App Pharmaceuticals, Llc

App Pharmaceuticals, Llc Drugs

• Epirubicin Hydrochlorid...
  

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  Epirubicin Hydrochloride

  

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  Epirubicin hydrochloride injection is administered to patients by intravenous infusion. Epirubicin hydrochloride injection is given in repeated 3-4 week cycles. The total dose of epirubicin hydrochloride may be given on Day 1 of each cycle or divided equally and given on Days 1 and 8 of each cycle. The recommended dosages of epirubicin hydrochloride are as follows:

  Starting Doses

  The recommended starting dose of epirubicin hyrochloride injection is 100 to 120 mg/m 2. The following regimens were used in the trials supporting use of epirubicin hyrochloride injection as a component of adjuvant therapy in patients with axillary-node positive breast cancer: CEF-120: Cyclophosphamide 75 mg/m2  PO D 1 to 14 Epirubicin Hydrochloride 60 mg/m2  I.V. D 1, 8 5-Fluorouracil 500 mg/m2  I.V. D 1, 8 Repeated every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m2 Epirubicin Hydrochloride 100 mg/m2 Cyclophosphamide 500 mg/m2 All drugs administered intravenously on Day 1 and repeated every 21 days for 6 cycles Patients administered the 120 mg/m 2  regimen of epirubicin hydrochloride also received prophylactic antibiotic therapy with trimethoprim-sulfamethoxazole (e.g., Septra ®, Bactrim ®) or a fluoroquinolone.

  Bone Marrow Dysfunction. Consideration should be given to administration of lower starting doses (75 to 90 mg/m2) for heavily pretreated patients, patients with pre-existing bone marrow depression, or in the presence of neoplastic bone marrow infiltration (see WARNINGS and PRECAUTIONS sections).

  Hepatic Dysfunction. Definitive recommendations regarding use of epirubicin hydrochloride in patients with hepatic dysfunction are not available because patients with hepatic abnormalities were excluded from participation in adjuvant trials of FEC-100/CEF-120 therapy. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions were recommended in clinical trials, although few patients experienced hepatic impairment:

  Bilirubin 1.2 to 3 mg/dL or AST 2 to 4 times upper limit of normal 1/2 of recommended starting dose Bilirubin >3 mg/dL or AST >4 times upper limit of normal 1/4 of recommended starting dose

  Information regarding experience in patients with hepatic dysfunction is provided in CLINICAL PHARMACOLOGY, Pharmacokinetics In Special Populations section.

  Renal Dysfunction. While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, lower doses should be considered in patients with severe renal impairment (serum creatinine >5 mg/dL).

  Dose Modifications

  Dosage adjustments after the first treatment cycle should be made based on hematologic and nonhematologic toxicities. Patients experiencing during treatment cycle nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity should have the Day 1 dose in subsequent cycles reduced to 75% of the Day 1 dose given in the current cycle. Day 1 chemotherapy in subsequent courses of treatment should be delayed until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤Grade 1.

  For patients receiving a divided dose of epirubicin hydrochloride (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000 to 100,000/mm3  and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grade 3/4 nonhematologic toxicity has occurred, the Day 8 dose should be omitted.

  Preparation & Administration Precautions

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures normally used for proper handling and disposal of anticancer drugs should be considered for use with epirubicin hydrochloride. Several guidelines on this subject have been published.1-8

  Protective measures. The following protective measures should be taken when handling epirubicin hydrochloride injection:

  Personnel should be trained in appropriate techniques for reconstitution and handling. Pregnant staff should be excluded from working with this drug. Personnel handling epirubicin hydrochloride should wear protective clothing: goggles, gowns and disposable gloves and masks. A designated area should be defined for syringe preparation (preferably under a laminar flow system), with the work surface 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 contaminated and cleaning materials should be placed in high-risk, waste-disposal bags for incineration. Accidental contact with the skin or eyes should be treated immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. However, do not abrade the skin by using a scrub brush. Medical attention should be sought. Always wash hands after removing gloves.

  Incompatibilities. Prolonged contact with any solution of an alkaline pH should be avoided as it will result in hydrolysis of the drug. Epirubicin hydrochloride should not be mixed with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

  Epirubicin hydrochloride can be used in combination with other antitumor agents, but it is not recommended that it be mixed with other drugs in the same syringe.

  Preparation of Infusion Solution

  Epirubicin hydrochloride injection is provided as a preservative-free, ready-to-use solution.

  Epirubicin hydrochloride injection should be administered into the tubing of a freely flowing intravenous infusion (0.9% sodium chloride or 5% glucose solution). Patients receiving initial therapy at the recommended starting doses of 100 to 120 mg/m2should generally have epirubicin infused over 15 to 20 minutes. For patients who require lower epirubicin starting doses due to organ dysfunction or who require modification of epirubicin doses during therapy, the epirubicin infusion time may be proportionally decreased, but should not be less than 3 minutes. This technique is intended to minimize the risk of thrombosis or perivenous extravasation, which could lead to severe cellulitis, vesication, or tissue necrosis. A direct push injection is not recommended due to the risk of extravasation, which may occur even in the presence of adequate blood return upon needle aspiration. Venous sclerosis may result from injection into small vessels or repeated injections into the same vein (see PRECAUTIONS section). Epirubicin hydrochloride injection should be used within 24 hours of first penetration of the rubber stopper. Discard any unused solution.

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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.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%) 15-30 75-150 15-30 2-4 Administration 7.5 (0.75%) 15-25 113-188 10-20 3-5 Surgery 10 (1%) 15-20 150-200 10-20 4-6 Lumbar Epidural 5 (0.5%) 20-30 100-150 15-25 2-4 Administration 7.5 (0.75%) 15-20 113-150 10-20 3-5 Cesarean Section Thoracic Epidural 5 (0.5%) 5-15 25-75 10-20 n/a*   Administration 7.5 (0.75%) 5-15 38-113 10-20 n/a*   Surgery Major Nerve Block†   5 (0.5%) 35-50 175-250 15-30 5-8 (eg, brachial plexus block) 7.5 (0.75%) 10-40 75-300 10-25 6-10 Field Block 5 (0.5%) 1-40 5-200 1-15 2-6

  (eg, minor nerve blocks

  and infiltration) LABOR PAIN MANAGEMENT Lumbar Epidural Administration Initial Dose 2 (0.2%) 10-20 20-40 10-15 0.5-1.5

  Continuous

  infusion‡   2 (0.2%)

  6-14

  mL/h

  12-28

  mg/h n/a*   n/a*  

  Incremental

  injections (top-up)‡   2 (0.2%)

  10-15

  mL/h

  20-30

  mg/h n/a*   n/a*   POSTOPERATIVE PAIN MANAGEMENT  Lumbar Epidural Administration 

  Continuous

  infusion§    2  (0.2%) 

  6-14

  mL/h  

  12-28

  mg/h  n/a*    n/a*   

  Thoracic Epidural

  Administration  2  (0.2%) 

  6-14

  mL/h 

  12-28

  mg/h  n/a*    n/a*    Continuous infusion§            Infiltration  2 (0.2%)  1-100  2-200  1-5  2-6  (eg, minor nerve block)   5  (0.5%)  1-40  5-200  1-5  2-6 

  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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• Polocaine
  

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  Polocaine

  

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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 mepivacaine hydrochloride should be reduced for elderly and 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 doses should be used when feasible.

              For specific techniques and procedures, refer to standard textbooks.

              The recommended single adult dose (or the total of a series of doses given in one procedure) of mepivacaine hydrochloride for unsedated, healthy, normal-sized individuals should not usually exceed 400 mg.  The recommended dosage is based on requirements for the average adult and should be reduced for elderly or debilitated patients.

              While maximum doses of 7 mg/kg (550 mg) have been administered without adverse effect, these are not recommended, except in exceptional circumstances and under no circumstances should the administration be repeated at intervals of less than 1½ hours.  The total dose for any 24-hour period should not exceed 1,000 mg because of a slow accumulation of the anesthetic or its derivatives or slower than normal metabolic degradation or detoxification with repeat administration (see CLINICAL PHARMACOLOGY and PRECAUTIONS).

              Pediatric patients tolerate the local anesthetic as well as adults.  However, the pediatric dose should be carefully measured as a percentage of the total adult dose based on weight, and should not exceed 5 mg/kg to 6 mg/kg (2.5 mg/lb to 3 mg/lb) in pediatric patients, especially those weighing less than 30 lbs.  In pediatric patients under 3 years of age or weighing less than 30 lbs concentrations less than 2% (eg, 0.5% to 1.5%) should be employed.

              Unused portions of solutions not containing preservatives, ie, those supplied in 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.

  Recommended Concentrations and Doses of Mepivacaine Hydrochloride

  Procedure

   

  Concentration

   

  mL

  Total Dose

   

  mg

     Comments

   

  Cervical,

   

  1%

   

  5-40

   

  50-400

   

     Pudendal block:

   

  brachial,

     one half of total

  intercostal,

     dose injected

  pudendal

  2%

  5-20

  100-400

     each side.

  nerve block

   

  Transvaginal

   

  1%

   

  up to 30

   

  up to 300

   

     One half of total

   

  block

  (both sides)

  (both sides)

     dose injected

  (paracervical

     each side.  See

  plus pudendal)

   

     PRECAUTIONS.

   

  Paracervical

   

  1%

   

  up to 20

   

  up to 200

   

     One half of total

   

  block

  (both sides)

  (both sides)

     dose injected each

     side.  This is maxi-

     mum recommended

     dose per 90-minute

     period in obstetrical

     and non-obstetrical

     patients.  Inject slowly,

     5 minutes between

     sides. See

     PRECAUTIONS.

   

  Caudal and

   

  1%

   

  15-30

   

           

  150-300

   

     *Use only single-dose

   

  Epidural block

  1.5%

  10-25

  150-375

     vials which do not

  2%

   

  10-20

   

  200-400

   

     contain a preservative.

   

  Infiltration

   

  1%

   

  up to 40

   

  up to 400

   

     An equivalent amount

   

     of a 0.5% solution

     (prepared by diluting

     the 1% solution with

     Sodium Chloride

     Injection, USP) may

     be used for large

     areas.

   

  Therapeutic

   

  1%

   

  1-5

   

  10-50

   

  block (pain

  2%

  1-5

  20-100

  management)

  Unused portions of solutions not containing preservatives should be discarded.

  * Dosage forms listed as POLOCAINE-MPF (Mepivacaine HCl Injection, USP) are single-dose solutions which do not contain a preservative.

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• Emla
  

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  Emla

  

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  Adult Patients−Intact Skin

  A thick layer of EMLA Cream is applied to intact skin and covered with an occlusive dressing (see INSTRUCTIONS FOR APPLICATION).

  Minor Dermal Procedures: For minor procedures such as intravenous cannulation and venipuncture, apply 2.5 grams of EMLA Cream (1/2 the 5 g tube) over 20 to 25 cm2 of skin surface for at least 1 hour. In controlled clinical trials using EMLA Cream, two sites were usually prepared in case there was a technical problem with cannulation or venipuncture at the first site.

  Major Dermal Procedures: For more painful dermatological procedures involving a larger skin area such as split thickness skin graft harvesting, apply 2 grams of EMLA Cream per 10 cm2 of skin and allow to remain in contact with the skin for at least 2 hours.

  Adult Male Genital Skin: As an adjunct prior to local anesthetic infiltration, apply a thick layer of EMLA Cream (1 g/10 cm2) to the skin surface for 15 minutes.  Local anesthetic infiltration should be performed immediately after removal of EMLA Cream.

  Dermal analgesia can be expected to increase for up to 3 hours under occlusive dressing and persist for 1 to 2 hours after removal of the cream. The amount of lidocaine and prilocaine absorbed during the period of application can be estimated from the information in Table 2, ** footnote, in Individualization of Dose.

  Adult Female Patients−Genital Mucous Membranes

  For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5 to 10 grams) of EMLA Cream for 5 to 10 minutes.

  Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients should be lying down during the EMLA Cream application, especially if no occlusion is used. The procedure or the local anesthetic infiltration should be performed immediately after the removal of EMLA Cream.

  Pediatric Patients−Intact Skin

  The following are the maximum recommended doses, application areas and application times for EMLA Cream based on a child’s age and weight:

  Age and Body Weight Requirements Maximum TotalDose of EMLA Cream Maximum Application Area  Maximum  Application Time 

  0 up to 3 months or < 5 kg

  1 g

  10 cm2

  1 hour

  3 up to 12 months and > 5 kg

  2 g

  20 cm2

  4 hours

  1 to 6 years and > 10 kg

  10 g

  100 cm2

  4 hours

  7 to 12 years and > 20 kg

  20 g

  200 cm2

  4 hours

  Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the maximum total dose of EMLA Cream should be restricted to that which corresponds to the patient’s weight (see INSTRUCTIONS FOR APPLICATION).

  Practitioners should carefully instruct caregivers to avoid application of excessive amounts of EMLA Cream (see PRECAUTIONS).

  When applying EMLA Cream to the skin of young children, care must be taken to maintain careful observation of the child to prevent accidental ingestion of EMLA Cream or the occlusive dressing.  A secondary protective covering to prevent inadvertent disruption of the application site may be useful.

  EMLA Cream should not be used in neonates with a gestational age less than 37 weeks nor in infants under the age of 12 months who are receiving treatment with methemoglobin-inducing agents (see Methemoglobinemia subsection of WARNINGS).

   

  When EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered (see Individualization of Dose).  The amount absorbed in the case of EMLA Cream is determined by the area over which it is applied and the duration of application under occlusion (see TABLE 2, ** footnote in Individualization of Dose ).

  Although the incidence of systemic adverse reactions with EMLA Cream is very low, caution should be exercised, particularly when applying it over large areas and leaving it on for longer than 2 hours.  The incidence of systemic adverse reactions can be expected to be directly proportional to the area and time of exposure (see Individualization of Dose).

  Adult Female Patients−Genital Mucous Membranes

  For minor procedures on the female external genitalia, such as removal of condylomata acuminata, as well as for use as pretreatment for anesthetic infiltration, apply a thick layer (5 to 10 grams) of EMLA Cream for 5 to 10 minutes.

  Occlusion is not necessary for absorption, but may be helpful to keep the cream in place. Patients should be lying down during the EMLA Cream application, especially if no occlusion is used. The procedure or the local anesthetic infiltration should be performed immediately after the removal of EMLA Cream.

  Pediatric Patients−Intact Skin

  The following are the maximum recommended doses, application areas and application times for EMLA Cream based on a child’s age and weight:

  Age and Body Weight Requirements Maximum TotalDose of EMLA Cream Maximum Application Area  Maximum  Application Time 

  0 up to 3 months or < 5 kg

  1 g

  10 cm2

  1 hour

  3 up to 12 months and > 5 kg

  2 g

  20 cm2

  4 hours

  1 to 6 years and > 10 kg

  10 g

  100 cm2

  4 hours

  7 to 12 years and > 20 kg

  20 g

  200 cm2

  4 hours

  Please note: If a patient greater than 3 months old does not meet the minimum weight requirement, the maximum total dose of EMLA Cream should be restricted to that which corresponds to the patient’s weight (see INSTRUCTIONS FOR APPLICATION).

  Practitioners should carefully instruct caregivers to avoid application of excessive amounts of EMLA Cream (see PRECAUTIONS).

  When applying EMLA Cream to the skin of young children, care must be taken to maintain careful observation of the child to prevent accidental ingestion of EMLA Cream or the occlusive dressing.  A secondary protective covering to prevent inadvertent disruption of the application site may be useful.

  EMLA Cream should not be used in neonates with a gestational age less than 37 weeks nor in infants under the age of 12 months who are receiving treatment with methemoglobin-inducing agents (see Methemoglobinemia subsection of WARNINGS).

   

  When EMLA Cream (lidocaine 2.5% and prilocaine 2.5%) is used concomitantly with other products containing local anesthetic agents, the amount absorbed from all formulations must be considered (see Individualization of Dose).  The amount absorbed in the case of EMLA Cream is determined by the area over which it is applied and the duration of application under occlusion (see TABLE 2, ** footnote in Individualization of Dose ).

  Although the incidence of systemic adverse reactions with EMLA Cream is very low, caution should be exercised, particularly when applying it over large areas and leaving it on for longer than 2 hours.  The incidence of systemic adverse reactions can be expected to be directly proportional to the area and time of exposure (see Individualization of Dose).

  Precautions

  1. Do not apply near eyes or open wounds.

  2. Keep out of the reach of children.

  3. If your child becomes very dizzy, excessively sleepy, or develops duskiness of the face or lips after applying EMLA Cream, remove the cream and contact the child’s physician at once.

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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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• Oxaliplatin
  

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  Oxaliplatin

  

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  Oxaliplatin for Injection 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 in combination with 5-fluorouracil (5-FU)/leucovorin (LV) 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 85 mg/m2intravenous (IV) infusion in 250 to 500 mL 5% Dextrose injection, USP (D5W) and leucovorin 200 mg/m2 IV infusion in D5W both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5-FU 400 mg/m2 IV bolus given over 2 to 4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion.

  Day 2: Leucovorin 200 mg/m2 IV infusion over 120 minutes, followed by 5-FU 400 mg/m2 IV bolus given over 2 to 4 minutes, followed by 5-FU 600 mg/m2 IV infusion in 500 mL D5W (recommended) as a 22-hour continuous infusion.

  Figure 1

  The administration of oxaliplatin 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 from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5-FU 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-FU/LV regimen need not be altered.

  A dose reduction of oxaliplatin to 75 mg/m2 and infusional 5-FU 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 Cancer

  Neuropathy 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 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 to 65 mg/m2 and 5-FU 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.

  2.3 Preparation of Infusion Solution

  Reconstitution or final dilution must never be performed with a sodium chloride solution or other chloride containing solutions.

  The lyophilized powder is reconstituted by adding 10 mL (for the 50 mg vial) or 20 mL (for the 100 mg vial) of Water for Injection, USP or 5% Dextrose Injection, USP. Do not administer the reconstituted solution without further dilution. The reconstituted solution must be further diluted in an infusion solution of 250 to 500 mL of 5% Dextrose Injection, USP.

  After reconstitution in the original vial, the solution may be stored up to 24 hours under refrigeration [2º to 8°C (36º to 46° F)]. After final dilution with 250 to 500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20º to 25°C (68º to 77°F)] or up to 24 hours under refrigeration [2º to 8°C (36º to 46°F)].

  Oxaliplatin for Injection is not light sensitive.

  Oxaliplatin is incompatible in solution with alkaline medications or media (such as basic solutions of 5-FU) 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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  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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  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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• Clindamycin
  

  ×

  Clindamycin

  

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  If diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box).

  Adults

  Parenteral IV administration

  Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600 to 1200 mg/day in 2, 3 or 4 equal doses.

  More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1200 to 2700 mg/day in 2, 3 or 4 equal doses.

  For more serious infections, these doses may have to be increased.

  In life-threatening situations due to either aerobes or anaerobes these doses may be increased.  Doses of as much as 4800 mg daily have been given intravenously to adults. See Dilution and Infusion Rates below.

  Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:

  To maintain serum

  clindamycin levels

  Rapid infusion

  rate

  Maintenance

  infusion rate

  Above 4 mcg/mL

  Above 5 mcg/mL

  Above 6 mcg/mL

  10 mg/min for 30 min

  15 mg/min for 30 min

  20 mg/min for 30 min

  0.75 mg/min

  1 mg/min

  1.25 mg/min

  Neonates (less than 1 month)

  15 to 20 mg/kg/day in 3 to 4 equal doses.  The lower dosage may be adequate for small prematures.

  Pediatric Patients (1 month of age to 16 years)

  Parenteral IV administration: 20 to 40 mg/kg/day in 3 or 4 equal doses.  The higher doses would be used for more severe infections.  As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m2/day for serious infections and 450 mg/m2/day for more severe infections.

  Parenteral therapy may be changed to oral clindamycin flavored granules (clindamycin palmitate hydrochloride) or clindamycin capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.

  In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

  Dilution and Infusion Rates

  Clindamycin Injection, USP must be diluted prior to IV administration.  The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.  Infusion rates should not exceed 30 mg per minute.  The usual infusion dilutions and rates are as follows:

  Dose

  Diluent

  Time

  300 mg

  600 mg

  900 mg

  1200 mg

  50 mL

  50 mL

  50 to 100 mL

  100 mL

  10 min

  20 min

  30 min

  40 min

  Administration of more than 1200 mg in a single 1-hour infusion is not recommended.

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

  Dilution and Compatibility

  Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin Injection, USP in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.  No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

  The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

  The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.

  For current information regarding compatibilities of clindamycin phosphate under specific conditions, please visit www.APPpharma.com or call our medical information and safety department toll-free at 1-800-551-7176.

  Physico-Chemical Stability of Diluted Solutions of Clindamycin

  Room temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in  5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.  Also 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

  Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C.

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at -10°C.

  Frozen solutions should be thawed at room temperature and not refrozen.

  Adults

  Parenteral IV administration

  Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600 to 1200 mg/day in 2, 3 or 4 equal doses.

  More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1200 to 2700 mg/day in 2, 3 or 4 equal doses.

  For more serious infections, these doses may have to be increased.

  In life-threatening situations due to either aerobes or anaerobes these doses may be increased.  Doses of as much as 4800 mg daily have been given intravenously to adults. See Dilution and Infusion Rates below.

  Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:

  To maintain serum

  clindamycin levels

  Rapid infusion

  rate

  Maintenance

  infusion rate

  Above 4 mcg/mL

  Above 5 mcg/mL

  Above 6 mcg/mL

  10 mg/min for 30 min

  15 mg/min for 30 min

  20 mg/min for 30 min

  0.75 mg/min

  1 mg/min

  1.25 mg/min

  Neonates (less than 1 month)

  15 to 20 mg/kg/day in 3 to 4 equal doses.  The lower dosage may be adequate for small prematures.

  Pediatric Patients (1 month of age to 16 years)

  Parenteral IV administration: 20 to 40 mg/kg/day in 3 or 4 equal doses.  The higher doses would be used for more severe infections.  As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m2/day for serious infections and 450 mg/m2/day for more severe infections.

  Parenteral therapy may be changed to oral clindamycin flavored granules (clindamycin palmitate hydrochloride) or clindamycin capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.

  In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

  Dilution and Infusion Rates

  Clindamycin Injection, USP must be diluted prior to IV administration.  The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.  Infusion rates should not exceed 30 mg per minute.  The usual infusion dilutions and rates are as follows:

  Dose

  Diluent

  Time

  300 mg

  600 mg

  900 mg

  1200 mg

  50 mL

  50 mL

  50 to 100 mL

  100 mL

  10 min

  20 min

  30 min

  40 min

  Administration of more than 1200 mg in a single 1-hour infusion is not recommended.

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

  Dilution and Compatibility

  Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin Injection, USP in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.  No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

  The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

  The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.

  For current information regarding compatibilities of clindamycin phosphate under specific conditions, please visit www.APPpharma.com or call our medical information and safety department toll-free at 1-800-551-7176.

  Physico-Chemical Stability of Diluted Solutions of Clindamycin

  Room temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in  5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.  Also 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

  Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C.

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time. Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at -10°C.

  Frozen solutions should be thawed at room temperature and not refrozen.

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• Fludarabine
  

  ×

  Fludarabine

  

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  Usual Dosage

  The recommended adult dose of Fludarabine Phosphate for Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.  Each 5 day course of treatment should commence every 28 days.  Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.  Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

  A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate for Injection, USP.  These include advanced age, renal insufficiency, and bone marrow impairment.  Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

  The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Fludarabine Phosphate for Injection, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

  Renal Insufficiency

  Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine Phosphate for Injection, USP.  Fludarabine Phosphate for Injection, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

  Preparation of Solutions

  Fludarabine Phosphate for  Injection should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP.  When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg fludarabine phosphate, 25 mg mannitol, and sodium hydroxide to adjust the pH to 7.7.  The pH range for the final product is 7.2 to 8.2.  In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP.        

  Reconstituted Fludarabine Phosphate for Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution.  Care must be taken to assure the sterility of prepared solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Handling and Disposal

  Procedures for proper handling and disposal should be considered.  Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1–8  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Caution should be exercised in the handling of Fludarabine Phosphate for Injection, USP.  The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.  If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.  Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

  Usual Dosage

  The recommended adult dose of Fludarabine Phosphate for Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.  Each 5 day course of treatment should commence every 28 days.  Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.  Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

  A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate for Injection, USP.  These include advanced age, renal insufficiency, and bone marrow impairment.  Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

  The optimal duration of treatment has not been clearly established. It is recommended that three additional cycles of Fludarabine Phosphate for Injection, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

  Renal Insufficiency

  Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine Phosphate for Injection, USP.  Fludarabine Phosphate for Injection, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

  Preparation of Solutions

  Fludarabine Phosphate for  Injection should be prepared for parenteral use by aseptically adding Sterile Water for Injection, USP.  When reconstituted with 2 mL of Sterile Water for Injection, USP, the solid cake should fully dissolve in 15 seconds or less; each mL of the resulting solution will contain 25 mg fludarabine phosphate, 25 mg mannitol, and sodium hydroxide to adjust the pH to 7.7.  The pH range for the final product is 7.2 to 8.2.  In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% Dextrose Injection, USP or 0.9% Sodium Chloride, USP.        

  Reconstituted Fludarabine Phosphate for Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of reconstitution.  Care must be taken to assure the sterility of prepared solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Handling and Disposal

  Procedures for proper handling and disposal should be considered.  Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs. Several guidelines on this subject have been published.1–8  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Caution should be exercised in the handling of Fludarabine Phosphate for Injection, USP.  The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.  If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.  Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

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• Clindamycin
  

  ×

  Clindamycin

  

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  If diarrhea occurs during therapy, this antibiotic should be discontinued (see WARNING box).

  Adults

  Parenteral (IM or IV administration)

  Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600 to 1200 mg/day in 2, 3 or 4 equal doses. 

  More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1200 to 2700 mg/day in 2, 3 or 4 equal doses.

  For more serious infections, these doses may have to be increased.

  In life-threatening situations due to either aerobes or anaerobes these doses may be increased.  Doses of as much as 4800 mg daily have been given intravenously to adults.  See Dilution and Infusion Rates below.

  Single intramuscular injections of greater than 600 mg are not recommended.

  Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:

  To maintain serum clindamycin levels

  Rapid infusion rate

  Maintenance infusion rate

  Above 4 mcg/mL

  10 mg/min for 30 min

  0.75 mg/min

  Above 5 mcg/mL

  15 mg/min for 30 min

  1 mg/min

  Above 6 mcg/mL

  20 mg/min for 30 min

  1.25 mg/min

  Neonates (less than 1 month)

  15 to 20 mg/kg/day in 3 to 4 equal doses.  The lower dosage may be adequate for small prematures.

  Pediatric Patients (1 month of age to 16 years)

  Parenteral (IM or IV) administration: 20 to 40 mg/kg/day in 3 or 4 equal doses.  The higher doses would be used for more severe infections.  As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m2/day for serious infections and 450 mg/m2/day for more severe infections.

  Parenteral therapy may be changed to clindamycin palmitate hydrochloride for oral solution or clindamycin capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.

  In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

  Dilution and Infusion Rates

  Clindamycin Injection, USP must be diluted prior to IV administration.  The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.  Infusion rates should not exceed 30 mg per minute.  The usual infusion dilutions and rates are as follows:

  Dose

  Diluent

  Time

  300 mg

  50 mL

  10 min

  600 mg

  50 mL

  20 min

  900 mg

  50 to 100 mL

  30 min

  1200 mg

  100 mL

  40 min

  Administration of more than 1200 mg in a single 1-hour infusion is not recommended.

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

  Dilution and Compatibility

  Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin Injection, USP in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.  No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

  The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

  The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.

  For current information regarding compatibilities of clindamycin phosphate under specific conditions, please visit www.APPpharma.com or call our medical information and safety department toll-free at 1-800-551-7176.

  Physico-Chemical Stability of Diluted Solutions of Clindamycin

  Room temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.  Also 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

  Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C. 

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible. 

  Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at –10°C.

  Frozen solutions should be thawed at room temperature and not refrozen.

  Adults

  Parenteral (IM or IV administration)

  Serious infections due to aerobic gram-positive cocci and the more susceptible anaerobes (NOT generally including Bacteroides fragilis, Peptococcus species and Clostridium species other than Clostridium perfringens): 600 to 1200 mg/day in 2, 3 or 4 equal doses. 

  More severe infections, particularly those due to proven or suspected Bacteroides fragilis, Peptococcus species, or Clostridium species other than Clostridium perfringens: 1200 to 2700 mg/day in 2, 3 or 4 equal doses.

  For more serious infections, these doses may have to be increased.

  In life-threatening situations due to either aerobes or anaerobes these doses may be increased.  Doses of as much as 4800 mg daily have been given intravenously to adults.  See Dilution and Infusion Rates below.

  Single intramuscular injections of greater than 600 mg are not recommended.

  Alternatively, drug may be administered in the form of a single rapid infusion of the first dose followed by continuous IV infusion as follows:

  To maintain serum clindamycin levels

  Rapid infusion rate

  Maintenance infusion rate

  Above 4 mcg/mL

  10 mg/min for 30 min

  0.75 mg/min

  Above 5 mcg/mL

  15 mg/min for 30 min

  1 mg/min

  Above 6 mcg/mL

  20 mg/min for 30 min

  1.25 mg/min

  Neonates (less than 1 month)

  15 to 20 mg/kg/day in 3 to 4 equal doses.  The lower dosage may be adequate for small prematures.

  Pediatric Patients (1 month of age to 16 years)

  Parenteral (IM or IV) administration: 20 to 40 mg/kg/day in 3 or 4 equal doses.  The higher doses would be used for more severe infections.  As an alternative to dosing on a body weight basis, pediatric patients may be dosed on the basis of square meters body surface: 350 mg/m2/day for serious infections and 450 mg/m2/day for more severe infections.

  Parenteral therapy may be changed to clindamycin palmitate hydrochloride for oral solution or clindamycin capsules (clindamycin hydrochloride) when the condition warrants and at the discretion of the physician.

  In cases of β-hemolytic streptococcal infections, treatment should be continued for at least 10 days.

  Dilution and Infusion Rates

  Clindamycin Injection, USP must be diluted prior to IV administration.  The concentration of clindamycin in diluent for infusion should not exceed 18 mg per mL.  Infusion rates should not exceed 30 mg per minute.  The usual infusion dilutions and rates are as follows:

  Dose

  Diluent

  Time

  300 mg

  50 mL

  10 min

  600 mg

  50 mL

  20 min

  900 mg

  50 to 100 mL

  30 min

  1200 mg

  100 mL

  40 min

  Administration of more than 1200 mg in a single 1-hour infusion is not recommended.

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

  Dilution and Compatibility

  Physical and biological compatibility studies monitored for 24 hours at room temperature have demonstrated no inactivation or incompatibility with the use of Clindamycin Injection, USP in IV solutions containing sodium chloride, glucose, calcium or potassium, and solutions containing vitamin B complex in concentrations usually used clinically.  No incompatibility has been demonstrated with the antibiotics cephalothin, kanamycin, gentamicin, penicillin or carbenicillin.

  The following drugs are physically incompatible with clindamycin phosphate: ampicillin sodium, phenytoin sodium, barbiturates, aminophylline, calcium gluconate, and magnesium sulfate.

  The compatibility and duration of stability of drug admixtures will vary depending on concentration and other conditions.

  For current information regarding compatibilities of clindamycin phosphate under specific conditions, please visit www.APPpharma.com or call our medical information and safety department toll-free at 1-800-551-7176.

  Physico-Chemical Stability of Diluted Solutions of Clindamycin

  Room temperature: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.  Also 18 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, in minibags, demonstrated physical and chemical stability for at least 16 days at 25°C.

  Refrigeration: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in glass bottles or minibags, demonstrated physical and chemical stability for at least 32 days at 4°C. 

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible. 

  Frozen: 6, 9 and 12 mg/mL (equivalent to clindamycin base) in 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or Lactated Ringers Injection in minibags demonstrated physical and chemical stability for at least eight weeks at –10°C.

  Frozen solutions should be thawed at room temperature and not refrozen.

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• Caffeine Citrate Soluti...
  

  ×

  Caffeine Citrate Solution

  

  ---

  Prior to initiation of caffeine citrate oral solution, 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 oral solution should be inspected visually for particulate matter and discoloration prior to administration.  Vials containing discolored solution or visible particulate matter should be discarded.

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• Ganciclovir
  

  ×

  Ganciclovir

  

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  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 1000 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:

      1.  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 1000 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:

      1.  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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• Irinotecan Hydrochlorid...
  

  ×

  Irinotecan Hydrochloride

  

  ---

  Single-Agent Dosage Schedules

  Dosage Regimens

  Irinotecan hydrochloride injection should be administered as an intravenous infusion over 90 minutes for both the weekly and once-every-3-week dosage schedules (see Preparation of Infusion Solution). Single-agent dosage regimens are shown in Table 7.

  Table 7. Single-Agent Regimens Of Irinotecan Hydrochloride Injection And Dose Modifications aSubsequent doses may be adjusted as high as 150 mg/m2 or to as low as 50 mg/m2 in 25 to 50 mg/m2 decrements depending upon individual patient tolerance.bSubsequent doses may be adjusted as low as 200 mg/m2 in 50 mg/m2 decrements depending upon individual patient tolerance.c Provided intolerable toxicity does not develop, treatment with additional cycles may be continued indefinitely as long as patients continue to experience clinical benefit. Weekly Regimena 125 mg/m2 IV over 90 min, d 1,8,15,22 then 2-wk rest Starting Dose and Modified Dose Levelsc (mg/m2) Starting Dose Dose Level-1 Dose Level-2 125 100 75 Once-Every-3-Week Regimenb 350 mg/m2 IV over 90 min, once every 3 wksc Starting Dose and Modified Dose Levels (mg/m2) Starting Dose Dose Level-1 Dose Level-2 350 300 250

  A reduction in the starting dose by one dose level of irinotecan hydrochloride injection may be considered for patients with any of the following conditions: prior pelvic/abdominal radiotherapy, performance status of 2, or increased bilirubin levels. Dosing for patients with bilirubin >2 mg/dL cannot be recommended because there is insufficient information to recommend a dose in these patients.

