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Mylan Institutional Llc Drugs

Levoleucovorin Calcium

Levoleucovorin Calcium

2.1 Administration Guidelines

Levoleucovorin injection is dosed at one-half the usual dose of racemic d,l-leucovorin.

Levoleucovorin injection is indicated for intravenous administration only. Do not administer intrathecally.

2.2 Co-administration of Levoleucovorin Injection with Other Agents

Due to the risk of precipitation, do not co-administer levoleucovorin injection with other agents in the same admixture.

2.3 Levoleucovorin Injection Rescue After High-Dose Methotrexate Therapy

The recommendations for levoleucovorin injection rescue are based on a methotrexate dose of 12 grams/m2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). Levoleucovorin injection rescue at a dose of 7.5 mg (approximately 5 mg/m2) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion.

Serum creatinine and methotrexate levels should be determined at least once daily. Levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10-8 M (0.05 micromolar). The levoleucovorin injection dose should be adjusted or rescue extended based on the following guidelines.
Table 1: Guidelines for Levoleucovorin Injection Dosage and Administration
Clinical Situation

Laboratory Findings

Levoleucovorin Injection Dosage and Duration

Normal Methotrexate Elimination

Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours

7.5 mg IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion).

Delayed Late Methotrexate Elimination

Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration.

Continue 7.5 mg IV q 6 hours, until methotrexate level is less than 0.05 micromolar.

Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury

Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more).

75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar.

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

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

Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin injection or prolonged administration may be indicated.

Although levoleucovorin injection may ameliorate the hematologic toxicity associated with high-dose methotrexate, levoleucovorin injection has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney.

2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage

Levoleucovorin injection rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and levoleucovorin injection rescue increases, levoleucovorin injection’s effectiveness in counteracting toxicity may decrease. Levoleucovorin injection 7.5 mg (approximately 5 mg/m2) should be administered IV every 6 hours until the serum methotrexate level is less than 10-8 M.

Serum creatinine and methotrexate levels should be determined at 24 hour intervals. If the 24 hour serum creatinine has increased 50% over baseline or if the 24 hour methotrexate level is greater than 5 x 10-6 M or the 48 hour level is greater than 9 x 10-7 M, the dose of levoleucovorin injection should be increased to 50 mg/m2 IV every 3 hours until the methotrexate level is less than 10-8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

2.6 Infusion Instructions

Levoleucovorin Injection
• Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. • Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. • Visually inspect the diluted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. • No more than 16 mL of levoleucovorin injection (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.
Ampicillin Sodium And S...

Ampicillin Sodium And Sulbactam Sodium

The pharmacy bulk package is for preparation of solutions for IV infusion only. Ampicillin and Sulbactam should be administered 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 for Injection 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 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 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. The safety and efficacy of Ampicillin and Sulbactam for Injection 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 (see CLINICAL STUDIESsection).

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:

TABLE 5

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 to q 8h

15 to 29

5

1.5 to 3 g q 12h

5 to 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) × (140 – age)

72 × serum creatinine

Females 0.85 × above value
Ampicillin Sodium And S...

Ampicillin Sodium And Sulbactam Sodium

Ampicillin and sulbactam for injection 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 may be administered by deep intramuscular injection. (see DIRECTIONS FOR USE-Preparation for Intramuscular Injection section).

The recommended adult dosage of ampicillin and sulbactam for injection 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, 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 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. The safety and efficacy of ampicillin and sulbactam for injection 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. (see CLINICAL STUDIES section).

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:
TABLE 5 AMPICILLIN AND SULBACTAM FOR INJECTION Dosage Guide for Patients with Renal Impairment Creatinine Clearance (mL/min/1.73m2) Ampicillin/Sulbactam Half-Life (Hours) Recommended Ampicillin and Sulbactam for Injection Dosage
≥30

1

1.5 to 3 g q 6h to q 8h

15 to 29

5

1.5 to 3 g q 12h

5 to 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)×(140 – age) 72 × serum creatinine

Females 0.85 × above value
Stomach Relief Cherry

Stomach Relief Cherry

Do not mix other medications or solutions with ARIXTRA. Administer ARIXTRA only subcutaneously.

2.1 Deep Vein Thrombosis Prophylaxis Following Hip Fracture, Hip Replacement, and Knee Replacement Surgery

In patients undergoing hip fracture, hip replacement, or knee replacement surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of therapy is 5 to 9 days; up to 11 days of therapy was administered in clinical trials.

In patients undergoing hip fracture surgery, an extended prophylaxis course of up to 24 additional days is recommended. In patients undergoing hip fracture surgery, a total of 32 days (peri-operative and extended prophylaxis) was administered in clinical trials. [See Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14).]

2.2 Deep Vein Thrombosis Prophylaxis Following Abdominal Surgery

In patients undergoing abdominal surgery, the recommended dose of ARIXTRA is 2.5 mg administered by subcutaneous injection once daily after hemostasis has been established. Administer the initial dose no earlier than 6 to 8 hours after surgery. Administration of ARIXTRA earlier than 6 hours after surgery increases the risk of major bleeding. The usual duration of administration is 5 to 9 days, and up to 10 days of ARIXTRA was administered in clinical trials.

2.3 Deep Vein Thrombosis and Pulmonary Embolism Treatment

In patients with acute symptomatic DVT and in patients with acute symptomatic PE, the recommended dose of ARIXTRA is 5 mg (body weight <50 kg), 7.5 mg (body weight 50 to 100 kg), or 10 mg (body weight >100 kg) by subcutaneous injection once daily (ARIXTRA treatment regimen). Initiate concomitant treatment with warfarin sodium as soon as possible, usually within 72 hours. Continue treatment with ARIXTRA for at least 5 days and until a therapeutic oral anticoagulant effect is established (INR 2 to 3). The usual duration of administration of ARIXTRA is 5 to 9 days; up to 26 days of ARIXTRA injection was administered in clinical trials. [See Warnings and Precautions (5.6), Adverse Reactions (6), and Clinical Studies (14).]

2.4 Hepatic Impairment

No dose adjustment is recommended in patients with mild to moderate hepatic impairment, based upon single-dose pharmacokinetic data. Pharmacokinetic data are not available for patients with severe hepatic impairment. Patients with hepatic impairment may be particularly vulnerable to bleeding during ARIXTRA therapy. Observe these patients closely for signs and symptoms of bleeding. [See Clinical Pharmacology (12.4).]

2.5 Instructions for Use

ARIXTRA Injection is provided in a single-dose, prefilled syringe affixed with an automatic needle protection system. ARIXTRA is administered by subcutaneous injection. It must not be administered by intramuscular injection. ARIXTRA is intended for use under a physician’s guidance. Patients may self-inject only if their physician determines that it is appropriate and the patients are trained in subcutaneous injection techniques.

Prior to administration, visually inspect ARIXTRA to ensure the solution is clear and free of particulate matter.

To avoid the loss of drug when using the prefilled syringe, do not expel the air bubble from the syringe before the injection. Administration should be made in the fatty tissue, alternating injection sites (e.g., between the left and right anterolateral or the left and right posterolateral abdominal wall).

To administer ARIXTRA:
• Wipe the surface of the injection site with an alcohol swab. • Hold the syringe with either hand and use your other hand to twist the rigid needle guard (covers the needle) counter-clockwise. Pull the rigid needle guard straight off the needle (Figure 1). Discard the needle guard. • Do not try to remove the air bubbles from the syringe before giving the injection. • Pinch a fold of skin at the injection site between your thumb and forefinger and hold it throughout the injection. • Hold the syringe with your thumb on the top pad of the plunger rod and your next 2 fingers on the finger grips on the syringe barrel. Pay attention to avoid sticking yourself with the exposed needle (Figure 2). • Insert the full length of the syringe needle perpendicularly into the skin fold held between the thumb and forefinger (Figure 3). • Push the plunger rod firmly with your thumb as far as it will go. This will ensure you have injected all the contents of the syringe (Figure 4). • When you have injected all the contents of the syringe, the plunger should be released. The plunger will then rise automatically while the needle withdraws from the skin and retracts into the security sleeve. Discard the syringe into the sharps container. • You will know that the syringe has worked when: 1. The needle is pulled back into the security sleeve and the white safety indicator appears above the upper body. 2. You may also hear or feel a soft click when the plunger rod is released fully.
Cytarabine

Cytarabine

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 - 7) or 100 mg/m2 IV every 12 hours (Days 1 - 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 ultraviolet assay 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.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Cytarabine

Cytarabine

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.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Ifosfamide

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 reduce the incidence of 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 (eg, 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.
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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (seeADVERSE REATIONS). Infusion-related events may occur, however, at any rate or concentration.

Patients with Normal Renal Function

Adults

The usual daily intravenous 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric Patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended 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 Meollering et al)4

Creatinine Clearance mL/min

Vancomycin Dose mg/24 hr

100

1,545

90

1,390

80

1,235

70

1,080

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 concentration 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. Otherwise, the estimated value for creatinine clearance is not 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 established.

Intermittent infusion is the recommended method of administration.

COMPATIBILITY WITH OTHER DRUGS AND IV FLUIDS

The following diluents are physically and chemically compatible (with 4g/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.

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE-NOT FOR DIRECT INFUSION

Pharmacy bulk packages are for use in pharmacy admixture service only in a suitable work area, such as a laminar flow hood. They should be hung by the integral hanger provided and suspended as a unit in the laminar flow hood. Using aseptic technique the container closure should be penetrated only one time after reconstitution utilizing a suitable sterile dispensing set which allows measured distribution of the contents. Use of a syringe and needle is not recommended as it may cause leakage. Swab vial stopper with an antiseptic solution.

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 closure entry may be permitted for complete fluid transfer operations. Discard the container no later than 4 hours after initial closure puncture. The time limit should begin with introduction of solvent or diluent in to Pharmacy Package bottle.

PREPARATION AND STABILITY

10 g Pharmacy Bulk Package bottle

At the time of use, reconstitute by adding 95 mL of Sterile Water for Injection, USP to the 10 g Pharmacy Bulk package bottle of dry, vancomycin powder at a time. The resultant solution is a tan coloured solution will contain vancomycin equivalent to 500 mg/5 mL (1 g/10 mL). AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED.

Reconstituted solutions of vancomycin (500 mg/5 mL) must be further diluted in at least 100 mL of a suitable infusion solution. For doses of 1 gram (10 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.

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 dosage 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 added to the solution to improve the taste for oral administration. The diluted solution may be administered via a nasogastric tube.
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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS). Infusion-related events may occur, however, at any rate or concentration.

Patients With Normal Renal Function

Adults

The usual daily intravenous dose is 2 g divided either as 500 mg every 6 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients.

Patients with Impaired Renal Function and Elderly Patients

Dosage adjustment must be made in patients with impaired renal function. In 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:

DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Meollering et al)4

Creatinine ClearancemL/min

Vancomycin Dosemg/24 hr

100

1,545

90

1,390

80

1,235

70

1,080

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 h. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis. In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended.

When only the serum creatinine concentration 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. Otherwise, the estimated value for creatinine clearance is not 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 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 established.

Intermittent infusion is the recommended method of administration.

Preparation and stability

At the time of use, reconstitute by adding either 10 mL of Sterile Water for Injection to the 500-mg vial or 20 mL of Sterile Water for Injection to the 1-g vial of dry, sterile vancomycin powder. FURTHER DILUTION IS REQUIRED.

After reconstitution with Sterile Water for Injection, 5% Dextrose Injection, or 0.9% Sodium Chloride Injection, the vials may be stored in a refrigerator for 14 days without significant loss of potency.

Reconstituted solutions containing 500 mg/10 mL must be further diluted with at least 100 mL of suitable infusion solution. Reconstituted solutions containing 1 g/20 mL must be further diluted with at least 200 mL of suitable infusion solution. The desired dose, diluted in this manner, should be administered by intermittent intravenous infusion over a period of at least 60 minutes.

Compatibility with Other Drugs and Intravenous Fluids

Solutions that are diluted with 5% Dextrose Injection or 0.9% Sodium Chloride Injection may be stored in a refrigerator for 14 days without significant loss of potency. Solutions that are diluted with the following infusion fluids may be stored in a refrigerator for 96 hours:

5% Dextrose Injection, USP

5% Dextrose and 0.9% Sodium Chloride Injection, USP

Lactated Ringer’s Injection, USP

Lactated Ringer’s and 5% Dextrose Injection, USP

Normosol®-M and 5% Dextrose

ISOLYTE® E

Vancomycin solution has a low pH and may cause physical instability when it is mixed with other compounds.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

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

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 infection. 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.
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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS). Infusion-related events may occur, however, at any rate or concentration.

Patients With Normal Renal Function

Adults

The usual daily intravenous dose is 2 g divided either as 500 mg every 6 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients.

Patients with Impaired Renal Function and Elderly Patients

Dosage adjustment must be made in patients with impaired renal function. In 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:

DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Meollering et al)4

Creatinine Clearance mL/min

Vancomycin Dose mg/24 hr

100

1,545

90

1,390

80

1,235

70

1,080

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 h. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis. In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended.

When only the serum creatinine concentration 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. Otherwise, the estimated value for creatinine clearance is not 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 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 established.

Intermittent infusion is the recommended method of administration.

Preparation and stability

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE – NOT FOR DIRECT INFUSION.

The Pharmacy Bulk Package is for use in the Hospital Pharmacy Admixture Service. Use of this product is restricted to a suitable work area, such as a laminar flow hood. Using aseptic technique, the closure should be penetrated one time using 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 transfer device or dispensing set, allows measured distribution of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After entry use entire content promptly. The withdrawal of the contents of the Pharmacy Bulk Package bottle should be completed within 4 hours after entry. This time limit should begin with the introduction of solvent or diluent into Pharmacy Bulk Package bottle.

At the time of use, reconstitute by adding 100 mL of Sterile Water for Injection to the 5 g Pharmacy Bulk Package. Reconstituted solution contains 500 mg/10 mL and 1 g/20 mL. AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION.

Reconstituted solutions with 10 mL containing 500 mg of vancomycin hydrochloride must be further diluted with at least 100 mL of diluent. Reconstituted solutions containing 1 gram/20 mL must be further diluted with at least 200 mL of diluent. The desired dose, diluted in this manner, should be administered by intermittent intravenous infusion over a period of at least 60 minutes.

Compatibility with Other Drugs and Intravenous Fluids

The following diluents are physically and chemically compatible (with 5 mg/mL vancomycin, present as the HCl):

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 when it is mixed with other compounds.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

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

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 infection. 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.
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 hemotologic 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 of 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 of renal toxicity, particularly in patients with preexisting renal insufficiency.

*Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4.0-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 ≥3.0 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 1.0 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 section).

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 1.0 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 benefit (see Clinical Trials section).

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.

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 and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride, 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, 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, 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, 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.
Carboplatin

Carboplatin

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.

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 should not be repeated until the neutrophil count is at least 2,000 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―300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide―600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. (See CLINICAL STUDIES.)

Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 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.

*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.
Platelets Neutrophils Adjusted Dose*(From Prior Course) >100,000 >2,000 125% 50 - 100,000 500 – 2,000 No Adjustment <50,000 <500 75%
Carboplatin 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 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 - 59 mL/min 250 mg/m2 16 - 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 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 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) x (GFR + 25) Note: With the Calvert formula, the total dose of Carboplatin Injection is calculated in mg, not mg/m2.
The target AUC of 4 mg/mL•min to 6 mg/mL•min using single-agent carboplatin 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 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 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 56 to 7 16%33% 13%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.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin.

Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.

When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution.
Methotrexate Sodium

Methotrexate Sodium

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal (Only preservative free) route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and similar trophoblastic diseases

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

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

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

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

Leukemia

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

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.

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

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

Meningeal Leukemia

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

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

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
AGE (years) DOSE (mg) <1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

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

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

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

Lymphomas

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

Mycosis fungoides (cutaneous T cell lymphoma)

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

Osteosarcoma

An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high-dose methotrexate treatment is 12 grams/m2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.
* Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606. † See each respective package insert for full prescribing information. Dosage modifications may be necessary because of drug-induced toxicity. Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 Leucovorin 15 mg orally every six hours for 10 doses starting at 24 hours afterstart of methotrexate infusion - - - Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42
When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.
Allergy Eye Relief

Allergy Eye Relief

2.1 Subcutaneous administration

Isosulfan blue injection 1% is to be administered subcutaneously, one-half (1/2) mL into three (3) interdigital spaces of each extremity per study. A maximum dose of 3 mL (30 mg) isosulfan blue is, therefore, injected.
Levetiracetam

Levetiracetam

2.1 General Information-Administration

Levetiracetam in Sodium Chloride Injection is for intravenous use only. It is available in three different concentrations single-use 100 mL bag, each containing a different total dosage of levetiracetam: 500 mg (5 mg/mL), 1000 mg (10 mg/mL), or 1500 mg (15 mg/mL).

A single 100 ml bag should be administered intravenously over a 15-minute IV infusion period.

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

Levetiracetam in Sodium Chloride Injection should not be further diluted prior to use. Any unused portion of the Levetiracetam in Sodium Chloride Injection contents should be discarded.

2.2 Initial Exposure to Levetiracetam

Levetiracetam can be initiated with either intravenous or oral administration.

Partial Onset Seizures

In clinical trials of oral levetiracetam, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice-daily dosing, were shown to be effective. Although in some studies there was a tendency toward greater response with higher dose [see Clinical Studies (14.1)], a consistent increase in response with increased dose has not been shown.

Treatment should be initiated with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. Doses greater than 3000 mg/day have been used in open-label studies with levetiracetam tablets for periods of 6 months and longer. There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been studied.

Primary Generalized Tonic-Clonic Seizures

Treatment should be initiated with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Dosage should be increased by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied.

2.3 Switching to Intravenous Dosing

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

2.4 Switching to Oral Dosing

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

2.5 Adult Patients with Impaired Renal Function

Levetiracetam dosing must be individualized according to the patient's renal function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in mL/min is needed.

Table 1: Dosing Adjustment Regimen for Adult Patients with Impaired Renal Function
* Following dialysis, a 250 to 500 mg supplemental dose is recommended. Group Creatinine Clearance(mL/min) Dosage(mg) Frequency Normal > 80 500 to 1,500 Every 12 hours Mild 50 – 80 500 to 1,000 Every 12 hours Moderate 30 – 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ---- 500 to 1,000 *Every 24 hours
For doses (e.g. 250 mg and 750 mg) not achievable with the available product strengths, using aseptic technique, withdraw the appropriate dose (see Table 1) from an intact commercial bag and place the measured dose in a separate empty, sterile infusion bag. Administer the prepared dose by intravenous infusion over a period of 15 minutes. The unused portion of the original commercial bag must be discarded. Do not store or reuse.

2.6 Compatibility With Other Antiepileptic Drugs

Levetiracetam in Sodium Chloride Injection is found to be physically compatible and chemically stable for at least 24 hours when mixed with lorazepam, diazepam, and valproate sodium and stored at controlled room temperature 15° to 30°C (59° to 86°F).

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

Indomethacin

The recommended dose based on controlled trials (see CLINICAL PHARMACOLOGY: Clinical Studies) is outlined in the Table below. Ibutilide infusion should be stopped as soon as the presenting arrhythmia is terminated or in the event of sustained or nonsustained ventricular tachycardia, or marked prolongation of QT or QTc.
Recommended Dose of Ibutilide Fumarate Injection Patient Weight Initial Infusion (over 10 minutes) Second Infusion
60 kg (132 lb) or more

One vial (1 mg ibutilide fumarate)

If the arrhythmia does not terminate within 10 minutes after the end of the initial infusion, a second 10-minute infusion of equal strength may be administered 10 minutes after completion of the first infusion.

Less than 60 kg (132 lb)

0.1 mL/kg (0.01 mg/kg ibutilide fumarate)

In a trial comparing ibutilide and sotalol (see CLINICAL PHARMACOLOGY: Clinical Studies), 2 mg ibutilide fumarate administered as a single infusion to patients weighing more than 60 kg was also effective in terminating atrial fibrillation or atrial flutter.

In the post-cardiac surgery study (see CLINICAL PHARMACOLOGY: Clinical Studies), one or two intravenous infusions of 0.5 mg (0.005 mg/kg per dose for patients weighing less than 60 kg) was effective in terminating atrial fibrillation or atrial flutter.

Patients should be observed with continuous ECG monitoring for at least 4 hours following infusion or until QTc has returned to baseline. Longer monitoring is required if any arrhythmic activity is noted. Skilled personnel and proper equipment (see WARNINGS, Proarrhythmia), such as a cardioverter/defibrillator, and medication for treatment of sustained ventricular tachycardia, including polymorphic ventricular tachycardia, must be available during administration of ibutilide fumarate injection and subsequent monitoring of the patient.

Dilution

Ibutilide fumarate injection may be administered undiluted or diluted in 50 mL of diluent. Ibutilide fumarate injection may be added to 0.9% Sodium Chloride injection or 5% Dextrose injection before infusion. The contents of one 10 mL vial (0.1 mg/mL) may be added to a 50 mL infusion bag to form an admixture of approximately 0.017 mg/mL ibutilide fumarate. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Compatibility and Stability

The following diluents are compatible with ibutilide fumarate injection (0.1 mg/mL):
5% Dextrose injection 0.9% Sodium Chloride injection.
The following intravenous solution containers are compatible with admixtures of ibutilide fumarate injection (0.1 mg/mL):
polyvinyl chloride plastic bags polyolefin bags.
Admixtures of the product, with approved diluents, are chemically and physically stable for 24 hours at room temperature (15° to 30°C or 59° to 86°F) and for 48 hours at refrigerated temperatures (2° to 8°C or 36° to 46°F). Strict adherence to the use of aseptic technique during the preparation of the admixture is recommended in order to maintain sterility.
Labetalol Hydrochloride...

Labetalol Hydrochloride

Labetalol hydrochloride injection is intended for intravenous use in hospitalized patients. DOSAGE MUST BE INDIVIDUALIZED depending upon the severity of hypertension and the response of the patient during dosing.

