)

  Dose for

   Life-Threatening

  Infections (Reduce

  As Soon As

  Clinically Indicated)

  1.7 mg/kg q8h**

  (5 mg/kg/day)

  kg

  (lb)

  mg/dose

  mL/dose

  mg/dose

  mL/dose

  q8h

  q8h

  40

  ( 88 )

  40

  1

  66

  1.6

  45

  ( 99)

  45

  1.1

  75

  1.9

  50

  (110)

  50

  1.25

  83

  2.1

  55

  (121)

  55

  1.4

  91

  2.25

  60

  (132)

  60

  1.5

  100

  2.5

  65

  (143)

  65

  1.6

  108

  2.7

  70

  (154)

  70

  1.75

  116

  2.9

  75

  (165)

  75

  1.9

  125

  3.1

  80

  (176)

  80

  2

  133

  3.3

  85

  (187)

  85

  2.1

  141

  3.5

  90

  (198)

  90

  2.25

  150

  3.75

  95

  (209)

  95

  2.4

  158

  4

  100

  (220)

  100

  2.5

  166

  4.2

   

  *  The dosage of aminoglycosides in obese patients should be based on

      an estimate of the lean body mass.

  **for q6h schedules, dosage should be recalculated.

   

  Children

  6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered every eight hours).

  Infants and Neonates

  7.5 mg/kg/day (2.5 mg/kg administered every eight hours).

  Premature or Full-Term Neonates One Week of Age or Less

  5 mg/kg/day (2.5 mg/kg administered every 12 hours).

  For further information concerning the use of gentamicin in infants and children, see gentamicin injection (pediatric) product information.

  The usual duration of treatment for all patients is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  FOR INTRAVENOUS ADMINISTRATION

  The IV administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns or those with reduced muscle mass.  For intermittent IV administration in adults, a single dose of gentamicin injection may be diluted in 50 to 200 mL of sterile isotonic saline solution or in a sterile solution of dextrose 5% in water; in infants and children, the volume of diluent should be less.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for IM and IV administration is identical.

  Gentamicin injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule. 

  PATIENTS WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels.  Whenever possible serum concentration of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table II).  For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.

  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

  TABLE II

  DOSAGE ADJUSTMENT GUIDE

  FOR PATIENTS WITH RENAL IMPAIRMENT

  (Dosage at Eight-Hour Intervals

  After the Usual Initial Dose)

  Serum

  Creatinine

  (mg %)

  Approximate

  Creatinine

  Clearance Rate

  (mL/min/1.73m2)

  Percent of

  Usual Doses

  (Shown in Table 1)

  ≤ 1

  > 100

  100

  1.1 to 1.3

  70 to 100

  80

  1.4 to 1.6

  55 to 70

  65

  1.7 to 1.9

  45 to 55

  55

  2 to 2.2

  40 to 45

  50

  2.3 to 2.5

  35 to 40

  40

  2.6 to 3

  30 to 35

  35

  3.1 to 3.5

  25 to 30

  30

  3.6 to 4

  20 to 25

  25

  4.1 to 5.1

  15 to 20

  20

  5.2 to 6.6

  10 to 15

  15

  6.7 to 8

  < 10

  10

  In adults with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  The recommended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of the infection.  In children, a dose of 2 mg/kg may be administered.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when measurement of gentamicin serum level is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Cisplatin
  

  ×

  Cisplatin

  

  ---

  Cisplatin is administered by slow intravenous infusion.  CISPLATIN SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.  

  Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin should not be used for preparation or administration.  Aluminum reacts with cisplatin, causing precipitate formation and a loss of potency.

  Metastatic Testicular Tumors

  The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.

  Metastatic Ovarian Tumors

  The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1).

  The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m2 IV once every 4 weeks (DAY 1).

  For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

  In combination therapy, cisplatin and cyclophosphamide are administered sequentially.

  As a single agent, cisplatin should be administered at a dose of 100 mg/m2 IV per cycle once every 4 weeks.

  Advanced Bladder Cancer

  Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy.  For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.

  All Patients

  Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended.  The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period.  If diluted solution is not to be used within 6 hours, protect solution from light.  Do not dilute cisplatin in just 5% Dextrose Injection.  Adequate hydration and urinary output must be maintained during the following 24 hours.

  A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL.  A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm3, WBC ≥ 4,000/mm3).   Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

  Preparation of Intravenous Solutions

  Preparation Precautions

  Caution should be exercised in handling the aqueous solution.  Procedures for proper handling and disposal of anticancer drugs should be utilized.  Several guidelines on this subject have been published.1-4   To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin.

  Skin reactions associated with accidental exposure to cisplatin may occur.  The use of gloves is recommended.  If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.  More information is available in the references listed below.

  Instructions for Preparation

  The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage.  Please call prescriber if dose is greater than 100 mg/m2 per cycle.  Aluminum and flip-off seal of vial have been imprinted with the following statement:

  CALL DR. IF DOSE > 100 MG/M2/CYCLE.

  Stability

  Cisplatin is a sterile, multiple dose vial without preservatives.

  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Do not refrigerate.  Protect unopened container from light.

  The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

  Metastatic Testicular Tumors

  The usual cisplatin dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.

  Metastatic Ovarian Tumors

  The usual cisplatin dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75 to 100 mg/m2 IV per cycle once every 4 weeks (DAY 1).

  The dose of cyclophosphamide when used in combination with cisplatin is 600 mg/m2 IV once every 4 weeks (DAY 1).

  For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

  In combination therapy, cisplatin and cyclophosphamide are administered sequentially.

  As a single agent, cisplatin should be administered at a dose of 100 mg/m2 IV per cycle once every 4 weeks.

  Advanced Bladder Cancer

  Cisplatin should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy.  For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.

  All Patients

  Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin dose is recommended.  The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6- to 8-hour period.  If diluted solution is not to be used within 6 hours, protect solution from light.  Do not dilute cisplatin in just 5% Dextrose Injection.  Adequate hydration and urinary output must be maintained during the following 24 hours.

  A repeat course of cisplatin should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL.  A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥ 100,000/mm3, WBC ≥ 4,000/mm3).   Subsequent doses of cisplatin should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.

  Preparation of Intravenous Solutions

  Preparation Precautions

  Caution should be exercised in handling the aqueous solution.  Procedures for proper handling and disposal of anticancer drugs should be utilized.  Several guidelines on this subject have been published.1-4   To minimize the risk of dermal exposure, always wear impervious gloves when handling vials and IV sets containing cisplatin.

  Skin reactions associated with accidental exposure to cisplatin may occur.  The use of gloves is recommended.  If cisplatin contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.  More information is available in the references listed below.

  Instructions for Preparation

  The aqueous solution should be used intravenously only and should be administered by IV infusion over a 6- to 8-hour period (see DOSAGE AND ADMINISTRATION).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  NOTE TO PHARMACIST: Exercise caution to prevent inadvertent cisplatin overdosage.  Please call prescriber if dose is greater than 100 mg/m2 per cycle.  Aluminum and flip-off seal of vial have been imprinted with the following statement:

  CALL DR. IF DOSE > 100 MG/M2/CYCLE.

  Stability

  Cisplatin is a sterile, multiple dose vial without preservatives.

  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Do not refrigerate.  Protect unopened container from light.

  The cisplatin remaining in the amber vial following initial entry is stable for 28 days protected from light or for 7 days under fluorescent room light.

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• Doxorubicin Hydrochlori...
  

  ×

  Doxorubicin Hydrochloride

  

  ---

  When possible, to reduce the risk of developing cardiotoxicity in patients receiving doxorubicin after stopping treatment with other cardiotoxic agents, especially those with long half-lives sch as trastuzumab, doxorubicin-based therapy should be delayed until the other agents have cleared from the circulation (see WARNINGS  and PRECAUTIONS,  General).

  Care in the administration of doxorubicin will reduce the chance of perivenous infiltration (see WARNINGS).  It may also decrease the chance of local reactions such as urticaria and erythematous streaking.  On intravenous administration of doxorubicin, extravasation may occur with or without an accompanying burning or stinging sensation, even if blood returns well on aspiration of the infusion needle.  If any signs or symptoms of extravasation have occurred, the injection or infusion should be immediately terminated and restarted in another vein.  If extravasation is suspected, intermittent application of ice to the site for 15 min. q.i.d. x 3 days may be useful.  The benefit of local administration of drugs has not been clearly established.  Because of the progressive nature of extravasation reactions, close observation and plastic surgery consultation is recommended.  Blistering, ulceration and/or persistent pain are indications for wide excision surgery, followed by split-thickness skin grafting.

  The most commonly used dose schedule when used as a single agent is 60 to 75 mg/m2 as a single intravenous injection administered at 21-day intervals.  The lower dosage should be given to patients with inadequate marrow reserves due to old age, or prior therapy, or neoplastic marrow infiltration.

  Doxorubicin has been used concurrently with other approved chemotherapeutic agents.  Evidence is available that in some types of neoplastic disease, combination chemotherapy is superior to single agents.  The benefits and risks of such therapy continue to be elucidated.  When used in combination with other chemotherapy drugs, the most commonly used dosage of doxorubicin is 40 to 60 mg/m2 given as a single intravenous injection every 21 to 28 days.

  In a large randomized study (NSABP B-15) of patients with early breast cancer involving axillary lymph nodes (see CLINICAL PHARMACOLOGY, CLINICAL STUDIES and ADVERSE REACTIONS, Adverse Reactions in Patients with Early Breast Cancer Receiving Doxorubicin-Containing Adjuvant Therapy), the combination dosage regimen of AC (doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2) was administered intravenously on day 1 of each 21-day treatment cycle.  Four cycles of treatment were administered.

  Dose Modifications

  Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection.  When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥ 1000 cells/mm3 and the platelet count was ≥ 100,000 cells/mm3 and nonhematologic toxicities had resolved.

  Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:

             Plasma bilirubin concentration (mg/dL)           

  Dosage reduction (%)

  1.2 to 3

  50

  3.1 to 5

  75

  Reconstitution Directions

  It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly® needle inserted preferably into a large vein.  If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.  The rate of administration is dependent on the size of the vein and the dosage.  However, the dose should be administered in not less than 3 to 5 minutes.  Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration.  A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein.  Perivenous infiltration may occur painlessly.

  Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form.  Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin.  Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Handling and Disposal

  Procedures for proper handling and disposal of anti-cancer drugs should be considered.  Several guidelines on this subject have been published.1-4  There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.  However, given the toxic nature of this substance, the following protective recommendations are provided:

  Personnel should be trained in good technique for reconstitution and handling. Pregnant staff should be excluded from working with this drug. Personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks. A designated area should be defined for reconstitution (preferably under a laminar flow system).  The work surface should be protected by disposable, plastic-backed, absorbent paper. All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as indicated previously. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution.  However, do not abrade the skin by using a scrub brush. In case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes.  Then seek medical evaluation by a physician. Always wash hands after removing gloves.

  Caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for at least 5 days after each treatment.

  Dose Modifications

  Patients in the NSABP B-15 study could have dose modifications of AC to 75% of the starting doses for neutropenic fever/infection.  When necessary, the next cycle of treatment cycle was delayed until the absolute neutrophil count (ANC) was ≥ 1000 cells/mm3 and the platelet count was ≥ 100,000 cells/mm3 and nonhematologic toxicities had resolved.

  Doxorubicin dosage must be reduced in case of hyperbilirubinemia as follows:

             Plasma bilirubin concentration (mg/dL)           

  Dosage reduction (%)

  1.2 to 3

  50

  3.1 to 5

  75

  Reconstitution Directions

  It is recommended that doxorubicin be slowly administered into the tubing of a freely running intravenous infusion of Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly® needle inserted preferably into a large vein.  If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.  The rate of administration is dependent on the size of the vein and the dosage.  However, the dose should be administered in not less than 3 to 5 minutes.  Local erythematous streaking along the vein as well as facial flushing may be indicative of too rapid an administration.  A burning or stinging sensation may be indicative of perivenous infiltration and, if this occurs, the infusion should be immediately terminated and restarted in another vein.  Perivenous infiltration may occur painlessly.

  Doxorubicin should not be mixed with heparin or fluorouracil since it has been reported that these drugs are incompatible to the extent that a precipitate may form.  Contact with alkaline solutions should be avoided since this can lead to hydrolysis of doxorubicin.  Until specific compatibility data are available, it is not recommended that doxorubicin be mixed with other drugs.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Handling and Disposal

  Procedures for proper handling and disposal of anti-cancer drugs should be considered.  Several guidelines on this subject have been published.1-4  There is no general agreement that all the procedures recommended in the guidelines are necessary or appropriate.  However, given the toxic nature of this substance, the following protective recommendations are provided:

  Personnel should be trained in good technique for reconstitution and handling. Pregnant staff should be excluded from working with this drug. Personnel handling doxorubicin should wear protective clothing: goggles, gowns and disposable gloves and masks. A designated area should be defined for reconstitution (preferably under a laminar flow system).  The work surface should be protected by disposable, plastic-backed, absorbent paper. All items used for reconstitution, administration or cleaning, including gloves, should be placed in high-risk waste-disposal bags for high-temperature incineration. Spillage or leakage should be treated with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. All cleaning materials should be disposed of as indicated previously. In case of skin contact, thoroughly wash the affected area with soap and water or sodium bicarbonate solution.  However, do not abrade the skin by using a scrub brush. In case of contact with the eye(s), hold back the eyelid(s) and flush the affected eye(s) with copious amounts of water for at least 15 minutes.  Then seek medical evaluation by a physician. Always wash hands after removing gloves.

  Caregivers of pediatric patients receiving doxorubicin should be counseled to take precautions (such as wearing latex gloves) to prevent contact with the patient’s urine and other body fluids for at least 5 days after each treatment.

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• Magnesium Sulfate
  

  ×

  Magnesium Sulfate

  

  ---

  Dosage of magnesium sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

  Both IV and IM administration are appropriate.  IM administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a therapeutic level almost immediately.  The rate of IV injection should generally not exceed 150 mg/minute, except in severe eclampsia with seizures (see below).  Continuous maternal administration of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Solutions for IV infusion must be diluted to a concentration of 20% or less prior to administration.  The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP.  Deep IM injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-Eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-Eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Gentamicin
  

  ×

  Gentamicin

  

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  Gentamicin injection may be given IM or IV.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  PATIENTS WITH NORMAL RENAL FUNCTION

  Adults

  The recommended dosage of gentamicin injection for patients with serious infections and normal renal function is 3 mg/kg/day, administered in three equal doses every eight hours (Table I).

  For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses.  This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table I).

  It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage.  When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after IM injection) is expected to be in the range of 4 to 6 mcg/mL.  When monitoring peak concentrations after IM or IV administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  TABLE I

  DOSAGE SCHEDULE GUIDE

  FOR ADULTS WITH NORMAL

  RENAL FUNCTION

  (Dosage at Eight-Hour Intervals)

  40 mg per mL

  Patient’s

  Weight*

  Usual Dose for

  Serious

  Infections

  1 mg/kg q8h

  (3 mg/kg/day)

  Dose for

   Life-Threatening

  Infections (Reduce

  As Soon As

  Clinically Indicated)

  1.7 mg/kg q8h**

  (5 mg/kg/day)

  kg

  (lb)

  mg/dose

  mL/dose

  mg/dose

  mL/dose

  q8h

  q8h

  40

  ( 88)

  40

  1

  66

  1.6

  45

  ( 99)

  45

  1.1

  75

  1.9

  50

  (110)

  50

  1.25

  83

  2.1

  55

  (121)

  55

  1.4

  91

  2.25

  60

  (132)

  60

  1.5

  100

  2.5

  65

  (143)

  65

  1.6

  108

  2.7

  70

  (154)

  70

  1.75

  116

  2.9

  75

  (165)

  75

  1.9

  125

  3.1

  80

  (176)

  80

  2

  133

  3.3

  85

  (187)

  85

  2.1

  141

  3.5

  90

  (198)

  90

  2.25

  150

  3.75

  95

  (209)

  95

  2.4

  158

  4

  100

  (220)

  100

  2.5

  166

  4.2

   

  *  The dosage of aminoglycosides in obese patients should be based on

      an estimate of the lean body mass.

  **for q6h schedules, dosage should be recalculated.

   

  Children

  6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered every eight hours).

  Infants and Neonates

  7.5 mg/kg/day (2.5 mg/kg administered every eight hours).

  Premature or Full-Term Neonates One Week of Age or Less

  5 mg/kg/day (2.5 mg/kg administered every 12 hours).

  For further information concerning the use of gentamicin in infants and children, see gentamicin injection (pediatric) product information.

  The usual duration of treatment for all patients is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  FOR INTRAVENOUS ADMINISTRATION

  The IV administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns or those with reduced muscle mass.  For intermittent IV administration in adults, a single dose of gentamicin injection may be diluted in 50 to 200 mL of sterile isotonic saline solution or in a sterile solution of dextrose 5% in water; in infants and children, the volume of diluent should be less.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for IM and IV administration is identical.

  Gentamicin injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule. 

  PATIENTS WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels.  Whenever possible serum concentration of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table II).  For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.

  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

  TABLE II

  DOSAGE ADJUSTMENT GUIDE

  FOR PATIENTS WITH RENAL IMPAIRMENT

  (Dosage at Eight-Hour Intervals

  After the Usual Initial Dose)

  Serum

  Creatinine

  (mg %)

  Approximate

  Creatinine

  Clearance Rate

  (mL/min/1.73m2)

  Percent of

  Usual Doses

  (Shown in Table I)

  ≤ 1

  > 100

  100

  1.1 to 1.3

  70 to 100

  80

  1.4 to 1.6

  55 to 70

  65

  1.7 to 1.9

  45 to 55

  55

  2 to 2.2

  40 to 45

  50

  2.3 to 2.5

  35 to 40

  40

  2.6 to 3

  30 to 35

  35

  3.1 to 3.5

  25 to 30

  30

  3.6 to 4

  20 to 25

  25

  4.1 to 5.1

  15 to 20

  20

  5.2 to 6.6

  10 to 15

  15

  6.7 to 8

  < 10

  10

  In adults with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  The recommended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of the infection.  In children, a dose of 2 mg/kg may be administered.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when measurement of gentamicin serum level is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Seconal Sodium
  

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  Seconal Sodium

  

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  Adults

  The dosage recommendations for imipenem and cilastatin for injection (I.V.) represent the quantity of imipenem to be administered. An equivalent amount of cilastatin is also present in the solution. Each 125 mg, 250 mg, or 500 mg dose should be given by intravenous administration over 20 to 30 minutes. Each 750 mg or 1000 mg dose should be infused over 40 to 60 minutes. In patients who develop nausea during the infusion, the rate of infusion may be slowed.

  The total daily dosage for imipenem and cilastatin for injection (I.V.) should be based on the type or severity of infection and given in equally divided doses based on consideration of degree of susceptibility of the pathogen(s), renal function, and body weight. Adult patients with impaired renal function, as judged by creatinine clearance ≤ 70 mL/min/1.73 m2, require adjustment of dosage as described in the succeeding section of these guidelines.

  Intravenous Dosage Schedule for Adults with Normal Renal Function and Body Weight ≥ 70 kg

  Doses cited in Table 3 are based on a patient with normal renal function and a body weight of 70 kg. These doses should be used for a patient with a creatinine clearance of ≥ 71 mL/min/1.73 m2 and a body weight of ≥ 70 kg. A reduction in dose must be made for a patient with a creatinine clearance of ≤ 70 mL/min/1.73 m2 and/or a body weight less than 70 kg. (see Tables 4 and 5).

  Dosage regimens in column A of Table 3 are recommended for infections caused by fully susceptible organisms which represent the majority of pathogenic species. Dosage regimens in column B of Table 3 are recommended for infections caused by organisms with moderate susceptibility to imipenem, primarily some strains of P. aeruginosa.

  TABLE 3

  INTRAVENOUS DOSAGE SCHEDULE FOR ADULTS WITH NORMAL RENAL FUNCTION AND BODY WEIGHT ≥ 70 kg

  Type orSeverityof Infection AFully susceptible organisms includinggram-positive and gram-negativeaerobes and anaerobes BModerately susceptible organisms, primarily some strains of P. aeruginosa Mild 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) 500 mg q 6 h(TOTAL DAILY DOSE = 2 g) Moderate 500 mg q 8 h(TOTAL DAILY DOSE = 1.5 g)or500 mg q 6 h(TOTAL DAILY DOSE = 2 g)  500 mg q 6 h(TOTAL DAILY DOSE = 2 g)or1 g q 8 h(TOTAL DAILY DOSE = 3 g) Severe, life threatening only 500 mg q 6 h(TOTAL DAILY DOSE = 2 g) 1 g q 8 h(TOTAL DAILY DOSE = 3 g)or1 g q 6 h(TOTAL DAILY DOSE = 4 g)  Uncomplicated urinary tract infection 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) 250 mg q 6 h(TOTAL DAILY DOSE = 1 g) Complicated urinary tract infection  500 mg q 6 h(TOTAL DAILY DOSE = 2 g) 500 mg q 6 h(TOTAL DAILY DOSE = 2 g)

  Due to the high antimicrobial activity of imipenem and cilastatin for injection (I.V.), it is recommended that the maximum total daily dosage not exceed 50 mg/kg/day or 4 g/day, whichever is lower. There is no evidence that higher doses provide greater efficacy. However, patients over twelve years of age with cystic fibrosis and normal renal function have been treated with imipenem and cilastatin for injection (I.V.) at doses up to 90 mg/kg/day in divided doses, not exceeding 4 g/day.

  Reduced Intravenous Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg

   Patients with creatinine clearance of ≤ 70 mL/min/1.73 m2 and/or body weight less than 70 kg require dosage reduction of imipenem and cilastatin for injection (I.V.) as indicated in the tables below. Creatinine clearance may be calculated from serum creatinine concentration by the following equation:

  To determine the dose for adults with impaired renal function and/or reduced body weight:

  Choose a total daily dose from Table 3 based on infection characteristics. a) If the total daily dose is 1 g, 1.5 g, or 2 g, use the appropriate subsection of Table 4 and continue with step 3. b) If the total daily dose is 3 g or 4 g, use the appropriate subsection of Table 5 and continue with step 3. From Table 4 or 5:a) Select the body weight on the far left which is closest to the patient's body weight (kg).b) Select the patient's creatinine clearance category.c) Where the row and column intersect is the reduced dosage regimen.   

   

  TABLE 4 REDUCED INTRAVENOUS DOSAGE OF IMIPENEM AND CILASTATIN FOR INJECTION (I.V.) IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg  

  If TOTAL DAILY DOSE from TABLE 3 is: And Body Weight (kg) is: 1 g/ day 1.5 g/day 2 g/day and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: ≥ 70 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 500 q 8 h 250 q 6 h 250 q 8 h 250 q 12 h 500 q 6 h 500 q 8 h 250 q 6 h 250 q 12 h 60 250 q 8 h 125 q 6 h 250 q 12 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 8 h 250 q 12 h 500 q 8 h 250 q 6 h 250 q 8 h 250 q 12 h 50 125 q 6 h 125 q 6 h 125 q 8 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 250 q 6 h 250 q 6 h 250 q 8 h 250 q 12 h 40 125 q 6 h 125 q 8 h 125 q 12 h 125 q 12 h 250 q 8 h 125 q 6 h 125 q 8 h 125 q 12 h 250 q 6 h 250 q 8 h 250 q 12 h 250 q 12 h 30 125 q 8 h 125 q 8 h 125 q 12 h 125 q 12 h 125 q 6 h 125 q 8 h 125 q 8 h 125 q 12 h 250 q 8 h 125 q 6 h 125 q 8 h 125 q 12 h

  TABLE 5 REDUCED INTRAVENOUS DOSAGE OF IMIPENEM AND CILASTATIN FOR INJECTION (I.V.) IN ADULT PATIENTS WITH IMPAIRED RENAL FUNCTION AND/OR BODY WEIGHT < 70 kg

  If TOTAL DAILY DOSE from TABLE 3 is: And Body Weight(kg)is: 3 g/ day 4 g/day and creatinine clearance (mL/min/1.73 m2) is: and creatinine clearance (mL/min/1.73 m2) is: ≥ 71 41 to 70 21 to 40 6 to 20 ≥ 71 41 to 70 21 to 40 6 to 20 then the reduced dosage regimen (mg) is: then the reduced dosage regimen (mg) is: ≥ 70 1000q 8 h 500q 6 h 500q 8 h 500q 12 h 1000q 6 h 750q 8 h 500q 6 h 500q 12 h 60 750q 8 h 500q 8 h 500q 8 h 500q 12 h 1000q 8 h 750q 8 h 500q 8 h 500q 12 h 50 500q 6 h 500q 8 h 250q 6 h 250q 12 h 750q 8 h 500q 6 h 500q 8 h 500q 12 h 40 500q 8 h 250q 6 h 250q 8 h 250q 12 h 500q 6 h 500q 8 h 250q 6 h 250q 12 h 30 250q 6 h 250q 8 h 250q 8 h 250q 12 h 500q 8 h 250q 6 h 250q 8 h 250q 12 h

  Patients with creatinine clearances of 6 to 20 mL/min/1.73 m2 should be treated with imipenem and cilastatin for injection (I.V.) 125 mg or 250 mg every 12 hours for most pathogens. There may be an increased risk of seizures when doses of 500 mg every 12 hours are administered to these patients.

  Patients with creatinine clearance ≤ 5 mL/min/1.73 m2 should not receive imipenem and cilastatin for injection (I.V.) unless hemodialysis is instituted within 48 hours. There is inadequate information to recommend usage of imipenem and cilastatin for injection (I.V.) for patients undergoing peritoneal dialysis. Hemodialysis

  When treating patients with creatinine clearances of ≤ 5 mL/min/1.73 m2who are undergoing hemodialysis, use the dosage recommendations for patients with creatinine clearances of 6 to 20 mL/min/1.73 m2. (See Reduced Intravenous Dosage Schedule for Adults with Impaired Renal Function and/or Body Weight < 70 kg.) Both imipenem and cilastatin are cleared from the circulation during hemodialysis. The patient should receive imipenem and cilastatin for injection (I.V.) after hemodialysis and at 12 hour intervals timed from the end of that hemodialysis session.  Dialysis patients, especially those with background CNS disease, should be carefully monitored; for patients on hemodialysis, imipenem and cilastatin for injection (I.V.) is recommended only when the benefit outweighs the potential risk of seizures. (see PRECAUTIONS).

  Pediatric Patients

  See PRECAUTIONS, Pediatric Patients.

  For pediatric patients ≥ 3 months of age, the recommended dose for non-CNS infections is 15 to 25 mg/kg/dose administered every six hours. Based on studies in adults, the maximum daily dose for treatment of infections with fully susceptible organisms is 2 g per day, and of infections with moderately susceptible organisms (primarily some strains of P. aeruginosa) is 4 g/day. Higher doses (up to 90 mg/kg/day in older children) have been used in patients with cystic fibrosis.

  For pediatric patients ≤ 3 months of age (weighing ≥ 1,500 g), the following dosage schedule is recommended for non-CNS infections:

        < 1 wk of age: 25 mg/kg every 12 hrs       1 to 4 wks of age: 25 mg/kg every 8 hrs       4 wks to 3 mos. of age: 25 mg/kg every 6 hrs.

  Doses less than or equal to 500 mg should be given by intravenous infusion over 15 to 30 minutes. Doses greater than 500 mg should be given by intravenous infusion over 40 to 60 minutes.

  Imipenem and cilastatin for injection (I.V.) is not recommended in pediatric patients with CNS infections because of the risk of seizures.

  Imipenem and cilastatin for injection (I.V.) is not recommended in pediatric patients < 30 kg with impaired renal function, as no data are available.

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• Gentamicin
  

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  Gentamicin

  

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  Gentamicin Injection may be given intramuscularly or intravenously.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

  DOSAGE FOR PATIENTS

  WITH NORMAL RENAL FUNCTION

  Children: 6 to 7.5 mg/kg/day. (2 to 2.5 mg/kg administered every 8 hours).

  Infants and Neonates: 7.5 mg/kg/day. (2.5 mg/kg administered every 8 hours).

  Premature or Full-term Neonates One Week of Age or Less: 5 mg/kg/day. (2.5 mg/kg administered every 12 hours).

  It is desirable to measure periodically both peak and trough serum concentrations of gentamicin when feasible during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after intramuscular injection) is expected to be in the range of 3 to 5 mcg/mL.  When monitoring peak concentrations after intramuscular or intravenous administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided. Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection, and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

  The usual duration of treatment is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory, and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

  For Intravenous Administration

  The intravenous administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns, or those with reduced muscle mass.

  For intermittent intravenous administration, a single dose of Gentamicin Injection may be diluted in 0.9% Sodium Chloride Injection or in 5% Dextrose Injection.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for intravenous and intramuscular administration is identical.

  Gentamicin Injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule.

  DOSAGE FOR PATIENTS

  WITH IMPAIRED RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate but not excessive, blood levels.  Whenever possible, serum concentrations of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  In adults, the interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).  These guidelines may be considered when treating infants and children with serious renal impairment.

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.

  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 1).  For example, after an initial dose of 20 mg (2 mg/kg), a child weighing 10 kg with a serum creatinine level of 2 mg/100 mL could be given 10 mg every eight hours (20 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

  TABLE 1

  DOSAGE ADJUSTMENT GUIDE

  FOR PATIENTS WITH RENAL IMPAIRMENT

  (Dosage at Eight-Hour Intervals

  After the Usual Initial Dose)

  Serum

  Creatinine

  (mg %)

  Approximate

  Creatinine

  Clearance Rate

  (mL/min/1.73m2)

  Percent of

  Usual Doses

  Shown Above

    ≤ 1

            > 100

  100

  1.1 to 1.3

  70 to 100

  80

  1.4 to 1.6

  55 to 70

  65

  1.7 to 1.9

  45 to 55

  55

     2 to 2.2

  40 to 45

  50

  2.3 to 2.5

  35 to 40

  40

    2.6 to 3

  30 to 35

  35

  3.1 to 3.5

  25 to 30

  30

    3.6 to 4

  20 to 25

  25

  4.1 to 5.1

  15 to 20

  20

  5.2 to 6.6

  10 to 15

  15

     6.7 to 8

           < 10

  10

  In patients with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  In children, the recommended dose at the end of each dialysis period is 2 to 2.5 mg/kg depending upon the severity of the infection.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when the measurement of gentamicin serum levels is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Rejuvesol
  

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  Rejuvesol

  

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  2.1 Intravenous Dosing

  Mesna injection may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

  Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide.  The total daily dose of mesna injection is 60% of the ifosfamide dose.  The recommended dosing schedule is outlined below in Table 1.

  Table 1:  Recommended Intravenous Dosing Schedule

    0 Hours 4 Hours 8 Hours Ifosfamide 1.2 g/m2 - - Mesna Injection1 240 mg/m2 240 mg/m2 240 mg/m2

  1The dosing schedule should be repeated on each day that ifosfamide is administered.  When the dosage of ifosfamide is increased or decreased, the ratio of mesna injection to ifosfamide should be maintained.

  2.2 Intravenous and Oral Dosing

  Mesna injection may be given on a fractionated dosing schedule of a single bolus injection followed by two oral administrations of mesna tablets as outlined below.  Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage (w/w) at the time of ifosfamide administration.  Mesna tablets are given orally in a dosage equal to 40% of the ifosfamide dose 2 and 6 hours after each dose of ifosfamide.  The total daily dose of mesna is 100% of the ifosfamide dose.  The recommended dosing schedule is outlined in Table 2.

  Table 2:  Recommended Intravenous and Oral Dosing Schedule

    0 Hours 2 Hours 6 Hours Ifosfamide 1.2 g/m2 - - Mesna Injection1 240 mg/m2 - - Mesna Tablets - 480 mg/m2 480 mg/m2

  1The dosing schedule should be repeated on each day that ifosfamide is administered.  When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.The efficacy and safety of this ratio of intravenous and oral mesna has not been established as being effective for daily doses of ifosfamide higher than 2 g/m2. Patients who vomit within two hours of taking oral mesna should repeat the dose or receive intravenous mesna injection.

  2.3 Monitoring for Hematuria

  Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria.  If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

  2.4 Preparation for Intravenous Administration and Stability

  Preparation Determine the volume of mesna injection for the intended dose.  Dilute the volume of mesna injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:

  5% Dextrose Injection, USP 5% Dextrose and 0.2% Sodium Chloride Injection, USP 5% Dextrose and 0.33% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP 0.9% Sodium Chloride Injection, USP Lactated Ringer’s Injection, USP

  Stability The mesna injection multiple dose vials may be stored and used for up to 8 days after initial puncture. Store diluted solutions at 25°C (77°F).  Use diluted solutions within 24 hours. Do not mix mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard. The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide.  Ifosfamide and mesna injection may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL.  Higher concentrations of ifosfamide may not be compatible with mesna injection and may reduce the stability of ifosfamide.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.

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• Healthy Accents Naproxe...
  

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  Healthy Accents Naproxen Sodium

  

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  (see also WARNINGS).

  Multiple Sclerosis

  The recommended dosage of Mitoxantrone Injection, USP is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months.  Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Mitoxantrone Injection, USP and all subsequent doses.  In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Mitoxantrone Injection, USP.  Mitoxantrone Injection, USP should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m2.  Complete blood counts, including platelets, should be monitored prior to each course of Mitoxantrone Injection, USP and in the event that signs or symptoms of infection develop.  Mitoxantrone Injection, USP generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3.  Liver function tests should also be monitored prior to each course.  Mitoxantrone Injection, USP therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantrone Injection, USP clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

  Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantrone Injection, USP (see WARNINGS, Pregnancy).

  Hormone-Refractory Prostate Cancer

  Based on data from two Phase 3 comparative trials of mitoxantrone injection plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.

  Combination Initial Therapy for ANLL in Adults

  For induction, the recommended dosage is 12 mg/m2 of Mitoxantrone Injection daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.

  Most complete remissions will occur following the initial course of induction therapy.  In the event of an incomplete antileukemic response, a second induction course may be given.  Mitoxantrone Injection should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

  If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

  Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5.  The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first.  Severe myelosuppression occurred (see CLINICAL PHARMACOLOGY).

  Hepatic Impairment

  For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations (see CLINICAL PHARMACOLOGY,   Special Populations, Hepatic Impairment).

  Preparation and Administration Precautions

  MITOXANTRONE INJECTION, USP  (CONCENTRATE) MUST BE DILUTED PRIOR TO USE.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP).  Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately.  DO NOT FREEZE.

  Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form.  Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs.  The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes.  Unused infusion solutions should be discarded immediately in an appropriate fashion.  In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP (concentrate) should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration.  DO NOT FREEZE.  CONTAINS NO PRESERVATIVE.

  Care in the administration of mitoxantrone will reduce the chance of extravasation.  Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.  If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.  Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes.  MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY.  If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein.  During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle.  If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated.  Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

  Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately.  The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.1-4  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Multiple Sclerosis

  The recommended dosage of Mitoxantrone Injection, USP is 12 mg/m2 given as a short (approximately 5 to 15 minutes) intravenous infusion every 3 months.  Left ventricular ejection fraction (LVEF) should be evaluated by echocardiogram or MUGA prior to administration of the initial dose of Mitoxantrone Injection, USP and all subsequent doses.  In addition, LVEF evaluations are recommended if signs or symptoms of congestive heart failure develop at any time during treatment with Mitoxantrone Injection, USP.  Mitoxantrone Injection, USP should not be administered to multiple sclerosis patients with an LVEF <50%, with a clinically significant reduction in LVEF, or to those who have received a cumulative lifetime dose of ≥ 140 mg/m2.  Complete blood counts, including platelets, should be monitored prior to each course of Mitoxantrone Injection, USP and in the event that signs or symptoms of infection develop.  Mitoxantrone Injection, USP generally should not be administered to multiple sclerosis patients with neutrophil counts less than 1500 cells/mm3.  Liver function tests should also be monitored prior to each course.  Mitoxantrone Injection, USP therapy in multiple sclerosis patients with abnormal liver function tests is not recommended because Mitoxantrone Injection, USP clearance is reduced by hepatic impairment and no laboratory measurement can predict drug clearance and dose adjustments.

  Women with multiple sclerosis who are biologically capable of becoming pregnant, even if they are using birth control, should have a pregnancy test, and the results should be known, before receiving each dose of Mitoxantrone Injection, USP (see WARNINGS, Pregnancy).

  Hormone-Refractory Prostate Cancer

  Based on data from two Phase 3 comparative trials of mitoxantrone injection plus corticosteroids versus corticosteroids alone, the recommended dosage of mitoxantrone is 12 to 14 mg/m2 given as a short intravenous infusion every 21 days.

  Combination Initial Therapy for ANLL in Adults

  For induction, the recommended dosage is 12 mg/m2 of Mitoxantrone Injection daily on Days 1 to 3 given as an intravenous infusion, and 100 mg/m2 of cytarabine for 7 days given as a continuous 24-hour infusion on Days 1 to 7.

  Most complete remissions will occur following the initial course of induction therapy.  In the event of an incomplete antileukemic response, a second induction course may be given.  Mitoxantrone Injection should be given for 2 days and cytarabine for 5 days using the same daily dosage levels.

  If severe or life-threatening nonhematologic toxicity is observed during the first induction course, the second induction course should be withheld until toxicity resolves.

  Consolidation therapy which was used in two large randomized multicenter trials consisted of mitoxantrone, 12 mg/m2 given by intravenous infusion daily on Days 1 and 2 and cytarabine, 100 mg/m2 for 5 days given as a continuous 24-hour infusion on Days 1 to 5.  The first course was given approximately 6 weeks after the final induction course; the second was generally administered 4 weeks after the first.  Severe myelosuppression occurred (see CLINICAL PHARMACOLOGY).

  Hepatic Impairment

  For patients with hepatic impairment, there is at present no laboratory measurement that allows for dose adjustment recommendations (see CLINICAL PHARMACOLOGY,   Special Populations, Hepatic Impairment).

  Preparation and Administration Precautions

  MITOXANTRONE INJECTION, USP  (CONCENTRATE) MUST BE DILUTED PRIOR TO USE.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The dose of mitoxantrone should be diluted to at least 50 mL with either 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP).  Mitoxantrone Injection, USP (concentrate) may be further diluted into Dextrose 5% in Water, Normal Saline or Dextrose 5% with Normal Saline and used immediately.  DO NOT FREEZE.

  Mitoxantrone should not be mixed in the same infusion as heparin since a precipitate may form.  Because specific compatibility data are not available, it is recommended that mitoxantrone not be mixed in the same infusion with other drugs.  The diluted solution should be introduced slowly into the tubing as a freely running intravenous infusion of 0.9% Sodium Chloride Injection (USP) or 5% Dextrose Injection (USP) over a period of not less than 3 minutes.  Unused infusion solutions should be discarded immediately in an appropriate fashion.  In the case of multidose use, after penetration of the stopper, the remaining portion of the undiluted Mitoxantrone Injection, USP (concentrate) should be stored not longer than 7 days between 15° to 25°C (59° to 77°F) or 14 days under refrigeration.  DO NOT FREEZE.  CONTAINS NO PRESERVATIVE.

  Care in the administration of mitoxantrone will reduce the chance of extravasation.  Mitoxantrone should be administered into the tubing of a freely running intravenous infusion of 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP.  The tubing should be attached to a Butterfly needle or other suitable device and inserted preferably into a large vein.  If possible, avoid veins over joints or in extremities with compromised venous or lymphatic drainage.  Care should be taken to avoid extravasation at the infusion site and to avoid contact of mitoxantrone with the skin, mucous membranes, or eyes.  MITOXANTRONE SHOULD NOT BE ADMINISTERED SUBCUTANEOUSLY.  If any signs or symptoms of extravasation have occurred, including burning, pain, pruritus, erythema, swelling, blue discoloration, or ulceration, the injection or infusion should be immediately terminated and restarted in another vein.  During intravenous administration of mitoxantrone extravasation may occur with or without an accompanying stinging or burning sensation even if blood returns well on aspiration of the infusion needle.  If it is known or suspected that subcutaneous extravasation has occurred, it is recommended that intermittent ice packs be placed over the area of extravasation and that the affected extremity be elevated.  Because of the progressive nature of extravasation reactions, the area of injection should be frequently examined and surgery consultation obtained early if there is any sign of a local reaction.

  Skin accidentally exposed to mitoxantrone should be rinsed copiously with warm water and if the eyes are involved, standard irrigation techniques should be used immediately.  The use of goggles, gloves, and protective gowns is recommended during preparation and administration of the drug.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.1-4  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Aztreonam
  

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  Aztreonam

  

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  Dosage in Adult Patients

  Aztreonam for injection may be administered intravenously or by intramuscular injection.  Dosage and route of administration should be determined by susceptibility of the causative organisms, severity and site of infection, and the condition of the patient.

                                                                           Table 4:  Aztreonam for Injection Dosage Guidelines for Adults*

   Type of Infection    Dose    Frequency  (hours) Urinary tract infections  500 mg or 1 g   8 or 12  Moderately severe systemic infections  1 g or 2 g   8 or 12  Severe systemic or life-threatening infections  2 g   6 or 8 

  * Maximum recommended dose is 8 g per day.

  Because of the serious nature of infections due to Pseudomonas aeruginosa, dosage of 2 g every six or eight hours is recommended, at least upon initiation of therapy, in systemic infections caused by this organism.

  The intravenous route is recommended for patients requiring single doses greater than 1 g or those with bacterial septicemia, localized parenchymal abscess (e.g., intra-abdominal abscess), peritonitis or other severe systemic or life-threatening infections.

  The duration of therapy depends on the severity of infection.  Generally, aztreonam for injection should be continued for at least 48 hours after the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.  Persistent infections may require treatment for several weeks.  Doses smaller than those indicated should not be used.

  Renal Impairment in Adult Patients

  Prolonged serum levels of aztreonam may occur in patients with transient or persistent renal insufficiency.  Therefore, the dosage of aztreonam for injection should be halved in patients with estimated creatinine clearances between 10 and 30 mL/min/1.73 m2 after an initial loading dose of 1 or 2 g.

  When only the serum creatinine concentration is available, the following formula (based on sex, weight, and age of the patient) may be used to approximate the creatinine clearance (Clcr).  The serum creatinine should represent a steady state of renal function.

                     Males: Clcr =       ­_weight (kg) x (140 - age)_

                                                   72 x serum creatinine (mg/dL)

                       Females: 0.85 x above value

  In patients with severe renal failure (creatinine clearance less than 10 mL/min/1.73 m2), such as those supported by hemodialysis, the usual dose of 500 mg, 1 g or 2 g should be given initially.  The maintenance dose should be one-fourth of the usual initial dose given at the usual fixed interval of 6, 8 or 12 hours.  For serious or life-threatening infections, in addition to the maintenance doses, one-eighth of the initial dose should be given after each hemodialysis session.

  Dosage in the Elderly

  Renal status is a major determinant of dosage in the elderly; these patients in particular may have diminished renal function.  Serum creatinine may not be an accurate determinant of renal status.  Therefore, as with all antibiotics eliminated by the kidneys, estimates of creatinine clearance should be obtained and appropriate dosage modifications made if necessary.

  Dosage in Pediatric Patients

  Aztreonam for injection should be administered intravenously to pediatric patients with normal renal function.  There are insufficient data regarding intramuscular administration to pediatric patients or dosing in pediatric patients with renal impairment (see PRECAUTION S, Pediatric Use).

                                                                    Table 5: Aztreonam for Injection Dosage Guidelines for Pediatric Patients* 

   Type of Infection    Dose    Frequency  (hours)  Mild to moderate infections   30 mg/kg   8   Moderate to severe infections   30 mg/kg   6 or 8 

  *Maximum recommended dose is 120 mg/kg/day.

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• Metoprolol
  

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  Metoprolol

  

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  Myocardial Infarction

  Early Treatment

  During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate as soon as possible after the patient’s arrival in the hospital.  Such treatment should be initiated in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized. 

  Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate injection each; give the injections at approximately 2-minute intervals.  During the intravenous administration of metoprolol tartrate injection, monitor blood pressure, heart rate, and electrocardiogram.

  In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continued for 48 hours.  Thereafter, the maintenance dosage is 100 mg orally twice daily.

  Start patients who appear not to tolerate the full intravenous on metoprolol tartrate tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows.  In patients with severe intolerance, discontinue metoprolol tartrate (see WARNINGS).

  Special Populations

  Pediatric Patients

  No pediatric studies have been performed.  The safety and efficacy of metoprolol tartrate in pediatric patients have not been established.

  Renal Impairment

  No dose adjustment of metoprolol tartrate is required in patients with renal impairment.

  Hepatic Impairment

  Metoprolol tartrate blood levels are likely to increase substantially in patients with hepatic impairment.  Therefore, metoprolol tartrate should be initiated at low doses with cautious gradual dose titration according to clinical response.

  Geriatric Patients (>65 years)

  In general, use a low initial starting dose in elderly patients given their greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

  Method of Administration

  Parenteral administration of metoprolol tartrate should be done in a setting with intensive monitoring.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Myocardial Infarction

  Early Treatment

  During the early phase of definite or suspected acute myocardial infarction, initiate treatment with metoprolol tartrate as soon as possible after the patient’s arrival in the hospital.  Such treatment should be initiated in a coronary care or similar unit immediately after the patient’s hemodynamic condition has stabilized. 

  Begin treatment in this early phase with the intravenous administration of three bolus injections of 5 mg of metoprolol tartrate injection each; give the injections at approximately 2-minute intervals.  During the intravenous administration of metoprolol tartrate injection, monitor blood pressure, heart rate, and electrocardiogram.

  In patients who tolerate the full intravenous dose (15 mg), initiate metoprolol tartrate tablets, 50 mg every 6 hours, 15 minutes after the last intravenous dose and continued for 48 hours.  Thereafter, the maintenance dosage is 100 mg orally twice daily.