  It is recommended that patients receive premedication with antiemetic agents. Prophylactic or therapeutic administration of atropine should be considered in patients experiencing cholinergic symptoms. See PRECAUTIONS, General section.

  Dose Modifications

  Patients should be carefully monitored for toxicity and doses of irinotecan hydrochloride injection should be modified as necessary to accommodate individual patient tolerance to treatment. Based on recommended dose-levels described in Table 7, Single-Agent Regimens of irinotecan hydrochloride injection and Dose Modifications, subsequent doses should be adjusted as suggested in Table 8, Recommended Dose Modifications for Single-Agent Schedules. All dose modifications should be based on the worst preceding toxicity.

  A new cycle of therapy should not begin until the toxicity has recovered to NCI grade 1 or less. Treatment may be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicity. If the patient has not recovered, consideration should be given to discontinuing this combination therapy. Provided intolerable toxicity does not develop, treatment with additional cycles of irinotecan hydrochloride injection may be continued indefinitely as long as patients continue to experience clinical benefit.

  Table 8. Recommended Dose Modifications For Single-Agent Schedulesa A new cycle of therapy should not begin until the granulocyte count has recovered to ≥1500/ mm3, and the platelet count has recovered to ≥100,000/ mm3, and treatment-related diarrhea is fully resolved. Treatment should be delayed 1 to 2 weeks to allow for recovery from treatment-related toxicities. If the patient has not recovered after a 2-week delay, consideration should be given to discontinuing irinotecan. aAll dose modifications should be based on the worst preceding toxicitybNational Cancer Institute Common Toxicity Criteria (version 1.0)cPretreatmentdExcludes alopecia, anorexia, asthenia Worst Toxicity NCI Gradeb(Value) During a Cycle of Therapy At the Start of the Next Cycles of Therapy(After Adequate Recovery), Compared withthe Starting Dose in the Previous Cyclea Weekly Weekly Once Every 3 Weeks No toxicity Maintain dose level ↑ 25 mg/m2 up to amaximum dose of150 mg/mm2 Maintain dose level Neutropenia       1 (1500 to 1999/ mm3) Maintain dose level Maintain dose level Maintain dose level 2 (1000 to 1499/ mm3) ↓ 25 mg/mm2 Maintain dose level Maintain dose level 3 (500 to 999/ mm3) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/mm2 ↓ 25 mg/mm2 ↓ 50 mg/mm2 4 (<500/ mm3) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/mm2 ↓ 50 mg/mm2   ↓ 50 mg/mm2 Neutropenic fever Omit dose until resolved, then↓ 50 mg/mm2 when resolved ↓ 50 mg/mm2 ↓ 50 mg/mm2 Other hematologictoxicities Dose modifications for leukopenia, thrombocytopenia, and anemia during a cycle of therapy and at the start of subsequent cycles of therapy are also based on NCI toxicity criteria and are the same as recommended for neutropenia above. Diarrhea       1 (2-3 stools/day > pretxc) Maintain dose level Maintain dose level Maintain dose level 2 (4-6 stools/day > pretx) ↓ 25 mg/mm2 Maintain dose level Maintain dose level 3 (7-9 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/mm2 ↓ 25 mg/mm2 ↓ 50 mg/mm2 4 (≥10 stools/day > pretx) Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/mm2 ↓ 50 mg/mm2   ↓ 50 mg/mm2 Othernonhematologicd toxicities       1 Maintain dose level Maintain dose level Maintain dose level 2 ↓ 25 mg/mm2 ↓ 25 mg/mm2 ↓ 50 mg/mm2 3 Omit dose until resolved to ≤ grade 2, then ↓ 25 mg/mm2 ↓ 25 mg/mm2   ↓ 50 mg/mm2   4 Omit dose until resolved to ≤ grade 2, then ↓ 50 mg/mm2 ↓ 50 mg/m2 ↓ 50 mg/mm2  

  Dosage in Patients with Reduced UGT1A1 Activity

  When administered as a single-agent, a reduction in the starting dose by at least one level of irinotecan hydrochloride injection should be considered for patients known to be homozygous for the UGT1A1*28 allele (see CLINICAL PHARMACOLOGY and WARNINGS sections). However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see tables 7 to 8).

  Preparation and Administration Precautions

  As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of infusion solutions prepared from irinotecan hydrochloride injection. The use of gloves is recommended. If a solution of irinotecan hydrochloride injection contacts the skin, wash the skin immediately and thoroughly with soap and water. If irinotecan hydrochloride injection contacts the mucous membranes, flush thoroughly with water.

  Several published guidelines for handling and disposal of anticancer agents are available.1-4

  Preparation of Infusion Solution

  Inspect vial contents for particulate matter and repeat inspection when drug product is withdrawn from vial into syringe.

  Irinotecan hydrochloride injection must be diluted prior to infusion. Irinotecan hydrochloride injection should be diluted in 5% Dextrose Injection, USP, (preferred) or 0.9% Sodium Chloride Injection, USP, to a final concentration range of 0.12 to 2.8 mg/mL. In most clinical trials, irinotecan hydrochloride injection was administered in 250 mL to 500 mL of 5% Dextrose Injection, USP.

  The solution is physically and chemically stable for up to 24 hours at room temperature (approximately 25°C) and in ambient fluorescent lighting. Solutions diluted in 5% Dextrose Injection, USP, and stored at refrigerated temperatures (approximately 2° to 8°C), and protected from light are physically and chemically stable for 48 hours. Refrigeration of admixtures using 0.9% Sodium Chloride Injection, USP, is not recommended due to a low and sporadic incidence of visible particulates. Freezing irinotecan hydrochloride injection and admixtures of irinotecan hydrochloride injection may result in precipitation of the drug and should be avoided. Because of possible microbial contamination during dilution, it is advisable to use the admixture prepared with 5% Dextrose Injection, USP, within 24 hours if refrigerated (2° to 8°C, 36° to 46°F). In the case of admixtures prepared with 5% Dextrose Injection, USP, or Sodium Chloride Injection, USP, the solutions should be used within 6 hours if kept at room temperature (15° to 30°C, 59° to 86°F).

  Other drugs should not be added to the infusion solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

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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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• Cefuroxime
  

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  Cefuroxime

  

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  This insert labeling is for a Pharmacy Bulk Package and is intended for preparing admixtures for intravenous infusion only.

  Dosage

  Adults: The usual adult dosage range for Cefuroxime for Injection, USP is 750 mg to 1.5 grams every 8 hours, usually for 5 to 10 days. In uncomplicated urinary tract infections, skin and skin structure infections, disseminated gonococcal infections, and uncomplicated pneumonia, a 750 mg dose every 8 hours is recommended. In severe or complicated infections, a 1.5 gram dose every 8 hours is recommended.

  In bone and joint infections, a 1.5 gram dose every 8 hours is recommended. In clinical trials, surgical intervention was performed when indicated as an adjunct to therapy with Cefuroxime for Injection, USP. A course of oral antibiotics was administered when appropriate following the completion of parenteral administration of Cefuroxime for Injection, USP.

  In life-threatening infections or infections due to less susceptible organisms, 1.5 grams every 6 hours may be required. In bacterial meningitis, the dosage should not exceed 3 grams every 8 hours. For preventive use for clean-contaminated or potentially contaminated surgical procedures, a 1.5 gram dose administered intravenously just before surgery (approximately one-half to 1 hour before the initial incision) is recommended. Thereafter, give 750 mg intravenously every 8 hours when the procedure is prolonged.

  For preventive use during open heart surgery, a 1.5 gram dose administered intravenously at the induction of anesthesia and every 12 hours thereafter for a total of 6 grams is recommended.

  Impaired Renal Function: A reduced dosage must be employed when renal function is impaired. Dosage should be determined by the degree of renal impairment and the susceptibility of the causative organism (see Table 2).

  Table 2:Dosage of Cefuroxime for Injection, USP in Adults With Reduced Renal Function * Since Cefuroxime for Injection, USP is dialyzable, patients on hemodialysis should be given a further dose at the end of the dialysis.

  Creatinine Clearance

  (mL/min) Dose Frequency >20 750 mg-1.5 grams q8h 10-20 750 mg q12h <10 750 mg q24h*

  When only serum creatinine is available, the following formula2 (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: clearance (mL/min) = Weight (kg) x (140 – age) 72 x serum creatinine (mg/dL) Females: 0.85 x male value

  NOTE: As with antibiotic therapy in general, administration of Cefuroxime for Injection, USP should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended in infections caused by Streptococcus pyogenes in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment for several weeks; and doses smaller than those indicated above should not be used. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

  Pediatric Patients Above 3 Months of Age: Administration of 50 to 100 mg/kg per day in equally divided doses every 6 to 8 hours has been successful for most infections susceptible to cefuroxime. The higher dosage of 100 mg/kg per day (not to exceed the maximum adult dosage) should be used for the more severe or serious infections.

  In bone and joint infections, 150 mg/kg per day (not to exceed the maximum adult dosage) is recommended in equally divided doses every 8 hours. In clinical trials, a course of oral antibiotics was administered to pediatric patients following the completion of parenteral administration of Cefuroxime for Injection, USP.

  In cases of bacterial meningitis, a larger dosage of Cefuroxime for Injection, USP is recommended, 200 to 240 mg/kg per day intravenously in divided doses every 6 to 8 hours.

  In pediatric patients with renal insufficiency, the frequency of dosing should be modified consistent with the recommendations for adults.

  Directions for Dispensing

  Pharmacy Bulk Package – Not for Direct Infusion: The pharmacy bulk package is for use in a pharmacy admixture service only under a laminar flow hood. Entry into the vial must be made with a sterile transfer set or other sterile dispensing device, and the contents dispensed in aliquots using aseptic technique, the closure should be penetrated only one time using a suitable sterile dispensing set; which allows measured dispensing of the contents. The use of a syringe and needle is not recommended as it may cause leakage (see DOSAGE AND ADMINISTRATION). AFTER INITIAL WITHDRAWAL USE ENTIRE CONTENTS OF VIAL PROMPTLY. ANY UNUSED PORTION MUST BE DISCARDED WITHIN 4 HOURS.

  Preparation of Solution

  Pharmacy Bulk Package – Not for Direct Infusion: This pharmacy bulk package is designed for use in the pharmacy in preparing admixtures for intravenous infusion only. Use of this product is restricted to a suitable work area, such as a laminar flow hood. The 7.5 grams pharmacy bulk package should be constituted with 77 mL of Sterile Water for Injection; each 8 mL of the resulting solution contains 750 mg of cefuroxime; 16 mL of solution contains 1.5 grams of cefuroxime (approximate cefuroxime concentration equals 95 mg/mL).

  THIS PACKAGE IS NOT TO BE DISPENSED AS A UNIT.

  Administration

  After constitution, the intent of this pharmacy bulk package is for the preparation of solutions for IV infusion only.

  Intravenous Administration: The IV route may be preferable for patients with bacterial septicemia or other severe or life-threatening infections or for patients who may be poor risks because of lowered resistance, particularly if shock is present or impending.

  For intermittent IV infusion with a Y-type administration set, dosing can be accomplished through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing Cefuroxime for Injection, USP, it is advisable to temporarily discontinue administration of any other solutions at the same site.

  For continuous IV infusion, a solution of Cefuroxime for Injection, USP may be added to an IV infusion pack containing one of the following fluids: 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 1/6 M Sodium Lactate Injection.

  Solutions of Cefuroxime for Injection, USP, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction.

  However, if concurrent therapy with Cefuroxime for Injection, USP and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

  Compatibility and Stability

  Intravenous: When the 7.5 g pharmacy bulk package is constituted as directed with Sterile Water for Injection the contents should be withdrawn without delay. However, should this not be possible, a maximum time of 4 hours from initial closure entry is permitted to complete fluid transfer operations. More dilute solutions, such as 750 mg or 1.5 g plus 100 mL of Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, also maintain satisfactory potency for 24 hours at room temperature and for 7 days under refrigeration.

  These solutions may be further diluted to concentrations of between 1 and 30 mg/mL in the following solutions and will lose not more than 10% activity for 24 hours at room temperature or for at least 7 days under refrigeration: 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; Ringer’s Injection, USP; Lactated Ringer’s Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 10% Dextrose Injection; and 10% Invert Sugar in Water for Injection.

  Unused solutions should be discarded after the time periods mentioned above.

  Cefuroxime for Injection, USP has also been found compatible for 24 hours at room temperature when admixed in IV infusion with heparin (10 and 50 U/mL) in 0.9% Sodium Chloride Injection and Potassium Chloride (10 and 40 mEq/L) in 0.9% Sodium Chloride Injection. Sodium Bicarbonate Injection, USP is not recommended for the dilution of Cefuroxime for Injection, USP.

  Frozen Stability: Constitute the 7.5 g pharmacy bulk package vial as directed for IV administration. Immediately withdraw 8 mL or 16 mL from the 7.5 g pharmacy bulk package vial and add to a minibag containing 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection and freeze. Frozen solutions are stable for 6 months when stored at -20°C. Frozen solutions should be thawed at room temperature and not refrozen. Do not force thaw by immersion in water baths or by microwave irradiation. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

  As with other cephalosporins, Cefuroxime for Injection, USP powder as well as solutions and suspensions tend to darken, depending on storage conditions, without adversely affecting product potency.

  The container may be hung by the attached bail band during dispensing of the contents.

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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/mm 3 and a platelet count of >100,000 cells/mm 3.

  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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• Xylocaine
  

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  Xylocaine

  

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  When Xylocaine 2% Jelly is used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind.

  The dosage varies and depends upon the area to be anesthetized, vascularity of the tissues, individual tolerance, and the technique of anesthesia.  The lowest dosage needed to provide effective anesthesia should be administered.  Dosages should be reduced for children and for elderly and debilitated patients.  Although the incidence of adverse effects with Xylocaine 2% Jelly is quite low, caution should be exercised, particularly when employing large amounts, since the incidence of adverse effects is directly proportional to the total dose of local anesthetic agent administered.

  For Surface Anesthesia of the Male Adult Urethra

  When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube.  The cone may be gas sterilized or cold sterilized, as preferred.  Slowly instill approximately 15 mL (300 mg of lidocaine HCl) into the urethra or until the patient has a feeling of tension.  A penile clamp is then applied for several minutes at the corona.  An additional dose of not more than 15 mL (300 mg) can be instilled for adequate anesthesia.

  Prior to sounding or cystoscopy, a penile clamp should be applied for 5 to 10 minutes to obtain adequate anesthesia.  A total dose of 30 mL (600 mg) is usually required to fill and dilate the male urethra.

  Prior to catheterization, smaller volumes of 5 to 10 mL (100 to 200 mg) are usually adequate for lubrication.

  For Surface Anesthesia of the Female Adult Urethra

  When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube.  The cone may be gas sterilized or cold sterilized, as preferred.  Slowly instill 3 to 5 mL (60 to 100 mg of lidocaine HCl) of the jelly into the urethra.  If desired, some jelly may be deposited on a cotton swab and introduced into the urethra.  In order to obtain adequate anesthesia, several minutes should be allowed prior to performing urological procedures.

  Lubrication for Endotracheal Intubation

  Apply a moderate amount of jelly to the external surface of the endotracheal tube shortly before use.  Care should be taken to avoid introducing the product into the lumen of the tube.  Do not use the jelly to lubricate endotracheal stylettes.  See WARNINGS and ADVERSE REACTIONS concerning rare reports of inner lumen occlusion.  It is also recommended that use of endotracheal tubes with dried jelly on the external surface be avoided for lack of lubricating effect.

  For Surface Anesthesia of the Male Adult Urethra

  When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube.  The cone may be gas sterilized or cold sterilized, as preferred.  Slowly instill approximately 15 mL (300 mg of lidocaine HCl) into the urethra or until the patient has a feeling of tension.  A penile clamp is then applied for several minutes at the corona.  An additional dose of not more than 15 mL (300 mg) can be instilled for adequate anesthesia.

  Prior to sounding or cystoscopy, a penile clamp should be applied for 5 to 10 minutes to obtain adequate anesthesia.  A total dose of 30 mL (600 mg) is usually required to fill and dilate the male urethra.

  Prior to catheterization, smaller volumes of 5 to 10 mL (100 to 200 mg) are usually adequate for lubrication.

  For Surface Anesthesia of the Female Adult Urethra

  When using Xylocaine 2% Jelly 30 mL tubes, sterilize the plastic cone for 5 minutes in boiling water, cool, and attach to the tube.  The cone may be gas sterilized or cold sterilized, as preferred.  Slowly instill 3 to 5 mL (60 to 100 mg of lidocaine HCl) of the jelly into the urethra.  If desired, some jelly may be deposited on a cotton swab and introduced into the urethra.  In order to obtain adequate anesthesia, several minutes should be allowed prior to performing urological procedures.

  Lubrication for Endotracheal Intubation

  Apply a moderate amount of jelly to the external surface of the endotracheal tube shortly before use.  Care should be taken to avoid introducing the product into the lumen of the tube.  Do not use the jelly to lubricate endotracheal stylettes.  See WARNINGS and ADVERSE REACTIONS concerning rare reports of inner lumen occlusion.  It is also recommended that use of endotracheal tubes with dried jelly on the external surface be avoided for lack of lubricating effect.

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• Carboplatin
  

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  Carboplatin

  

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  NOTE: Aluminum reacts with carboplatin causing precipitate formation and loss of potency, therefore, needles or intravenous sets containing aluminum parts that may come in contact with the drug must not be used for the preparation or administration of Carboplatin Injection.

  Single Agent Therapy

  Carboplatin Injection, as a single agent, has been shown to be effective in patients with recurrent ovarian carcinoma at a dosage of 360 mg/m2 IV on day 1 every 4 weeks (alternatively see Formula Dosing). In general, however, single intermittent courses of Carboplatin Injection should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Combination Therapy with Cyclophosphamide

  In the chemotherapy of advanced ovarian cancer, an effective combination for previously untreated patients consists of:

  Carboplatin Injection — 300 mg/m2 IV on day 1 every four weeks for six cycles (alternatively see Formula Dosing).

  Cyclophosphamide — 600 mg/m2 IV on day 1 every four weeks for six cycles. For directions regarding the use and administration of cyclophosphamide, please refer to its package insert (see CLINICAL STUDIES).

  Intermittent courses of Carboplatin Injection in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2000 and the platelet count is at least 100,000.

  Dose Adjustment Recommendations

  Pretreatment platelet count and performance status are important prognostic factors for severity of myelosuppression in previously treated patients.

  The suggested dose adjustments for single agent or combination therapy shown in the table below are modified from controlled trials in previously treated and untreated patients with ovarian carcinoma. Blood counts were done weekly, and the recommendations are based on the lowest post-treatment platelet or neutrophil value.

  Platelets Neutrophils Adjusted Dose *(From Prior Course) > 100,000 > 2000 125% 50 to 100,000 500 to 2000 No Adjustment < 50,000 < 500 75%

  * Percentages apply to Carboplatin Injection as a single agent or to both carboplatin and cyclophosphamide in combination. In the controlled studies, dosages were also adjusted at a lower level (50 to 60%) for severe myelosuppression. Escalations above 125% were not recommended for these studies.

  Carboplatin Injection is usually administered by an infusion lasting 15 minutes or longer. No pre- or post-treatment hydration or forced diuresis is required.

  Patients with Impaired Kidney Function

  Patients with creatinine clearance values below 60 mL/min are at increased risk of severe bone marrow suppression. In renally-impaired patients who received single agent Carboplatin Injection therapy, the incidence of severe leukopenia, neutropenia, or thrombocytopenia has been about 25% when the dosage modifications in the table below have been used.

  Baseline Creatinine    Clearance Recommended   Dose on Day 1 41 to 59 mL/min 250 mg/m2 16 to 40 mL/min 200 mg/m2

  The data available for patients with severely impaired kidney function (creatinine clearance below 15 mL/min) are too limited to permit a recommendation for treatment.

  These dosing recommendations apply to the initial course of treatment. Subsequent dosages should be adjusted according to the patient’s tolerance based on the degree of bone marrow suppression.

  Formula Dosing

  Another approach for determining the initial dose of Carboplatin Injection is the use of mathematical formulae, which are based on a patient’s pre-existing renal function or renal function and desired platelet nadir. Renal excretion is the major route of elimination for carboplatin (see CLINICAL PHARMACOLOGY). The use of dosing formulae, as compared to empirical dose calculation based on body surface area, allows compensation for patient variations in pretreatment renal function that might otherwise result in either underdosing (in patients with above average renal function) or overdosing (in patients with impaired renal function).

  A simple formula for calculating dosage, based upon a patient’s glomerular filtration rate (GFR in mL/min) and Carboplatin Injection target area under the concentration versus time curve (AUC in mg/mL•min), has been proposed by Calvert. In these studies, GFR was measured by 51Cr-EDTA clearance.

  CALVERT FORMULA FOR CARBOPLATIN DOSING Total Dose (mg) = (target AUC) × (GFR + 25) Note: With the Calvert formula, the total dose of carboplatin is calculated in mg, not mg/m2.

  The target AUC of 4 to 6 mg/mL•min using single agent Carboplatin Injection appears to provide the most appropriate dose range in previously treated patients. This study also showed a trend between the AUC of single agent Carboplatin Injection administered to previously treated patients and the likelihood of developing toxicity.

                                                             % Actual Toxicity in Previously Treated Patients     AUC (mg/mL•min)  Gr 3 or Gr 4Thrombocytopenia Gr 3 or Gr 4   Leukopenia     4 to 5  16% 13% 6 to 7 33% 34%

  Geriatric Dosing

  Because renal function is often decreased in elderly patients, formula dosing of carboplatin based on estimates of GFR should be used in elderly patients to provide predictable plasma carboplatin AUCs and thereby minimize the risk of toxicity.

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• Fluphenazine Decanoate
  

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  Fluphenazine Decanoate

  

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  Fluphenazine Decanoate Injection may be given IM or SC.  A dry syringe and needle of at least 21 gauge should be used.  Use of a wet needle or syringe may cause the solution to become cloudy.

  To begin therapy with Fluphenazine Decanoate Injection, the following regimens are suggested:

  For most patients, a dose of 12.5 to 25 mg (0.5 to 1 mL) may be given to initiate therapy.  The onset of action generally appears between 24 and 72 hours after injection and the effects of the drug on psychotic symptoms becomes significant within 48 to 96 hours.  Subsequent injections and the dosage interval are determined in accordance with the patient’s response.  When administered as maintenance therapy, a single injection may be effective in controlling schizophrenic symptoms up to four weeks or longer.  The response to a single dose has been found to last as long as six weeks in a few patients on maintenance therapy.

  It may be advisable that patients who have no history of taking phenothiazines should be treated initially with a shorter-acting form of fluphenazine before administering the decanoate to determine the patient’s response to fluphenazine and to establish appropriate dosage.  For psychotic patients who have been stabilized on a fixed daily dosage of Fluphenazine Hydrochloride Tablets, USP or Fluphenazine Hydrochloride Elixir, USP conversion of therapy from these short-acting oral forms to the long-acting Fluphenazine Decanoate Injection may be indicated.

  Appropriate dosage of Fluphenazine Decanoate Injection should be individualized for each patient and responses carefully monitored.  No precise formula can be given to convert to use of Fluphenazine Decanoate Injection; however, a controlled multicentered study,* in patients receiving oral doses from 5 to 60 mg fluphenazine hydrochloride daily, showed that 20 mg fluphenazine hydrochloride daily was equivalent to 25 mg (1 mL) of Fluphenazine Decanoate Injection every three weeks.  This represents an approximate conversion ratio of 12.5 mg (0.5 mL) of decanoate every three weeks for every 10 mg of fluphenazine hydrochloride daily.

  Once conversion to Fluphenazine Decanoate Injection is made, careful clinical monitoring of the patient and appropriate dosage adjustment should be made at the time of each injection.

  Severely agitated patients may be treated initially with a rapid-acting phenothiazine compound such as Fluphenazine Hydrochloride Injection—see Package Insert accompanying that product for complete information.  When acute symptoms have subsided, 25 mg (1 mL) of Fluphenazine Decanoate Injection may be administered; subsequent dosage is adjusted as necessary.

  ‘‘Poor risk’’ patients (those with known hypersensitivity to phenothiazines, or with disorders that predispose to undue reactions): Therapy may be initiated cautiously with oral or parenteral fluphenazine hydrochloride (see Package Inserts accompanying these products for complete information).  When the pharmacologic effects and an appropriate dosage are apparent, an equivalent dose of fluphenazine decanoate may be administered.  Subsequent dosage adjustments are made in accordance with the response of the patient.

  The optimal amount of the drug and the frequency of administration must be determined for each patient, since dosage requirements have been found to vary with clinical circumstances as well as with individual response to the drug.

  Dosage should not exceed 100 mg.  If doses greater than 50 mg are deemed necessary, the next dose and succeeding doses should be increased cautiously in increments of 12.5 mg.

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

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• Fluphenazine Hydrochlor...
  

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  Fluphenazine Hydrochloride

  

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  The average well tolerated starting dose for adult psychotic patients is 1.25 mg (0.5 mL) intramuscularly. Depending on the severity and duration of symptoms, initial total daily dosage may range from 2.5 to 10 mg and should be divided and given at six to eight hour intervals.

  The smallest amount that will produce the desired results must be carefully determined for each individual, since optimal dosage levels of this potent drug vary from patient to patient. In general, the parenteral dose for fluphenazine has been found to be approximately 1/3 to 1/2 the oral dose. Treatment may be instituted with a low initial dosage, which may be increased, if necessary, until the desired clinical effects are achieved. Dosages exceeding 10 mg daily should be used with caution.

  When symptoms are controlled, oral maintenance therapy can generally be instituted often with single daily doses. Continued treatment by the oral route, if possible, is needed to achieve maximum therapeutic benefits; further adjustments in dosage may be necessary during the course of therapy to meet the patient’s requirements.

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

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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 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, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel.

  For patients with carcinoma of the ovary, the following regimens are recommended (see CLINICAL STUDIES: Ovarian Carcinoma):

  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. In patients previously treated with chemotherapy for carcinoma of the ovary, Paclitaxel injection, USP 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):

  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 four courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used four courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma). 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 two 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:

  Reduce the dose of dexamethasone as one of the three premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel only if the neutrophil count is at least 1000 cells/mm3; Reduce the dose of subsequent courses of paclitaxel by 20% for patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer); and 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 should not be repeated until the neutrophil count is at least 1,500 cells/mm3 and the platelet count is at least 100,000 cells/mm3. Paclitaxel should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1,000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel therapy should have dosage reduced by 20% for subsequent courses of paclitaxel. 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 PHARMACOLOGYand 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 Data*

  Degree of Hepatic Impairment

  Recommended

  Paclitaxel Dose†

  TransaminaseLevels

  BilirubinLevels‡

  * These recommendations are based on dosages for patients without hepatic impairment of 135 mg/m 2 over 24 hours or 175 mg/m 2 over 3 hours; data are not available to make dose adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma). † Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance. ‡ Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to differences in clinical trial design.

  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 - 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 - 2. x ULN

  135 mg/m2

  <10 x ULN

  and

  2.01 - 5. x ULN

  90 mg/m2

  ≥10 x ULN

  or

  > 5. 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.1-4 To 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 PRECAUTIONS: Injection Site Reaction).

  Preparation for Intravenous Administration: Paclitaxel must be diluted prior to infusion. Paclitaxel 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 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 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 since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel solution.

  Stability: Unopened vials of Paclitaxel injection, USP are stable until the date indicated on the package when stored between 20 °C to 25 °C (68 °F to 77 °F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Upon refrigeration, components in the paclitaxel 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.

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

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• Heparin Lock Flush
  

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  Heparin Lock Flush

  

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  Parental drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.  Slight discoloration does not alter potency.

  Heparin Lock Flush Solution, USP is not recommended for use in the neonate (see WARNINGS).

  Maintenance of Patency of IV Devices

  To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device.  This solution should be replaced each time the device is used.  Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip.  If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, the heparin lock flush solution may be reinstilled into the device.  The device manufacturer’s instructions should be consulted for specifics concerning its use.  Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours.

  NOTE:  Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of a heparin lock set.

  Withdrawal of Blood Samples

  Heparin lock flush solution may also be used after each withdrawal of blood for laboratory tests.  When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample.

  Maintenance of Patency of IV Devices

  To prevent clot formation in a heparin lock set or central venous catheter following its proper insertion, Heparin Lock Flush Solution, USP is injected via the injection hub in a quantity sufficient to fill the entire device.  This solution should be replaced each time the device is used.  Aspirate before administering any solution via the device in order to confirm patency and location of needle or catheter tip.  If the drug to be administered is incompatible with heparin, the entire device should be flushed with normal saline before and after the medication is administered; following the second saline flush, the heparin lock flush solution may be reinstilled into the device.  The device manufacturer’s instructions should be consulted for specifics concerning its use.  Usually this dilute heparin solution will maintain anticoagulation within the device for up to 4 hours.

  NOTE:  Since repeated injections of small doses of heparin can alter tests for activated partial thromboplastin time (APTT), a baseline value for APTT should be obtained prior to insertion of a heparin lock set.

  Withdrawal of Blood Samples

  Heparin lock flush solution may also be used after each withdrawal of blood for laboratory tests.  When heparin would interfere with or alter the results of blood tests, the heparin solution should be cleared from the device by aspirating and discarding it before withdrawing the blood sample.

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• Nebupent
  

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  Nebupent

  

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  IMPORTANT: NEBUPENT MUST BE DISSOLVED ONLY IN STERILE WATER FOR INJECTION, USP. DO NOT USE SALINE SOLUTION FOR RECONSTITUTION BECAUSE THE DRUG WILL PRECIPITATE. DO NOT MIX THE NEBUPENT SOLUTION WITH ANY OTHER DRUGS. DO NOT USE THE RESPIRGARD® II NEBULIZER TO ADMINISTER A BRONCHODILATOR.

  Reconstitution

  The contents of one vial (300 mg) must be dissolved in 6 mL Sterile Water for Injection, USP. Place the entire reconstituted contents of the vial into the Respirgard® II nebulizer reservoir for administration.

  Dosage

  The recommended adult dosage of NebuPent for the prevention of Pneumocystis jiroveci pneumonia is 300 mg once every four weeks administered via the Respirgard® II nebulizer.

  The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 liters per minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 liters per minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

  Stability

  Freshly prepared solutions for aerosol use are ­recommended. After reconstitution with sterile water, the NebuPent solution is stable for 48 hours in the original vial at room temperature if protected from light.

  Reconstitution

  The contents of one vial (300 mg) must be dissolved in 6 mL Sterile Water for Injection, USP. Place the entire reconstituted contents of the vial into the Respirgard® II nebulizer reservoir for administration.

  Dosage

  The recommended adult dosage of NebuPent for the prevention of Pneumocystis jiroveci pneumonia is 300 mg once every four weeks administered via the Respirgard® II nebulizer.

  The dose should be delivered until the nebulizer chamber is empty (approximately 30 to 45 minutes). The flow rate should be 5 to 7 liters per minute from a 40 to 50 pounds per square inch (PSI) air or oxygen source. Alternatively, a 40 to 50 PSI air compressor can be used with flow limited by setting the flowmeter at 5 to 7 liters per minute or by setting the pressure at 22 to 25 PSI. Low pressure (less than 20 PSI) compressors should not be used.

  Stability

  Freshly prepared solutions for aerosol use are ­recommended. After reconstitution with sterile water, the NebuPent solution is stable for 48 hours in the original vial at room temperature if protected from light.

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• Terbutaline Sulfate
  

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  Terbutaline Sulfate

  

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  Terbutaline Sulfate Injection, USP should be used only for subcutaneous administration and not intravenous infusion.  Sterility and accurate dosing cannot be assured if the vials are not used in accordance with DOSAGE AND ADMINISTRATION.

  Discard unused portion after single patient use.

  The usual subcutaneous dose of Terbutaline Sulfate Injection, USP is 0.25 mg injected into the lateral deltoid area.  If significant clinical improvement does not occur within 15 to 30 minutes, a second dose of 0.25 mg may be administered.  If the patient then fails to respond within another 15 to 30 minutes, other therapeutic measures should be considered.  The total dose within 4 hours should not exceed 0.5 mg.

  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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• Chorionic Gonadotropin
  

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  Chorionic Gonadotropin

  

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  Intramuscular Use Only

  The dosage regimen employed in any particular case will depend upon the indication for use, the age and weight of the patient and the physician’s preference.  The following regimens have been advocated by various authorities.

  Prepubertal Cryptochidism Not Due To Anatomical Obstruction

  4,000 USP Units three times weekly for three weeks. 5,000 USP Units every second day for four injections. 15 injections of 500 to 1,000 USP Units over a period of six weeks. 500 USP Units three times weekly for four to six weeks. If this course of treatment is not successful, another is begun one month later giving 1,000 USP Units per injection.

  Selected Cases Of Hypogonadotropic Hypogonadism In Males

  500 to 1,000 USP Units three times a week for three weeks, followed by the same dose twice a week for three weeks. 4,000 USP Units three times weekly for six to nine months, following which the dosage may be reduced to 2,000 USP Units three times weekly for an additional three months.

  Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure and who has been appropriately pretreated with human menotropins (see prescribing information for menotropins for dosage and administration for that drug product).  5,000 to 10,000 USP Units one day following the last dose of menotropins.  (A dosage of 10,000 Units is recommended in the labeling for menotropins.)

  IMPORTANT: USE COMPLETELY WITHIN 60 DAYS AFTER RECONSTITUTION. REFRIGERATE AFTER RECONSTITUTION.

  Intramuscular Use Only

  The dosage regimen employed in any particular case will depend upon the indication for use, the age and weight of the patient and the physician’s preference.  The following regimens have been advocated by various authorities.

  Prepubertal Cryptochidism Not Due To Anatomical Obstruction

  4,000 USP Units three times weekly for three weeks. 5,000 USP Units every second day for four injections. 15 injections of 500 to 1,000 USP Units over a period of six weeks. 500 USP Units three times weekly for four to six weeks. If this course of treatment is not successful, another is begun one month later giving 1,000 USP Units per injection.

  Selected Cases Of Hypogonadotropic Hypogonadism In Males

  500 to 1,000 USP Units three times a week for three weeks, followed by the same dose twice a week for three weeks. 4,000 USP Units three times weekly for six to nine months, following which the dosage may be reduced to 2,000 USP Units three times weekly for an additional three months.

  Induction of ovulation and pregnancy in the anovulatory, infertile woman in whom the cause of anovulation is secondary and not due to primary ovarian failure and who has been appropriately pretreated with human menotropins (see prescribing information for menotropins for dosage and administration for that drug product).  5,000 to 10,000 USP Units one day following the last dose of menotropins.  (A dosage of 10,000 Units is recommended in the labeling for menotropins.)

  IMPORTANT: USE COMPLETELY WITHIN 60 DAYS AFTER RECONSTITUTION. REFRIGERATE AFTER RECONSTITUTION.

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• Fludarabine
  

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  Fludarabine

  

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  Usual Dose

  The recommended adult dose of Fludarabine Phosphate Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.  Each 5 day course of treatment should commence every 28 days.  Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.  Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

  A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate Injection, USP.  These include advanced age, renal insufficiency, and bone marrow impairment.  Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

  The optimal duration of treatment has not been clearly established.  It is recommended that three additional cycles of Fludarabine Phosphate Injection, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

  Renal Insufficiency

  Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine Phosphate Injection, USP.  Fludarabine Phosphate Injection, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

  Preparation of Solutions

  Fludarabine Phosphate Injection, USP: Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water for injection, q.s.; and sodium hydroxide to adjust the pH to 6.8.  The pH range for the final product is 6.0 to 7.1.  In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% dextrose injection USP or 0.9% sodium chloride USP.        

  Fludarabine Phosphate Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of initial entry.  Care must be taken to assure the sterility of prepared solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Handling and Disposal

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

  Procedures for proper handling and disposal should be considered.  Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs.  Several guidelines on this subject have been published.1–8  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Caution should be exercised in the handling of Fludarabine Phosphate Injection, USP.  The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.  If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.  Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

  Usual Dose

  The recommended adult dose of Fludarabine Phosphate Injection, USP is 25 mg/m2 administered intravenously over a period of approximately 30 minutes daily for five consecutive days.  Each 5 day course of treatment should commence every 28 days.  Dosage may be decreased or delayed based on evidence of hematologic or nonhematologic toxicity.  Physicians should consider delaying or discontinuing the drug if neurotoxicity occurs.

  A number of clinical settings may predispose to increased toxicity from Fludarabine Phosphate Injection, USP.  These include advanced age, renal insufficiency, and bone marrow impairment.  Such patients should be monitored closely for excessive toxicity and the dose modified accordingly.

  The optimal duration of treatment has not been clearly established.  It is recommended that three additional cycles of Fludarabine Phosphate Injection, USP be administered following the achievement of a maximal response and then the drug should be discontinued.

  Renal Insufficiency

  Adult patients with moderate impairment of renal function (creatinine clearance 30 to 70 mL/min/1.73 m2) should have a 20% dose reduction of Fludarabine Phosphate Injection, USP.  Fludarabine Phosphate Injection, USP should not be administered to patients with severely impaired renal function (creatinine clearance less than 30 mL/min/1.73 m2).

  Preparation of Solutions

  Fludarabine Phosphate Injection, USP: Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water for injection, q.s.; and sodium hydroxide to adjust the pH to 6.8.  The pH range for the final product is 6.0 to 7.1.  In clinical studies, the product has been diluted in 100 cc or 125 cc of 5% dextrose injection USP or 0.9% sodium chloride USP.        

  Fludarabine Phosphate Injection, USP contains no antimicrobial preservative and thus should be used within 8 hours of initial entry.  Care must be taken to assure the sterility of prepared solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

  Handling and Disposal

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

  Procedures for proper handling and disposal should be considered.  Consideration should be given to handling and disposal according to guidelines issued for cytotoxic drugs.  Several guidelines on this subject have been published.1–8  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Caution should be exercised in the handling of Fludarabine Phosphate Injection, USP.  The use of latex gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage.  If the solution contacts the skin or mucous membranes, wash thoroughly with soap and water; rinse eyes thoroughly with plain water.  Avoid exposure by inhalation or by direct contact of the skin or mucous membranes.

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• Cefuroxime
  

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  Cefuroxime

  

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  Dosage

  Adults: The usual adult dosage range for Cefuroxime for Injection, USP is 750 mg to 1.5 grams every 8 hours, usually for 5 to 10 days. In uncomplicated urinary tract infections, skin and skin structure infections, disseminated gonococcal infections, and uncomplicated pneumonia, a 750 mg dose every 8 hours is recommended. In severe or complicated infections, a 1.5 gram dose every 8 hours is recommended.

  In bone and joint infections, a 1.5 gram dose every 8 hours is recommended. In clinical trials, surgical intervention was performed when indicated as an adjunct to therapy with Cefuroxime for Injection, USP. A course of oral antibiotics was administered when appropriate following the completion of parenteral administration of Cefuroxime for Injection, USP.

  In life-threatening infections or infections due to less susceptible organisms, 1.5 grams every 6 hours may be required. In bacterial meningitis, the dosage should not exceed 3 grams every 8 hours. The recommended dosage for uncomplicated gonococcal infection is 1.5 grams given intramuscularly as a single dose at 2 different sites together with 1 gram of oral probenecid. For preventive use for clean-contaminated or potentially contaminated surgical procedures, a 1.5 gram dose administered intravenously just before surgery (approximately one-half to 1 hour before the initial incision) is recommended. Thereafter, give 750 mg intravenously or intramuscularly every 8 hours when the procedure is prolonged.

  For preventive use during open heart surgery, a 1.5 gram dose administered intravenously at the induction of anesthesia and every 12 hours thereafter for a total of 6 grams is recommended.

  Impaired Renal Function: A reduced dosage must be employed when renal function is impaired. Dosage should be determined by the degree of renal impairment and the susceptibility of the causative organism (see Table 2).

  Table 2:Dosage of Cefuroxime for Injection, USP in Adults With Reduced Renal Function * Since Cefuroxime for Injection, USP is dialyzable, patients on hemodialysis should be given a further dose at the end of the dialysis.

  Creatinine Clearance

  (mL/min) Dose Frequency >20 750 mg-1.5 grams q8h 10-20 750 mg q12h <10 750 mg q24h*

  When only serum creatinine is available, the following formula2 (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: Creatinine clearance (mL/min) = Weight (kg) x (140 – age) 72 x serum creatinine (mg/dL) Females: 0.85 x male value

  NOTE: As with antibiotic therapy in general, administration of Cefuroxime for Injection, USP should be continued for a minimum of 48 to 72 hours after the patient becomes asymptomatic or after evidence of bacterial eradication has been obtained; a minimum of 10 days of treatment is recommended in infections caused by Streptococcus pyogenes in order to guard against the risk of rheumatic fever or glomerulonephritis; frequent bacteriologic and clinical appraisal is necessary during therapy of chronic urinary tract infection and may be required for several months after therapy has been completed; persistent infections may require treatment for several weeks; and doses smaller than those indicated above should not be used. In staphylococcal and other infections involving a collection of pus, surgical drainage should be carried out where indicated.

  Pediatric Patients Above 3 Months of Age: Administration of 50 to 100 mg/kg per day in equally divided doses every 6 to 8 hours has been successful for most infections susceptible to cefuroxime. The higher dosage of 100 mg/kg per day (not to exceed the maximum adult dosage) should be used for the more severe or serious infections.

  In bone and joint infections, 150 mg/kg per day (not to exceed the maximum adult dosage) is recommended in equally divided doses every 8 hours. In clinical trials, a course of oral antibiotics was administered to pediatric patients following the completion of parenteral administration of Cefuroxime for Injection, USP.

  In cases of bacterial meningitis, a larger dosage of Cefuroxime for Injection, USP is recommended, 200 to 240 mg/kg per day intravenously in divided doses every 6 to 8 hours.

  In pediatric patients with renal insufficiency, the frequency of dosing should be modified consistent with the recommendations for adults.

  Preparation of Solution and Suspension

  The directions for preparing Cefuroxime for Injection, USP for both IV and IM use are summarized in Table 3.

  For Intramuscular Use: Each 750 mg vial of Cefuroxime for Injection, USP should be constituted with 3 mL of Sterile Water for Injection. Shake gently to disperse and withdraw completely the resulting suspension for injection.

  For Intravenous Use: Each 750 mg vial should be constituted with 8.3 mL of Sterile Water for Injection. Withdraw completely the resulting solution for injection.

  Each 1.5 gram vial should be constituted with 16 mL of Sterile Water for Injection, and the solution should be completely withdrawn for injection.

  Each 750 mg and 1.5 gram infusion bottle should be constituted with 100 mL of Sterile Water for Injection, 5% Dextrose Injection, 0.9% Sodium Chloride Injection, or any of the solutions listed under the Intravenous portion of the Compatibility and Stability section.

  Table 3: Preparation of Solution and Suspension * Note: Cefuroxime for Injection, USP is a suspension at IM concentrations. Strength

  Amount of

  Diluent to

  be Added (mL)

  Volume to be

  Withdrawn

  Approximate

  Cefuroxime

  Concentration

  (mg/mL) 750 mg Vial 3 (IM) Total* 225 750 mg Vial 8.3 (IV) Total 90 1.5 gram Vial 16 (IV) Total 90 750 mg Infusion bottle 100 (IV) - 7.5 1.5 gram Infusion bottle 100 (IV) - 15

  Administration

  After constitution, Cefuroxime for Injection, USP may be given intravenously or by deep IM injection into a large muscle mass (such as the gluteus or lateral part of the thigh). Before injecting intramuscularly, aspiration is necessary to avoid inadvertent injection into a blood vessel.

  Intravenous Administration: The IV route may be preferable for patients with bacterial septicemia or other severe or life-threatening infections or for patients who may be poor risks because of lowered resistance, particularly if shock is present or impending.

  For direct intermittent IV administration, slowly inject the solution into a vein over a period of 3 to 5 minutes or give it through the tubing system by which the patient is also receiving other IV solutions.

  For intermittent IV infusion with a Y-type administration set, dosing can be accomplished through the tubing system by which the patient may be receiving other IV solutions. However, during infusion of the solution containing Cefuroxime for Injection, USP, it is advisable to temporarily discontinue administration of any other solutions at the same site.

  For continuous IV infusion, a solution of Cefuroxime for Injection, USP may be added to an IV infusion pack containing one of the following fluids: 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 10% Dextrose Injection; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; or 1/6 M Sodium Lactate Injection.

  Solutions of Cefuroxime for Injection, USP, like those of most beta-lactam antibiotics, should not be added to solutions of aminoglycoside antibiotics because of potential interaction.

  However, if concurrent therapy with Cefuroxime for Injection, USP and an aminoglycoside is indicated, each of these antibiotics can be administered separately to the same patient.

  Compatibility and Stability

  Intramuscular: When constituted as directed with Sterile Water for Injection, suspensions of cefuroxime for IM injection maintain satisfactory potency for 24 hours at room temperature and for 48 hours under refrigeration (5°C).

  After the periods mentioned above any unused suspensions should be discarded.

  Intravenous: When the 750 mg and 1.5 g vials are constituted as directed with Sterile Water for Injection, the solutions Cefuroxime for Injection, USP for IV administration maintain satisfactory potency for 24 hours at room temperature and for 48 hours (750 mg and 1.5 g vials) under refrigeration (5°C). More dilute solutions, such as 750 mg or 1.5 g plus 100 mL of Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, also maintain satisfactory potency for 24 hours at room temperature and for 7 days under refrigeration.

  These solutions may be further diluted to concentrations of between 1 and 30 mg/mL in the following solutions and will lose not more than 10% activity for 24 hours at room temperature or for at least 7 days under refrigeration: 0.9% Sodium Chloride Injection; 1/6 M Sodium Lactate Injection; Ringer’s Injection, USP; Lactated Ringer’s Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection; 5% Dextrose Injection; 5% Dextrose and 0.45% Sodium Chloride Injection; 5% Dextrose and 0.225% Sodium Chloride Injection; 10% Dextrose Injection; and 10% Invert Sugar in Water for Injection.

  Unused solutions should be discarded after the time periods mentioned above.

  Cefuroxime for Injection, USP has also been found compatible for 24 hours at room temperature when admixed in IV infusion with heparin (10 and 50 U/mL) in 0.9% Sodium Chloride Injection and Potassium Chloride (10 and 40 mEq/L) in 0.9% Sodium Chloride Injection. Sodium Bicarbonate Injection, USP is not recommended for the dilution of Cefuroxime for Injection, USP.

  Frozen Stability: Constitute the 750 mg or 1.5 g vial as directed for IV administration in Table 3. Immediately withdraw the total contents of the 750 mg or 1.5 g vial and add to a minibag containing 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection and freeze. Frozen solutions are stable for 6 months when stored at -20°C. Frozen solutions should be thawed at room temperature and not refrozen. Do not force thaw by immersion in water baths or by microwave irradiation. Thawed solutions may be stored for up to 24 hours at room temperature or for 7 days in a refrigerator.

  Note: Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

  As with other cephalosporins, Cefuroxime for Injection, USP powder as well as solutions and suspensions tend to darken, depending on storage conditions, without adversely affecting product potency.

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• Letrozole
  

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  Letrozole

  

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  2.1 Recommended Dose

  The recommended dose of letrozole tablets, USP is one 2.5 mg tablet administered once a day, without regard to meals.

  2.2 Use in Adjuvant Treatment of Early Breast Cancer

  In the adjuvant setting, the optimal duration of treatment with letrozole is unknown. The planned duration of treatment in the study was 5 years with 73% of the patients having completed adjuvant therapy. Treatment should be discontinued at relapse [see Clinical Studies (14.1)].

  2.3 Use in Extended Adjuvant Treatment of Early Breast Cancer

  In the extended adjuvant setting, the optimal treatment duration with letrozole tablets, USP is not known. The planned duration of treatment in the study was 5 years. In the final updated analysis, conducted at a median follow-up of 62 months, the median treatment duration was 60 months. Seventy-one percent of patients were treated for at least 3 years and 58% of patients completed least 4.5 years of extended adjuvant treatment. The treatment should be discontinued at tumor relapse [see Clinical Studies (14.2)].

  2.4 Use in First and Second-Line Treatment of Advanced Breast Cancer

  In patients with advanced disease, treatment with letrozole tablets, USP should continue until tumor progression is evident. [see Clinical Studies ( 14.4 , 14.5 )]

  2.5 Use in Hepatic Impairment

  No dosage adjustment is recommended for patients with mild to moderate hepatic impairment, although letrozole tablets, USP blood concentrations were modestly increased in subjects with moderate hepatic impairment due to cirrhosis. The dose of letrozole tablets, USP in patients with cirrhosis and severe hepatic dysfunction should be reduced by 50% [see Warnings and Precautions ( 5.3 )]. The recommended dose of letrozole tablets, USP for such patients is 2.5 mg administered every other day. The effect of hepatic impairment on letrozole tablets, USP exposure in noncirrhotic cancer patients with elevated bilirubin levels has not been determined.

  2.6 Use in Renal Impairment

  No dosage adjustment is required for patients with renal impairment if creatinine clearance is ≥10 mL/min. [see Clinical Pharmacology ( 12.3 )].

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• Cefazolin
  

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  Cefazolin

  

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  After constitution, cefazolin can be administered by parenteral administration. However, the intent of this pharmacy bulk package is for the preparation of the solutions for intravenous infusion only.

  Usual Adult Dosage

  Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours

  Mild infections caused by susceptible

  gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia)* 1 gram to 1.5 grams every 6 hours

   *In rare instances, doses of up to 12 grams of cefazolin per day have been used.

  Perioperative Prophylactic Use

  To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

  a. 1 gram IV administered ½ hour to 1 hour prior to the start of surgery.

  b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV during surgery (administration modified depending on the duration of the operative procedure).

  c. 500 mg to 1 gram IV every 6 to 8 hours for 24 hours postoperatively.

  It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

  In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

  Dosage Adjustment for Patients With Reduced Renal Function

  Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialisi, see CLINICAL PHARMACOLOGY.

  Pediatric Dosage

  In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg /lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

  Pediatric Dosage Guide Weight

  25 mg/kg/day

  Divided into 3 Doses

  25 mg/kg/day

  Divided into 4 Doses lbs kg Approximate Single Dose mg/q8h

  Vol. (mL) needed with dilution of

  125 mg/mL Approximate Single Dose mg/q6h

  Vol. (mL) needed with dilution of

  125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  40 mg

  75 mg

  115 mg

  150 mg

  190 mg

  0.35 mL

  0.6 mL

  0.9 mL

  1.2 mL

  1.5 mL

  30 mg

  55 mg

  85 mg

  115 mg

  140 mg

  0.25 mL

  0.45 mL

  0.7 mL

  0.9 mL

  1.1 mL Weight

  50 mg/kg/day

  Divided into 3 Doses

  50 mg/kg/day

  Divided into 4 Doses lbs kg Approximate Single Dose mg/q8h

  Vol. (mL) needed with dilution of

  225 mg/mL Approximate Single Dose mg/q6h

  Vol. (mL) needed with dilution of

  225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  75 mg

  150 mg

  225 mg

  300 mg

  375 mg

  0.35 mL

  0.7 mL

  1 mL

  1.35 mL

  1.7 mL

  55 mg

  110 mg

  170 mg

  225 mg

  285 mg

  0.25 mL

  0.5 mL

  0.75 mL

  1 mL

  1.25 mL

  In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

  Perioperative Prophylactic Use

  To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

  a. 1 gram IV administered ½ hour to 1 hour prior to the start of surgery.

  b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV during surgery (administration modified depending on the duration of the operative procedure).

  c. 500 mg to 1 gram IV every 6 to 8 hours for 24 hours postoperatively.

  It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

  In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

  Dosage Adjustment for Patients With Reduced Renal Function

  Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialisi, see CLINICAL PHARMACOLOGY.

  Pediatric Dosage

  In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg /lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

  Pediatric Dosage Guide Weight

  25 mg/kg/day

  Divided into 3 Doses

  25 mg/kg/day

  Divided into 4 Doses lbs kg Approximate Single Dose mg/q8h

  Vol. (mL) needed with dilution of

  125 mg/mL Approximate Single Dose mg/q6h

  Vol. (mL) needed with dilution of

  125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  40 mg

  75 mg

  115 mg

  150 mg

  190 mg

  0.35 mL

  0.6 mL

  0.9 mL

  1.2 mL

  1.5 mL

  30 mg

  55 mg

  85 mg

  115 mg

  140 mg

  0.25 mL

  0.45 mL

  0.7 mL

  0.9 mL

  1.1 mL Weight

  50 mg/kg/day

  Divided into 3 Doses

  50 mg/kg/day

  Divided into 4 Doses lbs kg Approximate Single Dose mg/q8h

  Vol. (mL) needed with dilution of

  225 mg/mL Approximate Single Dose mg/q6h

  Vol. (mL) needed with dilution of

  225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  75 mg

  150 mg

  225 mg

  300 mg

  375 mg

  0.35 mL

  0.7 mL

  1 mL

  1.35 mL

  1.7 mL

  55 mg

  110 mg

  170 mg

  225 mg

  285 mg

  0.25 mL

  0.5 mL

  0.75 mL

  1 mL

  1.25 mL

  In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

  Intermittent or continuous infusion

  Intermittent or continuous infusion-Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

  Sodium Chloride Injection, USP

  5% or 10% Dextrose Injection, USP

  5% Dextrose in Lactated Ringer’s Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Lactated Ringer’s Injection, USP

  Invert Sugar 5% or 10% in Sterile Water for Injection

  Ringer’s Injection, USP

  5% Sodium Bicarbonate Injection, USP

  When diluted according to the instructions above, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C or 41°F).

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

  Intermittent or continuous infusion

  Intermittent or continuous infusion-Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

  Sodium Chloride Injection, USP

  5% or 10% Dextrose Injection, USP

  5% Dextrose in Lactated Ringer’s Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Lactated Ringer’s Injection, USP

  Invert Sugar 5% or 10% in Sterile Water for Injection

  Ringer’s Injection, USP

  5% Sodium Bicarbonate Injection, USP

  When diluted according to the instructions above, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C or 41°F).

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

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• Ceftriaxone
  

  ×

  Ceftriaxone

  

  ---

  Ceftriaxone for Injection, USP may be administered intravenously or intramuscularly. However, the intent of this pharmacy bulk package is for the preparation of solutions for intravenous infusion only. Ceftriaxone for Injection, USP should be administered intravenously by infusion over a period of 30 minutes.

  Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone for injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone for injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS).

  There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

  Neonates

  Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone (see CONTRAINDICATIONS).

  Ceftriaxone for injection is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).

  Pediatric Patients

  For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.

  For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

  For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.

  In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

  Adults

  The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve > 90% target attainment. The total daily dose should not exceed 4 grams.

  If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

  For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

  For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

  Generally, Ceftriaxone for Injection, USP therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

  When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

  No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

  Directions for Proper Use of Pharmacy Bulk Package

  The 10 gram vial should be reconstituted with 95 mL of an appropriate IV diluent in a suitable work area such as a laminar flow hood. The resulting solution will contain approximately 100 mg/mL of ceftriaxone. This closure may be penetrated only one time after reconstitution, using a suitable sterile transfer device or dispensing set which allows measured dispensing of the contents.

  The withdrawal of container contents should be accomplished without delay. However, should this not be possible, a maximum time of 4 HOURS from initial closure entry is permitted to complete fluid transfer operations.

  Unused portions of solution held longer than the recommended time periods should be discarded.

  Reconstituted Bulk Solutions Should Not Be Used For Direct Infusion.

   Transfer individual dose to appropriate intravenous solutions as soon as possible following reconstitution of the bulk package. The stability of the solution that has been transferred into a container varies according to diluent, concentration and temperature (see COMPATIBILITY AND STABILITY). Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired.

  Compatibility and Stability

  Ceftriaxone has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.

  Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

  Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result.

  Ceftriaxone solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).

  Ceftriaxone for injection sterile powder should be stored at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature] and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

  Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:

  * Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only Storage Diluent

  Room Temp.

  (25°C)

  Refrigerated

  (4°C) Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution*  2 days incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days incompatible

  The following intravenous ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

  After the indicated stability time periods, unused portions of solutions should be discarded.

  NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

  Ceftriaxone reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

  All frozen solutions of ceftriaxone for injection, including those frozen after reconstitution, should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

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• Ceftriaxone
  

  ×

  Ceftriaxone

  

  ---

  Ceftriaxone for injection may be administered intravenously or intramuscularly.

  Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection vials or to further dilute a reconstituted vial for IV administration because a precipitate can form. Precipitation of ceftriaxone-calcium can also occur when ceftriaxone for injection is mixed with calcium-containing solutions in the same IV administration line. Ceftriaxone for injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site. However, in patients other than neonates, ceftriaxone for injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS).

  There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

  Neonates

  Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection (see CONTRAINDICATIONS).

  Ceftriaxone for injection is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).

  Pediatric Patients

  For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day). The total daily dose should not exceed 2 grams.

  For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

  For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours. The total daily dose should not exceed 2 grams.

  In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams). Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended. The daily dose may be administered once a day (or in equally divided doses every 12 hours). The usual duration of therapy is 7 to 14 days.

  Adults

  The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection. For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve > 90% target attainment. The total daily dose should not exceed 4 grams.

  If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

  For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

  For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

  Generally, Ceftriaxone for Injection, USP therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared. The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

  When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

  No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

  DIRECTIONS FOR USE

  Intramuscular Administration

  Reconstitute Ceftriaxone for Injection, USP powder with the appropriate diluent (see COMPATIBILITY AND STABILITY).

  Inject diluent into vial, shake vial thoroughly to form solution. Withdraw entire contents of vial into syringe to equal total labeled dose.

  After reconstitution, each 1 mL of solution contains approximately 250 mg or 350 mg equivalent of ceftriaxone according to the amount of diluent indicated below. If required, more dilute solutions could be utilized. A 350 mg/mL concentration is not recommended for the 250 mg vial since it may not be possible to withdraw the entire contents.

  As with all intramuscular preparations, Ceftriaxone for Injection, USP should be injected well within the body of a relatively large muscle; aspiration helps to avoid unintentional injection into a blood vessel.

  Vial Dosage Size Amount of Diluent to be Added 250 mg/mL 350 mg/mL 250 mg 0.9 mL - 500 mg 1.8 mL 1.0 mL 1 g 3.6 mL 2.1 mL 2 g 7.2 mL 4.2 mL

  Intravenous Administration

  Ceftriaxone for Injection, USP should be administered intravenously by infusion over a period of 30 minutes. Concentrations between 10 mg/mL and 40 mg/mL are recommended; however, lower concentrations may be used if desired. Reconstitute vials with an appropriate IV diluent (see COMPATIBILITY AND STABILITY).

  Vial Dosage Size Amount of Diluent to be Added 250 mg 2.4 mL 500 mg 4.8 mL 1 g 9.6 mL 2 g 19.2 mL

  After reconstitution, each 1 mL of solution contains approximately 100 mg equivalent of ceftriaxone. Withdraw entire contents and dilute to the desired concentration with the appropriate IV diluent.

  Compatibility and Stability

  Ceftriaxone has been shown to be compatible with Flagyl® IV (metronidazole hydrochloride). The concentration should not exceed 5 to 7.5 mg/mL metronidazole hydrochloride with ceftriaxone 10 mg/mL as an admixture. The admixture is stable for 24 hours at room temperature only in 0.9% sodium chloride injection or 5% dextrose in water (D5W). No compatibility studies have been conducted with the Flagyl® IV RTU® (metronidazole) formulation or using other diluents. Metronidazole at concentrations greater than 8 mg/mL will precipitate. Do not refrigerate the admixture as precipitation will occur.

  Vancomycin, amsacrine, aminoglycosides, and fluconazole are physically incompatible with ceftriaxone in admixtures. When any of these drugs are to be administered concomitantly with ceftriaxone by intermittent intravenous infusion, it is recommended that they be given sequentially, with thorough flushing of the intravenous lines (with one of the compatible fluids) between the administrations.

  Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone vials or to further dilute a reconstituted vial for IV administration. Particulate formation can result.

  Ceftriaxone solutions should not be physically mixed with or piggybacked into solutions containing other antimicrobial drugs or into diluent solutions other than those listed above, due to possible incompatibility (see WARNINGS).

  Ceftriaxone for injection sterile powder should be stored at 20°-25°C (68°-77°F) [See USP Controlled Room Temperature] and protected from light. After reconstitution, protection from normal light is not necessary. The color of solutions ranges from light yellow to amber, depending on the length of storage, concentration and diluent used.

  Ceftriaxone intramuscular solutions remain stable (loss of potency less than 10%) for the following time periods.

  Diluent

  Concentration

  mg/mL Storage Room Temp. (25°C) Refrigerated (4°C) Sterile Water for Injection

  100

  250, 350

  2 days

  24 hours

  10 days

  3 days 0.9% Sodium Chloride Solution

  100

  250, 350

  2 days

  24 hours

  10 days

  3 days 5% Dextrose Solution

  100

  250, 350

  2 days

  24 hours

  10 days

  3 days

  Bacteriostatic Water +

  0.9% Benzyl Alcohol

  100

  250, 350

  24 hours

  24 hours

  10 days

  3 days 1% Lidocaine Solution (without epinephrine)

  100

  250, 350

  24 hours

  24 hours

  10 days

  3 days

  Ceftriaxone intravenous solutions, at concentrations of 10, 20 and 40 mg/mL, remain stable (loss of potency less than 10%) for the following time periods stored in glass or PVC containers:

  * Data available for 10 to 40 mg/mL concentrations in this diluent in PVC containers only Storage Diluent

  Room Temp.

  (25°C)

  Refrigerated

  (4°C) Sterile Water 2 days 10 days 0.9% Sodium Chloride Solution 2 days 10 days 5% Dextrose Solution 2 days 10 days 10% Dextrose Solution 2 days 10 days 5% Dextrose + 0.9% Sodium Chloride Solution*  2 days incompatible 5% Dextrose + 0.45% Sodium Chloride Solution 2 days incompatible

  The following intravenous Ceftriaxone solutions are stable at room temperature (25°C) for 24 hours, at concentrations between 10 mg/mL and 40 mg/mL: Sodium Lactate (PVC container), 10% Invert Sugar (glass container), 5% Sodium Bicarbonate (glass container), Freamine III (glass container), Normosol-M in 5% Dextrose (glass and PVC containers), Ionosol-B in 5% Dextrose (glass container), 5% Mannitol (glass container), 10% Mannitol (glass container).

  After the indicated stability time periods, unused portions of solutions should be discarded.

  NOTE: Parenteral drug products should be inspected visually for particulate matter before administration.

  Ceftriaxone reconstituted with 5% Dextrose or 0.9% Sodium Chloride solution at concentrations between 10 mg/mL and 40 mg/mL, and then stored in frozen state (-20°C) in PVC or polyolefin containers, remains stable for 26 weeks.

  All frozen solutions of ceftriaxone for injection, including those frozen after reconstitution, should be thawed at room temperature before use. After thawing, unused portions should be discarded. DO NOT REFREEZE.

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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 1 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 2) 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:

  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 2.

  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 2).

  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 1 - 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 3-4 grams 1 gram every 6-8 hours IV Moderately severe or severe infections 6-8 grams

  1 gram every 4 hours

  or

  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 2 - Maintenance Dosage of Cefoxitin for Injection in Adults with Reduced Renal Function

  Renal Function

  Creatinine

  Clearance

  (mL/min)

  Dose

  (grams) Frequency

  Mild impairment

  Moderate impairment

  Severe impairment

  Essentially no function

  50-30

  29-10

  9-5

  <5

  1-2

  1-2

  0.5-1

  0.5-1

  every 8-12 hours

  every 12-24 hours

  every 12-24 hours

  every 24-48 hours

  Table 3 - Preparation of Solution for Intravenous Administration

  Strength Amount of Diluent to be Added (mL)**

  Approximate

  Withdrawable

  Volume (mL)

  Approximate Average

  Concentration

  (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 3 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 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, 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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• Sumatriptan Succinate
  

  ×

  Sumatriptan Succinate

  

  ---

  The maximum single recommended adult dose of sumatriptan succinate injection is 6 mg injected subcutaneously.  If side effects are dose limiting, then lower doses may be used (see Table 1).

  The maximum recommended dose that may be given in 24 hours is two 6-mg injections separated by at least 1 hour.  Controlled clinical trials have failed to show that clear benefit is associated with the administration of a second 6-mg dose in patients who have failed to respond to a first injection.

  In patients receiving MAO inhibitors, decreased doses of sumatriptan should be considered (see WARNINGS: Concomitant Drug Use and CLINICAL PHARMACOLOGY: Drug Interactions, Monoamine Oxidase Inhibitors).

  Since the injection is intended to be given subcutaneously, intramuscular or intravascular delivery should be avoided.  Patients should be directed to use injection sites with an adequate skin and subcutaneous thickness to accommodate the length of the needle.

  In patients receiving doses other than 4 or 6 mg, only the 6-mg single-dose vial dosage form should be used.  Parenteral drug products should be inspected visually for particulate matter and discoloration before administration whenever solution and container permit.

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• Nafcillin
  

  ×

  Nafcillin

  

  ---

  Nafcillin for Injection is available for intramuscular and intravenous use.  The penicillinase-resistant penicillins are available for oral administration and for intramuscular and intravenous injection.  The sodium salts of methicillin, oxacillin, and nafcillin may be administered parenterally and the sodium salts of cloxacillin, dicloxacillin, oxacillin, and nafcillin are available for oral use.  The usual IV dosage for adults is 500 mg every 4 hours.  For severe infections, 1 g every 4 hours is recommended.  Administer slowly over at least 30 to 60 minutes to minimize the risk of vein irritation and extravasation. 

  RECOMMENDED DOSAGE FOR NAFCILLIN FOR INJECTION, USP

  Drug

  Adults

  Infants and Children <40 kg

  (88 lbs)

  Other Recommendations

  Nafcillin

  500 mg IM

  every 4 to 6 hours

  IV every 4 hours

  25 mg/kg IM

  twice daily

  Neonates 10 mg/kg IM

  twice daily

  Nafcillin

  1 gram IM or IV

  every 4 hours.

  (severe infections)

   

   

  Bacteriologic studies to determine the causative organisms and their susceptibility to nafcillin should always be performed.  Duration of therapy varies with the type and severity of infection as well as the overall condition of the patient; therefore, it should be determined by the clinical and bacteriological response of the patient.  In severe staphylococcal infections, therapy with nafcillin should be continued for at least 14 days.  Therapy should be continued for at least 48 hours after the patient has become afebrile, asymptomatic, and cultures are negative.  The treatment of endocarditis and osteomyelitis may require a longer duration of therapy.