Patients should always be kept in a supine position during the period of intravenous drug administration. A substantial fall in blood pressure on standing should be expected in these patients. The patient’s ability to tolerate an upright position should be established before permitting any ambulation, such as using toilet facilities.

Either of two methods of administration of labetalol hydrochloride injection may be used: a) repeated intravenous injection, or b) slow continuous infusion.

Repeated Intravenous Injection

Initially, labetalol hydrochloride injection should be given in a 20-mg dose (which corresponds to 0.25 mg/kg for an 80-kg patient) by slow intravenous injection over a 2-minute period.

Immediately before the injection and at 5 and 10 minutes after injection, supine blood pressure should be measured to evaluate response. Additional injections of 40 or 80 mg can be given at 10-minute intervals until a desired supine blood pressure is achieved or a total of 300 mg of labetalol HCl has been injected. The maximum effect usually occurs within

5 minutes of each injection.

Slow Continuous Infusion

Labetalol hydrochloride injection is prepared for continuous intravenous infusion by diluting the vial contents with commonly used intravenous fluids (see below). Examples of two methods of preparing the infusion solution are:

Add 40 mL of Labetalol hydrochloride injection to 160 mL of a commonly used intravenous fluid such that the resultant 200 mL of solution contains 200 mg of labetalol HCl, 1 mg/mL. The diluted solution should be administered at a rate of 2 mL /min to deliver 2 mg/min.

Alternatively, add 40 mL of Labetalol hydrochloride injection to 250 mL of a commonly used intravenous fluid. The resultant solution will contain 200 mg of labetalol HCl, approximately 2 mg/3 mL. The diluted solution should be administered at a rate of

3 mL/min to deliver approximately 2 mg/min.

The rate of infusion of the diluted solution may be adjusted according to the blood pressure response, at the discretion of the physician. To facilitate a desired rate of infusion, the diluted solution can be infused using a controlled administration mechanism, e.g., graduated burette or mechanically driven infusion pump.

Since the half-life of labetalol is 5 to 8 hours, steady-state blood levels (in the face of a constant rate of infusion) would not be reached during the usual infusion time period. The infusion should be continued until a satisfactory response is obtained and should then be stopped and oral labetalol HCl started (see below). The effective intravenous dose is usually in the range of 50 to 200 mg. A total dose of up to 300 mg may be required in some patients.

Blood Pressure Monitoring

The blood pressure should be monitored during and after completion of the infusion or intravenous injection. Rapid or excessive falls in either systolic or diastolic blood pressure during intravenous treatment should be avoided. In patients with excessive systolic hypertension, the decrease in systolic pressure should be used as an indicator of effectiveness in addition to the response of the diastolic pressure.

Initiation of Dosing With labetalol hydrochloride Tablets

Subsequent oral dosing with labetalol hydrochloride tablets should begin when it has been established that the supine diastolic blood pressure has begun to rise. The recommended initial dose is 200 mg, followed in 6 to 12 hours by an additional dose of 200 or 400 mg, depending on the blood pressure response. Thereafter, inpatient titration with labetalol hydrochloride tablets may proceed as follows:
Inpatient Titration Instructions Regimen Daily Dose* 200 mg b.i.d. 400 mg 400 mg b.i.d. 800 mg 800 mg b.i.d. 1600 mg 1200 mg b.i.d. 2400 mg
*If needed, the total daily dose may be given in three divided doses.

The dosage of labetalol hydrochloride tablets used in the hospital may be increased at 1-day intervals to achieve the desired blood pressure reduction.

For subsequent outpatient titration or maintenance dosing, see DOSAGE AND ADMINISTRATION in the labetalol hydrochloride tablets Product Information for additional recommendations.

Compatibility With Commonly Used Intravenous Fluids

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

Labetalol hydrochloride injection was tested for compatibility with commonly used intravenous fluids at final concentrations of 1.25 to 3.75 mg of labetalol HCl per milliliter of the mixture. Labetalol hydrochloride injection was found to be compatible with and stable (for 24 hours refrigerated or at room temperature) in mixtures with the following solutions: ringer’s injection, USP; lactated ringer’s injection, USP; 5% dextrose and ringer’s injection; 5% lactated ringer’s and 5% dextrose injection; 5% dextrose injection, USP; 0.9% sodium chloride injection, USP; 5% dextrose and 0.2% sodium chloride injection, USP; 2.5% dextrose and 0.45% sodium chloride injection, USP; 5% dextrose and 0.9% sodium chloride injection, USP; and 5% dextrose and 0.33% sodium chloride injection, USP.

Labetalol hydrochloride injection was NOT compatible with 5% sodium bicarbonate injection, USP. Care should be taken when administering alkaline drugs, including furosemide, in combination with labetalol. Compatibility should be assured prior to administering these drugs together.
Methotrexate

Methotrexate

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate Injection, USP (preservative free) formulations may be given by the intramuscular, intravenous, intra-arterial or intrathecal route. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and Similar Trophoblastic Diseases

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

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

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

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

Leukemia

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

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

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

Meningeal Leukemia

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

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

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
AGE (years) DOSE (mg) < 1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

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

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

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

Lymphomas

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

Mycosis Fungoides (Cutaneous T Cell Lymphoma)

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

Osteosarcoma

An effective adjuvant chemotherapy regimen requires the administration of several cytotoxic chemotherapeutic agents. In addition to high-dose methotrexate with leucovorin rescue, these agents may include doxorubicin, cisplatin, and the combination of bleomycin, cyclophosphamide and dactinomycin (BCD) in the doses and schedule shown in the table below. The starting dose for high dose methotrexate treatment is 12 grams/m 2. If this dose is not sufficient to produce a peak serum methotrexate concentration of 1,000 micromolar (10-3 mol/L) at the end of the methotrexate infusion, the dose may be escalated to 15 grams/m2 in subsequent treatments. If the patient is vomiting or is unable to tolerate oral medication, leucovorin is given IV or IM at the same dose and schedule.
Drug* Dose* Treatment Week After Surgery
*Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J of Med 1986; 314 (No.25): 1600-1606.

†See each respective package insert for full prescribing information. Dosage modifications may by necessary because of drug-induced toxicity.
Methotrexate 12g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 Leucovorin 15 mg orally every 6 hours for 10 doses starting at 24 hours after start of methotrexate infusion --- Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42
When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.

GUIDELINES FOR METHOTREXATE THERAPY WITH LEUCOVORIN RESCUE
Administration of methotrexate should be delayed until recovery if: the WBC count is less than 1500/microliter the neutrophil count is less than 200/microliter the platelet count is less than 75,000/microliter the serum bilirubin level is greater than 1.2 mg/dL the SGPT level is greater than 450 U mucositis is present, until there is evidence of healing persistent pleural effusion is present; this should be drained dry prior to infusion. Adequate renal function must be documented. Serum creatinine must be normal, and creatinine clearance must be greater than 60 mL/min, before initiation of therapy. Serum creatinine must be measured prior to each subsequent course of therapy. If serum creatinine has increased by 50% or more compared to a prior value, the creatinine clearance must be measured and documented to be greater than 60 mL/min (even if the serum creatinine is still within the normal range). Patients must be well hydrated, and must be treated with sodium bicarbonate for urinary alkalinization. Administer 1,000 mL/m2 of intravenous fluid over 6 hours prior to initiation of the methotrexate infusion. Continue hydration at 125 mL/m2/hr (3 liters/m2/day) during the methotrexate infusion, and for 2 days after the infusion has been completed. Alkalinize urine to maintain pH above 7.0 during methotrexate infusion and leucovorin calcium therapy. This can be accomplished by the administration of sodium bicarbonate orally or by incorporation into a separate intravenous solution. Repeat serum creatinine and serum methotrexate 24 hours after starting methotrexate and at least once daily until the methotrexate level is below 5 x 10-8 mol/L (0.05 micromolar). The table below provides guidelines for leucovorin calcium dosage based upon serum methotrexate levels. (See table below‡.) Patients who experience delayed early methotrexate elimination are likely to develop nonreversible oliguric renal failure. In addition to appropriate leucovorin therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. If necessary, acute, intermittent hemodialysis with a high-flux dialyzer may also be beneficial in these patients. Some patients will have abnormalities in methotrexate elimination, or abnormalities in renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table below. These abnormalities may or may not be associated with significant clinical toxicity. If significant toxicity is observed, leucovorin rescue should be extended for an additional 24 hours (total 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate binding to serum albumin, or elimination) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed.
CAUTION: DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY.

Psoriasis, Rheumatoid Arthritis, and Juvenile Rheumatoid Arthritis

Adult Rheumatoid Arthritis

Recommended Starting Dosage Schedules:
Single oral doses of 7.5 mg once weekly.† Divided oral dosages of 2.5 mg at 12 hour intervals for three doses given as a course once weekly.†
† Methotrexate Sodium Tablets for oral administration are available.

Polyarticular-Course Juvenile Rheumatoid Arthritis

The recommended starting dose is 10 mg/m2 given once weekly.

For either adult RA or polyarticular-course JRA, dosages may be adjusted gradually to achieve an optimal response. Limited experience shows a significant increase in the incidence and severity of serious toxic reactions, especially bone marrow suppression, at doses greater than 20 mg/wk in adults. Although there is experience with doses up to 30 mg/m 2/wk in children, there are too few published data to assess how doses over 20 mg/m2/wk might affect the risk of serious toxicity in children. Experience does suggest, however, that children receiving 20 to 30 mg/m2/wk (0.65 to 1.0 mg/kg/wk) may have better absorption and fewer gastrointestinal side effects if methotrexate is administered either intramuscularly or subcutaneously.

Therapeutic response usually begins within 3 to 6 weeks and the patient may continue to improve for another 12 weeks or more.

The optimal duration of therapy is unknown. Limited data available from long-term studies in adults indicate that the initial clinical improvement is maintained for at least 2 years with continued therapy. When methotrexate is discontinued, the arthritis usually worsens within 3 to 6 weeks.

The patient should be fully informed of the risks involved and should be under constant supervision of the physician. (See PRECAUTIONS: Information for Patients.) Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy. (See PRECAUTIONS.) Appropriate steps should be taken to avoid conception during methotrexate therapy. (See PRECAUTIONS and CONTRAINDICATIONS.)

All schedules should be continually tailored to the individual patient. An initial test dose may be given prior to the regular dosing schedule to detect any extreme sensitivity to adverse effects (see ADVERSE REACTIONS). Maximal myelosuppression usually occurs in 7 to 10 days.

Psoriasis

Recommended Starting Dose Schedule:
Weekly single oral, IM or IV dosage schedule: 10 mg to 25 mg per week until adequate response is achieved.† Divided oral dose schedule 2.5 mg at 12 hour intervals for three doses.†
†Methotrexate Sodium Tablets for oral administration are available.

Dosages in each schedule may be gradually adjusted to achieve optimal clinical response; 30 mg/week should not ordinarily be exceeded.

Once optimal clinical response has been achieved, each dosage schedule should be reduced to the lowest possible amount of drug and to the longest possible rest period. The use of methotrexate may permit the return to conventional topical therapy, which should be encouraged.

HANDLING AND DISPOSAL

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.

DILUTION INSTRUCTIONS FOR LIQUID METHOTREXATE INJECTION PRODUCT

If desired, the solution may be further diluted immediately prior to use with an appropriate sterile, preservative free medium such as 5% Dextrose Solution, USP or Sodium Chloride Injection, USP.
Fomepizole

Fomepizole

Treatment Guidelines

If ethylene glycol or methanol poisoning is left untreated, the natural progression of the poisoning leads to accumulation of toxic metabolites, including glycolic and oxalic acids (ethylene glycol intoxication) and formic acid (methanol intoxication). These metabolites can induce metabolic acidosis, nausea/vomiting, seizures, stupor, coma, calcium oxaluria, acute tubular necrosis, blindness, and death. The diagnosis of these poisonings may be difficult because ethylene glycol and methanol concentrations diminish in the blood as they are metabolized to their respective metabolites. Hence, both ethylene glycol and methanol concentrations and acid base balance, as determined by serum electrolyte (anion gap) and/or arterial blood gas analysis, should be frequently monitored and used to guide treatment.

Treatment consists of blocking the formation of toxic metabolites using inhibitors of alcohol dehydrogenase, such as fomepizole injection, and correction of metabolic abnormalities. In patients with high ethylene glycol or methanol concentrations (> 50 mg/dL), significant metabolic acidosis, or renal failure, hemodialysis should be considered to remove ethylene glycol or methanol and the respective toxic metabolites of these alcohols.

Treatment with Fomepizole Injection

Begin fomepizole injection treatment immediately upon suspicion of ethylene glycol or methanol ingestion based on patient history and/or anion gap metabolic acidosis, increased osmolar gap, visual disturbances, or oxalate crystals in the urine, OR a documented serum ethylene glycol or methanol concentration greater than 20 mg/dL.

Hemodialysis

Hemodialysis should be considered in addition to fomepizole injection in the case of renal failure, significant or worsening metabolic acidosis, or a measured ethylene glycol or methanol concentration of greater than or equal to 50 mg/dL. Patients should be dialyzed to correct metabolic abnormalities and to lower the ethylene glycol concentrations below 50 mg/dL.

Discontinuation of Fomepizole Injection Treatment

Treatment with fomepizole injection may be discontinued when ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH.

Dosing of Fomepizole Injection

A loading dose of 15 mg/kg should be administered, followed by doses of 10 mg/kg every 12 hours for 4 doses, then 15 mg/kg every 12 hours thereafter until ethylene glycol or methanol concentrations are undetectable or have been reduced below 20 mg/dL, and the patient is asymptomatic with normal pH. All doses should be administered as a slow intravenous infusion over 30 minutes (see Administration).

Dosage with Renal Dialysis

Fomepizole Injection is dialyzable and the frequency of dosing should be increased to every 4 hours during hemodialysis.
Fomepizole Injection Dosing in Patients Requiring Hemodialysis DOSE AT THE BEGINNING OF HEMODIALYSIS If < 6 hours since last Fomepizole Injection dose If > 6 hours since last Fomepizole Injection dose Do not administer dose Administer next scheduled dose DOSING DURING HEMODIALYSIS Dose every 4 hours DOSING AT THE TIME HEMODIALYSIS IS COMPLETED Time between last dose and the end of hemodialysis < 1 hour Do not administer dose at the end of hemodialysis 1 to 3 hours Administer 1/2 of the next scheduled dose > 3 hours Administer next scheduled dose MAINTENANCE DOSING OFF HEMODIALYSIS Give next scheduled dose 12 hours from last dose administered
Administration

Fomepizole injection solidifies at temperatures less than 25° C (77° F). If the fomepizole injection solution has become solid in the vial, the solution should be liquefied by running the vial under warm water or by holding in the hand. Solidification does not affect the efficacy, safety, or stability of fomepizole injection. Using sterile technique, the appropriate dose of fomepizole injection should be drawn from the vial with a syringe and injected into at least 100 mL of sterile 0.9% sodium chloride injection or dextrose 5% injection. Mix well. The entire contents of the resulting solution should be infused over 30 minutes. Fomepizole injection, like all parenteral products, should be inspected visually for particulate matter prior to administration.

Stability

Fomepizole injection diluted in 0.9% sodium chloride injection or dextrose 5% injection remains stable and sterile for at least 24 hours when stored refrigerated or at room temperature. Fomepizole injection does not contain preservatives. Therefore, maintain sterile conditions, and after dilution do not use beyond 24 hours. Solutions showing haziness, particulate matter, precipitate, discoloration, or leakage should not be used.
Oxcarbazepine Suspensio...

Oxcarbazepine Suspension

2.1 Recommended Dosage

In Combination with Cisplatin 100 mg/m2
• The recommended dose of Vinorelbine Injection, USP is 25 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes on days 1, 8, 15 and 21 of a 28 day cycle in combination with cisplatin 100 mg/m 2 on day 1 only of each 28 day cycle.
In Combination with Cisplatin 120 mg/m2
• The recommended dose of Vinorelbine Injection, USP is 30 mg/m 2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m 2 on days 1 and 29, then every 6 weeks.
Single-Agent
• The recommended dose of Vinorelbine Injection, USP is 30 mg/m 2 administered intravenously over 6 to 10 minutes once a week.
2.2 Dose Modifications

Hematologic Toxicity

[see Warnings and Precautions (5.1)]

Hold or decrease the dose of Vinorelbine Injection, USP in patients with decreased neutrophil counts using the following schema.
Neutrophils on Day of Treatment (Cells/mm3) Percentage of Starting Dose of Vinorelbine Injection, USP
≥ 1,500

100%

1,000 to 1,499

50%

< 1,000

Do not administer Vinorelbine Injection USP.

Repeat neutrophil count in one week.

If three consecutive weekly doses are held because Neutrophil count is < 1,000 cells/mm3, discontinue Vinorelbine Injection, USP

Note : For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine Injection, USP should be:

> 1,500

75%

1,000 to 1,499

37.5%

< 1,000

Do not administer Vinorelbine Injection, USP.

Repeat neutrophil count in one week.

Hepatic Impairment/Toxicity

[see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]

Reduce Vinorelbine Injection, USP dose in patients with elevated serum total bilirubin concentration according to the following schema:

Serum total bilirubin concentration (mg/dl)

Percentage of Starting Dose of Vinorelbine Injection, USP

≤ 2.0

100%

2.1 to 3.0

50%

> 3.0

25%

Concurrent Hematologic Toxicity and Hepatic Impairment

In patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of Vinorelbine Injection, USP determined from the above schemas.

Neurologic Toxicity

[see Warnings and Precautions (5.5) ]

Discontinue Vinorelbine Injection, USP for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.

2.3 Preparation and Administration

Preparation of Vinorelbine Injection, USP

Dilute Vinorelbine Injection, USP in either a syringe or intravenous bag using one of the recommended solutions.

Syringe

Dilute to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:
• 5% Dextrose Injection, USP • 0.9% Sodium Chloride Injection, USP
Intravenous Bag

Dilute to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
• 5% Dextrose Injection, USP • 0.9% Sodium Chloride Injection, USP • 0.45% Sodium Chloride Injection, USP • 5% Dextrose and 0.45% Sodium Chloride Injection, USP • Ringer's Injection, USP • Lactated Ringer's Injection, USP
Stabiliy

Diluted Vinorelbine Injection, USP may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F).

Administration

Administer diluted Vinorelbine Injection, USP over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.

Vinorelbine Injection, USP must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine Injection, USP is injected.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine Injection, USP should not be administered.

Management of Suspected Extravasation
• If Vinorelbine Injection, USP leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection, USP and initiate appropriate management measures in accordance with institutional policies. [see Warnings and Precautions (5.4).]
2.4 Procedures for Proper Handling and Disposal

Handle and dispose Vinorelbine Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs2.

Exercise caution in handling and preparing the solution of Vinorelbine Injection, USP. The use of gloves is recommended. If the solution of Vinorelbine Injection, USP contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Avoid contamination of the eye with Vinorelbine Injection, USP. If exposure occurs, flush the eyes with water immediately and thoroughly.
Melphalan Hydrochloride...

Melphalan Hydrochloride Kit

The usual IV dose is 16 mg/m2. Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS: General). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one third to one half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir and day of treatment should be considered.

Administration Precautions

As with other toxic compounds, caution should be exercised in handling and preparing the solution of Melphalan Hydrochloride. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of Melphalan Hydrochloride contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product.

Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS).

Preparation for Administration/Stability
1. Melphalan Hydrochloride for Injection must be reconstituted by rapidly injecting 10 mL of the supplied diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. 2. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg/mL. 3. Administer the diluted product over a minimum of 15 minutes. 4. Complete administration within 60 minutes of reconstitution.
The time between reconstitution/dilution and administration of Melphalan Hydrochloride for Injection should be kept to a minimum because reconstituted and diluted solutions of Melphalan Hydrochloride for Injection are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the reaction of Melphalan Hydrochloride with Sterile Diluent for Melphalan Hydrochloride for Injection. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes.

A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.
Fludarabine Phosphate

Fludarabine Phosphate

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 impairment, 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 Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30-79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine phosphate injection, USP should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal Impairment
Creatinine Clearance

Starting Dose

≥ 80 mL/min

25 mg/m2 (full dose)

50 - 79 mL/min

20 mg/m2

30 - 49 mL/min

15 mg/m2

30 mL/min

do not administer

Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

Preparation of Solutions

Fludarabine phosphate injection, USP: Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water for injection, qs; 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.1-4

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.
Methadone Hydrochloride...

Methadone Hydrochloride

Methadone differs from many other opioid agonists in several important ways. Methadone's pharmacokinetic properties, coupled with high interpatient variability in its absorption, metabolism, and relative analgesic potency, necessitate a cautious and highly individualized approach to prescribing. Particular vigilance is necessary during treatment initiation, during conversion from one opioid to another, and during dose titration.

While methadone's duration of analgesic action (typically 4 to 8 hours) in the setting of single-dose studies approximates that of morphine, methadone's plasma elimination half-life is substantially longer than that of morphine (typically 8 to 59 hours vs. 1 to 5 hours). Methadone's peak respiratory depressant effects typically occur later, and persist longer than its peak analgesic effects. Also, with repeated dosing, methadone may be retained in the liver and then slowly released, prolonging the duration of action despite low plasma concentrations. For these reasons, steady-state plasma concentrations, and full analgesic effects, are usually not attained until 3 to 5 days of dosing. Additionally, incomplete cross-tolerance between µ-opioid agonists makes determination of dosing during opioid conversion complex.

All of these characteristics make methadone dosing complex and can contribute to cases of iatrogenic overdose, particularly during treatment initiation and dose titration. A high degree of "opioid tolerance" does not eliminate the possibility of methadone overdose, iatrogenic or otherwise. Deaths have been reported during conversion to methadone from chronic, high-dose treatment with other opioid agonists.

Treatment of Pain

Optimal methadone initiation and dose titration strategies for the treatment of pain have not been determined. Published equianalgesic conversion ratios between methadone and other opioids are imprecise, providing at best, only population averages that cannot be applied consistently to all patients. It should be noted that many commonly cited equianalgesia tables only present relative analgesic potencies of single opioid doses in non-tolerant patients, thus greatly underestimating methadone's analgesic potency, and its potential for adverse effects in repeated-dose settings. Regardless of the dose determination strategy employed, methadone is most safely initiated and titrated using small initial doses and gradual dose adjustments.