  Start patients who appear not to tolerate the full intravenous on metoprolol tartrate tablets either 25 mg or 50 mg every 6 hours (depending on the degree of intolerance) 15 minutes after the last intravenous dose or as soon as their clinical condition allows.  In patients with severe intolerance, discontinue metoprolol tartrate (see WARNINGS).

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• Xiaflex
  

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  Xiaflex

  

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  Oxaliplatin Injection, USP should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

  2.1 Dosage

  Administer Oxaliplatin Injection, USP in combination with 5-fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):Day 1: Oxaliplatin injection, USP 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5-fluorouracil 400 mg/m2 intravenous bolus given over 2 to 4 minutes, followed by 5-fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose Injection, USP (recommended) as a 22-hour continuous infusion.

  The administration of oxaliplatin injection, USP does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.For information on 5-fluorouracil and leucovorin, see the respective package inserts.

  2.2 Dose Modification Recommendations

  Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for oxaliplatin injection, USP from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-fluorouracil and leucovorin do not need to be changed.Adjuvant Therapy in Patients with Stage III Colon Cancer Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5-fluorouracil/leucovorin regimen need not be altered.A dose reduction of oxaliplatin injection, USP to 75 mg/m2 and infusional 5-fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal CancerNeuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.0.For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin injection, USP to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5-fluorouracil/leucovorin regimen need not be altered.A dose reduction of oxaliplatin injection, USP to 65 mg/m2 and 5-fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.Dose Modifications in Therapy for Patients with Renal Impairment In patients with normal renal function or mild to moderate renal impairment, the recommended dose of oxaliplatin is 85 mg/m2. In patients with severe renal impairment, the initial recommended oxaliplatin injection, USP dose should be reduced to 65 mg/m2[see Use in Specific Populations (8.6)and Clinical Pharmacology (12.3)].

  2.3 Preparation of Infusion Solution

  Do not freeze and protect from light the concentrated solution.A final dilution must never be performed with a sodium chloride solution or other chloride-containing solutions. The solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection, USP.After dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20° to 25°C (68° to 77°F)] or up to 24 hours under refrigeration [2° to 8°C (36° to 46°F)]. After final dilution, protection from light is not required.Oxaliplatin injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose Injection, USP prior to administration of any concomitant medication. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration and discarded if present.Needles or intravenous administration sets containing aluminum parts that may come in contact with oxaliplatin should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.

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• Hydralazine Hydrochlori...
  

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  Hydralazine Hydrochloride

  

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  When there is urgent need, therapy in the hospitalized patient may be initiated intramuscularly or as a rapid intravenous bolus injection directly into the vein.  Hydralazine Hydrochloride Injection should be used only when the drug cannot be given orally.  The usual dose is 20-40 mg, repeated as necessary.

  Certain patients (especially those with marked renal damage) may require a lower dose.   Blood pressure should be checked frequently.  It may begin to fall within a few minutes after injection, with the average maximal decrease occurring in 10-80 minutes.  In cases where there has been increased intracranial pressure, lowering the blood pressure may increase cerebral ischemia.  Most patients can be transferred to oral hydralazine hydrochloride within 24-48 hours.

  The product should be used immediately after the vial is opened.  The product should not be added to infusion solutions.  Hydralazine Hydrochloride Injection may discolor upon contact with metal; discolored solutions should be discarded. 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Magnesium Sulfate
  

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  Magnesium Sulfate

  

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  Dosage of magnesium sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

  Both IV and IM administration are appropriate.  IM administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a therapeutic level almost immediately.  The rate of IV injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures (see below).  Continuous maternal administration of magnesium sulfate injection in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Solutions for IV infusion must be diluted to a concentration of 20% or less prior to administration.  The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP.  Deep IM injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded.  In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded.  In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Progesterone
  

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  Progesterone

  

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  Progesterone is administered by intramuscular injection.  It differs from other commonly used steroids in that it is irritating at the place of injection.

  Amenorrhea

  Five to 10 mg are given for six to eight consecutive days.  If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding 48 to 72 hours after the last injection.  This may be followed by spontaneous normal cycles.

  Functional Uterine Bleeding

  Five to 10 mg are given daily for six doses.  Bleeding may be expected to cease within six days.  When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy.  If menstrual flow begins during the course of injections of progesterone, they are discontinued.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

  Amenorrhea

  Five to 10 mg are given for six to eight consecutive days.  If there has been sufficient ovarian activity to produce a proliferative endometrium, one can expect withdrawal bleeding 48 to 72 hours after the last injection.  This may be followed by spontaneous normal cycles.

  Functional Uterine Bleeding

  Five to 10 mg are given daily for six doses.  Bleeding may be expected to cease within six days.  When estrogen is given as well, the administration of progesterone is begun after two weeks of estrogen therapy.  If menstrual flow begins during the course of injections of progesterone, they are discontinued.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.

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• Azithromycin
  

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  Azithromycin

  

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  (See INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY.)

  The recommended dose of Azithromycin for Injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for at least two days.  Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg tablets to complete a 7 to 10 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

  The recommended dose of Azithromycin for Injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for one or two days.  Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.  If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection.

  Renal Insufficiency

  No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0-120 was similar in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function.  Caution should be exercised when azithromycin is administered to subjects with severe renal impairment (see CLINICAL PHARMACOLOGY, Special Populations , Renal Insufficiency).

  Hepatic Insufficiency

  The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.  No dose adjustment recommendations can be made in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency).

  No dosage adjustment is recommended based on age or gender (see CLINICAL PHARMACOLOGY, Special Populations).

  The infusate concentration and rate of infusion for Azithromycin for Injection should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour.  Azithromycin for Injection should not be given as a bolus or as an intramuscular injection. 

  Preparation of the solution for intravenous administration is as follows:

  Reconstitution

  Prepare the initial solution of Azithromycin for Injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial and shaking the vial until all of the drug is dissolved.  Since Azithromycin for Injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed.  Each mL of reconstituted solution contains 100 mg azithromycin.  Reconstituted solution is stable for 24 hours when stored below 30°C (86°F).

  Parenteral drug products should be inspected visually for particulate matter prior to administration.  If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

  Dilute this solution further prior to administration as instructed below.

  Dilution

  To provide azithromycin over a concentration range of 1 to 2 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below:

  Normal Saline (0.9% sodium chloride)

  1/2 Normal Saline (0.45% sodium chloride)

  5% Dextrose in Water

  Lactated Ringer’s Solution

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl

  5% Dextrose in Lactated Ringer’s Solution

  5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)

  Normosol®-M in 5% Dextrose

  Normosol®-R in 5% Dextrose

   

  Final Infusion Solution

  Concentration (mg/mL)         Amount of Diluent (mL)

          1 mg/mL                                   500 mL

          2 mg/mL                                   250 mL

  It is recommended that a 500 mg dose of Azithromycin for Injection, diluted as above, be infused over a period of not less than 60 minutes.

  Azithromycin for Injection should not be given as a bolus or as an intramuscular injection.

  Other intravenous substances, additives, or medications should not be added to Azithromycin for Injection or infused simultaneously through the same intravenous line.

  Storage

  Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

  Storage

  Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

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• Ifosfamide
  

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  Ifosfamide

  

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  Ifosfamide for Injection should be administered intravenously at a dose of 1.2 g/m2 per day for 5 consecutive days.  Treatment is repeated every 3 weeks or after recovery from hematologic toxicity (Platelets ≥100,000/μL, WBC ≥4,000/μL).  In order to prevent bladder toxicity, Ifosfamide for Injection should be given with extensive hydration consisting of at least 2 liters of oral or intravenous fluid per day.  A protector, such as mesna, should also be used to prevent hemorrhagic cystitis.  Ifosfamide for Injection should be administered as a slow intravenous infusion lasting a minimum of 30 minutes.  Although Ifosfamide for Injection has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules of Ifosfamide for Injection in such patients have not been conducted.

  Preparation for Intravenous Administration/Stability

  Injections are prepared for parenteral use by adding Sterile Water for Injection, USP, or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve.  Use the quantity of diluent shown below to constitute the product:

  Dosage

  Strength

  Quantity of

  Diluent

  Final

  Concentration

  1 gram

  20 mL

  50 mg/mL

  3 grams

  60 mL

  50 mg/mL

  Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

      5% Dextrose Injection, USP

      0.9% Sodium Chloride Injection, USP

      Lactated Ringer’s Injection, USP

      Sterile Water for Injection, USP

  Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, Viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.

  Constituted or constituted and further diluted solutions of Ifosfamide for Injection should be refrigerated and used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Preparation for Intravenous Administration/Stability

  Injections are prepared for parenteral use by adding Sterile Water for Injection, USP, or Bacteriostatic Water for Injection, USP (benzyl alcohol or parabens preserved), to the vial and shaking to dissolve.  Use the quantity of diluent shown below to constitute the product:

  Dosage

  Strength

  Quantity of

  Diluent

  Final

  Concentration

  1 gram

  20 mL

  50 mg/mL

  3 grams

  60 mL

  50 mg/mL

  Solutions of ifosfamide may be diluted further to achieve concentrations of 0.6 to 20 mg/mL in the following fluids:

      5% Dextrose Injection, USP

      0.9% Sodium Chloride Injection, USP

      Lactated Ringer’s Injection, USP

      Sterile Water for Injection, USP

  Because essentially identical stability results were obtained for Sterile Water admixtures as for the other admixtures (5% Dextrose Injection, 0.9% Sodium Chloride Injection, and Lactated Ringer’s Injection), the use of large volume parenteral glass bottles, Viaflex bags or PAB™ bags that contain intermediate concentrations or mixtures of excipients (e.g., 2.5% Dextrose Injection, 0.45% Sodium Chloride Injection, or 5% Dextrose and 0.9% Sodium Chloride Injection) is also acceptable.

  Constituted or constituted and further diluted solutions of Ifosfamide for Injection should be refrigerated and used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

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• Thiamine
  

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  Thiamine

  

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  “Wet” beriberi with myocardial failure must be treated as an emergency cardiac condition, and thiamine must be administered slowly by the IV route in this situation (see WARNINGS).

  In the treatment of beriberi, 10 to 20 mg of thiamine hydrochloride are given IM three times daily for as long as two weeks.  (See WARNINGS regarding repeated injections of thiamine.)  An oral therapeutic multivitamin preparation containing 5 to 10 mg thiamine, administered daily for one month, is recommended to achieve body tissue saturation.

  Infantile beriberi that is mild may respond to oral therapy, but if collapse occurs, doses of 25 mg may cautiously be given IV.

  Poor dietary habits should be corrected and an abundant and well-balanced dietary intake should be prescribed.

  Patients with neuritis of pregnancy in whom vomiting is severe enough to preclude adequate oral therapy should receive 5 to 10 mg of thiamine hydrochloride IM daily.

  In the treatment of Wernicke-Korsakoff syndrome, thiamine hydrochloride has been administered IV in an initial dose of 100 mg, followed by IM doses of 50 to 100 mg daily until the patient is consuming a regular, balanced diet.  (See WARNINGS regarding repeated injections of thiamine.)

  Patients with marginal thiamine status to whom dextrose is being administered should receive 100 mg thiamine hydrochloride in each of the first few liters of IV fluid to avoid precipitating heart failure.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Levothyroxine Sodium
  

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  Levothyroxine Sodium

  

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  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death-in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL and 100 mcg per mL for the 100 mcg and 500 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity-including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death-in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL and 100 mcg per mL for the 100 mcg and 500 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Colistimethate
  

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  Colistimethate

  

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  Important

  Colistimethate for Injection, USP is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial.

  Reconstitution for Intravenous or Intramuscular Administration

  The 150 mg vial should be reconstituted with 2 mL Sterile Water for Injection, USP.  The reconstituted solution provides colistimethate sodium at a concentration equivalent to 75 mg/mL colistin base activity.

  During reconstitution swirl gently to avoid frothing. 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  If these conditions are observed, the product should not be used.

  Dosage

  Adults and Pediatric Patients-Intravenous or Intramuscular Administration

  The dose of Colistimethate for Injection, USP should be 2.5 to 5 mg/kg per day of colistin base in 2 to 4 divided doses for patients with normal renal function, depending on the severity of the infection.

  In obese individuals, dosage should be based on ideal body weight. 

  The daily dose and frequency should be reduced for the patients with renal impairment.  Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1.

  TABLE 1. Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function

  Degree of Renal Impairment

  Normal

  Mild

  Moderate

  Severe

  Creatinine Clearance (mL/min)  

  ≥ 80

  50 to 79

  30 to 49

  10 to 29

  Dosage Schedule

  2.5 to 5 mg/kg, divided into 2 to 4 doses per day 

  2.5 to 3.8 mg/kg, divided into 2 doses per day 

  2.5 mg/kg, once daily or divided into 2 doses per day 

  1.5 mg/kg, every 36 hours 

  Note: The suggested total daily dose is calculated from colistin base activity.

  Important

  Colistimethate for Injection, USP is supplied in vials containing colistimethate sodium equivalent to 150 mg colistin base activity per vial.

  Reconstitution for Intravenous or Intramuscular Administration

  The 150 mg vial should be reconstituted with 2 mL Sterile Water for Injection, USP.  The reconstituted solution provides colistimethate sodium at a concentration equivalent to 75 mg/mL colistin base activity.

  During reconstitution swirl gently to avoid frothing. 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  If these conditions are observed, the product should not be used.

  Dosage

  Adults and Pediatric Patients-Intravenous or Intramuscular Administration

  The dose of Colistimethate for Injection, USP should be 2.5 to 5 mg/kg per day of colistin base in 2 to 4 divided doses for patients with normal renal function, depending on the severity of the infection.

  In obese individuals, dosage should be based on ideal body weight. 

  The daily dose and frequency should be reduced for the patients with renal impairment.  Suggested modifications of dosage schedule for patients with renal impairment are presented in Table 1.

  TABLE 1. Suggested Modification of Dosage Schedules of Colistimethate for Injection, USP for Adults with Impaired Renal Function

  Degree of Renal Impairment

  Normal

  Mild

  Moderate

  Severe

  Creatinine Clearance (mL/min)  

  ≥ 80

  50 to 79

  30 to 49

  10 to 29

  Dosage Schedule

  2.5 to 5 mg/kg, divided into 2 to 4 doses per day 

  2.5 to 3.8 mg/kg, divided into 2 doses per day 

  2.5 mg/kg, once daily or divided into 2 doses per day 

  1.5 mg/kg, every 36 hours 

  Note: The suggested total daily dose is calculated from colistin base activity.

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• Hydralazine Hydrochlori...
  

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  Hydralazine Hydrochloride

  

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  When there is urgent need, therapy in the hospitalized patient may be initiated intramuscularly or as a rapid intravenous bolus injection directly into the vein.  Hydralazine Hydrochloride Injection should be used only when the drug cannot be given orally.  The usual dose is 20 to 40 mg, repeated as necessary.

  Certain patients (especially those with marked renal damage) may require a lower dose.  Blood pressure should be checked frequently.  It may begin to fall within a few minutes after injection, with the average maximal decrease occurring in 10 to 80 minutes.  In cases where there has been increased intracranial pressure, lowering the blood pressure may increase cerebral ischemia.  Most patients can be transferred to oral hydralazine hydrochloride within 24 to 48 hours.

  The product should be used immediately after the vial is opened.  The product should not be added to infusion solutions.  Hydralazine Hydrochloride Injection may discolor upon contact with metal; discolored solutions should be discarded.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Donepezil Hydrochloride...
  

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  Donepezil Hydrochloride

  

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  2.1 Dosing for Partial Onset Seizures

  Adults 16 Years and Older

  Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg.  There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

  Pediatric Patients

  1 Month to < 6 Months

  Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).  In the clinical trial, the mean daily dose was 35 mg/kg in this age group.  The effectiveness of lower doses has not been studied.

  6 Months to < 4 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

  4 Years to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 44 mg/kg.  The maximum daily dose was 3,000 mg/day.

  2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase the dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been studied.

  2.3 Dosing for Primary Generalized Tonic-Clonic Seizures

  Adults 16 Years and Older

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

  Pediatric Patients Ages 6 to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

  2.4 Switching from Oral Dosing

  When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

  2.5 Switching to Oral Dosing

  At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

  2.6 Preparation and Administration Instructions

   Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration.  If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.  Consideration should also be given to the total daily fluid intake of the patient.  Levetiracetam injection should be administered as a 15-minute IV infusion.  One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Product with particulate matter or discoloration should not be used. Any unused portion of the levetiracetam injection vial contents should be discarded. Adults

  See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1,000 mg, or 1,500 mg.

  Table 1:  Preparation and Administration of Levetiracetam Injection for Adults

  Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg 5 mL (5 mL vial) 100 mL 15 minutes 1,000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1,500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

  For example, to prepare a 1,000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

  Pediatric Patients When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).   The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

  Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 100 mg/mL

  2.7 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam injection dosing must be individualized according to the patient’s renal function status.  Recommended dosage adjustments for adults with renal impairment are shown in Table 2.  Information is unavailable for dosage adjustments in pediatric patients with renal impairment.  In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.  To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

  CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients) 72 x serum creatinine (mg/dL)

  Then CLcr is adjusted for body surface area (BSA) as follows:

  CLcr (mL/min/1.73 m2) = CLcr (mL/min) x 1.73 BSA subject (m2)

  Table 2:  Dosage Adjustment Regimen for Adult Patients with Renal Impairment

  Group Creatinine Clearance (mL/min/1.73 m2) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ------­ 500 to 1,0001 Every 24 hours1

  1    Following dialysis, a 250 to 500 mg supplemental dose is recommended.

  2.8 Compatibility and Stability

  Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

  Diluents

  Sodium chloride (0.9%) injection, USP

  Lactated Ringer’s injection

  Dextrose 5% injection, USP

  Other Antiepileptic Drugs

  Lorazepam

  Diazepam

  Valproate sodium

  There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

  2.1 Dosing for Partial Onset Seizures

  Adults 16 Years and Older

  Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg.  There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

  Pediatric Patients

  1 Month to < 6 Months

  Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily).  In the clinical trial, the mean daily dose was 35 mg/kg in this age group.  The effectiveness of lower doses has not been studied.

  6 Months to < 4 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

  4 Years to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced.  In the clinical trial, the mean daily dose was 44 mg/kg.  The maximum daily dose was 3,000 mg/day.

  2.2 Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase the dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been studied.

  2.3 Dosing for Primary Generalized Tonic-Clonic Seizures

  Adults 16 Years and Older

  Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily).  Increase dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg.  The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

  Pediatric Patients Ages 6 to < 16 Years

  Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).  Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily).  The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

  2.4 Switching from Oral Dosing

  When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

  2.5 Switching to Oral Dosing

  At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

  2.6 Preparation and Administration Instructions

   Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration.  If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution.  Consideration should also be given to the total daily fluid intake of the patient.  Levetiracetam injection should be administered as a 15-minute IV infusion.  One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.  Product with particulate matter or discoloration should not be used. Any unused portion of the levetiracetam injection vial contents should be discarded. Adults

  See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1,000 mg, or 1,500 mg.

  Table 1:  Preparation and Administration of Levetiracetam Injection for Adults

  Dose Withdraw Volume Volume of Diluent Infusion Time 500 mg 5 mL (5 mL vial) 100 mL 15 minutes 1,000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes 1,500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

  For example, to prepare a 1,000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

  Pediatric Patients When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).   The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

  Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg) 100 mg/mL

  2.7 Dosage Adjustments in Adult Patients with Renal Impairment

  Levetiracetam injection dosing must be individualized according to the patient’s renal function status.  Recommended dosage adjustments for adults with renal impairment are shown in Table 2.  Information is unavailable for dosage adjustments in pediatric patients with renal impairment.  In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated.  To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

  CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients) 72 x serum creatinine (mg/dL)

  Then CLcr is adjusted for body surface area (BSA) as follows:

  CLcr (mL/min/1.73 m2) = CLcr (mL/min) x 1.73 BSA subject (m2)

  Table 2:  Dosage Adjustment Regimen for Adult Patients with Renal Impairment

  Group Creatinine Clearance (mL/min/1.73 m2) Dosage (mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ------­ 500 to 1,0001 Every 24 hours1

  1    Following dialysis, a 250 to 500 mg supplemental dose is recommended.

  2.8 Compatibility and Stability

  Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

  Diluents

  Sodium chloride (0.9%) injection, USP

  Lactated Ringer’s injection

  Dextrose 5% injection, USP

  Other Antiepileptic Drugs

  Lorazepam

  Diazepam

  Valproate sodium

  There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

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• Hydrogen Peroxide Solut...
  

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  Hydrogen Peroxide Solution

  

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  2.1 Dosage in Adult Patients with Normal Renal Function

  The usual dose of levofloxacin in 5% dextrose injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1. 

  These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance < 50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)].

  Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) 

  Type of Infection*  Dosed Every 24 hours    Duration (days)†   Nosocomial Pneumonia  750 mg    7 to 14   Community-Acquired Pneumonia‡   500 mg    7 to 14   Community-Acquired Pneumonia§   750 mg    5   Acute Bacterial Sinusitis  750 mg   5   500 mg   10 to 14  Acute Bacterial Exacerbation of Chronic Bronchitis  500 mg    7   Complicated Skin and Skin Structure Infections (SSSI)  750 mg    7 to 14   Uncomplicated SSSI  500 mg    7 to 10   Chronic Bacterial Prostatitis  500 mg    28   Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)¶  750 mg    5   Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)#  250 mg    10   Uncomplicated Urinary Tract Infection  250 mg    3   Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kgÞ,β  Pediatric patients < 50 kg and ≥ 6 months of ageÞ,β   500 mg   see Table 2 below (2.2)  60β  60β Plague, adult and pediatric patients > 50 kgα Pediatric patients < 50 kg and ≥ 6 months of age  500 mg  See Table 2 below (2.2)  10 to 14 10 to 14

  * Due to the designated pathogens [see Indications and Usage (1)].

  † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

  ‡ Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1.2)].

  §  Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1.3)].

  ¶ This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia.

  # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli.

  Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint.  Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)].

  β The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied.  An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4) and Clinical Studies (14.9)].  Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk.α Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated.

  2.2 Dosage in Pediatric Patients

  The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.

             Table 2:  Dosage in Pediatric Patients ≥ 6 months of age

  Type of Infection*   Dose     Freq.   Once Every   Duration†   Inhalational Anthrax (post-exposure)‡, § Pediatric patients > 50 kg  500 mg   24 hr   60 days§   Pediatric patients < 50 kg and ≥ 6 months of age  8 mg/kg (not to exceed 250 mg per dose)  12 hr   60 days§   Plague¶ Pediatric patients > 50 kg  500 mg   24 hr   10 to 14 days  Pediatric patients < 50 kg and≥ 6 months of age  8 mg/kg (not to exceed 250 mg per dose)  12 hr   10 to 14 days 

  *  Due to Bacillus anthracis [see Indications and Usage (1.13)] and Yersinia pestis [see Indications and Usage (1.14).

  †   Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

  ‡   Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint.  Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)].

  §    The safety of levofloxacin in pediatric patients for durations of therapy beyond 14 days has not been studied.  An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4) and Clinical Studies (14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk.

  ¶   Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis.

  2.3 Dosage Adjustment in Adults with Renal Impairment

  Administer levofloxacin with caution in the presence of renal insufficiency.  Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. 

  No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min. 

  In patients with impaired renal function (creatinine clearance < 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)].

  Table 3 shows how to adjust dose based on creatinine clearance.

  Table 3:  Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 mL/min)

   Dosage in Normal Renal Function Every 24 hours    Creatinine Clearance 20 to 49 mL/min    Creatinine Clearance 10 to 19 mL/min    Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)    750 mg            750 mg every 48 hours    750 mg initial dose, then 500 mg every 48 hours    750 mg initial dose, then 500 mg every 48 hours    500 mg    500 mg initial dose, then 250 mg every 24 hours    500 mg initial dose, then 250 mg every 48 hours    500 mg initial dose, then 250 mg every 48 hours    250 mg    No dosage adjustment required    250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required    No information on dosing adjustment is available  

  2.4 Drug Interaction with Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

  Levofloxacin in 5% dextrose injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.6)].

  2.5 Administration Instructions

  Caution: Rapid or bolus intravenous infusion of levofloxacin has been associated with hypotension and must be avoided.  Levofloxacin in 5% dextrose injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage.  Levofloxacin in 5% dextrose injection should be administered only by intravenous infusion.  It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

  Hydration for Patients Receiving Levofloxacin in 5% Dextrose Injection

  Adequate hydration of patients receiving intravenous levofloxacin should be maintained to prevent the formation of highly concentrated urine.  Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].

  2.6 Preparation of Intravenous Product

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Because only limited data are available on the compatibility of levofloxacin in 5% dextrose injection with other intravenous substances, additives or other medications should not be added to Levofloxacin Injection Premix Solution in Single-Use Flexible Containers or infused simultaneously through the same intravenous line.  If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of levofloxacin in 5% dextrose injection with an infusion solution compatible with levofloxacin in 5% dextrose injection and with any other drug(s) administered via this common line.

  Levofloxacin Injection Premix in Single-Use Flexible Containers (5 mg/mL)

  Levofloxacin in 5% dextrose injection is supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use.  The 50 mL premixed flexible container contains 250 mg/50 mL of levofloxacin solution. The 100 mL premixed flexible container contains 500 mg/100 mL of levofloxacin solution.  The 150 mL premixed flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL.  No further dilution of these preparations is necessary.  Because the premix flexible containers are for single-use only, any unused portion should be discarded.

  Instructions for the Use of Levofloxacin Injection Premix in Single-Use Flexible Containers:

  1.  Tear outer wrap at the notch and remove solution container.

  2.  Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised.

  3.  Do not use if the solution is cloudy or a precipitate is present.

  4.  Use sterile equipment.

  5.  WARNING:  Do not admix with other drugs or additives.  Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

  Preparation for Administration:

  1.  Close flow control clamp of administration set.

  2.  Remove cover from port at bottom of container.

  3.  Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.  NOTE:  See full directions on administration set carton.

  4.  Suspend container from hanger.

  5.  Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levofloxacin Injection Premix in Flexible Containers.

  6.  Open flow control clamp to expel air from set. Close clamp.

  7.  Regulate rate of administration with flow control clamp.

  2.1 Dosage in Adult Patients with Normal Renal Function

  The usual dose of levofloxacin in 5% dextrose injection is 250 mg or 500 mg administered by slow infusion over 60 minutes every 24 hours or 750 mg administered by slow infusion over 90 minutes every 24 hours, as indicated by infection and described in Table 1. 

  These recommendations apply to patients with creatinine clearance ≥ 50 mL/min. For patients with creatinine clearance < 50 mL/min, adjustments to the dosing regimen are required [see Dosage and Administration (2.3)].

  Table 1: Dosage in Adult Patients with Normal Renal Function (creatinine clearance ≥ 50 mL/min) 

  Type of Infection*  Dosed Every 24 hours    Duration (days)†   Nosocomial Pneumonia  750 mg    7 to 14   Community-Acquired Pneumonia‡   500 mg    7 to 14   Community-Acquired Pneumonia§   750 mg    5   Acute Bacterial Sinusitis  750 mg   5   500 mg   10 to 14  Acute Bacterial Exacerbation of Chronic Bronchitis  500 mg    7   Complicated Skin and Skin Structure Infections (SSSI)  750 mg    7 to 14   Uncomplicated SSSI  500 mg    7 to 10   Chronic Bacterial Prostatitis  500 mg    28   Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)¶  750 mg    5   Complicated Urinary Tract Infection (cUTI) or Acute Pyelonephritis (AP)#  250 mg    10   Uncomplicated Urinary Tract Infection  250 mg    3   Inhalational Anthrax (Post-Exposure), adult and pediatric patients > 50 kgÞ,β  Pediatric patients < 50 kg and ≥ 6 months of ageÞ,β   500 mg   see Table 2 below (2.2)  60β  60β Plague, adult and pediatric patients > 50 kgα Pediatric patients < 50 kg and ≥ 6 months of age  500 mg  See Table 2 below (2.2)  10 to 14 10 to 14

  * Due to the designated pathogens [see Indications and Usage (1)].

  † Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

  ‡ Due to methicillin-susceptible Staphylococcus aureus, Streptococcus pneumoniae (including multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis, Chlamydophila pneumoniae, Legionella pneumophila, or Mycoplasma pneumoniae [see Indications and Usage (1.2)].

  §  Due to Streptococcus pneumoniae (excluding multi-drug-resistant isolates [MDRSP]), Haemophilus influenzae, Haemophilus parainfluenzae, Mycoplasma pneumoniae, or Chlamydophila pneumoniae [see Indications and Usage (1.3)].

  ¶ This regimen is indicated for cUTI due to Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and AP due to E. coli, including cases with concurrent bacteremia.

  # This regimen is indicated for cUTI due to Enterococcus faecalis, Enterococcus cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa; and for AP due to E. coli.

  Þ Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint.  Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)].

  β The safety of levofloxacin in adults for durations of therapy beyond 28 days or in pediatric patients for durations beyond 14 days has not been studied.  An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4) and Clinical Studies (14.9)].  Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk.α Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis. Higher doses of levofloxacin typically used for treatment of pneumonia can be used for treatment of plague, if clinically indicated.

  2.2 Dosage in Pediatric Patients

  The dosage in pediatric patients ≥ 6 months of age is described below in Table 2.

             Table 2:  Dosage in Pediatric Patients ≥ 6 months of age

  Type of Infection*   Dose     Freq.   Once Every   Duration†   Inhalational Anthrax (post-exposure)‡, § Pediatric patients > 50 kg  500 mg   24 hr   60 days§   Pediatric patients < 50 kg and ≥ 6 months of age  8 mg/kg (not to exceed 250 mg per dose)  12 hr   60 days§   Plague¶ Pediatric patients > 50 kg  500 mg   24 hr   10 to 14 days  Pediatric patients < 50 kg and≥ 6 months of age  8 mg/kg (not to exceed 250 mg per dose)  12 hr   10 to 14 days 

  *  Due to Bacillus anthracis [see Indications and Usage (1.13)] and Yersinia pestis [see Indications and Usage (1.14).

  †   Sequential therapy (intravenous to oral) may be instituted at the discretion of the physician.

  ‡   Drug administration should begin as soon as possible after suspected or confirmed exposure to aerosolized B. anthracis. This indication is based on a surrogate endpoint.  Levofloxacin plasma concentrations achieved in humans are reasonably likely to predict clinical benefit [see Clinical Studies (14.9)].

  §    The safety of levofloxacin in pediatric patients for durations of therapy beyond 14 days has not been studied.  An increased incidence of musculoskeletal adverse events compared to controls has been observed in pediatric patients [see Warnings and Precautions (5.10), Use in Specific Populations (8.4) and Clinical Studies (14.9)]. Prolonged levofloxacin therapy should only be used when the benefit outweighs the risk.

  ¶   Drug administration should begin as soon as possible after suspected or confirmed exposure to Yersinia pestis.

  2.3 Dosage Adjustment in Adults with Renal Impairment

  Administer levofloxacin with caution in the presence of renal insufficiency.  Careful clinical observation and appropriate laboratory studies should be performed prior to and during therapy since elimination of levofloxacin may be reduced. 

  No adjustment is necessary for patients with a creatinine clearance ≥ 50 mL/min. 

  In patients with impaired renal function (creatinine clearance < 50 mL/min), adjustment of the dosage regimen is necessary to avoid the accumulation of levofloxacin due to decreased clearance [see Use in Specific Populations (8.6)].

  Table 3 shows how to adjust dose based on creatinine clearance.

  Table 3:  Dosage Adjustment in Adult Patients with Renal Impairment (creatinine clearance < 50 mL/min)

   Dosage in Normal Renal Function Every 24 hours    Creatinine Clearance 20 to 49 mL/min    Creatinine Clearance 10 to 19 mL/min    Hemodialysis or Chronic Ambulatory Peritoneal Dialysis (CAPD)    750 mg            750 mg every 48 hours    750 mg initial dose, then 500 mg every 48 hours    750 mg initial dose, then 500 mg every 48 hours    500 mg    500 mg initial dose, then 250 mg every 24 hours    500 mg initial dose, then 250 mg every 48 hours    500 mg initial dose, then 250 mg every 48 hours    250 mg    No dosage adjustment required    250 mg every 48 hours. If treating uncomplicated UTI, then no dosage adjustment is required    No information on dosing adjustment is available  

  2.4 Drug Interaction with Chelation Agents: Antacids, Sucralfate, Metal Cations, Multivitamins

  Levofloxacin in 5% dextrose injection should not be co-administered with any solution containing multivalent cations, e.g., magnesium, through the same intravenous line [see Dosage and Administration (2.6)].

  2.5 Administration Instructions

  Caution: Rapid or bolus intravenous infusion of levofloxacin has been associated with hypotension and must be avoided.  Levofloxacin in 5% dextrose injection should be infused intravenously slowly over a period of not less than 60 or 90 minutes, depending on the dosage.  Levofloxacin in 5% dextrose injection should be administered only by intravenous infusion.  It is not for intramuscular, intrathecal, intraperitoneal, or subcutaneous administration.

  Hydration for Patients Receiving Levofloxacin in 5% Dextrose Injection

  Adequate hydration of patients receiving intravenous levofloxacin should be maintained to prevent the formation of highly concentrated urine.  Crystalluria and cylindruria have been reported with quinolones [see Adverse Reactions (6.1) and Patient Counseling Information (17.2)].

  2.6 Preparation of Intravenous Product

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Because only limited data are available on the compatibility of levofloxacin in 5% dextrose injection with other intravenous substances, additives or other medications should not be added to Levofloxacin Injection Premix Solution in Single-Use Flexible Containers or infused simultaneously through the same intravenous line.  If the same intravenous line is used for sequential infusion of several different drugs, the line should be flushed before and after infusion of levofloxacin in 5% dextrose injection with an infusion solution compatible with levofloxacin in 5% dextrose injection and with any other drug(s) administered via this common line.

  Levofloxacin Injection Premix in Single-Use Flexible Containers (5 mg/mL)

  Levofloxacin in 5% dextrose injection is supplied in flexible containers within a foil overwrap. These contain a premixed, ready to use levofloxacin solution in 5% dextrose (D5W) for single-use.  The 50 mL premixed flexible container contains 250 mg/50 mL of levofloxacin solution. The 100 mL premixed flexible container contains 500 mg/100 mL of levofloxacin solution.  The 150 mL premixed flexible container contains 750 mg/150 mL of levofloxacin solution. The concentration of each container is 5 mg/mL.  No further dilution of these preparations is necessary.  Because the premix flexible containers are for single-use only, any unused portion should be discarded.

  Instructions for the Use of Levofloxacin Injection Premix in Single-Use Flexible Containers:

  1.  Tear outer wrap at the notch and remove solution container.

  2.  Check the container for minute leaks by squeezing the inner bag firmly. If leaks are found, or if the seal is not intact, discard the solution, as the sterility may be compromised.

  3.  Do not use if the solution is cloudy or a precipitate is present.

  4.  Use sterile equipment.

  5.  WARNING:  Do not admix with other drugs or additives.  Such use could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is complete.

  Preparation for Administration:

  1.  Close flow control clamp of administration set.

  2.  Remove cover from port at bottom of container.

  3.  Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.  NOTE:  See full directions on administration set carton.

  4.  Suspend container from hanger.

  5.  Squeeze and release drip chamber to establish proper fluid level in chamber during infusion of Levofloxacin Injection Premix in Flexible Containers.

  6.  Open flow control clamp to expel air from set. Close clamp.

  7.  Regulate rate of administration with flow control clamp.

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• Levothyroxine Sodium
  

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  Levothyroxine Sodium

  

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  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity—including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death—in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL, 40 mcg per mL and  and 100 mcg per mL for the 100 mcg, 200 mcg and 500 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity—including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death—in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL, 40 mcg per mL and  and 100 mcg per mL for the 100 mcg, 200 mcg and 500 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Ondansetron
  

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  Ondansetron

  

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  The total dose of Acetylcysteine Injection is 300 mg/kg given as 3 separate doses and administered over a total of 21 hours. Please refer to the guidelines below for dose preparation based upon patient weight. The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction (see Tables 1 and 2).

  2.1 Administration Instructions (Three-Bag Method: Loading, Second and Third Dose)

  Dosing for Patients who weigh 5 kg to 20 kg ( Table 1):

  Loading Dose: 150 mg/kg diluted in 3 mL/kg of diluent* administered over 1 hr

  Second Dose: 50 mg/kg diluted in 7 mL/kg of diluent* administered over 4 hrs

  Third Dose: 100 mg/kg diluted in 14 mL/kg of diluent* administered over 16 hrs

  Table 1. Three Bag Method Dosage Guide by Weight in Patients 5 kg to 20 kg * Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water, 0.45% Sodium Chloride Injection, and Sterile Water for Injection. Body Weight (kg) Bag 1 (loading dose): 150 mg/kg in 3 mL/kg of diluent * infused over 1 hour Bag 2 (second dose): 50 mg/kg in 7mL/kg of diluent * infused over 4 hours Bag 3 (third dose): 100 mg/kg diluted in 14 mL/kg of diluent * infused over 16 hours Acetylcysteine Injection Total Dose Diluent volume Acetylcysteine Injection Total Dose Diluent volume Acetylcysteine Injection Total Dose Diluent volume 5 kg 750 mg 15 mL 250 mg 35 mL 500 mg 70 mL 10 kg 1,500 mg 30 mL 500 mg 70 mL 1,000 mg 140 mL 15 kg 2,250 mg 45 mL 750 mg 105 mL 1,500 mg 210 mL 20 kg 3,000 mg 60 mL 1,000 mg 140 mL 2,000 mg 280 mL

  See also Section 2.2 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction

  Dosing for patients who weigh 21 kg to 40 kg ( Table 2):

  Loading Dose: 150 mg/kg diluted in 100 mL of diluent* administered over 1 hr

  Second Dose: 50 mg/kg diluted in 250 mL of diluent* administered over 4 hrs

  Third Dose: : 100 mg/kg diluted in 500 mL of diluent* administered over 16 hrs

  Table 2. Three Bag Method Dosage Guide by Weight in Patients 21 kg to 40 kg * Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose in Water 0.45% Sodium Chloride Injection, and Sterile Water for Injection. Body Weight (kg) Bag 1 (loading dose): 150 mg/kg in 100 mL of diluent * infused over 1 hr Bag 2 (second dose): 50 mg/kg in 250 mL of diluent * infused over 4 hrs Bag 3 (third dose): 100 mg/kg in 500 mL of diluent * infused over 16 hrs Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose 21 kg 3,150 mg 1,050 mg 2,100 mg 30 kg 4,500 mg 1,500 mg 3,000 mg 40 kg 6,000 mg 2,000 mg 4,000 mg

  See also Section 2.2 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction.

  Dosing for patients who weigh 41 kg to 100 kg ( Table 3):

  Loading Dose: 150 mg/kg diluted in 200 mL of diluent* administered over 1 hr

  Second Dose: 50 mg/kg diluted in 500 mL of diluent* administered over 4 hrs

  Third Dose: 100 mg/kg diluted in 1,000 mL of diluent administered over 16 hrs

  Table 3. Three Bag Method Dosage Guide by Weight in Patients 41 kg to 100 kg * Acetylcysteine Injection is compatible with the following diluents; 5% Dextrose 0.45% Sodium Chloride Injection, and Sterile Water for Injection. Body Weight (kg) Bag 1 (loading dose): 150 mg/kg diluted in 200 mL of diluent * infused over 1 hr Bag 2 (second dose): 50 mg/kg diluted in 500 mL of diluent * infused over 4 hrs Bag 3 (third dose): 100 mg/kg diluted in 1,000 mL of diluent * infused over 16 hrs Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose Acetylcysteine Injection Total Dose 41 kg 6,150 mg 2,050 mg 4,100 mg 50 kg 7,500 mg 2,500 mg 5,000 mg 60 kg 9,000 mg 3,000 mg 6,000 mg 70 kg 10,500 mg 3,500 mg 7,000 mg 80 kg 12,000 mg 4,000 mg 8,000 mg 90 kg 13,500 mg 4,500 mg 9,000 mg 100 kg 15,000 mg 5,000 mg 10,000 mg

  Patients Weighing More Than 100 kg

  No specific studies have been conducted to evaluate the use of or necessity of dosing adjustments in patients weighing over 100 kg. Limited information is available regarding the dosing requirements of patients that weigh more than 100 kg. The dose of Acetylcysteine Injection recommended in these patients should be a loading dose of 15,000 mg infused over a period of one hour followed by a first maintenance dose of 5,000 mg over 4 hours and a second maintenance dose of 10,000 mg over 16 hours ( Table 3).

  Continued Therapy beyond 21 Hours

  While there is no clinical trial data to support infusions beyond 21 hours there is literature that supports continued infusion of acetylcysteine in some rare instances. In cases of suspected massive overdose, or with concomitant ingestion of other substances, or in patients with preexisting liver disease, the absorption and/or the half-life of acetaminophen may be prolonged, in such cases consideration should be given to the need for continued infusion of N-acetylcysteine beyond 21 hours. Acetaminophen levels and ALT/AST & INR should be checked before the end of the 21-hour infusion. If acetaminophen levels are still detectable, or in cases in which the ALT/AST are still increasing or the INR remains elevated, the infusion should be continued, and the treating physician should contact a US regional poison center at 1-800-222-1222, or alternatively, a “special health professional assistance line for acetaminophen overdose” at 1-800-525-6115 for assistance with dosing recommendations.

  2.2 Volume Adjustment: Patients less than 40 kg and Requiring Fluid Restriction

  The total volume administered should be adjusted for patients less than 40 kg and for those requiring fluid restriction. To avoid fluid overload, the volume of diluent should be reduced as clinically needed. If the volume of the infusion is not adjusted, fluid overload can occur, potentially resulting in hyponatremia, seizure and death. [ see Dosage and Administration (2)]

  As Acetylcysteine Injection is hyperosmolar (2600 mOsmol/L), caution is advised when the diluent volume is decreased as the hyperosmolarity of the solution is increased. See Table 4 below for examples.

  Table 4. Acetylcysteine Injection Concentration and Osmolarity * Osmolarity should be adjusted to a physiologically safe level, (generally not less than 150mOsmol/L in children). Acetylcysteine Injection Concentration (mg/mL) Osmolarity in ½ Normal Saline Osmolarity in D5W Osmolarity in Sterile Water for Injection 7 mg/mL 245 mOsmol/L 343 mOsmol/L 91 mOsmol/L * 24 mg/m/L 466 mOsmol/L 564 mOsmol/L 312 mOsmol/L

  Single dose vial, preservative-free, discard unused portion. If vial was previously opened, do not use for intravenous administration.

  Stability studies indicate that the diluted solution is stable for 24 hours at controlled room temperature.

  Note: The color of Acetylcysteine Injection may turn from essentially colorless to a slight pink or purple once the stopper is punctured. The color change does not affect the quality of the product.

  2.3 Renal Impairment

  No data are available to determine if a dose adjustment in patients with moderate or severe renal impairment is required.

  2.4 Hepatic Impairment

  Although there was a threefold increase in acetylcysteine plasma concentrations in patients with hepatic cirrhosis, no data are available to determine if a dose adjustment in these patients is required. The published medical literature does not indicate that the dose of acetylcysteine in patients with hepatic impairment should be reduced.

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• Tobramycin
  

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  Tobramycin

  

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  Tobramycin may be given intramuscularly or intravenously.  Recommended dosages are the same for both routes.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS).

  Administration for Patients with Normal Renal Function

  Adults with Serious Infections:  3 mg/kg/day in 3 equal doses every 8 hours (see Table 3).

  Adults With Life-Threatening Infections:  Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3).  The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).

  Table 3

  DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION

  (Dosage at 8-Hour Intervals)

  For

  Patient Weighing

  Usual Dose for Serious Infections

  Maximum Dose for Life-Threatening Infections

  (Reduce as soon as possible)

  1 mg/kg q8h

  1.66 mg/kg q8h

  kg

  lb

  (Total, 3 mg/kg/day)

  (Total, 5 mg/kg/day)

   

   

  mg/dose

   

  mL/dose*

  mg/dose

   

  mL/dose*

   

   

   

  q8h

   

   

  q8h

   

  120

  264

  120 mg

   

  3 mL

  200 mg

   

  5 mL

  115

  253

  115 mg

   

  2.9 mL

  191 mg

   

  4.75 mL

  110

  242

  110 mg

   

  2.75 mL

  183 mg

   

  4.5 mL

  105

  231

  105 mg

   

  2.6 mL

  175 mg

   

  4.4 mL

  100

  220

  100 mg

   

  2.5 mL

  166 mg

   

  4.2 mL

  95

  209

  95 mg

   

  2.4 mL

  158 mg

   

  4 mL

  90

  198

  90 mg

   

  2.25 mL

  150 mg

   

  3.75 mL

  85

  187

  85 mg

   

  2.1 mL

  141 mg

   

  3.5 mL

  80

  176

  80 mg

   

  2 mL

  133 mg

   

  3.3 mL

  75

  165

  75 mg

   

  1.9 mL

  125 mg

   

  3.1 mL

  70

  154

  70 mg

   

  1.75 mL

  116 mg

   

  2.9 mL

  65

  143

  65 mg

   

  1.6 mL

  108 mg

   

  2.7 mL

  60

  132

  60 mg

   

  1.5 mL

  100 mg

   

  2.5 mL

  55

  121

  55 mg

   

  1.4 mL

  91 mg

   

  2.25 mL

  50

  110

  50 mg

   

  1.25 mL

  83 mg

   

  2.1 mL

  45

  99

  45 mg

   

  1.1 mL

  75 mg

   

  1.9 mL

  40

  88

  40 mg

   

  1 mL

  66 mg

   

  1.6 mL

  *Applicable to all product forms except the tobramycin pediatric injection (see HOW SUPPLIED).