  Concurrent administration of the penicillinase-resistant penicillins and probenecid increases and prolongs serum penicillin levels.  Probenecid decreases the apparent volume of distribution and slows the rate of excretion by competitively inhibiting renal tubular secretion of penicillin.  Nafcillin-probenecid therapy is generally limited to those infections where very high serum levels of nafcillin are necessary. 

  Oral preparations of the penicillinase-resistant penicillins should not be used as initial therapy in serious life-threatening infections (see PRECAUTIONS, General).  Oral therapy with the penicillinase-resistant penicillins may be used to follow-up the previous use of a parenteral agent as soon as the clinical condition warrants.  For intramuscular gluteal injections, care should be taken to avoid sciatic nerve injury.  With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.

  No dosage alterations are necessary for patients with renal dysfunction, including those on hemodialysis. Hemodialysis does not accelerate nafcillin clearance from the blood.

  For patients with hepatic insufficiency and renal failure, measurement of nafcillin serum levels should be performed and dosage adjusted accordingly.

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

  Do not add supplementary medication to Nafcillin.

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• Cefazolin
  

  ×

  Cefazolin

  

  ---

  Usual Adult Dosage:

  Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life threatening infections (e.g., endocarditis, septicemia)* 1 gram to 1.5 grams every 6 hours

   *In rare instances, doses of up to 12 grams of cefazolin per day have been used.

  Perioperative Prophylactic Use

  To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are:

  a. 1 gram IV or IM administered one half to 1 hour prior to the start of surgery.

  b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).

  c. 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

  It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

  In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

  Dosage Adjustment for Patients with Reduced Renal Function

  Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis, see CLINICAL PHARMACOLOGY.

  Pediatric Dosage

  In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

  Pediatric Dosage Guide

  Weight 25 mg/kg/day Divided into 3 Doses lbs kg

  Approximate Single Dose

  mg/q8h Vol (mL) needed with dilution of 125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  40 mg

  75 mg

  115 mg

  150 mg

  190 mg

  0.35 mL

  0.6 mL

  0.9 mL

  1.2 mL

  1.5 mL Weight 25 mg/kg/day Divided into 4 Doses lbs kg

  Approximate Single Dose

  mg/q6h Vol (mL) needed with dilution of 125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  30 mg

  55 mg

  85 mg

  115 mg

  140 mg

  0.25 mL

  0.45 mL

  0.7 mL

  0.9 mL

  1.1 mL Weight 50 mg/kg/day Divided into 3 Doses lbs kg

  Approximate Single Dose

  mg/q8h Vol (mL) needed with dilution of 225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  75 mg

  150 mg

  225 mg

  300 mg

  375 mg

  0.35 mL

  0.7 mL

  1 mL

  1.35 mL

  1.7 mL Weight 50 mg/kg/day Divided into 4 Doses lbs kg

  Approximate Single Dose

  mg/q6h Vol (mL) needed with dilution of 225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  55 mg

  110 mg

  170 mg

  225 mg

  285 mg

  0.25 mL

  0.5 mL

  0.75 mL

  1 mL

  1.25 mL

   

  In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

  Perioperative Prophylactic Use

  To prevent postoperative infection in contaminated or potentially contaminated surgery, the recommended doses are:

  a. 1 gram IV or IM administered one half to 1 hour prior to the start of surgery.

  b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV or IM during surgery (administration modified depending on the duration of the operative procedure).

  c. 500 mg to 1 gram IV or IM every 6 to 8 hours for 24 hours postoperatively.

  It is important that (1) the preoperative dose be given just prior (one half to 1 hour) to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision and (2) cefazolin be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

  In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

  Dosage Adjustment for Patients with Reduced Renal Function

  Cefazolin may be used in patients with reduced renal function with the following dosage adjustments. Patients with a creatinine clearance of 55 mL/min or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min or serum creatinine of 3.1 to 4.5 mg % should be given one half the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min or less or serum creatinine of 4.6 mg % or greater should be given one half the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis, see CLINICAL PHARMACOLOGY.

  Pediatric Dosage

  In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

  Pediatric Dosage Guide

  Weight 25 mg/kg/day Divided into 3 Doses lbs kg

  Approximate Single Dose

  mg/q8h Vol (mL) needed with dilution of 125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  40 mg

  75 mg

  115 mg

  150 mg

  190 mg

  0.35 mL

  0.6 mL

  0.9 mL

  1.2 mL

  1.5 mL Weight 25 mg/kg/day Divided into 4 Doses lbs kg

  Approximate Single Dose

  mg/q6h Vol (mL) needed with dilution of 125 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  30 mg

  55 mg

  85 mg

  115 mg

  140 mg

  0.25 mL

  0.45 mL

  0.7 mL

  0.9 mL

  1.1 mL Weight 50 mg/kg/day Divided into 3 Doses lbs kg

  Approximate Single Dose

  mg/q8h Vol (mL) needed with dilution of 225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  75 mg

  150 mg

  225 mg

  300 mg

  375 mg

  0.35 mL

  0.7 mL

  1 mL

  1.35 mL

  1.7 mL Weight 50 mg/kg/day Divided into 4 Doses lbs kg

  Approximate Single Dose

  mg/q6h Vol (mL) needed with dilution of 225 mg/mL

  10

  20

  30

  40

  50

  4.5

  9

  13.6

  18.1

  22.7

  55 mg

  110 mg

  170 mg

  225 mg

  285 mg

  0.25 mL

  0.5 mL

  0.75 mL

  1 mL

  1.25 mL

   

  In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min), 60% of the normal daily dosage given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min), 25% of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min) may be given 10% of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

  Intramuscular Administration

  Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. Cefazolin for Injection, USP should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection, USP.

  Intravenous Administration

  Direct (bolus) injection–Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below).

  Intermittent or continuous infusion–Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

  Sodium Chloride Injection, USP

  5% or 10% Dextrose Injection, USP

  5% Dextrose in Lactated Ringer’s Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Lactated Ringer’s Injection, USP

  Invert Sugar 5% or 10% in Sterile Water for Injection

  Ringer’s Injection, USP

  5% Sodium Bicarbonate Injection, USP

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

  Intramuscular Administration

  Reconstitute vials with Sterile Water for Injection according to the dilution table above. Shake well until dissolved. Cefazolin for Injection, USP should be injected into a large muscle mass. Pain on injection is infrequent with Cefazolin for Injection, USP.

  Intravenous Administration

  Direct (bolus) injection–Following reconstitution according to the above table, further dilute vials with approximately 5 mL Sterile Water for Injection. Inject the solution slowly over 3 to 5 minutes, directly or through tubing for patients receiving parenteral fluids (see list below).

  Intermittent or continuous infusion–Dilute reconstituted Cefazolin for Injection, USP in 50 to 100 mL of one of the following solutions:

  Sodium Chloride Injection, USP

  5% or 10% Dextrose Injection, USP

  5% Dextrose in Lactated Ringer’s Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Lactated Ringer’s Injection, USP

  Invert Sugar 5% or 10% in Sterile Water for Injection

  Ringer’s Injection, USP

  5% Sodium Bicarbonate Injection, USP

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

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• Sodium Acetate
  

  ×

  Sodium Acetate

  

  ---

  Sodium acetate 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 sodium 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 IV fluids to provide any desired number of milliequivalents (mEq) of sodium with an equal number of acetate.

  Pharmacy bulk packages are for use in a pharmacy admixture service only in a laminar flow hood.  They should be inserted into the ring sling (plastic hanging device) provided and suspended as a unit in the laminar flow hood.  The container closure should be penetrated only one time utilizing a suitable sterile dispensing set which allows measured distribution of the contents.  Swab vial stopper with an antiseptic solution.  Insert the dispensing set into the vial using aseptic technique.  (See graphic illustration below.)

    

  Once the sterile dispensing set has been inserted into the container, withdrawal of the contents should be accomplished without delay.  However, if this is not possible, a maximum time of 4 hours from the initial entry may be allowed to complete fluid aliquoting/transferring operations. Discard the container no later than 4 hours after initial closure puncture.

  Do not administer unless solution is clear and seal is intact.

  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
  

  ×

  Tobramycin

  

  ---

  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 injection, USP, (Pediatric).

  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.

  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.

  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 should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

  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 injection, USP, (Pediatric).

  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.

  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.

  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 should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.

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• Folic Acid
  

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  Folic Acid

  

  ---

  Parenteral Administration: IM, IV and SC routes may be used if the disease is exceptionally severe or if gastrointestinal absorption may be, or is known to be, impaired.

  Usual Therapeutic Dosage—In adults and children (regardless of age): up to 1 mg daily.Resistant cases may require larger doses.

  Maintenance Level: When clinical symptoms have subsided and the blood picture has become normal, a maintenance level should be used, i.e., 0.1 mg for infants and up to 0.3 mg for children under four years of age, 0.4 mg for adults and children four or more years of age and 0.8 mg for pregnant and lactating women, per day, but never less than 0.1 mg per day. Patient should be kept under close supervision and adjustment of the maintenance level made if relapse appears imminent.

  In the presence of alcoholism, hemolytic anemia, anticonvulsant therapy or chronic infection, the maintenance level may need to be increased.

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

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• Anastrozole
  

  ×

  Anastrozole

  

  ---

  2.1 Recommended Dose

        The dose of anastrozole is one 1 mg tablet taken once a day. For patients with advanced breast cancer, anastrozole tablets 1 mg should be continued until tumor progression. Anastrozole tablets 1 mg can be taken with or without food.         For adjuvant treatment of early breast cancer in postmenopausal women, the optimal duration of therapy is unknown. In the ATAC trial, anastrozole tablets 1 mg were administered for five years [see Clinical Studies (14.1)].        No dosage adjustment is necessary for patients with renal impairment or for elderly patients [see Use in Specific Populations (8.6)].

  2.2 Patients with Hepatic Impairment

        No changes in dose are recommended for patients with mild-to-moderate hepatic impairment. Anastrozole tablets have not been studied in patients with severe hepatic impairment [see Use in Specific Populations (8.7)].

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• Bacitracin
  

  ×

  Bacitracin

  

  ---

  TO BE ADMINISTERED INTRAMUSCULARLY ONLY

  Infant dose

  For infants under 2500 grams - 900 units/kg/24 hours, in 2 or 3 divided doses.  For infants over 2500 grams - 1,000 units/kg/24 hours, in 2 or 3 divided doses.  Intramuscular injections of the solution should be given in the upper outer quadrant of the buttocks, alternating right and left and avoiding multiple injections in the same region because of the transient pain following injection.

  Preparation of Solutions

  Should be dissolved in sodium chloride injection containing 2 percent procaine hydrochloride.  The concentration of the antibiotic in the solution should not be less than 5,000 units per mL nor more than 10,000 units per mL.

  Diluents containing parabens should not be used to reconstitute bacitracin; cloudy solutions and precipitate formation have occurred.

  Reconstitution of the 50,000 unit vial with 9.8 mL of diluent will result in a concentration of 5,000 units per mL.

  Solutions are stable for one week when stored in a refrigerator 2° to 8°C (36° to 46°F).

  Infant dose

  For infants under 2500 grams - 900 units/kg/24 hours, in 2 or 3 divided doses.  For infants over 2500 grams - 1,000 units/kg/24 hours, in 2 or 3 divided doses.  Intramuscular injections of the solution should be given in the upper outer quadrant of the buttocks, alternating right and left and avoiding multiple injections in the same region because of the transient pain following injection.

  Preparation of Solutions

  Should be dissolved in sodium chloride injection containing 2 percent procaine hydrochloride.  The concentration of the antibiotic in the solution should not be less than 5,000 units per mL nor more than 10,000 units per mL.

  Diluents containing parabens should not be used to reconstitute bacitracin; cloudy solutions and precipitate formation have occurred.

  Reconstitution of the 50,000 unit vial with 9.8 mL of diluent will result in a concentration of 5,000 units per mL.

  Solutions are stable for one week when stored in a refrigerator 2° to 8°C (36° to 46°F).

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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

  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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• Gemcitabine Hydrochlori...
  

  ×

  Gemcitabine Hydrochloride

  

  ---

  Gemcitabine for Injection is for intravenous use only.  Gemcitabine may be administered on an outpatient basis.

  2.1 Ovarian Cancer

  Gemcitabine for Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.  Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts.  Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle. 

  Dose Modifications

  Gemcitabine for Injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy.  If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.  

  Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin

  Absolute granulocyte count

  (x 106/L)

  Platelet count

  (x 106/L)

  % of full dose

   ≥ 1500

  And

    ≥ 100,000

  100

  1000 to 1499

  and/or

  75,000 to 99,999

  50

  <1000

  and/or

  <75,000

  Hold

  In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician.  For carboplatin dosage adjustment, see manufacturer’s prescribing information.

  Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity.  The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:  

               •   Absolute granulocyte count <500 x 106/L for more than 5 days

               •   Absolute granulocyte count <100 x 106/L for more than 3 days

               •   Febrile neutropenia

               •   Platelets <25,000 x 106/L

               •   Cycle delay of more than one week due to toxicity

  If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m2.

  2.2 Breast Cancer

  Gemcitabine for Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.  Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine administration.  Patients should be monitored prior to each dose with a complete blood count, including differential counts.  Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle. 

  Dose Modifications

  Gemcitabine dosage adjustments for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy.  If marrow suppression is detected, gemcitabine dosage should be modified according to the guidelines in Table 2.

  Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with Paclitaxel

  Absolute granulocyte count

  (x 106/L)

  Platelet count

  (x 106/L)

  % of full dose

  ≥ 1200

  And

  > 75,000

  100

  1000 to 1199

  Or

  50,000 to 75,000

  75

  700 to 999

  And

  ≥ 50,000

  50

  < 700

  Or

  < 50,000

  Hold

  In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician.  For paclitaxel dosage adjustment, see manufacturer’s prescribing information.

  2.3 Non-Small Cell Lung Cancer

  Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, gemcitabine should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle.  Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine.  With the 3-week schedule, gemcitabine should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of gemcitabine on Day 1.  See prescribing information for cisplatin administration and hydration guidelines. 

  Dose Modifications

  Dosage adjustments for hematologic toxicity may be required for gemcitabine and for cisplatin.  Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts.  If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.  For cisplatin dosage adjustment, see manufacturer’s prescribing information.

  In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician.  During combination therapy with  cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin alone). 

  2.4 Pancreatic Cancer

  Gemcitabine for Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment.  Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

  Dose Modifications

  Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count.  If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.

  Table 3: Dosage Reduction Guidelines

  Absolute granulocyte count

  (x 106/L)

  Platelet count

  (x 106/L)

  % of full dose

  ≥ 1000

  And

  ≥ 100,000

  100

  500 to 999

  Or

  50,000 to 99,999

  75

  < 500

  Or

  < 50,000

  Hold

  Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter.  Gemcitabine for Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. 

  Patients treated with gemcitabine who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 106/L and 100,000 x 106/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1.  If patients tolerate the subsequent course of gemcitabine at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x106/L and 100,000 x 106/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

  2.5 Preparation and Administration Precautions

  Caution should be exercised in handling and preparing gemcitabine solutions.  The use of gloves is recommended.  If gemcitabine solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.

  Procedures for proper handling and disposal of anti-cancer drugs should be considered.  Several guidelines on this subject have been published [see References (15)].

  2.6 Preparation for Intravenous Infusion Administration

  The recommended diluent for reconstitution of gemcitabine is 0.9% Sodium Chloride Injection without preservatives.  Due to solubility considerations, the maximum concentration for gemcitabine upon reconstitution is 40 mg/mL.  Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.

  To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200 mg vial, 25 mL of 0.9% Sodium Chloride Injection to the 1g vial or 50 mL of 0.9 % Sodium Chloride Injection to the 2 gram vial.  Shake to dissolve.  These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200 mg vial, 1.3 mL for the 1g vial or 2.6 mL for the 2 gram vial).  The total volume upon reconstitution will be 5.26 mL, 26.3 mL or 52.6 mL, respectively.  Complete withdrawal of the vial contents will provide 200 mg, 1 g or 2 grams of gemcitabine, respectively.  Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. 

  Reconstituted gemcitabine is a clear, colorless to light straw-colored solution.  After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3.  The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit.  If particulate matter or discoloration is found, do not administer. 

  When prepared as directed, gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].  Discard unused portion.  Solutions of reconstituted gemcitabine should not be refrigerated, as crystallization may occur.

  The compatibility of gemcitabine with other drugs has not been studied.  No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

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• Pamidronate Disodium
  

  ×

  Pamidronate Disodium

  

  ---

  Hypercalcemia of Malignancy

  Consideration should be given to the severity of as well as the symptoms of hypercalcemia.  Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia.  Overhydration should be avoided in patients who have potential for cardiac failure.  In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful.

  Moderate Hypercalcemia

  The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium* of approximately 12 to 13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours.  Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  Severe Hypercalcemia

  The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours.  Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  _______________________

  *Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL).

  Retreatment

  A limited number of patients have received more than one treatment with pamidronate disodium for hypercalcemia.  Retreatment with pamidronate disodium, in patients who show complete or partial response initially, may be carried out 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.  The dose and manner of retreatment is identical to that of the initial therapy.

  Paget's Disease

  The recommended dose of pamidronate disodium in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.

  Retreatment

  A limited number of patients with Paget’s disease have received more than one treatment of pamidronate disodium in clinical trials.  When clinically indicated, patients should be retreated at the dose of initial therapy.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of pamidronate disodium in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.

  Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium infusion.

  Limited information is available on the use of pamidronate disodium in multiple myeloma patients with a serum creatinine ≥ 3 mg/dL.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment.  Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

     • For patients with normal baseline creatinine, increase of 0.5 mg/dL.

     • For patients with abnormal baseline creatinine, increase of 1 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits (see Clinical Trials).

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of pamidronate disodium in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

  Pamidronate disodium has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen.  It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment.  Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

     • For patients with normal baseline creatinine, increase of 0.5 mg/dL.

     • For patients with abnormal baseline creatinine, increase of 1 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits (see Clinical Trials).

  Calcium and Vitamin D Supplementation

  In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia.

  Preparation of Infusion

  Method of Administration

  DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF PAMIDRONATE DISODIUM SHOULD NOT EXCEED 90 MG (see WARNINGS).

  There must be strict adherence to the intravenous administration recommendations for pamidronate disodium in order to decrease the risk of deterioration in renal function.

  Hypercalcemia of Malignancy

  The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60 mg dose and the 90 mg doses.  The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.  This infusion solution is stable for up to 24 hours at room temperature.

  Paget’s Disease

  The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive days.

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3 to 4 weeks.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.

  Pamidronate disodium must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and should be given in a single intravenous solution and line separate from all other drugs.

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

  Hypercalcemia of Malignancy

  Consideration should be given to the severity of as well as the symptoms of hypercalcemia.  Vigorous saline hydration alone may be sufficient for treating mild, asymptomatic hypercalcemia.  Overhydration should be avoided in patients who have potential for cardiac failure.  In hypercalcemia associated with hematologic malignancies, the use of glucocorticoid therapy may be helpful.

  Moderate Hypercalcemia

  The recommended dose of pamidronate disodium in moderate hypercalcemia (corrected serum calcium* of approximately 12 to 13.5 mg/dL) is 60 to 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours.  Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  Severe Hypercalcemia

  The recommended dose of pamidronate disodium in severe hypercalcemia (corrected serum calcium* >13.5 mg/dL) is 90 mg given as a SINGLE-DOSE, intravenous infusion over 2 to 24 hours.  Longer infusions (i.e., >2 hours) may reduce the risk for renal toxicity, particularly in patients with preexisting renal insufficiency.

  _______________________

  *Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4-serum albumin, g/dL).

  Retreatment

  A limited number of patients have received more than one treatment with pamidronate disodium for hypercalcemia.  Retreatment with pamidronate disodium, in patients who show complete or partial response initially, may be carried out 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.  The dose and manner of retreatment is identical to that of the initial therapy.

  Paget's Disease

  The recommended dose of pamidronate disodium in patients with moderate to severe Paget’s disease of bone is 30 mg daily, administered as a 4-hour infusion on 3 consecutive days for a total dose of 90 mg.

  Retreatment

  A limited number of patients with Paget’s disease have received more than one treatment of pamidronate disodium in clinical trials.  When clinically indicated, patients should be retreated at the dose of initial therapy.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of pamidronate disodium in patients with osteolytic bone lesions of multiple myeloma is 90 mg administered as a 4-hour infusion given on a monthly basis.

  Patients with marked Bence-Jones proteinuria and dehydration should receive adequate hydration prior to pamidronate disodium infusion.

  Limited information is available on the use of pamidronate disodium in multiple myeloma patients with a serum creatinine ≥ 3 mg/dL.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment.  Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

     • For patients with normal baseline creatinine, increase of 0.5 mg/dL.

     • For patients with abnormal baseline creatinine, increase of 1 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not yet known, however, in a study of patients with myeloma, final analysis after 21 months demonstrated overall benefits (see Clinical Trials).

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of pamidronate disodium in patients with osteolytic bone metastases is 90 mg administered over a 2-hour infusion given every 3 to 4 weeks.

  Pamidronate disodium has been frequently used with doxorubicin, fluorouracil, cyclophosphamide, methotrexate, mitoxantrone, vinblastine, dexamethasone, prednisone, melphalan, vincristine, megesterol, and tamoxifen.  It has been given less frequently with etoposide, cisplatin, cytarabine, paclitaxel, and aminoglutethimide.

  Patients who receive pamidronate disodium should have serum creatinine assessed prior to each treatment.  Treatment should be withheld for renal deterioration. In a clinical study, renal deterioration was defined as follows:

     • For patients with normal baseline creatinine, increase of 0.5 mg/dL.

     • For patients with abnormal baseline creatinine, increase of 1 mg/dL.

  In this clinical study, pamidronate disodium treatment was resumed only when the creatinine returned to within 10% of the baseline value.

  The optimal duration of therapy is not known, however, in two breast cancer studies, final analyses performed after 24 months of therapy demonstrated overall benefits (see Clinical Trials).

  Calcium and Vitamin D Supplementation

  In the absence of hypercalcemia, patients with predominantly lytic bone metastases or multiple myeloma, who are at risk of calcium or vitamin D deficiency, and patients with Paget’s disease of the bone, should be given oral calcium and vitamin D supplementation in order to minimize the risk of hypocalcemia.

  Preparation of Infusion

  Method of Administration

  DUE TO THE RISK OF CLINICALLY SIGNIFICANT DETERIORATION IN RENAL FUNCTION, WHICH MAY PROGRESS TO RENAL FAILURE, SINGLE DOSES OF PAMIDRONATE DISODIUM SHOULD NOT EXCEED 90 MG (see WARNINGS).

  There must be strict adherence to the intravenous administration recommendations for pamidronate disodium in order to decrease the risk of deterioration in renal function.

  Hypercalcemia of Malignancy

  The daily dose must be administered as an intravenous infusion over at least 2 to 24 hours for the 60 mg dose and the 90 mg doses.  The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP.  This infusion solution is stable for up to 24 hours at room temperature.

  Paget’s Disease

  The recommended daily dose of 30 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period for 3 consecutive days.

  Osteolytic Bone Metastases of Breast Cancer

  The recommended dose of 90 mg should be diluted in 250 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 2-hour period every 3 to 4 weeks.

  Osteolytic Bone Lesions of Multiple Myeloma

  The recommended dose of 90 mg should be diluted in 500 mL of sterile 0.45% or 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, and administered over a 4-hour period on a monthly basis.

  Pamidronate disodium must not be mixed with calcium-containing infusion solutions, such as Ringer’s solution, and should be given in a single intravenous solution and line separate from all other drugs.

  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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• Famotidine
  

  ×

  Famotidine

  

  ---

  In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine injection may be administered until oral therapy can be instituted.

  The recommended dosage for famotidine injection in adult patients is 20 mg intravenously q 12 h.

  The doses and regimen for parenteral administration in patients with GERD have not been established.

  Dosage for Pediatric Patients

  See PRECAUTIONS, Pediatric Use.

  The studies described in PRECAUTIONS, Pediatric Use suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

  While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.  Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy.  Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

  No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.

  Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency

  In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased.  For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients.  Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response.

  Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

  Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

  The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient.  The recommended adult intravenous dose is 20 mg q 12 h. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated.  In some patients, a higher starting dose may be required.  Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

  Preparation of Intravenous Solutions

  To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability), to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.

  To prepare famotidine intravenous infusion solutions, aseptically dilute 2 mL of famotidine injection with 100 mL of 5% dextrose or other compatible solution (see Stability), and infuse over a 15 to 30 minute period.

  Concomitant Use of Antacids

  Antacids may be given concomitantly if needed.

  Stability

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

  When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer’s Injection, diluted famotidine injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.

  When added to or diluted with Sodium Bicarbonate Injection, 5%, famotidine injection at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.  However, a precipitate may form at higher concentrations of famotidine injection (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.

  Dosage for Pediatric Patients

  See PRECAUTIONS, Pediatric Use.

  The studies described in PRECAUTIONS, Pediatric Use suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

  While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.  Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy.  Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

  No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.

  Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency

  In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased.  For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients.  Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response.

  Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

  Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

  The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient.  The recommended adult intravenous dose is 20 mg q 12 h. Doses should be adjusted to individual patient needs and should continue as long as clinically indicated.  In some patients, a higher starting dose may be required.  Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

  Preparation of Intravenous Solutions

  To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability), to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.

  To prepare famotidine intravenous infusion solutions, aseptically dilute 2 mL of famotidine injection with 100 mL of 5% dextrose or other compatible solution (see Stability), and infuse over a 15 to 30 minute period.

  Concomitant Use of Antacids

  Antacids may be given concomitantly if needed.

  Stability

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

  When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer’s Injection, diluted famotidine injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.

  When added to or diluted with Sodium Bicarbonate Injection, 5%, famotidine injection at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.  However, a precipitate may form at higher concentrations of famotidine injection (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.

  Close
  More Info
• Famotidine
  

  ×

  Famotidine

  

  ---

  In some hospitalized patients with pathological hypersecretory conditions or intractable ulcers, or in patients who are unable to take oral medication, famotidine injection may be administered until oral therapy can be instituted.

  The recommended dosage for famotidine injection in adult patients is 20 mg intravenously q 12 h.

  The doses and regimen for parenteral administration in patients with GERD have not been established.

  Dosage for Pediatric Patients

  See PRECAUTIONS, Pediatric Use.

  The studies described in PRECAUTIONS, Pediatric Use suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

  While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.  Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy.  Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

  No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.

  Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency

  In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased.  For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients.  Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response.

  Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

  Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

  The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient.  The recommended adult intravenous dose is 20 mg q 12 h.  Doses should be adjusted to individual patient needs and should continue as long as clinically indicated.  In some patients, a higher starting dose may be required.  Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

  Preparation of Intravenous Solutions

  To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability), to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.

  To prepare famotidine intravenous infusion solutions, aseptically dilute 2 mL of famotidine injection with 100 mL of 5% dextrose or other compatible solution (see Stability), and infuse over a 15 to 30 minute period.

  Concomitant Use of Antacids

  Antacids may be given concomitantly if needed.

  Stability

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

  When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer’s Injection, diluted famotidine injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.

  When added to or diluted with Sodium Bicarbonate Injection, 5%, famotidine injection at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see  HOW SUPPLIED, Storage.  However, a precipitate may form at higher concentrations of famotidine injection (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.

  Dosage for Pediatric Patients

  See PRECAUTIONS, Pediatric Use.

  The studies described in PRECAUTIONS, Pediatric Use suggest that the starting dose in pediatric patients 1 to 16 years of age is 0.25 mg/kg intravenously (injected over a period of not less than two minutes or as a 15 minute infusion) q 12 h up to 40 mg/day.

  While published uncontrolled clinical studies suggest effectiveness of famotidine in the treatment of peptic ulcer, data in pediatric patients are insufficient to establish percent response with dose and duration of therapy.  Therefore, treatment duration (initially based on adult duration recommendations) and dose should be individualized based on clinical response and/or gastric pH determination and endoscopy.  Published uncontrolled studies in pediatric patients have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

  No pharmacokinetic or pharmacodynamic data are available on pediatric patients under 1 year of age.

  Dosage Adjustments for Patients with Moderate or Severe Renal Insufficiency

  In adult patients with moderate (creatinine clearance <50 mL/min) or severe (creatinine clearance <10 mL/min) renal insufficiency, the elimination half-life of famotidine is increased.  For patients with severe renal insufficiency, it may exceed 20 hours, reaching approximately 24 hours in anuric patients.  Since CNS adverse effects have been reported in patients with moderate and severe renal insufficiency, to avoid excess accumulation of the drug in patients with moderate or severe renal insufficiency, the dose of famotidine injection may be reduced to half the dose, or the dosing interval may be prolonged to 36 to 48 hours as indicated by the patient’s clinical response.

  Based on the comparison of pharmacokinetic parameters for famotidine in adults and pediatric patients, dosage adjustment in pediatric patients with moderate or severe renal insufficiency should be considered.

  Pathological Hypersecretory Conditions (e.g., Zollinger-Ellison Syndrome, Multiple Endocrine Adenomas)

  The dosage of famotidine in patients with pathological hypersecretory conditions varies with the individual patient.  The recommended adult intravenous dose is 20 mg q 12 h.  Doses should be adjusted to individual patient needs and should continue as long as clinically indicated.  In some patients, a higher starting dose may be required.  Oral doses up to 160 mg q 6 h have been administered to some adult patients with severe Zollinger-Ellison Syndrome.

  Preparation of Intravenous Solutions

  To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability), to a total volume of either 5 mL or 10 mL and inject over a period of not less than 2 minutes.

  To prepare famotidine intravenous infusion solutions, aseptically dilute 2 mL of famotidine injection with 100 mL of 5% dextrose or other compatible solution (see Stability), and infuse over a 15 to 30 minute period.

  Concomitant Use of Antacids

  Antacids may be given concomitantly if needed.

  Stability

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

  When added to or diluted with most commonly used intravenous solutions, e.g., Water for Injection, 0.9% Sodium Chloride Injection, 5% and 10% Dextrose Injection, or Lactated Ringer’s Injection, diluted famotidine injection is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see HOW SUPPLIED, Storage.

  When added to or diluted with Sodium Bicarbonate Injection, 5%, famotidine injection at a concentration of 0.2 mg/mL (the recommended concentration of famotidine intravenous infusion solutions) is physically and chemically stable (i.e., maintains at least 90% of initial potency) for 7 days at room temperature – see  HOW SUPPLIED, Storage.  However, a precipitate may form at higher concentrations of famotidine injection (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.

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• Vinblastine Sulfate
  

  ×

  Vinblastine Sulfate

  

  ---

  This preparation is for intravenous use only (see WARNINGS).

  Special Dispensing Information–WHEN DISPENSING VINBLASTINE SULFATE INJECTION IN OTHER THAN THE ORIGINAL CONTAINER, IT IS IMPERATIVE THAT IT BE PACKAGED IN THE PROVIDED OVERWRAP WHICH BEARS THE FOLLOWING STATEMENT: “DO NOT REMOVE COVERING UNTIL MOMENT OF INJECTION.  FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.” (see WARNINGS).  A syringe containing a specific dose must be labeled, using the auxiliary sticker provided to state: “FOR INTRAVENOUS USE ONLY – FATAL IF GIVEN BY OTHER ROUTES.”

  Caution–It is extremely important that the intravenous needle or catheter be properly positioned before any vinblastine sultate is injected.  Leakage into surrounding tissue during intravenous administration of vinblastine sulfate may cause considerable irritation.  If extravasation occurs, the injection should be discontinued immediately and any remaining portion of the dose should then be introduced into another vein. Local injection of hyaluronidase and the application of moderate heat to the area of leakage will help disperse the drug and may minimize discomfort and the possibility of cellulitis.

  There are variations in the depth of the leukopenic response that follows therapy with vinblastine sulfate.  For this reason, it is recommended that the drug be given no more frequently than once every seven days.

  Adult Patients

  It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m2 of body surface area (bsa).  Thereafter, white blood cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.

  A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows:

              First dose ....................................... 3.7 mg/m2 bsa

              Second dose .................................. 5.5 mg/m2 bsa

              Third dose ...................................... 7.4 mg/m2 bsa

              Fourth dose .................................. 9.25 mg/m2 bsa

              Fifth dose ..................................... 11.1 mg/m2 bsa

  The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m2 bsa for adults is reached.  The dose should not be increased after that dose which reduces the white cell count to approximately 3,000 cells/mm3.  In some adults, 3.7 mg/m2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m2 bsa; and, very rarely, as much as 18.5 mg/m2 bsa may be necessary.  For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m2 bsa.

  When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of one increment smaller than this should be administered at weekly intervals for maintenance. Thus, the patient is receiving the maximum dose that does not cause leukopenia.  It should be emphasized that, even though seven days have elapsed, the next dose of vinblastine sulfate should not be given until the white cell count has returned to at least 4,000/mm3.  In some cases, oncolytic activity may be encountered before leukopenic effect.  When this occurs, there is no need to increase the size of subsequent doses (see PRECAUTIONS).

  Pediatric Patients

  A review of published literature from 1993 to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen.  As a single agent for Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m2.  When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as 6 mg/m2.  For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m2 in a combination regimen.  Dose modifications should be guided by hematologic tolerance.

  Patients with Renal or Hepatic Impairment

  A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.  Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

  The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used.  There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP program in treating Hodgkin’s disease. Prolonged chemotherapy for maintaining remissions involves several risks, among which are life-threatening infectious diseases, sterility and possibly the appearance of other cancers through suppression of immune surveillance.

  In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy.  On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remissions in patients with testicular cancer, unless maintained for at least two years, often result in early relapse.