As with all opioid drugs, it is necessary to adjust the dosing regimen for each patient individually, taking into account the patient's prior analgesic treatment experience. The following dosing recommendations should only be considered as suggested approaches to what is actually a series of clinical decisions over time in the management of the pain of each individual patient. Prescribers should always follow appropriate pain management principles of careful assessment and ongoing monitoring.

In the selection of an initial dose of Methadone Hydrochloride Injection, attention should be given to the following:
1. The total daily dose, potency and specific characteristics of the opioid the patient had been taking previously, if any; 2. The relative potency estimate used to calculate an equianalgesic starting methadone dose, in particular, whether it is intended for use in acute or chronic methadone dosing; 3. The patient's degree of opioid tolerance; 4. The age, general condition and medical status of the patient; 5. Concurrent medications, particularly other CNS and respiratory depressants; 6. The type, severity and expected duration of the patient's pain; 7. The acceptable balance between pain control and adverse side effects.
Methadone Hydrochloride Injection may be administered intravenously, subcutaneously or intramuscularly. The absorption of subcutaneous and intramuscular methadone has not been well characterized and appears to be unpredictable. Local tissue reactions may occur.

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

Initiation of Therapy in Opioid Non-Tolerant Patients

When parenteral methadone is used as the first analgesic in patients who are not already being treated with, and tolerant to, opioids, the usual intravenous methadone starting dose is 2.5 mg to 10 mg every 8 to 12 hours, slowly titrated to effect. More frequent administration may be required during methadone initiation in order to maintain adequate analgesia, and extreme caution is necessary to avoid overdosage, taking into account methadone's long elimination half life.

Conversion from Oral Methadone to Parenteral Methadone

Conversion from oral methadone to parenteral methadone should initially use a 2:1 dose ratio (e.g., 10 mg oral methadone to 5 mg parenteral methadone).

Switching Patients to Parenteral Methadone from other Chronic Opioids

Switching a patient from another chronically administered opioid to methadone requires caution due to the uncertainty of dose conversion ratios and incomplete cross-tolerance. Deaths have occurred in opioid tolerant patients during conversion to methadone.

Conversion ratios in many commonly used equianalgesic dosing tables do not apply in the setting of repeated methadone dosing. Although with single-dose administration the onset and duration of analgesic action, as well as the analgesic potency of methadone and morphine, are similar methadone's potency increases over time with repeated dosing. Furthermore, the conversion ratio between methadone and other opiates varies dramatically depending on baseline opiate (morphine equivalent) use as shown in the table below.

The dose conversion scheme below is derived from various consensus guidelines for converting chronic pain patients to methadone from morphine. The guidelines used to construct this table, however, were all designed for converting patients from oral morphine to oral methadone. The third column assumes a 2:1 ratio for converting from oral to intravenous methadone. Clinicians should consult published conversion guidelines to determine the equivalent morphine dose for patients converting from other opioids.
Table 1. Oral Morphine to Intravenous Methadone Conversion for Chronic Administration Total Daily Baseline Oral Morphine Dose Estimated Daily Oral Methadone Requirement as Percent of Total Daily Morphine Dose Estimated Daily Intravenous Methadone as Percent of Total Daily Oral Morphine Dose* * The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
< 100 mg

20% to 30%

10% to 15%

100 to 300 mg

10% to 20%

5% to 10%

300 to 600 mg

8% to 12%

4% to 6%

600 mg to 1000 mg

5% to 10%

3% to 5%

> 1000 mg

< 5 %

< 3 %
Table 2. Parenteral Morphine to Intravenous Methadone Conversion for Chronic Administration (Derived from Table 1, assuming a 3:1 oral:parenteral morphine ratio) Total Daily Baseline Parenteral Morphine Dose Estimated Daily Parenteral Methadone Requirement as Percent of Total Daily Morphine Dose* * The total daily methadone dose derived from the table above may then be divided to reflect the intended dosing schedule (i.e., for administration every 8 hours, divide total daily methadone dose by 3).
10 mg to 30 mg

40% to 66%

30 mg to 50 mg

27% to 66%

50 mg to 100 mg

22% to 50%

100 mg to 200 mg

15% to 34%

200 mg to 500 mg

10% to 20%

Note: Equianalgesic methadone dosing varies not only between patients, but also within the same patient, depending on baseline morphine (or other opioid) dose. Tables 1 and 2 have been included in order to illustrate this concept and to provide a safe starting point for opioid conversion. Methadone dosing should not be based solely on these tables. Methadone conversion and dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use. The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects. If a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased.

Methadone conversion and dose titration methods should always be individualized to account for the patient's prior opioid exposure, general medical condition, concomitant medication, and anticipated breakthrough medication use. The endpoint of titration is achievement of adequate pain relief, balanced against tolerability of opioid side effects. If a patient develops intolerable opioid related side effects, the methadone dose, or dosing interval, may need to be decreased.

Dosage Adjustment During Pregnancy

Methadone clearance may be increased during pregnancy. Several small studies have demonstrated significantly lower trough methadone plasma concentrations and shorter methadone half-lives in women during their pregnancy compared to after their delivery. During pregnancy a woman's methadone dose may need to be increased, or their dosing interval decreased. Methadone should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Detoxification and Maintenance Treatment of Opiate Dependence

For detoxification and maintenance of opiate dependence, methadone should be administered in accordance with the treatment standards cited in 42CFR Section 8.12, including limitations on unsupervised administration. Injectable methadone products are not approved for the outpatient treatment of opioid dependence. Parenteral methadone should be used only for patients who are unable to take oral medication, such as during hospitalization. The patient's oral methadone dose should be converted to an equivalent parenteral dose using the considerations above.
Esmolol Hydrochloride

Esmolol Hydrochloride

Dosing Information:

SUPRAVENTRICULAR TACHYCARDIA

Dosage needs to be titrated, using ventricular rate as the guide.

An initial loading dose of 0.5 milligrams/kg (500 micrograms/kg) infused over a minute duration followed by a maintenance infusion of 0.05 milligrams/kg/min (50 micrograms/kg/min) for the next 4 minutes is recommended. This should give a rough guide with respect to the responsiveness of ventricular rate.

After the 4 minutes of initial maintenance infusion (total treatment duration being 5 minutes), depending upon the desired ventricular response, the maintenance infusion may be continued at 0.05 mg/kg/min or increased step-wise (e.g. 0.1 mg/kg/min, 0.15 mg/kg/min to a maximum of 0.2 mg/kg/min) with each step being maintained for 4 or more minutes.

If more rapid slowing of ventricular response is imperative, the 0.5 mg/kg loading dose infused over a 1 minute period may be repeated, followed by a maintenance infusion of 0.1 mg/kg/min for 4 minutes. Then, depending upon ventricular rate, another (and final) loading dose of 0.5 mg/kg/min infused over a 1 minute period may be administered followed by a maintenance infusion of 0.15 mg/kg/min. If needed, after 4 minutes of the 0.15 mg/kg/min maintenance infusion, the maintenance infusion may be increased to a maximum of 0.2 mg/kg/min.

In the absence of loading doses, constant infusion of a single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes. Maintenance infusions (with or without loading doses) may be continued for as long as 24 hours.

The following table summarizes the above and assumes that 3 loading doses (the maximum recommended) are infused over a 1 minute and incremental maintenance doses are required after each loading dose. There should be no 4th loading dose, but the maintenance dose may be incremented one more time.
* As the desired heart rate or endpoint is approached, the loading infusion may be omitted and the maintenance infusion titrated to 300 mcg/kg/min (0.3 mg/kg/min) or downward as appropriate. Maintenance dosages above 200 mcg/kg/min (0.2 mg/kg/min) have not been shown to have significantly increased benefits. The interval between titration steps may be increased.
Loading Dose

Maintenance Dose

Elapsed Time

(over 1 minute)

(over 4 minutes)

(minutes)

micrograms/

milligrams/

micrograms/

milligrams/

kg/min

kg/min

kg/min

kg/min

0 - 1

500

0.5

1 - 5

50

0.05

5 - 6

500

0.5

6 - 10

100

0.1

10 - 11

500

0.5

11 - 15

150

0.15

15 - 16

*

*

16 - 20

*200

*0.2

> 20

Maintenance dose titrated to heart rate or other clinical endpoint.

In the treatment of supraventricular tachycardia, responses to esmolol usually (over 95%) occur within the range of 50 to 200 micrograms/kg/min (0.05 to 0.2 milligrams/kg/min). The average effective dosage is approximately 100 micrograms/kg/min (0.1 milligrams/kg/min) although dosages as low as 25 micrograms/kg/min (0.025 milligrams/kg/min) have been adequate in some patients. Dosages as high as 300 micrograms/kg/min (0.3 milligrams/kg/min) have been used, but these provide little added effect and increase the rate of adverse effects, so doses greater than 200 micrograms/kg/min are not recommended. Dosage of esmolol in supraventricular tachycardia must be individualized by titration in which each step consists of a loading dosage followed by a maintenance dosage.

This specific dosage regimen has not been studied intraoperatively and, because of the time required for titration, may not be optimal for intraoperative use.

The safety of dosages above 300 mcg/kg/min (0.3 mg/kg/min) has not been studied.

In the event of an adverse reaction, the dosage of esmolol may be reduced or discontinued. If a local infusion site reaction develops, an alternate infusion site should be used and caution should be taken to prevent extravasation. The use of butterfly needles should be avoided.

Abrupt cessation of esmolol in patients has not been reported to produce the withdrawal effects which may occur with abrupt withdrawal of beta blockers following chronic use in coronary artery disease (CAD) patients. However, caution should still be used in abruptly discontinuing infusions of esmolol in CAD patients.

After achieving an adequate control of the heart rate and a stable clinical status in patients with supraventricular tachycardia, transition to alternative antiarrhythmic agents such as propranolol, digoxin, or verapamil, may be accomplished.

A recommended guideline for such a transition is given below but the physician should carefully consider the labeling instructions for the alternative agent selected.

Alternative Agent

Dosage

Propranolol hydrochloride

10 mg to 20 mg q 4 to 6 hrs

Digoxin

0.125 mg to 0.5 mg q 6 hrs (p.o. or i.v.)

Verapamil

80 mg q 6 hrs

The dosage of esmolol should be reduced as follows:
1. Thirty minutes following the first dose of the alternative agent, reduce the infusion rate of esmolol by one-half (50%). 2. Following the second dose of the alternative agent, monitor the patient’s response and if satisfactory control is maintained for the first hour, discontinue esmolol.
The use of infusions of esmolol up to 24 hours has been well documented; in addition, limited data from 24 to 48 hrs (N=48) indicate that esmolol is well tolerated up to 48 hours.

INTRAOPERATIVE AND POSTOPERATIVE TACHYCARDIA AND/OR HYPERTENSION

In the intraoperative and postoperative settings it is not always advisable to slowly titrate the dose of esmolol to a therapeutic effect. Therefore, two dosing options are presented: immediate control dosing and a gradual control when the physician has time to titrate.
1. Immediate Control
For intraoperative treatment of tachycardia and/or hypertension give an 80 mg (approximately 1 mg/kg) bolus dose over 30 seconds followed by a 150 mcg/kg/min infusion, if necessary. Adjust the infusion rate as required up to 300 mcg/kg/min to maintain desired heart rate and/or blood pressure.
2. Gradual Control
For postoperative tachycardia and hypertension, the dosing schedule is the same as that used in supraventricular tachycardia. To initiate treatment, administer a loading dosage infusion of 500 mcg/kg/min of esmolol for one minute followed by a four-minute maintenance infusion of 50 mcg/kg/min. If an adequate therapeutic effect is not observed within five minutes, repeat the same loading dosage and follow with a maintenance infusion increased to 100 mcg/kg/min (see above SUPRAVENTRICULAR TACHYCARDIA)

Notes:
1. Higher dosages (250 to 300 mcg/kg/min) may be required for adequate control of blood pressure than those required for the treatment of atrial fibrillation, flutter and sinus tachycardia. One third of the postoperative hypertensive patients required these higher doses. 2. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
Directions for Use of the 10 mL Ready-to-use Vial (10 milligrams/mL)

This dosage form is prediluted to provide a ready-to-use 10 mg/mL concentration recommended for esmolol intravenous administration. It may be used to administer the appropriate esmolol loading dosage infusions by hand-held syringe while the maintenance infusion is being prepared.

The 10 mL Ready-to-use Vial contains esmolol at a concentration of 10 milligram/mL. When using a 10 milligrams/mL concentration, a loading dose of 0.5 mg/kg infused over 1 minute period of time, for a 70 kg patient is 3.5 mL.
Isosulfan Blue

Isosulfan Blue

2.1 Subcutaneous administration

Isosulfan blue injection 1% is to be administered subcutaneously, one-half (1/2) mL into three (3) interdigital spaces of each extremity per study. A maximum dose of 3 mL (30 mg) isosulfan blue is, therefore, injected.
Magnesium Chloride

Magnesium Chloride

For intravenous infusion: 4 grams in 250 mL of 5%Dextrose Injection, at a rate not exceeding 3 mL per minute. Serum magnesium levels should serve as a guide to continued dosage.
Duraclon

Duraclon

The recommended starting dose of Duraclon for continuous epidural infusion is 30 mcg/hr. Although dosage may be titrated up or down depending on pain relief and occurrence of adverse events, experience with dosage rates above 40 mcg/hr is limited.

Familiarization with the continuous epidural infusion device is essential. Patients receiving epidural clonidine from a continuous infusion device should be closely monitored for the first few days to assess their response.

The 500 mcg/mL (0.5 mg/mL) strength product must be diluted prior to use in 0.9% Sodium Chloride for Injection, U.S.P., to a final concentration of 100 mcg/mL:

Volume of

Duraclon

500 mcg/mL

Volume of 0.9%

Sodium Chloride

for Injection, U.S.P.

Resulting Final Duraclon

Concentration

(100 mcg/mL)

1 mL

4 mL

500 mcg/5 mL

2 mL

8 mL

1000 mcg/10 mL

3 mL

12 mL

1500 mcg/15 mL

4 mL

16 mL

2000 mcg/20 mL

5 mL

20 mL

2500 mcg/25 mL

6 mL

24 mL

3000 mcg/30 mL

7 mL

28 mL

3500 mcg/35 mL

8 mL

32 mL

4000 mcg/40 mL

9 mL

36 mL

4500 mcg/45 mL

10 mL

40 mL

5000 mcg/50 mL

Renal Impairment

Dosage should be adjusted according to the degree of renal impairment, and patients should be carefully monitored. Since only a minimal amount of clonidine is removed during routine hemodialysis, there is no need to give supplemental clonidine following dialysis.

Duraclon must not be used with a preservative.

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

Enlon

ENLON Test in the Differential Diagnosis of Myasthenia Gravis7-14

Intravenous Dosage (Adults)

A tuberculin syringe containing 1 mL (10 mg) of ENLON is prepared with an intravenous needle, and 0.2 mL (2 mg) is injected intravenously within 15 to 30 seconds. The needle is left in situ. Only if no reaction occurs after 45 seconds is the remaining 0.8 mL (8 mg) injected. If a cholinergic reaction (muscarinic side effects, skeletal muscle fasciculations and increased muscle weakness) occurs after injection of 0.2 mL (2 mg), the test is discontinued and atropine sulfate, 0.4 mg to 0.5 mg, is administered intravenously. After one-half hour the test may be repeated.

Intramuscular Dosage (Adults)

In adults with inaccessible veins, dosage for intramuscular injection is 1 mL (10 mg) of ENLON. Subjects who demonstrate hyperreactivity to this injection (cholinergic reaction), should be retested after one-half hour with 0.2 mL (2 mg) of ENLON intramuscularly to rule out false-negative reactions.

Dosage in Pediatric Patients

The intravenous testing dose of ENLON in pediatric patients weighing up to 75 lbs is 0.1 mL (1 mg); above this weight, the dose is 0.2 mL (2 mg). If there is no response after 45 seconds, it may be titrated up to 0.5 mL (5 mg) in pediatric patients under 75 lbs, given in increments of 0.1 mL (1 mg) every 30 to 45 seconds and up to 1 mL (10 mg) in heavier patients. In infants, the recommended dose is 0.05 mL (0.5 mg). Because of technical difficulty with intravenous injection in pediatric patients, the intramuscular route may be used. In pediatric patients weighing up to 75 lbs, 0.2 mL (2 mg) is injected intramuscularly. In pediatric patients weighing more than 75 lbs, 0.5 mL (5 mg) is injected intramuscularly. All signs which would appear with the intravenous test appear with the intramuscular test except that there is a delay of 2 to 10 minutes before a reaction is noted.

ENLON Test for Evaluation of Treatment Requirements in Myasthenia Gravis

The recommended dose is 0.1 mL to 0.2 mL (1 mg to 2 mg) of ENLON, administered intravenously 1 hour after oral intake of the drug being used in treatment.7-11 Response will be myasthenic in the undertreated patient, adequate in the controlled patient, and cholinergic in the overtreated patient. Responses to ENLON in myasthenic and nonmyasthenic individuals are summarized in the following chart.8
* Myasthenic Response - occurs in untreated myasthenics and may serve to establish diagnosis; in patients under treatment, indicates that therapy is inadequate. † Adequate Response - observed in treated patients when therapy is stabilized: a typical response in normal individuals. In addition to this response in non-myasthenics, the phenomenon of forced lid closure is often observed in psychoneurotics. ‡ Cholinergic Response - seen in myasthenics who have been overtreated with anticholinesterase drugs.
Myasthenic*

Adequate†

Cholinergic‡

Muscle Strength (ptosis, diplopia dysphonia, dysphagia, dysarthria, respiration, limb strength)

Increased

No change

Decreased

Fasciculations (orbicularis oculi, facial muscles, limb muscles)

Absent

Present or absent

Present or absent

Side reactions (lacrimation diaphoresis, salivation, abdominal cramps, nausea, vomiting, diarrhea)

Absent

Minimal

Severe

ENLON Test in Crisis

The term crisis is applied to the myasthenic whenever severe respiratory distress with objective ventilatory inadequacy occurs and the response to medication is not predictable. This state may be secondary to a sudden increase in severity of myasthenia gravis (myasthenic crisis), or to overtreatment with anticholinesterase drugs (cholinergic crisis).

When a patient is apneic, controlled ventilation must be secured immediately in order to avoid cardiac arrest and irreversible central nervous system damage. No attempt is made to test with ENLON until respiratory exchange is adequate.

Dosage used at this time is most important

If the patient is cholinergic, ENLON will cause increased oropharyngeal secretions and further weakness in the muscles of respiration. If the crisis is myasthenic, the test clearly improves respiration and the patient can be treated with longer-acting intravenous anticholinesterase medication. When the test is performed, there should not be more than 0.2 mL (2 mg) ENLON in the syringe. An intravenous dose of 0.1 mL (1 mg) is given initially. The patient’s heart action is carefully observed. If, after an interval of 1 minute, this dose does not further impair the patient, the remaining 0.1 mL (1 mg) can be injected. If no clear improvement of respiration occurs after 0.2 mL (2 mg) dose, it is usually wisest to discontinue all anticholinesterase drug therapy and secure controlled ventilation by tracheostomy with assisted respiration.5

For Use as a Curare Antagonist

ENLON should be administered by intravenous injection in 1 mL (10 mg) doses given slowly over a period of 30 to 45 seconds so that the onset of cholinergic reaction can be detected. This dosage may be repeated whenever necessary. The maximal dose for any one patient should be 4 mL (40 mg). Because of its brief effect, ENLON should not be given prior to the administration of curare, tubocurarine, gallamine triethiodide or dimethyl-tubocurarine: it should be used at the time when its effect is needed. When given to counteract curare overdosage, the effect of each dose on the respiration should be carefully observed before it is repeated, and assisted ventilation should always be employed.

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

Octreotide Acetate

Octreotide acetate may be administered subcutaneously or intravenously. Subcutaneous injection is the usual route of administration of octreotide acetate for control of symptoms. Pain with subcutaneous administration may be reduced by using the smallest volume that will deliver the desired dose. Multiple subcutaneous injections at the same site within short periods of time should be avoided. Sites should be rotated in a systematic manner.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulates and/or discoloration are observed. Proper sterile technique should be used in the preparation of parenteral admixtures to minimize the possibility of microbial contamination. Octreotide acetate is not compatible in Total Parenteral Nutrition (TPN) solutions because of the formation of a glycosyl octreotide conjugate which may decrease the efficacy of the product.

Octreotide acetate is stable in sterile isotonic saline solutions or sterile solutions of dextrose 5% in water for 24 hours. It may be diluted in volumes of 50 mL to 200 mL and infused intravenously over 15 to 30 minutes or administered by IV push over 3 minutes. In emergency situations (e.g., carcinoid crisis) it may be given by rapid bolus.

The initial dosage is usually 50 mcg administered twice or three times daily. Upward dose titration is frequently required. Dosage information for patients with specific tumors follows.

Acromegaly

Dosage may be initiated at 50 mcg t.i.d. Beginning with this low dose may permit adaptation to adverse gastrointestinal effects for patients who will require higher doses. IGF-I (somatomedin C) levels every 2 weeks can be used to guide titration. Alternatively, multiple growth hormone levels at 0 to 8 hours after octreotide acetate administration permit more rapid titration of dose. The goal is to achieve growth hormone levels less than 5 ng/mL or IGF-I (somatomedin C) levels less than 1.9 U/mL in males and less than 2.2 U/mL in females. The dose most commonly found to be effective is 100 mcg t.i.d., but some patients require up to 500 mcg t.i.d. for maximum effectiveness. Doses greater than 300 mcg/day seldom result in additional biochemical benefit, and if an increase in dose fails to provide additional benefit, the dose should be reduced. IGF-I (somatomedin C) or growth hormone levels should be reevaluated at 6 month intervals.

Octreotide acetate should be withdrawn yearly for approximately 4 weeks from patients who have received irradiation to assess disease activity. If growth hormone or IGF-I (somatomedin C) levels increase and signs and symptoms recur, octreotide acetate therapy may be resumed.