   

  Pediatric Patients (greater than 1 week of age):  6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

  Premature or Full-Term Neonates 1 Week of Age or Less:  Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

  It is desirable to limit treatment to a short term.  The usual duration of treatment is 7 to 10 days.  A longer course of therapy may be necessary in difficult and complicated infections.  In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

  Dosage in Patients with Cystic Fibrosis

  In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose.  In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended.  This dosing regimen is suggested only as a guide.  The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

  Administration for Patients with Impaired Renal Function

  Whenever possible, serum tobramycin concentrations should be monitored during therapy.

  Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals.  Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly.  They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin.  The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.  Neither method should be used when dialysis is being performed.

  Reduced dosage at 8-hour intervals:  When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram.

   

   

   

  * Scales have been adjusted to facilitate dosage calculations.

  An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

  Normal dosage at prolonged intervals:  If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage frequency in hours for the dosage given in Table 3 can be determined by multiplying the patient’s serum creatinine by 6.

  Dosage in Obese Patients

  The appropriate dose may be calculated by using the patient’s estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

  Intramuscular Administration

  Tobramycin may be administered by withdrawing the approriate dose directly from a vial.

  Intravenous Administration

  For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses.  For pediatric patients, the volume of diluent should be proportionately less than that for adults.  The diluted solution usually should be infused over a period of 20 to 60 minutes.  Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

  Tobramycin injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

  Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

  Administration for Patients with Normal Renal Function

  Adults with Serious Infections:  3 mg/kg/day in 3 equal doses every 8 hours (see Table 3).

  Adults With Life-Threatening Infections:  Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3).  The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).

  Table 3

  DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION

  (Dosage at 8-Hour Intervals)

  For

  Patient Weighing

  Usual Dose for Serious Infections

  Maximum Dose for Life-Threatening Infections

  (Reduce as soon as possible)

  1 mg/kg q8h

  1.66 mg/kg q8h

  kg

  lb

  (Total, 3 mg/kg/day)

  (Total, 5 mg/kg/day)

   

   

  mg/dose

   

  mL/dose*

  mg/dose

   

  mL/dose*

   

   

   

  q8h

   

   

  q8h

   

  120

  264

  120 mg

   

  3 mL

  200 mg

   

  5 mL

  115

  253

  115 mg

   

  2.9 mL

  191 mg

   

  4.75 mL

  110

  242

  110 mg

   

  2.75 mL

  183 mg

   

  4.5 mL

  105

  231

  105 mg

   

  2.6 mL

  175 mg

   

  4.4 mL

  100

  220

  100 mg

   

  2.5 mL

  166 mg

   

  4.2 mL

  95

  209

  95 mg

   

  2.4 mL

  158 mg

   

  4 mL

  90

  198

  90 mg

   

  2.25 mL

  150 mg

   

  3.75 mL

  85

  187

  85 mg

   

  2.1 mL

  141 mg

   

  3.5 mL

  80

  176

  80 mg

   

  2 mL

  133 mg

   

  3.3 mL

  75

  165

  75 mg

   

  1.9 mL

  125 mg

   

  3.1 mL

  70

  154

  70 mg

   

  1.75 mL

  116 mg

   

  2.9 mL

  65

  143

  65 mg

   

  1.6 mL

  108 mg

   

  2.7 mL

  60

  132

  60 mg

   

  1.5 mL

  100 mg

   

  2.5 mL

  55

  121

  55 mg

   

  1.4 mL

  91 mg

   

  2.25 mL

  50

  110

  50 mg

   

  1.25 mL

  83 mg

   

  2.1 mL

  45

  99

  45 mg

   

  1.1 mL

  75 mg

   

  1.9 mL

  40

  88

  40 mg

   

  1 mL

  66 mg

   

  1.6 mL

  *Applicable to all product forms except the tobramycin pediatric injection (see HOW SUPPLIED).

   

  Pediatric Patients (greater than 1 week of age):  6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

  Premature or Full-Term Neonates 1 Week of Age or Less:  Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

  It is desirable to limit treatment to a short term.  The usual duration of treatment is 7 to 10 days.  A longer course of therapy may be necessary in difficult and complicated infections.  In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

  Dosage in Patients with Cystic Fibrosis

  In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose.  In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended.  This dosing regimen is suggested only as a guide.  The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

  Administration for Patients with Impaired Renal Function

  Whenever possible, serum tobramycin concentrations should be monitored during therapy.

  Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals.  Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly.  They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin.  The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary.  Neither method should be used when dialysis is being performed.

  Reduced dosage at 8-hour intervals:  When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram.

   

   

   

  * Scales have been adjusted to facilitate dosage calculations.

  An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient’s serum creatinine.

  Normal dosage at prolonged intervals:  If the creatinine clearance rate is not available and the patient’s condition is stable, a dosage frequency in hours for the dosage given in Table 3 can be determined by multiplying the patient’s serum creatinine by 6.

  Dosage in Obese Patients

  The appropriate dose may be calculated by using the patient’s estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

  Intramuscular Administration

  Tobramycin may be administered by withdrawing the approriate dose directly from a vial.

  Intravenous Administration

  For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses.  For pediatric patients, the volume of diluent should be proportionately less than that for adults.  The diluted solution usually should be infused over a period of 20 to 60 minutes.  Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

  Tobramycin injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

  Prior to administration, parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

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• Mannitol
  

  ×

  Mannitol

  

  ---

  For Intravenous Injection

  General Recommendations–Give mannitol injection only intravenously.  The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output.  Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours.  The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr). 

  Test Dose–In marked oliguria or inadequate renal function a test dose of mannitol should be given.  The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr).  If urine flow does not increase within two or three hours a second test dose may be given.  If there is an inadequate response the patient should be reevaluated. 

  Prevention of Acute Renal Failure (Oliguria)–When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given.  The concentration and amount will depend upon the fluid requirements of the patient.  Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis.  If diuresis does not occur the 20 g dose may be repeated.  If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. 

  Treatment of Oliguria–The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. 

  Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure–A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity.  When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes.  Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate.  Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol.  Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. 

  Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection. 

  Urinary Excretion of Toxic Substances–Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high.  The concentration will depend upon the fluid requirement and urinary output.  Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air.  If benefits are not observed after 200 g of mannitol are given, discontinue it. 

  For Urologic Irrigation

  A 2.5% solution is used.  The use of 2.5% mannitol solution minimizes the hemolytic effect of water alone, the entrance of hemolyzed blood into the circulation, and the resulting hemoglobinemia which is considered a major factor in producing serious renal complications. 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  For Intravenous Injection

  General Recommendations–Give mannitol injection only intravenously.  The total dosage, concentration and rate of administration should be governed by the nature and severity of the condition being treated, fluid requirement and urinary output.  Usual adult dosage ranges from 50 to 200 g in 24 hours but in most instances an adequate response will be achieved at a dosage of approximately 100 g in 24 hours.  The rate is usually adjusted to maintain an adequate urine flow (at least 30 to 50 mL/hr). 

  Test Dose–In marked oliguria or inadequate renal function a test dose of mannitol should be given.  The test dose may be approximately 0.2 g/kg (about 50 mL of a 25% solution) infused in three to five minutes to produce an adequate urine flow (at least 30 to 50 mL/hr).  If urine flow does not increase within two or three hours a second test dose may be given.  If there is an inadequate response the patient should be reevaluated. 

  Prevention of Acute Renal Failure (Oliguria)–When used during surgery, immediately postoperatively or following trauma, 50 to100 g of mannitol as a 5 to 25% solution maybe given.  The concentration and amount will depend upon the fluid requirements of the patient.  Following suspected or actual hemolytic transfusion reactions 20 g of mannitol may be given intravenously over a five minute period to provoke diuresis.  If diuresis does not occur the 20 g dose may be repeated.  If there is an adequate urine flow (30 to 50 mL/hr) then intravenous fluids containing not more than 50 to 75 mEq of sodium per liter should be given in sufficient volume to match the desired urine flow (100 mL/hr) until fluids can be taken orally. 

  Treatment of Oliguria–The usual dose for treatment of oliguria is 50 to 100 g as a 15 to 25% solution. 

  Reduction of Intracranial Pressure, Cerebral Edema or Intraocular Pressure–A 25% solution of mannitol is recommended since its effectiveness depends on establishing intravascular hyperosmolarity.  When used before or after surgery, a total dose of 1.5 to 2 g/kg can be given over a period of 30 to 60 minutes.  Careful evaluation must be made of the circulatory and renal reserve prior to and during use of mannitol at this relatively high dose and rapid infusion rate.  Careful attention must be paid to fluid and electrolyte balance, body weight, and total input and output before and after infusion of mannitol.  Evidence of reduced cerebral spinal fluid pressure may be observed within 15 minutes after starting infusion. 

  Maximal reduction of intraocular pressure occurs 30 to 60 minutes after injection. 

  Urinary Excretion of Toxic Substances–Mannitol in 5 to 25% solutions is used as an infusion as long as indicated if the level of urinary output remains high.  The concentration will depend upon the fluid requirement and urinary output.  Intravenous water and electrolytes must be given to replace the loss of these substances in the urine, sweat and expired air.  If benefits are not observed after 200 g of mannitol are given, discontinue it. 

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• Meropenem
  

  ×

  Meropenem

  

  ---

  2.1 Adult Patients

  The recommended dose of Meropenem for injection (I.V.) is 500 mg given every 8 hours for skin and skin structure infections and 1 gram given every 8 hours for intra-abdominal infections. When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 1 gram every 8 hours is recommended.  Meropenem for injection (I.V.) should be administered by intravenous infusion over approximately 15 minutes to 30 minutes. Doses of 1 gram may also be administered as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

  2.2 Use in Adult Patients with Renal Impairment

  Dosage should be reduced in patients with creatinine clearance of 50 mL/min or less. (See dosing table below.)

  When only serum creatinine is available, the following formula (Cockcroft and Gault equation)5 may be used to estimate creatinine clearance.

  Males: Creatinine Clearance (mL/min) = Weight (kg) x (140 - age)__

                                                                    72 x serum creatinine (mg/dL)

  Females: 0.85 x above value

  Recommended Meropenem for injection (I.V.) Dosage Schedule for Adult Patients With Renal Impairment  Creatinine Clearance  (mL/min) Dose (dependent on type of infection) Dosing Interval Greater than 50 Recommended dose (500 mg cSSSI and 1 gram Intra-abdominal) Every 8 hours Greater than 25 to 50 Recommended dose Every 12 hours 10 to 25 One-half recommended dose Every 12 hours Less than 10 One-half recommended dose Every 24 hours

  There is inadequate information regarding the use of Meropenem for injection (I.V.) in patients on hemodialysis or peritoneal dialysis.

  2.3 Use in Pediatric Patients

  Pediatric Patients 3 Months of Age and OlderFor pediatric patients from 3 months of age and older, the Meropenem for injection (I.V.) dose is 10 mg/kg, 20 mg/kg or 40 mg/kg every 8 hours (maximum dose is 2 grams every 8 hours), depending on the type of infection (complicated skin and skin structure, intra-abdominal or meningitis). (See dosing table below.) Pediatric patients weighing over 50 kg should be administered Meropenem for injection (I.V.) at a dose of 500 mg every 8 hours for complicated skin and skin structure infections, 1 gram every 8 hours for intra-abdominal infections and 2 grams every 8 hours for meningitis. Meropenem for injection (I.V.) should be given as intravenous infusion over approximately 15 minutes to 30 minutes or as an intravenous bolus injection (5 mL to 20 mL) over approximately 3 minutes to 5 minutes.

  There is limited safety data available to support the administration of a 40 mg/kg (up to a maximum of 2 grams) bolus dose.

  Recommended Meropenem for injection (I.V.) Dosage Schedule for Pediatric Patients 3 Months of Age and Older With Normal Renal Function Type of Infection Dose (mg/kg) Up to a Maximum Dose Dosing Interval Complicated skin and skin structure 10 500 mg Every 8 hours Intra-abdominal 20 1 gram Every 8 hours Meningitis 40 2 grams Every 8 hours

  There is no experience in pediatric patients with renal impairment.

  When treating complicated skin and skin structure infections caused by P. aeruginosa, a dose of 20 mg/Kg (or 1 gram for pediatric patients weighing over 50 kg) every 8 hours is recommended.

  Pediatric Patients Less Than 3 Months of Age

  For pediatric patients (with normal renal function) less than 3 months of age, with intra-abdominal infections, the Meropenem for injection (I.V.) dose is based on gestational age (GA) and postnatal age (PNA). (See dosing table below). Meropenem for injection (I.V.) should be given as intravenous infusion over 30 minutes.  

  Recommended Meropenem for injection (I.V.) Dosage Schedule for Pediatric Patients Less than 3 Months of Age with Complicated Intra-Abdominal Infections and Normal Renal Function Age group Dose (mg/kg) Dose Interval Infants less than 32 weeks GA and PNA less than 2 weeks 20 Every 12 hours Infants less than 32 weeks GA and PNA 2 weeks and older 20 Every 8 hours Infants 32 weeks and older GA and PNA less than 2 weeks 20 Every 8 hours Infants 32 weeks and older GA and PNA 2 weeks and older 30 Every 8 hours

  There is no experience in pediatric patients with renal impairment 

  2.4 Preparation of Solution

  For Intravenous Bolus Administration

  Constitute injection vials (500 mg and 1 gram) with sterile Water for Injection (see table below). Shake to dissolve and let stand until clear.

      Vial size Amount of Diluent Added (mL) Approximate Withdrawable Volume (mL) Approximate Average Concentration (mg/mL) 500 mg 10 10 50 1 gram 20 20 50

  For Infusion

  Infusion vials (500 mg and 1 gram) may be directly constituted with a compatible infusion fluid. Alternatively, an injection vial may be constituted, then the resulting solution added to an intravenous container and further diluted with an appropriate infusion fluid [see Dosage and Administration (2.5) and (2.6)].

  WARNING: Do not use flexible container in series connections.

  2.5 Compatibility

  Compatibility of Meropenem with other drugs has not been established. Meropenem should not be mixed with or physically added to solutions containing other drugs.

  2.6 Stability and Storage

  Freshly prepared solutions of Meropenem should be used. However, constituted solutions of Meropenem maintain satisfactory potency under the conditions described below. Solutions of intravenous Meropenem should not be frozen.

  Intravenous Bolus Administration

  Meropenem injection vials constituted with sterile Water for Injection for bolus administration (up to 50 mg/mL of Meropenem) may be stored for up to 3 hours at up to 25°C (77°F) or for 13 hours at up to 5°C (41°F).

  Intravenous Infusion Administration

  Solutions prepared for infusion (Meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Sodium Chloride Injection 0.9% may be stored for 1 hour at up to 25°C (77°F) or 15 hours at up to 5°C (41°F).Solutions prepared for infusion (Meropenem concentrations ranging from 1 mg/mL to 20 mg/mL) constituted with Dextrose Injection 5% should be used immediately.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Sumatriptan Succinate
  

  ×

  Sumatriptan Succinate

  

  ---

  [see Indications and Usage (1) and Clinical Pharmacology (12.3)]

  2.1 Community-Acquired Pneumonia

  The recommended dose of azithromycin for injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg tablets to complete a 7 to 10 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

  2.2 Pelvic Inflammatory Disease

  The recommended dose of azithromycin for injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is 500 mg as a single daily dose by the intravenous route for one or two days.  Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

  2.3 Preparation of the Solution for Intravenous Administration

  The infusate concentration and rate of infusion for azithromycin for injection should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour.  Azithromycin for injection should not be given as a bolus or as an intramuscular injection.

  Reconstitution

  Prepare the initial solution of azithromycin for injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial, and shaking the vial until all of the drug is dissolved.  Since azithromycin for injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed.  Each mL of reconstituted solution contains 100 mg azithromycin.  Reconstituted solution is stable for 24 hours when stored below 30°C (86°F).

  Parenteral drug products should be inspected visually for particulate matter prior to particulate matter is evident in reconstituted fluids, the drug solution should administration.  If be discarded.

  Dilute this solution further prior to administration as instructed below.

  Dilution

  To provide azithromycin over a concentration range of 1 to 2 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below:

  Normal Saline (0.9% sodium chloride)

  1/2 Normal Saline (0.45% sodium chloride)

  5% Dextrose in Water

  Lactated Ringer’s Solution

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl

  5% Dextrose in Lactated Ringer’s Solution

  5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)

  Normosol®-M in 5% Dextrose

  Normosol®-R in 5% Dextrose

  When used with the Vial-Mate® drug reconstitution device, please reference the Vial-Mate® instructions for assembly and reconstitution.

  Final Infusion Solution Concentration (mg/mL)                       Amount of Diluent (mL)

                          1 mg/mL                                                          500 mL

                          2 mg/mL                                                          250 mL

  Other intravenous substances, additives, or medications should not be added to azithromycin for injection or infused simultaneously through the same intravenous line.

  Storage

  Store the white to off-white lyophilized cake at 20º to 25ºC (68º to 77ºF) [see USP Controlled Room Temperature]. When diluted according to the instructions (1 mg/mL to 2 mg/mL), azithromycin for injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

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• Fosphenytoin
  

  ×

  Fosphenytoin

  

  ---

  The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE).  There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses.  Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE).  1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE.  The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).

  Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.

  Caution must be used when administering fosphenytoin sodium injection due to the risk of dosing errors (see WARNINGS).  Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE and 10 mL vials containing a total of 500 mg PE.  Both vials contain a concentration of 50 mg PE/mL.  Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE.  These errors have resulted in two- or ten-fold overdoses of fosphenytoin sodium injection since each of the vials actually contains a total of 100 mg PE or 500 mg PE.  In some cases, ten-fold overdoses were associated with fatal outcomes.  To help minimize confusion, the prescribed dose of fosphenytoin sodium injection should always be expressed in milligrams of phenytoin equivalents (mg PE).  Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL or 500 mg PE/10 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified.  Care should be taken to ensure the appropriate volume of fosphenytoin is withdrawn from the vial when preparing the dose for administration.  Attention to these details may prevent some fosphenytoin medication errors from occurring.

  Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL.  The maximum concentration of fosphenytoin in any solution should be 25 mg PE/mL.  When fosphenytoin is given as an intravenous infusion, fosphenytoin needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Status Epilepticus

  The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full anti-epileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.

  If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. 

  Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.

  Nonemergent Loading and Maintenance Dosing

  Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.

  The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM.  The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).

  The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.

  IM or IV Substitution for Oral Phenytoin Therapy

  When treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose.  Phenytoin sodium capsules are approximately 90% bioavailable by the oral route.  Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes.  For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites.  Some patients may require more frequent dosing.

  Dosing in Special Populations

  Patients with Renal or Hepatic Disease:  Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY, Special Populations).  Unbound phenytoin concentrations may be more useful in these patient populations.  After IV fosphenytoin sodium injection administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.  This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).

  Elderly Patients:  Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration.  Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

  Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients have not been established.

  Status Epilepticus

  The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full anti-epileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.

  If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. 

  Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.

  Nonemergent Loading and Maintenance Dosing

  Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.

  The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM.  The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).

  The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.

  IM or IV Substitution for Oral Phenytoin Therapy

  When treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose.  Phenytoin sodium capsules are approximately 90% bioavailable by the oral route.  Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes.  For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites.  Some patients may require more frequent dosing.

  Dosing in Special Populations

  Patients with Renal or Hepatic Disease:  Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY, Special Populations).  Unbound phenytoin concentrations may be more useful in these patient populations.  After IV fosphenytoin sodium injection administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.  This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).

  Elderly Patients:  Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration.  Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

  Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients have not been established.

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• Naropin
  

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  Naropin

  

  ---

  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used.  The smallest dose and concentration required to produce the desired result should be administered.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Naropin is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  Patients in poor general condition due to aging or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients.  To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly.

  Use an adequate test dose (3 to 5 mL of a short acting local anesthetic solution containing epinephrine) prior to induction of complete block.  This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.  Allow adequate time for onset of anesthesia following administration of each test dose.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Solutions which are discolored or which contain particulate matter should not be administered.

   

                                                                                   Table 7

                                                                 Dosage Recommendations

  Conc.

  Volume

  Dose

  Onset

  Duration

  mg/mL

  (%)

  mL

  mg

  min

  hours

  SURGICAL ANESTHESIA

  Lumbar Epidural

  5

  (0.5%)

  15 to 30

  75 to 150

  15 to 30

  2 to 4

  Administration

  7.5

  (0.75%)

  15 to 25

  113 to 188

  10 to 20

  3 to 5

  Surgery

  10

  (1%)

  15 to 20

  150 to 200

  10 to 20

  4 to 6

  Lumbar Epidural

  5

  (0.5%)

  20 to 30

  100 to 150

  15 to 25

  2 to 4

  Administration

  7.5

  (0.75%)

  15 to 20

  113 to 150

  10 to 20

  3 to 5

  Cesarean Section

  Thoracic Epidural

  5

  (0.5%)

  5 to 15

  25 to 75

  10 to 20

  n/a*

  Administration

  7.5

  (0.75%)

  5 to 15

  38 to 113

  10 to 20

  n/a*

  Surgery

  Major Nerve Block†

  5

  (0.5%)

  35 to 50

  175 to 250

  15 to 30

  5 to 8

  (eg, brachial plexus block)

  7.5

  (0.75%)

  10 to 40

  75 to 300

  10 to 25

  6 to 10

  Field Block

  5

  (0.5%)

  1 to 40

  5 to 200

  1 to 15

  2 to 6

  (eg, minor nerve blocks and infiltration)

  LABOR PAIN MANAGEMENT

  Lumbar Epidural Administration

  Initial Dose

  2

  (0.2%)

  10 to 20

  20 to 40

  10 to 15

  0.5 to 1.5

  Continuous infusion‡

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Incremental

  injections (top-up)‡

  2

  (0.2%)

  10 to 15

  mL/h

  20 to 30

  mg/h

  n/a*

  n/a*

  POSTOPERATIVE PAIN MANAGEMENT

  Lumbar Epidural Administration

  Continuous infusion§

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Thoracic Epidural

  Administration

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Continuous infusion§

  Infiltration

  2

  (0.2%)

  1 to 100

  2 to 200

  1 to 5

  2 to 6

  (eg, minor nerve block)

  5

  (0.5%)

  1 to 40

  5 to 200

  1 to 5

  2 to 6

  *  =  Not Applicable

  †  =  The dose for a major nerve block must be adjusted according to site of administration and patient status.  Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see PRECAUTIONS).

  ‡  =   Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.

  §  =  Cumulative doses up to 770 mg of Naropin over 24 hours (intraoperative block plus postoperative infusion);  Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, ie, 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.

   

  The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults.  Individual variations in onset and duration occur.  The figures reflect the expected average dose range needed.  For other local anesthetic techniques standard current textbooks should be consulted.

  When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered.  Experience to date indicates that a cumulative dose of up to 770 mg Naropin administered over 24 hours is well tolerated in adults when used for postoperative pain management: ie, 2016 mg.  Caution should be exercised when administering Naropin for prolonged periods of time, eg, > 70 hours in debilitated patients.

  For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL Naropin is induced via an epidural catheter.  Analgesia is maintained with an infusion of Naropin, 2 mg/mL (0.2%).  Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block.  With this technique a significant reduction in the need for opioids was demonstrated.  Clinical experience supports the use of Naropin epidural infusions for up to 72 hours.

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• Naropin
  

  ×

  Naropin

  

  ---

  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used.  The smallest dose and concentration required to produce the desired result should be administered.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Naropin is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  Patients in poor general condition due to aging or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients.  To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly. Use an adequate test dose (3 to 5 mL of a short-acting local anesthetic solution containing epinephrine) prior to induction of complete block.  This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.  Allow adequate time for onset of anesthesia following administration of each test dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Solutions which are discolored or which contain particulate matter should not be administered.

  Table 7 Dosage Recommendations * = Not Applicable   † = The dose for a major nerve block must be adjusted according to site of administration and patient status.  Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see PRECAUTIONS).   ‡ = Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.   § = Cumulative doses up to 770 mg of Naropin over 24 hours (intraoperative block plus postoperative infusion);  Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, ie, 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.   Conc. Volume Dose Onset Duration mg/mL (%) mL mg min hours SURGICAL ANESTHESIA Lumbar Epidural 5 (0.5%) 15 to 30 75 to 150 15 to 30 2 to 4 Administration 7.5 (0.75%) 15 to 25 113 to 188 10 to 20 3 to 5 Surgery 10 (1%) 15 to 20 150 to 200 10 to 20 4 to 6 Lumbar Epidural 5 (0.5%) 20 to 30 100 to 150 15 to 25 2 to 4 Administration 7.5 (0.75%) 15 to 20 113 to 150 10 to 20 3 to 5 Cesarean Section Thoracic Epidural 5 (0.5%) 5 to 15 25 to 75 10 to 20 n/a*      Administration 7.5 (0.75%) 5 to 15 38 to 113 10 to 20 n/a*      Surgery Major Nerve Block†      5 (0.5%) 35 to 50 175 to 250 15 to 30 5 to 8 (eg, brachial plexus block) 7.5 (0.75%) 10 to 40 75 to 300 10 to 25 6 to 10 Field Block 5 (0.5%) 1 to 40 5 to 200 1 to 15 2 to 6

  (eg, minor nerve blocks

  and infiltration) LABOR PAIN MANAGEMENT Lumbar Epidural Administration Initial Dose 2 (0.2%) 10 to 20 20 to 40 10 to 15 0.5 to 1.5

  Continuous

  infusion‡      2 (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h n/a*      n/a*     

  Incremental

  injections (top-up)‡      2 (0.2%)

  10 to 15

  mL/h

  20 to 30

  mg/h n/a*      n/a*      POSTOPERATIVE PAIN MANAGEMENT   Lumbar Epidural Administration  

  Continuous

  infusion§       2  (0.2%) 

  6 to 14

  mL/h  

  12 to 28

  mg/h  n/a*       n/a*      

  Thoracic Epidural

  Administration   2  (0.2%) 

  6 to 14

  mL/h 

  12 to 28

  mg/h  n/a*       n/a*       Continuous infusion§               Infiltration   2 (0.2%)  1 to 100  2 to 200  1 to 5  2 to 6  (eg, minor nerve block)   5  (0.5%)  1 to 40  5 to 200  1 to 5  2 to 6 

  The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults.  Individual variations in onset and duration occur.  The figures reflect the expected average dose range needed.  For other local anesthetic techniques standard current textbooks should be consulted. When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered.  Experience to date indicates that a cumulative dose of up to 770 mg Naropin administered over 24 hours is well tolerated in adults when used for postoperative pain management:  ie, 2016 mg.  Caution should be exercised when administering Naropin for prolonged periods of time, eg, >70 hours in debilitated patients. For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL  Naropin is induced via an epidural catheter.  Analgesia is maintained with an infusion of Naropin, 2 mg/mL (0.2%).  Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block.  With this technique a significant reduction in the need for opioids was demonstrated.  Clinical experience supports the use of Naropin epidural infusions for up to 72 hours.

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• Doxy 100
  

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  Doxy 100

  

  ---

  NOTE:  Rapid administration is to be avoided.  Parenteral therapy is indicated only when oral therapy is not indicated.  Oral therapy should be instituted as soon as possible.  If intravenous therapy is given over prolonged periods of time, thrombophlebitis may result.

  THE USUAL DOSAGE AND FREQUENCY OF ADMINISTRATION OF DOXYCYCLINE FOR INJECTION (100 to 200 MG/DAY) DIFFERS FROM THAT OF THE OTHER TETRACYCLINES (1 to 2 G/DAY).  EXCEEDING THE RECOMMENDED DOSAGE MAY RESULT IN AN INCREASED INCIDENCE OF SIDE EFFECTS.

  Studies to date have indicated that doxycycline hyclate at the usual recommended doses does not lead to excessive accumulation of the antibiotic in patients with renal impairment.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS, Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

  Adults

  The usual dosage of doxycycline for injection is 200 mg on the first day of treatment administered in one or two infusions.  Subsequent daily dosage is 100 to 200 mg depending upon the severity of infection, with 200 mg administered in one or two infusions.

  In the treatment of primary and secondary syphilis, the recommended dosage is 300 mg daily for at least 10 days.

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 100 mg of doxycycline, twice a day.  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  For Children Above Eight Years of Age

  The recommended dosage schedule for children weighing 100 pounds or less is 2 mg/lb of body weight on the first day of treatment, administered in one or two infusions.  Subsequent daily dosage is 1 to 2 mg/lb of body weight given as one or two infusions, depending on the severity of the infection.  For children over 100 pounds the usual adult dose should be used (see WARNINGS, Usage in Children).

  In the treatment of inhalational anthrax (post-exposure) the recommended dose is 1 mg/lb (2.2 mg/kg) of body weight, twice a day in children weighing less than 100 lb (45 kg).  Parenteral therapy is only indicated when oral therapy is not indicated and should not be continued over a prolonged period of time.  Oral therapy should be instituted as soon as possible.  Therapy must continue for a total of 60 days.

  General

  The duration of infusion may vary with the dose (100 to 200 mg/day), but is usually one to four hours.  A recommended minimum infusion time for 100 mg of a 0.5 mg/mL solution is one hour.  Therapy should be continued for at least 24 to 48 hours after symptoms and fever have subsided.  The therapeutic antibacterial serum activity will usually persist for 24 hours following recommended dosage.

  Intravenous solutions should not be injected intramuscularly or subcutaneously.  Caution should be taken to avoid the inadvertent introduction of the intravenous solution into the adjacent soft tissue.

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• Ganciclovir
  

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  Ganciclovir

  

  ---

  CAUTION – DO NOT ADMINISTER GANCICLOVIR FOR INJECTION, USP SOLUTION BY RAPID OR BOLUS INTRAVENOUS INJECTION. THE TOXICITY OF GANCICLOVIR FOR INJECTION, USP MAY BE INCREASED AS A RESULT OF EXCESSIVE PLASMA LEVELS.

  CAUTION – INTRAMUSCULAR OR SUBCUTANEOUS INJECTION OF RECONSTITUTED GANCICLOVIR FOR INJECTION, USP SOLUTION MAY RESULT IN SEVERE TISSUE IRRITATION DUE TO HIGH pH (11).

  Dosage

  THE RECOMMENDED DOSE FOR GANCICLOVIR FOR INJECTION, USP SOLUTION SHOULD NOT BE EXCEEDED.  THE RECOMMENDED INFUSION RATE FOR GANCICLOVIR FOR INJECTION SOLUTION SHOULD NOT BE EXCEEDED.

  For Treatment of CMV Retinitis in Patients with Normal Renal Function

  Induction Treatment

  The recommended initial dosage for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days.

  Maintenance Treatment

  Following induction treatment, the recommended maintenance dosage of ganciclovir for injection solution is 5 mg/kg given as a constant-rate intravenous infusion over 1 hour once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

  For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of ganciclovir, reinduction treatment is recommended.

  For the Prevention of CMV Disease in Transplant Recipients with Normal Renal Function

  The recommended initial dosage of ganciclovir for injection solution for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days, followed by 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

  The duration of treatment with ganciclovir for injection solution and in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with ganciclovir for injection was continued until day 100 to 120 posttransplantation.  CMV disease occurred in several patients who discontinued treatment with ganciclovir for injection solution prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with ganciclovir for injection was stopped at day 28 posttransplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population (see INDICATIONS AND USAGE section for a more detailed discussion).

  Renal Impairment

  For patients with impairment of renal function, refer to Table 8 for recommended doses of ganciclovir solution and adjust the dosing interval as indicated:

  Table 8  Dosing for Patients with Renal Impairment

  Creatinine

  Clearance*

  (mL/min)

  Ganciclovir for Injection

  Induction

  Dose (mg/kg)

  Dosing

  Interval

  (hours)

  Ganciclovir for Injection

  Maintenance

  Dose (mg/kg)

  Dosing

  Interval

  (hours)

  ≥70

  5

  12

  5

  24

  50 to 69

  2.5

  12

  2.5

  24

  25 to 49

  2.5

  24

  1.25

  24

  10 to 24

  1.25

  24

  0.625

  24

  <10

  1.25

  3 times per week, following hemodialysis

  0.625

  3 times per week, following hemodialysis

  *Creatinine clearance can be related to serum creatinine by the formulas given below.

  Creatinine clearance for males = (140-age[yrs]) (body wt [kg])

                                               (72) (serum creatinine [mg/dL])

  Creatinine clearance for females = 0.85 x male value

  Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week, following each hemodialysis session. Ganciclovir for injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.

  Patient Monitoring

  Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1,000 cells/mcL at the beginning of treatment.  Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

  Reduction of Dose

  Dosage reductions in renally impaired patients are required for ganciclovir for injection (see Renal Impairment).  Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE EVENTS). Ganciclovir for injection should not be administered in patients with severe neutropenia (ANC less than 500/mcL) or severe thrombocytopenia (platelets less than 25,000/mcL).

  Method of Preparation of Ganciclovir for Injection Solution

  Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir and 46 mg of sodium. The contents of the vial should be prepared for administration in the following manner:

  Reconstituted Solution:

            a.  Reconstitute lyophilized ganciclovir for injection by injecting 10 mL of Sterile Water for

                 Injection, USP into the vial.

                 DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING

                 PARABENS. IT IS INCOMPATIBLE WITH GANCICLOVIR FOR INJECTION AND MAY CAUSE PRECIPITATION.

             b.  Shake the vial to dissolve the drug.

             c.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion solution. Discard the

                  vial if particulate matter or discoloration is observed.

             d.  Reconstituted solution in the vial is stable at room temperature for 12 hours.  It should not be refrigerated. 

       2.  Infusion Solution:

           Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the

           vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour. Infusion concentrations greater than

           10 mg/mL are not recommended.  The following infusion fluids have been determined to be chemically and physically compatible with

           ganciclovir for injection solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer’s Injection and Lactated Ringer’s Injection, USP.

                Ganciclovir for injection, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored

           refrigerated at 5°C in polyvinyl chloride (PVC) bags, remains physically and chemically stable for 14 days.

                 However, because ganciclovir for injection is reconstituted with non-bacteriostatic sterile water, it is recommended that the infusion solution be

            used within 24 hours of dilution to reduce the risk of bacterial contamination. The infusion should be refrigerated. Freezing is not

           recommended.

  Handling and Disposal

  Caution should be exercised in the handling and preparation of solutions of ganciclovir for injection.  Solutions of ganciclovir for injection are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with ganciclovir for injection solutions. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

  Because ganciclovir shares some of the properties of anti-tumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs.  Several guidelines on this subject have been published.7-9

  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Dosage

  THE RECOMMENDED DOSE FOR GANCICLOVIR FOR INJECTION, USP SOLUTION SHOULD NOT BE EXCEEDED.  THE RECOMMENDED INFUSION RATE FOR GANCICLOVIR FOR INJECTION SOLUTION SHOULD NOT BE EXCEEDED.

  For Treatment of CMV Retinitis in Patients with Normal Renal Function

  Induction Treatment

  The recommended initial dosage for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 14 to 21 days.

  Maintenance Treatment

  Following induction treatment, the recommended maintenance dosage of ganciclovir for injection solution is 5 mg/kg given as a constant-rate intravenous infusion over 1 hour once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

  For patients who experience progression of CMV retinitis while receiving maintenance treatment with either formulation of ganciclovir, reinduction treatment is recommended.

  For the Prevention of CMV Disease in Transplant Recipients with Normal Renal Function

  The recommended initial dosage of ganciclovir for injection solution for patients with normal renal function is 5 mg/kg (given intravenously at a constant rate over 1 hour) every 12 hours for 7 to 14 days, followed by 5 mg/kg once daily, 7 days per week or 6 mg/kg once daily, 5 days per week.

  The duration of treatment with ganciclovir for injection solution and in transplant recipients is dependent upon the duration and degree of immunosuppression. In controlled clinical trials in bone marrow allograft recipients, treatment with ganciclovir for injection was continued until day 100 to 120 posttransplantation.  CMV disease occurred in several patients who discontinued treatment with ganciclovir for injection solution prematurely. In heart allograft recipients, the onset of newly diagnosed CMV disease occurred after treatment with ganciclovir for injection was stopped at day 28 posttransplant, suggesting that continued dosing may be necessary to prevent late occurrence of CMV disease in this patient population (see INDICATIONS AND USAGE section for a more detailed discussion).

  Renal Impairment

  For patients with impairment of renal function, refer to Table 8 for recommended doses of ganciclovir solution and adjust the dosing interval as indicated:

  Table 8  Dosing for Patients with Renal Impairment

  Creatinine

  Clearance*

  (mL/min)

  Ganciclovir for Injection

  Induction

  Dose (mg/kg)

  Dosing

  Interval

  (hours)

  Ganciclovir for Injection

  Maintenance

  Dose (mg/kg)

  Dosing

  Interval

  (hours)

  ≥70

  5

  12

  5

  24

  50 to 69

  2.5

  12

  2.5

  24

  25 to 49

  2.5

  24

  1.25

  24

  10 to 24

  1.25

  24

  0.625

  24

  <10

  1.25

  3 times per week, following hemodialysis

  0.625

  3 times per week, following hemodialysis

  *Creatinine clearance can be related to serum creatinine by the formulas given below.

  Creatinine clearance for males = (140-age[yrs]) (body wt [kg])

                                               (72) (serum creatinine [mg/dL])

  Creatinine clearance for females = 0.85 x male value

  Dosing for patients undergoing hemodialysis should not exceed 1.25 mg/kg 3 times per week, following each hemodialysis session. Ganciclovir for injection should be given shortly after completion of the hemodialysis session, since hemodialysis has been shown to reduce plasma levels by approximately 50%.

  Patient Monitoring

  Due to the frequency of granulocytopenia, anemia and thrombocytopenia in patients receiving ganciclovir (see ADVERSE EVENTS), it is recommended that complete blood counts and platelet counts be performed frequently, especially in patients in whom ganciclovir or other nucleoside analogues have previously resulted in cytopenia, or in whom neutrophil counts are less than 1,000 cells/mcL at the beginning of treatment.  Patients should have serum creatinine or creatinine clearance values followed carefully to allow for dosage adjustments in renally impaired patients (see DOSAGE AND ADMINISTRATION).

  Reduction of Dose

  Dosage reductions in renally impaired patients are required for ganciclovir for injection (see Renal Impairment).  Dosage reductions should also be considered for those with neutropenia, anemia and/or thrombocytopenia (see ADVERSE EVENTS). Ganciclovir for injection should not be administered in patients with severe neutropenia (ANC less than 500/mcL) or severe thrombocytopenia (platelets less than 25,000/mcL).

  Method of Preparation of Ganciclovir for Injection Solution

  Each 10 mL clear glass vial contains ganciclovir sodium equivalent to 500 mg of ganciclovir and 46 mg of sodium. The contents of the vial should be prepared for administration in the following manner:

  Reconstituted Solution:

            a.  Reconstitute lyophilized ganciclovir for injection by injecting 10 mL of Sterile Water for

                 Injection, USP into the vial.

                 DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING

                 PARABENS. IT IS INCOMPATIBLE WITH GANCICLOVIR FOR INJECTION AND MAY CAUSE PRECIPITATION.

             b.  Shake the vial to dissolve the drug.

             c.  Visually inspect the reconstituted solution for particulate matter and discoloration prior to proceeding with infusion solution. Discard the

                  vial if particulate matter or discoloration is observed.

             d.  Reconstituted solution in the vial is stable at room temperature for 12 hours.  It should not be refrigerated. 

       2.  Infusion Solution:

           Based on patient weight, the appropriate volume of the reconstituted solution (ganciclovir concentration 50 mg/mL) should be removed from the

           vial and added to an acceptable infusion fluid (typically 100 mL) for delivery over the course of 1 hour. Infusion concentrations greater than

           10 mg/mL are not recommended.  The following infusion fluids have been determined to be chemically and physically compatible with

           ganciclovir for injection solution: 0.9% Sodium Chloride, 5% Dextrose, Ringer’s Injection and Lactated Ringer’s Injection, USP.

                Ganciclovir for injection, when reconstituted with sterile water for injection, further diluted with 0.9% sodium chloride injection, and stored

           refrigerated at 5°C in polyvinyl chloride (PVC) bags, remains physically and chemically stable for 14 days.

                 However, because ganciclovir for injection is reconstituted with non-bacteriostatic sterile water, it is recommended that the infusion solution be

            used within 24 hours of dilution to reduce the risk of bacterial contamination. The infusion should be refrigerated. Freezing is not

           recommended.

  Handling and Disposal

  Caution should be exercised in the handling and preparation of solutions of ganciclovir for injection.  Solutions of ganciclovir for injection are alkaline (pH 11). Avoid direct contact of the skin or mucous membranes with ganciclovir for injection solutions. If such contact occurs, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.

  Because ganciclovir shares some of the properties of anti-tumor agents (ie, carcinogenicity and mutagenicity), consideration should be given to handling and disposal according to guidelines issued for antineoplastic drugs.  Several guidelines on this subject have been published.7-9

  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Magnesium Sulfate
  

  ×

  Magnesium Sulfate

  

  ---

  Dosage of magnesium sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

  Both IV and IM administration are appropriate.  IM administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a therapeutic level almost immediately.  The rate of IV injection should generally not exceed 150 mg/minute (1.5 mL of a 10% concentration or its equivalent), except in severe eclampsia with seizures (see below).  Continuous maternal administration of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Solutions for IV infusion must be diluted to a concentration of 20% or less prior to administration.  The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP.  Deep IM injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded.  In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded.  In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Fosphenytoin
  

  ×

  Fosphenytoin

  

  ---

  The dose, concentration, and infusion rate of fosphenytoin sodium injection should always be expressed as phenytoin sodium equivalents (PE).  There is no need to perform molecular weight-based adjustments when converting between fosphenytoin and phenytoin sodium doses.  Fosphenytoin sodium injection should always be prescribed and dispensed in phenytoin sodium equivalent units (PE).  1.5 mg of fosphenytoin sodium is equivalent to 1 mg phenytoin sodium, and is referred to as 1 mg PE.  The amount and concentration of fosphenytoin is always expressed in terms of mg of phenytoin sodium equivalents (mg PE).

  Do not confuse the concentration of fosphenytoin sodium injection with the total amount of drug in the vial.

  Caution must be used when administering fosphenytoin sodium injection due to the risk of dosing errors (see WARNINGS).  Medication errors associated with fosphenytoin have resulted in patients receiving the wrong dose of fosphenytoin. Fosphenytoin sodium injection is marketed in 2 mL vials containing a total of 100 mg PE.  Each vial contains a concentration of 50 mg PE/mL.  Errors have occurred when the concentration of the vial (50 mg PE/mL) was misinterpreted to mean that the total content of the vial was 50 mg PE.  These errors have resulted in two- or ten-fold overdoses of fosphenytoin sodium injection since each of the vials actually contains a total of 100 mg PE.  In some cases, ten-fold overdoses were associated with fatal outcomes.  To help minimize confusion, the prescribed dose of fosphenytoin sodium injection should always be expressed in milligrams of phenytoin equivalents (mg PE).  Additionally, when ordering and storing fosphenytoin, consider displaying the total drug content (i.e., 100 mg PE/2 mL) instead of concentration in computer systems, pre-printed orders, and automated dispensing cabinet databases to help ensure that total drug content can be clearly identified.  Care should be taken to ensure the appropriate volume of fosphenytoin is withdrawn from the vial when preparing the dose for administration.  Attention to these details may prevent some fosphenytoin medication errors from occurring.

  Prior to IV infusion, dilute fosphenytoin sodium injection in 5% dextrose or 0.9% saline solution for injection to a concentration ranging from 1.5 to 25 mg PE/mL.  The maximum concentration of fosphenytoin in any solution should be 25 mg PE/mL.  When fosphenytoin is given as an intravenous infusion, fosphenytoin needs to be diluted and should only be administered at a rate not exceeding 150 mg PE/min.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Status Epilepticus

  The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.

  If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. 

  Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.

  Nonemergent Loading and Maintenance Dosing

  Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.

  The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM.  The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).

  The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.

  IM or IV Substitution For Oral Phenytoin Therapy

  When treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose.  Phenytoin sodium capsules are approximately 90% bioavailable by the oral route.  Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes.  For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites.  Some patients may require more frequent dosing.

  Dosing in Special Populations

  Patients with Renal or Hepatic Disease:  Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY, Special Populations).  Unbound phenytoin concentrations may be more useful in these patient populations.  After IV fosphenytoin sodium injection administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.  This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).

  Elderly Patients:  Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration.  Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

  Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients has not been established.

  Status Epilepticus

  The loading dose of fosphenytoin sodium injection is 15 to 20 mg PE/kg administered at 100 to 150 mg PE/min. Because of the risk of hypotension, fosphenytoin should be administered no faster than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur, approximately 10 to 20 minutes after the end of fosphenytoin sodium injection infusions. Because the full antiepileptic effect of phenytoin, whether given as fosphenytoin sodium injection or parenteral phenytoin, is not immediate, other measures, including concomitant administration of an IV benzodiazepine, will usually be necessary for the control of status epilepticus. The loading dose should be followed by maintenance doses of either fosphenytoin sodium injection or phenytoin.

  If administration of fosphenytoin sodium injection does not terminate seizures, the use of other anticonvulsants and other appropriate measures should be considered. 

  Even though loading doses of fosphenytoin sodium injection have been given by the IM route for other indications when IV access is impossible, IM fosphenytoin should ordinarily not be used in the treatment of status epilepticus because therapeutic phenytoin concentrations may not be reached as quickly as with IV administration.

  Nonemergent Loading and Maintenance Dosing

  Because of the risks of cardiac and local toxicity associated with intravenous fosphenytoin, oral phenytoin should be used whenever possible.

  The loading dose of fosphenytoin sodium injection is 10 to 20 mg PE/kg given IV or IM.  The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  Continuous monitoring of the electrocardiogram, blood pressure, and respiratory function is essential and the patient should be observed throughout the period where maximal serum phenytoin concentrations occur (approximately 20 minutes after the end of fosphenytoin sodium injection infusion).

  The initial daily maintenance dose of fosphenytoin sodium injection is 4 to 6 mg PE/kg/day in divided doses.