  The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein.  The latter procedure is readily adaptable to outpatient therapy.  In either case, the injection may be completed in about one minute.  If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extra-vascularly, cellulitis and/or phlebitis will not occur.  To minimize further the possibility of extra vascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle.  The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation.

  Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis or varicosity.

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

  Procedures for proper handling and disposal of anti-cancer drugs should be considered.  Several guidelines on this subject have been published.4-10   There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Adult Patients

  It is wise to initiate therapy for adults by administering a single intravenous dose of 3.7 mg/m2 of body surface area (bsa).  Thereafter, white blood cell counts should be made to determine the patient’s sensitivity to vinblastine sulfate.

  A simplified and conservative incremental approach to dosage at weekly intervals for adults may be outlined as follows:

              First dose ....................................... 3.7 mg/m2 bsa

              Second dose .................................. 5.5 mg/m2 bsa

              Third dose ...................................... 7.4 mg/m2 bsa

              Fourth dose .................................. 9.25 mg/m2 bsa

              Fifth dose ..................................... 11.1 mg/m2 bsa

  The above-mentioned increases may be used until a maximum dose not exceeding 18.5 mg/m2 bsa for adults is reached.  The dose should not be increased after that dose which reduces the white cell count to approximately 3,000 cells/mm3.  In some adults, 3.7 mg/m2 bsa may produce this leukopenia; other adults may require more than 11.1 mg/m2 bsa; and, very rarely, as much as 18.5 mg/m2 bsa may be necessary.  For most adult patients, however, the weekly dosage will prove to be 5.5 to 7.4 mg/m2 bsa.

  When the dose of vinblastine sulfate which will produce the above degree of leukopenia has been established, a dose of one increment smaller than this should be administered at weekly intervals for maintenance. Thus, the patient is receiving the maximum dose that does not cause leukopenia.  It should be emphasized that, even though seven days have elapsed, the next dose of vinblastine sulfate should not be given until the white cell count has returned to at least 4,000/mm3.  In some cases, oncolytic activity may be encountered before leukopenic effect.  When this occurs, there is no need to increase the size of subsequent doses (see PRECAUTIONS).

  Pediatric Patients

  A review of published literature from 1993 to 1995 showed that initial doses of vinblastine sulfate in pediatric patients varied depending on the schedule used and whether vinblastine sulfate was administered as a single agent or incorporated within a particular chemotherapeutic regimen.  As a single agent for Letterer-Siwe disease (histiocytosis X), the initial dose of vinblastine sulfate was reported as 6.5 mg/m2.  When vinblastine sulfate was used in combination with other chemotherapeutic agents for the treatment of Hodgkin’s disease, the initial dose was reported as 6 mg/m2.  For testicular germ cell carcinomas, the initial dose of vinblastine sulfate was reported as 3 mg/m2 in a combination regimen.  Dose modifications should be guided by hematologic tolerance.

  Patients with Renal or Hepatic Impairment

  A reduction of 50% in the dose of vinblastine sulfate is recommended for patients having a direct serum bilirubin value above 3 mg/100 mL.  Since metabolism and excretion are primarily hepatic, no modification is recommended for patients with impaired renal function.

  The duration of maintenance therapy varies according to the disease being treated and the combination of antineoplastic agents being used.  There are differences of opinion regarding the duration of maintenance therapy with the same protocol for a particular disease; for example, various durations have been used with the MOPP program in treating Hodgkin’s disease. Prolonged chemotherapy for maintaining remissions involves several risks, among which are life-threatening infectious diseases, sterility and possibly the appearance of other cancers through suppression of immune surveillance.

  In some disorders, survival following complete remission may not be as prolonged as that achieved with shorter periods of maintenance therapy.  On the other hand, failure to provide maintenance therapy in some patients may lead to unnecessary relapse; complete remissions in patients with testicular cancer, unless maintained for at least two years, often result in early relapse.

  The dose of vinblastine sulfate (calculated to provide the desired amount) may be injected either into the tubing of a running intravenous infusion or directly into a vein.  The latter procedure is readily adaptable to outpatient therapy.  In either case, the injection may be completed in about one minute.  If care is taken to ensure that the needle is securely within the vein and that no solution containing vinblastine sulfate is spilled extra-vascularly, cellulitis and/or phlebitis will not occur.  To minimize further the possibility of extra vascular spillage, it is suggested that the syringe and needle be rinsed with venous blood before withdrawal of the needle.  The dose should not be diluted in large volumes of diluent (i.e., 100 to 250 mL) or given intravenously for prolonged periods (ranging from 30 to 60 minutes or more), since this frequently results in irritation of the vein and increases the chance of extravasation.

  Because of the enhanced possibility of thrombosis, it is considered inadvisable to inject a solution of vinblastine sulfate into an extremity in which the circulation is impaired or potentially impaired by such conditions as compressing or invading neoplasm, phlebitis or varicosity.

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

  Procedures for proper handling and disposal of anti-cancer drugs should be considered.  Several guidelines on this subject have been published.4-10   There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Cyanocobalamin
  

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  Cyanocobalamin

  

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  Avoid using the intravenous route.  Use of this product intravenously will result in almost all of the vitamin being lost in the urine.

  Pernicious Anemia

  Parenteral Vitamin B12 is the recommended treatment and will be required for the remainder of the patient’s life.  The oral form is not dependable.  A dose of 100 mcg daily for six or seven days should be administered by intramuscular or deep subcutaneous injection.  If there is clinical improvement and if a reticulocyte response is observed, the same amount may be given on alternate days for seven doses, then every three to four days for another two to three weeks.  By this time hematologic values should have become normal.  This regimen should be followed by 100 mcg monthly for life.  Folic acid should be administered concomitantly if needed.

  Patients With Normal Intestinal Absorption

  Where the oral route is not deemed adequate, initial treatment similar to that for patients with pernicious anemia may be indicated depending on the severity of the deficiency.  Chronic treatment should be with an oral B12 preparation.  If other vitamin deficiencies are present, they should be treated.

  Schilling test

  The flushing dose is 1000 mcg.

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

  Pernicious Anemia

  Parenteral Vitamin B12 is the recommended treatment and will be required for the remainder of the patient’s life.  The oral form is not dependable.  A dose of 100 mcg daily for six or seven days should be administered by intramuscular or deep subcutaneous injection.  If there is clinical improvement and if a reticulocyte response is observed, the same amount may be given on alternate days for seven doses, then every three to four days for another two to three weeks.  By this time hematologic values should have become normal.  This regimen should be followed by 100 mcg monthly for life.  Folic acid should be administered concomitantly if needed.

  Patients With Normal Intestinal Absorption

  Where the oral route is not deemed adequate, initial treatment similar to that for patients with pernicious anemia may be indicated depending on the severity of the deficiency.  Chronic treatment should be with an oral B12 preparation.  If other vitamin deficiencies are present, they should be treated.

  Schilling test

  The flushing dose is 1000 mcg.

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

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• Potassium Chloride
  

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  Potassium Chloride

  

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  Potassium Chloride for Injection Concentrate must be diluted before administration.  Care must be taken to ensure there is complete mixing of the potassium chloride with the large volume fluid, particularly if soft or bag type containers are used.

  The dose and rate of administration are dependent upon the specific condition of each patient.

  If the serum potassium level is greater than 2.5 mEq/L, potassium can be given at a rate not to exceed 10 mEq/hour and in a concentration of up to 40 mEq/L. The 24 hour total dose should not exceed 200 mEq.

  If urgent treatment is indicated (serum potassium level less than 2 mEq/L and electrocardiographic changes and/or muscle paralysis), potassium chloride may be infused very cautiously at a rate of up to 40 mEq/hour.  In such cases, continuous cardiac monitoring is essential.  As much as 400 mEq may be administered in a 24 hour period. In critical conditions, potassium chloride may be administered in saline (unless contraindicated) rather than in dextrose containing fluids, as dextrose may lower serum potassium levels.

  Prior to entering a vial, cleanse the rubber closure with a suitable antiseptic agent.

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

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• Dimenhydrinate
  

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  Dimenhydrinate

  

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  Dimenhydrinate in the injectable form is indicated when the oral form is impractical.

  Adults

  Nausea or vomiting may be expected to be controlled for approximately 4 hours with 50 mg, and prevented by a similar dose every 4 hours.  Its administration may be attended by some degree of drowsiness in some patients, and 100 mg every 4 hours may be given in conditions in which drowsiness is not objectionable or is even desirable.

  For intramuscular administration, each milliliter (50 mg) of solution is injected as needed, but for intravenous administration, each milliliter (50 mg) of solution must be diluted in 10 mL of 0.9% Sodium Chloride Injection, USP and injected over a period of 2 minutes.

  Pediatric

  For intramuscular administration, 1.25 mg/kg of body weight or 37.5 mg/m2 of body surface area is administered four times daily.  The maximum dose should not exceed 300 mg daily (see CONTRAINDICATIONS).

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

  Adults

  Nausea or vomiting may be expected to be controlled for approximately 4 hours with 50 mg, and prevented by a similar dose every 4 hours.  Its administration may be attended by some degree of drowsiness in some patients, and 100 mg every 4 hours may be given in conditions in which drowsiness is not objectionable or is even desirable.

  For intramuscular administration, each milliliter (50 mg) of solution is injected as needed, but for intravenous administration, each milliliter (50 mg) of solution must be diluted in 10 mL of 0.9% Sodium Chloride Injection, USP and injected over a period of 2 minutes.

  Pediatric

  For intramuscular administration, 1.25 mg/kg of body weight or 37.5 mg/m2 of body surface area is administered four times daily.  The maximum dose should not exceed 300 mg daily (see CONTRAINDICATIONS).

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

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• Iodopen Sodium Iodide
  

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  Iodopen Sodium Iodide

  

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  Iodopen provides 100 mcg iodine per mL.  For the metabolically stable adults receiving TPN, the suggested dosage level is 1 to 2 mcg iodine/kg/day (normal adults 75-150 mcg daily).  For pregnant and lactating mothers and growing children, the suggested additive level is 2 to 3 mcg iodine/kg/day.  Aseptic addition of Iodopen to TPN solutions under a laminar flow hood is recommended.  Iodine is physically compatible with electrolytes and other trace elements usually present in amino-acid/dextrose solutions used for TPN.

  Periodic monitoring of thyroid function is suggested as a guideline for adjusting dosage level.

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

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• Diphenhydramine
  

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  Diphenhydramine

  

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  THIS PRODUCT IS FOR INTRAVENOUS OR INTRAMUSCULAR ADMINISTRATION ONLY.

  Diphenhydramine hydrochloride in the injectable form is indicated when the oral form is impractical.

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

  DOSAGE SHOULD BE INDIVIDUALIZED ACCORDING TO THE NEEDS AND THE RESPONSE OF THE PATIENT.

  Pediatric Patients, other than premature infants and neonates: 5 mg/kg/24 hr or 150 mg/m2/24 hr.  Maximum daily dosage is 300 mg.  Divide into four doses, administered intravenously at a rate generally not exceeding 25 mg/min, or deep intramuscularly.

  Adults: 10 to 50 mg intravenously at a rate generally not exceeding 25 mg/min, or deep intramuscularly, 100 mg if required; maximum daily dosage is 400 mg.

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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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• 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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• Amiodarone Hydrochlorid...
  

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  Amiodarone Hydrochloride

  

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  Amiodarone shows considerable interindividual variation in response.  Thus, although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose as needed is essential.  The recommended starting dose of amiodarone HCl injection is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:

   

  AMIODARONE HCL INJECTION DOSE RECOMMENDATIONS– FIRST 24 HOURS –

  Loading infusions

  First Rapid:

  150 mg over the FIRST 10 minutes (15 mg/min).  Add 3 mL of Amiodarone HCl Injection (150 mg) to 100 mL D5W (concentration = 1.5 mg/mL). Infuse 100 mL over 10 minutes.

                    Followed by Slow:

  360 mg over the NEXT 6 hours (1 mg/min).  Add 18 mL of Amiodarone HCl Injection (900 mg) to 500 mL D5W (concentration = 1.8 mg/mL).

  Maintenance infusion

   

  540 mg over the REMAINING 18 hours (0.5 mg/min).  Decrease the rate of the slow loading infusion to 0.5 mg/min.

  After the first 24 hours, the maintenance infusion rate of 0.5 mg/min (720 mg/24 hours) should be continued utilizing a concentration of 1 to 6 mg/mL (Amiodarone HCl Injection concentrations greater than 2 mg/mL should be administered via a central venous catheter).  In the event of breakthrough episodes of VF or hemodynamically unstable VT, 150 mg supplemental infusions of amiodarone HCl injection mixed in 100 mL of D5W may be administered.  Such infusions should be administered over 10 minutes to minimize the potential for hypotension.  The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

  The first 24-hour dose may be individualized for each patient; however, in controlled clinical trials, mean daily doses above 2100 mg were associated with an increased risk of hypotension.  The initial infusion rate should not exceed 30 mg/min.

  Based on the experience from clinical studies of amiodarone HCl injection, a maintenance infusion of up to 0.5 mg/min can be cautiously continued for 2 to 3 weeks regardless of the patient's age, renal function, or left ventricular function.  There has been limited experience in patients receiving amiodarone HCl injection for longer than 3 weeks.

  The surface properties of solutions containing injectable amiodarone are altered such that the drop size may be reduced.  This reduction may lead to underdosage of the patient by up to 30% if drop counter infusion sets are used.  Amiodarone HCl injection must be delivered by a volumetric infusion pump.

  Amiodarone HCl injection should, whenever possible, be administered through a central venous catheter dedicated to that purpose.  An in-line filter should be used during administration.   Amiodarone HCl injection loading infusions at much higher concentrations and rates of infusion much faster than recommended have resulted in hepatocellular necrosis and acute renal failure, leading to death (see PRECAUTIONS, Liver Enzyme Elevations).

  Amiodarone HCl injection concentrations greater than 3 mg/mL in D5W have been associated with a high incidence of peripheral vein phlebitis; however, concentrations of 2.5 mg/mL or less appear to be less irritating.  Therefore, for infusions longer than 1 hour, amiodarone HCl injection concentrations should not exceed 2 mg/mL unless a central venous catheter is used (see ADVERSE REACTIONS, Postmarketing Reports).

  Amiodarone HCl injection infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5W.  Use of evacuated glass containers for admixing amiodarone HCl injection is not recommended as incompatibility with a buffer in the container may cause precipitation.

  It is well known that amiodarone adsorbs to polyvinyl chloride (PVC) tubing and the clinical trial dose administration schedule was designed to account for this adsorption.  All of the clinical trials were conducted using PVC tubing and its use is therefore recommended.  The concentrations and rates of infusion provided in DOSAGE AND ADMINISTRATION reflect doses identified in these studies.  Amiodarone HCl injection has been found to leach out plasticizers, including DEHP [di-(2-ethylhexyl)phthalate] from intravenous tubing (including PVC tubing).  The degree of leaching increases when infusing amiodarone HCl injection at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION.  In addition, polysorbate 80, a component of amiodarone HCl injection, is also known to leach DEHP from PVC (see DESCRIPTION).  Therefore, it is important that the recommendations in DOSAGE AND ADMINISTRATION be followed closely.

  Amiodarone HCl injection does not need to be protected from light during administration.

  Note: Parenteral drug products should be inspected visually for particulate matter, whenever solution and container permit.

  AMIODARONE HCL INJECTION SOLUTION STABILITY

  Solution

  Concentration (mg/mL)

  Container

  Comments

  5% Dextrose in Water (D5W)

  1 to 6

  PVC

  Physically compatible, with amiodarone loss <10% at 2 hours at room temperature.

  5% Dextrose in Water (D5W)

  1 to 6

  Polyolefin, Glass

  Physically compatible, with no amiodarone loss at 24 hours at room temperature.

  Admixture Incompatibility

  Amiodarone HCl injection in D5W is incompatible with the drugs shown below.

   

  Y-SITE INJECTION INCOMPATIBILITY

  Drug

  Vehicle

  Amiodarone Concentration

  Comments

  Aminophylline

  D5W

  4 mg/mL

  Precipitate

  Cefamandole Nafate

  D5W

  4 mg/mL

  Precipitate

  Cefazolin Sodium

  D5W

  4 mg/mL

  Precipitate

  Mezlocillin Sodium

  D5W

  4 mg/mL

  Precipitate

  Heparin Sodium

  D5W

  ----

  Precipitate

  Sodium Bicarbonate

  D5W

  3 mg/mL

  Precipitate

  Intravenous to Oral Transition

  Patients whose arrhythmias have been suppressed by amiodarone HCl injection may be switched to oral amiodarone.  The optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of amiodarone HCl injection already administered, as well as the bioavailability of oral amiodarone.  When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients.

  Since there are some differences between the safety and efficacy profiles of the intravenous and oral formulations, the prescriber is advised to review the package insert for oral amiodarone when switching from intravenous to oral amiodarone therapy.

  Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see PRECAUTIONS, Drug Interactions).

  The following table provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone HCl injection administration.  These recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone.

   

  RECOMMENDATIONS FOR ORAL DOSAGE AFTER IV INFUSION

  Duration of Amiodarone HCl Injection Infusion#

  Initial Daily Dose of Oral Amiodarone

  <1 week

  800 to 1600 mg

  1 to 3 weeks

  600 to 800 mg

  > 3 weeks*

  400 mg

  #Assuming a 720 mg/day infusion (0.5 mg/min).

  *Amiodarone HCl Injection is not intended for maintenance treatment.

  Admixture Incompatibility

  Amiodarone HCl injection in D5W is incompatible with the drugs shown below.

   

  Y-SITE INJECTION INCOMPATIBILITY

  Drug

  Vehicle

  Amiodarone Concentration

  Comments

  Aminophylline

  D5W

  4 mg/mL

  Precipitate

  Cefamandole Nafate

  D5W

  4 mg/mL

  Precipitate

  Cefazolin Sodium

  D5W

  4 mg/mL

  Precipitate

  Mezlocillin Sodium

  D5W

  4 mg/mL

  Precipitate

  Heparin Sodium

  D5W

  ----

  Precipitate

  Sodium Bicarbonate

  D5W

  3 mg/mL

  Precipitate

  Intravenous to Oral Transition

  Patients whose arrhythmias have been suppressed by amiodarone HCl injection may be switched to oral amiodarone.  The optimal dose for changing from intravenous to oral administration of amiodarone will depend on the dose of amiodarone HCl injection already administered, as well as the bioavailability of oral amiodarone.  When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients.

  Since there are some differences between the safety and efficacy profiles of the intravenous and oral formulations, the prescriber is advised to review the package insert for oral amiodarone when switching from intravenous to oral amiodarone therapy.

  Since grapefruit juice is known to inhibit CYP3A4-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, grapefruit juice should not be taken during treatment with oral amiodarone (see PRECAUTIONS, Drug Interactions).

  The following table provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone HCl injection administration.  These recommendations are made on the basis of a comparable total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone.

   

  RECOMMENDATIONS FOR ORAL DOSAGE AFTER IV INFUSION

  Duration of Amiodarone HCl Injection Infusion#

  Initial Daily Dose of Oral Amiodarone

  <1 week

  800 to 1600 mg

  1 to 3 weeks

  600 to 800 mg

  > 3 weeks*

  400 mg

  #Assuming a 720 mg/day infusion (0.5 mg/min).

  *Amiodarone HCl Injection is not intended for maintenance treatment.

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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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• Xylocaine
  

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  Xylocaine

  

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  Adults

  Single Direct Intravenous Injection (bolus)

  The usual dose is 50 to 100 mg of lidocaine hydrochloride (0.7 to 1.4 mg/kg; 0.32 to 0.63 mg/lb) administered intravenously under ECG monitoring.  This dose may be administered at the rate of approximately 25 to 50 mg/min (0.35 to 0.7 mg/kg/min; 0.16 to 0.32 mg/lb/min).  Sufficient time should be allowed to enable a slow circulation to carry the drug to the site of action.  If the initial injection of 50 to 100 mg does not produce a desired response, a second dose may be injected after 5 minutes.  NO MORE THAN 200 TO 300 mg OF LIDOCAINE HYDROCHLORIDE SHOULD BE ADMINISTERED DURING A ONE HOUR PERIOD.

  Continuous Intravenous Infusion

  Following bolus administration, intravenous infusions of Xylocaine may be initiated at the rate of 1 to 4 mg/min of lidocaine hydrochloride (0.014 to 0.057 mg/kg/min; 0.006 to 0.026 mg/lb/min).  The rate of intravenous infusions should be reassessed as soon as the patient’s basic cardiac rhythm appears to be stable or at the earliest signs of toxicity.  It should rarely be necessary to continue intravenous infusions of lidocaine for prolonged periods.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.  Do not use if solution is discolored or cloudy.

  Pediatric

  Controlled clinical studies in the pediatric population to establish dosing schedules have not been conducted.

  Geriatric

  In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

  Adults

  Single Direct Intravenous Injection (bolus)

  The usual dose is 50 to 100 mg of lidocaine hydrochloride (0.7 to 1.4 mg/kg; 0.32 to 0.63 mg/lb) administered intravenously under ECG monitoring.  This dose may be administered at the rate of approximately 25 to 50 mg/min (0.35 to 0.7 mg/kg/min; 0.16 to 0.32 mg/lb/min).  Sufficient time should be allowed to enable a slow circulation to carry the drug to the site of action.  If the initial injection of 50 to 100 mg does not produce a desired response, a second dose may be injected after 5 minutes.  NO MORE THAN 200 TO 300 mg OF LIDOCAINE HYDROCHLORIDE SHOULD BE ADMINISTERED DURING A ONE HOUR PERIOD.

  Continuous Intravenous Infusion

  Following bolus administration, intravenous infusions of Xylocaine may be initiated at the rate of 1 to 4 mg/min of lidocaine hydrochloride (0.014 to 0.057 mg/kg/min; 0.006 to 0.026 mg/lb/min).  The rate of intravenous infusions should be reassessed as soon as the patient’s basic cardiac rhythm appears to be stable or at the earliest signs of toxicity.  It should rarely be necessary to continue intravenous infusions of lidocaine for prolonged periods.

  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit.  Do not use if solution is discolored or cloudy.

  Pediatric

  Controlled clinical studies in the pediatric population to establish dosing schedules have not been conducted.

  Geriatric

  In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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• Xylocaine-mpf
  

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  Xylocaine-mpf

  

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  When 4% Xylocaine-MPF Sterile Solution is used concomitantly with other products containing lidocaine, the total dose contributed by all formulations must be kept in mind.

  The dosage varies and depends upon the area to be anesthetized, vascularity of the tissues, individual tolerance and the technique of anesthesia.  The lowest dosage needed to provide effective anesthesia should be administered.  Dosages should be reduced for children and for elderly and debilitated patients.

  Although the incidence of adverse effects with 4% Xylocaine-MPF Sterile Solution is quite low, caution should be exercised, particularly when employing large volumes and concentrations of 4% Xylocaine-MPF Sterile Solution since the incidence of adverse effects is directly proportional to the total dose of local anesthetic agent administered.  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.  4% Xylocaine-MPF is not approved for this use (see WARNINGS and DOSAGE AND ADMINISTRATION). 

  The dosages below are for normal, healthy adults.

  RETROBULBAR INJECTION: The suggested dose for a 70 kg person is 3 to 5 mL (120 to 200 mg of lidocaine HCl), ie, 1.7 to 3 mg/kg or 0.9 to 1.5 mg/lb body weight.  A portion of this is injected retrobulbarly and the rest may be used to block the facial nerve.

  TRANSTRACHEAL INJECTION: For local anesthesia by the transtracheal route 2 to 3 mL should be injected through a large enough needle so that the injection can be made rapidly.  By injecting during inspiration some of the drug will be carried into the bronchi and the resulting cough will distribute the rest of the drug over the vocal cords and the epiglottis.

  Occasionally it may be necessary to spray the pharynx by oropharyngeal spray to achieve complete analgesia.  For the combination of the injection and spray, it should rarely be necessary to utilize more than 5 mL (200 mg of lidocaine HCl), ie, 3 mg/kg or 1.5 mg/lb body weight.

  TOPICAL APPLICATION: For laryngoscopy, bronchoscopy and endotracheal intubation, the pharynx may be sprayed with 1 to 5 mL (40 to 200 mg of lidocaine HCl), ie, 0.6 to 3 mg/kg or 0.3 to 1.5 mg/lb body weight.

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• Gemcitabine Hydrochlori...
  

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  Gemcitabine Hydrochloride

  

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  Gemcitabine for Injection is for intravenous use only. Gemcitabine may be administered on an outpatient basis.

  2.1 Ovarian Cancer

  Gemcitabine for Injection should be administered intravenously at a dose of 1000 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Carboplatin AUC 4 should be administered intravenously on Day 1 after gemcitabine for injection administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts.  Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

  Dose Modifications

  Gemcitabine for Injection dosage adjustment for hematological toxicity within a cycle of treatment is based on the granulocyte and platelet counts taken on Day 8 of therapy. If marrow suppression is detected, gemcitabine for injection dosage should be modified according to guidelines in Table 1.

  Table 1: Day 8 Dosage Reduction Guidelines for Gemcitabine for Injection in Combination with Carboplatin

  Absolute granulocyte count(x 106/L)   Platelet count(x 106/L) % of full dose  ≥ 1500 And ≥ 100,000 100 1000 to 1499 and/or 75,000 to 99,999 50 < 1000 and/or < 75,000 Hold

  In general, for severe (Grade 3 or 4) non-hematological toxicity, except nausea/vomiting, therapy with gemcitabine for injection should be held or decreased by 50% depending on the judgment of the treating physician.  For carboplatin dosage adjustment, see manufacturer’s prescribing information.

  Dose adjustment for gemcitabine for injection in combination with carboplatin for subsequent cycles is based upon observed toxicity. The dose of gemcitabine for injection in subsequent cycles should be reduced to 800 mg/m2 on Days 1 and 8 in case of any of the following hematologic toxicities:

  Absolute granulocyte count <500 x 106/L for more than 5 days Absolute granulocyte count <100 x 106/L for more than 3 days Febrile neutropenia Platelets <25,000 x 106/L Cycle delay of more than one week due to toxicity If any of the above toxicities recur after the initial dose reduction, for the subsequent cycle, gemcitabine for injection should be given on Day 1 only at 800 mg/m 2.

  2.2 Breast Cancer

  Gemcitabine for Injection should be administered intravenously at a dose of 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle.  Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3-hour intravenous infusion before gemcitabine administration. Patients should be monitored prior to each dose with a complete blood count, including differential counts.  Patients should have an absolute granulocyte count ≥1500 x 106/L and a platelet count ≥100,000 x 106/L prior to each cycle.

  Dose Modifications

  Gemcitabine dosage adjustments for hematological toxicity is based on the granulocyte and platelet counts taken on Day 8 of therapy.  If marrow suppression is detected, gemcitabine dosage should be modified according to the guidelines in Table 2.

  Table 2: Day 8 Dosage Reduction Guidelines for Gemcitabine in Combination with Paclitaxel

  Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose  ≥ 1200 And > 75, 000  100 1000 to 1199 Or 50,000 to 75,000 75 700 to 999 And ≥ 50,000 50 < 700 Or <50,000 Hold In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine should be held or decreased by 50% depending on the judgment of the treating physician.  For paclitaxel dosage adjustment, see manufacturer’s prescribing information.

  2.3 Non-Small Cell Lung Cancer

  Two schedules have been investigated and the optimum schedule has not been determined [see Clinical Studies (14.3)]. With the 4-week schedule, gemcitabine should be administered intravenously at 1000 mg/m2 over 30 minutes on Days 1, 8, and 15 of each 28-day cycle. Cisplatin should be administered intravenously at 100 mg/m2 on Day 1 after the infusion of gemcitabine. With the 3-week schedule, gemcitabine should be administered intravenously at 1250 mg/m2 over 30 minutes on Days 1 and 8 of each 21-day cycle. Cisplatin at a dose of 100 mg/m2 should be administered intravenously after the infusion of gemcitabine on Day 1.  See prescribing information for cisplatin administration and hydration guidelines.

  Dose Modifications

  Dosage adjustments for hematologic toxicity may be required for gemcitabine and for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on the granulocyte and platelet counts taken on the day of therapy. Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet counts. If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3. For cisplatin dosage adjustment, see manufacturer’s prescribing information.

  In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or decreased by 50% depending on the judgment of the treating physician. During combination therapy with cisplatin, serum creatinine, serum potassium, serum calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin alone).

  2.4 Pancreatic Cancer

  Gemcitabine for Injection should be administered by intravenous infusion at a dose of 1000 mg/m2 over 30 minutes once weekly for up to 7 weeks (or until toxicity necessitates reducing or holding a dose), followed by a week of rest from treatment. Subsequent cycles should consist of infusions once weekly for 3 consecutive weeks out of every 4 weeks.

  Dose Modifications

  Dosage adjustment is based upon the degree of hematologic toxicity experienced by the patient [see Warnings and Precautions (5.2)]. Clearance in women and the elderly is reduced and women were somewhat less able to progress to subsequent cycles [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3)].

  Patients receiving gemcitabine should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count.  If marrow suppression is detected, therapy should be modified or suspended according to the guidelines in Table 3.

  Table 3: Dosage Reduction Guidelines Absolute granulocyte count(x106/L) Platelet count(x106/L)  % of full dose   ≥ 1000 And  ≥ 100,000 100 500 to 999 Or 50,000 to 99,999 75 < 500 Or < 50,000 Hold

  Laboratory evaluation of renal and hepatic function, including transaminases and serum creatinine, should be performed prior to initiation of therapy and periodically thereafter.  Gemcitabine for Injection should be administered with caution in patients with evidence of significant renal or hepatic impairment as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations.

  Patients treated with gemcitabine who complete an entire cycle of therapy may have the dose for subsequent cycles increased by 25%, provided that the absolute granulocyte count (AGC) and platelet nadirs exceed 1500 x 10 6/L and 100,000 x 10 6/L, respectively, and if non-hematologic toxicity has not been greater than WHO Grade 1. If patients tolerate the subsequent course of gemcitabine at the increased dose, the dose for the next cycle can be further increased by 20%, provided again that the AGC and platelet nadirs exceed 1500 x 10 6/L and 100,000 x 10 6/L, respectively, and that non-hematologic toxicity has not been greater than WHO Grade 1.

  2.5 Preparation and Administration Precautions

  Caution should be exercised in handling and preparing gemcitabine solutions. The use of gloves is recommended.  If gemcitabine solution contacts the skin or mucosa, immediately wash the skin thoroughly with soap and water or rinse the mucosa with copious amounts of water. Although acute dermal irritation has not been observed in animal studies, 2 of 3 rabbits exhibited drug-related systemic toxicities (death, hypoactivity, nasal discharge, shallow breathing) due to dermal absorption.

  Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published [see References (15)].

  2.6 Preparation for Intravenous Infusion Administration

  The recommended diluent for reconstitution of gemcitabine is 0.9% Sodium Chloride Injection without preservatives.  Due to solubility considerations, the maximum concentration for gemcitabine upon reconstitution is 40 mg/mL.  Reconstitution at concentrations greater than 40 mg/mL may result in incomplete dissolution, and should be avoided.

  To reconstitute, add 5 mL of 0.9% Sodium Chloride Injection to the 200-mg vial, 25 mL of 0.9% Sodium Chloride Injection to the 1-g vial or 50 mL of 0.9% Sodium Chloride Injection to the 2-g vial. Shake to dissolve. These dilutions each yield a gemcitabine concentration of 38 mg/mL which includes accounting for the displacement volume of the lyophilized powder (0.26 mL for the 200-mg vial, 1.3 mL for the 1-g vial or 2.6 mL for the 2-g vial). The total volume upon reconstitution will be 5.26 mL, 26.3 mL or 52.6 mL, respectively. Complete withdrawal of the vial contents will provide 200 mg, 1 g or 2 g of gemcitabine, respectively. Prior to administration the appropriate amount of drug must be diluted with 0.9% Sodium Chloride Injection. Final concentrations may be as low as 0.1 mg/mL. Reconstituted gemcitabine is a clear, colorless to light straw-colored solution.  After reconstitution with 0.9% Sodium Chloride Injection, the pH of the resulting solution lies in the range of 2.7 to 3.3.  The solution should be inspected visually for particulate matter and discoloration prior to administration, whenever solution or container permit.  If particulate matter or discoloration is found, do not administer.

  When prepared as directed, gemcitabine solutions are stable for 24 hours at controlled room temperature 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Discard unused portion. Solutions of reconstituted gemcitabine should not be refrigerated, as crystallization may occur.

  The compatibility of gemcitabine with other drugs has not been studied. No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.

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• Pentam 300
  

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  Pentam 300

  

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  CAUTION: DO NOT USE SODIUM CHLORIDE INJECTION, USP FOR INITIAL RECONSTITUTION BECAUSE PRECIPITATION WILL OCCUR.  Pentamidine isethionate should be administered IM or IV only.  The recommended regimen for adults and pediatric patients beyond 4 months of age is 4 mg/kg once a day for 14 to 21 days.  Therapy for longer than 21 days with pentamidine isethionate has also been used but may be associated with increased toxicity.

  Intramuscular Injection

  The contents of one vial (300 mg) should be dissolved in 3 mL of Sterile Water for Injection, USP at 22° - 30°C (72° - 86°F).  The calculated daily dose should then be withdrawn and administered by deep IM injection.

  Intravenous Injection

  The contents of one vial (300 mg) should first be dissolved in 3 to 5 mL of Sterile Water for Injection, USP, or 5% Dextrose Injection, USP at 22°- 30°C (72° - 86°F).  The calculated dose of pentamidine isethionate should then be withdrawn and diluted further in 50 to 250 mL of 5% Dextrose Injection, USP.