Carcinoid Tumors

The suggested daily dosage of octreotide acetate during the first 2 weeks of therapy ranges from 100 to 600 mcg/day in 2 to 4 divided doses (mean daily dosage is 300 mcg). In the clinical studies, the median daily maintenance dosage was approximately 450 mcg, but clinical and biochemical benefits were obtained in some patients with as little as 50 mcg, while others required doses up to 1500 mcg/day.

However, experience with doses above 750 mcg/day is limited.

VIPomas

Daily dosages of 200 to 300 mcg in 2 to 4 divided doses are recommended during the initial 2 weeks of therapy (range 150 to 750 mcg) to control symptoms of the disease. On an individual basis, dosage may be adjusted to achieve a therapeutic response, but usually doses above 450 mcg/day are not required.
Etomidate

Etomidate

Etomidate injection is intended for administration only by the intravenous route (see CLINICAL PHARMACOLOGY). The dose for induction of anesthesia in adult patients and in pediatric patients above the age of ten (10) years will vary between 0.2 and 0.6 mg/kg of body weight, and it must be individualized in each case. The usual dose for induction in these patients is 0.3 mg/kg, injected over a period of 30 to 60 seconds. There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of ten (10) years; therefore, such use is not recommended. Geriatric patients may require reduced doses of etomidate.

Smaller increments of intravenous etomidate may be administered to adult patients during short operative procedures to supplement subpotent anesthetic agents, such as nitrous oxide. The dosage employed under these circumstances, although usually smaller than the original induction dose, must be individualized. There are insufficient data to support this use of etomidate for longer adult procedures or for any procedures in pediatric patients; therefore, such use is not recommended. The use of intravenous fentanyl and other neuroactive drugs employed during the conduct of anesthesia may alter the etomidate dosage requirements. Consult the prescribing information for all other such drugs before using.

Premedication

Etomidate injection is compatible with commonly administered pre-anesthetic medications, which may be employed as indicated. See also CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and dosage recommendations for maintenance of anesthesia.

Etomidate hypnosis does not significantly alter the usual dosage requirements of neuromuscular blocking agents employed for endotracheal intubation or other purposes shortly after induction of anesthesia.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. To prevent needle-stick injuries, needles should not be recapped, purposely bent, or broken by hand.
Sotradecol

Sotradecol

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if precipitated or discolored.

Sotradecol (sodium tetradecyl sulfate injection) is for intravenous use only. The strength of solution required depends on the size and degree of varicosity. In general, the 1% solution will be found most useful with the 3% solution preferred for larger varicosities. The dosage should be kept small, using 0.5 mL to 2 mL (preferably 1 mL maximum) for each injection, and the maximum single treatment should not exceed 10 mL.
Mesna

Mesna

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL should be administered by deep intramuscular injection. A 21 gauge needle is recommended. The maximum volume per injection site should not exceed 3 mL. DO NOT ADMINISTER INTRAVENOUSLY.

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

Haloperidol decanoate injection, 50 mg/mL and haloperidol decanoate injection, 100 mg/mL are intended for use in schizophrenic patients who require prolonged parenteral antipsychotic therapy. These patients should be previously stabilized on antipsychotic medication before considering a conversion to haloperidol decanoate, USP. Furthermore, it is recommended that patients being considered for haloperidol decanoate, USP therapy have been treated with, and tolerate well, short-acting haloperidol, USP in order to reduce the possibility of an unexpected adverse sensitivity to haloperidol, USP. Close clinical supervision is required during the initial period of dose adjustment in order to minimize the risk of overdosage or reappearance of psychotic symptoms before the next injection. During dose adjustment or episodes of exacerbation of symptoms of schizophrenia, haloperidol decanoate, USP therapy can be supplemented with short-acting forms of haloperidol, USP.

The dose of haloperidol decanoate injection, 50 mg/mL or haloperidol decanoate injection, 100 mg/mL should be expressed in terms of its haloperidol, USP content. The starting dose of haloperidol decanoate, USP should be based on the patient's age, clinical history, physical condition, and response to previous antipsychotic therapy. The preferred approach to determining the minimum effective dose is to begin with lower initial doses and to adjust the dose upward as needed. For patients previously maintained on low doses of antipsychotics (e.g. up to the equivalent of 10 mg/day oral haloperidol), it is recommended that the initial dose of haloperidol decanoate, USP be 10 to 15 times the previous daily dose in oral haloperidol equivalents; limited clinical experience suggests that lower initial doses may be adequate.

Initial Therapy

Conversion from oral haloperidol to haloperidol decanoate, USP can be achieved by using an initial dose of haloperidol decanoate, USP that is 10 to 20 times the previous daily dose in oral haloperidol equivalents.

In patients who are elderly, debilitated, or stable on low doses of oral haloperidol (e.g. up to the equivalent of 10 mg/day oral haloperidol), a range of 10 to 15 times the previous daily dose in oral haloperidol equivalents is appropriate for initial conversion.

In patients previously maintained on higher doses of antipsychotics for whom a low dose approach risks recurrence of psychiatric decompensation and in patients whose long-term use of haloperidol, USP has resulted in a tolerance to the drug, 20 times the previous daily dose in oral haloperidol equivalents should be considered for initial conversion, with downward titration on succeeding injections.

The initial dose of haloperidol decanoate, USP should not exceed 100 mg regardless of previous antipsychotic dose requirements. If, therefore, conversion requires more than 100 mg of haloperidol decanoate, USP as an initial dose, that dose should be administered in two injections, i.e. a maximum of 100 mg initially followed by the balance in 3 to 7 days.

Maintenance Therapy

The maintenance dosage of haloperidol decanoate, USP must be individualized with titration upward or downward based on therapeutic response. The usual maintenance range is 10 to 15 times the previous daily dose in oral haloperidol equivalents dependent on the clinical response of the patient.
HALOPERIDOL DECANOATE, USP DOSING RECOMMENDATIONS Patients Monthly 1st Month Maintenance Stabilized on low daily oral doses (up to 10 mg/day)Elderly or Debilitated 10-15 x Daily Oral Dose 10-15 x Previous Daily Oral Dose High doseDose Risk of relapse Tolerant to oral haloperidol 20 x Daily Oral Dose 10-15 x Previous Daily Oral Dose
Close clinical supervision is required during initiation and stabilization of haloperidol decanoate, USP therapy. Haloperidol decanoate, USP is usually administered monthly or every 4 weeks. However, variation in patient response may dictate a need for adjustment of the dosing interval as well as the dose (See CLINICAL PHARMACOLOGY).

Clinical experience with haloperidol decanoate, USP at doses greater than 450 mg per month has been limited.
Diphenhydramine Hydroch...

Diphenhydramine Hydrochloride

THIS PRODUCT IS FOR INTRAVENOUS OR INTRAMUSCULAR ADMINISTRATION ONLY.

Diphenhydramine hydrochloride injection, USP 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 mg 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.
Cosyntropin

Cosyntropin

Cosyntropin for injection may be administered intramuscularly or as a direct intravenous injection when used as a rapid screening test of adrenal function. It may also be given as an intravenous infusion over a 4 to 8 hour period to provide a greater stimulus to the adrenal glands. Doses of cosyntropin 0.25 to 0.75 mg have been used in clinical studies and a maximal response noted with the smallest dose.

A suggested method for a rapid screening test of adrenal function has been described by Wood and Associates (1). A control blood sample of 6 to 7 mL is collected in a heparinized tube. Reconstitute 0.25 mg of cosyntropin with 1 mL of 0.9% sodium chloride injection and inject intramuscularly. The reconstituted drug product should be inspected visually for particulate matter and discoloration prior to injection. Reconstituted cosyntropin should not be retained. In the pediatric population, aged 2 years or less, a dose of 0.125 mg will often suffice. A second blood sample is collected exactly 30 minutes later. Both blood samples should be refrigerated until sent to the laboratory for determination of the plasma cortisol response by some appropriate method. If it is not possible to send them to the laboratory or perform the fluorimetric procedure within 12 hours, then the plasma should be separated and refrigerated or frozen according to need.

Two alternative methods of administration are intravenous injection and infusion. Cosyntropin can be injected intravenously in 2 to 5 mL of saline over a 2 minute period. When given as an intravenous infusion: cosyntropin, 0.25 mg may be added to glucose or saline solutions and given at the rate of approximately 40 micrograms per hour over a 6 hour period. It should not be added to blood or plasma as it is apt to be inactivated by enzymes. Adrenal response may be measured in the usual manner by determining urinary steroid excretion before and after treatment or by measuring plasma cortisol levels before and at the end of the infusion. The latter is preferable because the urinary steroid excretion does not always accurately reflect the adrenal or plasma cortisol response to ACTH.

The usual normal response in most cases is an approximate doubling of the basal level, provided that the basal level does not exceed the normal range. Patients receiving cortisone, hydrocortisone or spironolactone should omit their pre-test doses on the day selected for testing. Patients taking inadvertent doses of cortisone or hydrocortisone on the test day and patients taking spironolactone or women taking drugs which contain estrogen may exhibit abnormally high basal plasma cortisol levels.

A paradoxical response may be noted in the cortisone or hydrocortisone group as seen in a decrease in plasma cortisol values following a stimulating dose of cosyntropin.

In the spironolactone or estrogen group only a normal incremental response is to be expected. Many patients with normal adrenal function, however, do not respond to the expected degree so that the following criteria have been established to denote a normal response:
1. The control plasma cortisol level should exceed 5 micrograms/100 mL. 2. The 30 minute level should show an increment of at least 7 micrograms/100 mL above the basal level. 3. The 30 minute level should exceed 18 micrograms/100 mL. Comparable figures have been reported by Greig and co-workers (2).
Plasma cortisol levels usually peak about 45 to 60 minutes after an injection of cosyntropin and some prefer the 60 minute interval for testing for this reason. While it is true that the 60 minute values are usually higher than the 30 minute values, the difference may not be significant enough in most cases to outweigh the disadvantage of a longer testing period. If the 60 minute test period is used, the criterion for a normal response is an approximate doubling of the basal plasma cortisol value.

In patients with a raised plasma bilirubin or in patients where the plasma contains free hemoglobin, falsely high fluorescence measurements will result. The test may be performed at any time during the day but because of the physiological diurnal variation of plasma cortisol the criteria listed by Wood cannot apply. It has been shown that basal plasma cortisol levels and the post cosyntropin increment exhibit diurnal changes. However, the 30-minute plasma cortisol level remains unchanged throughout the day so that only this single criterion should be used (3).

Parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit. Reconstituted cosyntropin should not be retained.
Ascorbic Acid

Ascorbic Acid

Ascorbic acid is usually administered orally. When oral administration is not feasible or when malabsorption is suspected, the drug may be administered intramuscularly, intravenously or subcutaneously. When given parenterally, utilization of the vitamin reportedly is best after IM administration, which is the preferred parenteral route.

For intravenous injection, dilution into a large volume parenteral such as Normal Saline or Glucose is recommended to minimize the adverse reactions associated with intravenous injection.

The average protective dose of ascorbic acid for adults is 70 to 150 mg daily. In the presence of scurvy, doses of 300 mg to 1 gram daily are recommended. However, as much as 6 grams have been administered parenterally to normal adults without evidence of toxicity.

To enhance wound-healing, doses of 300 to 500 mg daily for a week to ten days, both preoperatively and postoperatively, are generally considered adequate, although considerably larger amounts have been recommended. In the treatment of burns, doses are governed by the extent of tissue injury. For severe burns, daily doses of 1 to 2 grams are recommended. In other conditions in which the need for ascorbic acid is increased, three to five times the daily optimum allowances appear to be adequate.

WARNING

PRESSURE MAY DEVELOP WITHIN THE VIAL UPON STORAGE.

Exercise care when withdrawing and/or relieve pressure by first inserting sterile empty syringe into vial thus allowing pressure to equilibrate.

When using dispensing vials use aseptic technique. Dispense entire contents in aliquots under a laminar flow hood without delay or within 4 hours after entry or discard remaining content after first withdrawal. Prepare stoppers with a suitable antiseptic solution. Do not use unless solution is clear and seal is intact.

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

Vitamin B Complex

Usually 0.25 to 2 mL by intramuscular or slow intravenous injection. High concentrations given intravenously may be diluted using parenteral infusion solutions. (See PRECAUTIONS.)

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever the solution and container permit (see HOW SUPPLIED).
Amiodarone Hydrochlorid...

Amiodarone Hydrochloride

Amiodarone shows considerable interindividual variation in response. Although a starting dose adequate to suppress life-threatening arrhythmias is needed, close monitoring with adjustment of dose is essential. The recommended starting dose of amiodarone is about 1000 mg over the first 24 hours of therapy, delivered by the following infusion regimen:
Table 1: AMIODARONE DOSE RECOMMENDATIONS: FIRST 24 HOURS
Loading infusions

First Rapid:

150 mg over the FIRST 10 minutes (15 mg/min). Add 3 mL of amiodarone (150 mg) to 100 mLD5W (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 (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, continue the maintenance infusion rate of 0.5 mg/min (720 mg per 24 hours) utilizing a concentration of 1 to 6 mg/mL (Use a central venous catheter for amiodarone concentrations greater than 2 mg/mL). The rate of the maintenance infusion may be increased to achieve effective arrhythmia suppression.

In the event of breakthrough episodes of VF or hemodynamically unstable VT, use 150 mg supplemental infusions of amiodarone (mixed in 100 mL of D5W and infused over 10 minutes to minimize the potential for hypotension).

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. Do not exceed an initial infusion rate of 30 mg/min.

Based on the experience from clinical studies of intravenous amiodarone, a maintenance infusion of up to 0.5 mg/min can be 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 intravenous amiodarone 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 must be delivered by a volumetric infusion pump.

Administer amiodarone, whenever possible, through a central venous catheter dedicated to that purpose. Use an in-line filter during administration.

Intravenous amiodarone 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 Warnings and Precautions (5.3)].

Intravenous amiodarone 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, do not exceed amiodarone concentrations of 2 mg/mL, unless a central venous catheter is used [see Adverse Reactions (6.2)].

Amiodarone infusions exceeding 2 hours must be administered in glass or polyolefin bottles containing D5W. Do not use evacuated glass containers for admixing, as incompatibility with a buffer in the container may cause precipitation.

Amiodarone adsorbs to polyvinyl chloride (PVC) tubing, but all of the clinical experience has been with PVC tubing and the concentrations and rates of infusion provided in DOSAGE AND ADMINISTRATION reflect dosing in these studies.

Amiodarone 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 at higher concentrations and lower flow rates than provided in DOSAGE AND ADMINISTRATION. Polysorbate 80, a component of amiodarone injection, is also known to leach DEHP from PVC [see Description (11)].

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

NOTE: Inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit.
Table 2: AMIODARONE HCl 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 in D5W is incompatible with the drugs shown in Table 3.
Table 3: 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 may be switched to oral amiodarone. When changing to oral amiodarone therapy, clinical monitoring is recommended, particularly for elderly patients. See package insert for oral amiodarone.

Since grapefruit juice is known to inhibit CYP3A-mediated metabolism of oral amiodarone in the intestinal mucosa, resulting in increased plasma levels of amiodarone, do not drink grapefruit juice during treatment with oral amiodarone [see Drug Interactions (7)].

Table 4 provides suggested doses of oral amiodarone to be initiated after varying durations of amiodarone administration. These recommendations are made on the basis of a similar total body amount of amiodarone delivered by the intravenous and oral routes, based on 50% bioavailability of oral amiodarone.
Table 4: RECOMMENDATIONS FOR ORAL DOSAGE AFTER INTRAVENOUS INFUSION Duration of Amiodarone Infusion* Initial Daily Dose of Oral Amiodarone * Assuming a 720 mg/day infusion (0.5 mg/min). † Intravenous amiodarone is not intended for maintenance treatment.
< 1 week

800 to 1600 mg

1 - 3 weeks

600 to 800 mg

> 3 weeks†

400 mg
Ketamine Hydrochloride

Ketamine Hydrochloride

Note: Barbiturates and ketamine hydrochloride injection, being chemically incompatible because of precipitate formation should not be injected from the same syringe.

If the ketamine hydrochloride injection dose is augmented with diazepam, the two drugs must be given separately. Do not mix Ketamine hydrochloride injection and diazepam in syringe or infusion flask. For additional information on the use of diazepam, refer to the WARNINGS and DOSAGE AND ADMINISTRATION Sections of the diazepam insert.

Preoperative Preparations
1. While vomiting has been reported following ketamine hydrochloride injection administration, some airway protection may be afforded because of active laryngeal-pharyngeal reflexes. However, since aspiration may occur with ketamine hydrochloride injection and since protective reflexes may also be diminished by supplementary anesthetics and muscle relaxants, the possibility of aspiration must be considered. Ketamine hydrochloride injection is recommended for use in the patient whose stomach is not empty when, in the judgment of the practitioner, the benefits of the drug outweigh the possible risks. 2. Atropine, scopolamine, or another drying agent should be given at an appropriate interval prior to induction.
Onset and Duration

Because of rapid induction following the initial intravenous injection, the patient should be in a supported position during administration.

The onset of action of ketamine hydrochloride injection is rapid; an intravenous dose of 2 mg/kg (1 mg/lb) of body weight usually produces surgical anesthesia within 30 seconds after injection, with the anesthetic effect usually lasting five to ten minutes. If a longer effect is desired, additional increments can be administered intravenously or intramuscularly to maintain anesthesia without producing significant cumulative effects.

Intramuscular doses, in a range of 9 to 13 mg/kg (4 to 6 mg/lb) usually produce surgical anesthesia within 3 to 4 minutes following injection, with the anesthetic effect usually lasting 12 to 25 minutes.
Cidofovir

Cidofovir

CIDOFOVIR INJECTION MUST NOT BE ADMINISTERED BY INTRAOCULAR INJECTION.

Dosage

THE RECOMMENDED DOSAGE, FREQUENCY, OR INFUSION RATE MUST NOT BE EXCEEDED. CIDOFOVIR INJECTION MUST BE DILUTED IN 100 MILLILITERS 0.9% (NORMAL) SALINE PRIOR TO ADMINISTRATION. TO MINIMIZE POTENTIAL NEPHROTOXICITY, PROBENECID AND INTRAVENOUS SALINE PREHYDRATION MUST BE ADMINISTERED WITH EACH CIDOFOVIR INJECTION INFUSION.

Induction Treatment

The recommended induction dose of cidofovir injection for patients with a serum creatinine of ≤ 1.5 mg/dL, a calculated creatinine clearance > 55 mL/min, and a urine protein < 100 mg/dL (equivalent to < 2+ proteinuria) is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over 1 hr) administered once weekly for two consecutive weeks.

Because serum creatinine in patients with advanced AIDS and CMV retinitis may not provide a complete picture of the patient's underlying renal status, it is important to utilize the Cockcroft-Gault formula to more precisely estimate creatinine clearance (CrCl). As creatinine clearance is dependent on serum creatinine and patient weight, it is necessary to calculate clearance prior to initiation of cidofovir injection. CrCl (mL/min) should be calculated according to the following formula:

Creatinine clearance for males =

[140-age (years)] × [body wt (kg)]

72 × [serum creatinine (mg/dL)]

Creatinine clearance for females =

[140-age (years)] × [body wt (kg)]× 0.85

72 × [serum creatinine (mg/dL)]

Maintenance Treatment

The recommended maintenance dose of cidofovir injection is 5 mg/kg body weight (given as an intravenous infusion at a constant rate over one hr), administered once every 2 weeks.

Dose Adjustment

Changes in Renal Function During Cidofovir Injection Therapy

The maintenance dose of cidofovir injection must be reduced from 5 mg/kg to 3 mg/kg for an increase in serum creatinine of 0.3 to 0.4 mg/dL above baseline. Cidofovir injection therapy must be discontinued for an increase in serum creatinine of ≥ 0.5 mg/dL above baseline or development of ≥ 3+ proteinuria.

Preexisting Renal Impairment

Cidofovir injection is contraindicated in patients with a serum creatinine concentration > 1.5 mg/dL, a calculated creatinine clearance ≤ 55 mL/min, or a urine protein ≥ 100 mg/dL (equivalent to ≥ 2+ proteinuria).

Probenecid

Probenecid must be administered orally with each cidofovir injection dose. Two grams must be administered 3 hr prior to the cidofovir injection dose and one gram administered at 2 and again at 8 hr after completion of the one hr cidofovir injection infusion (for a total of 4 grams).

Ingestion of food prior to each dose of probenecid may reduce drug-related nausea and vomiting. Administration of an antiemetic may reduce the potential for nausea associated with probenecid ingestion. In patients who develop allergic or hypersensitivity symptoms to probenecid, the use of an appropriate prophylactic or therapeutic antihistamine and/or acetaminophen should be considered (see CONTRAINDICATIONS).

Hydration

Patients must receive at least one liter of 0.9% (normal) saline solution intravenously with each infusion of cidofovir injection. The saline solution should be infused over a 1 to 2 hr period immediately before the cidofovir injection infusion. Patients who can tolerate the additional fluid load should receive a second liter. If administered, the second liter of saline should be initiated either at the start of the cidofovir injection infusion or immediately afterwards, and infused over a 1 to 3 hr period.

Method of Preparation and Administration

Inspect vials visually for particulate matter and discoloration prior to administration. If particulate matter or discoloration is observed, the vial should not be used. With a syringe, extract the appropriate volume of cidofovir injection from the vial and transfer the dose to an infusion bag containing 100 mL 0.9% (normal) saline solution. Infuse the entire volume intravenously into the patient at a constant rate over a one hr period. Use of a standard infusion pump for administration is recommended.

It is recommended that cidofovir injection infusion admixtures be administered within 24 hr of preparation and that refrigerator or freezer storage not be used to extend this 24 hr limit.

If admixtures are not intended for immediate use, they may be stored under refrigeration (2°C to 8°C) for no more than 24 hr. Refrigerated admixtures should be allowed to equilibrate to room temperature prior to use.