  IM or IV Substitution For Oral Phenytoin Therapy

  When treatment with oral phenytoin is not possible, fosphenytoin sodium injection can be substituted for oral phenytoin at the same total daily dose.  Phenytoin sodium capsules are approximately 90% bioavailable by the oral route.  Phenytoin, supplied as fosphenytoin sodium injection, is 100% bioavailable by both the IM and IV routes.  For this reason, plasma phenytoin concentrations may increase modestly when IM or IV fosphenytoin sodium injection is substituted for oral phenytoin sodium therapy. The rate of administration for IV fosphenytoin sodium injection should be no greater than 150 mg PE/min.  In controlled trials, IM fosphenytoin sodium injection was administered as a single daily dose utilizing either 1 or 2 injection sites.  Some patients may require more frequent dosing.

  Dosing in Special Populations

  Patients with Renal or Hepatic Disease:  Due to an increased fraction of unbound phenytoin in patients with renal or hepatic disease, or in those with hypoalbuminemia, the interpretation of total phenytoin plasma concentrations should be made with caution (see CLINICAL PHARMACOLOGY, Special Populations).  Unbound phenytoin concentrations may be more useful in these patient populations.  After IV fosphenytoin sodium injection administration to patients with renal and/or hepatic disease, or in those with hypoalbuminemia, fosphenytoin clearance to phenytoin may be increased without a similar increase in phenytoin clearance.  This has the potential to increase the frequency and severity of adverse events (see PRECAUTIONS).

  Elderly Patients:  Age does not have a significant impact on the pharmacokinetics of fosphenytoin following fosphenytoin sodium injection administration.  Phenytoin clearance is decreased slightly in elderly patients and lower or less frequent dosing may be required.

  Pediatric: The safety and efficacy of fosphenytoin sodium injection in pediatric patients has not been established.

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• Indomethacin
  

  ×

  Indomethacin

  

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  For intravenous administration only.

  Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy.  A course of therapy is defined as three intravenous doses of Indomethacin for Injection given at 12 to 24 hour intervals, with careful attention to urinary output.  If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Indomethacin for Injection, do not give additional doses until laboratory studies indicate that renal function has returned to normal [see Warnings and Precautions (5.7)].

  Dosage according to age is as follows:

  AGE at 1st dose

  DOSAGE (mg/kg)

   

  Less than 48 hours

  1st

  0.2

  2nd

  0.1

  3rd

  0.1

  2 to 7 days

  0.2

  0.2

  0.2

  Over 7 days

  0.2

  0.25

  0.25

  If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course of Indomethacin for Injection, no further doses are necessary.  If the ductus arteriosus re-opens, a second course of 1 to 3 doses may be given, each dose separated by a 12 to 24 hour interval as described above.

  If the neonate remains unresponsive to therapy with Indomethacin for Injection after 2 courses, surgery may be necessary for closure of the ductus arteriosus.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

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  Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients.  Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.  An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

  Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

  When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

  Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.  

  For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia.  With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

  Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. 

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

   

                                            Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl    =   5 mcg of alfentanil (for bolus)

                                  =   10 mcg of alfentanil (for maintenance)

                                        or

                                  =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

   

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION ).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

   

                                            Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl    =   5 mcg of alfentanil (for bolus)

                                  =   10 mcg of alfentanil (for maintenance)

                                        or

                                  =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

   

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION ).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

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• Vasopressin
  

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  Vasopressin

  

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  Vasopressin Injection may be administered IM or subcutaneously.

  Ten units (0.5 mL) of Vasopressin Injection will usually elicit full physiologic response in adult patients; 5 units (0.25 mL) will be adequate in many cases.  Vasopressin Injection should be given IM at three or four hour intervals as needed.  The dosage should be proportionately reduced for pediatric patients.  (For an additional discussion of dosage, consult the sections below.)

  When determining the dose of Vasopressin Injection for a given case, the following should be kept in mind:

  It is particularly desirable to give a dose not much larger than is just sufficient to elicit the desired physiologic response.  Excessive doses may cause undesirable side effects–blanching of the skin, abdominal cramps, nausea–which, though not serious, may be alarming to the patient.  Spontaneous recovery from such side effects occurs in a few minutes.  It has been found that one or two glasses of water given at the time Vasopressin Injection is administered reduces such symptoms.

  Abdominal Distention

  In the average postoperative adult patient, give 5 units (0.25 mL) initially, increase to 10 units (0.5 mL) at subsequent injections if necessary.  It is recommended that Vasopressin Injection be given IM and that injections be repeated at three or four hour intervals as required.  Dosage to be reduced proportionately for pediatric patients.

  Vasopressin Injection used in this manner will frequently prevent, or relieve, postoperative distention.  These recommendations apply also to distention complicating pneumonia or other acute toxemias.

  Abdominal Roentgenography

  For the average case, two injections of 10 units (0.5 mL) each are suggested.  These should be given two hours and one-half hour, respectively, before films are exposed.  Many roentgenologists advise giving an enema prior to the first dose of Vasopressin Injection.

  Diabetes Insipidus

  Vasopressin Injection may be given by injection or administered intranasally on cotton pledgets, by nasal spray, or by dropper.  The dose by injection is 5 to 10 units (0.25 to 0.5 mL) repeated two or three times daily as needed.  When Vasopressin Injection is administered intranasally by spray or on pledgets, the dosage and interval between treatments must be determined for each patient.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Abdominal Distention

  In the average postoperative adult patient, give 5 units (0.25 mL) initially, increase to 10 units (0.5 mL) at subsequent injections if necessary.  It is recommended that Vasopressin Injection be given IM and that injections be repeated at three or four hour intervals as required.  Dosage to be reduced proportionately for pediatric patients.

  Vasopressin Injection used in this manner will frequently prevent, or relieve, postoperative distention.  These recommendations apply also to distention complicating pneumonia or other acute toxemias.

  Abdominal Roentgenography

  For the average case, two injections of 10 units (0.5 mL) each are suggested.  These should be given two hours and one-half hour, respectively, before films are exposed.  Many roentgenologists advise giving an enema prior to the first dose of Vasopressin Injection.

  Diabetes Insipidus

  Vasopressin Injection may be given by injection or administered intranasally on cotton pledgets, by nasal spray, or by dropper.  The dose by injection is 5 to 10 units (0.25 to 0.5 mL) repeated two or three times daily as needed.  When Vasopressin Injection is administered intranasally by spray or on pledgets, the dosage and interval between treatments must be determined for each patient.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Fluorouracil
  

  ×

  Fluorouracil

  

  ---

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS.)

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS.)

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Methotrexate
  

  ×

  Methotrexate

  

  ---

  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate for Injection, USP may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area: 

  Age (years)

  Dose (mg)

      < 1

        6

         1

        8

         2

       10

  3 or older

       12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity.  Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis Fungoides (cutaneous T cell lymphoma)

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.  

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion(starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

   

  Doxorubicin† 

  as a single drug

  30 mg/m2/day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin† 

  Cyclophosphamide†

   Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

   *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

  †See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

   When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

  Neoplastic Diseases

  Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained.  Methotrexate for Injection, USP may be given by the intramuscular, intravenous, intra-arterial or intrathecal route.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Choriocarcinoma and Similar Trophoblastic Diseases

  Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course.  Such courses are usually repeated for 3 to 5 times as required, with rest periods of one or more weeks interposed between courses, until any manifesting toxic symptoms subside.  The effectiveness of therapy is ordinarily evaluated by 24 hour quantitative analysis of urinary chorionic gonadotropin (hCG), which should return to normal or less than 50 IU/24 hr usually after the third or fourth course and usually be followed by a complete resolution of measurable lesions in 4 to 6 weeks.  One to two courses of methotrexate after normalization of hCG is usually recommended.  Before each course of the drug careful clinical assessment is essential.  Cyclic combination therapy of methotrexate with other antitumor drugs has been reported as being useful.

  Since hydatidiform mole may precede choriocarcinoma, prophylactic chemotherapy with methotrexate has been recommended.

  Chorioadenoma destruens is considered to be an invasive form of hydatidiform mole.  Methotrexate is administered in these disease states in doses similar to those recommended for choriocarcinoma.

  Leukemia

  Acute lymphoblastic leukemia in pediatric patients and young adolescents is the most responsive to present day chemotherapy.  In young adults and older patients, clinical remission is more difficult to obtain and early relapse is more common.

  Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias.  More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.  When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks.  Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions.  When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2.  It has also been given in doses of 2.5 mg/kg intravenously every 14 days.  If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

  A variety of combination chemotherapy regimens have been used for both induction and maintenance therapy in acute lymphoblastic leukemia.  The physician should be familiar with the new advances in antileukemic therapy.

  Meningeal Leukemia

  In the treatment or prophylaxis of meningeal leukemia, methotrexate must be administered intrathecally.  Preservative free methotrexate is diluted to a concentration of 1 mg/mL in an appropriate sterile, preservative free medium such as 0.9% Sodium Chloride Injection, USP.

  The cerebrospinal fluid volume is dependent on age and not on body surface area.  The CSF is at 40% of the adult volume at birth and reaches the adult volume in several years.

  Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults.  The following dosage regimen is based on age instead of body surface area: 

  Age (years)

  Dose (mg)

      < 1

        6

         1

        8

         2

       10

  3 or older

       12

  In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity.  Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

  Because the CSF volume and turnover may decrease with age, a dose reduction may be indicated in elderly patients.

  For the treatment of meningeal leukemia, intrathecal methotrexate may be given at intervals of 2 to 5 days.  However, administration at intervals of less than 1 week may result in increased subacute toxicity. Methotrexate is administered until the cell count of the cerebrospinal fluid returns to normal.  At this point one additional dose is advisable.  For prophylaxis against meningeal leukemia, the dosage is the same as for treatment except for the intervals of administration.  On this subject, it is advisable for the physician to consult the medical literature.

  Untoward side effects may occur with any given intrathecal injection and are commonly neurological in character.  Large doses may cause convulsions.  Methotrexate given by the intrathecal route appears significantly in the systemic circulation and may cause systemic methotrexate toxicity.  Therefore, systemic antileukemic therapy with the drug should be appropriately adjusted, reduced, or discontinued. Focal leukemic involvement of the central nervous system may not respond to intrathecal chemotherapy and is best treated with radiotherapy.

  Lymphomas

  In Burkitt’s tumor, Stages I-II, methotrexate has produced prolonged remissions in some cases. Recommended dosage is 10 to 25 mg/day orally for 4 to 8 days.  In Stage III, methotrexate is commonly given concomitantly with other antitumor agents.  Treatment in all stages usually consists of several courses of the drug interposed with 7 to 10 day rest periods.  Lymphosarcomas in Stage III may respond to combined drug therapy with methotrexate given in doses of 0.625 to 2.5 mg/kg daily.

  Mycosis Fungoides (cutaneous T cell lymphoma)

  Therapy with methotrexate as a single agent appears to produce clinical responses in up to 50% of patients treated.  Dosage in early stages is usually 5 to 50 mg once weekly.  Dose reduction or cessation is guided by patient response and hematologic monitoring.  Methotrexate has also been administered twice weekly in doses ranging from 15 to 37.5 mg in patients who have responded poorly to weekly therapy.  Combination chemotherapy regimens that include intravenous methotrexate administered at higher doses with leucovorin rescue have been utilized in advanced stages of the disease.

  Osteosarcoma

  An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents.  In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below.  The starting dose for high-dose methotrexate treatment is 12 grams/m2.  If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments.  If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.  

  Drug*

  Dose*

  Treatment Week After Surgery

  Methotrexate

  12 g/m2 IV as 4 hour infusion(starting dose)

  4,5,6,7,11,12,15,16,29,30,44,45

  Leucovorin

  15 mg orally every six hours for 10 doses starting at 24 hours after start of methotrexate infusion.

   

  Doxorubicin† 

  as a single drug

  30 mg/m2/day IV x 3 days

  8,17

  Doxorubicin†

  Cisplatin†

  50 mg/m2 IV

  100 mg/m2 IV

  20,23,33,36

  20,23,33,36

  Bleomycin† 

  Cyclophosphamide†

   Dactinomycin†

  15 units/m2 IV x 2 days

  600 mg/m2 IV x 2 days

  0.6 mg/m2 IV x 2 days

  2,13,26,39,42

  2,13,26,39,42

  2,13,26,39,42

   *Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314(No.25):1600-1606.

  †See each respective package insert for full prescribing information.  Dosage modifications may be necessary because of drug-induced toxicity.

   When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

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• Protamine Sulfate
  

  ×

  Protamine Sulfate

  

  ---

  Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.

  Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg (see WARNINGS).

  Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used.  Diluted solutions should not be stored since they contain no preservative.

  Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.

  Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin.  For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.

  The dosage of protamine sulfate should be guided by blood coagulation studies (see WARNINGS).

  Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Sunmark Childrens Pain ...
  

  ×

  Sunmark Childrens Pain And Fever

  

  ---

  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity–including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death–in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL and 40 mcg per mL for the 100 mcg and 200 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  2.1 Dosage

  An initial intravenous loading dose of Levothyroxine Sodium for Injection between 300 to 500 mcg, followed by once daily intravenous maintenance doses between 50 and 100 mcg, should be administered, as clinically indicated, until the patient can tolerate oral therapy.  The age, general physical condition, cardiac risk factors, and clinical severity of myxedema and duration of myxedema symptoms should be considered when determining the starting and maintenance dosages of Levothyroxine Sodium for Injection.

  Levothyroxine Sodium for Injection produces a gradual increase in the circulating concentrations of the hormone with an approximate half-life of 9 to 10 days in hypothyroid patients.  Daily administration of Levothyroxine Sodium for Injection should be maintained until the patient is capable of tolerating an oral dose and is clinically stable.  For chronic treatment of hypothyroidism, an oral dosage form of levothyroxine should be used to maintain a euthyroid state.  Relative bioavailability between Levothyroxine Sodium for Injection and oral levothyroxine products has not been established.  Based on medical practice, the relative bioavailability between oral and intravenous administration of Levothyroxine Sodium for Injection is estimated to be from 48 to 74%.  Due to differences in absorption characteristics of patients and the oral levothyroxine product formulations, TSH and thyroid hormone levels should be measured a few weeks after initiating oral levothyroxine and dose adjusted accordingly.

  2.2 Dosing in the Elderly and in Patients with Cardiovascular Disease

  Intravenous levothyroxine may be associated with cardiac toxicity–including arrhythmias, tachycardia, myocardial ischemia and infarction, or worsening of congestive heart failure and death–in the elderly and in those with underlying cardiovascular disease.  Therefore, cautious use, including doses in the lower end of the recommended range, may be warranted in these populations.

  2.3 Reconstitution Directions

  Reconstitute the lyophilized Levothyroxine Sodium for Injection by aseptically adding 5 mL of 0.9% Sodium Chloride Injection, USP only.  Shake vial to ensure complete mixing. The resultant solution will have a final concentration of approximately 20 mcg per mL and 40 mcg per mL for the 100 mcg and 200 mcg vials, respectively.  Reconstituted drug product is preservative free and is stable for 4 hours.  Discard any unused portion.  DO NOT ADD LEVOTHYROXINE SODIUM FOR INJECTION TO OTHER IV FLUIDS.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Fluorouracil
  

  ×

  Fluorouracil

  

  ---

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Acyclovir
  

  ×

  Acyclovir

  

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  CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS).

  INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (see WARNINGS).

  Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. 

  A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

  Dosage

  HERPES SIMPLEX INFECTIONS

  MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

  INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

   

  HERPES SIMPLEX ENCEPHALITIS:

  Adults and Adolescents (12 years of age and older): 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Pediatrics (3 months to 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

  VARICELLA-ZOSTER INFECTIONS

  ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older: 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

  Obese Patients

  Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

  PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

   

  Table 5: Dosage Adjustments for Patients with Renal Impairment

  Creatinine Clearance

  (mL/min/1.73 m2)

  Percent of

  Recommended Dose

  Dosing Interval

  (hours)

  >50

  25 to 50

  10 to 25

  0 to 10

  100%

  100%

  100%

  50%

  8

  12

  24

  24

  Hemodialysis

  For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

  Peritoneal Dialysis

  No supplemental dose appears to be necessary after adjustment of the dosing interval.

  Administration

  The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

  Once diluted for administration, each dose should be used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Dosage

  HERPES SIMPLEX INFECTIONS

  MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

  INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

   

  HERPES SIMPLEX ENCEPHALITIS:

  Adults and Adolescents (12 years of age and older): 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Pediatrics (3 months to 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

  VARICELLA-ZOSTER INFECTIONS

  ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older: 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

  Obese Patients

  Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

  PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

   

  Table 5: Dosage Adjustments for Patients with Renal Impairment

  Creatinine Clearance

  (mL/min/1.73 m2)

  Percent of

  Recommended Dose

  Dosing Interval

  (hours)

  >50

  25 to 50

  10 to 25

  0 to 10

  100%

  100%

  100%

  50%

  8

  12

  24

  24

  Hemodialysis

  For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

  Peritoneal Dialysis

  No supplemental dose appears to be necessary after adjustment of the dosing interval.

  Administration

  The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

  Once diluted for administration, each dose should be used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Leucovorin Calcium
  

  ×

  Leucovorin Calcium

  

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  Advanced Colorectal Cancer

  Either of the following two regimens is recommended:

   Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

  5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days.  This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.  The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

  Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.  However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens.

  Leucovorin Rescue After High-Dose Methotrexate Therapy

  The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).4  Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.  In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

   

                                                                                                           GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

                                                                                                                      DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

  Clinical Situation

  Laboratory Findings

  Leucovorin Dosage and Duration

  Normal Methotrexate Elimination

  Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.

  15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

  Delayed Late Methotrexate Elimination

  Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.

  Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.

  Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury

  Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).

  150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

  Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.  In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

  Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above.  These abnormalities may or may not be associated with significant clinical toxicity.  If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.  The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  Impaired Methotrexate Elimination or Inadvertent Overdosage

  Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS).  Leucovorin 10 mg/m2 should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at 24 hour intervals.  If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

  Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly.  The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

  Megaloblastic Anemia Due to Folic Acid Deficiency

  Up to 1 mg daily.  There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

  Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

  Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see WARNINGS).

  Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

  Advanced Colorectal Cancer

  Either of the following two regimens is recommended:

   Leucovorin is administered at 200 mg/m2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m2 by intravenous injection. Leucovorin is administered at 20 mg/m2 by intravenous injection followed by 5-fluorouracil at 425 mg/m2 by intravenous injection.

  5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate.

  Treatment is repeated daily for five days.  This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course.

  In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course.  The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS, Laboratory Tests).  For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity.

  Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease.  However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens.

  Leucovorin Rescue After High-Dose Methotrexate Therapy

  The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information).4  Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.  In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar).  The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines:

   

                                                                                                           GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION

                                                                                                                      DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY

  Clinical Situation

  Laboratory Findings

  Leucovorin Dosage and Duration

  Normal Methotrexate Elimination

  Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours.

  15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

  Delayed Late Methotrexate Elimination

  Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.

  Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar.

  Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury

  Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).

  150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

  Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure.  In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved.

  Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than abnormalities described in the table above.  These abnormalities may or may not be associated with significant clinical toxicity.  If significant clinical toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy.  The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.

  Impaired Methotrexate Elimination or Inadvertent Overdosage

  Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is a delayed excretion (see WARNINGS).  Leucovorin 10 mg/m2 should be administered IM, IV, or PO every 6 hours until the serum methotrexate level is less than 10-8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally.  Do not administer leucovorin intrathecally.

  Serum creatinine and methotrexate levels should be determined at 24 hour intervals.  If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of leucovorin should be increased to 100 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M.

  Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly.  The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

  Megaloblastic Anemia Due to Folic Acid Deficiency

  Up to 1 mg daily.  There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg.

  Each 200 mg vial of Leucovorin Calcium for Injection when reconstituted with 20 mL, of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Each 500 mg vial of Leucovorin Calcium for Injection when reconstituted with 50 mL of sterile diluent yields a leucovorin concentration of 10 mg per mL.  Leucovorin Calcium for Injection contains no preservative.  Reconstitute the lyophilized vial products with Bacteriostatic Water for Injection, USP (benzyl alcohol preserved), or Sterile Water for Injection, USP.  When reconstituted with Bacteriostatic Water for Injection, USP, the resulting solution must be used within 7 days.  If the product is reconstituted with Sterile Water for Injection, USP, use immediately and discard any unused portion.

  Because of the benzyl alcohol contained in Bacteriostatic Water for Injection, USP, when doses greater than 10 mg/m2 are administered, Leucovorin Calcium for Injection should be reconstituted with Sterile Water for Injection, USP, and used immediately (see WARNINGS).

  Because of the calcium content of the leucovorin solution, no more than 160 mg of leucovorin should be injected intravenously per minute (16 mL of a 10 mg/mL, or 8 mL of a 20 mg/mL solution per minute).

  Parenteral products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Leucovorin should not be mixed in the same infusion as 5-fluorouracil, since this may lead to the formation of a precipitate.

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• Heparin Sodium
  

  ×

  Heparin Sodium

  

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  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient (see WARNINGS, Fatal Medication Errors).  The 1 mL vial must not be confused with a “catheter lock flush” vial or other 1 mL vial of inappropriate strength.  Confirm that you have selected the correct medication and strength prior to administration of the drug.

  When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution.

  Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection.  The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.

  The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results.  When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every four hours in the early stages of treatment.  When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter.  Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value.  After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn four to six hours after the injection.

  Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration.

  Converting to Oral Anticoagulant

  When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time.  This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose.  If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

  In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals.  To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range.  Heparin therapy may then be discontinued without tapering.

  Therapeutic Anticoagulant Effect with Full-Dose Heparin

  Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

  METHOD OF ADMINISTRATION

  FREQUENCY

  RECOMMENDED

  DOSE (based on

  150 lb [68 kg] patient)

  Deep Subcutaneous (Intrafat) Injection

   

   

   

   

  A different site should be used for each injection to prevent the development of massive hematoma

  Initial Dose

   

   

   

   

   

   

   

  5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously

  Every 8 hours

  8,000 to 10,000 units of a concentrated solution

   or

  Every 12 hours

  15,000 to 20,000 units of a concentrated solution

  Intermittent Intravenous Injection

   

   

   

   

   

  Initial Dose

   

   

  10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Every 4

  to 6 hours

  5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Intravenous Infusion

   Initial Dose

  5,000 units by IV injection

   Continuous

  20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

  Pediatric Use

  Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS, Benzyl Alcohol Toxicity and PRECAUTIONS, Pediatric Use).

  There are no adequate and well-controlled studies on heparin use in pediatric patients.  Pediatric dosing recommendations are based on clinical experience.  In general, the following dosage schedule may be used as a guideline in pediatric patients:

   

              Initial Dose               75 to 100 units/kg (IV bolus over 10 minutes)

              Maintenance Dose    Infants: 25 to 30 units/kg/hour;

                                                Infants < 2 months have the highest requirements

                                               (average 28 units/kg/hour)

                                                Children > 1 year of age: 18 to 20 units/kg/hour;

                                                Older children may require less heparin, similar to weight-adjusted

                                                adult dosage

              Monitoring               Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this

                                               reflects an anti-Factor Xa level of 0.35 to 0.70.

  Geriatric Use

  Patients over 60 years of age may require lower doses of heparin.

  Surgery of the Heart and Blood Vessels

  Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.  Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

  Low-Dose Prophylaxis of Postoperative Thromboembolism

  A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.  The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.  The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma.  A concentrated solution of heparin sodium is recommended.  Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery.  Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS).  The value of such prophylaxis in hip surgery has not been established.  The possibility of increased bleeding during surgery or postoperatively should be borne in mind.  If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable.  If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated.  All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery.  Coagulation test values should be normal or only slightly elevated.  There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

  Extracorporeal Dialysis

  Follow equipment manufacturers’ operating directions carefully.

  Blood Transfusion

  Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.  Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

  Laboratory Samples

  Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample.  Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin.  Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

  Converting to Oral Anticoagulant

  When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time.  This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose.  If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

  In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals.  To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range.  Heparin therapy may then be discontinued without tapering.

  Therapeutic Anticoagulant Effect with Full-Dose Heparin

  Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

  METHOD OF ADMINISTRATION

  FREQUENCY

  RECOMMENDED

  DOSE (based on

  150 lb [68 kg] patient)

  Deep Subcutaneous (Intrafat) Injection

   

   

   

   

  A different site should be used for each injection to prevent the development of massive hematoma

  Initial Dose

   

   

   

   

   

   

   

  5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously

  Every 8 hours

  8,000 to 10,000 units of a concentrated solution

   or

  Every 12 hours

  15,000 to 20,000 units of a concentrated solution

  Intermittent Intravenous Injection

   

   

   

   

   

  Initial Dose

   

   

  10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Every 4

  to 6 hours

  5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Intravenous Infusion

   Initial Dose

  5,000 units by IV injection

   Continuous

  20,000 to 40,000 units/24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

  Pediatric Use

  Use preservative-free HEPARIN SODIUM INJECTION in neonates and infants (see WARNINGS, Benzyl Alcohol Toxicity and PRECAUTIONS, Pediatric Use).

  There are no adequate and well-controlled studies on heparin use in pediatric patients.  Pediatric dosing recommendations are based on clinical experience.  In general, the following dosage schedule may be used as a guideline in pediatric patients:

   

              Initial Dose               75 to 100 units/kg (IV bolus over 10 minutes)

              Maintenance Dose    Infants: 25 to 30 units/kg/hour;

                                                Infants < 2 months have the highest requirements

                                               (average 28 units/kg/hour)

                                                Children > 1 year of age: 18 to 20 units/kg/hour;

                                                Older children may require less heparin, similar to weight-adjusted

                                                adult dosage

              Monitoring               Adjust heparin to maintain aPTT of 60 to 85 seconds, assuming this

                                               reflects an anti-Factor Xa level of 0.35 to 0.70.

  Geriatric Use

  Patients over 60 years of age may require lower doses of heparin.

  Surgery of the Heart and Blood Vessels

  Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.  Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

  Low-Dose Prophylaxis of Postoperative Thromboembolism

  A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.  The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.  The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma.  A concentrated solution of heparin sodium is recommended.  Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery.  Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS).  The value of such prophylaxis in hip surgery has not been established.  The possibility of increased bleeding during surgery or postoperatively should be borne in mind.  If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable.  If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated.  All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery.  Coagulation test values should be normal or only slightly elevated.  There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

  Extracorporeal Dialysis

  Follow equipment manufacturers’ operating directions carefully.

  Blood Transfusion

  Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.  Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

  Laboratory Samples

  Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample.  Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin.  Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

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  Diprivan

  

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  Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients.  Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.  An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

  Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

  When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

  Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.  

  For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia.  With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

  Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. 

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                 or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients 

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                 or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients 

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

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• Naropin
  

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  Naropin

  

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  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should always be used.  The smallest dose and concentration required to produce the desired result should be administered.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Naropin is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  Patients in poor general condition due to aging or other compromising factors such as partial or complete heart conduction block, advanced liver disease or severe renal dysfunction require special attention although regional anesthesia is frequently indicated in these patients.  To reduce the risk of potentially serious adverse reactions, attempts should be made to optimize the patient's condition before major blocks are performed, and the dosage should be adjusted accordingly.

  Use an adequate test dose (3 to 5 mL of a short acting local anesthetic solution containing epinephrine) prior to induction of complete block.  This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.  Allow adequate time for onset of anesthesia following administration of each test dose.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Solutions which are discolored or which contain particulate matter should not be administered.

   

                                                         Table 7

                                        Dosage Recommendations

  Conc.

  Volume

  Dose

  Onset

  Duration

  mg/mL

  (%)

  mL

  mg

  min

  hours

  SURGICAL ANESTHESIA

  Lumbar Epidural

  5

  (0.5%)

  15 to 30

  75 to 150

  15 to 30

  2 to 4

  Administration

  7.5

  (0.75%)

  15 to 25

  113 to 188

  10 to 20

  3 to 5

  Surgery

  10

  (1%)

  15 to 20

  150 to 200

  10 to 20

  4 to 6

  Lumbar Epidural

  5

  (0.5%)

  20 to 30

  100 to 150

  15 to 25

  2 to 4

  Administration

  7.5

  (0.75%)

  15 to 20

  113 to 150

  10 to 20

  3 to 5

  Cesarean Section

  Thoracic Epidural

  5

  (0.5%)

  5 to 15

  25 to 75

  10 to 20

  n/a*

  Administration

  7.5

  (0.75%)

  5 to 15

  38 to 113

  10 to 20

  n/a*

  Surgery

  Major Nerve Block†

  5

  (0.5%)

  35 to 50

  175 to 250

  15 to 30

  5 to 8

  (eg, brachial plexus block)

  7.5

  (0.75%)

  10 to 40

  75 to 300

  10 to 25

  6 to 10

  Field Block

  5

  (0.5%)

  1 to 40

  5 to 200

  1 to 15

  2 to 6

  (eg, minor nerve blocks and infiltration)

  LABOR PAIN MANAGEMENT

  Lumbar Epidural Administration

  Initial Dose

  2

  (0.2%)

  10 to 20

  20 to 40

  10 to 15

  0.5 to 1.5

  Continuous infusion‡

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Incremental

  injections (top-up)‡

  2

  (0.2%)

  10 to 15

  mL/h

  20 to 30

  mg/h

  n/a*

  n/a*

  POSTOPERATIVE PAIN MANAGEMENT

  Lumbar Epidural Administration

  Continuous infusion§

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Thoracic Epidural

  Administration

  2

  (0.2%)

  6 to 14

  mL/h

  12 to 28

  mg/h

  n/a*

  n/a*

  Continuous infusion§

  Infiltration

  2

  (0.2%)

  1 to 100

  2 to 200

  1 to 5

  2 to 6

  (eg, minor nerve block)

  5

  (0.5%)

  1 to 40

  5 to 200

  1 to 5

  2 to 6

  *  =  Not Applicable

  †  =  The dose for a major nerve block must be adjusted according to site of administration and patient status.  Supraclavicular brachial plexus blocks may be associated with a higher frequency of serious adverse reactions, regardless of the local anesthetic used (see PRECAUTIONS).

  ‡  =   Median dose of 21 mg per hour was administered by continuous infusion or by incremental injections (top-ups) over a median delivery time of 5.5 hours.

  §  =  Cumulative doses up to 770 mg of Naropin over 24 hours (intraoperative block plus postoperative infusion);  Continuous epidural infusion at rates up to 28 mg per hour for 72 hours have been well tolerated in adults, ie, 2016 mg plus surgical dose of approximately 100 to 150 mg as top-up.

   

  The doses in the table are those considered to be necessary to produce a successful block and should be regarded as guidelines for use in adults.  Individual variations in onset and duration occur.  The figures reflect the expected average dose range needed.  For other local anesthetic techniques standard current textbooks should be consulted.

  When prolonged blocks are used, either through continuous infusion or through repeated bolus administration, the risks of reaching a toxic plasma concentration or inducing local neural injury must be considered.  Experience to date indicates that a cumulative dose of up to 770 mg Naropin administered over 24 hours is well tolerated in adults when used for postoperative pain management: ie, 2016 mg.  Caution should be exercised when administering Naropin for prolonged periods of time, eg, > 70 hours in debilitated patients.

  For treatment of postoperative pain, the following technique can be recommended: If regional anesthesia was not used intraoperatively, then an initial epidural block with 5 to 7 mL Naropin is induced via an epidural catheter.  Analgesia is maintained with an infusion of Naropin, 2 mg/mL (0.2%).  Clinical studies have demonstrated that infusion rates of 6 to 14 mL (12 to 28 mg) per hour provide adequate analgesia with nonprogressive motor block.  With this technique a significant reduction in the need for opioids was demonstrated.  Clinical experience supports the use of Naropin epidural infusions for up to 72 hours.

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• Diprivan
  

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  Diprivan

  

  ---

  Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients.  Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.  An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

  Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

  When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

  Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.  

  For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia.  With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

  Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. 

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

   

                                                                Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                       or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

   

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

   

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

   

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

   

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

   

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

   

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid – 100 to 150 mcg/kg/min.

   

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid – 50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

   

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

   

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus technique.  Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

   

  Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.

   

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial  rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused portions of DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate informaiton including the date and time the vial was opened.  Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

   

                                                                Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                       or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

   

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

   

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

   

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

   

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

   

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

   

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid – 100 to 150 mcg/kg/min.

   

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid – 50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

   

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

   

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3 to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus technique.  Most patients require an infusion of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or sedative agents, in most patients the initial infusion should be 5 mcg/kg/min (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).

   

  Evaluation of clinical effect and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN Injectable Emulsion required for sedation.

   

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product should be discarded after 12 hours because DIPRIVAN Injectable Emulsion contains no preservatives and is capable of supporting growth of microorganisms (see WARNINGS and DOSAGE AND ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial  rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused portions of DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate informaiton including the date and time the vial was opened.  Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

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• Nifedipine
  

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  Nifedipine

  

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  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be administered.  Dosages of Sensorcaine should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease.  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

  For specific techniques and procedures, refer to standard textbooks.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Sensorcaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  In recommended doses, Sensorcaine (bupivacaine HCl) produces complete sensory block, but the effect on motor function differs among the three concentrations.

  0.25%—when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block.  Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently. Onset of action may be slower than with the 0.5% or 0.75% solutions.

  0.5%—provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential.

  0.75%—produces complete motor block.  Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia.  Not for obstetrical anesthesia.

  The duration of anesthesia with Sensorcaine is such that for most indications, a single dose is sufficient.

  Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site.  Most experience to date is with single doses of Sensorcaine up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case.

  These doses may be repeated up to once every three hours.  In clinical studies to date, total daily doses have been up to 400 mg.  Until further experience is gained, this dose should not be exceeded in 24 hours.  The duration of anesthetic effect may be prolonged by the addition of epinephrine.

  The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult.  These dosages should be reduced for elderly or debilitated patients. Until further experience is gained, Sensorcaine is not recommended for pediatric patients younger than 12 years.  Sensorcaine is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block).

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single dose ampules and single dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

  TABLE 1.  Recommended Concentrations and Doses of Sensorcaine (bupivacaine HCl) Injections

   Each Dose   Type of Block     Conc.   (mL)   (mg)  Motor Block1  Local Infiltration   0.25%4    up to max.   up to max.              —  Epidural   0.75%2,4    10 to 20   75 to 150  complete  0.5%4    10 to 20   50 to 100  moderate to complete  0.25%4    10 to 20   25 to 50  partial to moderate  Caudal   0.5%4    15 to 30   75 to 150  moderate to complete  0.25%4    15 to 30   37.5 to 75  moderate  Peripheral Nerves   0.5%4    5 to max.   25 to max.  moderate to complete   0.25%4    5 to max.   12.5 to max.  moderate to complete  Retrobulbar3    0.75%4    2 to 4   15 to 30  complete  Sympathetic   0.25%   20 to 50   50 to 125              —   Dental3 0.5% w/epi 1.8 to 3.6 per site 9 to 18 per site             —    Epidural3    0.5%   2 to 3  10 to 15             —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single dose ampules and single dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

  TABLE 1.  Recommended Concentrations and Doses of Sensorcaine (bupivacaine HCl) Injections

   Each Dose   Type of Block     Conc.   (mL)   (mg)  Motor Block1  Local Infiltration   0.25%4    up to max.   up to max.              —  Epidural   0.75%2,4    10 to 20   75 to 150  complete  0.5%4    10 to 20   50 to 100  moderate to complete  0.25%4    10 to 20   25 to 50  partial to moderate  Caudal   0.5%4    15 to 30   75 to 150  moderate to complete  0.25%4    15 to 30   37.5 to 75  moderate  Peripheral Nerves   0.5%4    5 to max.   25 to max.  moderate to complete   0.25%4    5 to max.   12.5 to max.  moderate to complete  Retrobulbar3    0.75%4    2 to 4   15 to 30  complete  Sympathetic   0.25%   20 to 50   50 to 125              —   Dental3 0.5% w/epi 1.8 to 3.6 per site 9 to 18 per site             —    Epidural3    0.5%   2 to 3  10 to 15             —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

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• Rocuronium
  

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  Rocuronium

  

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  Rocuronium Bromide Injection is for intravenous use only.  This drug should only be administered by experienced clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents.  Doses of Rocuronium Bromide Injection should be individualized and a peripheral nerve stimulator should be used to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered. 

  The dosage information which follows is derived from studies based upon units of drug per unit of body weight.  It is intended to serve as an initial guide to clinicians familiar with other neuromuscular blocking agents to acquire experience with Rocuronium Bromide Injection.

  In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.9, 5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.10) , and Use in Specific Populations (8.6)].

  2.1 Dose for Tracheal Intubation

  The recommended initial dose of Rocuronium Bromide Injection, regardless of anesthetic technique, is 0.6 mg/kg.  Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4 to 6) minute(s) and most patients have intubation completed within 2 minutes.  Maximum blockade is achieved in most patients in less than 3 minutes.  This dose may be expected to provide 31 (15 to 85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia.  Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions (7.3)].

  A lower dose of Rocuronium Bromide Injection (0.45 mg/kg) may be used.  Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8 to 6.2) minute(s), and most patients have intubation completed within 2 minutes.  Maximum blockade is achieved in most patients in less than 4 minutes.  This dose may be expected to provide 22 (12 to 31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia.  Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes.

  A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)].

  2.2 Rapid Sequence Intubation

  In appropriately premedicated and adequately anesthetized patients, Rocuronium Bromide Injection 0.6 to 1.2 mg/kg will provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies (14.1)].

  2.3 Maintenance Dosing

  Maintenance doses of 0.1, 0.15, and 0.2 mg/kg Rocuronium Bromide Injection, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2 to 31), 17 (6 to 50), and 24 (7 to 69) minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology (12.2)].  In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until recovery of neuromuscular function is evident.  A clinically insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical Pharmacology (12.2)].

  2.4 Use by Continuous Infusion

  Infusion at an initial rate of 10 to 12 mcg/kg/min of Rocuronium Bromide Injection should be initiated only after early evidence of spontaneous recovery from an intubating dose.  Due to rapid redistribution [see Clinical Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T1) may necessitate additional bolus doses to maintain adequate block for surgery.

  Upon reaching the desired level of neuromuscular block, the infusion of Rocuronium Bromide Injection must be individualized for each patient.  The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator.  In clinical trials, infusion rates have ranged from 4 to 16 mcg/kg/min.

  Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants.  In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30% to 50%, at 45 to 60 minutes after the intubating dose.

  Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)].

  Infusion solutions of Rocuronium Bromide Injection can be prepared by mixing Rocuronium Bromide Injection with an appropriate infusion solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.6)].  These infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

  Infusion rates of Rocuronium Bromide Injection can be individualized for each patient using the following tables for 3 different concentrations of rocuronium bromide solution as guidelines:

  TABLE 1: Infusion Rates Using Rocuronium Bromide Injection (0.5 mg/mL)*

  Patient

  Weight

  Drug Delivery Rate (mcg/kg/min)

  (kg)

  (lbs)

  4

  5

  6

  7

  8

  9

  10

  12

  14

  16

  Infusion Delivery Rate (mL/hr)

  10

  22

  4.8

  6

  7.2

  8.4

  9.6

  10.8

  12

  14.4

  16.8

  19.2

  15

  33

  7.2

  9

  10.8

  12.6

  14.4

  16.2

  18

  21.6

  25.2

  28.8

  20

  44

  9.6

  12

  14.4

  16.8

  19.2

  21.6

  24

  28.8

  33.6

  38.4

  25

  55

  12

  15

  18

  21

  24

  27

  30

  36

  42

  48

  35

  77

  16.8

  21

  25.2

  29.4

  33.6

  37.8

  42

  50.4

  58.8

  67.2

  50

  110

  24

  30

  36

  42

  48

  54

  60

  72

  84

  96

  60

  132

  28.8

  36

  43.2

  50.4

  57.6

  64.8

  72

  86.4

  100.8

  115.2

  70

  154

  33.6

  42

  50.4

  58.8

  67.2

  75.6

  84

  100.8

  117.6

  134.4

  80

  176

  38.4

  48

  57.6

  67.2

  76.8

  86.4

  96

  115.2

  134.4

  153.6

  90

  198

  43.2

  54

  64.8

  75.6

  86.4

  97.2

  108

  129.6

  151.2

  172.8

  100

  220

  48

  60

  72

  84

  96

  108

  120

  144

  168

  192

  * 50 mg Rocuronium Bromide Injection in 100 mL solution

  TABLE 2: Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)*

  Patient

  Weight

  Drug Delivery Rate (mcg/kg/min)

  (kg)

  (lbs)

  4

  5

  6

  7

  8

  9

  10

  12

  14

  16

  Infusion Delivery Rate (mL/hr)

  10

  22

  2.4

  3

  3.6

  4.2

  4.8

  5.4

  6

  7.2

  8.4

  9.6

  15

  33

  3.6

  4.5

  5.4

  6.3

  7.2

  8.1

  9

  10.8

  12.6

  14.4

  20

  44

  4.8

  6

  7.2

  8.4

  9.6

  10.8

  12

  14.4

  16.8

  19.2

  25

  55

  6

  7.5

  9

  10.5

  12

  13.5

  15

  18

  21

  24

  35

  77

  8.4

  10.5

  12.6

  14.7

  16.8

  18.9

  21

  25.2

  29.4

  33.6

  50

  110

  12

  15

  18

  21

  24

  27

  30

  36

  42

  48

  60

  132

  14.4

  18

  21.6

  25.2

  28.8

  32.4

  36

  43.2

  50.4

  57.6

  70

  154

  16.8

  21

  25.2

  29.4

  33.6

  37.8

  42

  50.4

  58.8

  67.2

  80

  176

  19.2

  24

  28.8

  33.6

  38.4

  43.2

  48

  57.6

  67.2

  76.8

  90

  198

  21.6

  27

  32.4

  37.8

  43.2

  48.6

  54

  64.8

  75.6

  86.4

  100

  220

  24

  30

  36

  42

  48

  54

  60

  72

  84

  96

  * 100 mg Rocuronium Bromide Injection in 100 mL solution

  TABLE 3: Infusion Rates Using Rocuronium Bromide Injection (5 mg/mL)*

  Patient

  Weight

  Drug Delivery Rate (mcg/kg/min)

  (kg)

  (lbs)

  4

  5

  6

  7

  8

  9

  10

  12

  14

  16

  Infusion Delivery Rate (mL/hr)

  10

  22

  0.5

  0.6

  0.7

  0.8

  1

  1.1

  1.2

  1.4

  1.7

  1.9

  15

  33

  0.7

  0.9

  1.1

  1.3

  1.4

  1.6

  1.8

  2.2

  2.5

  2.9

  20

  44

  1

  1.2

  1.4

  1.7

  1.9

  2.2

  2.4

  2.9

  3.4

  3.8

  25

  55

  1.2

  1.5

  1.8

  2.1

  2.4

  2.7

  3

  3.6

  4.2

  4.8

  35

  77

  1.7

  2.1

  2.5

  2.9

  3.4

  3.8

  4.2

  5

  5.9

  6.7

  50

  110

  2.4

  3

  3.6

  4.2

  4.8

  5.4

  6

  7.2

  8.4

  9.6

  60

  132

  2.9

  3.6

  4.3

  5

  5.8

  6.5

  7.2

  8.6

  10.1

  11.5

  70

  154

  3.4

  4.2

  5

  5.9

  6.7

  7.6

  8.4

  10.1

  11.8

  13.4

  80

  176

  3.8

  4.8

  5.8

  6.7

  7.7

  8.6

  9.6

  11.5

  13.4

  15.4

  90

  198

  4.3

  5.4

  6.5

  7.6

  8.6

  9.7

  10.8

  13

  15.1

  17.3

  100

  220

  4.8

  6

  7.2

  8.4

  9.6

  10.8

  12

  14.4

  16.8

  19.2

  * 500 mg Rocuronium Bromide Injection in 100 mL solution

  2.5 Dosage in Specific Populations

  Pediatric Patients: 

  The recommended initial intubation dose of Rocuronium Bromide Injection is 0.6 mg/kg; however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient.

  For sevoflurane (induction) Rocuronium Bromide Injection doses of 0.45 mg/kg and 0.6 mg/kg in general produce excellent to good intubating conditions within 75 seconds.  When halothane is used, a 0.6 mg/kg dose of Rocuronium Bromide Injection resulted in excellent to good intubating conditions within 60 seconds.

  The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.

  When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general anesthesia, maintenance dosing of Rocuronium Bromide Injection can be administered as bolus doses of 0.15 mg/kg at reappearance of T3 in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T2 at a rate of 7 to 10 mcg/kg/min, with the lowest dose requirement for neonates (birth to less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years).

  When halothane is used for general anesthesia, patients ranging from 3 months old through adolescence can be administered Rocuronium Bromide Injection maintenance doses of 0.075 to 0.125 mg/kg upon return of T1 to 0.25% to provide clinical relaxation for 7 to 10 minutes.  Alternatively, a continuous infusion of Rocuronium Bromide Injection initiated at a rate of 12 mcg/kg/min upon return of T1 to 10% (one twitch present in train-of-four) may also be used to maintain neuromuscular blockade in pediatric patients.

  Additional information for administration to pediatric patients of all age groups is presented elsewhere in the label [see Clinical Pharmacology (12.2)].

  The infusion of Rocuronium Bromide Injection must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator.  Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology (12.2)].

  Rocuronium Bromide Injection is not recommended for rapid sequence intubation in pediatric patients.

  Geriatric Patients:

  Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of 46 (22 to 73), 62 (49 to 75), and 94 (64 to 138) minutes under opioid/nitrous oxide/oxygen anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively.  No differences in duration of neuromuscular blockade following maintenance doses of Rocuronium Bromide Injection were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.2, 12.3)].

  Patients with Renal or Hepatic Impairment:

  No differences from patients with normal hepatic and kidney function were observed for onset time at a dose of 0.6 mg/kg Rocuronium Bromide Injection.  When compared to patients with normal renal and hepatic function, the mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is about 1.5 times longer in patients with hepatic disease.  Patients with renal failure may have a greater variation in duration of effect [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

  Obese Patients:

  In obese patients, the initial dose of Rocuronium Bromide Injection 0.6 mg/kg should be based upon the patient’s actual body weight [see Clinical Studies (14.1)].