  The diluted IV solutions containing pentamidine isethionate should be infused over a period of 60 to 120 minutes.

  Aseptic technique should be employed in preparation of all solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Stability

  After reconstitution with sterile water, the Pentam solution is stable for 48 hours in the original vial at room temperature if protected from light.  To avoid crystallization,store at 22° - 30°C (72° - 86°F).  Intravenous infusion solutions of pentamidine isethionate at 1 mg/mL and 2.5 mg/mL prepared in 5% Dextrose Injection, USP are stable at room temperature for up to 24 hours.

  Intravenous (IV) solutions of pentamidine isethionate have been shown to be incompatible with fluconazole and foscarnet sodium.  IV solutions of pentamidine isethionate have been shown to be compatible with IV solutions of zidovudine (AZT) and diltiazem hydrochloride.

  Intramuscular Injection

  The contents of one vial (300 mg) should be dissolved in 3 mL of Sterile Water for Injection, USP at 22° - 30°C (72° - 86°F).  The calculated daily dose should then be withdrawn and administered by deep IM injection.

  Intravenous Injection

  The contents of one vial (300 mg) should first be dissolved in 3 to 5 mL of Sterile Water for Injection, USP, or 5% Dextrose Injection, USP at 22°- 30°C (72° - 86°F).  The calculated dose of pentamidine isethionate should then be withdrawn and diluted further in 50 to 250 mL of 5% Dextrose Injection, USP.

  The diluted IV solutions containing pentamidine isethionate should be infused over a period of 60 to 120 minutes.

  Aseptic technique should be employed in preparation of all solutions.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Stability

  After reconstitution with sterile water, the Pentam solution is stable for 48 hours in the original vial at room temperature if protected from light.  To avoid crystallization,store at 22° - 30°C (72° - 86°F).  Intravenous infusion solutions of pentamidine isethionate at 1 mg/mL and 2.5 mg/mL prepared in 5% Dextrose Injection, USP are stable at room temperature for up to 24 hours.

  Intravenous (IV) solutions of pentamidine isethionate have been shown to be incompatible with fluconazole and foscarnet sodium.  IV solutions of pentamidine isethionate have been shown to be compatible with IV solutions of zidovudine (AZT) and diltiazem hydrochloride.

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• Kanamycin
  

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  Kanamycin

  

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  Kanamycin injection may be given intramuscularly or intravenously.  The patient’s pretreatment body weight should be obtained for calculation of the correct dosage.  The dosage of an aminoglycoside in obese patients should be based on an estimate of the lean body mass.  The status of renal function should be determined by measurement of serum creatinine concentration or calculation of the endogenous creatinine clearance rate.  The blood urea nitrogen (BUN) level is much less reliable for this purpose.  Renal function should be reassessed frequently during therapy.

  It is desirable to measure both peak and trough serum concentrations intermittently during therapy since both concentrations are used to determine the adequacy and safety of the dose and to adjust the dosage during treatment.  Peak serum concentrations (30 to 90 minutes after injection) above 35 mcg per mL and trough concentrations (just prior to the next dose) above 10 mcg per mL should be avoided.

  Intramuscular Route

  Inject deeply into the upper outer quadrant of the gluteal muscle.  The recommended dose for adults or children is 15 mg/kg/day in two equally divided dosages administered at equally divided intervals; i.e., 7.5 mg/kg q12h.  If continuously high blood levels are desired, the daily dose of 15 mg/kg may be given in equally divided doses every 6 or 8 hours.  Treatment of patients in the heavier weight classes, i.e., 100 kg, should not exceed 1.5 g/day.

  In patients with impaired renal function, it is desirable to follow therapy by appropriate serum assays.  If this is not feasible, a suggested method is to reduce the frequency of administration in patients with renal dysfunction.  The interval between doses may be calculated with the following formula:

  Serum creatinine (mg/100 mL) x 9 = Dosage Interval (in hours); e.g., if the serum creatinine is 2 mg, the recommended dose (7.5 mg/kg) should be administered every 18 hours.  Changes in creatinine concentration during therapy would, of course, necessitate changes in the dosage frequency.

  It is desirable to limit the duration of treatment with kanamycin to short-term.  The usual duration of treatment is 7 to 10 days.  Total daily dose by all routes of administration should not exceed 1.5 g/day.  If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose.  These patients should be carefully monitored for changes in renal, auditory, and vestibular function.  Dosage should be adjusted as needed.  The risks of toxicity multiply as the length of treatment increases.

  At the recommended dosage level, uncomplicated infections due to kanamycin-susceptible organisms should respond to therapy in 24 to 48 hours.  If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.  Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

  Intravenous Administration

  The dose should not exceed 15 mg/kg per day and must be administered slowly.  The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 to 200 mL of sterile diluent such as Normal Saline or 5% Dextrose in Water, or the contents of a 1g vial to 200 to 400 mL of sterile diluent.  The appropriate dose is administered over a 30- to 60-minute period.  The total daily dose should be divided into 2 or 3 equally divided doses.

  Kanamycin Injection, USP should not be physically mixed with other antibacterial agents but each should be administered separately in accordance with its recommended route of administration and dosage schedule.

  Intraperitoneal Use

  (Following exploration for established peritonitis or after peritoneal contamination due to fecal spill during surgery.)

  Adults

  500 mg diluted in 20 mL sterile distilled water may be instilled through a polyethylene catheter sutured into the wound at closure.  If possible, instillation should be postponed until the patient has fully recovered from the effects of anesthesia and muscle-relaxing drugs (see duration of treatment statement above and WARNING box).  Serum levels should be carefully monitored during treatment.

  NOTE: The pediatric dosage form “75 mg/2 mL” should be used for pediatric patients.

  Aerosol Treatment

  250 mg two to four times a day.  Withdraw 250 mg (1mL) from a 500 mg vial and dilute it with 3 mL Physiological Saline and nebulize.  Serum levels should be carefully monitored during treatment.

  Other Routes of Administration

  Kanamycin injection in concentrations of 0.25 percent (2.5 mg/mL) has been used as an irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities.  Possible absorption of kanamycin by such routes must be taken into account and dosage adjustments should be arranged so that a maximum total dose of 1.5 g/day by all routes of administration is not exceeded.  Serum levels should be carefully monitored during treatment.

  Intramuscular Route

  Inject deeply into the upper outer quadrant of the gluteal muscle.  The recommended dose for adults or children is 15 mg/kg/day in two equally divided dosages administered at equally divided intervals; i.e., 7.5 mg/kg q12h.  If continuously high blood levels are desired, the daily dose of 15 mg/kg may be given in equally divided doses every 6 or 8 hours.  Treatment of patients in the heavier weight classes, i.e., 100 kg, should not exceed 1.5 g/day.

  In patients with impaired renal function, it is desirable to follow therapy by appropriate serum assays.  If this is not feasible, a suggested method is to reduce the frequency of administration in patients with renal dysfunction.  The interval between doses may be calculated with the following formula:

  Serum creatinine (mg/100 mL) x 9 = Dosage Interval (in hours); e.g., if the serum creatinine is 2 mg, the recommended dose (7.5 mg/kg) should be administered every 18 hours.  Changes in creatinine concentration during therapy would, of course, necessitate changes in the dosage frequency.

  It is desirable to limit the duration of treatment with kanamycin to short-term.  The usual duration of treatment is 7 to 10 days.  Total daily dose by all routes of administration should not exceed 1.5 g/day.  If longer therapy is required, measurement of kanamycin peak and trough serum concentrations is particularly important as a basis for determining the adequacy and safety of the dose.  These patients should be carefully monitored for changes in renal, auditory, and vestibular function.  Dosage should be adjusted as needed.  The risks of toxicity multiply as the length of treatment increases.

  At the recommended dosage level, uncomplicated infections due to kanamycin-susceptible organisms should respond to therapy in 24 to 48 hours.  If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.  Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

  Intravenous Administration

  The dose should not exceed 15 mg/kg per day and must be administered slowly.  The solution for intravenous use is prepared by adding the contents of a 500 mg vial to 100 to 200 mL of sterile diluent such as Normal Saline or 5% Dextrose in Water, or the contents of a 1g vial to 200 to 400 mL of sterile diluent.  The appropriate dose is administered over a 30- to 60-minute period.  The total daily dose should be divided into 2 or 3 equally divided doses.

  Kanamycin Injection, USP should not be physically mixed with other antibacterial agents but each should be administered separately in accordance with its recommended route of administration and dosage schedule.

  Intraperitoneal Use

  (Following exploration for established peritonitis or after peritoneal contamination due to fecal spill during surgery.)

  Adults

  500 mg diluted in 20 mL sterile distilled water may be instilled through a polyethylene catheter sutured into the wound at closure.  If possible, instillation should be postponed until the patient has fully recovered from the effects of anesthesia and muscle-relaxing drugs (see duration of treatment statement above and WARNING box).  Serum levels should be carefully monitored during treatment.

  NOTE: The pediatric dosage form “75 mg/2 mL” should be used for pediatric patients.

  Aerosol Treatment

  250 mg two to four times a day.  Withdraw 250 mg (1mL) from a 500 mg vial and dilute it with 3 mL Physiological Saline and nebulize.  Serum levels should be carefully monitored during treatment.

  Other Routes of Administration

  Kanamycin injection in concentrations of 0.25 percent (2.5 mg/mL) has been used as an irrigating solution in abscess cavities, pleural space, peritoneal and ventricular cavities.  Possible absorption of kanamycin by such routes must be taken into account and dosage adjustments should be arranged so that a maximum total dose of 1.5 g/day by all routes of administration is not exceeded.  Serum levels should be carefully monitored during treatment.

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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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• Deferoxamine
  

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  Deferoxamine

  

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  Acute Iron Intoxication

  Intramuscular Administration

  This route is preferred and should be used for ALL PATIENTS NOT IN SHOCK.

  A dose of 1000 mg should be administered initially.  This may be followed by 500 mg every 4 hours for two doses.  Depending upon the clinical response, subsequent doses of 500 mg may be administered every 4 to 12 hours.  The total amount administered should not exceed 6000 mg in 24 hours.  For reconstitution instructions for intramuscular administration see Table 1.

  Intravenous Administration

  THIS ROUTE SHOULD BE USED ONLY FOR PATIENTS IN A STATE OF CARDIOVASCULAR COLLAPSE AND THEN ONLY BY SLOW INFUSION.  THE RATE OF INFUSION SHOULD NOT EXCEED 15 MG/KG/HR FOR THE FIRST 1000 MG ADMINISTERED. SUBSEQUENT IV DOSING, IF NEEDED, MUST BE AT A SLOWER RATE, NOT TO EXCEED 125 MG/HR.

  For reconstitution instructions for intravenous administration see Table 2.  The reconstituted solution is added to physiologic saline (e.g., 0.9% sodium chloride, 0.45% sodium chloride), glucose in water, or Ringer’s lactate solution.

  An initial dose of 1000 mg should be administered at a rate NOT TO EXCEED 15 mg/kg/hr.  This may be followed by 500 mg over 4 hours for two doses.  Depending upon the clinical response, subsequent doses of 500 mg may be administered over 4 to 12 hours.  The total amount administered should not exceed 6000 mg in 24 hours.

  As soon as the clinical condition of the patient permits, intravenous administration should be discontinued and the drug should be administered intramuscularly.

   

  CHRONIC IRON OVERLOAD

   Subcutaneous Administration A daily dose of 1000 to 2000 mg (20 to 40 mg/kg/day) should be administered over 8 to 24 hours, utilizing a small portable pump capable of providing continuous mini-infusion.  The duration of infusion must be individualized.  In some patients, as much iron will be excreted after a short infusion of 8 to 12 hours as with the same dose given over 24 hours.  For reconstitution instructions for subcutaneous administration see Table 3.

   Intravenous Administration The standard recommended method of deferoxamine mesylate administration is via slow subcutaneous infusion over 8 to 12 hours.  In patients with intravenous access, the daily dose of deferoxamine mesylate can be administered intravenously.  The standard dose is 20 to 40 mg/kg/day for children and 40 to 50 mg/kg/day over 8 to 12 hours in adults for 5 to 7 days per week.  In children, average doses should not exceed 40 mg/kg/day until growth has ceased.  In adults, average doses should not exceed 60 mg/kg/day.  The intravenous infusion rate should not exceed 15 mg/kg/hour.  For reconstitution instructions for intravenous administration see Table 2.

  In patients who are poorly compliant, deferoxamine mesylate may be administered prior to or following same day blood transfusion (for example 1 gram over 4 hours on the day of transfusion); however, the contribution of this mode of administration to iron balance is limited.  Deferoxamine mesylate should not be administered concurrently with the blood transfusion as this can lead to errors in interpreting side effects such as rash, anaphylaxis and hypotension.

  Intramuscular Administration A daily dose of 500 to 1000 mg may be administered intramuscularly.  The total daily dose should not exceed 1000 mg.  For reconstitution instructions for intramuscular administration see Table 1.  Reconstitution and Preparation  

  Table 1: Preparation for Intramuscular Administration

  RECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION WITH STERILE WATER FOR INJECTION

  Vial Size

  Amount of Sterile Water for Injection Required for Reconstitution

  Total Drug Content after Reconstitution

  Final Concentration per mL after Reconstitution

  500 mg

  2 mL

  500 mg/2.35 mL

  213 mg/mL

  2 grams

  8 mL

  2 grams/9.4 mL

  213 mg/mL

  Table 2: Preparation for Intravenous Administrations  RECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION WITH STERILE WATER FOR INJECTION

  Vial Size

  Amount of Sterile Water for Injection Required for Reconstitution

  Total Drug Content after Reconstitution

  Final Concentration per mL after Reconstitution

  500 mg

  5 mL

  500 mg/5.3 mL

  95 mg/mL

  2 grams

  20 mL

  2 grams/21.1 mL

  95 mg/mL

   

  Table 3: Preparation for Subcutaneous Administration 

   RECONSTITUTE DEFEROXAMINE MESYLATE FOR INJECTION WITH STERILE WATER FOR INJECTION

  Vial Size

  Amount of Sterile Water for Injection Required for Reconstitution

  Total Drug Content after Reconstitution

  Final Concentration per mL after Reconstitution

  500 mg

  5 mL

  500 mg/5.3 mL

  95 mg/mL

  2 grams

  20 mL

  2 grams/21.1 mL

  95 mg/mL

  The reconstituted deferoxamine mesylate for injection solution is an isotonic, clear and colorless to slightly yellowish solution.  The drug should be completely dissolved before the solution is withdrawn.  Deferoxamine mesylate reconstituted with Sterile Water for Injection IS FOR SINGLE USE ONLY.  Discard unused portion. 

  The product should be used immediately after reconstitution (commencement of treatment within 3 hours) for microbiological safety.  When reconstitution is carried out under validated aseptic conditions (in a sterile laminar flow hood using aseptic technique), the product may be stored at room temperature for a maximum period of 24 hours before use.  Do not refrigerate reconstituted solution.  Reconstituting deferoxamine mesylate for injection in solvents or under conditions other than indicated may result in precipitation.  Turbid solutions should not be used.

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• Ceftriaxone
  

  ×

  Ceftriaxone

  

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  Ceftriaxone for Injection may be administered intravenously or intramuscularly.

  Do not use diluents containing calcium, such as Ringer’s solution or Hartmann’s solution, to reconstitute ceftriaxone for injection vials or to further dilute a reconstituted vial for IV administration because a precipitate can form.  Precipitation of ceftriaxone-calcium can also occur when ceftriaxone for injection is mixed with calcium-containing solutions in the same IV administration line.  Ceftriaxone for injection must not be administered simultaneously with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition via a Y-site.  However, in patients other than neonates, ceftriaxone for injection and calcium-containing solutions may be administered sequentially of one another if the infusion lines are thoroughly flushed between infusions with a compatible fluid (see WARNINGS).

  There have been no reports of an interaction between ceftriaxone and oral calcium-containing products or interaction between intramuscular ceftriaxone and calcium-containing products (IV or oral).

  Neonates

  Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection (see CONTRAINDICATIONS).

  Ceftriaxone for injection is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).

  Pediatric Patients

  For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day).  The total daily dose should not exceed 2 grams.

  For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

  For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours.  The total daily dose should not exceed 2 grams.

  In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams).  Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended.  The daily dose may be administered once a day (or in equally divided doses every 12 hours).  The usual duration of therapy is 7 to 14 days.

  Adults

  The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection.  For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve >90% target attainment.  The total daily dose should not exceed 4 grams.

  If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

  For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

  For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

  Generally, Ceftriaxone for Injection therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared.  The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

  When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

  No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

  Neonates

  Hyperbilirubinemic neonates, especially prematures, should not be treated with ceftriaxone for injection (see CONTRAINDICATIONS).

  Ceftriaxone for injection is contraindicated in neonates if they require (or are expected to require) treatment with calcium-containing IV solutions, including continuous calcium-containing infusions such as parenteral nutrition because of the risk of precipitation of ceftriaxone-calcium (see CONTRAINDICATIONS).

  Pediatric Patients

  For the treatment of skin and skin structure infections, the recommended total daily dose is 50 to 75 mg/kg given once a day (or in equally divided doses twice a day).  The total daily dose should not exceed 2 grams.

  For the treatment of acute bacterial otitis media, a single intramuscular dose of 50 mg/kg (not to exceed 1 gram) is recommended (see INDICATIONS AND USAGE).

  For the treatment of serious miscellaneous infections other than meningitis, the recommended total daily dose is 50 to 75 mg/kg, given in divided doses every 12 hours.  The total daily dose should not exceed 2 grams.

  In the treatment of meningitis, it is recommended that the initial therapeutic dose be 100 mg/kg (not to exceed 4 grams).  Thereafter, a total daily dose of 100 mg/kg/day (not to exceed 4 grams daily) is recommended.  The daily dose may be administered once a day (or in equally divided doses every 12 hours).  The usual duration of therapy is 7 to 14 days.

  Adults

  The usual adult daily dose is 1 to 2 grams given once a day (or in equally divided doses twice a day) depending on the type and severity of infection.  For infections caused by Staphylococcus aureus (MSSA), the recommended daily dose is 2 to 4 grams, in order to achieve >90% target attainment.  The total daily dose should not exceed 4 grams.

  If Chlamydia trachomatis is a suspected pathogen, appropriate antichlamydial coverage should be added, because ceftriaxone sodium has no activity against this organism.

  For the treatment of uncomplicated gonococcal infections, a single intramuscular dose of 250 mg is recommended.

  For preoperative use (surgical prophylaxis), a single dose of 1 gram administered intravenously 1/2 to 2 hours before surgery is recommended.

  Generally, Ceftriaxone for Injection therapy should be continued for at least 2 days after the signs and symptoms of infection have disappeared.  The usual duration of therapy is 4 to 14 days; in complicated infections, longer therapy may be required.

  When treating infections caused by Streptococcus pyogenes, therapy should be continued for at least 10 days.

  No dosage adjustment is necessary for patients with impairment of renal or hepatic function.

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• Cefotetan
  

  ×

  Cefotetan

  

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  Treatment

  The usual adult dosage is 1 or 2 grams of Cefotetan for Injection, USP administered intravenously every 12 hours for 5 to 10 days.  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

  1 or 2 g every 24 hours IV

  1 or 2 g every 12 hours IV

  Skin & Skin Structure

     Mild - Moderatea

      Severe 2 grams

  2 g every 24 hours IV

  1 g every 12 hours IV

   4 grams  2 g every 12 hours IV

  Other Sites

  2 to 4 grams

  1 or 2 g every 12 hours IV

  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.

  bMaximum 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 Pharmacy Bulk Package for Intravenous Use - NOT FOR DIRECT INFUSION

   

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

  Reconstitute with Sterile Water for Injection; 5% Dextrose Injection; or 0.9% Sodium Chloride Injection.  Shake to dissolve and let stand until clear (see DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

  Pharmacy

  Bulk

  Package bottle

  Amount of

  Diluent to be

  Added (mL)

  Approximate Withdrawable

  Vol (mL)

  Approximate

  Average Concentration(mg/mL)

  10 gram

  Pharmacy Bulk

  50

  55

  180

  10 gram

  Pharmacy Bulk

  100

  105

  95

  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 cefotetan may be administered over 20 to 60 minutes 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 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 SUPLEMENTATARY MEDICATION.

  Treatment

  The usual adult dosage is 1 or 2 grams of Cefotetan for Injection, USP administered intravenously every 12 hours for 5 to 10 days.  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

  1 or 2 g every 24 hours IV

  1 or 2 g every 12 hours IV

  Skin & Skin Structure

     Mild - Moderatea

      Severe 2 grams

  2 g every 24 hours IV

  1 g every 12 hours IV

   4 grams  2 g every 12 hours IV

  Other Sites

  2 to 4 grams

  1 or 2 g every 12 hours IV

  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.

  bMaximum 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 Pharmacy Bulk Package for Intravenous Use - NOT FOR DIRECT INFUSION

   

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

  Reconstitute with Sterile Water for Injection; 5% Dextrose Injection; or 0.9% Sodium Chloride Injection.  Shake to dissolve and let stand until clear (see DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE).

  Pharmacy

  Bulk

  Package bottle

  Amount of

  Diluent to be

  Added (mL)

  Approximate Withdrawable

  Vol (mL)

  Approximate

  Average Concentration(mg/mL)

  10 gram

  Pharmacy Bulk

  50

  55

  180

  10 gram

  Pharmacy Bulk

  100

  105

  95

  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 cefotetan may be administered over 20 to 60 minutes 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 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 SUPLEMENTATARY MEDICATION.

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• Cefazolin
  

  ×

  Cefazolin

  

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  After reconstitution, the intent of this Cefazolin for Injection, USP pharmacy bulk package is for the preparation of the solutions for intravenous infusion only.

  Usual Adult Dosage

  Type of Infection Dose Frequency Moderate to severe infections 500 mg to 1 gram every 6 to 8 hours Mild infections caused by susceptible gram-positive cocci 250 mg to 500 mg every 8 hours Acute, uncomplicated urinary tract infections 1 gram every 12 hours Pneumococcal pneumonia 500 mg every 12 hours Severe, life-threatening infections (e.g., endocarditis, septicemia)* 1 gram to 1.5 grams every 6 hours

  *In rare instances, doses of up to 12 grams of cefazolin per day have been used.

  Perioperative Prophylactic Use

  To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

  a. 1 gram IV administered ½  hour to 1 hour prior to the start of surgery.

  b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram IV during surgery (administration modified depending on the duration of the operative procedure).

  c. 500 mg to 1 gram IV every 6 to 8 hours for 24 hours postoperatively.

  It is important that (1) the preoperative dose be given just (½  to 1 hour) prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision; and (2) cefazolin for injection be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

  In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin for injection may be continued for 3 to 5 days following the completion of surgery.

  Dosage Adjustment for Patients With Reduced Renal Function

  Cefazolin may be used in patients with reduced renal function with the following dosage adjustments: Patients with a creatinine clearance of 55 mL/min. or greater or a serum creatinine of 1.5 mg % or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min. or serum creatinine of 1.6 to 3 mg % can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg % should be given ½ the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min. or less or serum creatinine of 4.6 mg % or greater should be given ½  the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis: See CLINICAL PHARMACOLOGY.

  Pediatric Dosage

  In pediatric patients, a total daily dosage of 25 to 50 mg/kg (approximately 10 to 20 mg/lb) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg/kg (45 mg/lb) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin in these patients is not recommended.

   

  In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min.), 60 percent of the normal daily dose given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min.), 25 percent of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min.) may be given 10 percent of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

  Reconstitution

  Preparation of Parenteral Solution

  Parenteral drug products should be SHAKEN WELL when reconstituted, and inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded.

  Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.

  Directions for Proper Use of Pharmacy Bulk Package – NOT FOR DIRECT INFUSION

  The pharmacy bulk package is for use in a hospital pharmacy admixture service only in a suitable work area, such as a laminar flow hood. Using aseptic technique, the closure may be penetrated only one time after reconstitution using a suitable sterile dispensing set that allows measured dispensing of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After entry, use entire contents of bottle promptly. The entire contents of the bottle should be dispensed within 4 hours of initial entry. Discard Pharmacy Bulk Package bottle within 4 hours after initial entry.

  Pharmacy Bulk Bottles

  Add Sterile Water for Injection, Bacteriostatic Water for Injection, or Sodium Chloride Injection according to the table below. SHAKE WELL. Use promptly. (Discard bottle within 4 hours after initial entry.)

  Bottle Size Amount of Diluent Approximate Concentration Approximate Available Volume 10 grams 45 mL 1 gram/5 mL 51 mL 10 grams 96 mL 1 gram/10 mL 102 mL 20 grams 90 mL 1 gram/5 mL 102 mL

  For ease of dispensing, invert reconstituted bottle and hang by bail band in a laminar flow hood. Dispense aliquots from the bottle into the infusion fluids using a suitable sterile dispensing device. See Intermittent Intravenous Infusion for suitable infusion fluids.

  Administration

  Intravenous Administration

  Intermittent or continuous infusion: Dilute reconstituted Cefazolin for Injection in 50 to 100 mL of 1 of the following solutions:

  Sodium Chloride Injection, USP

  5% or 10% Dextrose Injection, USP

  5% Dextrose in Lactated Ringer’s Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% Dextrose and 0.2% Sodium Chloride Injection, USP

  Lactated Ringer’s Injection, USP

  Invert Sugar 5% or 10% in Sterile Water for Injection

  Ringer’s Injection, USP

  5% Sodium Bicarbonate Injection, USP

  When diluted according to the instructions above, cefazolin is stable for 24 hours at room temperature or for 10 days if stored under refrigeration (5°C or 41°F). Prior to administration parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.

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• Floxuridine
  

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  Floxuridine

  

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  Each vial must be reconstituted with 5 mL of sterile water for injection to yield a solution containing approximately 100 mg of floxuridine/mL.  The calculated daily dose(s) of the drug is then diluted with 5% dextrose or 0.9% sodium chloride injection to a volume appropriate for the infusion apparatus to be used.  The administration of floxuridine is best achieved with the use of an appropriate pump to overcome pressure in large arteries and to ensure a uniform rate of infusion.

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

  The recommended therapeutic dosage schedule of floxuridine by continuous arterial infusion is 0.1 to 0.6 mg/kg/day.  The higher dosage ranges (0.4 to 0.6 mg) are usually employed for hepatic artery infusion because the liver metabolizes the drug, thus reducing the potential for systemic toxicity.  Therapy can be given until adverse reactions appear.  (See PRECAUTIONS).  When these side effects have subsided, therapy may be resumed.  The patients should be maintained on therapy as long as response to floxuridine continues.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.1-7  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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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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• Cytarabine
  

  ×

  Cytarabine

  

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  Cytarabine Injection is not active orally.  The schedule and method of administration varies with the program of therapy to be used.  Cytarabine Injection may be given by intravenous infusion or injection, subcutaneously, or intrathecally (preservative free preparation only).

  Thrombophlebitis has occurred at the site of drug injection or infusion in some patients, and rarely patients have noted pain and inflammation at subcutaneous injection sites.  In most instances, however, the drug has been well tolerated.

  Patients can tolerate higher total doses when they receive the drug by rapid intravenous injection as compared with slow infusion.  This phenomenon is related to the drug’s rapid inactivation and brief exposure of susceptible normal and neoplastic cells to significant levels after rapid injection.  Normal and neoplastic cells seem to respond in somewhat parallel fashion to these different modes of administration and no clear-cut clinical advantage has been demonstrated for either.

  In the induction therapy of acute non-lymphocytic leukemia, the usual cytarabine dose in combination with other anticancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1 to 7) or 100 mg/m2 IV every 12 hours (Days 1 to 7).

  The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

  Intrathecal Use in Meningeal Leukemia

  Cytarabine Injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area.  The frequency of administration varied from once a day for 4 days to once every 4 days.  The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment.  The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  Cytarabine Injection given intrathecally may cause systemic toxicity and careful monitoring of the hematopoietic system is indicated.  Modification of other anti-leukemia therapy may be necessary.  Major toxicity is rare.  The most frequently reported reactions after intrathecal administration were nausea, vomiting, and fever; these reactions are mild and self-limiting.  Paraplegia has been reported.  Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation.  Isolated neurotoxicity has been reported.  Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal Cytarabine Injection.

  When Cytarabine Injection is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal Cytarabine Injection is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal Cytarabine Injection and may better be treated with radiotherapy.

  Chemical Stability of Infusion Solutions

  Chemical stability studies were performed by HPLC on Cytarabine Injection in infusion solutions.  These studies showed that when Cytarabine Injection was added to Water for Injection, 5% Dextrose in Water or Sodium Chloride Injection, 94 to 96 percent of the cytarabine was present after 192 hours storage at room temperature.

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

  Intrathecal Use in Meningeal Leukemia

  Cytarabine Injection has been used intrathecally in acute leukemia in doses ranging from 5 mg/m2 to 75 mg/m2 of body surface area.  The frequency of administration varied from once a day for 4 days to once every 4 days.  The most frequently used dose was 30 mg/m2 every 4 days until cerebrospinal fluid findings were normal, followed by one additional treatment.  The dosage schedule is usually governed by the type and severity of central nervous system manifestations and the response to previous therapy.

  Cytarabine Injection given intrathecally may cause systemic toxicity and careful monitoring of the hematopoietic system is indicated.  Modification of other anti-leukemia therapy may be necessary.  Major toxicity is rare.  The most frequently reported reactions after intrathecal administration were nausea, vomiting, and fever; these reactions are mild and self-limiting.  Paraplegia has been reported.  Necrotizing leukoencephalopathy occurred in 5 children; these patients had also been treated with intrathecal methotrexate and hydrocortisone, as well as by central nervous system radiation.  Isolated neurotoxicity has been reported.  Blindness occurred in two patients in remission whose treatment had consisted of combination systemic chemotherapy, prophylactic central nervous system radiation and intrathecal Cytarabine Injection.

  When Cytarabine Injection is administered both intrathecally and intravenously within a few days, there is an increased risk of spinal cord toxicity, however, in serious life-threatening disease, concurrent use of intravenous and intrathecal Cytarabine Injection is left to the discretion of the treating physician.

  Focal leukemic involvement of the central nervous system may not respond to intrathecal Cytarabine Injection and may better be treated with radiotherapy.

  Chemical Stability of Infusion Solutions

  Chemical stability studies were performed by HPLC on Cytarabine Injection in infusion solutions.  These studies showed that when Cytarabine Injection was added to Water for Injection, 5% Dextrose in Water or Sodium Chloride Injection, 94 to 96 percent of the cytarabine was present after 192 hours storage at room temperature.

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

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• Etoposide
  

  ×

  Etoposide

  

  ---

  Note: Plastic devices made of acrylic or ABS (a polymer composed of acrylonitrile, butadiene, and styrene) have been reported to crack and leak when used with undiluted Etoposide Injection, USP.

  The usual dose of Etoposide Injection, USP in testicular cancer in combination with other approved chemotherapeutic agents ranges from 50 to 100 mg/m2/day on days 1 through 5 to 100 mg/m2/day on days 1, 3, and 5.

  In small cell lung cancer, the Etoposide Injection, USP dose in combination with other approved chemotherapeutic drugs ranges from 35 mg/m2/day for 4 days to 50 mg/m2/day for 5 days.

  For recommended dosing adjustments in patients with renal impairment (see PRECAUTIONS).

  Chemotherapy courses are repeated at 3- to 4-week intervals after adequate recovery from any toxicity.

  The dosage, by either route, should be modified to take into account the myelosuppressive effects of other drugs in the combination or the effects of prior x-ray therapy or chemotherapy which may have compromised bone marrow reserve.

  Administration Precautions

  As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide.  Skin reactions associated with accidental exposure to etoposide may occur.  The use of gloves is recommended.  If etoposide solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

  Preparation for Intravenous Administration

  Etoposide Injection, USP must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL.  If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur.  Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the etoposide solution be administered over a 30- to 60-minute period.  A longer duration of administration may be used if the volume of fluid to be infused is a concern.  Etoposide should not be given by rapid intravenous injection.

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

  Stability

  Unopened vials of Etoposide Injection, USP are stable for 24 months at room temperature (25°C).  Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published4-10.  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

  Administration Precautions

  As with other potentially toxic compounds, caution should be exercised in handling and preparing the solution of etoposide.  Skin reactions associated with accidental exposure to etoposide may occur.  The use of gloves is recommended.  If etoposide solution contacts the skin or mucosa, immediately and thoroughly wash the skin with soap and water and flush the mucosa with water.

  Preparation for Intravenous Administration

  Etoposide Injection, USP must be diluted prior to use with either 5% Dextrose Injection, USP, or 0.9% Sodium Chloride Injection, USP, to give a final concentration of 0.2 to 0.4 mg/mL.  If solutions are prepared at concentrations above 0.4 mg/mL, precipitation may occur.  Hypotension following rapid intravenous administration has been reported, hence, it is recommended that the etoposide solution be administered over a 30- to 60-minute period.  A longer duration of administration may be used if the volume of fluid to be infused is a concern.  Etoposide should not be given by rapid intravenous injection.

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

  Stability

  Unopened vials of Etoposide Injection, USP are stable for 24 months at room temperature (25°C).  Vials diluted as recommended to a concentration of 0.2 or 0.4 mg/mL are stable for 96 and 24 hours, respectively, at room temperature (25°C) under normal room fluorescent light in both glass and plastic containers.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published4-10.  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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• Propranolol
  

  ×

  Propranolol

  

  ---

  The usual dose is 1 mg to 3 mg administered under careful monitoring, such as electrocardiographiy and central venous pressure.  The rate of administration should not exceed 1 mg (1 mL) per minute to diminish the possibility of lowering blood pressure and causing cardiac standstill.