The chemical stability of cidofovir injection admixtures was demonstrated in polyvinyl chloride composition and ethylene/propylene copolymer composition commercial infusion bags, and in glass bottles. No data are available to support the addition of other drugs or supplements to the cidofovir admixture for concurrent administration.

Cidofovir Injection is supplied in single-use vials. Partially used vials should be discarded (see Handling and Disposal).

Compatibility with Ringer's solution, Lactated Ringer's solution or bacteriostatic infusion fluids has not been evaluated.

Handling and Disposal

Due to the mutagenic properties of cidofovir, adequate precautions including the use of appropriate safety equipment are recommended for the preparation, administration, and disposal of cidofovir injection. The National Institutes of Health presently recommends that such agents be prepared in a Class II laminar flow biological safety cabinet and that personnel preparing drugs of this class wear surgical gloves and a closed front surgical-type gown with knit cuffs. If cidofovir injection contacts the skin, wash membranes and flush thoroughly with water. Excess cidofovir injection and all other materials used in the admixture preparation and administration should be placed in a leak-proof, puncture-proof container. The recommended method of disposal is high temperature incineration.

Patient Monitoring

Serum creatinine and urine protein must be monitored within 48 hours prior to each dose. White blood cell counts with differential should be monitored prior to each dose. In patients with proteinuria, intravenous hydration should be administered and the test repeated. Intraocular pressure, visual acuity and ocular symptoms should be monitored periodically.
Rimso-50

Rimso-50

Instillation of 50 mL of RIMSO-50® (dimethyl sulfoxide) directly into the bladder may be accomplished by catheter or asepto syringe and allow to remain for 15 minutes. Application of an analgesic lubricant gel such as lidocaine jelly to the urethra is suggested prior to insertion of the catheter to avoid spasm. The medication is expelled by spontaneous voiding. It is recommended that the treatment be repeated every two weeks until maximum symptomatic relief is obtained. Thereafter, time intervals between therapy may be increased appropriately.

Administration of oral analgesic medication or suppositories containing belladonna and opium prior to the instillation of RIMSO-50® can reduce bladder spasm.

In patients with severe interstitial cystitis with very sensitive bladders, the initial treatment, and possibly the second and third (depending on patient response) should be done under anesthesia. (Saddle block has been suggested).
Ketamine Hydrochloride

Ketamine Hydrochloride

KETAMINE HCl is well tolerated by cats and subhuman primates when administered by intramuscular injection.

Fasting prior to induction of anesthesia or restraint with KETAMINE HCl is not essential; however, when preparing for elective surgery, it is advisable to withhold food for at least six hours prior to administration of KETAMINE HCl.

Anesthesia may be of shorter duration in immature cats. Restraint in subhuman primate neonates (less than 24 hours of age) is difficult to achieve.

As with other anesthetic agents, the individual response to KETAMINE HCl is somewhat varied depending upon the dose, general condition and age of the subject so that dosage recommendations cannot be absolutely fixed.

Dosage –

Cats: A dose of 11 mg/kg (5 mg/lb) is recommended to produce restraint. Dosages from 22 to 33 mg/kg (10 to 15 mg/lb) produce anesthesia that is suitable for diagnostic or minor surgical procedures that do not require skeletal muscle relaxation.

Subhuman Primates: The recommended restraint dosages of KETAMINE HCl for the following species are: Cercocebus torquatus (white-collared mangabey), Papio cynocephalus (yellow baboon), Pantroglodytes verus (chimpanzee), Papio anubis (olive baboon), Pongo pygmaeus (orangutan), Macaca nemestrina (pig-tailed macaque) 5 to 7.5 mg/kg; Presbytis entellus (entellus langur) 3 to 5 mg/kg; Gorilla gorilla gorilla (gorilla) 7 to 10 mg/kg; Aotus trivirgatus (night monkey) 10 to 12 mg/kg; Macaca mulatta (rhesus monkey) 5 to 10 mg/kg; Cebus capucinus (white-throated capuchin) 13 to 15 mg/kg; and Macaca fascicularis (crab-eating macaque), Macaca radiata (bonnet macaque) and Saimiri sciureus (squirrel monkey) 12 to 15 mg/kg.

A single intramuscular injection produces restraint suitable for TB testing, radiography, physical examination or blood collection.
Losartan Potassium

Losartan Potassium

2.1 Prevention of Nausea and Vomiting Associated with Initial and Repeat Courses of Emetogenic Chemotherapy

Ondansetron injection should be diluted in 50 mL of 5% Dextrose Injection or 0.9% Sodium Chloride Injection before administration.

Adults

The recommended adult intravenous dosage of Ondansetron injection is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical Pharmacology (12.2)]. The first dose is infused over 15 minutes beginning 30 minutes before the start of emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of Ondansetron injection.

Pediatrics

For pediatric patients 6 months through 18 years of age, the intravenous dosage of Ondansetron injection is three 0.15-mg/kg doses up to a maximum of 16 mg per dose [see Clinical Studies (14.1), Clinical Pharmacology (12.2,12.3)]. The first dose is to be administered 30 minutes before the start of moderately to highly emetogenic chemotherapy. Subsequent doses (0.15 mg/kg up to a maximum of 16 mg per dose) are administered 4 and 8 hours after the first dose of Ondansetron injection. The drug should be infused intravenously over 15 minutes.

2.2 Prevention of Postoperative Nausea and Vomiting

Ondansetron injection should not be mixed with solutions for which physical and chemical compatibility have not been established. In particular, this applies to alkaline solutions as a precipitate may form.

Adults

The recommended adult intravenous dosage of Ondansetron injection is 4 mg undiluted administered intravenously in not less than 30 seconds, preferably over 2 to 5 minutes, immediately before induction of anesthesia, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring within 2 hours after surgery. Alternatively, 4 mg undiluted may be administered intramuscularly as a single injection for adults. While recommended as a fixed dose for patients weighing more than 40 kg, few patients above 80 kg have been studied. In patients who do not achieve adequate control of postoperative nausea and vomiting following a single, prophylactic, preinduction, intravenous dose of ondansetron 4 mg, administration of a second intravenous dose of 4 mg ondansetron postoperatively does not provide additional control of nausea and vomiting.

Pediatrics

For pediatric patients 1 month through 12 years of age, the dosage is a single 0.1-mg/kg dose for patients weighing 40 kg or less, or a single 4-mg dose for patients weighing more than 40 kg. The rate of administration should not be less than 30 seconds, preferably over 2 to 5 minutes immediately prior to or following anesthesia induction, or postoperatively if the patient did not receive prophylactic antiemetics and experiences nausea and/or vomiting occurring shortly after surgery. Prevention of further nausea and vomiting was only studied in patients who had not received prophylactic Ondansetron injection.

2.3 Stability and Handling

After dilution, do not use beyond 24 hours. Although Ondansetron injection is chemically and physically stable when diluted as recommended, sterile precautions should be observed because diluents generally do not contain preservative.

Ondansetron injection is stable at room temperature under normal lighting conditions for 48 hours after dilution with the following intravenous fluids: 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, and 3% Sodium Chloride Injection.

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

Precaution: Occasionally, ondansetron precipitates at the stopper/vial interface in vials stored upright. Potency and safety are not affected. If a precipitate is observed, resolubilize by shaking the vial vigorously.

2.4 Dosage Adjustment for Patients with Impaired Hepatic Function

In patients with severe hepatic impairment (Child-Pugh score of 10 or greater), a single maximal daily dose of 8 mg infused over 15 minutes beginning 30 minutes before the start of the emetogenic chemotherapy is recommended. There is no experience beyond first-day administration of ondansetron in these patients [see Clinical Pharmacology (12.3)].
Thiamine Hydrochloride

Thiamine Hydrochloride

"Wet" beriberi with myocardial failure must be treated as an emergency cardiac condition, and thiamine must be administered slowly by the IV route in this situation (see WARNINGS).

In the treatment of beriberi, 10 mg to 20 mg of thiamine hydrochloride are given IM 3 times daily for as long as 2 weeks. (See WARNINGS regarding repeated injection of thiamine.) An oral therapeutic multivitamin preparation containing 5 mg to 10 mg thiamine, administered daily for one month, is recommended to achieve body tissue saturation.

Infantile beriberi that is mild may respond to oral therapy, but if collapse occurs, doses of 25 mg may cautiously be given IV.

Poor dietary habits should be corrected and an abundant and well-balanced dietary intake should be prescribed.

Patients with neuritis of pregnancy in whom vomiting is severe enough to preclude adequate oral therapy should receive 5 mg to 10 mg of thiamine hydrochloride IM daily.

In the treatment of Wernicke-Korsakoff syndrome, thiamine hydrochloride has been administered IV in an initial dose of 100 mg, followed by IM doses of 50 mg to 100 mg daily until the patient is consuming a regular, balanced diet. (See WARNINGS regarding repeated injections of thiamine.)

Patients with marginal thiamine status to whom dextrose is being administered should receive 100 mg thiamine hydrochloride in each of the first few liters of IV fluid to avoid precipitating heart failure.

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

Tranexamic Acid

Immediately before tooth extraction in patients with hemophilia, administer 10 mg per kg body weight of tranexamic acid injection intravenously together with replacement therapy (see PRECAUTIONS). Following tooth extraction, intravenous therapy, at a dose of 10 mg per kg body weight 3 to 4 times daily, may be used for 2 to 8 days.

Note: For patients with moderate to severe impaired renal function, the following dosages are recommended:
Serum Creatinine (µmol/L) Tranexamic Acid I.V. Dosage
120 to 250 (1.36 to 2.83 mg/dL)

10 mg/kg BID

250 to 500 (2.83 to 5.66 mg/dL)

10 mg/kg daily

> 500 (> 5.66 mg/dL)

10 mg/kg every 48 hours or5 mg/kg every 24 hours

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

Vancomycin Hydrochloride

Vancomycin hydrochloride is intended for intravenous use only.

Vancomycin hydrochloride is not to be administered orally. 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) (see ADVERSE REACTIONS). 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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS). Infusion related events may occur, however, at any rate or concentration.

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 intravenous dose is 2 g divided either as 500 mg every 6 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric Patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of one month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of one month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients.

Patients with Impaired Renal Function and Elderly Patients

Dosage adjustment must be made in patients with impaired renal function. In 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:
DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION (Adapted from Moellering et al)4
Creatinine Clearance

Vancomycin Dose

mL/min

mg/24 h

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 h. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 mg 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 the serum creatinine concentration 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) × (140 - age in years)

72 × serum creatinine concentration (mg/dL)

Women:

0.85 × above value

The serum creatinine must represent a steady-state of renal function. Otherwise, the estimated value for creatinine clearance is not 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 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) routes have not been established.

Intermittent infusion is the recommended method of administration.

Preparation and Stability

At the time of use, reconstitute vials of vancomycin hydrochloride 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

1g

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.
Topcare Nicotine

Topcare Nicotine

Dexamethasone sodium phosphate injection, USP 4 mg/mL is for intravenous, intramuscular, intra-articular, intralesional and soft tissue injection.

Dexamethasone sodium phosphate injection, USP 10 mg/mL is for intravenous or intramuscular use only.

Dexamethasone sodium phosphate injection, USP can be given directly from the vial, or it can be added to sodium chloride injection or dextrose injection and administered by intravenous drip.

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

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

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

A. Intravenous and Intramuscular Injection:

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

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

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

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

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

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

Shock

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

Author*

Dosage

Cavanagh1

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

Dietzman2

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

Frank3

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

Oaks4

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

Schumer5

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

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

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

Cerebral Edema

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

Acute Allergic Disorders

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

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

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

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

B. Intra-Articular, Intralesional and Soft Tissue Injection:

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

Some of the usual single doses are:

Site of Injection

Amount of Dexamethasone

Phosphate (mg)

Large joints (e.g., Knee)

2 to 4

Small joints (e.g., Interphalangeal, Temporomandibular)

0.8 to 1

Bursae

2 to 3

Tendon sheaths

0.4 to 1

Soft tissue infiltration

2 to 6

Ganglia

1 to 2

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

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

Ampicillin And Sulbactam

Ampicillin and sulbactam may be administered by either the intravenous or the intramuscular 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 may be administered by deep intramuscular injection. (See Preparation for Intramuscular Injection.)

Pediatric Patients One Year of Age or Older

The recommended daily dose of ampicillin and sulbactam for injection 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. The safety and efficacy of ampicillin and sulbactam for injection 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 (see CLINICAL STUDIES section).

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:
Table 5: Ampicillin and Sulbactam for Injection Dosage Guide for Patients With Renal Impairment Creatinine Clearance (mL/min/1.73m2) Ampicillin/Sulbactam Half-Life (Hours) Recommended Ampicillin and Sulbactam for Injection Dosage
≥30

1

1.5 g to 3 g q 6h to q 8h

15 to 29

5

1.5 g to 3 g q 12h

5 to 14

9

1.5 g 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) × (140 - age)
72 × serum creatinine

Females

0.85 × above value
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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS ).Infusion-related events may occur, however, at any rate or concentration.

Patients with Normal Renal Function

Adults

The usual daily intravenous 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric Patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended 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 PATIENTS WITH IMPAIRED RENAL FUNCTION

                                                                                                                       (Adapted from Moellering et al) 4
Creatinine Clearance mL/min Vancomycin Dose mg/24 hr 100908070605040302010 1,5451,3901,2351,080925770620465310155
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 concentration 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. Otherwise, the estimated value for creatinine clearance is not 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 established.

Intermittent infusion is the recommended method of administration.

COMPATIBILITY WITH OTHER DRUGS AND IV FLUIDS

The following diluents are physically and chemically compatible (with 4g/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.

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE-NOT FOR DIRECT INFUSION

Pharmacy bulk packages are for use in pharmacy admixture service only in a suitable work area, such as a laminar flow hood. They should be hung by the integral hanger provided and suspended as a unit in the laminar flow hood. Using aseptic technique the container closure should be penetrated only one time after reconstitution utilizing a suitable sterile dispensing set which allows measured distribution of the contents. Use of a syringe and needle is not recommended as it may cause leakage. Swab vial stopper with an antiseptic solution.

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 closure entry may be permitted to complete fluid transfer operations. Discard the container no later than 4 hours after initial closure puncture. The time limit should begin with introduction of solvent or diluent into Pharmacy package bottle.

PREPARATION AND STABILITY

10 g Pharmacy Bulk Package bottle

At the time of use, reconstitute by adding 95 mL of Sterile Water for Injection, USP to the 10 g Pharmacy Bulk package bottle of dry, vancomycin powder at a time. The resultant solution is a tan colored solution and will contain vancomycin equivalent to 500 mg/5 mL (1 g/10 mL). AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED.

Reconstituted solutions of vancomycin (500 mg/5 mL) must be further diluted in at least 100 mL of a suitable infusion solution. For doses of 1 gram (10 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.

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 dosage 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.
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. An infusion rate of 10 mg/min or less is associated with fewer infusion-related events (see ADVERSE REACTIONS). Infusion-related events may occur, however, at any rate or concentration.

Patients With Normal Renal Function

Adults

The usual daily intravenous dose is 2 g divided either as 500 mg every 6 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 patient factors, such as age or obesity, may call for modification of the usual intravenous daily dose.

Pediatric patients

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. Close monitoring of serum concentrations of vancomycin may be warranted in these patients.

Neonates

In pediatric patients up to the age of 1 month, the total daily intravenous dosage may be lower. In neonates, an initial dose of 15 mg/kg is suggested, followed by 10 mg/kg every 12 hours for neonates in the 1st week of life and every 8 hours thereafter up to the age of 1 month. Each dose should be administered over 60 minutes. In premature infants, vancomycin clearance decreases as postconceptional age decreases. Therefore, longer dosing intervals may be necessary in premature infants. Close monitoring of serum concentrations of vancomycin is recommended in these patients.

Patients with Impaired Renal Function and Elderly Patients

Dosage adjustment must be made in patients with impaired renal function. In 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:

                                                                   DOSAGE TABLE FOR VANCOMYCIN IN PATIENTS WITH IMPAIRED RENAL FUNCTION

                                                                                                                                   (Adapted from Meollering et al) 4
Creatinine Clearance mL/min Vancomycin Dose mg/24 hr 100 1,545 90 1,390 80 1,235 70 1,080 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 h. In patients with marked renal impairment, it may be more convenient to give maintenance doses of 250 to 1,000 mg once every several days rather than administering the drug on a daily basis. In anuria, a dose of 1,000 mg every 7 to 10 days has been recommended.

When only the serum creatinine concentration 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. Otherwise, the estimated value for creatinine clearance is not 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 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 established.

Intermittent infusion is the recommended method of administration.

Preparation and stability

DIRECTIONS FOR PROPER USE OF PHARMACY BULK PACKAGE – NOT FOR DIRECT INFUSION.

The Pharmacy Bulk Package is for use in the Hospital Pharmacy Admixture Service. Use of this product is restricted to a suitable work area, such as a laminar flow hood. Using aseptic technique, the closure should be penetrated one time using 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 transfer device or dispensing set, allows measured distribution of the contents. Use of a syringe and needle is not recommended as it may cause leakage. After entry use entire content promptly. The withdrawal of the contents of the Pharmacy Bulk Package bottle should be completed within 4 hours after entry. This time limit should begin with the introduction of solvent or diluent into Pharmacy Bulk Package bottle.

At the time of use, reconstitute by adding 100 mL of Sterile Water for Injection to the 5 g Pharmacy Bulk Package. Reconstituted solution contains 500 mg/10 mL and 1 g/20 mL. AFTER RECONSTITUTION FURTHER DILUTION IS REQUIRED. RECONSTITUTED BULK SOLUTION SHOULD NOT BE USED FOR DIRECT INFUSION.

Reconstituted solutions with 10 mL containing 500 mg of vancomycin hydrochloride must be diluted with at least 100 mL of diluent. Reconstituted solutions containing 1 gram/20 mL must be further diluted with at least 200 mL of diluent. . The desired dose, diluted in this manner, should be administered by intermittent intravenous infusion over a period of at least 60 minutes.

Compatibility with Other Drugs and Intravenous Fluids

The following diluents are physically and chemically compatible (with 5 mg/mL vancomycin, present as the HCl):

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 when it is mixed with other compounds.

Mixtures of solutions of vancomycin and beta-lactam antibiotics have been shown to be physically incompatible. The likelihood of precipitation increases with higher concentrations of vancomycin. It is recommended to adequately flush the intravenous lines between the administration of these antibiotics. It is also recommended to dilute solutions of vancomycin to 5 mg/mL or less.

Although intravitreal injection is not an approved route of administration for vancomycin, precipitation has been reported after intravitreal injection of vancomycin and ceftazidime for endophthalmitis using different syringes and needles. The precipitates dissolved gradually, with complete clearing of the vitreous cavity over two months and with improvement of visual acuity.

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

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 infection. 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.
Pain Relief Childrens

Pain Relief Childrens

ULTIVA is for IV use only. Continuous infusions of ULTIVA should be administered only by an infusion device. The injection site should be close to the venous cannula and all IV tubing should be cleared at the time of discontinuation of infusion.

During General Anesthesia

ULTIVA is not recommended as the sole agent in general anesthesia because loss of consciousness cannot be assured and because of a high incidence of apnea, muscle rigidity, and tachycardia. ULTIVA is synergistic with other anesthetics; therefore, clinicians may need to reduce doses of thiopental, propofol, isoflurane, and midazolam by up to 75% with the coadministration of ULTIVA. The administration of ULTIVA must be individualized based on the patient's response.

Table 10 summarizes the recommended doses in adult patients, predominately ASA physical status I, II, or III.
Table 10: Dosing Guidelines in Adults — General Anesthesia and Continuing as an Analgesic into the Postoperative Care Unit or Intensive Care Setting* Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Infusion Dose Range of ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) * An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.
Induction of Anesthesia   (through intubation)

0.5 - 1*

Maintenance of anesthesia with:

  Nitrous oxide (66%)

0.4

0.1 - 2

1

  Isoflurane (0.4 to 1.5 MAC)

0.25

0.05 - 2

1

  Propofol    (100 to 200 mcg/kg/min)

0.25

0.05 - 2

1

Continuation as an analgesic into the immediate postoperative period

0.1

0.025 - 0.2

not recommended

Table 11 summarizes the recommended doses in pediatric patients, predominantly ASA physical status I, II, or III. In pediatric patients, remifentanil was administered with nitrous oxide or nitrous oxide in combination with halothane, sevoflurane, or isoflurane.
Table 11: Dosing Guidelines in Pediatric Patients — Maintenance of Anesthesia Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Infusion Dose Range of ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA(mcg/kg) * An initial dose of 1 mcg/kg may be administered over 30 to 60 seconds. † The initial maintenance infusion regimen of Ultiva evaluated in full term pediatric patients from birth to 2 months of age undergoing pyloromyotomy was 0.4 mcg/kg/min, the approved adult regimen for use with N 2O. The clearance rate observed in neonates was highly variable and on average was two times higher than in the young healthy adult population. Therefore, while a starting infusion of 0.4 mcg/kg/min may be appropriate for some neonates, an increased infusion rate may be necessary to maintain adequate surgical anesthesia, and additional bolus doses may be required. The individual dose for each patient should be carefully titrated. The use of atropine may blunt the potential for bradycardia that can occur upon administration of Ultiva. (See CLINICAL PHARMACOLOGY: Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, During Maintenance of Anesthesia). ‡ Boluses of 1 mcg/kg were studied in ASA 1 and 2, full-term patients weighing at least 2500 gm, undergoing pyloromyotomy who received pretreatment with atropine. Some neonates, particularly those receiving supplementation with potent inhalation agents or neuraxial anesthesia, those with significant co-morbidities or undergoing significant fluid shifts, or those who have not been pretreated with atropine, may require smaller bolus doses to avoid hypotension and/or bradycardia.
*Maintenance of anesthesia in patients aged 1 to 12 years old with:







  Halothane (0.3 to 1.5 MAC)

0.25

0.05 - 1.3

1

  Sevoflurane (0.3 to 1.5 MAC)

0.25

0.05 - 1.3

1

  Isoflurane (0.4 to 1.5 MAC)

0.25

0.05 - 1.3

1

Maintenance of anesthesia for patients from birth to 2 months of age with:







  Nitrous oxide (70%)†

0.4

0.4 - 1.0

1‡

During Induction of Anesthesia

ULTIVA should be administered at an infusion rate of 0.5 to 1 mcg/kg/min with a hypnotic or volatile agent for the induction of anesthesia. If endotracheal intubation is to occur less than 8 minutes after the start of the infusion of ULTIVA, then an initial dose of 1 mcg/kg may be administered over 30 to 60 seconds.