  An analysis across all US controlled clinical studies indicates that the pharmacodynamics of Rocuronium Bromide Injection are not different between obese and nonobese patients when dosed based upon their actual body weight.

  Patients with Reduced Plasma Cholinesterase Activity:

  Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in patients with reduced plasma cholinesterase activity.

  Patients with Prolonged Circulation Time:

  Because higher doses of Rocuronium Bromide Injection produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible, more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.7)].

  Patients with Drugs or Conditions Causing Potentiation of Neuromuscular Block:

  The neuromuscular blocking action of Rocuronium Bromide Injection is potentiated by isoflurane and enflurane anesthesia.  Potentiation is minimal when administration of the recommended dose of Rocuronium Bromide Injection occurs prior to the administration of these potent inhalation agents.  The median clinical duration of a dose of 0.57 to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane maintenance anesthesia, respectively.  During 1 to 2 hours of infusion, the infusion rate of Rocuronium Bromide Injection required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [see Drug Interactions (7.3)].

  2.6 Preparation for Administration of Rocuronium Bromide Injection

  Diluent Compatibility:

  Rocuronium Bromide Injection is compatible in solution with:

       0.9% NaCl solution                        sterile water for injection

       5% glucose in water                       lactated Ringers

       5% glucose in saline

  Rocuronium Bromide Injection is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room temperature in plastic bags, glass bottles, and plastic syringe pumps.

  Drug Admixture Incompatibility:

  Rocuronium Bromide Injection is physically incompatible when mixed with the following drugs:

       amphotericin                      hydrocortisone sodium succinate

       amoxicillin                         insulin

       azathioprine                        intralipid

       cefazolin                             ketorolac

       cloxacillin                           lorazepam

       dexamethasone                   methohexital

       diazepam                            methylprednisolone

       erythromycin                      thiopental

       famotidine                          trimethoprim

       furosemide                         vancomycin

   

  If Rocuronium Bromide Injection is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed between administration of Rocuronium Bromide Injection and drugs for which incompatibility with Rocuronium Bromide Injection has been demonstrated or for which compatibility with Rocuronium Bromide Injection has not been established.

  Infusion solutions should be used within 24 hours of mixing.  Unused portions of infusion solutions should be discarded.

  Rocuronium Bromide Injection should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)].

  Visual Inspection:

  Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit.  Do not use solution if particulate matter is present.

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• Thiamine
  

  ×

  Thiamine

  

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  “Wet” beriberi with myocardial failure must be treated as an emergency cardiac condition, and thiamine must be administered slowly by the IV route in this situation (see WARNINGS).

  In the treatment of beriberi, 10 to 20 mg of thiamine hydrochloride are given IM three times daily for as long as two weeks.  (See WARNINGS regarding repeated injections of thiamine.)  An oral therapeutic multivitamin preparation containing 5 to 10 mg thiamine, administered daily for one month, is recommended to achieve body tissue saturation.

  Infantile beriberi that is mild may respond to oral therapy, but if collapse occurs, doses of 25 mg may cautiously be given IV.

  Poor dietary habits should be corrected and an abundant and well-balanced dietary intake should be prescribed.

  Patients with neuritis of pregnancy in whom vomiting is severe enough to preclude adequate oral therapy should receive 5 to 10 mg of thiamine hydrochloride IM daily.

  In the treatment of Wernicke-Korsakoff syndrome, thiamine hydrochloride has been administered IV in an initial dose of 100 mg, followed by IM doses of 50 to 100 mg daily until the patient is consuming a regular, balanced diet.  (See WARNINGS regarding repeated injections of thiamine.)

  Patients with marginal thiamine status to whom dextrose is being administered should receive 100 mg thiamine hydrochloride in each of the first few liters of IV fluid to avoid precipitating heart failure.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Diprivan
  

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  Diprivan

  

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  Propofol blood concentrations at steady-state are generally proportional to infusion rates, especially in individual patients.  Undesirable effects such as cardiorespiratory depression are likely to occur at higher blood concentrations which result from bolus dosing or rapid increases in the infusion rate.  An adequate interval (3 to 5 minutes) must be allowed between dose adjustments to allow for and assess the clinical effects.

  Shake well before use.  Do not use if there is evidence of excessive creaming or aggregation, if large droplets are visible, or if there are other forms of phase separation indicating that the stability of the product has been compromised.  Slight creaming, which should disappear after shaking, may be visible upon prolonged standing.

  When administering DIPRIVAN Injectable Emulsion by infusion, syringe or volumetric pumps are recommended to provide controlled infusion rates.  When infusing DIPRIVAN Injectable Emulsion to patients undergoing magnetic resonance imaging, metered control devices may be utilized if mechanical pumps are impractical.

  Changes in vital signs indicating a stress response to surgical stimulation or the emergence from anesthesia may be controlled by the administration of 25 mg (2.5 mL) to 50 mg (5 mL) incremental boluses and/or by increasing the infusion rate of DIPRIVAN Injectable Emulsion.  

  For minor surgical procedures (e.g., body surface) nitrous oxide (60% to 70%) can be combined with a variable rate DIPRIVAN Injectable Emulsion infusion to provide satisfactory anesthesia.  With more stimulating surgical procedures (e.g., intra-abdominal), or if supplementation with nitrous oxide is not provided, administration rate(s) of DIPRIVAN Injectable Emulsion and/or opioids should be increased in order to provide adequate anesthesia.

  Infusion rates should always be titrated downward in the absence of clinical signs of light anesthesia until a mild response to surgical stimulation is obtained in order to avoid administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times.

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase CNS depression induced by propofol.  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary propofol injection maintenance infusion rate and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication. 

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                 or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients 

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

   

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

  Induction of General Anesthesia

  Adult Patients

  Most adult patients under 55 years of age and classified as ASA-PS I or II require 2 to 2.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when premedicated with oral benzodiazepines or intramuscular opioids.  For induction, DIPRIVAN Injectable Emulsion should be titrated (approximately 40 mg every 10 seconds) against the response of the patient until the clinical signs show the onset of anesthesia.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.

  Elderly, Debilitated, or ASA-PS III or IV Patients

  It is important to be familiar and experienced with the intravenous use of DIPRIVAN Injectable Emulsion before treating elderly, debilitated, or ASA-PS III or IV patients.  Due to the reduced clearance and higher blood concentrations, most of these patients require approximately 1 to 1.5 mg/kg (approximately 20 mg every 10 seconds) of DIPRIVAN Injectable Emulsion for induction of anesthesia according to their condition and responses.  A rapid bolus should not be used, as this will increase the likelihood of undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and/or oxygen desaturation (see DOSAGE AND ADMINISTRATION).

  Pediatric Patients

  Most patients aged 3 years through 16 years and classified ASA-PS I or II require 2.5 to 3.5 mg/kg of DIPRIVAN Injectable Emulsion for induction when unpremedicated or when lightly premedicated with oral benzodiazepines or intramuscular opioids.  Within this dosage range, younger pediatric patients may require higher induction doses than older pediatric patients.  As with other sedative-hypnotic agents, the amount of intravenous opioid and/or benzodiazepine premedication will influence the response of the patient to an induction dose of DIPRIVAN Injectable Emulsion.  A lower dosage is recommended for pediatric patients classified as ASA-PS III or IV.  Attention should be paid to minimize pain on injection when administering DIPRIVAN Injectable Emulsion to pediatric patients.  Boluses of DIPRIVAN Injectable Emulsion may be administered via small veins if pretreated with lidocaine or via antecubital or larger veins (see PRECAUTIONS, General).

  Neurosurgical Patients

  Slower induction is recommended using boluses of 20 mg every 10 seconds.  Slower boluses or infusions of DIPRIVAN Injectable Emulsion for induction of anesthesia, titrated to clinical responses, will generally result in reduced induction dosage requirements (1 to 2 mg/kg) (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).

  Cardiac Anesthesia

  DIPRIVAN Injectable Emulsion has been well-studied in patients with coronary artery disease, but experience in patients with hemodynamically significant valvular or congenital heart disease is limited.  As with other anesthetic and sedative-hypnotic agents, DIPRIVAN Injectable Emulsion in healthy patients causes a decrease in blood pressure that is secondary to decreases in preload (ventricular filling volume at the end of the diastole) and afterload (arterial resistance at the beginning of the systole).  The magnitude of these changes is proportional to the blood and effect site concentrations achieved.  These concentrations depend upon the dose and speed of the induction and maintenance infusion rates.

  In addition, lower heart rates are observed during maintenance with DIPRIVAN Injectable Emulsion, possibly due to reduction of the sympathetic activity and/or resetting of the baroreceptor reflexes.  Therefore, anticholinergic agents should be administered when increases in vagal tone are anticipated.

  As with other anesthetic agents, DIPRIVAN Injectable Emulsion reduces myocardial oxygen consumption.  Further studies are needed to confirm and delineate the extent of these effects on the myocardium and the coronary vascular system.  

  Morphine premedication (0.15 mg/kg) with nitrous oxide 67% in oxygen has been shown to decrease the necessary DIPRIVAN Injectable Emulsion maintenance infusion rates and therapeutic blood concentrations when compared to non-narcotic (lorazepam) premedication.  The rate of DIPRIVAN Injectable Emulsion administration should be determined based on the patient's premedication and adjusted according to clinical responses.  

  A rapid bolus induction should be avoided.  A slow rate of approximately 20 mg every 10 seconds until induction onset (0.5 to 1.5 mg/kg) should be used.  In order to assure adequate anesthesia, when DIPRIVAN Injectable Emulsion is used as the primary agent, maintenance infusion rates should not be less than 100 mcg/kg/min and should be supplemented with analgesic levels of continuous opioid administration.  When an opioid is used as the primary agent, DIPRIVAN Injectable Emulsion maintenance rates should not be less than 50 mcg/kg/min, and care should be taken to ensure amnesia.  Higher doses of DIPRIVAN Injectable Emulsion will reduce the opioid requirements (see Table 4).  When DIPRIVAN Injectable Emulsion is used as the primary anesthetic, it should not be administered with the high-dose opioid technique as this may increase the likelihood of hypotension (see PRECAUTIONS, Cardiac Anesthesia).

                                                   Table 4.  Cardiac Anesthesia Techniques

              Primary Agent

              Rate

                       Secondary Agent/Rate

         (Following Induction with Primary Agent)

  DIPRIVAN Injectable Emulsion

  OPIOIDa/0.05 to 0.075 mcg/kg/min (no bolus)

              Preinduction

              Anxiolysis

  25 mcg/kg/min

              Induction

  0.5 to 1.5 mg/kg

  over 60 sec

              Maintenance

              (Titrated to Clinical

                Response)

  100 to 150 mcg/kg/min

  OPIOIDb

  DIPRIVAN Injectable Emulsion/50 to 100 mcg/kg/min

  (no bolus)

              Induction

  25 to 50 mcg/kg

              Maintenance

  0.2 to 0.3 mcg/kg/min

  aOPIOID is defined in terms of fentanyl equivalents, i.e.,

  1 mcg of fentanyl   =   5 mcg of alfentanil (for bolus)

                                 =   10 mcg of alfentanil (for maintenance)

                                 or

                                 =    0.1 mcg of sufentanil

  bCare should be taken to ensure amnesia.

  Maintenance of General Anesthesia

  DIPRIVAN Injectable Emulsion has been used with a variety of agents commonly used in anesthesia such as atropine, scopolamine, glycopyrrolate, diazepam, depolarizing and nondepolarizing muscle relaxants, and opioid analgesics, as well as with inhalational and regional anesthetic agents.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid bolus doses should not be used, as this will increase cardiorespiratory effects including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Adult Patients 

  In adults, anesthesia can be maintained by administering DIPRIVAN Injectable Emulsion by infusion or intermittent IV bolus injection.  The patient's clinical response will determine the infusion rate or the amount and frequency of incremental injections.

  Continuous Infusion

  DIPRIVAN Injectable Emulsion 100 to 200 mcg/kg/min administered in a variable rate infusion with 60% to 70% nitrous oxide and oxygen provides anesthesia for patients undergoing general surgery.  Maintenance by infusion of DIPRIVAN Injectable Emulsion should immediately follow the induction dose in order to provide satisfactory or continuous anesthesia during the induction phase.  During this initial period following the induction dose, higher rates of infusion are generally required (150 to 200 mcg/kg/min) for the first 10 to 15 minutes.  Infusion rates should subsequently be decreased 30% to 50% during the first half-hour of maintenance.  Generally, rates of 50 to 100 mcg/kg/min in adults should be achieved during maintenance in order to optimize recovery times. 

  Other drugs that cause CNS depression (hypnotics/sedatives, inhalational anesthetics, and opioids) can increase the CNS depression induced by propofol.  

  Intermittent Bolus

  Increments of DIPRIVAN Injectable Emulsion 25 mg (2.5 mL) to 50 mg (5 mL) may be administered with nitrous oxide in adult patients undergoing general surgery.  The incremental boluses should be administered when changes in vital signs indicate a response to surgical stimulation or light anesthesia.

  Pediatric Patients

  DIPRIVAN Injectable Emulsion administered as a variable rate infusion supplemented with nitrous oxide 60% to 70% provides satisfactory anesthesia for most children 2 months of age or older, ASA-PS I or II, undergoing general anesthesia.

  In general, for the pediatric population, maintenance by infusion of DIPRIVAN Injectable Emulsion at a rate of 200 to 300 mcg/kg/min should immediately follow the induction dose.  Following the first half-hour of maintenance, infusion rates of 125 to 150 mcg/kg/min are typically needed.  DIPRIVAN Injectable Emulsion should be titrated to achieve the desired clinical effect.  Younger pediatric patients may require higher maintenance infusion rates than older pediatric patients.  (See Table 2 Clinical Trials.)

  Monitored Anesthesia Care (MAC) Sedation

  Adult Patients

  When DIPRIVAN Injectable Emulsion is administered for MAC sedation, rates of administration should be individualized and titrated to clinical response.  In most patients, the rates of DIPRIVAN Injectable Emulsion administration will be in the range of 25 to 75 mcg/kg/min.

  During initiation of MAC sedation, slow infusion or slow injection techniques are preferable over rapid bolus administration.  During maintenance of MAC sedation, a variable rate infusion is preferable over intermittent bolus dose administration.  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  A rapid bolus injection can result in undesirable cardiorespiratory depression including hypotension, apnea, airway obstruction, and oxygen desaturation.

  Initiation of MAC Sedation

  For initiation of MAC sedation, either an infusion or a slow injection method may be utilized while closely monitoring cardiorespiratory function.  With the infusion method, sedation may be initiated by infusing DIPRIVAN Injectable Emulsion at 100 to 150 mcg/kg/min (6 to 9 mg/kg/h) for a period of 3 to 5 minutes and titrating to the desired clinical effect while closely monitoring respiratory function.  With the slow injection method for initiation, patients will require approximately 0.5 mg/kg administered over 3 to 5 minutes and titrated to clinical responses.  When DIPRIVAN Injectable Emulsion is administered slowly over 3 to 5 minutes, most patients will be adequately sedated, and the peak drug effect can be achieved while minimizing undesirable cardiorespiratory effects occurring at high plasma levels.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration should be over 3 to 5 minutes and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  Maintenance of MAC Sedation

  For maintenance of sedation, a variable rate infusion method is preferable over an intermittent bolus dose method.  With the variable rate infusion method, patients will generally require maintenance rates of 25 to 75 mcg/kg/min (1.5 to 4.5 mg/kg/h) during the first 10 to 15 minutes of sedation maintenance.  Infusion rates should subsequently be decreased over time to 25 to 50 mcg/kg/min and adjusted to clinical responses.  In titrating to clinical effect, allow approximately 2 minutes for onset of peak drug effect.

  Infusion rates should always be titrated downward in the absence of clinical signs of light sedation until mild responses to stimulation are obtained in order to avoid sedative administration of DIPRIVAN Injectable Emulsion at rates higher than are clinically necessary.

  If the intermittent bolus dose method is used, increments of DIPRIVAN Injectable Emulsion 10 mg (1 mL) or 20 mg (2 mL) can be administered and titrated to desired clinical effect.  With the intermittent bolus method of sedation maintenance, there is increased potential for respiratory depression, transient increases in sedation depth, and prolongation of recovery.

  In the elderly, debilitated, or ASA-PS III or IV patients, rapid (single or repeated) bolus dose administration should not be used for MAC sedation (see WARNINGS).  The rate of administration and the dosage of DIPRIVAN Injectable Emulsion should be reduced to approximately 80% of the usual adult dosage in these patients according to their condition, responses, and changes in vital signs (see DOSAGE AND ADMINISTRATION).

  DIPRIVAN Injectable Emulsion can be administered as the sole agent for maintenance of MAC sedation during surgical/diagnostic procedures.  When DIPRIVAN Injectable Emulsion sedation is supplemented with opioid and/or benzodiazepine medications, these agents increase the sedative and respiratory effects of DIPRIVAN Injectable Emulsion and may also result in a slower recovery profile (see PRECAUTIONS, Drug Interactions).

  ICU Sedation

  (See WARNINGS and DOSAGE AND ADMINISTRATION, Handling Procedures.)

  Abrupt discontinuation of DIPRIVAN Injectable Emulsion prior to weaning or for daily evaluation of sedation levels should be avoided.  This may result in rapid awakening with associated anxiety, agitation, and resistance to mechanical ventilation.  Infusions of DIPRIVAN Injectable Emulsion should be adjusted to assure a minimal level of sedation is maintained throughout the weaning process and when assessing the level of sedation (see PRECAUTIONS).

  Adult Patients

  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension (see DOSAGE AND ADMINISTRATION).  

  Most adult ICU patients recovering from the effects of general anesthesia or deep sedation will require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) individualized and titrated to clinical response (see DOSAGE AND ADMINISTRATION).  With medical ICU patients or patients who have recovered from the effects of general anesthesia or deep sedation, the rate of administration of 50 mcg/kg/min or higher may be required to achieve adequate sedation.  These higher rates of administration may increase the likelihood of patients developing hypotension.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS). 

  Dosage and rate of administration should be individualized and titrated to the desired effect, according to clinically relevant factors including the patient’s underlying medical problems, preinduction and concomitant medications, age, ASA-PS classification, and level of debilitation of the patient.  The elderly, debilitated, and ASA-PS III or IV patients may have exaggerated hemodynamic and respiratory responses to rapid bolus doses (see WARNINGS).

  DIPRIVAN Injectable Emulsion should be individualized according to the patient's condition and response, blood lipid profile, and vital signs (see PRECAUTIONS, Intensive Care Unit Sedation).  For intubated, mechanically ventilated adult patients, Intensive Care Unit (ICU) sedation should be initiated slowly with a continuous infusion in order to titrate to desired clinical effect and minimize hypotension.  When indicated, initiation of sedation should begin at 5 mcg/kg/min (0.3 mg/kg/h).  The infusion rate should be increased by increments of 5 to 10 mcg/kg/min (0.3 to 0.6 mg/kg/h) until the desired level of sedation is achieved.  A minimum period of 5 minutes between adjustments should be allowed for onset of peak drug effect.  Most adult patients require maintenance rates of 5 to 50 mcg/kg/min (0.3 to 3 mg/kg/h) or higher.  Administration should not exceed 4 mg/kg/hour unless the benefits outweigh the risks (see WARNINGS).  Dosages of DIPRIVAN Injectable Emulsion should be reduced in patients who have received large dosages of narcotics.  The DIPRIVAN Injectable Emulsion dosage requirement may also be reduced by adequate management of pain with analgesic agents.  As with other sedative medications, there is interpatient variability in dosage requirements, and these requirements may change with time (see SUMMARY OF DOSAGE GUIDELINES).  Evaluation of level of sedation and assessment of CNS function should be carried out daily throughout maintenance to determine the minimum dose of DIPRIVAN required for sedation (see Clinical Trials, Intensive Care Unit (ICU) Sedation).  Bolus administration of 10 or 20 mg should only be used to rapidly increase depth of sedation in patients where hypotension is not likely to occur.  Patients with compromised myocardial function, intravascular volume depletion, or abnormally low vascular tone (e.g., sepsis) may be more susceptible to hypotension (see PRECAUTIONS).

  SUMMARY OF DOSAGE GUIDELINES:

  Dosages and rates of administration in the following table should be individualized and titrated to clinical response.  Safety and dosing requirements for induction of anesthesia in pediatric patients have only been established for children 3 years of age or older.  Safety and dosing requirements for the maintenance of anesthesia have only been established for children 2 months of age and older. 

  For complete dosage information, see DOSAGE AND ADMINISTRATION.

  INDICATION

  DOSAGE AND ADMINISTRATION

  Induction of General Anesthesia:

  Healthy Adults Less Than 55 Years of Age:

  40 mg every 10 seconds until induction onset (2 to 2.5 mg/kg).

  Elderly, Debilitated, or ASA-PS III or IV Patients:

  20 mg every 10 seconds until induction onset (1 to 1.5 mg/kg).

  Cardiac Anesthesia:

  20 mg every 10 seconds until induction onset  (0.5 to 1.5 mg/kg).

  Neurosurgical Patients:

  20 mg every 10 seconds until induction onset (1 to 2 mg/kg).

  Pediatric Patients - healthy, from 3 years to 16 years of age:

  2.5 to 3.5 mg/kg administered over 20 to 30 seconds.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Infusion

  Healthy Adults Less Than 55 Years of Age:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Elderly, Debilitated, ASA-PS III or IV Patients:

  50 to 100 mcg/kg/min (3 to 6 mg/kg/h).

  Cardiac Anesthesia:  Most patients require:

  Primary DIPRIVAN Injectable Emulsion with Secondary Opioid –

  100 to 150 mcg/kg/min.

  Low-Dose DIPRIVAN Injectable Emulsion with Primary Opioid –

  50 to 100 mcg/kg/min.

  (see DOSAGE AND ADMINISTRATION, Table 4)

  Neurosurgical Patients:

  100 to 200 mcg/kg/min (6 to 12 mg/kg/h).

  Pediatric Patients - healthy, from 2 months of age to 16 years of age:

  125 to 300 mcg/kg/min (7.5 to 18 mg/kg/h).

  Following the first half hour of maintenance, if clinical signs of light

  anesthesia are not present, the infusion rate should be decreased.

  (see PRECAUTIONS, Pediatric Use and CLINICAL

  PHARMACOLOGY, Pediatrics)

  Maintenance of General Anesthesia:

  Intermittent Bolus

  Healthy Adults Less Than 55 Years of Age:

  Increments of 20 to 50 mg as needed.

  Initiation of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  Slow infusion or slow injection techniques are recommended to avoid apnea

  or hypotension.  Most patients require an infusion of 100 to 150 mcg/kg/min

  (6 to 9 mg/kg/h) for 3 to 5 minutes or a slow injection of 0.5 mg/kg over 3

  to 5 minutes followed immediately by a maintenance infusion.

  Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require dosages similar to healthy adults.

  Rapid boluses are to be avoided (see WARNINGS).

  Maintenance of MAC Sedation:

  Healthy Adults Less Than 55 Years of Age:

  A variable rate infusion technique is preferable over an intermittent bolus

  technique.  Most patients require an infusion of 25 to 75 mcg/kg/min

  (1.5 to 4.5 mg/kg/h) or incremental bolus doses of 10 mg or 20 mg.

   

  In Elderly, Debilitated, Neurosurgical, or ASA-PS III or IV Patients:

  Most patients require 80% of the usual adult dose.  A rapid (single or

  repeated) bolus dose should not be used (see WARNINGS).

  Initiation and Maintenance of ICU Sedation in Intubated, Mechanically Ventilated

  Adult Patients - Because of the residual effects of previous anesthetic or

  sedative agents, in most patients the initial infusion should be 5 mcg/kg/min

  (0.3 mg/kg/h) for at least 5 minutes.  Subsequent increments of 5 to 10

  mcg/kg/min (0.3 to 0.6 mg/kg/h) over 5 to 10 minutes may be used until

  desired clinical effect is achieved.  Maintenance rates of 5 to 50 mcg/kg/min

  (0.3 to 3 mg/kg/h) or higher may be required.  Administration should not

  exceed 4 mg/kg/hour unless the benefits outweigh the risks (see

  WARNINGS).

  Evaluation of clinical effect and assessment of CNS function should be

  carried out daily throughout maintenance to determine the minimum

  dose of DIPRIVAN Injectable Emulsion required for sedation.

  The tubing and any unused DIPRIVAN Injectable Emulsion drug product

  should be discarded after 12 hours because DIPRIVAN Injectable

  Emulsion contains no preservatives and is capable of supporting growth

  of microorganisms (see WARNINGS and DOSAGE AND

  ADMINISTRATION).

  Administration with Lidocaine

  If lidocaine is to be administered to minimize pain on injection of DIPRIVAN Injectable Emulsion, it is recommended that it be administered prior to DIPRIVAN Injectable Emulsion administration or that it be added to DIPRIVAN Injectable Emulsion immediately before administration and in quantities not exceeding 20 mg lidocaine/200 mg DIPRIVAN.

  Compatibility and Stability

  DIPRIVAN Injectable Emulsion should not be mixed with other therapeutic agents prior to administration.

  Dilution Prior to Administration

  DIPRIVAN Injectable Emulsion is provided as a ready-to-use formulation.  However, should dilution be necessary, it should only be diluted with 5% Dextrose Injection, USP, and it should not be diluted to a concentration less than 2 mg/mL because it is an emulsion.  In diluted form it has been shown to be more stable when in contact with glass than with plastic (95% potency after 2 hours of running infusion in plastic).

  Administration with Other Fluids

  Compatibility of DIPRIVAN Injectable Emulsion with the coadministration of blood/serum/plasma has not been established (see WARNINGS).  When administered using a y-type infusion set, DIPRIVAN Injectable Emulsion has been shown to be compatible with the following intravenous fluids.

  -  5% Dextrose Injection, USP

  -  Lactated Ringers Injection, USP

  -  Lactated Ringers and 5% Dextrose Injection

  -  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  -  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Handling Procedures

  General 

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Clinical experience with the use of in-line filters and DIPRIVAN Injectable Emulsion during anesthesia or ICU/MAC sedation is limited.  DIPRIVAN Injectable Emulsion should only be administered through a filter with a pore size of 5 micron or greater unless it has been demonstrated that the filter does not restrict the flow of DIPRIVAN Injectable Emulsion and/or cause the breakdown of the emulsion.  Filters should be used with caution and where clinically appropriate.  Continuous monitoring is necessary due to the potential for restricted flow and/or breakdown of the emulsion.

  Do not use if there is evidence of separation of the phases of the emulsion.

  Rare cases of self-administration of DIPRIVAN Injectable Emulsion by health care professionals have been reported, including some fatalities (see DRUG ABUSE AND DEPENDENCE).

  Strict aseptic technique must always be maintained during handling.  DIPRIVAN Injectable Emulsion is a single access parenteral product (single patient infusion vial) which contains 0.005% disodium edetate to inhibit the rate of growth of microorganisms, up to 12 hours, in the event of accidental extrinsic contamination.  However, DIPRIVAN Injectable Emulsion can still support the growth of microorganisms as it is not an antimicrobially preserved product under USP standards.  Do not use if contamination is suspected.  Discard unused drug product as directed within the required time limits.  There have been reports in which failure to use aseptic technique when handling DIPRIVAN Injectable Emulsion was associated with microbial contamination of the product and with fever, infection/sepsis, other life-threatening illness, and/or death.

  There have been reports, in the literature and other public sources, of the transmission of bloodborne pathogens (such as Hepatitis B, Hepatitis C, and HIV) from unsafe injection practices, and use of propofol vials intended for single use on multiple persons.  DIPRIVAN Injectable Emulsion vials are never to be accessed more than once or used on more than one person.

  Diprivan, with EDTA inhibits microbial growth for up to 12 hours, as demonstrated by test data for representative USP microorganisms.

  Guidelines for Aseptic Technique for General Anesthesia/MAC Sedation

  DIPRIVAN Injectable Emulsion must be prepared for use just prior to initiation of each individual anesthetic/sedative procedure.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  DIPRIVAN Injectable Emulsion should be drawn into a sterile syringe immediately after vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from vials, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Any unused DIPRIVAN Injectable Emulsion drug product, reservoirs, dedicated administration tubing and/or solutions containing DIPRIVAN Injectable Emulsion must be discarded at the end of the anesthetic procedure or at 12 hours, whichever occurs sooner.  The IV line should be flushed every 12 hours and at the end of the anesthetic procedure to remove residual DIPRIVAN Injectable Emulsion.

  Guidelines for Aseptic Technique for ICU Sedation

  DIPRIVAN Injectable Emulsion must be prepared for single-patient use only.  Strict aseptic techniques must be followed.  The vial rubber stopper should be disinfected using 70% isopropyl alcohol.  A sterile vent spike and sterile tubing must be used for administration of DIPRIVAN Injectable Emulsion.  As with other lipid emulsions, the number of IV line manipulations should be minimized.  Administration should commence promptly and must be completed within 12 hours after the vial has been spiked.  The tubing and any unused DIPRIVAN Injectable Emulsion drug product must be discarded after 12 hours.

  If DIPRIVAN Injectable Emulsion is transferred to a syringe prior to administration, it should be drawn into a sterile syringe immediately after a vial is opened.  When withdrawing DIPRIVAN Injectable Emulsion from a vial, a sterile vent spike should be used.  The syringe should be labelled with appropriate information including the date and time the vial was opened. Administration should commence promptly and be completed within 12 hours after the vial has been opened.  DIPRIVAN Injectable Emulsion should be discarded and administration lines changed after 12 hours.

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• Oxytocin
  

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  Oxytocin

  

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  Dosage of oxytocin is determined by uterine response.  The following dosage information is based upon the various regimens and indications in general use.

  Induction or Stimulation of Labor

  Intravenous infusion (drip method) is the only acceptable method of administration for the induction or stimulation of labor.

  Accurate control of the rate of infusion flow is essential.  An infusion pump or other such device and frequent monitoring of strength of contractions and fetal heart rate are necessary for the safe administration of oxytocin for the induction or stimulation of labor.  If uterine contractions become too powerful, the infusion can be abruptly stopped, and oxytocic stimulation of the uterine musculature will soon wane.

  An intravenous infusion of a non-oxytocin containing solution should be started.  Physiologic electrolyte solutions should be used except under unusual circumstances.

  To prepare the usual solution for intravenous infusion–one mL (10 units) is combined aseptically with 1,000 mL of a non-hydrating diluent.

  The combined solution, rotated in the infusion bottle to insure thorough mixing, contains 10 mU/mL.  Add the container with dilute oxytocic solution to the system through the use of a constant infusion pump or other such device to control accurately the rate of infusion.

  The initial dose should be no more than 1 to 2 mU/min.  The dose may be gradually increased in increments of no more than 1 to 2 mU/min., until a contraction pattern has been established which is similar to normal labor.

  The fetal heart rate, resting uterine tone, and the frequency, duration, and force of contractions should be monitored.

  The oxytocin infusion should be discontinued immediately in the event of uterine hyperactivity or fetal distress.   Oxygen should be administered to the mother.  The mother and fetus must be evaluated by the responsible physician.

  Control of Postpartum Uterine Bleeding

  Intravenous Infusion (Drip Method)—To control postpartum bleeding, 10 to 40 units of oxytocin may be added to 1,000 mL of a nonhydrating diluent and run at a rate necessary to control uterine atony.

  Intramuscular Administration—1 mL (10 units) of oxytocin can be given after delivery of the placenta.

  Treatment of Incomplete or Inevitable Abortion

  Intravenous infusion with physiologic saline solution, 500 mL, or 5% dextrose in physiologic saline solution to which 10 units of oxytocin have been added should be infused at a rate of 20 to 40 drops/minute.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Induction or Stimulation of Labor

  Intravenous infusion (drip method) is the only acceptable method of administration for the induction or stimulation of labor.

  Accurate control of the rate of infusion flow is essential.  An infusion pump or other such device and frequent monitoring of strength of contractions and fetal heart rate are necessary for the safe administration of oxytocin for the induction or stimulation of labor.  If uterine contractions become too powerful, the infusion can be abruptly stopped, and oxytocic stimulation of the uterine musculature will soon wane.

  An intravenous infusion of a non-oxytocin containing solution should be started.  Physiologic electrolyte solutions should be used except under unusual circumstances.

  To prepare the usual solution for intravenous infusion–one mL (10 units) is combined aseptically with 1,000 mL of a non-hydrating diluent.

  The combined solution, rotated in the infusion bottle to insure thorough mixing, contains 10 mU/mL.  Add the container with dilute oxytocic solution to the system through the use of a constant infusion pump or other such device to control accurately the rate of infusion.

  The initial dose should be no more than 1 to 2 mU/min.  The dose may be gradually increased in increments of no more than 1 to 2 mU/min., until a contraction pattern has been established which is similar to normal labor.

  The fetal heart rate, resting uterine tone, and the frequency, duration, and force of contractions should be monitored.

  The oxytocin infusion should be discontinued immediately in the event of uterine hyperactivity or fetal distress.   Oxygen should be administered to the mother.  The mother and fetus must be evaluated by the responsible physician.

  Control of Postpartum Uterine Bleeding

  Intravenous Infusion (Drip Method)—To control postpartum bleeding, 10 to 40 units of oxytocin may be added to 1,000 mL of a nonhydrating diluent and run at a rate necessary to control uterine atony.

  Intramuscular Administration—1 mL (10 units) of oxytocin can be given after delivery of the placenta.

  Treatment of Incomplete or Inevitable Abortion

  Intravenous infusion with physiologic saline solution, 500 mL, or 5% dextrose in physiologic saline solution to which 10 units of oxytocin have been added should be infused at a rate of 20 to 40 drops/minute.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Azithromycin
  

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  Azithromycin

  

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  (See INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY.)

  The recommended dose of Azithromycin for Injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for at least two days.  Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg tablets to complete a 7 to 10 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.

  The recommended dose of Azithromycin for Injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is: 500 mg as a single daily dose by the intravenous route for one or two days.  Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 250 mg to complete a 7 day course of therapy.  The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response.  If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with Azithromycin for Injection.

  Renal Insufficiency

  No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0-120 was similar in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function.  Caution should be exercised when azithromycin is administered to subjects with severe renal impairment (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency).

  Hepatic Insufficiency

  The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.  No dose adjustment recommendations can be made in patients with impaired hepatic function (see CLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency).

  No dosage adjustment is recommended based on age or gender (see CLINICAL PHARMACOLOGY, Special Populations).

  The infusate concentration and rate of infusion for Azithromycin for Injection should be either 1 mg/mL over 3 hours or 2 mg/mL over 1 hour.  Azithromycin for Injection should not be given as a bolus or as an intramuscular injection. 

  Preparation of the solution for intravenous administration is as follows:

  Reconstitution

  Prepare the initial solution of Azithromycin for Injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial and shaking the vial until all of the drug is dissolved.  Since Azithromycin for Injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed.  Each mL of reconstituted solution contains 100 mg azithromycin.  Reconstituted solution is stable for 24 hours when stored below 30°C (86°F).

  Parenteral drug products should be inspected visually for particulate matter prior to administration.  If particulate matter is evident in reconstituted fluids, the drug solution should be discarded.

  Dilute this solution further prior to administration as instructed below.

  Dilution

  To provide azithromycin over a concentration range of 1 to 2 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below:

  Normal Saline (0.9% sodium chloride)

  1/2 Normal Saline (0.45% sodium chloride)

  5% Dextrose in Water

  Lactated Ringer’s Solution

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride) with 20 mEq KCl

  5% Dextrose in Lactated Ringer’s Solution

  5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride)

  5% Dextrose in 1/2 Normal Saline (0.45% sodium chloride)

  Normosol®-M in 5% Dextrose

  Normosol®-R in 5% Dextrose

   

  Final Infusion Solution

  Concentration (mg/mL)         Amount of Diluent (mL)

          1 mg/mL                                   500 mL

          2 mg/mL                                   250 mL

  It is recommended that a 500 mg dose of Azithromycin for Injection, diluted as above, be infused over a period of not less than 60 minutes.

  Azithromycin for Injection should not be given as a bolus or as an intramuscular injection.

  Other intravenous substances, additives, or medications should not be added to Azithromycin for Injection or infused simultaneously through the same intravenous line.

  Storage

  Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

  Storage

  Store the white to off-white lyophilized cake at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  When diluted according to the instructions (1 mg/mL to 2 mg/mL), Azithromycin for Injection is stable for 24 hours at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F).

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• Protamine Sulfate
  

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  Protamine Sulfate

  

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  Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.

  Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg (see WARNINGS).

  Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used.  Diluted solutions should not be stored since they contain no preservative.

  Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.

  Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin.  For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.

  The dosage of protamine sulfate should be guided by blood coagulation studies (see WARNINGS).

  Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Protamine Sulfate
  

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  Protamine Sulfate

  

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  Each mg of protamine sulfate, calculated on the dried basis, neutralizes not less than 100 USP Heparin Units.

  Protamine sulfate injection should be given by very slow intravenous injection over a 10-minute period in doses not to exceed 50 mg (see WARNINGS).

  Protamine sulfate is intended for injection without further dilution; however, if further dilution is desired, D5-W or normal saline may be used.  Diluted solutions should not be stored since they contain no preservative.

  Protamine sulfate should not be mixed with other drugs without knowledge of their compatibility, because protamine sulfate has been shown to be incompatible with certain antibiotics, including several of the cephalosporins and penicillins.

  Because heparin disappears rapidly from the circulation, the dose of protamine sulfate required also decreases rapidly with the time elapsed following intravenous injection of heparin.  For example, if the protamine sulfate is administered 30 minutes after the heparin, one-half the usual dose may be sufficient.

  The dosage of protamine sulfate should be guided by blood coagulation studies (see WARNINGS).

  Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Indomethacin
  

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  Indomethacin

  

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  For intravenous administration only.

  Dosage recommendations for closure of the ductus arteriosus depend on the age of the infant at the time of therapy.  A course of therapy is defined as three intravenous doses of Indomethacin for Injection given at 12 to 24 hour intervals, with careful attention to urinary output.  If anuria or marked oliguria (urinary output <0.6 mL/kg/hr) is evident at the scheduled time of the second or third dose of Indomethacin for Injection, do not give additional doses until laboratory studies indicate that renal function has returned to normal [see Warnings and Precautions (5.7)].

  Dosage according to age is as follows:

  AGE at 1st dose

  DOSAGE (mg/kg)

   

  Less than 48 hours

  1st

  0.2

  2nd

  0.1

  3rd

  0.1

  2 to 7 days

  0.2

  0.2

  0.2

  Over 7 days

  0.2

  0.25

  0.25

  If the ductus arteriosus closes or is significantly reduced in size after an interval of 48 hours or more from completion of the first course of Indomethacin for Injection, no further doses are necessary.  If the ductus arteriosus re-opens, a second course of 1 to 3 doses may be given, each dose separated by a 12 to 24 hour interval as described above.

  If the neonate remains unresponsive to therapy with Indomethacin for Injection after 2 courses, surgery may be necessary for closure of the ductus arteriosus.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

  2.1 Directions for Use

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  The reconstituted solution, pH 6.0 to 7.5, is clear, slightly yellow and essentially free from visible particles. 

  Prepare the solution with 1 to 2 mL of preservative-free Sterile Sodium Chloride Injection, 0.9 percent or preservative-free Sterile Water for Injection.  Benzyl alcohol as a preservative has been associated with toxicity in neonates.  Therefore, do not use diluents that contain preservatives.  If 1 mL of diluent is used, the concentration of indomethacin in the solution will equal approximately 0.1 mg/0.1 mL; if 2 mL of diluent are used, the concentration of the solution will equal approximately 0.05 mg/0.1 mL.  Discard any unused portion of the solution as it does not contain a preservative.  Prepare a fresh solution just prior to each administration.  Once reconstituted, the indomethacin solution may be injected intravenously.  While the optimal rate of injection has not been established, published literature suggests an infusion rate over 20 to 30 minutes. 

  Further dilution with intravenous infusion solutions is not recommended.

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• Extra Strength Non-aspi...
  

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  Extra Strength Non-aspirin Pain Reliever

  

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  Treatment

  The usual adult dosage is 1 or 2 grams of Cefotetan for Injection, USP administered intravenously or intramuscularly.  Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organism.

  General Guidelines For Dosage of Cefotetan for Injection, USP Type of Infection Daily Dose Frequency and Route Urinary Tract 1 to 4 grams 500 mg every 12 hours IV or IM1 or 2 g every 24 hours IV or IM 1 or 2 g every 12 hours IV or IM Skin & Skin Structure      Mild - Moderatea       Severe  2 grams 4 grams  2 g every 24 hours IV1 g every 12 hours IV or IM2 g every 12 hours IV Other Sites 2 to 4 grams 1 or 2 g every 12 hours IV or IM Severe 4 grams 2 g every 12 hours IV Life-Threatening 6 gramsb 3 g every 12 hours IV a Klebsiella pneumoniae skin and skin structure infections should be treated with 1 or   2 grams every 12 hours IV or IM. b Maximum daily dosage should not exceed 6 grams.

  If Chlamydia trachomatis is a suspected pathogen in gynecologic infections, appropriate antichlamydial coverage should be added, since cefotetan has no activity against this organism.

  Prophylaxis

  To prevent postoperative infection in clean contaminated or potentially contaminated surgery in adults, the recommended dosage is 1 or 2 g of Cefotetan for Injection, USP administered once, intravenously, 30 to 60 minutes prior to surgery.  In patients undergoing cesarean section, the dose should be administered as soon as the umbilical cord is clamped.

  Impaired Renal Function

  When renal function is impaired, a reduced dosage schedule must be employed.  The following dosage guidelines may be used.

   DOSAGE GUIDELINES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION    Creatinine Clearance  mL/min  Dose    Frequency    > 30   Usual Recommended Dosage*   Every 12 hours   10 to 30   Usual Recommended Dosage*   Every 24 hours   < 10   Usual Recommended Dosage*   Every 48 hours 

  * Dose determined by the type and severity of infection, and susceptibility of the causative organism.

  Alternatively, the dosing interval may remain constant at 12 hour intervals, but the dose reduced to one-half the usual recommended dose for patients with a creatinine clearance of 10 to 30 mL/min, and one-quarter the usual recommended dose for patients with a creatinine clearance of less than 10 mL/min.

  When only serum creatinine levels are available, creatinine clearance may be calculated from the following formula.  The serum creatinine level should represent a steady state of renal function.

  Males:                 Weight (kg) x (140 - age)       

                        72 x serum creatinine (mg/100 mL)

  Females:   0.85 x value for males

  Cefotetan is dialyzable and it is recommended that for patients undergoing intermittent hemodialysis, one-quarter of the usual recommended dose be given every 24 hours on days between dialysis and one-half the usual recommended dose on the day of dialysis.

  Preparation of Solution

  For Intravenous Use

  Reconstitute with Sterile Water for Injection.  Shake to dissolve and let stand until clear.

  Vial Size   Amount of  Diluent Added (mL)  Approximate Withdrawable  Vol (mL)  Approximate  Average Concentration (mg/mL)  1 gram   10   10.5   95   2 gram   10 to 20   11 to 21   182 to 95 

  For Intramuscular Use

  Reconstitute with Sterile Water for Injection; Bacteriostatic Water for Injection; Sodium Chloride Injection 0.9%, USP; 0.5% Lidocaine HCl; or 1% Lidocaine HCl.  Shake to dissolve and let stand until clear.

  Vial Size   Amount of  Diluent Added (mL)  Approximate Withdrawable  Vol (mL)  Approximate  Average Concentration(mg/mL)  1 gram   2   2.5   400   2 gram   3   4   500 

  Intravenous Administration

  The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

  For intermittent intravenous administration, a solution containing 1 gram or 2 grams of Cefotetan for Injection, USP in Sterile Water for Injection can be injected over a period of three to five minutes.  Using an infusion system, the solution may also be given over a longer period of time through the tubing system by which the patient may be receiving other intravenous solutions.  Butterfly® or scalp vein-type needles are preferred for this type of infusion.  However, during infusion of the solution containing Cefotetan for Injection, USP, it is advisable to discontinue temporarily the administration of other solutions at the same site.

  NOTE: Solutions of cefotetan must not be admixed with solutions containing aminoglycosides.  If cefotetan and aminoglycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection.

  Intramuscular Administration

  As with all intramuscular preparations, Cefotetan for Injection, USP should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel.

  Compatibility and Stability

  Frozen samples should be thawed at room temperature before use.  After the periods mentioned below, any unused solutions or frozen material should be discarded.  DO NOT REFREEZE.

  NOTE:  Solutions of Cefotetan for Injection, USP must not be admixed with solutions containing aminoglycosides.  If Cefotetan for Injection, USP and aminoglycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection.  DO NOT ADD SUPPLEMENTARY MEDICATION.

  Cefotetan for Injection, USP reconstituted as described above (see DOSAGE AND ADMINISTRATION, Preparation of Solution) maintains satisfactory potency for 24 hours at room temperature (25°C/77°F), for 96 hours under refrigeration (5°C/41°F), and for at least 1 week in the frozen state (-20°C/-4°F).  After reconstitution and subsequent storage in disposable glass or plastic syringes, Cefotetan for Injection, USP is stable for 24 hours at room temperature and 96 hours under refrigeration.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Treatment

  The usual adult dosage is 1 or 2 grams of Cefotetan for Injection, USP administered intravenously or intramuscularly.  Proper dosage and route of administration should be determined by the condition of the patient, severity of the infection, and susceptibility of the causative organism.