  Sufficient time should be allowed for the drug to reach the site of action even when a slow circulation is present.  If necessary, a second dose may be given after two minutes.  Thereafter, additional drug should not be given in less than four hours.  Additional propranolol hydrochloride should not be given when the desired alteration in rate and/or rhythm is achieved.

  Transfer to oral therapy as soon as possible.

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

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• Sodium Chloride
  

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  Sodium Chloride

  

  ---

  Sodium chloride injection is administered intravenously only after addition to a larger volume of fluid.

  The dose, dilution and rate of injection are dependent upon the individual needs of each patient.

  All or part of the contents of one or more additive containers may be added to an intravenous solution container.  Concentrations of up to 5% sodium chloride have been administered.

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

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• Bacteriostatic Sodium C...
  

  ×

  Bacteriostatic Sodium Chloride

  

  ---

  NOT FOR INHALATION.  Before Bacteriostatic Sodium Chloride Injection, USP, 0.9% is used as a vehicle for the administration of a drug, specific references should be checked for any possible incompatibility with sodium chloride or the bacteriostatic agents.

  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.

  Isotonic solutions may be given subcutaneously, intravenously, and occasionally, intramuscularly.

  Use Bacteriostatic Sodium Chloride Injection, USP, 0.9% with due regard for the compatibility of the antimicrobial agents it contains with the particular medicinal substance that is to be dissolved or diluted.

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

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• Bacteriostatic Sodium C...
  

  ×

  Bacteriostatic Sodium Chloride

  

  ---

  NOT FOR INHALATION.  Before Bacteriostatic Sodium Chloride Injection, USP, 0.9% is used as a vehicle for the administration of a drug, specific references should be checked for any possible incompatibility with sodium chloride or benzyl alcohol.

  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.

  Isotonic solutions may be given subcutaneously, intravenously, and occasionally, intramuscularly.

  Use Bacteriostatic Sodium Chloride Injection, USP, 0.9% with due regard for the compatibility of the benzyl alcohol it contains with the particular medicinal substance that is to be dissolved or diluted.

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

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• Acyclovir
  

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  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 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/1.73m2)

  Percent of Recommended Dose

  Dosing Interval

  (hours)

  >50

  25-50

  10-25

  0-10

  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.

  Method of Preparation:

  Each 10 mL vial contains acyclovir sodium equivalent to 500 mg of acyclovir.  The contents of the vial should be dissolved with 10 mL Sterile Water for Injection.

  The resulting solution contains 50 mg acyclovir per mL.  The pH of the solution is approximately 11.  Shake the vial well to assure complete dissolution before measuring and transferring each individual dose.  The reconstituted solution should be used within 12 hours.  Refrigeration of reconstituted solution may result in the formation of a precipitate which will redissolve at room temperature. 

  DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING BENZYL ALCOHOL OR PARABENS.

  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 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/1.73m2)

  Percent of Recommended Dose

  Dosing Interval

  (hours)

  >50

  25-50

  10-25

  0-10

  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.

  Method of Preparation:

  Each 10 mL vial contains acyclovir sodium equivalent to 500 mg of acyclovir.  The contents of the vial should be dissolved with 10 mL Sterile Water for Injection.

  The resulting solution contains 50 mg acyclovir per mL.  The pH of the solution is approximately 11.  Shake the vial well to assure complete dissolution before measuring and transferring each individual dose.  The reconstituted solution should be used within 12 hours.  Refrigeration of reconstituted solution may result in the formation of a precipitate which will redissolve at room temperature. 

  DO NOT USE BACTERIOSTATIC WATER FOR INJECTION CONTAINING BENZYL ALCOHOL OR PARABENS.

  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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• Scopolamine Hydrobromid...
  

  ×

  Scopolamine Hydrobromide

  

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  Adult

  For obstetric amnesia or preoperative sedation, 0.32 to 0.65 mg (320 to 650 mcg).

  For sedation or tranquilization, 0.6 mg (600 mcg) 3 or 4 times a day.

  Subcutaneous, as an antiemetic, 0.6 to 1 mg.

  Pediatric

  Age 6 mo. to 3 yr., 0.1 to 0.15 mg (100 to 150 mcg).  Age 3 to 6 yr., 0.2 to 0.3 mg (200 to 300 mcg).

  Subcutaneous, as antiemetic, 0.006 mg (6 mcg) per kg.

   

                Dosage Equivalents

  1 mg (1000 mcg)/mL

  1     mg

        (1000 mcg)        

  1    mL

  0.8  mg

  (800 mcg)

  0.8  mL

  0.6  mg

  (600 mcg)

  0.6  mL

  0.5  mg

  (500 mcg)

  0.5  mL

  0.4  mg

  (400 mcg)

  0.4  mL

  0.3  mg

  (300 mcg)

  0.3  mL

  0.2  mg

  (200 mcg)

  0.2  mL

  0.1  mg

  (100 mcg)

  0.1  mL

  0.4 mg (400 mcg)/mL

  0.4  mg

  (400 mcg)

  1    mL

  0.3  mg

  (300 mcg)

     0.75 mL  

     0.25 mg  

  (250 mcg)

  0.63 mL

  0.2  mg

  (200 mcg)

  0.50 mL

  0.15 mg

  (150 mcg)

  0.38 mL

  Belladonna alkaloids provide a therapeutic effect in about 1 or 2 hours with a duration of about 4 hours.

  Geriatric and debilitated patients may respond to the usual doses with excitement, agitation, drowsiness or confusion; lower doses may be required in such patients.

  Close supervision is recommended for infants, blondes, mongoloids and children with spastic paralysis or brain damage, since an increased responsiveness to belladonna alkaloids has been reported in these patients and dosage adjustments are often required.

  Administration of belladonna alkaloids and barbiturates 30 to 60 minutes before meals is recommended to maximize absorption and, when issued for reducing stomach acid formation, to allow its effect to coincide better with antacid administration following the meal.

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

  Adult

  For obstetric amnesia or preoperative sedation, 0.32 to 0.65 mg (320 to 650 mcg).

  For sedation or tranquilization, 0.6 mg (600 mcg) 3 or 4 times a day.

  Subcutaneous, as an antiemetic, 0.6 to 1 mg.

  Pediatric

  Age 6 mo. to 3 yr., 0.1 to 0.15 mg (100 to 150 mcg).  Age 3 to 6 yr., 0.2 to 0.3 mg (200 to 300 mcg).

  Subcutaneous, as antiemetic, 0.006 mg (6 mcg) per kg.

   

                Dosage Equivalents

  1 mg (1000 mcg)/mL

  1     mg

        (1000 mcg)        

  1    mL

  0.8  mg

  (800 mcg)

  0.8  mL

  0.6  mg

  (600 mcg)

  0.6  mL

  0.5  mg

  (500 mcg)

  0.5  mL

  0.4  mg

  (400 mcg)

  0.4  mL

  0.3  mg

  (300 mcg)

  0.3  mL

  0.2  mg

  (200 mcg)

  0.2  mL

  0.1  mg

  (100 mcg)

  0.1  mL

  0.4 mg (400 mcg)/mL

  0.4  mg

  (400 mcg)

  1    mL

  0.3  mg

  (300 mcg)

     0.75 mL  

     0.25 mg  

  (250 mcg)

  0.63 mL

  0.2  mg

  (200 mcg)

  0.50 mL

  0.15 mg

  (150 mcg)

  0.38 mL

  Belladonna alkaloids provide a therapeutic effect in about 1 or 2 hours with a duration of about 4 hours.

  Geriatric and debilitated patients may respond to the usual doses with excitement, agitation, drowsiness or confusion; lower doses may be required in such patients.

  Close supervision is recommended for infants, blondes, mongoloids and children with spastic paralysis or brain damage, since an increased responsiveness to belladonna alkaloids has been reported in these patients and dosage adjustments are often required.

  Administration of belladonna alkaloids and barbiturates 30 to 60 minutes before meals is recommended to maximize absorption and, when issued for reducing stomach acid formation, to allow its effect to coincide better with antacid administration following the meal.

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

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• Midazolam
  

  ×

  Midazolam

  

  ---

  Midazolam injection is a potent sedative agent that requires slow administration and individualization of dosage.  Clinical experience has shown midazolam to be 3 to 4 times as potent per mg as diazepam.  BECAUSE SERIOUS AND LIFE-THREATENING CARDIORESPIRATORY ADVERSE EVENTS HAVE BEEN REPORTED, PROVISION FOR MONITORING, DETECTION AND CORRECTION OF THESE REACTIONS MUST BE MADE FOR EVERY PATIENT TO WHOM MIDAZOLAM INJECTION IS ADMINISTERED, REGARDLESS OF AGE OR HEALTH STATUS.  Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest.  The potential for these latter effects is increased in debilitated patients, those receiving concomitant medications capable of depressing the CNS, and patients without an endotracheal tube but undergoing a procedure involving the upper airway such as endoscopy or dental (see BOXED WARNING and WARNINGS).

  Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients.  Should such reactions occur, caution should be exercised before continuing administration of midazolam (see WARNINGS).

  Midazolam injection should only be administered IM or IV (see WARNINGS).

  Care should be taken to avoid intra-arterial injection or extravasation (see WARNINGS).

  Midazolam injection may be mixed in the same syringe with the following frequently used premedications: morphine sulfate, meperidine, atropine sulfate or scopolamine. Midazolam, at a concentration of 0.5 mg/mL, is compatible with 5% dextrose in water and 0.9% sodium chloride for up to 24 hours and with lactated Ringer’s solution for up to 4 hours.  Both the 1 mg/mL and 5 mg/mL formulations of midazolam may be diluted with 0.9% sodium chloride or 5% dextrose in water.

  Monitoring

  Patient response to sedative agents, and resultant respiratory status, is variable.  Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes.  This is especially true in pediatric patients.  Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants.  Continuous monitoring of respiratory and cardiac function is required (ie, pulse oximetry).

  Adults and Pediatrics:  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as physical examination including a focused examination of the airway for abnormalities.  Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration.  It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation.  Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration.  This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics:  For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Monitoring

  Patient response to sedative agents, and resultant respiratory status, is variable.  Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes.  This is especially true in pediatric patients.  Sedative doses should be individually titrated, taking into account patient age, clinical status and concomitant use of other CNS depressants.  Continuous monitoring of respiratory and cardiac function is required (ie, pulse oximetry).

  Adults and Pediatrics:  Sedation guidelines recommend a careful presedation history to determine how a patient’s underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as physical examination including a focused examination of the airway for abnormalities.  Further recommendations include appropriate presedation fasting.

  Titration to effect with multiple small doses is essential for safe administration.  It should be noted that adequate time to achieve peak central nervous system effect (3 to 5 minutes) for midazolam should be allowed between doses to minimize the potential for oversedation.  Sufficient time must elapse between doses of concomitant sedative medications to allow the effect of each dose to be assessed before subsequent drug administration.  This is an important consideration for all patients who receive intravenous midazolam.

  Immediate availability of resuscitative drugs and age- and size-appropriate equipment and personnel trained in their use and skilled in airway management should be assured (see WARNINGS).

  Pediatrics:  For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

  Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available.

  Continous Intravenous Infusion (Non-Neontal)

  Usual Pediatric Dose (Non-Neonatal)

  For sedation/anxiolysis/ amnesia in critical care settings.

  To initiate sedation, an intravenous loading dose of 0.05 to 0.2 mg/kg administered over at least 2 to 3 minutes can be used to establish the desired clinical effect IN PATIENTS WHOSE TRACHEA IS INTUBATED.  (Midazolam should not be administered as a rapid intravenous dose.)  This loading dose may be followed by a continuous intravenous infusion to maintain the effect.  An infusion of midazolam has been used in patients whose trachea was intubated but who were allowed to breathe spontaneously.  Assisted ventilation is recommended for pediatric patients who are receiving other central nervous system depressant medications such as opioids.  Based on pharmacokinetic parameters and reported clinical experience, continuous intravenous infusions of midazolam should be initiated at a rate of 0.06 to 0.12 mg/kg/hr (1 to 2 mcg/kg/min).  The rate of infusion can be increased or decreased (generally by 25% of the initial or sub sequent infusion rate) as required, or supplemental intravenous doses of midazolam can be administered to increase or maintain the desired effect.  Frequent assessment at regular intervals using standard pain/sedation scales is recommended.  Drug elimination may be delayed in patients receiving erythromycin and/or other P450 3A4 enzyme inhibitors (see PRECAUTIONS: Drug Interactions) and in patients with liver dysfunction, low cardiac output (especially those requiring inotropic support), and in neonates.  Hypotension may be observed in patients who are critically ill, particularly those receiving opioids and/or when midazolam is rapidly administered.

   

  When initiating an infusion with midazolam in hemodynamically compromised patients, the usual loading dose of midazolam should be titrated in small increments and the patient monitored for hemodynamic instability (eg, hypotension).  These patients are also vulnerable to the respiratory depressant effects of midazolam and require careful monitoring of respiratory rate and oxygen saturation.

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

  Continuous Intravenous Infusion (Neonatal)

  For sedation in critical care setting.

  Usual Neonatal Dose

  Based on pharmacokinetic parameters and reported clinical experience in preterm and term neonates WHOSE TRACHEA WAS INTUBATED, continuous intravenous infusions of midazolam injection should be initiated at a rate of 0.03 mg/kg/hr (0.5 mcg/kg/min) in neonates <32 weeks and 0.06 mg/kg/hr (1 mcg/kg/min) in neonates >32 weeks.  Intravenous loading doses should not be used in neonates, rather the infusion may be run more rapidly for the first several hours to establish therapeutic plasma levels.  The rate of infusion should be carefully and frequently reassessed, particularly after the first 24 hours so as to administer the lowest possible effective dose and reduce the potential for drug accumulation.  This is particularly important because of the potential for adverse effects related to metabolism of the benzyl alcohol (see WARNINGS: Usage in Preterm Infants and Neonates).  Hypotension may be observed in patients who are critically ill and in preterm and term infants, particularly those receiving fentanyl and/or when midazolam is administered rapidly.  Due to an increased risk of apnea, extreme caution is advised when sedating preterm and former preterm patients whose trachea is not intubated.

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• Flumazenil
  

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  Flumazenil

  

  ---

  Flumazenil Injection, USP is recommended for intravenous use only.  It is compatible with 5% dextrose in water, lactated Ringer’s and normal saline solutions.  If Flumazenil Injection, USP is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours.  For optimum sterility, Flumazenil Injection, USP should remain in the vial until just before use.  As with all parenteral drug products, Flumazenil Injection, USP should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  To minimize the likelihood of pain at the injection site, Flumazenil Injection, USP should be administered through a freely running intravenous infusion into a large vein.

  Reversal of Conscious Sedation

  Adult Patients

  For the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).  The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see Individualization of Dosage).

  In the event of resedation, repeated doses may be administered at 20-minute intervals as needed.  For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  Pediatric Patients

  For the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 1 year of age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower.  The dose should be individualized based on the patient’s response.  The mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to 1 mg).  Approximately one-half of patients required the maximum of five injections.

  Resedation occurred in 7 of 60 patients who were fully alert 10 minutes after the start of Flumazenil Injection, USP administration (see PRECAUTIONS: Pediatric Use).  The safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  The safety and efficacy of Flumazenil Injection, USP in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established.

  Reversal of General Anesthesia in Adult Patients

  For the reversal of the sedative effects of benzodiazepines administered for general anesthesia, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).  The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see Individualization of Dosage).

  In the event of resedation, repeated doses may be administered at 20-minute intervals as needed.  For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  Management of Suspected Benzodiazepine Overdose in Adult Patients

  For initial management of a known or suspected benzodiazepine overdose, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 30 seconds.  If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL) can be administered over another 30 seconds.  Further doses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.

  Do not rush the administration of Flumazenil Injection, USP.  Patients should have a secure airway and intravenous access before administration of the drug and be awakened gradually (see PRECAUTIONS).

  Most patients with a benzodiazepine overdose will respond to a cumulative dose of 1 mg to 3 mg of Flumazenil Injection, USP, and doses beyond 3 mg do not reliably produce additional effects.  On rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner).

  If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg of Flumazenil Injection, USP, the major cause of sedation is likely not to be due to benzodiazepines, and additional Flumazenil Injection, USP is likely to have no effect.

  In the event of resedation, repeated doses may be given at 20-minute intervals if needed.  For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour.

  Safety and Handling

  Flumazenil Injection, USP is supplied in sealed dosage forms and poses no known risk to the healthcare provider.  Routine care should be taken to avoid aerosol generation when preparing syringes for injection, and spilled medication should be rinsed from the skin with cool water.

  Reversal of Conscious Sedation

  Adult Patients

  For the reversal of the sedative effects of benzodiazepines administered for conscious sedation, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).  The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see Individualization of Dosage).

  In the event of resedation, repeated doses may be administered at 20-minute intervals as needed.  For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  Pediatric Patients

  For the reversal of the sedative effects of benzodiazepines administered for conscious sedation in pediatric patients greater than 1 year of age, the recommended initial dose is 0.01 mg/kg (up to 0.2 mg) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, further injections of 0.01 mg/kg (up to 0.2 mg) can be administered and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 0.05 mg/kg or 1 mg, whichever is lower.  The dose should be individualized based on the patient’s response.  The mean total dose administered in the pediatric clinical trial of flumazenil was 0.65 mg (range: 0.08 mg to 1 mg).  Approximately one-half of patients required the maximum of five injections.

  Resedation occurred in 7 of 60 patients who were fully alert 10 minutes after the start of Flumazenil Injection, USP administration (see PRECAUTIONS: Pediatric Use).  The safety and efficacy of repeated flumazenil administration in pediatric patients experiencing resedation have not been established.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  The safety and efficacy of Flumazenil Injection, USP in the reversal of conscious sedation in pediatric patients below the age of 1 year have not been established.

  Reversal of General Anesthesia in Adult Patients

  For the reversal of the sedative effects of benzodiazepines administered for general anesthesia, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 15 seconds.  If the desired level of consciousness is not obtained after waiting an additional 45 seconds, a further dose of 0.2 mg (2 mL) can be injected and repeated at 60-second intervals where necessary (up to a maximum of 4 additional times) to a maximum total dose of 1 mg (10 mL).  The dosage should be individualized based on the patient’s response, with most patients responding to doses of 0.6 mg to 1 mg (see Individualization of Dosage).

  In the event of resedation, repeated doses may be administered at 20-minute intervals as needed.  For repeat treatment, no more than 1 mg (given as 0.2 mg/min) should be administered at any one time, and no more than 3 mg should be given in any one hour.

  It is recommended that Flumazenil Injection, USP be administered as the series of small injections described (not as a single bolus injection) to allow the practitioner to control the reversal of sedation to the approximate endpoint desired and to minimize the possibility of adverse effects (see Individualization of Dosage).

  Management of Suspected Benzodiazepine Overdose in Adult Patients

  For initial management of a known or suspected benzodiazepine overdose, the recommended initial dose of Flumazenil Injection, USP is 0.2 mg (2 mL) administered intravenously over 30 seconds.  If the desired level of consciousness is not obtained after waiting 30 seconds, a further dose of 0.3 mg (3 mL) can be administered over another 30 seconds.  Further doses of 0.5 mg (5 mL) can be administered over 30 seconds at 1-minute intervals up to a cumulative dose of 3 mg.

  Do not rush the administration of Flumazenil Injection, USP.  Patients should have a secure airway and intravenous access before administration of the drug and be awakened gradually (see PRECAUTIONS).

  Most patients with a benzodiazepine overdose will respond to a cumulative dose of 1 mg to 3 mg of Flumazenil Injection, USP, and doses beyond 3 mg do not reliably produce additional effects.  On rare occasions, patients with a partial response at 3 mg may require additional titration up to a total dose of 5 mg (administered slowly in the same manner).

  If a patient has not responded 5 minutes after receiving a cumulative dose of 5 mg of Flumazenil Injection, USP, the major cause of sedation is likely not to be due to benzodiazepines, and additional Flumazenil Injection, USP is likely to have no effect.

  In the event of resedation, repeated doses may be given at 20-minute intervals if needed.  For repeat treatment, no more than 1 mg (given as 0.5 mg/min) should be given at any one time and no more than 3 mg should be given in any one hour.

  Safety and Handling

  Flumazenil Injection, USP is supplied in sealed dosage forms and poses no known risk to the healthcare provider.  Routine care should be taken to avoid aerosol generation when preparing syringes for injection, and spilled medication should be rinsed from the skin with cool water.

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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 Fuction 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.

  Preparation and Stability

  At the time of use, reconstitute vials of vancomycin with Sterile Water for Injection to a concentration of 50 mg of vancomycin/mL. (See following table for volume of diluent.)

   Concentration/Vial  Volume of Diluent  500 mg  10 mL  1 g  20 mL

  After reconstitution, the vials may be stored in a refrigerator for 96 hours without significant loss of potency.

  Reconstituted solutions of vancomycin (500 mg/10 mL) must be further diluted in at least 100 mL of a suitable infusion solution.  For doses of 1 gram (20 mL), at least 200 mL of solution must be used.  The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes.

  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.

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

  For Oral Administration

  Oral vancomycin is used in treating antibiotic-associated pseudomembranous colitis caused by C. difficile and for staphylococcal enterocolitis.  Vancomycin is not effective by the oral route for other types of infections.  The usual adult total daily dosage is 500 mg to 2 g given in 3 or 4 divided doses for 7 to 10 days.  The total daily dose in children is 40 mg/kg of body weight in 3 or 4 divided doses for 7 to 10 days.  The total daily dosage should not exceed 2 g.  The appropriate dose may be diluted in 1 oz of water and given to the patient to drink.  Common flavoring syrups may be added to the solution to improve the taste for oral administration.  The diluted solution may be administered via a nasogastric tube.

  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 Fuction 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.

  Preparation and Stability

  At the time of use, reconstitute vials of vancomycin with Sterile Water for Injection to a concentration of 50 mg of vancomycin/mL. (See following table for volume of diluent.)

   Concentration/Vial  Volume of Diluent  500 mg  10 mL  1 g  20 mL

  After reconstitution, the vials may be stored in a refrigerator for 96 hours without significant loss of potency.

  Reconstituted solutions of vancomycin (500 mg/10 mL) must be further diluted in at least 100 mL of a suitable infusion solution.  For doses of 1 gram (20 mL), at least 200 mL of solution must be used.  The desired dose diluted in this manner should be administered by intermittent IV infusion over a period of at least 60 minutes.

  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.

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

  For Oral Administration

  Oral vancomycin is used in treating antibiotic-associated pseudomembranous colitis caused by C. difficile and for staphylococcal enterocolitis.  Vancomycin is not effective by the oral route for other types of infections.  The usual adult total daily dosage is 500 mg to 2 g given in 3 or 4 divided doses for 7 to 10 days.  The total daily dose in children is 40 mg/kg of body weight in 3 or 4 divided doses for 7 to 10 days.  The total daily dosage should not exceed 2 g.  The appropriate dose may be diluted in 1 oz of water and given to the patient to drink.  Common flavoring syrups may be added to the solution to improve the taste for oral administration.  The diluted solution may be administered via a nasogastric tube.

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• Ifosfamide
  

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  Ifosfamide

  

  ---

  Ifosfamide 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 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 should be administered as a slow intravenous infusion lasting a minimum of 30 minutes.  Although ifosfamide has been administered to a small number of patients with compromised hepatic and/or renal function, studies to establish optimal dose schedules of ifosfamide in such patients have not been conducted.

  Preparation for Intravenous Administration/Stability

  Ifosfamide injection may be diluted 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.

  Further diluted solutions of ifosfamide 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

  Ifosfamide injection may be diluted 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.

  Further diluted solutions of ifosfamide 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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• Sodium Chloride
  

  ×

  Sodium Chloride

  

  ---

  Before Sodium Chloride Injection, USP, 0.9% is used as a vehicle for the administration of a drug, specific references should be checked for any possible incompatibility with sodium chloride.

  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.

  Sodium Chloride Injection, USP, 0.9% is also indicated for use in flushing intravenous catheters.  Prior to and after administration of the medication, the intravenous catheter should be flushed in its entirety with Sodium Chloride Injection, USP, 0.9%.  Use in accord with any warnings or precautions appropriate to the medication being administered.

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

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• Sodium Chloride
  

  ×

  Sodium Chloride

  

  ---

  Before Sodium Chloride Injection, USP, 0.9% is used as a vehicle for the administration of a drug, specific references should be checked for any possible incompatibility with sodium chloride.

  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.

  Sodium Chloride Injection, USP, 0.9% is also indicated for use in flushing intravenous catheters.  Prior to and after administration of the medication, the intravenous catheter must be flushed in its entirety with 2 mL of Sodium Chloride Injection, USP, 0.9%.  Use in accord with any warnings or precautions appropriate to the medication being administered.

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

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• Lidocaine
  

  ×

  Lidocaine

  

  ---

  Adult

  For Direct Injection–The usual dose is 50 to 100 mg administered intravenously under ECG monitoring.  This dose may be administered at the rate of approximately 25 to 50 mg/min.  Sufficient time should be allowed to enable a slow circulation to carry the drug to the site of action.  If the initial injection of 50 to 100 mg does not produce a desired response, a second dose may be repeated after 5 minutes.

  NO MORE THAN 200 TO 300 MG OF LIDOCAINE HYDROCHLORIDE INJECTION, USP SHOULD BE ADMINISTERED DURING A ONE HOUR PERIOD.

  This product is for DIRECT INJECTION ONLY.  For continuous infusion protocol, see prescribing information for lidocaine hydrochloride, USP for infusion solution.

  Pediatric

  Although controlled clinical studies to establish pediatric dosing schedules have not been conducted, the American Heart Association’s Standards and Guidelines recommends a bolus dose of 1 mg/kg followed by an infusion rate of 30 mcg/kg/min.

  This product is for DIRECT INJECTION ONLY.  For continuous infusion protocol, see prescribing information for lidocaine hydrochloride, USP for infusion solution.

  Sterilization, Storage and Technical Procedures

  It is recommended that chemical disinfection be accomplished by wiping the vial thoroughly with cotton or gauze that has been moistened with either 91% isopropyl alcohol or 70% ethyl alcohol, just prior to use.  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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

  Adult

  For Direct Injection–The usual dose is 50 to 100 mg administered intravenously under ECG monitoring.  This dose may be administered at the rate of approximately 25 to 50 mg/min.  Sufficient time should be allowed to enable a slow circulation to carry the drug to the site of action.  If the initial injection of 50 to 100 mg does not produce a desired response, a second dose may be repeated after 5 minutes.

  NO MORE THAN 200 TO 300 MG OF LIDOCAINE HYDROCHLORIDE INJECTION, USP SHOULD BE ADMINISTERED DURING A ONE HOUR PERIOD.

  This product is for DIRECT INJECTION ONLY.  For continuous infusion protocol, see prescribing information for lidocaine hydrochloride, USP for infusion solution.

  Pediatric

  Although controlled clinical studies to establish pediatric dosing schedules have not been conducted, the American Heart Association’s Standards and Guidelines recommends a bolus dose of 1 mg/kg followed by an infusion rate of 30 mcg/kg/min.

  This product is for DIRECT INJECTION ONLY.  For continuous infusion protocol, see prescribing information for lidocaine hydrochloride, USP for infusion solution.

  Sterilization, Storage and Technical Procedures

  It is recommended that chemical disinfection be accomplished by wiping the vial thoroughly with cotton or gauze that has been moistened with either 91% isopropyl alcohol or 70% ethyl alcohol, just prior to use.  Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

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

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• Sodium Chloride
  

  ×

  Sodium Chloride

  

  ---

  The dosage of Sodium Chloride Injection, USP, 23.4%, as an additive in parenteral fluid therapy is predicated on specific requirements of the patient after necessary clinical and laboratory information is considered and correlated.  The appropriate volume is then withdrawn for proper dilution.  Having determined the milliequivalents of sodium chloride to be added, divide by four to calculate the numbers of milliliters (mL) of sodium chloride to be used.  Withdraw this volume aseptically and transfer the additive solution into appropriate intravenous solutions such as 5% Dextrose Injection.  The properly diluted solutions may be given intravenously.

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

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• Vancomycin Hydrochlorid...
  

  ×

  Vancomycin Hydrochloride

  

  ---

  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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• Sodium Chloride
  

  ×

  Sodium Chloride

  

  ---

  Sodium chloride injection is administered intravenously only after addition to a larger volume of fluid.

  The dose, dilution and rate of injection are dependent upon the individual needs of each patient. 

  All or part of the contents of one or more additive containers may be added to an intravenous solution container.  Concentrations of up to 5% sodium chloride have been administered.

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• Sodium Bicarbonate Solu...
  

  ×

  Sodium Bicarbonate Solution

  

  ---

  One vial (5 mL) of Sodium Bicarbonate 4.2% Neutralizing Additive Solution added to a liter (1,000 mL) of any of the following parenteral solutions will increase the pH to a more physiologic range.  Specific pH may vary slightly from lot to lot.

  5% Alcohol and D5-W

  5% Dextrose and Ringer’s

  5% Dextrose and 0.45% Sodium Chloride Injection, USP

  2.5% Dextrose and 0.45% Sodium Chloride Injection, USP

  5% and 0.225% Sodium Chloride Injection, USP

  5% Dextrose and 0.9% Sodium Chloride Injection, USP

  2.5% Dextrose Injection, USP

  5% Dextrose Injection, USP

  10% Dextrose Injection, USP

  20% Dextrose Injection, USP

  10% Invert Sugar

  Lactated Ringer’s

  Ringer’s Injection

  0.9% Sodium Chloride Injection, USP

  0.45% Sodium Chloride Injection, USP

  Sodium Lactate 1/6 Molar

   

  NOTE: Some products such as amino acid solutions and multiple electrolyte solutions

   containing dextrose will NOT be brought to near physiologic pH by the addition of

   Sodium Bicarbonate 4.2% Neutralizing Additive Solution.  This is due to the relatively

   high buffer capacity of these fluids.

   

  COMPATIBILITY AND EFFECTIVENESS OF SODIUM BICARBONATE 4.2% NEUTRALIZING ADDITIVE SOLUTION WITH ADDITIVES TO 5% DEXTROSE INJECTION (D5-W)

  When medications are added to intravenous solutions, the resultant admixture may or may not be compatible in solutions containing Sodium Bicarbonate 4.2% Neutralizing Additive Solution.  (See Compatibility section under Sodium Bicarbonate in Handbook on Injectable Drugs by Lawrence A. Trissel.)

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

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• Furosemide
  

  ×

  Furosemide

  

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  Adults

  Parenteral therapy with furosemide injection should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical.

  Edema

  The usual initial dose of furosemide is 20 to 40 mg given as a single dose, injected IM or IV. The IV dose should be given slowly (one to two minutes).  Ordinarily a prompt diuresis ensues. If needed, another dose may be administered in the same manner two hours later or the dose may be increased.  The dose may be raised by 20 mg and given not sooner than two hours after the previous dose until the desired diuretic effect has been obtained.  This individually determined single dose should then be given once or twice daily.

  Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.  Close medical supervision is necessary.

  If the physician elects to use high dose parenteral therapy, add the furosemide to either Sodium Chloride Injection USP, Lactated Ringer’s Injection USP, or Dextrose Injection 5% USP, after pH has been adjusted to above 5.5, and administer as a controlled IV infusion at a rate not greater than 4 mg/min.  Furosemide injection is a buffered alkaline solution with a pH of about 9 and the drug may precipitate at pH values below 7.  Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range.  Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide.  In addition, furosemide injection should not be added to a running intravenous line containing any of these acidic products.

  Acute Pulmonary Edema

  The usual initial dose of furosemide is 40 mg injected slowly IV (over one to two minutes).  If a satisfactory response does not occur within one hour, the dose may be increased to 80 mg injected slowly IV (over one to two minutes).

  If necessary, additional therapy (e.g., digitalis, oxygen) may be administered concomitantly.

  Geriatric Patients

  In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS : Geriatric Use ).

  Pediatric Patients

  Parenteral therapy should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical.

  The usual initial dose of furosemide injection (IM or IV) in pediatric patients is 1 mg/kg body weight and should be given slowly under close medical supervision.  If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than two hours after the previous dose, until the desired diuretic effect has been obtained.  Doses greater than 6 mg/kg body weight are not recommended.

  Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day (see WARNINGS, Pediatric Use).

  Furosemide injection should be inspected visually for particulate matter and discoloration before administration.  Do not use if solution is discolored.

  Adults

  Parenteral therapy with furosemide injection should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical.

  Edema

  The usual initial dose of furosemide is 20 to 40 mg given as a single dose, injected IM or IV. The IV dose should be given slowly (one to two minutes).  Ordinarily a prompt diuresis ensues. If needed, another dose may be administered in the same manner two hours later or the dose may be increased.  The dose may be raised by 20 mg and given not sooner than two hours after the previous dose until the desired diuretic effect has been obtained.  This individually determined single dose should then be given once or twice daily.

  Therapy should be individualized according to patient response to gain maximal therapeutic response and to determine the minimal dose needed to maintain that response.  Close medical supervision is necessary.

  If the physician elects to use high dose parenteral therapy, add the furosemide to either Sodium Chloride Injection USP, Lactated Ringer’s Injection USP, or Dextrose Injection 5% USP, after pH has been adjusted to above 5.5, and administer as a controlled IV infusion at a rate not greater than 4 mg/min.  Furosemide injection is a buffered alkaline solution with a pH of about 9 and the drug may precipitate at pH values below 7.  Care must be taken to ensure that the pH of the prepared infusion solution is in the weakly alkaline to neutral range.  Acid solutions, including other parenteral medications (e.g., labetalol, ciprofloxacin, amrinone, milrinone) must not be administered concurrently in the same infusion because they may cause precipitation of the furosemide.  In addition, furosemide injection should not be added to a running intravenous line containing any of these acidic products.