During Maintenance of Anesthesia

After endotracheal intubation, the infusion rate of ULTIVA should be decreased in accordance with the dosing guidelines in Tables 10 (adults) and 11 (pediatric patients). Due to the fast onset and short duration of action of ULTIVA, the rate of administration during anesthesia can be titrated upward in 25% to 100% increments in adult patients or up to 50% increments in pediatric patients, or downward in 25% to 50% decrements every 2 to 5 minutes to attain the desired level of µ-opioid effect. In response to light anesthesia or transient episodes of intense surgical stress, supplemental bolus doses of 1 mcg/kg may be administered every 2 to 5 minutes. At infusion rates >1 mcg/kg/min, increases in the concomitant anesthetic agents should be considered to increase the depth of anesthesia. See CLINICAL PHARMACOLOGY: Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, Table 11 for additional information.

Continuation as an Analgesic into the Immediate Postoperative Period Under the Direct Supervision of an Anesthesia Practitioner

Infusions of ULTIVA may be continued into the immediate postoperative period for select patients for whom later transition to longer acting analgesics may be desired. The use of bolus injections of ULTIVA to treat pain during the postoperative period is not recommended. When used as an IV analgesic in the immediate postoperative period, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min. The infusion rate may be adjusted every 5 minutes in 0.025-mcg/kg/min increments to balance the patient's level of analgesia and respiratory rate. Infusion rates greater than 0.2 mcg/kg/min are associated with respiratory depression (respiratory rate less than 8 breaths/min).

Guidelines for Discontinuation

Upon discontinuation of ULTIVA, the IV tubing should be cleared to prevent the inadvertent administration of ULTIVA at a later time.

Due to the rapid offset of action of ULTIVA, no residual analgesic activity will be present within 5 to 10 minutes after discontinuation. For patients undergoing surgical procedures where postoperative pain is generally anticipated, alternative analgesics should be administered prior to discontinuation of ULTIVA. The choice of analgesic should be appropriate for the patient's surgical procedure and the level of follow-up care (see CLINICAL TRIALS).

Analgesic Component of Monitored Anesthesia Care

It is strongly recommended that supplemental oxygen be supplied to the patient whenever ULTIVA is administered.

Table 12 summarizes the recommended doses for monitored anesthesia care in adult patients, predominately ASA physical status I, II, or III. ULTIVA has not been studied for use in children in monitored anesthesia care.
Table 12: Dosing Guidelines in Adults — Monitored Anesthesia Care Method Timing ULTIVA Alone ULTIVA + 2 mg Midazolam
Single IV Dose

Given 90 seconds before local anesthetic

1 mcg/kg over30 to 60 seconds

0.5 mcg/kg over30 to 60 seconds

Continuous IV Infusion

Beginning 5 minutes before local anesthetic

0.1 mcg/kg/min

0.05 mcg/kg/min

After local anesthetic

0.05 mcg/kg/min(Range: 0.025 -0.2 mcg/kg/min)

0.025 mcg/kg/min(Range: 0.025 -0.2 mcg/kg/min)

Single Dose

A single IV dose of 0.5 to 1 mcg/kg over 30 to 60 seconds of ULTIVA may be given 90 seconds before the placement of the local or regional anesthetic block (see PRECAUTIONS).

Continuous Infusion

When used alone as an IV analgesic component of monitored anesthesia care, ULTIVA should be initially administered by continuous infusion at a rate of 0.1 mcg/kg/min beginning 5 minutes before placement of the local or regional anesthetic block. Because of the risk for hypoventilation, the infusion rate of ULTIVA should be decreased to 0.05 mcg/kg/min following placement of the block. Thereafter, rate adjustments of 0.025 mcg/kg/min at 5-minute intervals may be used to balance the patient's level of analgesia and respiratory rate. Rates greater than 0.2 mcg/kg/min are generally associated with respiratory depression (respiratory rates less than 8 breaths/min). Bolus doses of ULTIVA administered simultaneously with a continuous infusion of ULTIVA to spontaneously breathing patients are not recommended.

Individualization of Dosage

Use in Geriatric Patients

The starting doses of ULTIVA should be decreased by 50% in elderly patients (>65 years). ULTIVA should then be cautiously titrated to effect.

Use in Pediatric Patients

See Table 11 for dosing recommendations for use of ULTIVA in pediatric patients from birth to 12 years of age for maintenance of anesthesia. See CLINICAL PHARMACOLOGY: Special Populations: Pediatric Patients, and DOSAGE AND ADMINISTRATION, Table 11 and During Maintenance of Anesthesia for additional information.

ULTIVA has not been studied in pediatric patients for use in the immediate postoperative period or for use as a component of monitored anesthesia care.

Use in Coronary Artery Bypass Surgery

Table 13 summarizes the recommended doses for induction, maintenance, and continuation as an analgesic into the ICU in adult patients, predominantly ASA physical status III or IV. To avoid hypotension during the induction phase, it is important to consider the concomitant medication regimens described in the CLINICAL TRIALS: Coronary Artery Bypass Surgery subsection.
Table 13: Dosing Recommendations* — Coronary Artery Bypass Surgery Phase Continuous IV Infusion of ULTIVA (mcg/kg/min) Infusion Dose Range of ULTIVA (mcg/kg/min) Supplemental IV Bolus Dose of ULTIVA (mcg/kg) * See CLINICAL TRIALS: Coronary Artery Bypass Surgery subsection for concomitant medication regimens.
Induction of Anesthesia (through intubation)

1

Maintenance of Anesthesia

1

0.125 - 4

0.5 - 1

Continuation as an analgesic into ICU

1

0.05 - 1

Use in Obese Patients

The starting doses of ULTIVA should be based on ideal body weight (IBW) in obese patients (greater than 30% over their IBW).

Preanesthetic Medication

The need for premedication and the choice of anesthetic agents must be individualized. In clinical studies, patients who received ULTIVA frequently received a benzodiazepine premedication.

Preparation for Administration

To reconstitute solution, add 1 mL of diluent per mg of remifentanil. Shake well to dissolve. When reconstituted as directed, the solution contains approximately 1 mg of remifentanil activity per 1 mL. ULTIVA should be diluted to a recommended final concentration of 20, 25, 50, or 250 mcg/mL prior to administration (see Table 14). ULTIVA should not be administered without dilution.
Table 14: Reconstitution and Dilution of ULTIVA Final Concentration Amount of ULTIVA in Each Vial Final Volume After Reconstitution and Dilution
20 mcg/mL

1 mg

50 mL

2 mg

100 mL

5 mg

250 mL

25 mcg/mL

1 mg

40 mL

2 mg

80 mL

5 mg

200 mL

50 mcg/mL

1 mg

20 mL

2 mg

40 mL

5 mg

100 mL

250 mcg/mL

5 mg

20 mL

Continuous IV infusions of ULTIVA should be administered only by an infusion device. Infusion rates of ULTIVA can be individualized for each patient using Table 15:
Table 15: IV Infusion Rates of ULTIVA (mL/kg/h) Drug Delivery Rate (mcg/kg/min) Infusion Delivery Rate (mL/kg/h) 20 mcg/mL 25 mcg/mL 50 mcg/mL 250 mcg/mL
0.0125

0.038

0.03

0.015

not recommended

0.025

0.075

0.06

0.03

not recommended

0.05

0.15

0.12

0.06

0.012

0.075

0.23

0.18

0.09

0.018

0.1

0.3

0.24

0.12

0.024

0.15

0.45

0.36

0.18

0.036

0.2

0.6

0.48

0.24

0.048

0.25

0.75

0.6

0.3

0.06

0.5

1.5

1.2

0.6

0.12

0.75

2.25

1.8

0.9

0.18

1.0

3.0

2.4

1.2

0.24

1.25

3.75

3.0

1.5

0.3

1.5

4.5

3.6

1.8

0.36

1.75

5.25

4.2

2.1

0.42

2.0

6.0

4.8

2.4

0.48

When ULTIVA is used as an analgesic component of monitored analgesia care, a final concentration of 25 mcg/mL is recommended. When ULTIVA is used for pediatric patients 1 year of age and older, a final concentration of 20 or 25 mcg/mL is recommended. Table 16 is a guideline for milliliter-per-hour delivery for a solution of 20 mcg/mL with an infusion device.
Table 16: IV Infusion Rates of ULTIVA (mL/h) for a 20-mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 5 10 20 30 40 50 60
0.0125

0.188

0.375

0.75

1.125

1.5

1.875

2.25

0.025

0.375

0.75

1.5

2.25

3.0

3.75

4.5

0.05

0.75

1.5

3.0

4.5

6.0

7.5

9.0

0.075

1.125

2.25

4.5

6.75

9.0

11.25

13.5

0.1

1.5

3.0

6.0

9.0

12.0

15.0

18.0

0.15

2.25

4.5

9.0

13.5

18.0

22.5

27.0

0.2

3.0

6.0

12.0

18.0

24.0

30.0

36.0

0.25

3.75

7.5

15.0

22.5

30.0

37.5

45.0

0.3

4.5

9.0

18.0

27.0

36.0

45.0

54.0

0.35

5.25

10.5

21.0

31.5

42.0

52.5

63.0

0.4

6.0

12.0

24.0

36.0

48.0

60.0

72.0

Table 17 is a guideline for milliliter-per-hour delivery for a solution of 25 mcg/mL with an infusion device.
Table 17: IV Infusion Rates of ULTIVA (mL/h) for a 25-mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 10 20 30 40 50 60 70 80 90 100
0.0125

0.3

0.6

0.9

1.2

1.5

1.8

2.1

2.4

2.7

3.0

0.025

0.6

1.2

1.8

2.4

3.0

3.6

4.2

4.8

5.4

6.0

0.05

1.2

2.4

3.6

4.8

6.0

7.2

8.4

9.6

10.8

12.0

0.075

1.8

3.6

5.4

7.2

9.0

10.8

12.6

14.4

16.2

18.0

0.1

2.4

4.8

7.2

9.6

12.0

14.4

16.8

19.2

21.6

24.0

0.15

3.6

7.2

10.8

14.4

18.0

21.6

25.2

28.8

32.4

36.0

0.2

4.8

9.6

14.4

19.2

24.0

28.8

33.6

38.4

43.2

48.0

Table 18 is a guideline for milliliter-per-hour delivery for a solution of 50 mcg/mL with an infusion device.
Table 18: IV Infusion Rates of ULTIVA (mL/h) for a 50-mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 30 40 50 60 70 80 90 100
0.025

2.1

2.4

2.7

3.0

0.05

2.4

3.0

3.6

4.2

4.8

5.4

6.0

0.075

2.7

3.6

4.5

5.4

6.3

7.2

8.1

9.0

0.1

3.6

4.8

6.0

7.2

8.4

9.6

10.8

12.0

0.15

5.4

7.2

9.0

10.8

12.6

14.4

16.2

18.0

0.2

7.2

9.6

12.0

14.4

16.8

19.2

21.6

24.0

0.25

9.0

12.0

15.0

18.0

21.0

24.0

27.0

30.0

0.5

18.0

24.0

30.0

36.0

42.0

48.0

54.0

60.0

0.75

27.0

36.0

45.0

54.0

63.0

72.0

81.0

90.0

1.0

36.0

48.0

60.0

72.0

84.0

96.0

108.0

120.0

1.25

45.0

60.0

75.0

90.0

105.0

120.0

135.0

150.0

1.5

54.0

72.0

90.0

108.0

126.0

144.0

162.0

180.0

1.75

63.0

84.0

105.0

126.0

147.0

168.0

189.0

210.0

2.0

72.0

96.0

120.0

144.0

168.0

192.0

216.0

240.0

Table 19 is a guideline for milliliter-per-hour delivery for a solution of 250 mcg/mL with an infusion device.
Table 19: IV Infusion Rates of ULTIVA (mL/h) for a 250-mcg/mL Solution Infusion Rate (mcg/kg/min) Patient Weight (kg) 30 40 50 60 70 80 90 100
0.1

0.72

0.96

1.20

1.44

1.68

1.92

2.16

2.40

0.15

1.08

1.44

1.80

2.16

2.52

2.88

3.24

3.60

0.2

1.44

1.92

2.40

2.88

3.36

3.84

4.32

4.80

0.25

1.80

2.40

3.00

3.60

4.20

4.80

5.40

6.00

0.5

3.60

4.80

6.00

7.20

8.40

9.60

10.80

12.00

0.75

5.40

7.20

9.00

10.80

12.60

14.40

16.20

18.00

1.0

7.20

9.60

12.00

14.40

16.80

19.20

21.60

24.00

1.25

9.00

12.00

15.00

18.00

21.00

24.00

27.00

30.00

1.5

10.80

14.40

18.00

21.60

25.20

28.80

32.40

36.00

1.75

12.60

16.80

21.00

25.20

29.40

33.60

37.80

42.00

2.0

14.40

19.20

24.00

28.80

33.60

38.40

43.20

48.00
Haloperidol Lactate

Haloperidol Lactate

There is considerable variation from patient to patient in the amount of medication required for treatment. As with all drugs used to treat schizophrenia, dosage should be individualized according to the needs and response of each patient. Dosage adjustments, either upward or downward, should be carried out as rapidly as practicable to achieve optimum therapeutic control.

To determine the initial dosage, consideration should be given to the patient's age, severity of illness, previous response to other antipsychotic drugs, and any concomitant medication or disease state. Debilitated or geriatric patients, as well as those with a history of adverse reactions to antipsychotic drugs, may require less haloperidol. The optimal response in such patients is usually obtained with more gradual dosage adjustments and at lower dosage levels.

Parenteral medication, administered intramuscularly in doses of 2 to 5 mg, is utilized for prompt control of the acutely agitated schizophrenic patient with moderately severe to very severe symptoms. Depending on the response of the patient, subsequent doses may be given, administered as often as every hour, although 4 to 8 hour intervals may be satisfactory.

Controlled trials to establish the safety and effectiveness of intramuscular administration in children have not been conducted.

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

Switchover Procedure

An oral form should supplant the injectable as soon as practicable. In the absence of bioavailability studies establishing bioequivalence between these two dosage forms the following guidelines for dosage are suggested. For an initial approximation of the total daily dose required, the parenteral dose administered in the preceding 24 hours may be used. Since this dose is only an initial estimate, it is recommended that careful monitoring of clinical signs and symptoms, including clinical efficacy, sedation, and adverse effects, be carried out periodically for the first several days following the initiation of switchover. In this way, dosage adjustments, either upward or downward, can be quickly accomplished. Depending on the patient's clinical status, the first oral dose should be given within 12 to 24 hours following the last parenteral dose.
Enlon Plus

Enlon Plus

Dosages of ENLON-PLUS (edrophonium chloride, USP and atropine sulfate, USP) Injection range from 0.05-0.1 mL/kg given slowly over 45 seconds to 1 minute at a point of at least 5% recovery of twitch response to neuromuscular stimulation (95% block). The dosage delivered is 0.5-1.0 mg/kg of edrophonium chloride and 0.007-0.014 mg/kg of atropine sulfate. A total dosage of 1.0 mg/kg of edrophonium chloride should rarely be exceeded. Response should be monitored carefully and assisted or controlled ventilation secured. Satisfactory reversal permits adequate voluntary respiration and neuromuscular transmission (as tested with a peripheral nerve stimulator). Recurarization has not been reported after satisfactory reversal has been attained.

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

Rifampin

Rifampin can be administered by IV infusion (see INDICATIONS AND USAGE).

See CLINICAL PHARMACOLOGY for dosing information in patients with renal failure.

Tuberculosis

Adults: 10 mg/kg, in a single daily administration, not to exceed 600 mg/day, IV

Pediatric Patients: 10-20 mg/kg, not to exceed 600 mg/day, IV

Rifampin is indicated in the treatment of all forms of tuberculosis. A three-drug regimen consisting of rifampin, isoniazid, and pyrazinamide is recommended in the initial phase of short-course therapy which is usually continued for 2 months. The Advisory Council for the Elimination of Tuberculosis, the American Thoracic Society, and the Centers for Disease Control and Prevention recommend that either streptomycin or ethambutol be added as a fourth drug in a regimen containing isoniazid (INH), rifampin and pyrazinamide for initial treatment of tuberculosis unless the likelihood of INH resistance is very low. The need for a fourth drug should be reassessed when the results of susceptibility testing are known. If community rates of INH resistance are currently less than 4%, an initial treatment regimen with less than four drugs may be considered.

Following the initial phase, treatment should be continued with rifampin and isoniazid (e.g., RIFAMATE® manufactured by Sanofi Aventis) for at least 4 months. Treatment should be continued for longer if the patient is still sputum or culture positive, if resistant organisms are present, or if the patient is HIV positive.

Preparation of Solution for IV Infusion: Reconstitute the lyophilized powder by transferring 10 mL of sterile water for injection to a vial containing 600 mg of rifampin for injection. Swirl vial gently to completely dissolve the antibiotic. The reconstituted solution contains 60 mg rifampin per mL and is stable at room temperature for 24 hours. Prior to administration, withdraw from the reconstituted solution a volume equivalent to the amount of rifampin calculated to be administered and add to 500 mL of infusion medium. Mix well and infuse at a rate allowing for complete infusion within 3 hours. Alternatively, the amount of rifampin calculated to be administered may be added to 100 mL of infusion medium and infused in 30 minutes.

Dilutions in dextrose 5% for injection (D5W) are stable at room temperature for up to 4 hours and should be prepared and used within this time. Precipitation of rifampin from the infusion solution may occur beyond this time. Dilutions in normal saline are stable at room temperature for up to 24 hours and should be prepared and used within this time. Other infusion solutions are not recommended.

Incompatibilities: Physical incompatibility (precipitate) was observed with undiluted (5 mg/mL) and diluted (1 mg/mL in normal saline) diltiazem hydrochloride and rifampin (6 mg/mL in normal saline) during simulated Y-site administration.

Meningococcal Carriers

Adults: For adults, it is recommended that 600 mg rifampin be administered twice daily for two days.

Pediatric Patients: Pediatric patients 1 month of age or older: 10 mg/kg (not to exceed 600 mg per dose) every 12 hours for two days.

Pediatric patients under 1 month of age: 5 mg/kg every 12 hours for two days.
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 hemotologic 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 of 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 of renal toxicity, particularly in patients with preexisting renal insufficiency.

*Albumin-corrected serum calcium (CCa, mg/dL) = serum calcium, mg/dL + 0.8 (4.0-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 ≥3.0 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 1.0 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 section).

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 1.0 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 benefit (see Clinical Trials section).

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.

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 and 90 mg doses. The recommended dose should be diluted in 1000 mL of sterile 0.45% or 0.9% Sodium Chloride, 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, 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, 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, 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.
Cisplatin

Cisplatin

Cisplatin injection is administered by slow intravenous infusion. CISPLATIN INJECTION SHOULD NOT BE GIVEN BY RAPID INTRAVENOUS INJECTION.

Note: Needles or intravenous sets containing aluminum parts that may come in contact with cisplatin injection should not be used for preparation or administration. Aluminum reacts with cisplatin injection, causing precipitate formation and a loss of potency.

Metastatic Testicular Tumors

The usual cisplatin injection dose for the treatment of testicular cancer in combination with other approved chemotherapeutic agents is 20 mg/m2 IV daily for 5 days per cycle.

Metastatic Ovarian Tumors

The usual Cisplatin injection dose for the treatment of metastatic ovarian tumors in combination with cyclophosphamide is 75–100 mg/m2 IV per cycle once every four weeks (DAY 1).

The dose of cyclophosphamide when used in combination with Cisplatin injection is 600 mg/m2 IV once every 4 weeks (DAY 1).

For directions for the administration of cyclophosphamide, refer to the cyclophosphamide package insert.

In combination therapy, Cisplatin injection and cyclophosphamide are administered sequentially.

As a single agent, Cisplatin injection should be administered at a dose of 100 mg/m2 IV per cycle once every four weeks.

Advanced Bladder Cancer

Cisplatin injection should be administered as a single agent at a dose of 50 to 70 mg/m2 IV per cycle once every 3 to 4 weeks depending on the extent of prior exposure to radiation therapy and/or prior chemotherapy. For heavily pretreated patients an initial dose of 50 mg/m2 per cycle repeated every 4 weeks is recommended.

All Patients

Pretreatment hydration with 1 to 2 liters of fluid infused for 8 to 12 hours prior to a cisplatin injection dose is recommended. The drug is then diluted in 2 liters of 5% Dextrose in 1/2 or 1/3 normal saline containing 37.5 g of mannitol, and infused over a 6 to 8 hour period. If diluted solution is not to be used within 6 hours, protect solution from light. Do not dilute cisplatin injection in just 5% Dextrose Injection. Adequate hydration and urinary output must be maintained during the following 24 hours.

A repeat course of cisplatin injection should not be given until the serum creatinine is below 1.5 mg/100 mL, and/or the BUN is below 25 mg/100 mL. A repeat course should not be given until circulating blood elements are at an acceptable level (platelets ≥100,000/mm3, WBC ≥4,000/mm3). Subsequent doses of cisplatin injection should not be given until an audiometric analysis indicates that auditory acuity is within normal limits.
Cytarabine

Cytarabine

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.

HANDLING AND DISPOSAL

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Ifosfamide

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 reduce the incidence of 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 (eg, 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.
Fludarabine Phosphate

Fludarabine Phosphate

Usual Dose

The recommended adult dose of fludarabine phosphate injection 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. These include advanced age, renal impairment, 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 be administered following the achievement of a maximal response and then the drug should be discontinued.