  General Guidelines For Dosage of Cefotetan for Injection, USP Type of Infection Daily Dose Frequency and Route Urinary Tract 1 to 4 grams 500 mg every 12 hours IV or IM1 or 2 g every 24 hours IV or IM 1 or 2 g every 12 hours IV or IM Skin & Skin Structure      Mild - Moderatea       Severe  2 grams 4 grams  2 g every 24 hours IV1 g every 12 hours IV or IM2 g every 12 hours IV Other Sites 2 to 4 grams 1 or 2 g every 12 hours IV or IM Severe 4 grams 2 g every 12 hours IV Life-Threatening 6 gramsb 3 g every 12 hours IV a Klebsiella pneumoniae skin and skin structure infections should be treated with 1 or   2 grams every 12 hours IV or IM. b Maximum daily dosage should not exceed 6 grams.

  If Chlamydia trachomatis is a suspected pathogen in gynecologic infections, appropriate antichlamydial coverage should be added, since cefotetan has no activity against this organism.

  Prophylaxis

  To prevent postoperative infection in clean contaminated or potentially contaminated surgery in adults, the recommended dosage is 1 or 2 g of Cefotetan for Injection, USP administered once, intravenously, 30 to 60 minutes prior to surgery.  In patients undergoing cesarean section, the dose should be administered as soon as the umbilical cord is clamped.

  Impaired Renal Function

  When renal function is impaired, a reduced dosage schedule must be employed.  The following dosage guidelines may be used.

   DOSAGE GUIDELINES FOR PATIENTS WITH IMPAIRED RENAL FUNCTION    Creatinine Clearance  mL/min  Dose    Frequency    > 30   Usual Recommended Dosage*   Every 12 hours   10 to 30   Usual Recommended Dosage*   Every 24 hours   < 10   Usual Recommended Dosage*   Every 48 hours 

  * Dose determined by the type and severity of infection, and susceptibility of the causative organism.

  Alternatively, the dosing interval may remain constant at 12 hour intervals, but the dose reduced to one-half the usual recommended dose for patients with a creatinine clearance of 10 to 30 mL/min, and one-quarter the usual recommended dose for patients with a creatinine clearance of less than 10 mL/min.

  When only serum creatinine levels are available, creatinine clearance may be calculated from the following formula.  The serum creatinine level should represent a steady state of renal function.

  Males:                 Weight (kg) x (140 - age)       

                        72 x serum creatinine (mg/100 mL)

  Females:   0.85 x value for males

  Cefotetan is dialyzable and it is recommended that for patients undergoing intermittent hemodialysis, one-quarter of the usual recommended dose be given every 24 hours on days between dialysis and one-half the usual recommended dose on the day of dialysis.

  Preparation of Solution

  For Intravenous Use

  Reconstitute with Sterile Water for Injection.  Shake to dissolve and let stand until clear.

  Vial Size   Amount of  Diluent Added (mL)  Approximate Withdrawable  Vol (mL)  Approximate  Average Concentration (mg/mL)  1 gram   10   10.5   95   2 gram   10 to 20   11 to 21   182 to 95 

  For Intramuscular Use

  Reconstitute with Sterile Water for Injection; Bacteriostatic Water for Injection; Sodium Chloride Injection 0.9%, USP; 0.5% Lidocaine HCl; or 1% Lidocaine HCl.  Shake to dissolve and let stand until clear.

  Vial Size   Amount of  Diluent Added (mL)  Approximate Withdrawable  Vol (mL)  Approximate  Average Concentration(mg/mL)  1 gram   2   2.5   400   2 gram   3   4   500 

  Intravenous Administration

  The intravenous route is preferable for patients with bacteremia, bacterial septicemia, or other severe or life-threatening infections, or for patients who may be poor risks because of lowered resistance resulting from such debilitating conditions as malnutrition, trauma, surgery, diabetes, heart failure, or malignancy, particularly if shock is present or impending.

  For intermittent intravenous administration, a solution containing 1 gram or 2 grams of Cefotetan for Injection, USP in Sterile Water for Injection can be injected over a period of three to five minutes.  Using an infusion system, the solution may also be given over a longer period of time through the tubing system by which the patient may be receiving other intravenous solutions.  Butterfly® or scalp vein-type needles are preferred for this type of infusion.  However, during infusion of the solution containing Cefotetan for Injection, USP, it is advisable to discontinue temporarily the administration of other solutions at the same site.

  NOTE: Solutions of cefotetan must not be admixed with solutions containing aminoglycosides.  If cefotetan and aminoglycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection.

  Intramuscular Administration

  As with all intramuscular preparations, Cefotetan for Injection, USP should be injected well within the body of a relatively large muscle such as the upper outer quadrant of the buttock (i.e., gluteus maximus); aspiration is necessary to avoid inadvertent injection into a blood vessel.

  Compatibility and Stability

  Frozen samples should be thawed at room temperature before use.  After the periods mentioned below, any unused solutions or frozen material should be discarded.  DO NOT REFREEZE.

  NOTE:  Solutions of Cefotetan for Injection, USP must not be admixed with solutions containing aminoglycosides.  If Cefotetan for Injection, USP and aminoglycosides are to be administered to the same patient, they must be administered separately and not as a mixed injection.  DO NOT ADD SUPPLEMENTARY MEDICATION.

  Cefotetan for Injection, USP reconstituted as described above (see DOSAGE AND ADMINISTRATION, Preparation of Solution) maintains satisfactory potency for 24 hours at room temperature (25°C/77°F), for 96 hours under refrigeration (5°C/41°F), and for at least 1 week in the frozen state (-20°C/-4°F).  After reconstitution and subsequent storage in disposable glass or plastic syringes, Cefotetan for Injection, USP is stable for 24 hours at room temperature and 96 hours under refrigeration.

  NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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• Heparin Sodium
  

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  Heparin Sodium

  

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  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 

  Confirm the choice of the correct Heparin Sodium Injection vial prior to administration of the drug to a patient (see WARNINGS, Fatal Medication Errors). The 1 mL vial must not be confused with a ‘‘catheter lock flush’’ vial or other 1 mL vial of inappropriate strength.  Confirm that you have selected the correct medication and strength prior to administration of the drug.

  When heparin is added to an infusion solution for continuous intravenous administration, the container should be inverted at least six times to ensure adequate mixing and prevent pooling of the heparin in the solution.

  Heparin sodium is not effective by oral administration and should be given by intermittent intravenous injection, intravenous infusion, or deep subcutaneous (intrafat, i.e., above the iliac crest or abdominal fat layer) injection.  The intramuscular route of administration should be avoided because of the frequent occurrence of hematoma at the injection site.

  The dosage of heparin sodium should be adjusted according to the patient’s coagulation test results. When heparin is given by continuous intravenous infusion, the coagulation time should be determined approximately every four hours in the early stages of treatment.  When the drug is administered intermittently by intravenous injection, coagulation tests should be performed before each injection during the early stages of treatment and at appropriate intervals thereafter. Dosage is considered adequate when the activated partial thromboplastin time (APTT) is 1.5 to 2 times normal or when the whole blood clotting time is elevated approximately 2.5 to 3 times the control value.  After deep subcutaneous (intrafat) injections, tests for adequacy of dosage are best performed on samples drawn four to six hours after the injection.

  Periodic platelet counts, hematocrits and tests for occult blood in stool are recommended during the entire course of heparin therapy, regardless of the route of administration.

  Converting to Oral Anticoagulant

  When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time.  This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose.  If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

  In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals.  To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range.  Heparin therapy may then be discontinued without tapering.

  Therapeutic Anticoagulant Effect with Full-Dose Heparin

  Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

  METHOD OF

  ADMINISTRATION

  FREQUENCY

  RECOMMENDED DOSE (based on 150 lb [68 kg] patient)

  Deep Subcutaneous

  (Intrafat) Injection

   

  A different site

  should be used for

  each injection to

  prevent the development

  of massive hematoma

   Initial Dose

   5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously

   

  Every

  8 hours

   

  or

   Every

  12 hours

   

  8,000 to 10,000 units of a concentrated solution

   

   

   

  15,000 to 20,000 units of a concentrated solution

  Intermittent

  Intravenous

  Injection

   

  Initial Dose

  10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Every 4 to

  6 hours

   5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Intravenous

  Infusion

  Initial Dose

  5,000 units by IV injection

   

  Continuous

   

  20,000 to 40,000 units/ 24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

  Pediatric Use

  Follow recommendations of appropriate pediatric reference texts.  In general, the following dosage schedule may be used as a guideline:

  Initial Dose: 50 units/kg (IV, infusion)

  Maintenance Dose: 100 units/kg (IV, infusion) every four hours, or 20,000 units/m2/24 hours continuously

  Geriatric Use

  Patients over 60 years of age may require lower doses of heparin.

  Surgery of the Heart and Blood Vessels

  Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.  Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

  Low-Dose Prophylaxis of Postoperative Thromboembolism

  A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.  The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.  The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma.  A concentrated solution of heparin sodium is recommended.  Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery.  Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS).  The value of such prophylaxis in hip surgery has not been established.  The possibility of increased bleeding during surgery or postoperatively should be borne in mind.  If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable.  If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated.  All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery.  Coagulation test values should be normal or only slightly elevated.  There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

  Extracorporeal Dialysis

  Follow equipment manufacturers’ operating directions carefully.

  Blood Transfusion

  Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.  Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

  Laboratory Samples

  Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample.  Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin.  Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

  Converting to Oral Anticoagulant

  When an oral anticoagulant of the coumarin or similar type is to be begun in patients already receiving heparin sodium, baseline and subsequent tests of prothrombin activity must be determined at a time when heparin activity is too low to affect the prothrombin time.  This is about five hours after the last IV bolus and 24 hours after the last subcutaneous dose.  If continuous IV heparin infusion is used, prothrombin time can usually be measured at any time.

  In converting from heparin to an oral anticoagulant, the dose of the oral anticoagulant should be the usual initial amount and thereafter prothrombin time should be determined at the usual intervals.  To ensure continuous anticoagulation, it is advisable to continue full heparin therapy for several days after the prothrombin time has reached the therapeutic range.  Heparin therapy may then be discontinued without tapering.

  Therapeutic Anticoagulant Effect with Full-Dose Heparin

  Although dosage must be adjusted for the individual patient according to the results of suitable laboratory tests, the following dosage schedules may be used as guidelines:

  METHOD OF

  ADMINISTRATION

  FREQUENCY

  RECOMMENDED DOSE (based on 150 lb [68 kg] patient)

  Deep Subcutaneous

  (Intrafat) Injection

   

  A different site

  should be used for

  each injection to

  prevent the development

  of massive hematoma

   Initial Dose

   5,000 units by IV injection, followed by 10,000 to 20,000 units of a concentrated solution, subcutaneously

   

  Every

  8 hours

   

  or

   Every

  12 hours

   

  8,000 to 10,000 units of a concentrated solution

   

   

   

  15,000 to 20,000 units of a concentrated solution

  Intermittent

  Intravenous

  Injection

   

  Initial Dose

  10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Every 4 to

  6 hours

   5,000 to 10,000 units, either undiluted or in 50 to 100 mL of 0.9% Sodium Chloride Injection, USP

  Intravenous

  Infusion

  Initial Dose

  5,000 units by IV injection

   

  Continuous

   

  20,000 to 40,000 units/ 24 hours in 1,000 mL of 0.9% Sodium Chloride Injection, USP (or in any compatible solution) for infusion

  Pediatric Use

  Follow recommendations of appropriate pediatric reference texts.  In general, the following dosage schedule may be used as a guideline:

  Initial Dose: 50 units/kg (IV, infusion)

  Maintenance Dose: 100 units/kg (IV, infusion) every four hours, or 20,000 units/m2/24 hours continuously

  Geriatric Use

  Patients over 60 years of age may require lower doses of heparin.

  Surgery of the Heart and Blood Vessels

  Patients undergoing total body perfusion for open-heart surgery should receive an initial dose of not less than 150 units of heparin sodium per kilogram of body weight.  Frequently, a dose of 300 units of heparin sodium per kilogram of body weight is used for procedures estimated to last less than 60 minutes, or 400 units per kilogram for those estimated to last longer than 60 minutes.

  Low-Dose Prophylaxis of Postoperative Thromboembolism

  A number of well-controlled clinical trials have demonstrated that low-dose heparin prophylaxis, given just prior to and after surgery, will reduce the incidence of postoperative deep vein thrombosis in the legs (as measured by the I-125 fibrinogen technique and venography) and of clinical pulmonary embolism.  The most widely used dosage has been 5,000 units 2 hours before surgery and 5,000 units every 8 to 12 hours thereafter for seven days or until the patient is fully ambulatory, whichever is longer.  The heparin is given by deep subcutaneous injection in the arm or abdomen with a fine needle (25 to 26 gauge) to minimize tissue trauma.  A concentrated solution of heparin sodium is recommended.  Such prophylaxis should be reserved for patients over the age of 40 who are undergoing major surgery.  Patients with bleeding disorders and those having neurosurgery, spinal anesthesia, eye surgery or potentially sanguineous operations should be excluded, as well as patients receiving oral anticoagulants or platelet-active drugs (see WARNINGS).  The value of such prophylaxis in hip surgery has not been established.  The possibility of increased bleeding during surgery or postoperatively should be borne in mind.  If such bleeding occurs, discontinuance of heparin and neutralization with protamine sulfate are advisable.  If clinical evidence of thromboembolism develops despite low-dose prophylaxis, full therapeutic doses of anticoagulants should be given unless contraindicated.  All patients should be screened prior to heparinization to rule out bleeding disorders, and monitoring should be performed with appropriate coagulation tests just prior to surgery.  Coagulation test values should be normal or only slightly elevated.  There is usually no need for daily monitoring of the effect of low-dose heparin in patients with normal coagulation parameters.

  Extracorporeal Dialysis

  Follow equipment manufacturers’ operating directions carefully.

  Blood Transfusion

  Addition of 400 to 600 USP units per 100 mL of whole blood is usually employed to prevent coagulation.  Usually, 7,500 USP units of heparin sodium are added to 100 mL of 0.9% Sodium Chloride Injection, USP (or 75,000 USP units/1,000 mL of 0.9% Sodium Chloride Injection, USP) and mixed; from this sterile solution, 6 to 8 mL are added per 100 mL of whole blood.

  Laboratory Samples

  Addition of 70 to 150 units of heparin sodium per 10 to 20 mL sample of whole blood is usually employed to prevent coagulation of the sample.  Leukocyte counts should be performed on heparinized blood within two hours after addition of the heparin.  Heparinized blood should not be used for isoagglutinin, complement, or erythrocyte fragility tests or platelet counts.

  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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• Dexamethasone Sodium Ph...
  

  ×

  Dexamethasone Sodium Phosphate

  

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  Dexamethasone sodium phosphate injection, 4 mg/mL – For intravenous, intramuscular, intra-articular, intralesional, and soft tissue injection.

  Dexamethasone sodium phosphate injection can be given directly from the vial, or it can be added to Sodium Chloride Injection or Dextrose Injection and administered by intravenous drip.

  Solutions used for intravenous administration or further dilution of this product should be preservative free when used in the neonate, especially the premature infant.

  When it is mixed with an infusion solution, sterile precautions should be observed.  Since infusion solutions generally do not contain preservatives, mixtures should be used within 24 hours.

   

  DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.

  Intravenous and Intramuscular Injection

  The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated.  In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

  The initial dosage should be maintained or adjusted until the patient’s response is satisfactory.  If a satisfactory clinical response does not occur after a reasonable period of time, discontinue dexamethasone sodium phosphate injection and transfer the patient to other therapy.

  After a favorable initial response, the proper maintenance dosage should be determined by decreasing the initial dosage in small amounts to the lowest dosage that maintains an adequate clinical response.

  Patients should be observed closely for signs that might require dosage adjustment, including changes in clinical status resulting from remissions or exacerbations of the disease, individual drug responsiveness, and the effect of stress (e.g., surgery, infection, trauma).  During stress it may be necessary to increase dosage temporarily.

  If the drug is to be stopped after more than a few days of treatment, it usually should be withdrawn gradually.

  When the intravenous route of administration is used, dosage usually should be the same as the oral dosage.  In certain overwhelming, acute, life-threatening situations, however, administration in dosages exceeding the usual dosages may be justified and may be in multiples of the oral dosages.  The slower rate of absorption by intramuscular administration should be recognized.

  Shock

  There is a tendency in current medical practice to use high (pharmacologic) doses of corticosteroids for the treatment of unresponsive shock.  The following dosages of dexamethasone sodium phosphate injection have been suggested by various authors:

  Author

   Dosage

  Cavanagh1

  3 mg/kg of body weight per 24 hours by constant intravenous infusion after an initial intravenous injection of 20 mg

  Dietzman2

  2 to 6 mg/kg of body weight as a single intravenous injection

  Frank3

  40 mg initially followed by repeat

  intravenous injection every 4 to 6 hours while shock persists

  Oaks4

  40 mg initially followed by repeat

  intravenous injection every 2 to 6 hours while shock persists

  Schumer5

  1 mg/kg of body weight as a single intravenous injection

  Administration of high dose corticosteroid therapy should be continued only until the patient’s condition has stabilized and usually not longer than 48 to 72 hours.

  Although adverse reactions associated with high dose, short term corticosteroid therapy are uncommon, peptic ulceration may occur.

  Cerebral Edema

  Dexamethasone sodium phosphate injection is generally administered initially in a dosage of 10 mg intravenously followed by four mg every six hours intramuscularly until the symptoms of cerebral edema subside.  Response is usually noted within 12 to 24 hours and dosage may be reduced after two to four days and gradually discontinued over a period of five to seven days.  For palliative management of patients with recurrent or inoperable brain tumors, maintenance therapy with two mg two or three times a day may be effective.

  Acute Allergic Disorders

  In acute, self-limited allergic disorders or acute exacerbations of chronic allergic disorders, the following dosage schedule combining parenteral and oral therapy is suggested:

  Dexamethasone sodium phosphate injection, 4 mg/mL: first day, 1 or 2 mL (4 or 8 mg), intramuscularly.

  Dexamethasone tablets, 0.75 mg: second and third days, 4 tablets in two divided doses each day; fourth day, 2 tablets in two divided doses; fifth and sixth days, 1 tablet each day; seventh day, no treatment; eighth day, follow-up visit.

  This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.

  Intra-articular, Intralesional and Soft Tissue Injection

  Intra-articular, intralesional, and soft tissue injections are generally employed when the affected joints or areas are limited to one or two sites.  Dosage and frequency of injection varies depending on the condition and the site of injection.  The usual dose is from 0.2 to 6 mg.  The frequency usually ranges from once every three to five days to once every two to three weeks.  Frequent intra-articular injection may result in damage to joint tissues.

  Some of the usual single doses are:

  Site of Injection

  Amount of

  Dexamethasone

  Phosphate (mg)

  Large Joints

  (e.g., Knee)

  2 to 4

  Small Joints

  (e.g., Interphalangeal,

  Temporomandibular)

  0.8 to 1

  Bursae

  2 to 3

  Tendon Sheaths

  0.4 to 1

  Soft Tissue Infiltration

  2 to 6

  Ganglia

  1 to 2

  Dexamethasone sodium phosphate injection is particularly recommended for use in conjunction with one of the less soluble, longer-acting steroids for intra-articular and soft tissue injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

  Intra-articular, Intralesional and Soft Tissue Injection

  Intra-articular, intralesional, and soft tissue injections are generally employed when the affected joints or areas are limited to one or two sites.  Dosage and frequency of injection varies depending on the condition and the site of injection.  The usual dose is from 0.2 to 6 mg.  The frequency usually ranges from once every three to five days to once every two to three weeks.  Frequent intra-articular injection may result in damage to joint tissues.

  Some of the usual single doses are:

  Site of Injection

  Amount of

  Dexamethasone

  Phosphate (mg)

  Large Joints

  (e.g., Knee)

  2 to 4

  Small Joints

  (e.g., Interphalangeal,

  Temporomandibular)

  0.8 to 1

  Bursae

  2 to 3

  Tendon Sheaths

  0.4 to 1

  Soft Tissue Infiltration

  2 to 6

  Ganglia

  1 to 2

  Dexamethasone sodium phosphate injection is particularly recommended for use in conjunction with one of the less soluble, longer-acting steroids for intra-articular and soft tissue injection.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit.

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• Octreotide
  

  ×

  Octreotide

  

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  Octreotide Acetate Injection may be administered subcutaneously or intravenously.  Subcutaneous injection is the usual route of administration of Octreotide Acetate Injection for control of symptoms.  Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose.  Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.  Do not use if particulates and/or discoloration are observed.  Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination.  Octreotide Acetate Injection is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

  Octreotide Acetate Injection is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours.  It may be diluted in volumes of 50 to 200 mL and infused intravenously over 15 to 30 minutes or administered by IV push over 3 minutes.  In emergency situations (e.g.: carcinoid crisis) it may be given by rapid bolus.

  The initial dosage is usually 50 mcg administered twice or three times daily.  Upward dose titration is frequently required.  Dosage information for patients with specific tumors follows.

  Acromegaly

  Dosage may be initiated at 50 mcg t.i.d.  Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses.  IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration.  Alternatively, multiple growth hormone levels at 0 to 8 hours after Octreotide Acetate Injection administration permit more rapid titration of dose.  The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females.  The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness.  Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced.  IGF-I (somatomedin C) or growth hormone levels should be re-evaluated at 6 month intervals.

  Octreotide Acetate Injection should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity.  If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, Octreotide Acetate Injection therapy may be resumed.

  Carcinoid Tumors

  The suggested daily dosage of Octreotide Acetate Injection during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg).  In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1,500 mcg/day.  However, experience with doses above 750 mcg/day is limited.

  VIPomas

  Daily dosages of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range 150 to 750 mcg) to control symptoms of the disease.  On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.

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• Haloperidol
  

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  Haloperidol

  

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  There is considerable variation from patient to patient in the amount of medication required for treatment.  As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient.  Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control.

  To determine the initial dosage, consideration should be given to the patient’s age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state.  Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less Haloperidol Injection.  The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels.

  Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms.  Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory.

  Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Switchover Procedure

  An oral form should supplant the injectable as soon as practicable.  In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested.  For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used.  Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover.  In this way, dosage adjustments, either upward or downward, can be quickly accomplished.  Depending on the patient’s clinical status, the first oral dose should be given within 12 to 24 hours following the last parenteral dose.

  Switchover Procedure

  An oral form should supplant the injectable as soon as practicable.  In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested.  For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used.  Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover.  In this way, dosage adjustments, either upward or downward, can be quickly accomplished.  Depending on the patient’s clinical status, the first oral dose should be given within 12 to 24 hours following the last parenteral dose.

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• Magnesium Sulfate
  

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  Magnesium Sulfate

  

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  Dosage of magnesium sulfate must be carefully adjusted according to individual requirements and response, and administration of the drug should be discontinued as soon as the desired effect is obtained.

  Both IV and IM administration are appropriate.  IM administration of the undiluted 50% solution results in therapeutic plasma levels in 60 minutes, whereas IV doses will provide a therapeutic level almost immediately.  The rate of IV injection should generally not exceed 150 mg/minute, except in severe eclampsia with seizures (see below).  Continuous maternal administration of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Solutions for IV infusion must be diluted to a concentration of 20% or less prior to administration.  The diluents commonly used are 5% Dextrose Injection, USP and 0.9% Sodium Chloride Injection, USP.  Deep IM injection of the undiluted (50%) solution is appropriate for adults, but the solution should be diluted to a 20% or less concentration prior to such injection in children.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  In Magnesium Deficiency

  In the treatment of mild magnesium deficiency, the usual adult dose is 1 g, equivalent to 8.12 mEq of magnesium (2 mL of the 50% solution) injected IM every six hours for four doses (equivalent to a total of 32.5 mEq of magnesium per 24 hours).  For severe hypomagnesemia, as much as 250 mg (approximately 2 mEq) per kg of body weight (0.5 mL of the 50% solution) may be given IM within a period of four hours if necessary.  Alternatively, 5 g (approximately 40 mEq) can be added to one liter of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP for slow IV infusion over a three-hour period.  In the treatment of deficiency states, caution must be observed to prevent exceeding the renal excretory capacity.

  In Hyperalimentation

  In TPN, maintenance requirements for magnesium are not precisely known.  The maintenance dose used in adults ranges from 8 to 24 mEq (1 to 3 g) daily; for infants, the range is 2 to 10 mEq (0.25 to 1.25 g) daily.

  In Pre-eclampsia or Eclampsia

  In severe pre-eclampsia or eclampsia, the total initial dose is 10 to 14 g of magnesium sulfate. Intravenously, a dose of 4 to 5 g in 250 mL of 5% Dextrose Injection, USP or 0.9% Sodium Chloride Injection, USP may be infused.  Simultaneously, IM doses of up to 10 g (5 g or 10 mL of the undiluted 50% solution in each buttock) are given.  Alternatively, the initial IV dose of 4 g may be given by diluting the 50% solution to a 10 or 20% concentration; the diluted fluid (40 mL of a 10% solution or 20 mL of a 20% solution) may then be injected IV over a period of three to four minutes.  Subsequently, 4 to 5 g (8 to 10 mL of the 50% solution) are injected IM into alternate buttocks every four hours as needed, depending on the continuing presence of the patellar reflex and adequate respiratory function.  Alternatively, after the initial IV dose, some clinicians administer 1 to 2 g/hour by constant IV infusion.  Therapy should continue until paroxysms cease.  A serum magnesium level of 6 mg/100 mL is considered optimal for control of seizures.  A total daily (24 hr) dose of 30 to 40 g should not be exceeded. In the presence of severe renal insufficiency, the maximum dosage of magnesium sulfate is 20 grams/48 hours and frequent serum magnesium concentrations must be obtained.  Continuous use of magnesium sulfate in pregnancy beyond 5 to 7 days can cause fetal abnormalities.

  Other uses

  In counteracting the muscle-stimulating effects of barium poisoning, the usual dose of magnesium sulfate is 1 to 2 g given IV.

  For controlling seizures associated with epilepsy, glomerulonephritis or hypothyroidism, the usual adult dose is 1 g administered IM or IV.

  In paroxysmal atrial tachycardia, magnesium should be used only if simpler measures have failed and there is no evidence of myocardial damage.  The usual dose is 3 to 4 g (30 to 40 mL of a 10% solution) administered IV over 30 seconds with extreme caution.

  For reduction of cerebral edema, 2.5 g (25 mL of a 10% solution) is given IV.

  Incompatibilities

  Magnesium sulfate in solution may result in a precipitate formation when mixed with solutions containing:

  Alcohol (in high concentrations)

  Heavy metals

  Alkali carbonates and bicarbonates

  Hydrocortisone sodium succinate

  Alkali hydroxides

  Phosphates

  Arsenates

  Polymyxin B sulfate

  Barium

  Procaine hydrochloride

  Calcium

  Salicylates

  Clindamycin phosphate

  Strontium

   

  Tartrates

  The potential incompatibility will often be influenced by the changes in the concentration of reactants and the pH of the solutions.

  It has been reported that magnesium may reduce the antibiotic activity of streptomycin, tetracycline and tobramycin when given together.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Norethindrone Acetate A...
  

  ×

  Norethindrone Acetate And Ethinyl Estradiol

  

  ---

  CAUTION - RAPID OR BOLUS INTRAVENOUS INJECTION MUST BE AVOIDED (see WARNINGS and PRECAUTIONS).

  INTRAMUSCULAR OR SUBCUTANEOUS INJECTION MUST BE AVOIDED (see WARNINGS).

  Therapy should be initiated as early as possible following onset of signs and symptoms of herpes infections. 

  A maximum dose equivalent to 20 mg/kg every 8 hours should not be exceeded for any patient.

  Dosage

  HERPES SIMPLEX INFECTIONS

  MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

  INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

   

  HERPES SIMPLEX ENCEPHALITIS:

  Adults and Adolescents (12 years of age and older): 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Pediatrics (3 months to 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

  VARICELLA-ZOSTER INFECTIONS

  ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older: 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

  Obese Patients

  Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

  PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

  Table 5: Dosage Adjustments for Patients with Renal Impairment

  Creatinine Clearance

  (mL/min/1.73 m2)

  Percent of

  Recommended Dose

  Dosing Interval

  (hours)

  >50

  25 to 50

  10 to 25

  0 to 10

  100%

  100%

  100%

  50%

  8

  12

  24

  24

  Hemodialysis

  For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

  Peritoneal Dialysis

  No supplemental dose appears to be necessary after adjustment of the dosing interval.

  Administration

  The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

  Once diluted for administration, each dose should be used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Dosage

  HERPES SIMPLEX INFECTIONS

  MUCOSAL AND CUTANEOUS HERPES SIMPLEX (HSV-1 and HSV-2)

  INFECTIONS IN IMMUNOCOMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  SEVERE INITIAL CLINICAL EPISODES OF HERPES GENITALIS:

  Adults and Adolescents (12 years of age and older):

  5 mg/kg infused at a constant rate over 1 hour, every 8 hours for 5 days.

   

  HERPES SIMPLEX ENCEPHALITIS:

  Adults and Adolescents (12 years of age and older): 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Pediatrics (3 months to 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.

   

  Neonatal Herpes Simplex Virus Infections (Birth to 3 months):

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 10 days.  In neonatal herpes simplex infections, doses of 15 mg/kg or 20 mg/kg (infused at a constant rate over 1 hour every 8 hours) have been used; the safety and efficacy of these doses are not known.

  VARICELLA-ZOSTER INFECTIONS

  ZOSTER IN IMMUNO­COMPROMISED PATIENTS:

  Adults and Adolescents (12 years of age and older: 

  10 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

   

  Pediatrics (Under 12 years of age):

  20 mg/kg infused at a constant rate over 1 hour, every 8 hours for 7 days.

  Obese Patients

  Obese patients should be dosed at the recommended adult dose using Ideal Body Weight.

  PATIENTS WITH ACUTE OR CHRONIC RENAL IMPAIRMENT: Refer to DOSAGE AND ADMINISTRATION section for recommended doses, and adjust the dosing interval as indicated in Table 5.

  Table 5: Dosage Adjustments for Patients with Renal Impairment

  Creatinine Clearance

  (mL/min/1.73 m2)

  Percent of

  Recommended Dose

  Dosing Interval

  (hours)

  >50

  25 to 50

  10 to 25

  0 to 10

  100%

  100%

  100%

  50%

  8

  12

  24

  24

  Hemodialysis

  For patients who require dialysis, the mean plasma half-life of acyclovir during hemodialysis is approximately 5 hours.  This results in a 60% decrease in plasma concentrations following a six-hour dialysis period.  Therefore, the patient’s dosing schedule should be adjusted so that an additional dose is administered after each dialysis.

  Peritoneal Dialysis

  No supplemental dose appears to be necessary after adjustment of the dosing interval.

  Administration

  The calculated dose should be further diluted in an appropriate intravenous solution at a volume selected for administration during each 1 hour infusion.  Infusion concentrations of approximately 7 mg/mL or lower are recommended.  In clinical studies, the average 70 kg adult received between 60 and 150 mL of fluid per dose.  Higher concentrations (e.g., 10 mg/mL) may produce phlebitis or inflammation at the injection site upon inadvertent extravasation.  Standard, commercially available electrolyte and glucose solutions are suitable for intravenous administration; biologic or colloidal fluids (e.g., blood products, protein solutions, etc.) are not recommended.

  Once diluted for administration, each dose should be used within 24 hours.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Vasopressin
  

  ×

  Vasopressin

  

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  Vasopressin Injection may be administered IM or subcutaneously.

  Ten units (0.5 mL) of Vasopressin Injection will usually elicit full physiologic response in adult patients; 5 units (0.25 mL) will be adequate in many cases.  Vasopressin Injection should be given IM at three or four hour intervals as needed.  The dosage should be proportionately reduced for pediatric patients.  (For an additional discussion of dosage, consult the sections below.)

  When determining the dose of Vasopressin Injection for a given case, the following should be kept in mind:

  It is particularly desirable to give a dose not much larger than is just sufficient to elicit the desired physiologic response.  Excessive doses may cause undesirable side effects–blanching of the skin, abdominal cramps, nausea–which, though not serious, may be alarming to the patient.  Spontaneous recovery from such side effects occurs in a few minutes.  It has been found that one or two glasses of water given at the time Vasopressin Injection is administered reduces such symptoms.

  Abdominal Distention

  In the average postoperative adult patient, give 5 units (0.25 mL) initially, increase to 10 units (0.5 mL) at subsequent injections if necessary.  It is recommended that Vasopressin Injection be given IM and that injections be repeated at three or four hour intervals as required.  Dosage to be reduced proportionately for pediatric patients.

  Vasopressin Injection used in this manner will frequently prevent, or relieve, postoperative distention.  These recommendations apply also to distention complicating pneumonia or other acute toxemias.

  Abdominal Roentgenography

  For the average case, two injections of 10 units (0.5 mL) each are suggested.  These should be given two hours and one-half hour, respectively, before films are exposed.  Many roentgenologists advise giving an enema prior to the first dose of Vasopressin Injection.

  Diabetes Insipidus

  Vasopressin Injection may be given by injection or administered intranasally on cotton pledgets, by nasal spray, or by dropper.  The dose by injection is 5 to 10 units (0.25 to 0.5 mL) repeated two or three times daily as needed.  When Vasopressin Injection is administered intranasally by spray or on pledgets, the dosage and interval between treatments must be determined for each patient.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Abdominal Distention

  In the average postoperative adult patient, give 5 units (0.25 mL) initially, increase to 10 units (0.5 mL) at subsequent injections if necessary.  It is recommended that Vasopressin Injection be given IM and that injections be repeated at three or four hour intervals as required.  Dosage to be reduced proportionately for pediatric patients.

  Vasopressin Injection used in this manner will frequently prevent, or relieve, postoperative distention.  These recommendations apply also to distention complicating pneumonia or other acute toxemias.

  Abdominal Roentgenography

  For the average case, two injections of 10 units (0.5 mL) each are suggested.  These should be given two hours and one-half hour, respectively, before films are exposed.  Many roentgenologists advise giving an enema prior to the first dose of Vasopressin Injection.

  Diabetes Insipidus

  Vasopressin Injection may be given by injection or administered intranasally on cotton pledgets, by nasal spray, or by dropper.  The dose by injection is 5 to 10 units (0.25 to 0.5 mL) repeated two or three times daily as needed.  When Vasopressin Injection is administered intranasally by spray or on pledgets, the dosage and interval between treatments must be determined for each patient.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Sensorcaine Mpf
  

  ×

  Sensorcaine Mpf

  

  ---

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be administered.  Dosages of Sensorcaine should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease.  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

  For specific techniques and procedures, refer to standard textbooks.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Sensorcaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  In recommended doses, Sensorcaine (bupivacaine HCl) produces complete sensory block, but the effect on motor function differs among the three concentrations.

  0.25%—when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block.  Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently.  Onset of action may be slower than with the 0.5% or 0.75% solutions.

  0.5%—provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential.

  0.75%—produces complete motor block.  Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia.  Not for obstetrical anesthesia.

   

  The duration of anesthesia with Sensorcaine is such that for most indications, a single dose is sufficient.

  Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site.  Most experience to date is with single doses of Sensorcaine up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case.

  These doses may be repeated up to once every three hours.  In clinical studies to date, total daily doses have been up to 400 mg.  Until further experience is gained, this dose should not be exceeded in 24 hours.  The duration of anesthetic effect may be prolonged by the addition of epinephrine.

  The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult.  These dosages should be reduced for elderly or debilitated patients.  Until further experience is gained, Sensorcaine is not recommended for pediatric patients younger than 12 years.  Sensorcaine is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block).

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampules and single-dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

  TABLE 1.  Recommended Concentrations and Doses of Sensocaine (bupivacaine HCl) Injections

  Each Dose

  Type of Block

    Conc.

  (mL)

  (mg)

  Motor Block1

  Local Infiltration

  0.25%4

  up to max.

  up to max.

              —

  Epidural

  0.75%2,4

  10 to 20

  75 to 150

  complete

  0.5%4

  10 to 20

  50 to 100

  moderate to complete

  0.25%4

  10 to 20

  25 to 50

  partial to moderate

  Caudal

  0.5%4

  15 to 30

  75 to 150

  moderate to complete

  0.25%4

  15 to 30

  37.5 to 75

  moderate

  Peripheral Nerves

  0.5%4

  5 to max.

  25 to max.

  moderate to complete

   0.25%4

  5 to max.

  12.5 to max.

  moderate to complete

  Retrobulbar3

  0.75%4

  2 to 4

  15 to 30

  complete

  Sympathetic

  0.25%

  20 to 50

  50 to 125

  —

  Dental3

  0.5%

  w/epi

  1.8 to 3.6 per site

  9 to 18 per site

  —

  Epidural3

  0.5%

  2 to 3 10 to 15 —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single-dose ampules and single-dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

  TABLE 1.  Recommended Concentrations and Doses of Sensocaine (bupivacaine HCl) Injections

  Each Dose

  Type of Block

    Conc.

  (mL)

  (mg)

  Motor Block1

  Local Infiltration

  0.25%4

  up to max.

  up to max.

              —

  Epidural

  0.75%2,4

  10 to 20

  75 to 150

  complete

  0.5%4

  10 to 20

  50 to 100

  moderate to complete

  0.25%4

  10 to 20

  25 to 50

  partial to moderate

  Caudal

  0.5%4

  15 to 30

  75 to 150

  moderate to complete

  0.25%4

  15 to 30

  37.5 to 75

  moderate

  Peripheral Nerves

  0.5%4

  5 to max.

  25 to max.

  moderate to complete

   0.25%4

  5 to max.

  12.5 to max.

  moderate to complete

  Retrobulbar3

  0.75%4

  2 to 4

  15 to 30

  complete

  Sympathetic

  0.25%

  20 to 50

  50 to 125

  —

  Dental3

  0.5%

  w/epi

  1.8 to 3.6 per site

  9 to 18 per site

  —

  Epidural3

  0.5%

  2 to 3 10 to 15 —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

  Close
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• Sensorcaine Mpf
  

  ×

  Sensorcaine Mpf

  

  ---

  The dose of any local anesthetic administered varies with the anesthetic procedure, the area to be anesthetized, the vascularity of the tissues, the number of neuronal segments to be blocked, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, individual tolerance, and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be administered.  Dosages of Sensorcaine should be reduced for elderly and/or debilitated patients and patients with cardiac and/or liver disease.  The rapid injection of a large volume of local anesthetic solution should be avoided and fractional (incremental) doses should be used when feasible.

  For specific techniques and procedures, refer to standard textbooks.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures. Sensorcaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION).

  In recommended doses, Sensorcaine (bupivacaine HCl) produces complete sensory block, but the effect on motor function differs among the three concentrations.

  0.25%—when used for caudal, epidural, or peripheral nerve block, produces incomplete motor block.  Should be used for operations in which muscle relaxation is not important, or when another means of providing muscle relaxation is used concurrently.  Onset of action may be slower than with the 0.5% or 0.75% solutions.

  0.5%—provides motor blockade for caudal, epidural, or nerve block, but muscle relaxation may be inadequate for operations in which complete muscle relaxation is essential.

  0.75%—produces complete motor block.  Most useful for epidural block in abdominal operations requiring complete muscle relaxation, and for retrobulbar anesthesia.  Not for obstetrical anesthesia.

  The duration of anesthesia with Sensorcaine is such that for most indications, a single dose is sufficient.

  Maximum dosage limit must be individualized in each case after evaluating the size and physical status of the patient, as well as the usual rate of systemic absorption from a particular injection site.  Most experience to date is with single doses of Sensorcaine up to 225 mg with epinephrine 1:200,000 and 175 mg without epinephrine; more or less drug may be used depending on individualization of each case.

  These doses may be repeated up to once every three hours.  In clinical studies to date, total daily doses have been up to 400 mg.  Until further experience is gained, this dose should not be exceeded in 24 hours.  The duration of anesthetic effect may be prolonged by the addition of epinephrine.

  The dosages in Table 1 have generally proved satisfactory and are recommended as a guide for use in the average adult.  These dosages should be reduced for elderly or debilitated patients.  Until further experience is gained, Sensorcaine is not recommended for pediatric patients younger than 12 years.  Sensorcaine is contraindicated for obstetrical paracervical blocks, and is not recommended for intravenous regional anesthesia (Bier Block).

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single dose ampules and single dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

   

  TABLE 1.  Recommended Concentrations and Doses of Sensorcaine (bupivacaine HCl) Injections

  Each Dose

  Type of Block

    Conc.

  (mL)

  (mg)

  Motor Block1

  Local Infiltration

  0.25%4

  up to max.

  up to max.

              —

  Epidural

  0.75%2,4

  10 to 20

  75 to 150

  complete

  0.5%4

  10 to 20

  50 to 100

  moderate to complete

  0.25%4

  10 to 20

  25 to 50

  partial to moderate

  Caudal

  0.5%4

  15 to 30

  75 to 150

  moderate to complete

  0.25%4

  15 to 30

  37.5 to 75

  moderate

  Peripheral Nerves

  0.5%4

  5 to max.

  25 to max.

  moderate to complete

   0.25%4

  5 to max.

  12.5 to max.

  moderate to complete

  Retrobulbar3

  0.75%4

  2 to 4

  15 to 30

  complete

  Sympathetic

  0.25%

  20 to 50

  50 to 125

              —

    Dental3 0.5%

  w/epi

  1.8 to 3.6

  per site

  9 to 18

  per site

              —

    Epidural3

  0.5%

  2 to 3

  10 to 15

              —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

  Use in Epidural Anesthesia

  During epidural administration of Sensorcaine, 0.5% and 0.75% solutions should be administered in incremental doses of 3 mL to 5 mL with sufficient time between doses to detect toxic manifestations of unintentional intravascular or intrathecal injection.  In obstetrics, only the 0.5% and 0.25% concentrations should be used; incremental doses of 3 mL to 5 mL of the 0.5% solution not exceeding 50 mg to 100 mg at any dosing interval are recommended.  Repeat doses should be preceded by a test dose containing epinephrine if not contraindicated.  Use only the single dose ampules and single dose vials for caudal or epidural anesthesia; the multiple dose vials contain a preservative and therefore should not be used for these procedures.

  Use in Dentistry

  The 0.5% concentration with epinephrine is recommended for infiltration and block injection in the maxillary and mandibular area when a longer duration of local anesthetic action is desired, such as for oral surgical procedures generally associated with significant postoperative pain. The average dose of 1.8 mL (9 mg) per injection site will usually suffice; an occasional second dose of 1.8 mL (9 mg) may be used if necessary to produce adequate anesthesia after making allowance for 2 to 10 minutes onset time (see CLINICAL PHARMACOLOGY). The lowest effective dose should be employed and time should be allowed between injections; it is recommended that the total dose for all injection sites, spread out over a single dental sitting, should not ordinarily exceed 90 mg for a healthy adult patient (ten 1.8 mL injections of 0.5% sensorcaine with epinephrine). Injections should be made slowly and with frequent aspirations. Until further experience is gained, sensorcaine in dentistry is not recommended for pediatric patients younger than 12 years.

  Unused portions of solution not containing preservatives, i.e., those supplied in single dose ampules and single dose vials, should be discarded following initial use.

  This product should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Solutions which are discolored or which contain particulate matter should not be administered.

   

  TABLE 1.  Recommended Concentrations and Doses of Sensorcaine (bupivacaine HCl) Injections

  Each Dose

  Type of Block

    Conc.

  (mL)

  (mg)

  Motor Block1

  Local Infiltration

  0.25%4

  up to max.

  up to max.

              —

  Epidural

  0.75%2,4

  10 to 20

  75 to 150

  complete

  0.5%4

  10 to 20

  50 to 100

  moderate to complete

  0.25%4

  10 to 20

  25 to 50

  partial to moderate

  Caudal

  0.5%4

  15 to 30

  75 to 150

  moderate to complete

  0.25%4

  15 to 30

  37.5 to 75

  moderate

  Peripheral Nerves

  0.5%4

  5 to max.

  25 to max.

  moderate to complete

   0.25%4

  5 to max.

  12.5 to max.

  moderate to complete

  Retrobulbar3

  0.75%4

  2 to 4

  15 to 30

  complete

  Sympathetic

  0.25%

  20 to 50

  50 to 125

              —

    Dental3 0.5%

  w/epi

  1.8 to 3.6

  per site

  9 to 18

  per site

              —

    Epidural3

  0.5%

  2 to 3

  10 to 15

              —

  1 With continuous (intermittent) techniques, repeat doses increase the degree of motor block.  The first repeat dose of 0.5% may produce complete motor block.  Intercostal nerve block with 0.25% may also produce complete motor block for intra-abdominal surgery.

  2 For single dose use, not for intermittent epidural technique.  Not for obstetrical anesthesia.

  3 See PRECAUTIONS.

  4 Solutions with or without epinephrine.

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• Fluorouracil
  

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  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Zydelig
  

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  Zydelig

  

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  The recommended adult and pediatric dosages and routes of administration are outlined in the following table 10. Cefepime for injection should be administered intravenously over approximately 30 minutes.

  Table 10: Recommended Dosage Schedule for Cefepime for Injection in Patients with CrCL Greater Than 60 mL/min Site and Type of Infection Dose Frequency  Duration  (days) Adults Moderate to Severe Pneumonia due to S. pneumoniae*, P. aeruginosa§, K. pneumoniae, or Enterobacter species 1 to 2 g IV Every 12 hours 10 Empiric therapy for febrile neutropenic patients (see INDICATIONS AND USAGE and CLINICAL STUDIES.) 2 g IV Every 8 hours 7** Mild to Moderate Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli, K. pneumoniae, or P. mirabilis* 0.5 to 1 g IV/IM*** Every 12 hours 7 to 10 Severe Uncomplicated or Complicated Urinary Tract Infections, including pyelonephritis, due to E. coli or K. pneumoniae* 2 g IV Every 12 hours 10 Moderate to Severe Uncomplicated Skin and Skin Structure Infections due to S. aureus or S. pyogenes 2 g IV Every 12 hours 10 Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by E. coli, viridans group streptococci,  P. aeruginosa, K. pneumoniae, Enterobacter species, or B. fragilis (see CLINICAL STUDIES.) 2 g IV Every 8 to 12 hours 7 to 10 Pediatric Patients (2 months up to 16 years) The maximum dose for pediatric patients should not exceed the recommended adult dose. The usual recommended dosage in pediatric patients up to 40 kg in weight for uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia is 50 mg per kg per dose, administered every 12 hours (50 mg per kg per dose, every 8 hours for febrile neutropenic patients), for durations as given above.