  Acute Pulmonary Edema

  The usual initial dose of furosemide is 40 mg injected slowly IV (over one to two minutes).  If a satisfactory response does not occur within one hour, the dose may be increased to 80 mg injected slowly IV (over one to two minutes).

  If necessary, additional therapy (e.g., digitalis, oxygen) may be administered concomitantly.

  Geriatric Patients

  In general, dose selection for the elderly patient should be cautious, usually starting at the low end of the dosing range (see PRECAUTIONS : Geriatric Use ).

  Pediatric Patients

  Parenteral therapy should be used only in patients unable to take oral medication or in emergency situations and should be replaced with oral therapy as soon as practical.

  The usual initial dose of furosemide injection (IM or IV) in pediatric patients is 1 mg/kg body weight and should be given slowly under close medical supervision.  If the diuretic response to the initial dose is not satisfactory, dosage may be increased by 1 mg/kg not sooner than two hours after the previous dose, until the desired diuretic effect has been obtained.  Doses greater than 6 mg/kg body weight are not recommended.

  Literature reports suggest that the maximum dose for premature infants should not exceed 1 mg/kg/day (see WARNINGS, Pediatric Use).

  Furosemide injection should be inspected visually for particulate matter and discoloration before administration.  Do not use if solution is discolored.

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• Dacarbazine
  

  ×

  Dacarbazine

  

  ---

  Malignant Melanoma

  The recommended dosage is 2 to 4.5 mg/kg/day for 10 days.  Treatment may be repeated at 4 week intervals.2

  An alternate recommended dosage is 250 mg/square meter body surface/day I.V. for 5 days.  Treatment may be repeated every 3 weeks.3,4

  Hodgkin's Disease

  The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs.  Treatment may be repeated every 4 weeks.5  An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days.6

  Dacarbazine for Injection, USP 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, of Sterile Water for Injection, USP.  The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0.  The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously.

  The reconstituted solution may be further diluted with 5% Dextrose Injection or Sodium Chloride Injection and administered as an intravenous infusion.

  After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours.  If the reconstituted solution is further diluted in 5% Dextrose Injection or Sodium Chloride Injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.7-13  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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

  Malignant Melanoma

  The recommended dosage is 2 to 4.5 mg/kg/day for 10 days.  Treatment may be repeated at 4 week intervals.2

  An alternate recommended dosage is 250 mg/square meter body surface/day I.V. for 5 days.  Treatment may be repeated every 3 weeks.3,4

  Hodgkin's Disease

  The recommended dosage of Dacarbazine for Injection, USP in the treatment of Hodgkin’s disease is 150 mg/square meter body surface/day for 5 days, in combination with other effective drugs.  Treatment may be repeated every 4 weeks.5  An alternative recommended dosage is 375 mg/square meter body surface on day 1, in combination with other effective drugs, to be repeated every 15 days.6

  Dacarbazine for Injection, USP 100 mg/vial and 200 mg/vial are reconstituted with 9.9 mL and 19.7 mL, respectively, of Sterile Water for Injection, USP.  The resulting solution contains 10 mg/mL of dacarbazine having a pH of 3.0 to 4.0.  The calculated dose of the resulting solution is drawn into a syringe and administered only intravenously.

  The reconstituted solution may be further diluted with 5% Dextrose Injection or Sodium Chloride Injection and administered as an intravenous infusion.

  After reconstitution and prior to use, the solution in the vial may be stored at 4°C for up to 72 hours or at normal room conditions (temperature and light) for up to 8 hours.  If the reconstituted solution is further diluted in 5% Dextrose Injection or Sodium Chloride Injection, the resulting solution may be stored at 4°C for up to 24 hours or at normal room conditions for up to 8 hours.

  Procedures for proper handling and disposal of anticancer drugs should be considered.  Several guidelines on this subject have been published.7-13  There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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

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• Methylprednisolone Sodi...
  

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  Methylprednisolone Sodium Succinate

  

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  When high dose therapy is desired, the recommended dose of Methylprednisolone Sodium Succinate for Injection, USP 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.

  Although adverse effects associated with high dose short-term corticoid therapy are uncommon, peptic ulceration may occur. Prophylactic antacid therapy may be indicated.

  In other indications initial dosage will vary from 10 to 40 mg of methylprednisolone depending on the clinical problem being treated. The larger doses may be required for short-term management of severe, acute conditions.  The initial dose usually should be given intravenously over a period of several minutes. Subsequent doses may be given intravenously or intramuscularly at intervals dictated by the patient’s response and clinical condition. Corticoid therapy is an adjunct to, and not replacement for conventional therapy.

  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.

  Methylprednisolone Sodium Succinate for Injection, USP 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, reconstitute the 40 mg/vial product with 1 mL of Bacteriostatic Water for Injection with Benzyl Alcohol, or reconstitute the 125 mg/vial product with 2 mL of Bacteriostatic Water for Injection with Benzyl Alcohol. 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.

  Multiple Sclerosis

  In treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).

  Multiple Sclerosis

  In treatment of acute exacerbations of multiple sclerosis, daily doses of 200 mg of prednisolone for a week followed by 80 mg every other day for 1 month have been shown to be effective (4 mg of methylprednisolone is equivalent to 5 mg of prednisolone).

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• Penicillin G Potassium
  

  ×

  Penicillin G Potassium

  

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  Penicillin G Potassium for Injection, USP should be administered by intravenous infusion.  The usual dose recommendations are as follows:

  Adult patients 

  (*) Because of its short half-life, Penicillin G is administered in divided doses, usually every 4 to 6 hours with the exception of meningococcal meningitis/septicemia, i.e., every 2 hours.

  CLINICAL INDICATION

  DOSAGE

  Serious infections due to susceptible strains of streptococci (including S. pneumoniae)

  12 to 24 million units/day depending on the infection and its severity administered in equally divided doses every 4 to 6 hours.

  -septicemia, empyema, pneumonia, pericarditis, endocarditis and meningitis

  Serious infections due to susceptible strains of staphylococci

  5 to 24 million units/day depending on the infection and its severity administered in equally divided doses every 4 to 6 hours.

  -septicemia, empyema, pneumonia, pericarditis, endocarditis and meningitis

  Anthrax

  Minimum of 8 million units/day in divided doses every 6 hours.  Higher does may be required depending on susceptibility of organism.

  Actinomycosis

    Cervicofacial disease

    Thoracic and abdominal disease

  1 to 6 million units/day(*)

  10 to 20 million units/day(*)

  Clostridial infections

     Botulism (adjunctive therapy to antitoxin)

     Gas gangrene (debridement and/or surgery as indicated)

     Tetanus (adjunctive therapy to human tetanus immune globulin)

  20 million units/day(*)

  Diphtheria (adjunctive therapy to antitoxin and for prevention of the carrier state)

  2 to 3 million units/day in divided doses for 10 to 12 days(*)

  Erysipelothrix endocarditis

  12 to 20 million units/day for 4 to 6 weeks(*)

  Fusospirochetosis (severe infections of the oropharynx [Vincent’s], lower respiratory tract and genital area)

  5 to 10 million units/day(*)

  Listeria infections

    Meningitis

    Endocarditis

  15 to 20 million units/day for 2 weeks(*)

  15 to 20 million units/day for 4 weeks(*)

  Pasteurella infections including bacteremia and meningitis

  4 to 6 million units/day for 2 weeks(*)

  Haverhill fever, Rat-bite fever

  12 to 20 million units/day for 3 to 4 weeks(*)

  Disseminated gonococcal infections, such as meningitis, endocarditis, arthritis, etc., caused by penicillin-susceptible organisms

  10 million units/day(*), duration depends on the type of infection

  Syphilis (neurosyphilis)

  12 to 24 million units/day, as 2 to 4 MU every 4 hours for 10 to 14 days; many experts recommend additional therapy with Benzathine PCN G 2.4 MU IM weekly for 3 doses after completion of IV therapy

  Meningococcal meningitis and/or septicemia

  24 million units/day as 2 million units every 2 hours

  Pediatric patients

  This product should not be administered to patients requiring less than one million units per dose (see PRECAUTIONS, Pediatric Use).

  CLINICAL INDICATION

  DOSAGE

  Serious infections, such as pneumonia and endocarditis, due to susceptible strains of streptococci (including S. pneumoniae) and meningococcus

  150,000 to 300,000 units/kg/day divided in equal doses every 4 to 6 hours, duration depends on infecting organism and type of infection

  Meningitis caused by susceptible strains of pneumococcus and meningococcus

  250,000 units/kg/day divided in equal doses every 4 hours for 7 to 14 days depending on the infecting organism (maximum dose of 12 to 20 million units/day)

  Disseminated Gonococcal Infections (penicillin-susceptible strains)

  Weight less than 45 kg:

       Arthritis

  100,000 units/kg/day in 4 equally divided doses for 7 to 10 days

       Meningitis

  250,000 units/kg/day in equal doses every 4 hours for 10 to 14 days

       Endocarditis

  250,000 units/kg/day in equal doses every 4 hours for 4 weeks

       Arthritis, meningitis, endocarditis

  Weight 45 kg or greater: 10 million units/day in 4 equally divided doses with the duration of therapy depending on the type of infection

  Syphilis (congenital and neurosyphilis) after the newborn period

  200,000 to 300,000 units/kg/day (administered as 50,000 units/kg every 4 to 6 hours) for 10 to 14 days

  Diphtheria (adjunctive therapy to antitoxin and for prevention of the carrier state)

  150,000 to 250,000 units/kg/day in equal doses

  every 6 hours for 7 to 10 days

  Rat-bite fever; Haverhill fever (with endocarditis caused by S. moniliformis)

  150,000 to 250,000 units/kg/day in equal doses every 4 hours for 4 weeks

  Renal Impairment

  Penicillin G is relatively nontoxic, and dosage adjustments are generally required only in cases of severe renal impairment.  The recommended dosage regimens are as follows:

  Creatinine clearance less than 10 mL/min/1.73 m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 8 to 10 hours.

  Uremic patients with a creatinine clearance greater than 10 mL/min/1.73 m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 4 to 5 hours.  Additional dosage modifications should be made in patients with hepatic disease and renal impairment.

  For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic.  Antibiotic therapy for Group A β-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Reconstitution

  The following table shows the amount of solvent required for solution of various concentrations:

  Approx. Desired Concentration (units/mL)

  Approx. Volume (mL) 1,000,000 units

  Solvent for Vial of 5,000,000 units

  Infusion Only 20,000,000 units

  50,000

  20

  -

  -

  100,000

  10

  -

  -

  250,000

  4

  18.2

  75

  500,000

  1.8

  8.2

  33

  750,000

  -

  4.8

  -

  1,000,000

  -

  3.2

  11.5

  When the required volume of solvent is greater than the capacity of the vial, the penicillin can be dissolved by first injecting only a portion of the solvent into the vial, then withdrawing the resultant solution and combining it with the remainder of the solvent in a larger sterile container.

  Buffered Penicillin G Potassium for Injection is highly water soluble.  It may be dissolved in small amounts of Water for Injection, or Sterile Isotonic Sodium Chloride Solution for Parenteral Use.  All solutions should be stored in a refrigerator at 2º to 8ºC (36º to 46ºF).  When refrigerated, penicillin solutions may be stored for seven days without significant loss of potency.  DISCARD UNUSED SOLUTION AFTER 7 DAYS.

  Buffered Penicillin G Potassium for Injection may be given intramuscularly or by continuous intravenous drip for dosages of 500,000, 1,000,000, or 5,000,000 units.  It is also suitable for intrapleural, intra-articular, and other local instillations.

  THE 20,000,000 UNIT DOSAGE MAY BE ADMINISTERED BY INTRAVENOUS INFUSION ONLY.

  (1) Intramuscular Injection:  Keep total volume of injection small.  The intramuscular route is the preferred route of administration.  Solutions containing up to 100,000 units of penicillin per mL of diluent may be used with a minimum of discomfort.  Greater concentration of penicillin G per mL is physically possible and may be employed where therapy demands.  When large dosages are required, it may be advisable to administer aqueous solutions of penicillin by means of continuous intravenous drip.

  (2) Continuous Intravenous Drip:  Determine the volume of fluid and rate of its administration required by the patient in a 24 hour period in the usual manner for fluid therapy, and add the appropriate daily dosage of penicillin to this fluid.  For example, if an adult patient requires 2 liters of fluid in 24 hours and a daily dosage of 10 million units of penicillin, add 5 million units to 1 liter and adjust the rate of flow so the liter will be infused in 12 hours.

  (3) Intrapleural or Other Local Infusion:  If fluid is aspirated, give infusion in a volume equal to 1/4 or 1/2 the amount of fluid aspirated, otherwise, prepare as for intramuscular injection.

  (4) Intrathecal Use:  The intrathecal use of penicillin in meningitis must be highly individualized.  It should be employed only with full consideration of the possible irritating effects of penicillin when used by this route.  The preferred route of therapy in bacterial meningitides is intravenous, supplemented by intramuscular injection.

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

  Renal Impairment

  Penicillin G is relatively nontoxic, and dosage adjustments are generally required only in cases of severe renal impairment.  The recommended dosage regimens are as follows:

  Creatinine clearance less than 10 mL/min/1.73 m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 8 to 10 hours.

  Uremic patients with a creatinine clearance greater than 10 mL/min/1.73 m2; administer a full loading dose (see recommended dosages in the tables above) followed by one-half of the loading dose every 4 to 5 hours.  Additional dosage modifications should be made in patients with hepatic disease and renal impairment.

  For most acute infections, treatment should be continued for at least 48 to 72 hours after the patient becomes asymptomatic.  Antibiotic therapy for Group A β-hemolytic streptococcal infections should be maintained for at least 10 days to reduce the risk of rheumatic fever.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

  Reconstitution

  The following table shows the amount of solvent required for solution of various concentrations:

  Approx. Desired Concentration (units/mL)

  Approx. Volume (mL) 1,000,000 units

  Solvent for Vial of 5,000,000 units

  Infusion Only 20,000,000 units

  50,000

  20

  -

  -

  100,000

  10

  -

  -

  250,000

  4

  18.2

  75

  500,000

  1.8

  8.2

  33

  750,000

  -

  4.8

  -

  1,000,000

  -

  3.2

  11.5

  When the required volume of solvent is greater than the capacity of the vial, the penicillin can be dissolved by first injecting only a portion of the solvent into the vial, then withdrawing the resultant solution and combining it with the remainder of the solvent in a larger sterile container.

  Buffered Penicillin G Potassium for Injection is highly water soluble.  It may be dissolved in small amounts of Water for Injection, or Sterile Isotonic Sodium Chloride Solution for Parenteral Use.  All solutions should be stored in a refrigerator at 2º to 8ºC (36º to 46ºF).  When refrigerated, penicillin solutions may be stored for seven days without significant loss of potency.  DISCARD UNUSED SOLUTION AFTER 7 DAYS.

  Buffered Penicillin G Potassium for Injection may be given intramuscularly or by continuous intravenous drip for dosages of 500,000, 1,000,000, or 5,000,000 units.  It is also suitable for intrapleural, intra-articular, and other local instillations.

  THE 20,000,000 UNIT DOSAGE MAY BE ADMINISTERED BY INTRAVENOUS INFUSION ONLY.

  (1) Intramuscular Injection:  Keep total volume of injection small.  The intramuscular route is the preferred route of administration.  Solutions containing up to 100,000 units of penicillin per mL of diluent may be used with a minimum of discomfort.  Greater concentration of penicillin G per mL is physically possible and may be employed where therapy demands.  When large dosages are required, it may be advisable to administer aqueous solutions of penicillin by means of continuous intravenous drip.

  (2) Continuous Intravenous Drip:  Determine the volume of fluid and rate of its administration required by the patient in a 24 hour period in the usual manner for fluid therapy, and add the appropriate daily dosage of penicillin to this fluid.  For example, if an adult patient requires 2 liters of fluid in 24 hours and a daily dosage of 10 million units of penicillin, add 5 million units to 1 liter and adjust the rate of flow so the liter will be infused in 12 hours.

  (3) Intrapleural or Other Local Infusion:  If fluid is aspirated, give infusion in a volume equal to 1/4 or 1/2 the amount of fluid aspirated, otherwise, prepare as for intramuscular injection.

  (4) Intrathecal Use:  The intrathecal use of penicillin in meningitis must be highly individualized.  It should be employed only with full consideration of the possible irritating effects of penicillin when used by this route.  The preferred route of therapy in bacterial meningitides is intravenous, supplemented by intramuscular injection.

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

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• Ampicillin And Sulbacta...
  

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  Ampicillin And Sulbactam

  

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  DOSAGE AND ADMINISTRATION:

  Ampicillin and Sulbactam for Injection, USP may be administered by either the IV or the IM routes.

  For IV administration, the dose can be given by slow intravenous injection over at least 10 to 15 minutes or can also be delivered, in greater dilutions with 50 to 100 mL of a compatible diluent as an intravenous infusion over 15 to 30 minutes.

  Ampicillin and Sulbactam for Injection, USP may be administered by deep intramuscular injection (see Preparation tor Intramuscular Injection).

  The recommended adult dosage of Ampicillin and Sulbactam for Injection, USP is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of Ampicillin and Sulbactam for Injection, USP, and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.

  Pediatric Patients 1 Year of Age or Older

  The recommended daily dose of Ampicillin and Sulbactam for Injection, USP in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of Ampicillin and Sulbactam for Injection, USP, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. The safety and efficacy of Ampicillin and Sulbactam for Injection, USP administered via intramuscular injection in pediatric patients have not been established. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous Ampicillin and Sulbactam for Injection, USP (see CLINICAL STUDIES).

  Impaired Renal Function

  In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of Ampicillin and Sulbactam for Injection, USP in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:

  Ampicillin and Sulbactam for Injection, USP Dosage Guide For Patients With Renal Impairment Creatinine Clearance (mL/min/1.73m2) Ampicillin/Sulbactam Half-Life (Hours) Recommended Ampicillin and Sulbactam for Injection, USP Dosage ≥ 30 1 1.5 to 3 g q 6h-q 8h 15-29 5 1.5 to 3 g q 12h 5-14 9 1.5 to 3 g q 24h

  When only serum creatinine 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 Females 0.85 x above value

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• Ampicillin And Sulbacta...
  

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  Ampicillin And Sulbactam

  

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  DOSAGE AND ADMINISTRATION:

  Ampicillin and Sulbactam for Injection, USP may be used for parenteral administration (following dilution). THE INTENT OF THIS PHARMACY BULK PACKAGE IS FOR PREPARATION OF SOLUTIONS FOR IV INFUSION ONLY.

  For IV administration, the dose can be given by slow intravenous injection over at least 10 to 15 minutes or can also be delivered, in greater dilutions with 50 to 100 mL of a compatible diluent as an intravenous infusion over 15 to 30 minutes.

  The recommended adult dosage of ampicillin and sulbactam is 1.5 g (1 g ampicillin as the sodium salt plus 0.5 g sulbactam as the sodium salt) to 3 g (2 g ampicillin as the sodium salt plus 1 g sulbactam as the sodium salt) every six hours. This 1.5 to 3 g range represents the total of ampicillin content plus the sulbactam content of Ampicillin and Sulbactam for Injection, USP and corresponds to a range of 1 g ampicillin/0.5 g sulbactam to 2 g ampicillin/1 g sulbactam. The total dose of sulbactam should not exceed 4 grams per day.

  Pediatric Patients 1 Year of Age or Older

  The recommended daily dose of Ampicillin and Sulbactam for Injection, USP in pediatric patients is 300 mg per kg of body weight administered via intravenous infusion in equally divided doses every 6 hours. This 300 mg/kg/day dosage represents the total ampicillin content plus the sulbactam content of ampicillin and sulbactam for injection, and corresponds to 200 mg ampicillin/100 mg sulbactam per kg per day. Pediatric patients weighing 40 kg or more should be dosed according to adult recommendations, and the total dose of sulbactam should not exceed 4 grams per day. The course of intravenous therapy should not routinely exceed 14 days. In clinical trials, most children received a course of oral antimicrobials following initial treatment with intravenous Ampicillin and Sulbactam for Injection, USP (see CLINICAL STUDIES).

  Impaired Renal Function

  In patients with impairment of renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of Ampicillin and Sulbactam for Injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin and according to the following recommendations:

  Ampicillin and Sulbactam for Injection, USP Dosage Guide For Patients With Renal Impairment Creatinine Clearance (mL/min/1.73m2) Ampicillin/Sulbactam Half-Life (Hours) Recommended Ampicillin and Sulbactam for Injection, USP Dosage ≥ 30 1 1.5 to 3g q6h-q8h 15-29 5 1.5 to 3g q12h 5-14 9 1.5 to 3g q24h

  When only serum creatinine 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 Females 0.85 x above value

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• Nafcillin
  

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  Nafcillin

  

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  Nafcillin for Injection, in the Pharmacy Bulk Package Bottle is for intravenous injection only.

  The usual IV dosage for adults is 500 mg every 4 hours.  For severe infections, 1 g every 4 hours is recommended.  Administer slowly over at least 30 to 60 minutes to minimize the risk of vein irritation and extravasation.  Bacteriologic studies to determine the causative organisms and their susceptibility to nafcillin should always be performed.  Duration of therapy varies with the type and severity of infection as well as the overall condition of the patient; therefore, it should be determined by the clinical and bacteriological response of the patient.  In severe staphylococcal infections, therapy with nafcillin should be continued for at least 14 days.  Therapy should be continued for at least 48 hours after the patient has become afebrile, asymptomatic, and cultures are negative.  The treatment of endocarditis and osteomyelitis may require a longer duration of therapy.

  Nafcillin-probenecid therapy is generally limited to those infections where very high serum levels of nafcillin are necessary.

  No dosage alterations are necessary for patients with renal dysfunction, including those on hemodialysis.  Hemodialysis does not accelerate nafcillin clearance from the blood.

  For patients with hepatic insufficiency and renal failure, measurement of nafcillin serum levels should be performed and dosage adjusted accordingly.

  With intravenous administration, particularly in elderly patients, care should be taken because of the possibility of thrombophlebitis.

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

  Do not add supplementary medication to Nafcillin for Injection, USP.

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• Ampicillin
  

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  Ampicillin

  

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  This insert is for a Pharmacy Bulk Package and is intended for preparing IV admixtures only.  Dosage recommendations for intravenous injection are for informational purposes only.

  Infections of the respiratory tract and soft tissues.

  Patients weighing 40 kg (88 lbs) or more: 250 to 500 mg every 6 hours.

  Patients weighing less than 40 kg (88 lbs): 25 to 50 mg/kg/day in equally divided doses at 6- to 8- hour intervals.

  Infections of the gastrointestinal and genitourinary tracts (including those caused by Neisseria gonorrhoeae in females).

  Patients weighing 40 kg (88 lbs) or more: 500 mg every 6 hours.

  Patients weighing less than 40 kg (88 lbs): 50 mg/kg/day in equally divided doses at 6- to 8- hour intervals.

  In the treatment of chronic urinary tract and intestinal infections, frequent bacteriological and clinical appraisal is necessary. Smaller doses than those recommended above should not be used.  Higher doses should be used for stubborn or severe infections.  In stubborn infections, therapy may be required for several weeks.  It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy.

  Urethritis in males due to N. gonorrhoeae.

  Adults - Two doses of 500 mg each at an interval of 8 to 12 hours. Treatment may be repeated if necessary or extended if required.  In the treatment of complications of gonorrheal urethritis, such as prostatitis and epididymitis, prolonged and intensive therapy is recommended. Cases of gonorrhea with a suspected primary lesion of syphilis should have darkfield examinations before receiving treatment.  In all other cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of four months.

  The doses for the preceding infections may be given by either the intramuscular or intravenous route.  A change to oral ampicillin may be made when appropriate.

  Bacterial Meningitis

  Adults and children – 150 to 200 mg/kg/day in equally divided doses every 3 to 4 hours.  (Treatment may be initiated with intravenous drip therapy and continued with intramuscular injections.) The doses for other infections may be given by either the intravenous or intramuscular route.

  Septicemia

  Adults and children – 150 to 200 mg/kg/day. Start with intravenous administration for at least three days and continue with the intramuscular route every 3 to 4 hours. 

  Treatment of all infections should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.  A minimum of 10-days treatment is recommended for any infection caused by Group A beta-hemolytic streptococci to help prevent the occurrence of acute rheumatic fever or acute glomerulonephritis.

  For Administration by Intravenous Infusion

  Reconstitute as directed below (Directions for Proper Use of Pharmacy Bulk Package) prior to diluting with an intravenous solution.

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Stability studies on ampicillin sodium at several concentrations in various intravenous solutions indicate the drug will lose less than 10% activity at the temperatures noted for the time periods stated.

   

  Room Temperature (25°C)

   

  Diluent

   

  Concentrations

   

  Stability Periods

   

  Sterile Water for Injection

   

  up to 30 mg/mL

   

  8 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  up to 30 mg/mL

   

  8 hours

   

  5% Dextrose in Water

   

  10 to 20 mg/mL

   

  1 hour

   

  5% Dextrose in Water

   

  up to 2 mg/mL

   

  2 hours

   

  5% Dextrose in 0.45% NaCl Inj.

   

  up to 2 mg/mL

   

  2 hours

   

  Lactated Ringer’s Solution

   

  up to 30 mg/mL

   

  8 hours

   

  Refrigerated (4°C)

   

  Sterile Water for Injection

   

  30 mg/mL

   

  48 hours

   

  Sterile Water for Injection

   

  up to 20 mg/mL

   

  72 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  30 mg/mL

   

  24 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  up to 20 mg/mL

   

  48 hours

   

  Lactated Ringer’s Solution

   

  up to 30 mg/mL

   

  24 hours

   

  5% Dextrose in Water

   

  up to 20 mg/mL

   

  1 hour

   

  5% Dextrose and 0.45% NaCl Inj.

   

  up to 10 mg/mL

   

  1 hour

   

  Only those solutions listed above should be used for the intravenous infusion of Ampicillin for Injection, USP.  The concentrations should fall within the range specified.  The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of ampicillin is administered before the drug loses its stability in the solution in use.

  Directions For Proper Use Of Pharmacy Bulk Package

  This glass Pharmacy Bulk Package bottle contains 10 grams ampicillin and is designed for use in the pharmacy in preparing IV admixtures.

  a) Add 94 mL Sterile Water for Injection USP.  The resulting solution will contain 100 milligrams ampicillin activity per mL, and is stable up to ONE HOUR at room temperature.

  b) Dilute further within ONE HOUR to a concentration of 5 mg to 10 mg per mL.  See Table for suitable fluid.  Use promptly.  This chemical stability information in no way indicates that it would be acceptable practice to use this product well after preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  c) Using aseptic technique under a laminar flow hood, the closure should be penetrated only one time after reconstitution using a suitable sterile dispensing set; which allows measured dispensing of the contents.  Use of a syringe and needle is not recommended as it may cause leakage.

  d) After entry, use entire contents of Pharmacy Bulk Package bottle promptly.  The entire contents of the Pharmacy Bulk Package bottle must be dispensed within ONE HOUR of reconstitution.  This time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package bottle.

  e) A plastic ball attached to the pharmacy bulk package provides a suitable hanging device while dispensing contents. 

  Use of this product is restricted to a suitable work area, such as a laminar flow hood.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

  Infections of the respiratory tract and soft tissues.

  Patients weighing 40 kg (88 lbs) or more: 250 to 500 mg every 6 hours.

  Patients weighing less than 40 kg (88 lbs): 25 to 50 mg/kg/day in equally divided doses at 6- to 8- hour intervals.

  Infections of the gastrointestinal and genitourinary tracts (including those caused by Neisseria gonorrhoeae in females).

  Patients weighing 40 kg (88 lbs) or more: 500 mg every 6 hours.

  Patients weighing less than 40 kg (88 lbs): 50 mg/kg/day in equally divided doses at 6- to 8- hour intervals.

  In the treatment of chronic urinary tract and intestinal infections, frequent bacteriological and clinical appraisal is necessary. Smaller doses than those recommended above should not be used.  Higher doses should be used for stubborn or severe infections.  In stubborn infections, therapy may be required for several weeks.  It may be necessary to continue clinical and/or bacteriological follow-up for several months after cessation of therapy.

  Urethritis in males due to N. gonorrhoeae.

  Adults - Two doses of 500 mg each at an interval of 8 to 12 hours. Treatment may be repeated if necessary or extended if required.  In the treatment of complications of gonorrheal urethritis, such as prostatitis and epididymitis, prolonged and intensive therapy is recommended. Cases of gonorrhea with a suspected primary lesion of syphilis should have darkfield examinations before receiving treatment.  In all other cases where concomitant syphilis is suspected, monthly serological tests should be made for a minimum of four months.

  The doses for the preceding infections may be given by either the intramuscular or intravenous route.  A change to oral ampicillin may be made when appropriate.

  Bacterial Meningitis

  Adults and children – 150 to 200 mg/kg/day in equally divided doses every 3 to 4 hours.  (Treatment may be initiated with intravenous drip therapy and continued with intramuscular injections.) The doses for other infections may be given by either the intravenous or intramuscular route.

  Septicemia

  Adults and children – 150 to 200 mg/kg/day. Start with intravenous administration for at least three days and continue with the intramuscular route every 3 to 4 hours. 

  Treatment of all infections should be continued for a minimum of 48 to 72 hours beyond the time that the patient becomes asymptomatic or evidence of bacterial eradication has been obtained.  A minimum of 10-days treatment is recommended for any infection caused by Group A beta-hemolytic streptococci to help prevent the occurrence of acute rheumatic fever or acute glomerulonephritis.

  For Administration by Intravenous Infusion

  Reconstitute as directed below (Directions for Proper Use of Pharmacy Bulk Package) prior to diluting with an intravenous solution.

  IMPORTANT: This chemical stability information in no way indicates that it would be acceptable practice to use this product well after the preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  Stability studies on ampicillin sodium at several concentrations in various intravenous solutions indicate the drug will lose less than 10% activity at the temperatures noted for the time periods stated.

   

  Room Temperature (25°C)

   

  Diluent

   

  Concentrations

   

  Stability Periods

   

  Sterile Water for Injection

   

  up to 30 mg/mL

   

  8 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  up to 30 mg/mL

   

  8 hours

   

  5% Dextrose in Water

   

  10 to 20 mg/mL

   

  1 hour

   

  5% Dextrose in Water

   

  up to 2 mg/mL

   

  2 hours

   

  5% Dextrose in 0.45% NaCl Inj.

   

  up to 2 mg/mL

   

  2 hours

   

  Lactated Ringer’s Solution

   

  up to 30 mg/mL

   

  8 hours

   

  Refrigerated (4°C)

   

  Sterile Water for Injection

   

  30 mg/mL

   

  48 hours

   

  Sterile Water for Injection

   

  up to 20 mg/mL

   

  72 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  30 mg/mL

   

  24 hours

   

  Sodium Chloride Injection USP, 0.9%

   

  up to 20 mg/mL

   

  48 hours

   

  Lactated Ringer’s Solution

   

  up to 30 mg/mL

   

  24 hours

   

  5% Dextrose in Water

   

  up to 20 mg/mL

   

  1 hour

   

  5% Dextrose and 0.45% NaCl Inj.

   

  up to 10 mg/mL

   

  1 hour

   

  Only those solutions listed above should be used for the intravenous infusion of Ampicillin for Injection, USP.  The concentrations should fall within the range specified.  The drug concentration and the rate and volume of the infusion should be adjusted so that the total dose of ampicillin is administered before the drug loses its stability in the solution in use.

  Directions For Proper Use Of Pharmacy Bulk Package

  This glass Pharmacy Bulk Package bottle contains 10 grams ampicillin and is designed for use in the pharmacy in preparing IV admixtures.

  a) Add 94 mL Sterile Water for Injection USP.  The resulting solution will contain 100 milligrams ampicillin activity per mL, and is stable up to ONE HOUR at room temperature.

  b) Dilute further within ONE HOUR to a concentration of 5 mg to 10 mg per mL.  See Table for suitable fluid.  Use promptly.  This chemical stability information in no way indicates that it would be acceptable practice to use this product well after preparation time.  Good professional practice suggests that compounded admixtures should be administered as soon after preparation as is feasible.

  c) Using aseptic technique under a laminar flow hood, the closure should be penetrated only one time after reconstitution using a suitable sterile dispensing set; which allows measured dispensing of the contents.  Use of a syringe and needle is not recommended as it may cause leakage.

  d) After entry, use entire contents of Pharmacy Bulk Package bottle promptly.  The entire contents of the Pharmacy Bulk Package bottle must be dispensed within ONE HOUR of reconstitution.  This time limit should begin with the introduction of solvent or diluent into the Pharmacy Bulk Package bottle.

  e) A plastic ball attached to the pharmacy bulk package provides a suitable hanging device while dispensing contents. 

  Use of this product is restricted to a suitable work area, such as a laminar flow hood.  Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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• Oxaliplatin
  

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  Oxaliplatin

  

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  Oxaliplatin 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 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 85 mg/m2 intravenous infusion in 250 to 500 mL 5% Dextrose Injection and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose Injection 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 (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 (recommended) as a 22 hour continuous infusion.

  Figure 1

  The administration of oxaliplatin 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 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 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 × 109/L and platelets ≥ 75 × 109/L.

  Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients With Advanced Colorectal Cancer

  Neuropathy was graded using a study-specific neurotoxicity scale [see Warnings and Precautions (5.2)]. Other toxicities were graded by the NCI CTC, Version 2.

  For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of oxaliplatin 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 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 × 109/L and platelets ≥ 75 × 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 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.

  After dilution with 250 to 500 mL of 5% Dextrose Injection, 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 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 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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