  †Adjust dose in patients with CrCL less than or equal to 60 mL/min *including cases associated with concurrent bacteremia.**or until resolution of neutropenia. In patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be re-evaluated frequently.***Intramuscular route of administration is indicated only for mild to moderate, uncomplicated or complicated UTIs due to  E. coli when the intramuscular route is considered to be a more appropriate route of drug administration.§For Pseudomonas aeruginosa, use 2 g IV every 8 hours (50 mg per kg per dose in pediatric patients 2 months up to 16 years) 

  Patients with Hepatic Impairment

  No adjustment is necessary for patients with hepatic impairment.

  Patients with Renal Impairment

  In patients with creatinine clearance less than or equal to 60 mL/min, the dose of cefepime for injection should be adjusted to compensate for the slower rate of renal elimination. The recommended initial dose of cefepime for injection should be the same as in patients with normal renal function except in patients undergoing hemodialysis. The recommended doses of cefepime for injection in patients with renal impairment are presented in Table 11.

  When only serum creatinine is available, the following formula (Cockcroft and Gault equation)4 may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

  Males: Creatinine Clearance (mL/min) = Weight (kg) × (140 - age) 72 × serum creatinine (mg/dL)

  Females: 0.85 × above value

  Table 11: Recommended Dosing Schedule for Cefepime for Injection in Adult Patients (Normal Renal Function, Renal Impairment, and Hemodialysis) Creatinine Clearance (mL/min) Recommended Maintenance Schedule Greater than 60 Normal recommended dosing schedule  500 mg  every 12 hours  1 g  every 12 hours  2 g  every 12 hours  2 g every 8 hours 30 to 60  500 mg  every 24 hours  1 g  every 24 hours  2 g  every 24 hours  2 g  every 12 hours 11 to 29  500 mg  every 24 hours  500 mg  every 24 hours  1 g  every 24 hours  2 g  every 24 hours Less than 11  250 mg  every 24 hours  250 mg every 24 hours  500 mg every 24 hours  1 g every 24 hours CAPD  500 mg every 48 hours  1 g  every 48 hours  2 g  every 48 hours  2 g  every 48 hours Hemodialysis* 1 g on day 1, then 500 mg every 24 hours thereafter 1 g   every 24 hours

  *On hemodialysis days, cefepime should be administered following hemodialysis. Whenever possible, cefepime should be administered at the same time each day.

  In patients undergoing continuous ambulatory peritoneal dialysis, cefepime for injection may be administered at normally recommended doses at a dosage interval of every 48 hours (see Table 11).In patients undergoing hemodialysis, approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period. The dosage of cefepime for injection for hemodialysis patients is 1 g on Day 1 followed by 500 mg every 24 hours for the treatment of all infections except febrile neutropenia, which is 1 g every 24 hours. Cefepime for injection should be administered at the same time each day and following the completion of hemodialysis on hemodialysis days (see Table 11).Data in pediatric patients with impaired renal function are not available; however, since cefepime pharmacokinetics are similar in adults and pediatric patients (see CLINICAL PHARMACOLOGY), changes in the dosing regimen proportional to those in adults (see Tables 10 and 11) are recommended for pediatric patients.

  Administration

  For Intravenous Infusion, Dilute with a suitable parenteral vehicle prior to intravenous infusion. Constitute the 1 g, or 2 g vial, and add an appropriate quantity of the resulting solution to an intravenous container with one of the compatible intravenous fluids listed in the Compatibility and Stability subsection. THE RESULTING SOLUTION SHOULD BE ADMINISTERED OVER APPROXIMATELY 30 MINUTES.

  Intermittent intravenous infusion with a Y-type administration set can be accomplished with compatible solutions. However, during infusion of a solution containing cefepime, it is desirable to discontinue the other solution.

  Intramuscular Administration: For intramuscular administration, cefepime for injection should be constituted with one of the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol (refer to Table 12).

  Preparation of cefepime for injection solutions is summarized in Table 12.

  Table 12: Preparation of Solutions of Cefepime for Injection Single-Dose Vials for Intravenous/Intramuscular Administration Amount of Diluent to be added (mL) Approximate Available Volume (mL) Approximate Cefepime Concentration (mg/mL) cefepime vial content 1 g (IV) 10 11.3 100  1 g (IM) 2.4 3.6 280 2 g (IV)  10   12.5  160 

  Compatibility and Stability

  Intravenous: Cefepime for injection is compatible at concentrations between 1 mg per mL and 40 mg per mL with the following intravenous infusion fluids: 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, M/6 Sodium Lactate Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringers and 5% Dextrose Injection, NormosolTM-R, and NormosolTM-M in 5% Dextrose Injection. These solutions may be stored up to 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) or 7 days in a refrigerator 2° to 8°C (36° to 46°F). Cefepime for injection admixture compatibility information is summarized in Table 13.

  Table 13: Cefepime Admixture Stability Stability Time for Cefepime for Injection Concentration Admixture and Concentration IV Infusion Solutions   RT/L  (20º to 25ºC)   Refrigeration  (2º to 8ºC) 40 mg/mL  Amikacin   6 mg/mL NS or D5W 24 hours 7 days 40 mg/mL  Ampicillin   1 mg/mL D5W 8 hours 8 hours 40 mg/mL  Ampicillin   10 mg/mL D5W 2 hours 8 hours 40 mg/mL  Ampicillin   1 mg/mL NS 24 hours 48 hours 40 mg/mL  Ampicillin   10 mg/mL NS 8 hours 48 hours 4 mg/mL  Ampicillin   40 mg/mL NS 8 hours 8 hours 4 to 40 mg/mL Clindamycin Phosphate 0.25 to 6 mg/mL NS or D5W 24 hours 7 days 4 mg/mL  Heparin   10 to 50 units/mL NS or D5W 24 hours 7 days 4 mg/mL  Potassium Chloride   10 to 40 mEq/L NS or D5W 24 hours 7 days 4 mg/mL Theophylline 0.8 mg/mL D5W 24 hours 7 days 1 to 4 mg/mL na AminosynTM II 4.25% with electrolytes and calcium 8 hours 3 days 0.125 to 0.25 mg/mL na InpersolTM with 4.25% dextrose 24 hours 7 days

  NS = 0.9% Sodium Chloride Injection

  D5W = 5% Dextrose Injection

  na = not applicable

  RT/L = Ambient room temperature and light

  Solutions of cefepime for injection, like those of most beta-lactam antibiotics, should not be added to solutions of ampicillin at a concentration greater than 40 mg per mL, and should not be added to metronidazole, vancomycin, gentamicin, tobramycin, netilmicin sulfate, or aminophylline because of potential interaction. However, if concurrent therapy with cefepime for injection is indicated, each of these antibiotics can be administered separately.

  Intramuscular: Cefepime for injection constituted as directed is stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) or for 7 days in a refrigerator 2° to 8°C (36° to 46°F) with the following diluents: Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol, or 0.5% or 1% Lidocaine Hydrochloride.

  NOTE: PARENTERAL DRUGS SHOULD BE INSPECTED VISUALLY FOR PARTICULATE MATTER BEFORE ADMINISTRATION. IF PARTICULATE MATTER IS EVIDENT IN RECONSTITUTED FLUIDS, THE DRUG SOLUTION SHOULD BE DISCARDED.

  As with other cephalosporins, the color of cefepime for injection powder, as well as its solutions, tend to darken depending on storage conditions; however, when stored as recommended, the product potency is not adversely affected.

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• Haloperidol Decanoate
  

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  Haloperidol Decanoate

  

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  Haloperidol Decanoate Injection should be administered by deep intramuscular injection.  A 21 gauge needle is recommended.  The maximum volume per injection site should not exceed 3 mL.  DO NOT ADMINISTER INTRAVENOUSLY.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Haloperidol Decanoate Injection is intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy.  These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate.  Furthermore, it is recommended that patients being considered for haloperidol decanoate therapy have been treated with, and tolerate well, short-acting haloperidol in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol.  Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection.  During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate therapy can be supplemented with short-acting forms of haloperidol.

  The dose of haloperidol decanoate should be expressed in terms of its haloperidol content.  The starting dose of haloperidol decanoate should be based on the patient’s age, clinical history, physical condition, and response to previous antipsychotic therapy.  The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed.  For patients previously maintained on low doses of antipsychotics  (e.g., up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate be 10 to 15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate.

  Initial Therapy

  Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.

  In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g., up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.

  In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.

  The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements.  If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e., a maximum of 100 mg initially followed by the balance in 3 to 7 days.

  Maintenance Therapy

  The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient.

                     HALOPERIDOL DECANOATE DOSING RECOMMENDATIONS

  Patients  Monthly  1st Month  Maintenance   Stabilized on low daily oral doses (up to 10 mg/day)  10 to 15 x Daily Oral Dose  10 to 15 x Previous Daily Oral Dose Elderly or Debilitated     High dose  20 x Daily Oral Dose  10 to 15 x Previous Daily Oral Dose Risk of relapse     Tolerant to oral haloperidol    

  Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy.  Haloperidol decanoate is usually administered monthly or every 4 weeks.  However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (see CLINICAL PHARMACOLOGY).

  Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited.

  Initial Therapy

  Conversion from oral haloperidol to haloperidol decanoate can be achieved by using an initial dose of haloperidol decanoate that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.

  In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g., up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.

  In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.

  The initial dose of haloperidol decanoate should not exceed 100 mg regardless of previous antipsychotic dose requirements.  If, therefore, conversion requires more than 100 mg of haloperidol decanoate as an initial dose, that dose should be administered in two injections, i.e., a maximum of 100 mg initially followed by the balance in 3 to 7 days.

  Maintenance Therapy

  The maintenance dosage of haloperidol decanoate must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient.

                     HALOPERIDOL DECANOATE DOSING RECOMMENDATIONS

  Patients  Monthly  1st Month  Maintenance   Stabilized on low daily oral doses (up to 10 mg/day)  10 to 15 x Daily Oral Dose  10 to 15 x Previous Daily Oral Dose Elderly or Debilitated     High dose  20 x Daily Oral Dose  10 to 15 x Previous Daily Oral Dose Risk of relapse     Tolerant to oral haloperidol    

  Close clinical supervision is required during initiation and stabilization of haloperidol decanoate therapy.  Haloperidol decanoate is usually administered monthly or every 4 weeks.  However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (see CLINICAL PHARMACOLOGY).

  Clinical experience with haloperidol decanoate at doses greater than 450 mg per month has been limited.

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• Sodium Bicarbonate
  

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  Sodium Bicarbonate

  

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  Sodium bicarbonate injection is administered by the intravenous route. 

  In cardiac arrest, a rapid intravenous dose of 200 to 300 mEq of bicarbonate, given as a 7.5% or 8.4% solution, is suggested for adults.  Caution should be observed in emergencies where very rapid infusion of large quantities of bicarbonate is indicated.  Bicarbonate solutions are hypertonic and may produce an undesirable rise in plasma sodium concentration in the process of correcting the metabolic acidosis.  In cardiac arrest, however, the risks from acidosis exceed those of hypernatremia. 

  In infants (up to two years of age), a solution diluted to 4.2% is recommended for intravenous administration at a dose not to exceed 8 mEq/kg/day.  Slow administration rates with a solution diluted to 4.2% are recommended in neonates, to guard against the possibility of producing hypernatremia, decreasing cerebrospinal fluid pressure and inducing intracranial hemorrhage. 

  In less urgent forms of metabolic acidosis sodium bicarbonate injection may be added to other intravenous fluids.  The amount of bicarbonate to be given to older children and adults over a four-to-eight-hour period is approximately 2 to 5 mEq/kg of body weight depending upon the severity of the acidosis as judged by the lowering of total CO2 content, blood pH and clinical condition of the patient.  Bicarbonate therapy should always be planned in a stepwise fashion since the degree of response from a given dose is not precisely predictable.  Initially an infusion of 2 to 5 mEq/kg body weight over a period of four to eight hours will produce a measurable improvement in the abnormal acid-base status of the blood.  The next step of therapy is dependent upon the clinical response of the patient.  If severe symptoms have abated, then the frequency of administration and the size of the dose may be reduced. 

  In general, it is unwise to attempt full correction of a low total CO2 content during the first 24 hours of therapy, since this may be accompanied by an unrecognized alkalosis because of a delay in the readjustment of ventilation to normal.  Owing to this lag, the achievement of total CO2 content of about 20 mEq/L at the end of the first day of therapy will usually be associated with a normal blood pH.  Further modification of the acidosis to completely normal values usually occurs in the presence of normal kidney function when and if the cause of the acidosis can be controlled.  Values for total CO2 which are brought to normal or above normal within the first day of therapy are very likely to be associated with grossly alkaline values for blood pH, with ensuing undesired side effects. 

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• Fluorouracil
  

  ×

  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent.  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Paclitaxel
  

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  Paclitaxel

  

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  Note: Contact of the undiluted concentrate with plasticized PVC equipment or devices used to prepare solutions for infusion is not recommended. In order to minimize patient exposure to the plasticizer DEHP [di-(2-ethylhexyl)phthalate], which may be leached from PVC infusion bags or sets, diluted Paclitaxel Injection USP solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

  All patients should be premedicated prior to Paclitaxel Injection USP administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before Paclitaxel Injection USP, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to Paclitaxel Injection USP, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before Paclitaxel Injection USP.

  For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

  1) For previously untreated patients with carcinoma of the ovary, one of the following recommended regimens may be given every 3 weeks. In selecting the appropriate regimen, differences in toxicities should be considered (see TABLE 11 in ADVERSE REACTIONS: Disease-Specific Adverse Event Experiences).

  Paclitaxel administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin at a dose of 75 mg/m2.

  2) In patients previously treated with chemotherapy for carcinoma of the ovary, paclitaxel has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel 135 mg/m2 or 175 mg/m2 administered intravenously over 3 hours every 3 weeks.

  For patients with carcinoma of the breast, the following regimens are recommended (see CLINICAL STUDIES: Breast Carcinoma):

  1) For the adjuvant treatment of node-positive breast cancer, the recommended regimen is paclitaxel, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma).

  2) After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel at a dose of 175 mg/m2 administered intravenously over 3 hours every 3 weeks has been shown to be effective.

  For patients with non-small cell lung carcinoma, the recommended regimen, given every 3 weeks, is paclitaxel administered intravenously over 24 hours at a dose of 135 mg/m2 followed by cisplatin, 75 mg/m2.

  For patients with AIDS-related Kaposi’s sarcoma, paclitaxel administered at a dose of 135 mg/m2 given intravenously over 3 hours every 3 weeks or at a dose of 100 mg/m2 given intravenously over 3 hours every 2 weeks is recommended (dose intensity 45 to 50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

  Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:

  1) Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO);

  2) Initiate or repeat treatment with Paclitaxel Injection USP only if the neutrophil count is at least 1000 cells/mm3;

  3) Reduce the dose of subsequent courses of Paclitaxel Injection USP by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and

  4) Initiate concomitant hematopoietic growth factor (G-CSF) as clinically indicated.

  For the therapy of patients with solid tumors (ovary, breast, and NSCLC), courses of Paclitaxel Injection USP should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel Injection USP should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during Paclitaxel Injection USP therapy should have dosage reduced by 20% for subsequent courses of Paclitaxel Injection USP. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

  Hepatic Impairment: Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.

  TABLE 17 RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATIC IMPAIRMENT BASED ON CLINICAL TRIAL DATAa   Degree of Hepatic Impairment      Transaminase Levels   Bilirubin Levelsb   Recommended PACLITAXEL Dosec   a These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).   b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.   c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.   24-hour infusion   <2 x ULN   and   ≤1.5 mg/dL   135 mg/m2   2 to <10 x ULN   and   ≤1.5 mg/dL   100 mg/m2   <10 x ULN   and   1.6 to 7.5 mg/dL   50 mg/m2   ≥10 x ULN   or   >7.5 mg/dL   Not recommended   3-hour infusion   <10 x ULN   and   ≤1.25 x ULN   175 mg/m2   <10 x ULN   and   1.26 to 2.0 x ULN   135 mg/m2   <10 x ULN   and   2.01 to 5.0 x ULN   90 mg/m2   ≥10 x ULN   or   >5.0 x ULN   Not recommended

  Preparation and Administration Precautions

  Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-4To minimize the risk of dermal exposure, always wear impervious gloves when handling vials containing Paclitaxel Injection USP. If Paclitaxel Injection USP solution contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure, events have included tingling, burning, and redness. If Paclitaxel Injection USP contacts mucous membranes, the membranes should be flushed thoroughly with water. Upon inhalation, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported.

  Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration (see PRECAUTION: Injection Site Reaction).

  Preparation for Intravenous Administration 

  Paclitaxel Injection USP must be diluted prior to infusion. Paclitaxel Injection USP should be diluted in 0.9% Sodium Chloride Injection, USP, 5% Dextrose Injection, USP, 5% Dextrose and 0.9% Sodium Chloride Injection, USP, or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

  Data collected for the presence of the extractable plasticizer DEHP [di-(2-ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel Injection USP solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

  Paclitaxel Injection USP should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

  The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of Paclitaxel Injection USP since they can cause the stopper to collapse resulting in loss of sterile integrity of the Paclitaxel Injection USP solution.

  Parenteral products should be visually inspected for particulate matter.

  Stability

  Unopened vials of Paclitaxel Injection USP are stable until the date indicated on the package when stored between 20°–25° C (68°–77° F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the Paclitaxel Injection USP vial may precipitate, but will redissolve upon reaching room temperature with little or no agitation. There is no impact on product quality under these circumstances. If the solution remains cloudy or if an insoluble precipitate is noted, the vial should be discarded. Solutions for infusion prepared as recommended are stable at ambient temperature (approximately 25° C) and lighting conditions for up to 27 hours.

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• Caffeine Citrate
  

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  Caffeine Citrate

  

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  Prior to initiation of caffeine citrate injection, baseline serum levels of caffeine should be measured in infants previously treated with theophylline, since preterm infants metabolize theophylline to caffeine.  Likewise, baseline serum levels of caffeine should be measured in infants born to mothers who consumed caffeine prior to delivery, since caffeine readily crosses the placenta.

  The recommended loading dose and maintenance doses of caffeine citrate follow.

  Dose of Caffeine Citrate

  Volume

  Dose of Caffeine Citrate

  mg/kg

  Route

  Frequency

  Loading Dose

  1 mL/kg

  20 mg/kg

  Intravenous* (over 30 minutes)

  One Time

  Maintenance Dose

  0.25 mL/kg

  5 mg/kg

  Intravenous* (over 10 minutes) or Orally

  Every 24 hours**

  *using a syringe infusion pump

  **beginning 24 hours after the loading dose

   

  NOTE THAT THE DOSE OF CAFFEINE BASE IS ONE-HALF THE DOSE WHEN EXPRESSED AS CAFFEINE CITRATE (e.g., 20 mg of caffeine citrate is equivalent to 10 mg of caffeine base).

  Serum concentrations of caffeine may need to be monitored periodically throughout treatment to avoid toxicity.  Serious toxicity has been associated with serum levels greater than 50 mg/L.

  Caffeine citrate injection should be inspected visually for particulate matter and discoloration prior to administration.  Vials containing discolored solution or visible particulate matter should be discarded.

  Drug Compatibility

  To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid® admixture, which was combined as 80 mL/80 mL.  The physical appearance of the combined solutions was evaluated for precipitation.  The admixtures were mixed for 10 minutes and then assayed for caffeine.  The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

  Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.

  • Dextrose Injection, USP 5%

  • 50% Dextrose Injection USP

  • Intralipid® 20% IV Fat Emulsion

  • Aminosyn® 8.5% Crystalline Amino Acid Solution

  • Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5%

  • Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL)

  • Heparin Sodium Injection, USP 1,000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%

  • Fentanyl Citrate Injection, USP 50 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%

  Drug Compatibility

  To test for drug compatibility with common intravenous solutions or medications, 20 mL of caffeine citrate injection were combined with 20 mL of a solution or medication, with the exception of an Intralipid® admixture, which was combined as 80 mL/80 mL.  The physical appearance of the combined solutions was evaluated for precipitation.  The admixtures were mixed for 10 minutes and then assayed for caffeine.  The admixtures were then continually mixed for 24 hours, with further sampling for caffeine assays at 2, 4, 8, and 24 hours.

  Based on this testing, caffeine citrate injection, 60 mg/3 mL is chemically stable for 24 hours at room temperature when combined with the following test products.

  • Dextrose Injection, USP 5%

  • 50% Dextrose Injection USP

  • Intralipid® 20% IV Fat Emulsion

  • Aminosyn® 8.5% Crystalline Amino Acid Solution

  • Dopamine HCI Injection, USP 40 mg/mL diluted to 0.6 mg/mL with Dextrose Injection, USP 5%

  • Calcium Gluconate Injection, USP 10% (0.465 mEq/Ca+2/mL)

  • Heparin Sodium Injection, USP 1,000 units/mL diluted to 1 unit/mL with Dextrose Injection, USP 5%

  • Fentanyl Citrate Injection, USP 50 mcg/mL diluted to 10 mcg/mL with Dextrose Injection, USP 5%

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• Rifampin
  

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  Rifampin

  

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  Rifampin for Injection, USP is administered by IV infusion (see INDICATIONS AND USAGE).

  See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

  Tuberculosis

  Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, IV

  Pediatric Patients: 10 to 20 mg/kg, not to exceed 600 mg/day, IV

  Rifampin is indicated in the treatment of all forms of tuberculosis.  A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide (e.g., RIFATER®) is recommended in the initial phase of short-course therapy which is usually continued for 2 months.  The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low.  The need for a fourth drug should be reassessed when the results of susceptibility testing are known.  If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

  Following the initial phase, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE®) for at least 4 months.  Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

  Preparation of Solution for IV Infusion

  Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection.  Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for 24 hours.  Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours.  Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

  Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time.  Precipitation of rifampin from the infusion solution may occur beyond this time.  Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

  Incompatibilities

  Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and rifampin (6 mg/mL in normal saline) during simulated Y-site administration.

  Meningococcal Carriers

  Adults: For adults, it is recommended that 600 mg rifampin be administered twice daily for two days.

  Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

  Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.

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• Acetylcysteine Solution...
  

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  Acetylcysteine Solution

  

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  General

  Acetylcysteine is available in rubber stoppered glass vials containing 4, 10, or 30 mL. The 20% solution may be diluted to a lesser concentration with either Sodium Chloride Injection, Sodium Chloride Inhalation Solution, Sterile Water for Injection, or Sterile Water for Inhalation. The 10% solution may be used undiluted.

  Acetylcysteine does not contain an antimicrobial agent, and care must be taken to minimize contamination of the sterile solution. If only a portion of the solution in a vial is used for inhalation, store the remainder in a refrigerator and use within 96 hours.

  Nebulization-face mask, mouth piece, tracheostomy

  When nebulized into a face mask, mouth piece, or tracheostomy, 1 to 10 mL of the 20% solution or 2 to 20 mL of the 10% solution may be given every 2 to 6 hours; the recommended dose for most patients is 3 to 5 mL of the 20% solution or 6 to 10 mL of the 10% solution 3 to 4 times a day.

  Nebulization tent, Croupette

  In special circumstances it may be necessary to nebulize into a tent or Croupette, and this method of use must be individualized to take into account the available equipment and the patient's particular needs. This form of administration requires very large volumes of the solution, occasionally as much as 300 mL during a single treatment period.

  If a tent or Croupette must be used, the recommended dose is the volume of acetylcysteine (using 10% or 20%) that will maintain a very heavy mist in the tent or Croupette for the desired period. Administration for intermittent or continuous prolonged periods, including overnight, may be desirable.

  Direct Instillation

  When used by direct instillation, 1 to 2 mL of a 10% to 20% solution may be given as often as every hour. When used for the routine nursing care of patients with tracheostomy, 1 to 2 mL of a 10% to 20% solution may be given every 1 to 4 hours by instillation into the tracheostomy.

  Acetylcysteine may be introduced directly into a particular segment of the bronchopulmonary tree by inserting (under local anesthesia and direct vision) a small plastic catheter into the trachea. Two to 5 mL of the 20% solution may then be instilled by means of a syringe connected to the catheter.

  Acetylcysteine may also be given through a percutaneous intratracheal catheter. One to 2 mL of the 20% or 2 to 4 mL of the 10% solution every 1 to 4 hours may then be given by a syringe attached to the catheter.

  Diagnostic Bronchograms

  For diagnostic bronchial studies, two or three administrations of 1 to 2 mL of the 20% solution or 2 to 4 mL of the 10% solution should be given by nebulization or by instillation intratracheally, prior to the procedure.

  Administration of Aerosol

  Materials

  Acetylcysteine may be administered using conventional nebulizers made of plastic or glass. Certain materials used in nebulization equipment react with acetylcysteine. The most reactive of these are certain metals (notably iron and copper) and rubber. Where materials may come into contact with acetylcysteine solution, parts made of the following acceptable materials should be used: glass, plastic, aluminum, anodized aluminum, chromed metal, tantalum, sterling silver, or stainless steel. Silver may become tarnished after exposure, but this is not harmful to the drug action or to the patient.

  Nebulizing Gases

  Compressed tank gas (air) or an air compressor should be used to provide pressure for nebulizing the solution. Oxygen may also be used but should be used with the usual precautions in patients with severe respiratory disease and CO2 retention.

  Apparatus

  Acetylcysteine is usually administered as fine nebulae and the nebulizer used should be capable of providing optimal quantities of a suitable range of particle sizes.

  Commercially available nebulizers will produce nebulae of acetylcysteine satisfactory for retention in the respiratory tract. Most of the nebulizers tested will supply a high proportion of the drug solution as particles of less than 10 microns in diameter. Mitchell2 has shown that particles less than 10 microns should be retained in the respiratory tract satisfactorily.

  Various intermittent positive pressure breathing devices nebulized acetylcysteine with a satisfactory efficiency including: No. 40 De Vilbiss (The De Vilbiss Co., Somerset, Pennsylvania), and the Bennett Twin-Jet Nebulizer (Puritan Bennett Corp., Oak at 13th., Kansas City, Missouri).

  The nebulized solution may be inhaled directly from the nebulizer. Nebulizers may also be attached to the plastic face masks or plastic mouthpieces. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines. The nebulizing equipment should be cleaned immediately after use because the residues may clog the smaller orifices or corrode metal parts.

  Hand bulbs are not recommended for routine use in nebulizing acetylcysteine because their output is generally too small. Also, some hand-operated nebulizers deliver particles that are larger than optimum for inhalation therapy.

  Acetylcysteine should not be placed directly into the chamber of a heated (hot pot) nebulizer. A heated nebulizer may be part of the nebulization assembly to provide a warm saturated atmosphere if the acetylcysteine aerosol is introduced by means of a separate unheated nebulizer. Usual precautions for administration of warm saturated nebulae should be observed.

  The nebulized solution may be breathed directly from the nebulizer. Nebulizers may also be attached to plastic face masks, plastic face tents, plastic mouth pieces, conventional plastic oxygen tents, or head tents. Suitable nebulizers may also be fitted for use with the various intermittent positive pressure breathing (IPPB) machines.

  The nebulizing equipment should be cleaned immediately after use, otherwise the residues may occlude the fine orifices or corrode metal parts.

  Prolonged Nebulization

  When three fourths of the initial volume of acetylcysteine solution have been nebulized, a quantity of Sterile Water for Injection, USP (approximately equal to the volume of solution remaining) should be added to the nebulizer. This obviates any concentration of the agent in the residual solvent remaining after prolonged nebulization.

  Compatibility

  The physical and chemical compatibility of acetylcysteine solutions with certain other drugs that might be concomitantly administered by nebulization, direct instillation, or topical application has been studied.

  Acetylcysteine should not be mixed with certain antibiotics. For example, the antibiotics, tetracycline hydrochloride, oxytetracycline hydrochloride, and erythromycin lactobionate, were found to be incompatible when mixed in the same solution. These agents may be administered from separate solutions if administration of these agents is desirable.

  The supplying of these data should not be interpreted as a recommendation for combining acetylcysteine with other drugs. The table is not presented as positive assurance that no incompatibility will be present, since these data are based only on short-term compatibility studies done in the Mead Johnson Research Center. Manufacturers may change their formulations, and this could alter compatibilities. These data are intended to serve only as a guide for predicting compounding problems.

  If it is deemed advisable to prepare an admixture, it should be administered as soon as possible after preparation. Do not store unused mixtures.

  IN VITRO COMPATIBILITY1 TESTS OF ACETYLCYSTEINE

  PRODUCT AND/OR

  AGENT

  COMPATIBILITY

  RATING

  RATIO TESTED6

  ACETYLCYSTEINE

  PRODUCT

  OR AGENT

  ANESTHETIC GAS

  Halothane

  Compatible

  20%

  Infinite

  Nitrous Oxide

  Compatible

  20%

  Infinite

  ANESTHETIC LOCAL

  Cocaine HCl

  Compatible

  10%

  5%

  Lidocaine HCl

  Compatible

  10%

  2%

  Tetracaine HCl

  Compatible

  10%

  1%

  ANTIBACTERIALS (A parenteral form of each antibiotic was used)

  Bacitracin2,3 (mix and use at once)

  Compatible

  10%

  5,000 U/mL

  Chloramphenicol Sodium Succinate

  Compatible

  20%

  20 mg/mL

  Carbenicillin Disodium2

  (mix and use at once)

  Compatible

  10%

  125 mg/mL

  Gentamicin Sulfate2

  Compatible

  10%

  20 mg/mL

  Kanamycin Sulfate2

  (mix and use at once)

  Compatible

  10%

  167 mg/mL

     

  Compatible

  17% 85 mg/mL

  Lincomycin HCl2

  Compatible

  10%

  150 mg/mL

  Neomycin Sulfate2

  Compatible

  10%

  100 mg/mL

  Novobiocin Sodium2

  Compatible

  10%

  25 mg/mL

  Penicillin G Potassium2

  (mix and use at once)

  Compatible

  10%

  25,000 U/mL

     

  Compatible

  10% 100,000 U/mL

  Polymyxin B Sulfate2

  Compatible

  10%

  50,000 U/mL

  Cephalothin Sodium

  Compatible

  10%

  110 mg/mL

  Colistimethate Sodium2

  (mix and use at once)

  Compatible

  10%

  37.5 mg/mL

  Vancomycin HCl2

  Compatible

  10%

  25 mg/mL

  Amphotericin B

  Incompatible

  4% to 15%

  1 to 4 mg/mL

  Chlortetracycline HCl2

  Incompatible

  10%

  12.5 mg/mL

  Erythromycin Lactobionate

  Incompatible

  10%

  15 mg/mL

  Oxytetracycline HCl

  Incompatible

  10%

  12.5 mg/mL

  Ampicillin Sodium

  Incompatible

  10%

  50 mg/mL

  Tetracycline HCl

  Incompatible

  10%

  12.5 mg/mL

  BRONCHODILATORS

  Isoproterenol HCl2

  Compatible

  3.0%

  0.5%

  Isoproterenol HCl2

  Compatible

  10%

  0.05%

  Isoproterenol HCl2

  Compatible

  20%

  0.05%

  Isoproterenol HCl

  Compatible

  13.3% (2 parts)

  0.33% (1 part)

  Isoetharine HCl

  Compatible

  13.3% (2 parts)

  (1 part)

  Epinephrine HCl

  Compatible

  13.3% (2 parts)

  0.33% (1 part)

  CONTRAST MEDIA

  Iodized Oil

  Incompatible

  20%/20 mL

  40%/10 mL

  DECONGESTANTS

  Phenylephrine HCl2

  Compatible

  3.0%

  0.25%

  Phenylephrine HCl

  Compatible

  13.3% (2 parts)

  0.17% (1 part)

  ENZYMES

  Chymotrypsin

  Incompatible

  5%

  400 γ/mL

  Trypsin

  Incompatible

  5%

  400 γ/mL

  SOLVENTS

  Alcohol

  Compatible

  12%

  10% to 20%

  Propylene Glycol

  Compatible

  3%

  10%

  STEROIDS

  Dexamethasone Sodium Phosphate

  Compatible

  16%

  0.8 mg/mL

  Prednisolone Sodium Phosphate5

  Compatible

  16.7%

  3.3 mg/mL

  OTHER AGENTS

  Hydrogen Peroxide

  Incompatible

  (All ratios)

  Sodium Bicarbonate

  Compatible

  20% (1 part)

  4.2% (1 part)

  The rating, Incompatible, is based on the formulation of a precipitate, a change in clarity, immiscibility or a rapid loss of potency of acetylcysteine or the active ingredient of the PRODUCT AND/OR AGENT in the admixture.

  The rating, Compatible, means that there was no significant physical change in the admixture when compared with a control solution of the PRODUCT AND/OR AGENT, and that there was no predicted chemical incompatibility. All of the admixtures have been tested for short-term chemical compatibility by assaying for the concentration of acetylcysteine after mixing.

  The active ingredient in the PRODUCT AND/OR AGENT was also assayed after mixing. Some of the admixtures developed minor physical changes which were considered to be insufficient to rate the admixtures incompatible. These are listed in footnotes 3, 4, and 5.

  A strong odor developed after storage for 24 hours at room temperature.

  The admixture was a slightly darker shade of yellow than a control solution of the PRODUCT AND/OR AGENT.

  A light tan color developed after storage for 24 hours at room temperature.

  Entries are final concentrations. Values in parentheses relate volumes of acetylcysteine solutions to volume of test solutions.

   

  General

  Regardless of the quantity of acetaminophen reported to have been ingested, administer acetylcysteine immediately if 24 hours or less have elapsed from the reported time of ingestion of an overdose of acetaminophen. Do not await results of assays for acetaminophen level before initiating treatment with acetylcysteine. The following procedures are recommended:

  The stomach should be emptied promptly by lavage or by inducing emesis with syrup of ipecac. Syrup of ipecac should be given in a dose of 15 mL for children up to age 12 and 30 mL for adolescents and adults followed immediately by drinking copious amounts of water. The dose should be repeated if emesis does not occur in 20 minutes.

  In the case of a mixed drug overdose activated charcoal may be indicated. However, if activated charcoal has been administered, lavage before administering acetylcysteine treatment. Activated charcoal adsorbs acetylcysteine in vitro and may do so in patients and thereby may reduce its effectiveness.

  Draw blood for predetoxification acetaminophen plasma assay and baseline SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes.

  Administer the loading dose of acetylcysteine, 140 mg per kg of body weight. (Prepare acetylcysteine for oral administration as described in the Dosage Guide and Preparation table).

  Determine subsequent action based on predetoxification plasma acetaminophen information. Choose ONE of the following four courses of therapy.

  A. Predetoxification plasma acetaminophen level is clearly in the toxic range (See Acetaminophen Assays - Interpretation and Methodology below):

  Administer a first maintenance dose (70 mg/kg acetylcysteine) 4 hours after the loading dose. The maintenance dose is then repeated at 4-hour intervals for a total of 17 doses. Monitor hepatic and renal function and electrolytes throughout the detoxification process.

  B. Predetoxification acetaminophen level could not be obtained: Proceed as in A.

  C. Predetoxification acetaminophen level is clearly in the non-toxic range (beneath the dashed line on the nomogram) and you know that acetaminophen overdose occurred at least 4 hours before the predetoxification acetaminophen plasma assays: Discontinue administration of acetylcysteine.

  D. Predetoxification acetaminophen level was in the non-toxic range, but time of ingestion was unknown or less than 4 hours.

  Because the level of acetaminophen at the time of predetoxification assay may not be a peak value (peak may not be achieved before 4 hours post-ingestion), obtain a second plasma level in order to decide whether or not the full 17-dose detoxification treatment is necessary.

  If the patient vomits an oral dose within 1 hour of administration, repeat that dose.

  In the occasional instances where the patient is persistently unable to retain the orally administered acetylcysteine, the antidote may be administered by duodenal intubation.

  Repeat SGOT, SGPT, bilirubin, prothrombin time, creatinine, BUN, blood sugar and electrolytes daily if the acetaminophen plasma level is in the potentially toxic range as discussed below.

  Preparation of Acetylcysteine for Oral Administration

  Oral administration requires dilution of the 20% solution with diet cola or other diet soft drinks, to a final concentration of 5% (see Dosage Guide and Preparation table). If administered via gastric tube or Miller-Abbott tube, water may be used as the diluent. The dilutions should be freshly prepared and utilized within one hour. Remaining undiluted solutions in opened vials can be stored in the refrigerator up to 96 hours.

  ACETYLCYSTEINE IS NOT APPROVED FOR PARENTERAL INJECTION.

  ACETAMINOPHEN ASSAYS - INTERPRETATION AND METHODOLOGY

  The acute ingestion of acetaminophen in quantities of 150 mg/kg or greater may result in hepatic toxicity. However, the reported history of the quantity of a drug ingested as an overdose is often inaccurate and is not a reliable guide to therapy of the overdose. THEREFORE, PLASMA OR SERUM ACETAMINOPHEN CONCENTRATIONS, DETERMINED AS EARLY AS POSSIBLE, BUT NO SOONER THAN 4 HOURS FOLLOWING AN ACUTE OVERDOSE, ARE ESSENTIAL IN ASSESSING THE POTENTIAL RISK OF HEPATOTOXICITY. IF AN ASSAY FOR ACETAMINOPHEN CANNOT BE OBTAINED, IT IS NECESSARY TO ASSUME THAT THE OVERDOSE IS POTENTIALLY TOXIC.

  INTERPRETATION OF ACETAMINOPHEN ASSAYS:

  When results of the plasma acetaminophen assay are available refer to the nomogram below to determine if plasma concentration is in the potentially toxic range. Values above the solid line connecting 200 mcg/mL at least 4 hours with 50 mcg/mL at 12 hours are associated with a possibility of hepatic toxicity if an antidote is not administered. (Do not wait for assay results to begin acetylcysteine treatment.)

  If the predetoxification plasma level is above the broken line continue with maintenance doses of acetylcysteine. It is better to err on the safe side and thus the broken line is placed 25% below the solid line which defines possible toxicity.

  If the predetoxification plasma level is below the broken line described above, there is minimal risk of hepatic toxicity and acetylcysteine treatment can be discontinued.

  ACETAMINOPHEN ASSAY METHODOLOGY

  Assay procedures most suitable for determining acetaminophen concentrations utilize high pressure liquid chromatography (HPLC) or gas liquid chromatography (GLC). The assay should measure only parent acetaminophen and not conjugated. The assay procedures listed below fulfill this requirement:

  SELECTED TECHNIQUES (NON INCLUSIVE)

  HPLC:

  1. Blair D, Rumack, BH, Clin Chem, 1977 ; 23(4):743−745.

  2. Howie D, Andriaenssens Pl, Prescott LF. J. Pharm Pharmacol 1977; 29(4):235−237. GLC

  3. Prescott LF. J. Pharm Pharmacol, 1971; 23(10):807-808. Colorimetric

  4. Glynn JP. Kendal SE, Lancet 1975; 1(May 17):1147-1148.

  Supportive Treatment of Acetaminophen Overdose

  Maintain fluid and electrolyte balance based on clinical evaluation of state of hydration and serum electrolytes.

  Treat as necessary for hypoglycemia.

  Administer vitamin K1 if prothrombin time ratio exceeds 1.5 or fresh frozen plasma if the prothrombin time ratio exceeds 3.0.

  Diuretics and forced diuresis should be avoided.

  DOSAGE GUIDE AND PREPARATION:

  Doses in relation to body weight are:

  Loading Dose of Acetylcysteine**

  Body Weight

  Grams Acetylcysteine

  mL of 20% Acetylcysteine

  mL of Diluent

  Total mL of 5% Solution

  (kg)

  (lb)

  100 to 109

  220 to 240

  15

  75

  225

  300

  90 to 99

  198 to 218

  14

  70

  210

  280

  80 to 89

  176 to 196

  13

  65

  195

  260

  70 to 79

  154 to 174

  11

  55

  165

  220

  60 to 69

  132 to 152

  10

  50

  150

  200

  50 to 59

  110 to 130

  8

  40

  120

  160

  40 to 49

  88 to 108

  7

  35

  105

  140

  30 to 39

  66 to 86

  6

  30

  90

  120

  20 to 29

  44 to 64

  4

  20

  60

  80

  Maintenance Dose**

  (kg)

  (lb)

  100 to 109

  220 to 240

  7.5

  37

  113

  150

  90 to 99

  198 to 218

  7

  35

  105

  140

  80 to 89

  176 to 196

  6.5

  33

  97

  130

  70 to 79

  154 to 174

  5.5

  28

  82

  110

  60 to 69

  132 to 152

  5

  25

  75

  100

  50 to 59

  110 to 130

  4

  20

  60

  80

  40 to 49

  88 to 108

  3.5

  18

  52

  70

  30 to 39

  66 to 86

  3

  15

  45

  60

  20 to 29

  44 to 64

  2

  10

  30

  40

  **If patient weighs less than 20 kg (usually patients younger than 6 years), calculate the doses of Acetylcysteine. Each mL of 20% Acetylcysteine contains 200 mg of acetylcysteine. The loading dose is 140 mg per kilogram of body weight. The maintenance dose is 70 mg/kg. Three (3) mL of diluent are added to each mL of 20% Acetylcysteine Solution. Do not decrease the proportion of diluent.

  Estimating Potential for Hepatotoxicity

  The following nomogram has been developed to estimate the probability that plasma levels in relation to intervals post ingestion will result in hepatotoxicity.

  Adapted from Rumack and Matthews, Pediatrics 1975; 55:871−876.

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• Zoledronic Acid
  

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  Zoledronic Acid

  

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  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  2.1 Hypercalcemia of Malignancy

  The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal to12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

  Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

  Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

  Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

  Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

  2.2. Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

  The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance (CrCl) greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

  Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same area under curve (AUC) as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].

  Table 1: Reduced Doses for Patients with Baseline CrCl Less than or Equal to 60 mL/min * Doses calculated assuming target AUC of 0.66(mg•hr/L) (CrCl = 75 mL/min) Baseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose* greater than 60 4 mg 50-60 3.5 mg 40-49 3.3 mg 30-39 3 mg

  During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:For patients with normal baseline creatinine, increase of 0.5 mg/dLFor patients with abnormal baseline creatinine, increase of 1.0 mg/dLIn the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

  2.3. Preparation of Solution

  Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer’s solution, and should be administered as a single intravenous solution in a line separate from all other drugs.4 mg/5 mL Single-Use Vial Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 2).

  Table 2: Preparation of Reduced Doses - Zoledronic Acid Injection Concentrate Remove and Use Zoledronic Acid Injection Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3.0

  The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

  If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C-8°C (36°F-46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

  2.4. Method of Administration

  Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.

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• Nesacaine
  

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  Nesacaine

  

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  Chloroprocaine may be administered as a single injection or continuously through an indwelling catheter.  As with all local anesthetics, the dose administered varies with the anesthetic procedure, the vascularity of the tissues, the depth of anesthesia and degree of muscle relaxation required, the duration of anesthesia desired, and the physical condition of the patient.  The smallest dose and concentration required to produce the desired result should be used.  Dosage should be reduced for children, elderly and debilitated patients and patients with cardiac and/or liver disease.  The maximum single recommended doses of chloroprocaine in adults are: without epinephrine, 11 mg/kg, not to exceed a maximum total dose of 800 mg; with epinephrine (1:200,000), 14 mg/kg, not to exceed a maximum total dose of 1000 mg.  For specific techniques and procedures, refer to standard textbooks.

  There have been adverse event reports of chondrolysis in patients receiving intra-articular infusions of local anesthetics following arthroscopic and other surgical procedures.  Nesacaine is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION). 

  Caudal and Lumbar Epidural Block: In order to guard against adverse experiences sometimes noted following unintended penetration of the subarachnoid space, the following procedure modifications are recommended: 

  Use an adequate test dose (3 mL of Nesacaine-MPF 3% Injection or 5 mL of Nesacaine-MPF 2% Injection) prior to induction of complete block.  This test dose should be repeated if the patient is moved in such a fashion as to have displaced the epidural catheter.  Allow adequate time for onset of anesthesia following administration of each test dose. Avoid the rapid injection of a large volume of local anesthetic injection through the catheter.  Consider fractional doses, when feasible. In the event of the known injection of a large volume of local anesthetic injection into the subarachnoid space, after suitable resuscitation and if the catheter is in place, consider attempting the recovery of drug by draining a moderate amount of cerebrospinal fluid (such as 10 mL) through the epidural catheter.

  As a guide for some routine procedures, suggested doses are given below:

  Infiltration and Peripheral Nerve Block: NESACAINE or NESACAINE-MPF (chloroprocaine HCl Injection, USP)

  Anesthetic

  Procedure

  Solution Concentration %

  Volume

  (mL)

  Total

  Dose

  (mg)

  Mandibular

  Infraorbital

  Brachial plexus

  Digital (without epinephrine)

  Pudendal

  Paracervical (see also PRECAUTIONS)

  2

  2

  2

  1

  2

  1

  2  to 3

  0.5 to 1

  30 to 40

  3 to 4

  10 each side

  3 per each

  of 4 sites

  40 to 60

  10 to 20

  600 to 800

  30 to 40

  400

  up to 120

   

           2. Caudal and Lumbar Epidural Block: NESACAINE-MPF INJECTION.

           For caudal anesthesia, the initial dose is 15 to 25 mL of a 2% or 3% solution.  Repeated doses may be given at 40 to 60 minute intervals.

           For lumbar epidural anesthesia, 2 to 2.5 mL per segment of a 2% or 3% solution can be used.  The usual total volume of Nesacaine-MPF Injection is from 15 to 25 mL.  Repeated doses 2 to 6 mL less than the original dose may be given at 40 to 50 minute intervals.

  The above dosages are recommended as a guide for use in the average adult.  Maximum dosages of all local anesthetics must be individualized after evaluating the size and physical condition of the patient and the rate of systemic absorption from a particular injection site.

  Pediatric Dosage: It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight.  For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight and should not exceed 11 mg/kg (5 mg/lb).  For example, in a child of 5 years weighing 50 lbs (23 kg), the dose of chloroprocaine HCl without epinephrine would be 250 mg.  Concentrations of 0.5 to 1% are suggested for infiltration and 1 to 1.5% for nerve block.  In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times.  Some of the lower concentrations for use in infants and smaller children are not available in prepackaged containers; it will be necessary to dilute available concentrations with the amount of 0.9% sodium chloride injection necessary to obtain the required final concentration of chloroprocaine injection.

  Preparation of Epinephrine Injections—To prepare a 1:200,000 epinephrine-chloroprocaine HCl injection, add 0.1 mL of a 1 to 1000 Epinephrine Injection USP to 20 mL of Nesacaine-MPF Injection.

  Chloroprocaine is incompatible with caustic alkalis and their carbonates, soaps, silver salts, iodine and iodides.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever injection and container permit.  As with other anesthetics having a free aromatic amino group, Nesacaine and Nesacaine-MPF Injections are slightly photosensitive and may become discolored after prolonged exposure to light.  It is recommended that these vials be stored in the original outer containers, protected from direct sunlight.  Discolored injection should not be administered.  If exposed to low temperatures, Nesacaine and Nesacaine-MPF Injections may deposit crystals of chloroprocaine HCl which will redissolve with shaking when returned to room temperature.  The product should not be used if it contains undissolved (eg, particulate) material.

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• Perikabiven
  

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  Perikabiven

  

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  2.1 Administration

  PERIKABIVEN® is for intravenous infusion into a peripheral or central vein [see Warnings and Precautions (5.8)].  Use a 1.2 micron in-line filter. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Use a dedicated line without any connections.  Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.  Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as PERIKABIVEN® via a Y-site due to precipitation.  However, ceftriaxone and PERIKABIVEN® may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Warnings and Precautions (5.9)]. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP).  Administration sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer.

  2.2 Important Preparation Instructions

  Inspect the bag prior to activation.  Discard the bag in the following situations: Evidence of damage to the bag More than one chamber is white Solution is yellow Any seal is already broken Activate the bag [see Dosage and Administration (2.3)]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports.  The upper sections of the vertical seals above the bend and the horizontal seal may remain closed. It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure a homogenous admixture. Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [see Dosage and Administration (2.3)]. For total parenteral nutrition add multivitamins and trace elements via the additive port.   Any other additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. When introducing additives, it is recommended to use 18 to 23 gauge needles with a maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition,  use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect PERIKABIVEN® to ensure: Precipitates have not formed during the mixing or addition of additives.  The emulsion has not separated.  Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. 

             Discard the admixture if any of the above are observed.

  PERIKABIVEN® should be used immediately after mixing and the introduction of additives.  If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at 2° to 8°C (36° to 46°F).  After removal from storage at 2° to 8°C (36° to 46°F), the admixture should be infused within 24 hours.  Any mixture remaining must be discarded.

  2.3 Instructions for Use

    

                   

          

          

          

  2.4 Dosing Considerations

  The dosage of PERIKABIVEN® should be individualized based on the patient’s clinical condition (ability to adequately metabolize protein, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient.

  PERIKABIVEN® is a combination of amino acids, electrolytes, dextrose, and lipid in a fixed volume and concentration.  The dosage selection is based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [see Table 1].   PERIKABIVEN® meets the total nutritional requirements for protein, dextrose and lipids in stable patients, and can be individualized to meet specific needs with the addition of nutrients.  The maximum infusion rate is based upon the dextrose component.

  Prior to administration of PERIKABIVEN®, correct severe fluid, electrolyte and acid-base disorders.  Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. 

  Recommended Adult Dosage

  The recommended dosage of PERIKABIVEN® in adults is 27 to 40 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by PERIKABIVEN® are shown in Table 1.

  The maximum daily dosage of PERIKABIVEN® in adults should not exceed 40 mL/kg/day.

  In patients with serum triglyceride concentrations above 400 mg/dL, stop the PERIKABIVEN® infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart PERIKABIVEN® at a lower infusion rate and advance rate  in smaller increments, towards target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)].

  Table 1:  Nutritional Comparison

  Nutrition Provided by PERIKABIVEN®   recommended dosage Recommended Nutritional Requirements1 Stable Patients Critically Ill Patients* Fluid mL/kg/day 27 to 40 30 to 40 Minimum needed to deliver adequate macronutrients Protein** g/kg/dayNitrogen g/kg/day 0.64 to 0.94 0.1 to 0.15 0.8 to 1.0 0.13 to 0.16 1.5 to 2 0.24 to 0.3 Dextrose g/kg/day 1.8 to 2.7 ≤10 ≤5.8 Lipids g/kg/day 0.95 to 1.4 1 ≤1 Total Energy Requirement kcal/kg/day 18 to 27 20 to 30 25 to 30

  * Do not use in patients with conditions that are contraindicated [see Contraindications (4)].

  ** Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein.

  Treatment with PERIKABIVEN® may be continued for as long as is required by the patient’s condition.

  Dosing in Renal Impairment

  In patients with renal impairment, the dosage of PERIKABIVEN® should be the recommended adult dosage (see above). Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of PERIKABIVEN® administered as required [see Warnings and Precautions (5.11)].

  Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day. Patients on dialysis or continuous renal replacement therapy should receive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses2. The PERIKABIVEN® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein indicated. Additional protein may be added to PERIKABIVEN® bag or infused separately. If required, additional amino acids may be added to the PERIKABIVEN® bag or infused separately.  Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs.

  Infusion Duration and Rate

  The recommended duration of infusion for PERIKABIVEN® is between 12 and 24 hours, depending on the clinical situation.

  The maximum infusion rate of PERIKABIVEN® is 3.7 mL/kg/hour.  This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose (the rate limiting factor), and 0.13 g/kg/hour of lipids.

  Dosing Instructions

  Determine the fluid requirements (27 to 40 mL/kg/day) to be delivered, and then select the corresponding PERIKABIVEN® bag. Determine the preferred duration of infusion (12 to 24 hours). Ensure that the rate of infusion (PERIKABIVEN® dosage in mL/kg/day divided by the preferred duration of infusion (hours) does not exceed the maximum infusion rate for the patient (i.e., 3.7 mL/kg/hour).  The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has selected, calculate the infusion rate (mL/hour) using the patient’s weight. Compare the patient’s nutrient requirements with the amount supplied by PERIKABIVEN®. Discuss with a pharmacist any additions that may be required.

  2.1 Administration

  PERIKABIVEN® is for intravenous infusion into a peripheral or central vein [see Warnings and Precautions (5.8)].  Use a 1.2 micron in-line filter. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Use a dedicated line without any connections.  Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed.  Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as PERIKABIVEN® via a Y-site due to precipitation.  However, ceftriaxone and PERIKABIVEN® may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Warnings and Precautions (5.9)]. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP).  Administration sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer.

  2.2 Important Preparation Instructions

  Inspect the bag prior to activation.  Discard the bag in the following situations: Evidence of damage to the bag More than one chamber is white Solution is yellow Any seal is already broken Activate the bag [see Dosage and Administration (2.3)]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports.  The upper sections of the vertical seals above the bend and the horizontal seal may remain closed. It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure a homogenous admixture. Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [see Dosage and Administration (2.3)]. For total parenteral nutrition add multivitamins and trace elements via the additive port.   Any other additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. When introducing additives, it is recommended to use 18 to 23 gauge needles with a maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition,  use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect PERIKABIVEN® to ensure: Precipitates have not formed during the mixing or addition of additives.  The emulsion has not separated.  Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion. 

             Discard the admixture if any of the above are observed.

  PERIKABIVEN® should be used immediately after mixing and the introduction of additives.  If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at 2° to 8°C (36° to 46°F).  After removal from storage at 2° to 8°C (36° to 46°F), the admixture should be infused within 24 hours.  Any mixture remaining must be discarded.

  2.3 Instructions for Use

    

                   

          

          

          

  2.4 Dosing Considerations

  The dosage of PERIKABIVEN® should be individualized based on the patient’s clinical condition (ability to adequately metabolize protein, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient.

  PERIKABIVEN® is a combination of amino acids, electrolytes, dextrose, and lipid in a fixed volume and concentration.  The dosage selection is based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [see Table 1].   PERIKABIVEN® meets the total nutritional requirements for protein, dextrose and lipids in stable patients, and can be individualized to meet specific needs with the addition of nutrients.  The maximum infusion rate is based upon the dextrose component.

  Prior to administration of PERIKABIVEN®, correct severe fluid, electrolyte and acid-base disorders.  Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. 

  Recommended Adult Dosage

  The recommended dosage of PERIKABIVEN® in adults is 27 to 40 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by PERIKABIVEN® are shown in Table 1.

  The maximum daily dosage of PERIKABIVEN® in adults should not exceed 40 mL/kg/day.

  In patients with serum triglyceride concentrations above 400 mg/dL, stop the PERIKABIVEN® infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart PERIKABIVEN® at a lower infusion rate and advance rate  in smaller increments, towards target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)].

  Table 1:  Nutritional Comparison

  Nutrition Provided by PERIKABIVEN®   recommended dosage Recommended Nutritional Requirements1 Stable Patients Critically Ill Patients* Fluid mL/kg/day 27 to 40 30 to 40 Minimum needed to deliver adequate macronutrients Protein** g/kg/dayNitrogen g/kg/day 0.64 to 0.94 0.1 to 0.15 0.8 to 1.0 0.13 to 0.16 1.5 to 2 0.24 to 0.3 Dextrose g/kg/day 1.8 to 2.7 ≤10 ≤5.8 Lipids g/kg/day 0.95 to 1.4 1 ≤1 Total Energy Requirement kcal/kg/day 18 to 27 20 to 30 25 to 30

  * Do not use in patients with conditions that are contraindicated [see Contraindications (4)].

  ** Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein.

  Treatment with PERIKABIVEN® may be continued for as long as is required by the patient’s condition.

  Dosing in Renal Impairment

  In patients with renal impairment, the dosage of PERIKABIVEN® should be the recommended adult dosage (see above). Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of PERIKABIVEN® administered as required [see Warnings and Precautions (5.11)].

  Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day. Patients on dialysis or continuous renal replacement therapy should receive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses2. The PERIKABIVEN® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein indicated. Additional protein may be added to PERIKABIVEN® bag or infused separately. If required, additional amino acids may be added to the PERIKABIVEN® bag or infused separately.  Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs.

  Infusion Duration and Rate

  The recommended duration of infusion for PERIKABIVEN® is between 12 and 24 hours, depending on the clinical situation.

  The maximum infusion rate of PERIKABIVEN® is 3.7 mL/kg/hour.  This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose (the rate limiting factor), and 0.13 g/kg/hour of lipids.

  Dosing Instructions

  Determine the fluid requirements (27 to 40 mL/kg/day) to be delivered, and then select the corresponding PERIKABIVEN® bag. Determine the preferred duration of infusion (12 to 24 hours). Ensure that the rate of infusion (PERIKABIVEN® dosage in mL/kg/day divided by the preferred duration of infusion (hours) does not exceed the maximum infusion rate for the patient (i.e., 3.7 mL/kg/hour).  The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has selected, calculate the infusion rate (mL/hour) using the patient’s weight. Compare the patient’s nutrient requirements with the amount supplied by PERIKABIVEN®. Discuss with a pharmacist any additions that may be required.

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• Gentamicin
  

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  Gentamicin

  

  ---

  Gentamicin injection may be given IM or IV.  The patient’s pretreatment body weight should be obtained for calculation of correct dosage.  The dosage of aminoglycosides in obese patients should be based on an estimate of the lean body mass.  It is desirable to limit the duration of treatment with aminoglycosides to short term.

                                                                PATIENTS WITH NORMAL

                                                                   RENAL FUNCTION

  Adults

  The recommended dosage of gentamicin injection for patients with serious infections and normal renal function is 3 mg/kg/day, administered in three equal doses every eight hours (Table 3).

  For patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses.  This dosage should be reduced to 3 mg/kg/day as soon as clinically indicated (Table 3).

  It is desirable to measure both peak and trough serum concentrations of gentamicin to determine the adequacy and safety of the dosage.  When such measurements are feasible, they should be carried out periodically during therapy to assure adequate but not excessive drug levels.  For example, the peak concentration (at 30 to 60 minutes after IM injection) is expected to be in the range of 4 to 6 mcg/mL.  When monitoring peak concentrations after IM or IV administration, dosage should be adjusted so that prolonged levels above 12 mcg/mL are avoided.  When monitoring trough concentrations (just prior to the next dose), dosage should be adjusted so that levels above 2 mcg/mL are avoided.  Determination of the adequacy of a serum level for a particular patient must take into consideration the susceptibility of the causative organism, the severity of the infection and the status of the patient’s host-defense mechanisms.

  In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides.  In such patients treated with gentamicin, measurement of serum concentrations is recommended as a basis for dosage adjustment.

   

   TABLE 3 DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION

                                (Dosage at Eight-Hour Intervals)

                                             40 mg per mL

  Patient’s

  Weight*

  Usual Dose for

  Serious

  Infections

  1 mg/kg q8h

  (3 mg/kg/day)

  Dose for

   Life-Threatening

  Infections (Reduce

  As Soon As

  Clinically Indicated)

  1.7 mg/kg q8h**

  (5 mg/kg/day)

  kg

  (lb)

  mg/dose

  mL/dose

  mg/dose

  mL/dose

  q8h

  q8h

  40

  ( 88 )

  40

  1

  66

  1.6

  45

  ( 99)

  45

  1.1

  75

  1.9

  50

  (110)

  50

  1.25

  83

  2.1

  55

  (121)

  55

  1.4

  91

  2.25

  60

  (132)

  60

  1.5

  100

  2.5

  65

  (143)

  65

  1.6

  108

  2.7

  70

  (154)

  70

  1.75

  116

  2.9

  75

  (165)

  75

  1.9

  125

  3.1

  80

  (176)

  80

  2

  133

  3.3

  85

  (187)

  85

  2.1

  141

  3.5

  90

  (198)

  90

  2.25

  150

  3.75

  95

  (209)

  95

  2.4

  158

  4

  100

  (220)

  100

  2.5

  166

  4.2

                                                                                                           

  *The dosage of aminoglycosides in obese patients should be based on

      an estimate of the lean body mass.

  **for q6h schedules, dosage should be recalculated.

  Children

  6 to 7.5 mg/kg/day (2 to 2.5 mg/kg administered every eight hours).

  Infants and Neonates

  7.5 mg/kg/day (2.5 mg/kg administered every eight hours).

  Premature or Full-Term Neonates One Week of Age or Less

  5 mg/kg/day (2.5 mg/kg administered every 12 hours).

  For further information concerning the use of gentamicin in infants and children, see gentamicin injection (pediatric) product information.

  The usual duration of treatment for all patients is 7 to 10 days.  In difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory and vestibular functions is recommended, since toxicity is more apt to occur with treatment extended for more than 10 days.  Dosage should be reduced if clinically indicated.

                                                                FOR INTRAVENOUS ADMINISTRATION

  The IV administration of gentamicin may be particularly useful for treating patients with bacterial septicemia or those in shock.  It may also be the preferred route of administration for some patients with congestive heart failure, hematologic disorders, severe burns or those with reduced muscle mass.  For intermittent IV administration in adults, a single dose of gentamicin injection may be diluted in 50 to 200 mL of sterile isotonic saline solution or in a sterile solution of dextrose 5% in water; in infants and children, the volume of diluent should be less.  The solution may be infused over a period of one-half to two hours.

  The recommended dosage for IM and IV administration is identical.

  Gentamicin injection should not be physically premixed with other drugs, but should be administered separately in accordance with the recommended route of administration and dosage schedule. 

                                                                        PATIENTS WITH IMPAIRED

                                                                             RENAL FUNCTION

  Dosage must be adjusted in patients with impaired renal function to assure therapeutically adequate, but not excessive blood levels.  Whenever possible serum concentration of gentamicin should be monitored.  One method of dosage adjustment is to increase the interval between administration of the usual doses.  Since the serum creatinine concentration has a high correlation with the serum half-life of gentamicin, this laboratory test may provide guidance for adjustment of the interval between doses.  The interval between doses (in hours) may be approximated by multiplying the serum creatinine level (mg/100 mL) by 8.  For example, a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 60 mg (1 mg/kg) every 16 hours (2 x 8).

  In patients with serious systemic infections and renal impairment, it may be desirable to administer the antibiotic more frequently but in reduced dosage.  In such patients, serum concentrations of gentamicin should be measured so that adequate but not excessive levels result.  A peak and trough concentration measured intermittently during therapy will provide optimal guidance for adjusting dosage.  After the usual initial dose, a rough guide for determining reduced dosage at eight-hour intervals is to divide the normally recommended dose by the serum creatinine level (Table 4).  For example, after an initial dose of 60 mg (1 mg/kg), a patient weighing 60 kg with a serum creatinine level of 2 mg/100 mL could be given 30 mg every eight hours (60 ÷ 2).  It should be noted that the status of renal function may be changing over the course of the infectious process.

  It is important to recognize that deteriorating renal function may require a greater reduction in dosage than that specified in the above guidelines for patients with stable renal impairment.

   

  TABLE 4 DOSAGE ADJUSTMENT GUIDE FOR PATIENTS WITH RENAL IMPAIRMENT

  (Dosage at Eight-Hour Intervals After the Usual Initial Dose)

  Serum

  Creatinine

  (mg %)

  Approximate

  Creatinine

  Clearance Rate

  (mL/min/1.73m2)

  Percent of

  Usual Doses

  Shown Above

  ≤1

      > 100

  100

    1.1 to 1.3

   70 to 100

  80

    1.4 to 1.6

  55 to 70

  65

    1.7 to 1.9

  45 to 55

  55

       2 to 2.2

  40 to 45

  50

    2.3 to 2.5

  35 to 40

  40

    2.6 to 3

  30 to 35

  35

    3.1 to 3.5

  25 to 30

  30

    3.6 to 4

  20 to 25

  25

    4.1 to 5.1

  15 to 20

  20

    5.2 to 6.6

  10 to 15

  15

    6.7 to 8

       < 10

  10

  In adults with renal failure undergoing hemodialysis, the amount of gentamicin removed from the blood may vary depending upon several factors including the dialysis method used.  An eight-hour hemodialysis may reduce serum concentrations of gentamicin by approximately 50%.  The recommended dosage at the end of each dialysis period is 1 to 1.7 mg/kg depending upon the severity of the infection.  In children, a dose of 2 mg/kg may be administered.

  The above dosage schedules are not intended as rigid recommendations but are provided as guides to dosage when measurement of gentamicin serum level is not feasible.

  A variety of methods are available to measure gentamicin concentrations in body fluids; these include microbiologic, enzymatic and radioimmunoassay techniques.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Kabiven
  

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  Kabiven

  

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  2.1 Administration

  KABIVEN® is for intravenous infusion only into a central vein [see Warnings and Precautions (5.8)].  Use a 1.2 micron in-line filter. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Use a dedicated line without any connections.  Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as KABIVEN® via a Y-site due to precipitation.  However, ceftriaxone and KABIVEN® may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Warnings and Precautions (5.9)]. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP).  Administration sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer.

  2.2 Important Preparation Instructions

  Inspect the bag prior to activation.  Discard the bag in the following situations: Evidence of damage to the bag More than one chamber is white Solution is yellow Any seal is already broken Activate the bag [see Dosage and Administration (2.3)]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports.  The upper sections of the vertical seals above the bend and the horizontal seal may remain closed. It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure a homogenous admixture. Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [see Dosage and Administration (2.3)]. For total parenteral nutrition add multivitamins and trace elements via the additive port.   Any other additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. When introducing additives, it is recommended to use 18 to 23 gauge needles with a maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition,  use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect KABIVEN® to ensure: Precipitates have not formed during the mixing or addition of additives. The emulsion has not separated.  Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion.

             Discard the admixture if any of the above are observed.

  KABIVEN® should be used immediately after mixing and the introduction of additives.  If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at 2° to 8°C (36° to 46°F).  After removal from storage at 2° to 8°C (36° to 46°F), the admixture should be infused within 24 hours.  Any mixture remaining must be discarded.

  2.3 Instructions for Use

        

  2.4 Dosing Considerations

  The dosage of KABIVEN® should be individualized based on the patient’s clinical condition (ability to adequately metabolize amino acids, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient.

  KABIVEN® is a combination of amino acids, electrolytes, dextrose, and lipids in a fixed volume and concentration.  The dosage selection is based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [See Table 1]. KABIVEN® meets the total nutritional requirements for protein, dextrose, and lipids in stable patients, and can be individualized to meet specific needs with the addition of nutrients.  The maximum infusion rate is based upon the dextrose component. Prior to administration of KABIVEN®, correct severe fluid electrolyte and acid-base disorders.  Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. Recommended Adult Dosage The recommended dosage of KABIVEN® in adults is 19 to 38 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by KABIVEN® are shown in Table 1. The maximum daily dosage of KABIVEN® in adults should not exceed 40 mL/kg/day. In patients with serum triglyceride concentrations above 400 mg/dL, stop the KABIVEN® infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart KABIVEN® at a lower infusion rate and advance rate  in smaller increments towards target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)]. Table 1:  Nutritional Comparison Nutrition Provided by KABIVEN®   recommended dosage Recommended Nutritional Requirements1 Stable Patients Critically Ill Patients* Fluid mL/kg/day 19 to 38 30 to 40 Minimum needed to deliver adequate macronutrients Protein** g/kg/day Nitrogen g/kg/day 0.6 to 1.3 0.1 to 0.2 0.8 to 1.0 0.13 to 0.16 1.5 to 2 0.24 to 0.3 Dextrose g/kg/day 1.9 to 3.7 ≤10 ≤5.8 Lipids g/kg/day 0.7 to 1.5 1 ≤1 Total Energy Requirement kcal/kg/day 16 to 32 20 to 30 25 to 30 * Do not use in patients with conditions that are contraindicated [see Contraindications (4)]. ** Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. Treatment with KABIVEN® may be continued for as long as is required by the patient’s condition. Dosing in Renal Impairment In patients with renal impairment, the dosage of KABIVEN® should be the recommended adult dosage (see above). Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of KABIVEN® administered as required [see Warnings and Precautions (5.11)]. Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day.  Serum electrolyte levels should be closely monitored. Patients on hemodialysis or continuous renal replacement therapy should receive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses2. The KABIVEN® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated. If required, additional amino acids may be added to the KABIVEN® bag or infused separately.  Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. Infusion Duration and Rate The recommended duration of infusion for KABIVEN® is between 12 and 24 hours, depending on the clinical situation. The maximum infusion rate of KABIVEN® is 2.6 mL/kg/hour.  This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose (the rate limiting factor) and 0.1 g/kg/hour of lipids. Dosing Instructions Determine the fluid requirements (19 to 38 mL/kg/day) and the patient’s nutritional requirements (see Table 1) to be delivered, and then select the corresponding KABIVEN® bag. Determine the preferred duration of infusion (12 to 24 hours). Ensure that the rate of infusion (KABIVEN® dosage in mL/kg/day divided by the preferred duration of infusion (hours) does not exceed the maximum infusion rate for the patient (i.e., 2.6 mL/kg/hour).  The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has selected, calculate the infusion rate (mL/hour) using the patient’s weight. Compare the patient’s nutrient requirements with the amount supplied by KABIVEN®. Discuss with a pharmacist any additions that may be required.

  2.1 Administration

  KABIVEN® is for intravenous infusion only into a central vein [see Warnings and Precautions (5.8)].  Use a 1.2 micron in-line filter. Use of a vented intravenous administration set with the vent in the open position could result in air embolism. Use a dedicated line without any connections.  Multiple connections could result in air embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Ceftriaxone must not be administered simultaneously with calcium-containing intravenous solutions such as KABIVEN® via a Y-site due to precipitation.  However, ceftriaxone and KABIVEN® may be administered sequentially if the infusion lines are thoroughly flushed between infusions with a compatible fluid [see Warnings and Precautions (5.9)]. Do not use administration sets and lines that contain di-2-ethylhexyl phthalate (DEHP).  Administration sets that contain polyvinyl chloride (PVC) components have DEHP as a plasticizer.

  2.2 Important Preparation Instructions

  Inspect the bag prior to activation.  Discard the bag in the following situations: Evidence of damage to the bag More than one chamber is white Solution is yellow Any seal is already broken Activate the bag [see Dosage and Administration (2.3)]. Once the bag is activated, ensure the vertical seals between chambers are broken at least from the bend in the seals and down to the ports.  The upper sections of the vertical seals above the bend and the horizontal seal may remain closed. It is recommended to mix the contents thoroughly by inverting the bag upside down to ensure a homogenous admixture. Ensure the vertical seals between chambers are broken and the contents of all three chambers are mixed together prior to infusion [see Dosage and Administration (2.3)]. For total parenteral nutrition add multivitamins and trace elements via the additive port.   Any other additions to the bag should be evaluated by a pharmacist for compatibility. Questions about compatibility may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. When introducing additives, it is recommended to use 18 to 23 gauge needles with a maximum length of 1.5 inches (40 mm) and to mix thoroughly after each addition,  use aseptic technique and add after the vertical seals have been broken (i.e. bag has been activated) and the three components are mixed [see Dosage and Administration (2.3)]. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Inspect KABIVEN® to ensure: Precipitates have not formed during the mixing or addition of additives. The emulsion has not separated.  Separation of the emulsion can be visibly identified by a yellowish streaking or the accumulation of yellowish droplets in the mixed emulsion.

             Discard the admixture if any of the above are observed.

  KABIVEN® should be used immediately after mixing and the introduction of additives.  If not used immediately, the storage time and conditions prior to use should not be longer than 24 hours at 2° to 8°C (36° to 46°F).  After removal from storage at 2° to 8°C (36° to 46°F), the admixture should be infused within 24 hours.  Any mixture remaining must be discarded.

  2.3 Instructions for Use

        

  2.4 Dosing Considerations

  The dosage of KABIVEN® should be individualized based on the patient’s clinical condition (ability to adequately metabolize amino acids, dextrose and lipids), body weight and nutritional/fluid requirements, as well as additional energy given orally/enterally to the patient.

  KABIVEN® is a combination of amino acids, electrolytes, dextrose, and lipids in a fixed volume and concentration.  The dosage selection is based upon fluid requirements which can be used in conjunction with the nutritional requirements to determine final dosage [See Table 1]. KABIVEN® meets the total nutritional requirements for protein, dextrose, and lipids in stable patients, and can be individualized to meet specific needs with the addition of nutrients.  The maximum infusion rate is based upon the dextrose component. Prior to administration of KABIVEN®, correct severe fluid electrolyte and acid-base disorders.  Before starting the infusion, obtain serum triglyceride levels to establish the baseline value. Recommended Adult Dosage The recommended dosage of KABIVEN® in adults is 19 to 38 mL/kg/day. The recommended daily nutritional requirements for protein, dextrose and lipids compared to the amount of nutrition provided by KABIVEN® are shown in Table 1. The maximum daily dosage of KABIVEN® in adults should not exceed 40 mL/kg/day. In patients with serum triglyceride concentrations above 400 mg/dL, stop the KABIVEN® infusion and monitor serum triglyceride levels. Once the triglycerides are <400 mg/dL, restart KABIVEN® at a lower infusion rate and advance rate  in smaller increments towards target dosage, checking the triglyceride levels prior to each adjustment [see Contraindications (4) and Warnings and Precautions (5.12)]. Table 1:  Nutritional Comparison Nutrition Provided by KABIVEN®   recommended dosage Recommended Nutritional Requirements1 Stable Patients Critically Ill Patients* Fluid mL/kg/day 19 to 38 30 to 40 Minimum needed to deliver adequate macronutrients Protein** g/kg/day Nitrogen g/kg/day 0.6 to 1.3 0.1 to 0.2 0.8 to 1.0 0.13 to 0.16 1.5 to 2 0.24 to 0.3 Dextrose g/kg/day 1.9 to 3.7 ≤10 ≤5.8 Lipids g/kg/day 0.7 to 1.5 1 ≤1 Total Energy Requirement kcal/kg/day 16 to 32 20 to 30 25 to 30 * Do not use in patients with conditions that are contraindicated [see Contraindications (4)]. ** Protein is provided as amino acids. When infused intravenously amino acids are metabolized and utilized as the building blocks of protein. Treatment with KABIVEN® may be continued for as long as is required by the patient’s condition. Dosing in Renal Impairment In patients with renal impairment, the dosage of KABIVEN® should be the recommended adult dosage (see above). Prior to administration, correct severe fluid or electrolyte imbalances. Closely monitor serum electrolyte levels and adjust the volume of KABIVEN® administered as required [see Warnings and Precautions (5.11)]. Renal patients not needing dialysis require 0.6 to 0.8 g of protein/kg/day.  Serum electrolyte levels should be closely monitored. Patients on hemodialysis or continuous renal replacement therapy should receive 1.2 to 1.8 g of protein/kg/day up to a maximum of 2.5 g of protein/kg/day based on nutritional status and estimated protein losses2. The KABIVEN® dosage can be adjusted based on the treatment for the renal impairment, supplementing protein as indicated. If required, additional amino acids may be added to the KABIVEN® bag or infused separately.  Compatibility of additions should be evaluated by a pharmacist and questions may be directed to Fresenius Kabi USA, LLC Vigilance and Medical Affairs. Infusion Duration and Rate The recommended duration of infusion for KABIVEN® is between 12 and 24 hours, depending on the clinical situation. The maximum infusion rate of KABIVEN® is 2.6 mL/kg/hour.  This corresponds to 0.09 g/kg/hour of amino acids, 0.25 g/kg/hour of dextrose (the rate limiting factor) and 0.1 g/kg/hour of lipids. Dosing Instructions Determine the fluid requirements (19 to 38 mL/kg/day) and the patient’s nutritional requirements (see Table 1) to be delivered, and then select the corresponding KABIVEN® bag. Determine the preferred duration of infusion (12 to 24 hours). Ensure that the rate of infusion (KABIVEN® dosage in mL/kg/day divided by the preferred duration of infusion (hours) does not exceed the maximum infusion rate for the patient (i.e., 2.6 mL/kg/hour).  The infusion rate may need to be reduced and duration of infusion increased in order not to exceed the maximum infusion rate. Once the infusion rate in mL/kg/hour has selected, calculate the infusion rate (mL/hour) using the patient’s weight. Compare the patient’s nutrient requirements with the amount supplied by KABIVEN®. Discuss with a pharmacist any additions that may be required.

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• Bleomycin
  

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  Bleomycin

  

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  Because of the possibility of an anaphylactoid reaction, lymphoma patients should be treated with 2 units or less for the first 2 doses.  If no acute reaction occurs, then the regular dosage schedule may be followed.

  The following dose schedule is recommended:

  Squamous cell carcinoma, non-Hodgkin’s lymphoma, testicular carcinoma– 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.

  Hodgkin’s Disease – 0.25 to 0.5 units/kg (10 to 20 units/m2) given intravenously, intramuscularly, or subcutaneously weekly or twice weekly.  After a 50% response, a maintenance dose of 1 unit daily or 5 units weekly intravenously or intramuscularly should be given.

  Pulmonary toxicity of Bleomycin for Injection, USP appears to be dose-related with a striking increase when the total dose is over 400 units.  Total doses over 400 units should be given with great caution.

  Note: When Bleomycin for Injection, USP is used in combination with other antineoplastic agents, pulmonary toxicities may occur at lower doses.

  Improvement of Hodgkin’s disease and testicular tumors is prompt and noted within 2 weeks.  If no improvement is seen by this time, improvement is unlikely. Squamous cell cancers respond more slowly, sometimes requiring as long as 3 weeks before any improvement is noted.

  Malignant Pleural Effusion – 60 units administered as a single dose bolus intrapleural injection (see ADMINISTRATION, Intrapleural).

  Use in Patients with Renal Insufficiency

  The following dosing reductions are proposed for patients with creatinine clearance (CrCL) values of less than 50 mL/min:

  Patient CrCL

  (mL/min)

  Bleomycin

  for Injection, USP

  Dose (%)

  50 and above

  100

  40 to 50

  70

  30 to 40

  60

  20 to 30

  55

  10 to 20

  45

  5 to 10

  40

  CrCL can be estimated from the individual patient’s measured serum creatinine (Scr) values using the Cockcroft and Gault formula:

  Males    CrCL = [weight x (140 – Age)]/(72 x Scr)

  Females CrCL = 0.85 x [weight x (140 – Age)]/(72 x Scr)

  Where CrCL in mL/min/1.73m2, weight in kg, age in years, and Scr in mg/dL.

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• Clonidine
  

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  Clonidine

  

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  The recommended starting dose of Clonidine Hydrochloride Injection for continuous epidural infusion is 30 mcg/hr.  Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 mcg/hr is limited. 

  Familiarization with the continuous epidural infusion device is essential.  Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the first few days to assess their response.

  The 500 mcg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, USP, to a final concentration of 100 mcg/mL:

  Volume of Clonidine Hydrochloride Injection 500 mcg/mL

  Volume of 0.9%Sodium Chloride for Injection, USP

  Resulting Final Clonidine Hydrochloride Injection Concentration

  (100 mcg/mL)

  1 mL

  4 mL

  500 mcg/5 mL

  2 mL

  8 mL

  1000 mcg/10 mL

  3 mL

  12 mL

  1500 mcg/15 mL

  4 mL

  16 mL

  2000 mcg/20 mL

  5 mL

  20 mL

  2500 mcg/25 mL

  6 mL

  24 mL

  3000 mcg/30 mL

  7 mL

  28 mL

  3500 mcg/35 mL

  8 mL

  32 mL

  4000 mcg/40 mL

  9 mL

  36 mL

  4500 mcg/45 mL

  10 mL

  40 mL

  5000 mcg/50 mL

  Renal Impairment: Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored.  Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

  Clonidine Hydrochloride Injection must not be used with a preservative.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Fluorouracil
  

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  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

      1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

      2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

   

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Fluorouracil
  

  ×

  Fluorouracil

  

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  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

  General Instructions

  Fluorouracil Injection, USP should be administered only intravenously, using care to avoid extravasation.  No dilution is required. 

  All dosages are based on the patient’s actual weight.  However, the estimated lean body mass (dry weight) is used if the patient is obese or if there has been a spurious weight gain due to edema, ascites or other forms of abnormal fluid retention.

  It is recommended that prior to treatment each patient be carefully evaluated in order to estimate as accurately as possible the optimum initial dosage of Fluorouracil.

  Dosage

  12 mg/kg are given intravenously once daily for 4 successive days.  The daily dose should not exceed 800 mg.  If no toxicity is observed, 6 mg/kg are given on the 6th, 8th, 10th and 12th days unless toxicity occurs.  No therapy is given on the 5th, 7th, 9th or 11th days.  Therapy is to be discontinued at the end of the 12th day, even if no toxicity has become apparent  (see WARNINGS and PRECAUTIONS).

  Poor risk patients or those who are not in an adequate nutritional state (see CONTRAINDICATIONS and WARNINGS sections) should receive 6 mg/kg/day for 3 days.  If no toxicity is observed, 3 mg/kg may be given on the 5th, 7th and 9th days unless toxicity occurs.  No therapy is given on the 4th, 6th or 8th days.  The daily dose should not exceed 400 mg.

  A sequence of injections on either schedule constitutes a “course of therapy.”

  Maintenance Therapy

  In instances where toxicity has not been a problem, it is recommended that therapy be continued using either of the following schedules:

        1. Repeat dosage of first course every 30 days after the last day of the previous course of treatment.

        2. When toxic signs resulting from the initial course of therapy have subsided, administer a maintenance dosage of 10 to 15 mg/kg/week as a single dose.  Do not exceed 1 g per week.

  The patient’s reaction to the previous course of therapy should be taken into account in determining the amount of the drug to be used, and the dosage should be adjusted accordingly.  Some patients have received from 9 to 45 courses of treatment during periods which ranged from 12 to 60 months.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.2-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Note

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Although the Fluorouracil solution may discolor slightly during storage, the potency and safety are not adversely affected.  If a precipitate occurs due to exposure to low temperatures, resolubilize by heating to 140°F and shaking vigorously; allow to cool to body temperature before using.

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• Docusate Plus Senna
  

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  Docusate Plus Senna

  

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  All patients should be evaluated for a bleeding disorder before administration of enoxaparin sodium, unless the medication is needed urgently. Since coagulation parameters are unsuitable for monitoring enoxaparin activity, routine monitoring of coagulation parameters is not required [see Warnings and Precautions (5.9)].

  For subcutaneous use, enoxaparin sodium should not be mixed with other injections or infusions. For intravenous use (i.e., for treatment of acute STEMI), enoxaparin sodium can be mixed with normal saline solution (0.9%) or 5% dextrose in water.

  Enoxaparin sodium is not intended for intramuscular administration.

  2.1 Adult Dosage

  Abdominal Surgery: In patients undergoing abdominal surgery who are at risk for thromboembolic complications, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection with the initial dose given 2 hours prior to surgery. The usual duration of administration is 7 to 10 days; up to 12 days administration has been administered in clinical trials.

  Hip or Knee Replacement Surgery: In patients undergoing hip or knee replacement surgery, the recommended dose of enoxaparin sodium is 30 mg every 12 hours administered by SC injection. Provided that hemostasis has been established, the initial dose should be given 12 to 24 hours after surgery. For hip replacement surgery, a dose of 40 mg once a day SC, given initially 12 (±3) hours prior to surgery, may be considered. Following the initial phase of thromboprophylaxis in hip replacement surgery patients, it is recommended that continued prophylaxis with enoxaparin sodium 40 mg once a day be administered by SC injection for 3 weeks. The usual duration of administration is 7 to 10 days; up to 14 days administration has been administered in clinical trials.

  Medical Patients During Acute Illness: In medical patients at risk for thromboembolic complications due to severely restricted mobility during acute illness, the recommended dose of enoxaparin sodium is 40 mg once a day administered by SC injection. The usual duration of administration is 6 to 11 days; up to 14 days of enoxaparin sodium has been administered in the controlled clinical trial.

  Treatment of Deep Vein Thrombosis with or without Pulmonary Embolism: In outpatient treatment, patients with acute deep vein thrombosis without pulmonary embolism who can be treated at home, the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC. In inpatient (hospital) treatment, patients with acute deep vein thrombosis with pulmonary embolism or patients with acute deep vein thrombosis without pulmonary embolism (who are not candidates for outpatient treatment), the recommended dose of enoxaparin sodium is 1 mg/kg every 12 hours administered SC or 1.5 mg/kg once a day administered SC at the same time every day. In both outpatient and inpatient (hospital) treatments, warfarin sodium therapy should be initiated when appropriate (usually within 72 hours of enoxaparin sodium). Enoxaparin sodium should be continued for a minimum of 5 days and until a therapeutic oral anticoagulant effect has been achieved (International Normalization Ratio 2.0 to 3.0). The average duration of administration is 7 days; up to 17 days of enoxaparin sodium administration has been administered in controlled clinical trials.

  Unstable Angina and Non-Q-Wave Myocardial Infarction: In patients with unstable angina or non-Q-wave myocardial infarction, the recommended dose of enoxaparin sodium is 1 mg/kg administered SC every 12 hours in conjunction with oral aspirin therapy (100 to 325 mg once daily). Treatment with enoxaparin sodium should be prescribed for a minimum of 2 days and continued until clinical stabilization. The usual duration of treatment is 2 to 8 days; up to 12.5 days of enoxaparin sodium has been administered in clinical trials [see Warnings and Precautions (5.2) and Clinical Studies (14.5)].

  Treatment of Acute ST-Segment Elevation Myocardial Infarction: In patients with acute ST-segment elevation myocardial infarction, the recommended dose of enoxaparin sodium is a single IV bolus of 30 mg plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC every 12 hours (maximum 100 mg for the first two doses only, followed by 1 mg/kg dosing for the remaining doses). Dosage adjustments are recommended in patients ≥75 years of age [see Dosage and Administration (2.3)]. All patients should receive aspirin as soon as they are identified as having STEMI and maintained with 75 to 325 mg once daily unless contraindicated. When administered in conjunction with a thrombolytic (fibrin-specific or non-fibrin specific), enoxaparin sodium should be given between 15 minutes before and 30 minutes after the start of fibrinolytic therapy. In the pivotal clinical study, the enoxaparin sodium treatment duration was 8 days or until hospital discharge, whichever came first. An optimal duration of treatment is not known, but it is likely to be longer than 8 days.

  For patients managed with percutaneous coronary intervention (PCI): If the last enoxaparin sodium SC administration was given less than 8 hours before balloon inflation, no additional dosing is needed. If the last enoxaparin sodium SC administration was given more than 8 hours before balloon inflation, an IV bolus of 0.3 mg/kg of enoxaparin sodium should be administered [see Warnings and Precautions (5.2)].

  2.2 Renal Impairment

  Although no dose adjustment is recommended in patients with moderate (creatinine clearance 30–50 mL/min) and mild (creatinine clearance 50–80 mL/min) renal impairment, all such patients should be observed carefully for signs and symptoms of bleeding.

  The recommended prophylaxis and treatment dosage regimens for patients with severe renal impairment (creatinine clearance <30 mL/min) are described in Table 1 [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

  Table 1 Dosage Regimens for Patients with Severe Renal Impairment(creatinine clearance <30mL/minute) Indication Dosage Regimen Prophylaxis in abdominal surgery 30 mg administered SC once daily Prophylaxis in hip or knee replacement surgery 30 mg administered SC once daily Prophylaxis in medical patients during acute illness 30 mg administered SC once daily Inpatient treatment of acute deep vein thrombosis with or without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Outpatient treatment of acute deep vein thrombosis without pulmonary embolism, when administered in conjunction with warfarin sodium 1 mg/kg administered SC once daily Prophylaxis of ischemic complications of unstable angina and non-Q-wave myocardial infarction, when concurrently administered with aspirin 1 mg/kg administered SC once daily Treatment of acute ST-segment elevation myocardial infarction in patients <75 years of age, when administered in conjunction with aspirin 30 mg single IV bolus plus a 1 mg/kg SC dose followed by 1 mg/kg administered SC once daily. Treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, when administered in conjunction with aspirin 1 mg/kg administered SC once daily (no initial bolus)

  2.3 Geriatric Patients with Acute ST-Segment Elevation Myocardial Infarction

  For treatment of acute ST-segment elevation myocardial infarction in geriatric patients ≥75 years of age, do not use an initial IV bolus. Initiate dosing with 0.75 mg/kg SC every 12 hours (maximum 75 mg for the first two doses only, followed by 0.75 mg/kg dosing for the remaining doses) [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].

  No dose adjustment is necessary for other indications in geriatric patients unless kidney function is impaired [see Dosage and Administration (2.2)].

  2.4 Administration

  Enoxaparin sodium injection is a clear, colorless to pale yellow sterile solution, and as with other parenteral drug products, should be inspected visually for particulate matter and discoloration prior to administration.

  The use of a tuberculin syringe or equivalent is recommended when using enoxaparin sodium multiple-dose vials to assure withdrawal of the appropriate volume of drug.

  Enoxaparin sodium must not be administered by intramuscular injection. Enoxaparin sodium is intended for use under the guidance of a physician.

  For subcutaneous administration, patients may self-inject only if their physicians determine that it is appropriate and with medical follow-up, as necessary. Proper training in subcutaneous injection technique (with or without the assistance of an injection device) should be provided.

  Subcutaneous Injection Technique: Patients should be lying down and enoxaparin sodium administered by deep SC injection. To avoid the loss of drug when using the 30 and 40 mg prefilled syringes, do not expel the air bubble from the syringe before the injection. Administration should be alternated between the left and right anterolateral and left and right posterolateral abdominal wall. The whole length of the needle should be introduced into a skin fold held between the thumb and forefinger; the skin fold should be held throughout the injection. To minimize bruising, do not rub the injection site after completion of the injection.

  Enoxaparin sodium prefilled syringes and graduated prefilled syringes are for single, one-time use only and are available with a system that shields the needle after injection.

  Remove the prefilled syringe from the blister packaging by peeling at the arrow as directed on the blister. Do not remove by pulling on the plunger as this may damage the syringe.

  Remove the needle shield by pulling it straight off the syringe (see Figure A). If adjusting the dose is required, the dose adjustment must be done prior to injecting the prescribed dose to the patient.Figure A

  Inject using standard technique, pushing the plunger to the bottom of the syringe (see Figure B).Figure B

  Remove the syringe from the injection site keeping your finger on the plunger rod (see Figure C).Figure C

  Orient the needle away from you and others, and activate the safety system by firmly pushing the plunger rod. The protective sleeve will automatically cover the needle and an audible "click" will be heard to confirm shield activation (see Figure D).Figure D

  Immediately dispose of the syringe in the nearest sharps container (see Figure E).Figure E

  NOTE:

  The safety system can only be activated once the syringe has been emptied. Activation of the safety system must be done only after removing the needle from the patient's skin. Do not replace the needle shield after injection. The safety system should not be sterilized.

  Activation of the safety system may cause minimal splatter of fluid. For optimal safety activate the system while orienting it downwards away from yourself and others.

  Intravenous (Bolus) Injection Technique: For intravenous injection, the multiple-dose vial should be used. Enoxaparin sodium should be administered through an intravenous line. Enoxaparin sodium should not be mixed or co-administered with other medications. To avoid the possible mixture of enoxaparin sodium with other drugs, the intravenous access chosen should be flushed with a sufficient amount of saline or dextrose solution prior to and following the intravenous bolus administration of enoxaparin sodium to clear the port of drug. Enoxaparin sodium may be safely administered with normal saline solution (0.9%) or 5% dextrose in water.

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