Renal Impairment

Adjustments to the starting dose are recommended to provide appropriate drug exposure in patients with creatinine clearance 30-79 mL/min, as estimated by the Cockroft-Gault equations. These adjustments are based on a pharmacokinetic study in patients with renal impairment. Fludarabine Phosphate Injection, should not be administered to patients with creatinine clearance less than 30 mL/min.
Starting Dose Adjustment for Renal Impairment Creatinine Clearance Starting Dose ≥ 80 mL/min 25 mg/m2 (full dose) 50 - 79 mL/min 20 mg/m2 30 - 49 mL/min 15 mg/m2 < 30 mL/min do not administer
Renally impaired patients should be monitored closely for excessive toxicity and the dose modified accordingly.

Preparation of Solutions

Fludarabine Phosphate Injection; Each mL contains 25 mg fludarabine phosphate, 25 mg mannitol, water for injection, qs; and sodium hydroxide to adjust the pH to 6.8. The pH range for the final product is 6.0–7.1. 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, 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.

Fludarabine Phosphate Injection, should not be mixed with other drugs.

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. 1-4

Caution should be exercised in the handling of fludarabine phosphate injection. 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.
Flumazenil

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 is drawn into a syringe or mixed with any of these solutions, it should be discarded after 24 hours. For optimum sterility, flumazenil injection should remain in the vial until just before use. As with all parenteral drug products, flumazenil injection 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 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 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 second 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 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 1.00 mg). Approximately one-half of patients required the maximum of five injections.

Resedation occurred in 7 of 60 pediatric patients who were fully alert 10 minutes after the start of flumazenil injection 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 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 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 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 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 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. 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, 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, the major cause of sedation is likely not to be due to benzodiazepines, and additional flumazenil 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 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.
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, USP may be administered until oral therapy can be instituted.

The recommended dosage for famotidine injection, USP 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 <1 year of age Gastroesophageal Reflux Disease (GERD)

See PRECAUTIONS, Pediatric Patients <1 year of age.

The studies described in PRECAUTIONS, Pediatric Patients <1 year of age suggest the following starting doses in pediatric patients <1 year of age: Gastroesophageal Reflux Disease (GERD) - 0.5 mg/kg/dose of famotidine oral suspension for the treatment of GERD for up to 8 weeks once daily in patients <3 months of age and 0.5 mg/kg/dose twice daily in patients 3 months to <1 year of age. Patients should also be receiving conservative measures (e.g., thickened feedings). The use of intravenous famotidine in pediatric patients <1 year of age with GERD has not been adequately studied.

Dosage for Pediatric Patients 1-16 years of age

See PRECAUTIONS, Pediatric Patients 1 to 16 years of age.

The studies described in PRECAUTIONS, Pediatric Patients 1 to 16 years of age 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 1 to 16 years of age have demonstrated gastric acid suppression with doses up to 0.5 mg/kg intravenously q 12 h.

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, USP 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.

To prepare famotidine intravenous solutions, aseptically dilute 2 mL of famotidine injection, USP (solution containing 10 mg/mL) with 0.9% Sodium Chloride Injection or other compatible intravenous solution (see Stability, Famotidine Injection, USP) 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, USP with 100 mL of 5% dextrose or other compatible solution (see Stability, Famotidine Injection, USP), 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.

Famotidine Injection, USP

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, USP 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, USP 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, USP (>0.2 mg/mL) in Sodium Bicarbonate Injection, 5%.
Carboplatin

Carboplatin

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.

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 should not be repeated until the neutrophil count is at least 2,000 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―300 mg/m2 IV on day 1 every 4 weeks for 6 cycles (alternatively see Formula Dosing).

Cyclophosphamide―600 mg/m2 IV on day 1 every 4 weeks for 6 cycles. For directions regarding the use and administration of cyclophosphamide please refer to its package insert. (See CLINICAL STUDIES.)

Intermittent courses of carboplatin in combination with cyclophosphamide should not be repeated until the neutrophil count is at least 2,000 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.

*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.
Platelets Neutrophils Adjusted Dose*(From Prior Course) >100,000 >2,000 125% 50 - 100,000 500 – 2,000 No Adjustment <50,000 <500 75%
Carboplatin 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 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 - 59 mL/min 250 mg/m2 16 - 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 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 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) x (GFR + 25) Note: With the Calvert formula, the total dose of Carboplatin Injection is calculated in mg, not mg/m2.
The target AUC of 4 mg/mL•min to 6 mg/mL•min using single-agent carboplatin 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 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 4 Thrombocytopenia Gr 3 or Gr 4 Leukopenia 4 to 56 to 7 16%33% 13%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.

PREPARATION OF INTRAVENOUS SOLUTIONS

Carboplatin injection is a premixed aqueous solution of 10 mg/mL carboplatin.

Carboplatin aqueous solution can be further diluted to concentrations as low as 0.5 mg/mL with 5% Dextrose in Water (D5W) or 0.9% Sodium Chloride Injection, USP.

When prepared as directed, carboplatin aqueous solutions are stable for 8 hours at room temperature (25° C). Since no antibacterial preservative is contained in the formulation, it is recommended that carboplatin aqueous solutions be discarded 8 hours after dilution.
Naloxone Hydrochloride

Naloxone Hydrochloride

Naloxone hydrochloride injection may be administered intravenously, intramuscularly, or subcutaneously. The most rapid onset of action is achieved by intravenous administration, which is recommended in emergency situations.

Since the duration of action of some opioids may exceed that of naloxone, the patient should be kept under continued surveillance and repeated doses of naloxone should be administered, as necessary.

Intravenous Infusion

Naloxone hydrochloride injection may be diluted for intravenous infusion in normal saline or 5% dextrose solutions. The addition of 2 mg of naloxone hydrochloride in 500 mL of either solution provides a concentration of 0.004 mg/mL. Mixtures should be used within 24 hours. After 24 hours, the remaining unused mixture must be discarded. The rate of administration should be titrated in accordance with the patient’s response.

Naloxone hydrochloride injection should not be mixed with preparations containing bisulfite, metabisulfite, long-chain or high molecular weight anions, or any solution having an alkaline pH. No drug or chemical agent should be added to naloxone hydrochloride injection unless its effect on the chemical and physical stability of the solution has first been established.

Usage in Adults

Opioid Overdose – Known or Suspected

An initial dose of 0.4 mg to 2 mg of naloxone hydrochloride may be administered intravenously. If the desired degree of counteraction and improvement in respiratory functions are not obtained, it may be repeated at 2 to 3 minute intervals. If no response is observed after 10 mg of naloxone hydrochloride have been administered, the diagnosis of opioid-induced or partial opioid-induced toxicity should be questioned. Intramuscular or subcutaneous administration may be necessary if the intravenous route is not available.

Postoperative Opioid Depression

For the partial reversal of opioid depression following the use of opioids during surgery, smaller doses of naloxone hydrochloride are usually sufficient. The dose of naloxone should be titrated according to the patient’s response. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.1 mg to 0.2 mg intravenously at 2 to 3 minute intervals to the desired degree of reversal, i.e., adequate ventilation and alertness without significant pain or discomfort. Larger than necessary dosage of naloxone may result in significant reversal of analgesia and increase in blood pressure. Similarly, too rapid reversal may induce nausea, vomiting, sweating or circulatory stress.

Repeat doses of naloxone may be required within 1 to 2 hour intervals depending upon the amount, type (i.e., short or long acting) and time interval since last administration of an opioid. Supplemental intramuscular doses have been shown to produce a longer lasting effect.

Septic Shock

The optimal dosage of naloxone or duration of therapy for the treatment of hypotension in septic shock patients has not been established (see CLINICAL PHARMACOLOGY).

Usage in Pediatric Population

Opioid Overdose – Known or Suspected

The usual initial dose in pediatric patients is 0.01 mg/kg body weight given I.V. If this dose does not result in the desired degree of clinical improvement, a subsequent dose of 0.1 mg/kg body weight may be administered. If an I.V. route of administration is not available, naloxone hydrochloride may be administered I.M. or S.C. in divided doses. If necessary, naloxone hydrochloride injection can be diluted with sterile water for injection.

Postoperative Opioid Depression

Follow the recommendations and cautions under Adult Postoperative Depression. For the initial reversal of respiratory depression, naloxone hydrochloride should be injected in increments of 0.005 mg to 0.01 mg intravenously at 2 to 3 minute intervals to the desired degree of reversal.

Usage in Neonates

Opioid-Induced Depression

The usual initial dose is 0.01 mg/kg body weight administered I.V., I.M. or S.C. This dose may be repeated in accordance with adult administration guidelines for postoperative opioid depression.

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

Do not administer unless solution is clear and container is undamaged. Discard unused portion.
Epirubicin Hydrochlorid...

Epirubicin Hydrochloride

When possible, to reduce the risk of developing cardiotoxicity in patients receiving Epirubicin Hydrochloride Injection after stopping treatment with other cardiotoxic agents, especially those with long half-lives such as trastuzumab, Epirubicin Hydrochloride Injection -based therapy should be delayed until the other agents have cleared from the circulation [see Warnings and Precautions (5.3)].

Administer Epirubicin Hydrochloride Injection by intravenous infusion. Give Epirubicin Hydrochloride Injection in repeated 3- to 4-week cycles. The total dose of Epirubicin Hydrochloride Injection 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 Injection are as follows:

2.1 Recommended Dose

The recommended dose of Epirubicin Hydrochloride Injection is 100 to 120 mg/m2. The following regimens are recommended:
CEF-120: Cyclophosphamide 75 mg/m2 PO D 1-14 Epirubicin Hydrochloride Injection 60 mg/m2 IV D 1, 8 5-Fluorouracil 500 mg/m2 IV D 1, 8 Repeated every 28 days for 6 cycles FEC-100: 5-Fluorouracil 500 mg/m2 Epirubicin Hydrochloride Injection 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/m2 regimen of Epirubicin Hydrochloride Injection should receive prophylactic antibiotic therapy.

2.2 Dose Modifications

Epirubicin Hydrochloride Injection dosage adjustments for hematologic and non-hematologic toxicities within a cycle of treatment, is based on nadir platelet counts <50,000/mm3, absolute neutrophil counts (ANC) <250/mm3, neutropenic fever, or Grades 3/4 nonhematologic toxicity. Reduce Epirubicin Hydrochloride Injection Day 1 dose in subsequent cycles to 75% of the Day 1 dose given in the current cycle. Delay Day 1 chemotherapy in subsequent courses of treatment until platelet counts are ≥100,000/mm3, ANC ≥1500/mm3, and nonhematologic toxicities have recovered to ≤ Grade 1.

Bone Marrow Dysfunction

Consider administering a lower starting dose (75-90 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 (5)]. For patients receiving a divided dose of Epirubicin Hydrochloride Injection (Day 1 and Day 8), the Day 8 dose should be 75% of Day 1 if platelet counts are 75,000-100,000/mm3 and ANC is 1000 to 1499/mm3. If Day 8 platelet counts are <75,000/mm3, ANC <1000/mm3, or Grades 3/4 nonhematologic toxicity has occurred, omit the Day 8 dose.

Hepatic Impairment

Recommendations regarding use of Epirubicin Hydrochloride Injection in patients with hepatic impairment are not available because patients with hepatic abnormalities were not included in the adjuvant trials [see Warnings and Precautions (5.5) and Clinical Pharmacology (12.3)]. In patients with elevated serum AST or serum total bilirubin concentrations, the following dose reductions are recommended:
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
Renal Impairment

While no specific dose recommendation can be made based on the limited available data in patients with renal impairment, consider lower doses in patients with severe renal impairment (serum creatinine > 5 mg/dL) [see Warnings and Precautions (5.6) and Clinical Pharmacology (12.3)].

2.3 Preparation and Administration Precautions

Storage of the solution for injection at refrigerated conditions can result in the formation of a gelled product. This gelled product will return to a slightly viscous to mobile solution after 2 to a maximum of 4 hours equilibration at controlled room temperature (15° to 25°C).

Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Procedures for proper handling and disposal of anticancer drugs should be used when handling and preparing Epirubicin Hydrochloride Injection. Several guidelines on this subject have been published.1-4 [see References (15)].

Protective Measures

Take the following protective measures when handling Epirubicin Hydrochloride Injection:
Train personnel in appropriate techniques for reconstitution and handling. Exclude pregnant staff from working with this drug. Wear protective clothing: goggles, gowns, and disposable gloves and masks when handling Epirubicin Hydrochloride Injection. Define a designated area for syringe preparation (preferably under a laminar flow system), with the work surface protected by disposable, plastic-backed, absorbent paper. Place all items used for reconstitution, administration, or cleaning (including gloves) in high-risk, waste-disposal bags for high temperature incineration. Treat spillage or leakage with dilute sodium hypochlorite (1% available chlorine) solution, preferably by soaking, and then water. Place all contaminated and cleaning materials in high-risk, waste-disposal bags for incineration. Treat accidental contact with the skin or eyes 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. Seek medical attention. Always wash hands after removing gloves.
Incompatibilities

Avoid prolonged contact with any solution of an alkaline pH as it will result in hydrolysis of the drug. Do not mix Epirubicin Hydrochloride Injection with heparin or fluorouracil due to chemical incompatibility that may lead to precipitation.

Epirubicin Hydrochloride Injection can be used in combination with other antitumor agents, but do not mix with other drugs in the same syringe.

Preparation of Infusion Solution

Administer Epirubicin Hydrochloride Injection 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/m2 should generally have Epirubicin Hydrochloride Injection infused over 15 to 20 minutes. For patients who require lower Epirubicin Hydrochloride Injection starting doses due to organ dysfunction or who require modification of Epirubicin Hydrochloride Injection doses during therapy, the Epirubicin Hydrochloride Injection 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 Warnings and Precautions (5.9)]. Use Epirubicin Hydrochloride Injection within 24 hours of first penetration of the rubber stopper. Discard any unused solution.
Oxaliplatin

Oxaliplatin

Oxaliplatin 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 Injection in combination with 5- fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin Injection 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5- fluorouracil 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5- fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5- fluorouracil 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5- fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose injection, USP (recommended) as a 22-hour continuous infusion.

Figure 1

The administration of Oxaliplatin Injection does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin Injection 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 Injection to 75 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The infusional 5- fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 75 mg/m2 and infusional 5- fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal 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 Injection to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5- fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin Injection to 65 mg/m2 and 5- fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy for Patients with Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin Injection is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin Injection 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 250-500 mL of 5% Dextrose Injection, USP.

After dilution with 250-500 mL of 5% Dextrose Injection, USP, the shelf life is 6 hours at room temperature [20-25°C (68-77°F)] or up to 24 hours under refrigeration [2-8°C (36-46°F)]. After final dilution, protection from light is not required.

Oxaliplatin Injection is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose injection, USP prior to administration of any concomitant medication.

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

Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin Injection should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Lidocaine Hydrochloride...

Lidocaine Hydrochloride

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

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

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

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

For intravenous regional anesthesia, only the 50 mL single dose vial containing lidocaine hydrochloride 0.5% injection should be used.

Epidural Anesthesia

For epidural anesthesia, only the following available specific product of Lidocaine Hydrochloride Injection is recommended:

1% without epinephrine 30 mL single dose solution

Although this solution is intended specifically for epidural anesthesia, it may also be used for infiltration and peripheral nerve block, provided it is employed as a single dose unit. This solution contain no bacteriostatic agent.

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

Caudal and Lumbar Epidural Block

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.

Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Lidocaine Hydrochloride Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

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

MAXIMUM RECOMMENDED DOSAGES

NOTE: The products accompanying this insert do not contain epinephrine.

Adults

For normal healthy adults, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia.

The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides. (See also discussion of paracervical block in PRECAUTIONS.)

For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults.

Children

It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child's age and weight. For example, in a child of 5 years weighing 50 lbs the dose of lidocaine hydrochloride should not exceed 75 to100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (i.e., 0.25-0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children.

In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The Injection is not to be used if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

* Dose determined by number of dermatomes to be anesthetized (2-3 mL/dermatome).
Table 1 Recommended Dosages Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1 1-60 5-300 Intravenous regional 0.5 10-60 50-300 Peripheral Nerve Blocks, eg, Brachial 1.5 15-20 225-300 Dental 2 1-5 20-100 Intercostal 1 3 30 Paravertebral 1 3-5 30-50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic nerve blocks, eg, Cervical (stellate ganglion) 1 5 50 Lumbar 1 5-10 50-100 Central Neural Blocks Epidural* Thoracic 1 20–30 200–300 Lumbar Analgesia 1 25–30 250–300 Anesthesia 1.5 15–20 225–300 2 10–15 200–300 Caudal Obstetrical analgesia 1 20–30 200–300 Surgical anesthesia 1.5 15–20 225–300
THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED.

Sterilization, Storage and Technical Procedures:

Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection as they have been related to incidents of swelling and edema. When chemical disinfection of multi-dose vials is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. Many commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of USP grade, contain denaturants which are injurious to rubber and therefore are not to be used.
Lidocaine Hydrochloride...

Lidocaine Hydrochloride

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

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

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

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

For intravenous regional anesthesia, only the 50 mL single dose vial containing lidocaine hydrochloride 0.5% injection should be used.

Epidural Anesthesia

For epidural anesthesia, only the following available specific product of Lidocaine Hydrochloride Injection is recommended:

1% without epinephrine 30 mL single dose solutions

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

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

Caudal and Lumbar Epidural Block:

As a precaution against the adverse experience sometimes observed following unintentional penetration of the subarachnoid space, a test dose such as 2 to 3 mL of 1.5% lidocaine hydrochloride should be administered at least 5 minutes prior to injecting the total volume required for a lumbar or caudal epidural block. The test dose should be repeated if the patient is moved in a manner that may have displaced the catheter.

Adequate time should be allowed for onset of anesthesia after administration of each test dose. The rapid injection of a large volume of Lidocaine Hydrochloride Injection through the catheter should be avoided, and, when feasible, fractional doses should be administered.

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

MAXIMUM RECOMMENDED DOSAGES

NOTE: The products accompanying this insert do not contain epinephrine.

Adults

For normal healthy adults, the maximum individual dose should not exceed 4.5 mg/kg (2 mg/lb) of body weight, and in general it is recommended that the maximum total dose does not exceed 300 mg. For continuous epidural or caudal anesthesia, the maximum recommended dosage should not be administered at intervals of less than 90 minutes. When continuous lumbar or caudal epidural anesthesia is used for non-obstetrical procedures, more drug may be administered if required to produce adequate anesthesia.

The maximum recommended dose per 90 minute period of lidocaine hydrochloride for paracervical block in obstetrical patients and non-obstetrical patients is 200 mg total. One half of the total dose is usually administered to each side. Inject slowly, five minutes between sides. (See also discussion of paracervical block in PRECAUTIONS.)

For intravenous regional anesthesia, the dose administered should not exceed 4 mg/kg in adults.

Children

It is difficult to recommend a maximum dose of any drug for children, since this varies as a function of age and weight. For children over 3 years of age who have a normal lean body mass and normal body development, the maximum dose is determined by the child’s age and weight. For example, in a child of 5 years weighing 50 lbs the dose of lidocaine hydrochloride should not exceed 75 to100 mg (1.5 to 2 mg/lb). The use of even more dilute solutions (ie, 0.25 to 0.5%) and total dosages not to exceed 3 mg/kg (1.4 mg/lb) are recommended for induction of intravenous regional anesthesia in children.

In order to guard against systemic toxicity, the lowest effective concentration and lowest effective dose should be used at all times. In some cases it will be necessary to dilute available concentrations with 0.9% sodium chloride injection in order to obtain the required final concentration.

NOTE: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever the solution and container permit. The Injection is not to be used if its color is pinkish or darker than slightly yellow or if it contains a precipitate.

* Dose determined by number of dermatomes to be anesthetized (2-3 mL/dermatome).
Table 1 Recommended Dosages Procedure Lidocaine Hydrochloride Injection (without epinephrine) Conc (%) Vol (mL) Total Dose (mg) Infiltration Percutaneous 0.5 or 1 1-60 5-300 Intravenous regional 0.5 10-60 50-300 Peripheral Nerve Blocks, eg, Brachial 1.5 15-20 225-300 Dental 2 1-5 20-100 Intercostal 1 3 30 Paravertebral 1 3-5 30-50 Pudendal (each side) 1 10 100 Paracervical Obstetrical analgesia (each side) 1 10 100 Sympathetic nerve blocks, eg, Cervical (stellate ganglion) 1 5 50 Lumbar 1 5-10 50-100 Central Neural Blocks Epidural* Thoracic 1 20–30 200–300 Lumbar Analgesia 1 25–30 250–300 Anesthesia 1.5 15–20 225–300 2 10–15 200–300 Caudal Obstetrical analgesia 1 20–30 200–300 Surgical anesthesia 1.5 15–20 225–300
THE ABOVE SUGGESTED CONCENTRATIONS AND VOLUMES SERVE ONLY AS A GUIDE. OTHER VOLUMES AND CONCENTRATIONS MAY BE USED PROVIDED THE TOTAL MAXIMUM RECOMMENDED DOSE IS NOT EXCEEDED.

Sterilization, Storage And Technical Procedures:

Disinfecting agents containing heavy metals, which cause release of respective ions (mercury, zinc, copper, etc.) should not be used for skin or mucous membrane disinfection as they have been related to incidents of swelling and edema. When chemical disinfection of multi-dose vials is desired, either isopropyl alcohol (91%) or ethyl alcohol (70%) is recommended. Many commercially available brands of rubbing alcohol, as well as solutions of ethyl alcohol not of USP grade, contain denaturants which are injurious to rubber and therefore are not to be used.
Vecuronium Bromide

Vecuronium Bromide

Vecuronium bromide for injection is for intravenous use only.

This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see PRECAUTIONS, Drug Interactions).

To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.

The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.

Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.

During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.

Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)

Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Use by Continuous Infusion

After an intubating dose of 80 to 100 mcg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 minutes later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations. (See PRECAUTIONS, Long Term Use in ICU.)

The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60 percent, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see CLINICAL PHARMACOLOGY).

Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
*10 mg of Vecuronium bromide in 100 mL solution ‡20 mg of Vecuronium bromide in 100 mL solution
Drug Delivery Rate(mcg/kg/min)

Infusion Delivery Rate

(mL/kg/min)

0.1 mg/mL*

0.2 mg/mL‡

0.7

0.007

0.0035

0.8

0.008

0.0040

0.9

0.009

0.0045

1.0

0.010

0.0050

1.1

0.011

0.0055

1.2

0.012

0.0060

1.3

0.013

0.0065

The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
VECURONIUM BROMIDE INFUSION RATE - mL/min NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one-half.
Amount of Drugmcg/kg/min

Patient Weight - kg

40

50

60

70

80

90

100

0.7

0.28

0.35

0.42

0.49

0.56

0.63

0.70

0.8

0.32

0.40

0.48

0.56

0.64

0.72

0.80

0.9

0.36

0.45

0.54

0.63

0.72

0.81

0.90

1.0

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.1

0.44

0.55

0.66

0.77

0.88

0.99

1.10

1.2

0.48

0.60

0.72

0.84

0.96

1.08

1.20

1.3

0.52

0.65

0.78

0.91

1.04

1.17

1.30

Use in Pediatrics

Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.

Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1 1/2 times as long to recover. See also subsection of PRECAUTIONS titled Pediatric Use. Information presently available does not permit recommendation on usage in pediatric patients less then 7 weeks of age (see PRECAUTIONS - Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.

COMPATIBILITY

Vecuronium bromide is compatible in solution with:

Sodium Chloride 0.9% Injection

Dextrose 5% Injection

Sterile Water for Injection

Dextrose 5% in Sodium Chloride 0.9% Injection

Lactated Ringer's Injection

Use within 24 hours of mixing with the above solutions.

Vecuronium bromide is also compatible in solution with:

Bacteriostatic Water for Injection (NOT FOR USE IN NEWBORNS)

Use within 5 days of mixing with the above solution.

Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.

After Reconstitution

See DOSAGE AND ADMINISTRATION-COMPATIBILITY for diluents compatible with Vecuronium Bromide for Injection.

Single-Dose Use

When reconstituted with compatible IV solutions not containing an antimicrobial preservative (e.g., Sterile Water for Injection), refrigerate and use within 24 hours. Discard unused portion.

Multi-Dose Use (NOT FOR USE IN NEWBORNS)

When reconstituted with bacteriostatic Water for Injection, use within 5 days. The reconstituted solution may be stored at room temperature or refrigerated.

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

Dexamethasone Sodium Phosphate

Dexamethasone sodium phosphate injection, USP 4 mg/mL is for intravenous, intramuscular, intra-articular, intralesional and soft tissue injection.

Dexamethasone sodium phosphate injection, USP 10 mg/mL is for intravenous or intramuscular use only.

Dexamethasone sodium phosphate injection, USP can be given directly from the vial, or it can be added to sodium chloride injection or dextrose injection and administered by intravenous drip.

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

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

DOSAGE REQUIREMENTS ARE VARIABLE AND MUST BE INDIVIDUALIZED ON THE BASIS OF THE DISEASE AND THE RESPONSE OF THE PATIENT.
• Intravenous and Intramuscular Injection:
The initial dosage of dexamethasone sodium phosphate injection varies from 0.5 to 9 mg a day depending on the disease being treated. In less severe diseases doses lower than 0.5 mg may suffice, while in severe diseases doses higher than 9 mg may be required.

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

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

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

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

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

Shock

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

Author*

Dosage

Cavanagh1

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

Dietzman2

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

Frank3

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

Oaks4

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

Schumer5

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

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

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

Cerebral Edema

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

Acute Allergic Disorders

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

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

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

This schedule is designed to ensure adequate therapy during acute episodes, while minimizing the risk of overdosage in chronic cases.
• Intra-Articular, Intralesional and Soft Tissue Injection:
Intra-articular, intralesional and soft tissue injections are generally employed when affected joints or areas are limited to one or two sites. Dosage and frequency of injection varies depending on the condition and the site of injection. The usual dose is from 0.2 to 6 mg. The frequency usually ranges from once every three to five days to once every two to three weeks. Frequent intra-articular injection may result in damage to joint tissues.

Some of the usual single doses are:

Site of Injection

Amount of Dexamethasone

Phosphate (mg)

Large joints (e.g., Knee)

2 to 4

Small joints (e.g., Interphalangeal, Temporomandibular)

0.8 to 1

Bursae

2 to 3

Tendon sheaths

0.4 to 1

Soft tissue infiltration

2 to 6

Ganglia

1 to 2

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

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

Tobramycin

Tobramycin may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. The patient's pretreatment body weight should be obtained for calculation of correct dosage. It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS).

Administration for Patients with Normal Renal Function

Adults with Serious Infections: 3 mg/kg/day in 3 equal doses every 8 hours (See Table 3).

Adults With Life-Threatening Infections: Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3). The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).
Table 3 DOSAGE SCHEDULE GUIDE FOR TOBRAMYCIN INJECTION ADULTS WITH NORMAL RENAL FUNCTION(Dosage at 8-Hour Intervals)
(continued)
For Patient Weighing Usual Dose for Serious Infections kg lb 1mg/kg q 8h (Total, 3mg/kg/day) 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 Table 3DOSAGE SCHEDULE GUIDE FOR TOBRAMYCIN INJECTION ADULTS WITH NORMAL RENAL FUNCTION(Dosage at 8-Hour Intervals)
*Applicable to all product forms except Tobramycin Injection Pediatric, 10 mg/mL. See HOW SUPPLIED.
For Patient Weighing Maximum Dose for Life-Threatening Infections (Reduce as soon as possible) kg lb 1.66mg/kg 8h (Total, 5mg/kg/day) 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
Pediatric Patients (greater than 1 week of age): 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

Premature or Full-Term Neonates 1 Week of Age or Less: Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

It is desirable to limit treatment to a short term. The usual duration of treatment is 7 to 10 days. A longer course of therapy may be necessary in difficult and complicated infections. In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

Dosage in Patients with Cystic Fibrosis

In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose. In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended. This dosing regimen is suggested only as a guide. The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

Administration for Patients with Impaired Renal Function

Whenever possible, serum tobramycin concentrations should be monitored during therapy.

Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals. Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin. The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. Neither method should be used when dialysis is being performed.

Reduced dosage at 8-hour intervals:

When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram.

* Scales have been adjusted to facilitate dosage calculations.

An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine.

Normal dosage at prolonged intervals:

If the creatinine clearance rate is not available and the patient's condition is stable, a dosage frequency in hours for the dosage given in Table 3 can be determined by multiplying the patient's serum creatinine by 6.

Dosage in Obese Patients

The appropriate dose may be calculated by using the patient's estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

Intramuscular Administration

Tobramycin may be administered by withdrawing the appropriate dose directly from a vial.

Intravenous Administration

For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses. For pediatric patients, the volume of diluent should be proportionately less than that for adults. The diluted solution usually should be infused over a period of 20 to 60 minutes. Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

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

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

Tobramycin

Tobramycin may be given intramuscularly or intravenously. Recommended dosages are the same for both routes. The patient's pretreatment body weight should be obtained for calculation of correct dosage. It is desirable to measure both peak and trough serum concentrations (see WARNINGS box and PRECAUTIONS).

Administration for Patients with Normal Renal Function

Adults with Serious Infections: 3 mg/kg/day in 3 equal doses every 8 hours (See Table 3).

Adults With Life-Threatening Infections: Up to 5 mg/kg/day may be administered in 3 or 4 equal doses (see Table 3). The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5 mg/kg/day unless serum levels are monitored (see WARNINGS box and PRECAUTIONS).
Table 3 DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals)
(continued)
For Patient Weighing Usual Dose for Serious Infections kg lb 1mg/kg q 8h (Total, 3mg/kg/day) 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
*Applicable to all product forms except Tobramycin Injection Pediatric, 10 mg/mL. See HOW SUPPLIED.
For Patient Weighing Maximum Dose for Life-Threatening Infections (Reduce as soon as possible) kg lb 1.66mg/kg 8h (Total, 5mg/kg/day) 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
Pediatric Patients (greater than 1 week of age): 6 to 7.5 mg/kg/day in 3 or 4 equally divided doses (2 to 2.5 mg/kg every 8 hours or 1.5 to 1.89 mg/kg every 6 hours).

Premature or Full-Term Neonates 1 Week of Age or Less: Up to 4 mg/kg/day may be administered in 2 equal doses every 12 hours.

It is desirable to limit treatment to a short term. The usual duration of treatment is 7 to 10 days. A longer course of therapy may be necessary in difficult and complicated infections. In such cases, monitoring of renal, auditory, and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended longer than 10 days.

Dosage in Patients with Cystic Fibrosis

In patients with cystic fibrosis, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. Measurement of tobramycin serum concentration during treatment is especially important as a basis for determining appropriate dose. In patients with severe cystic fibrosis, an initial dosing regimen of 10 mg/kg/day in 4 equally divided doses is recommended. This dosing regimen is suggested only as a guide. The serum levels of tobramycin should be measured directly during treatment due to wide interpatient variability.

Administration for Patients with Impaired Renal Function

Whenever possible, serum tobramycin concentrations should be monitored during therapy.

Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with reduced doses administered at 8-hour intervals or with normal doses given at prolonged intervals. Both of these methods are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. They are based on either the creatinine clearance level or the serum creatinine level of the patient because these values correlate with the half-life of tobramycin. The dosage schedule derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary. Neither method should be used when dialysis is being performed.

Reduced dosage at 8-hour intervals:

When the creatinine clearance rate is 70 mL or less per minute or when the serum creatinine value is known, the amount of the reduced dose can be determined by multiplying the normal dose from Table 3 by the percent of normal dose from the accompanying nomogram.

* Scales have been adjusted to facilitate dosage calculations.

An alternate rough guide for determining reduced dosage at 8-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine.

Normal dosage at prolonged intervals:

If the creatinine clearance rate is not available and the patient's condition is stable, a dosage frequency in hours for the dosage given in Table 3 can be determined by multiplying the patient's serum creatinine by 6.

Dosage in Obese Patients

The appropriate dose may be calculated by using the patient's estimated lean body weight plus 40% of the excess as the basic weight on which to figure mg/kg.

Intramuscular Administration

Tobramycin may be administered by withdrawing the appropriate dose directly from a vial.

Intravenous Administration

For intravenous administration, the usual volume of diluent (0.9% Sodium Chloride Injection or 5% Dextrose Injection) is 50 to 100 mL for adult doses. For pediatric patients, the volume of diluent should be proportionately less than that for adults. The diluted solution usually should be infused over a period of 20 to 60 minutes. Infusion periods of less than 20 minutes are not recommended because peak serum levels may exceed 12 mcg/mL (see WARNINGS box).

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

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

Mesna

2.1 Intravenous Dosing

Mesna injection may be given on a fractionated dosing schedule of three bolus intravenous injections as outlined below.

Mesna injection is given as intravenous bolus injections in a dosage equal to 20% of the ifosfamide dosage weight by weight (w/w) at the time of ifosfamide administration and 4 and 8 hours after each dose of ifosfamide. The total daily dose of mesna injection is 60% of the ifosfamide dose. The recommended dosing schedule is outlined below in Table 1.
Table 1: Recommended Intravenous Dosing Schedule * The dosing schedule should be repeated on each day that ifosfamide is administered. When the dosage of ifosfamide is increased or decreased, the ratio of mesna to ifosfamide should be maintained.
0 Hours

4 Hours

8 Hours

Ifosfamide

1.2 g/m2

--

--

Mesna Injection*

240 mg/m2

240 mg/m2

240 mg/m2

2.3 Monitoring for Hematuria

Maintain adequate hydration and sufficient urinary output, as required for ifosfamide treatment, and monitor urine for the presence of hematuria. If severe hematuria develops when mesna injection is given according to the recommended dosage schedule, dosage reductions or discontinuation of ifosfamide therapy may be required.

2.4 Preparation for Intravenous Administration and Stability

Preparation

Determine the volume of mesna injection for the intended dose.

Dilute the volume of mesna injection for the dose in any of the following fluids to obtain a final concentration of 20 mg/mL:
• 5% Dextrose Injection, USP • 5% Dextrose and 0.2% Sodium Chloride Injection, USP • 5% Dextrose and 0.33% Sodium Chloride Injection, USP • 5% Dextrose and 0.45% Sodium Chloride Injection, USP • 0.9% Sodium Chloride Injection, USP • Lactated Ringer’s Injection, USP
Stability

The mesna injection multidose vials may be stored and used for up to 8 days after initial puncture.

Store diluted solutions at 25°C (77°F). Use diluted solutions within 24 hours.

Do not mix mesna injection with epirubicin, cyclophosphamide, cisplatin, carboplatin, and nitrogen mustard.

The benzyl alcohol contained in mesna injection vials can reduce the stability of ifosfamide. Ifosfamide and mesna injection may be mixed in the same bag provided the final concentration of ifosfamide does not exceed 50 mg/mL. Higher concentrations of ifosfamide may not be compatible with mesna injection and may reduce the stability of ifosfamide.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any solutions which are discolored, hazy, or contain visible particulate matter should not be used.
Gemcitabine Hydrochlori...

Gemcitabine Hydrochloride

2.1 Ovarian Cancer

Recommended Dose and Schedule

The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle, in combination with carboplatin AUC 4 intravenously after Gemcitabine for Injection, USP administration on Day 1 of each 21-day cycle. Refer to carboplatin prescribing information for additional information.

Dose Modifications

Recommended Gemcitabine for Injection, USP dose modifications for myelosuppression are described Table 1 and Table 2 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Table 1: Dosage Reduction Guidelines for Gemcitabine for Injection, USP for Myelosuppression on Day of Treatment in Ovarian Cancer TreatmentDay Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose Day 1 ≥1500<1500 andor ≥100,000<100,000 100%Delay Treatment Cycle Day 8 ≥15001000-1499<1000 andoror ≥100,00075,000-99,999<75,000 10050Hold Table 2: Gemcitabine for Injection, USP Dose Modification for Myelosuppression in Previous Cycle in Ovarian Cancer Occurrence Myelosuppression During Treatment cycle Dose Modification Initial Occurrence Absolute granulocyte count less than 500 x 106/L Permanently reduce Gemcitabine for more than 5 days for Injection, USP to 800 mg/m2 on Absolute granulocyte count less than 100 x 106/L Days 1 and 8 for more than 3 days Febrile neutropenia Platelets less than 25,000x106/L Cycle delay of more than one week due to toxicity Subsequent Occurrence If any of the above toxicities occur after the initial Permanently reduce Gemcitabine dose reduction for Injection, USP dose to 800 mg/m2 on Day 1 only
2.2 Breast Cancer

Recommended Dose and Schedule

The recommended dose of Gemcitabine for Injection, USP is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 of each 21-day cycle that includes paclitaxel. Paclitaxel should be administered at 175 mg/m2 on Day 1 as a 3 hour intravenous infusion before Gemcitabine for Injection, USP administration.

Dose Modifications

Recommended dose modifications for Gemcitabine for Injection, USP for myelosuppression are described in Table.3 [see Warnings and Precautions (5.2)].

Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions.
Table 3: Recommended Dose Reductions for Gemcitabine for Injection, USP for Myelosuppression on Day of Treatment in Breast Cancer Treatment day Absolute granulocyte count (x 106 /L) Platelet count(x 106/L) % of full dose Day 1 ≥1500 and ≥100,000 100% less than 1500 or less than 100,000 Hold Day 8 ≥1200 and >75,000 100% 1000-1199 or 50,000-75,000 75% 700-999 and ≥50,000 50% <700 or <50,000 Hold
2.3 Non-Small Cell Lung Cancer

Recommended Dose and Schedule

Every 4-week schedule

The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 intravenously over 30 minutes on Days 1, 8, and 15 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine for Injection, USP.

Every 3-week schedule

The recommended dose of Gemcitabine for Injection, USP is 1250 mg/m2 intravenously over 30 minutes on Days 1 and 8 in combination with cisplatin therapy. Administer cisplatin intravenously at 100 mg/m2 on Day 1 after the infusion of Gemcitabine for Injection, USP.

Dose Modifications

Recommended dose modifications for Gemcitabine for Injection, USP myelosuppression are described in Table 4 [see Warnings and Precautions(5.2)]. Refer to Dosage and Administration (2.5) for Gemcitabine for Injection, USP recommendations for non-hematologic adverse reactions.

2.4 Pancreatic Cancer

Recommended Dose and Schedule

The recommended dose of Gemcitabine for Injection, USP is 1000 mg/m2 over 30 minutes intravenously. The recommended treatment schedule.
Weeks 1-8: weekly dosing for the first 7 weeks followed by one week rest. After week 8: weekly dosing on Days 1, 8, and 15 of 28-day cycles.
Dose Modifications

Recommended dose modifications for Gemcitabine for Injection, USP for myelosuppression are described in Table 4 [see Warnings and Precautions (5.2)]. Refer to Dosage and Administration (2.5) for recommendations for non-hematologic adverse reactions. Patients receiving Gemcitabine for Injection, USP 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 4.
Table 4: Recommended Dose Reductions for Gemcitabine for Injection, USP for Myelosuppression in Pancreatic Cancer and Non-Small Cell Lung Cancer Absolute granulocyte count(x 106/L) Platelet count(x 106/L) % of full dose ≥1000 And ≥100,000 100 500-999 Or 50,000-99,999 75 <500 Or <50,000 Hold
2.5 Dose Modifications for Non-Hematologic Adverse Reactions

Permanently discontinue Gemcitabine for Injection, USP for any of the following
Unexplained dyspnea or other evidence of severe pulmonary toxicity Severe hepatic toxicity Hemolytic-Uremic Syndrome Capillary Leak Syndrome Posterior reversible encephalopathy syndrome
Withhold Gemcitabine for Injection, USP or reduce dose by 50% for other severe (Grade 3 or 4) non-hematological toxicity until resolved. No dose modifications are recommended for alopecia, nausea, or vomiting.

2.6 Preparation and Administration Precautions

Exercise caution and wear gloves when preparing Gemcitabine for Injection, USP solutions. Immediately wash the skin thoroughly or rinse the mucosa with copious amounts of water if Gemcitabine for Injection, USP contacts the skin or mucus membranes. Death has occurred in animal studies due to dermal absorption. For further guidance on handling Gemcitabine for Injection, USP go to "OSHA Hazardous Drugs" (refer to antineoplastic weblinks including OSHA Technical Manual) at OSHA. http://www.osha.gov/SLTC/hazardousdrugs/index.html.

2.7 Preparation for Intravenous Infusion Administration

Reconstitute the vials with 0.9% Sodium Chloride Injection without preservatives.

Add 5 mL to the 200-mg vial or 25 mL to the 1-g vial or 50 mL to the 2-g vial. These dilutions each yield a Gemcitabine concentration of 38 mg/mL. Complete withdrawal of the vial contents will provide 200 mg or 1 g or 2g of Gemcitabine. 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 for Injection, USP is a clear, colorless to light straw-colored solution. Inspect visually prior to administration and discard for particulate matter or discoloration. Gemcitabine for injection, USP solutions are stable for 24 hours at controlled room temperature of 20° to 25°C (68° to 77°F). Do not refrigerate as crystallization can occur.

No incompatibilities have been observed with infusion bottles or polyvinyl chloride bags and administration sets.
Paclitaxel

Paclitaxel

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 solutions should be stored in bottles (glass, polypropylene) or plastic bags (polypropylene, polyolefin) and administered through polyethylene-lined administration sets.

All patients should be premedicated prior to paclitaxel injection administration in order to prevent severe hypersensitivity reactions. Such premedication may consist of dexamethasone 20 mg PO administered approximately 12 and 6 hours before paclitaxel injection, diphenhydramine (or its equivalent) 50 mg IV 30 to 60 minutes prior to paclitaxel injection, and cimetidine (300 mg) or ranitidine (50 mg) IV 30 to 60 minutes before paclitaxel injection.

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 Injection administered intravenously over 3 hours at a dose of 175 mg/m2 followed by cisplatin at a dose of 75 mg/m2; or Paclitaxel Injection 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 has been used at several doses and schedules; however, the optimal regimen is not yet clear. The recommended regimen is paclitaxel injection 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 injection, at a dose of 175 mg/m2 intravenously over 3 hours every 3 weeks for 4 courses administered sequentially to doxorubicin-containing combination chemotherapy. The clinical trial used 4 courses of doxorubicin and cyclophosphamide (see CLINICAL STUDIES: Breast Carcinoma ). After failure of initial chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy, paclitaxel injection 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 injection 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 injection 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 45–50 mg/m2/week). In the 2 clinical trials evaluating these schedules (see CLINICAL STUDIES: AIDS-Related Kaposi’s Sarcoma ), the former schedule (135 mg/m2 every 3 weeks) was more toxic than the latter. In addition, all patients with low performance status were treated with the latter schedule (100 mg/m2 every 2 weeks).

Based upon the immunosuppression in patients with advanced HIV disease, the following modifications are recommended in these patients:
Reduce the dose of dexamethasone as 1 of the 3 premedication drugs to 10 mg PO (instead of 20 mg PO); Initiate or repeat treatment with paclitaxel injection only if the neutrophil count is atleast 1000 cells/mm3; Reduce the dose of subsequent courses of paclitaxel injection 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 injection should not be repeated until the neutrophil count is at least 1500 cells/mm3 and the platelet count is at least    100,000 cells/mm3. Paclitaxel Injection should not be given to patients with AIDS-related Kaposi’s sarcoma if the baseline or subsequent neutrophil count is less than 1000 cells/mm3. Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe peripheral neuropathy during paclitaxel injection therapy should have dosage reduced by 20% for subsequent courses of paclitaxel injection. The incidence of neurotoxicity and the severity of neutropenia increase with dose.

Hepatic Impairment

Patients with hepatic impairment may be at increased risk of toxicity, particularly grade III–IV myelosuppression (see CLINICAL PHARMACOLOGY and PRECAUTIONS: Hepatic ). Recommendations for dosage adjustment for the first course of therapy are shown in TABLE 17 for both 3- and 24-hour infusions. Further dose reduction in subsequent courses should be based on individual tolerance. Patients should be monitored closely for the development of profound myelosuppression.
TABLE 17RECOMMENDATIONS FOR DOSING IN PATIENTS WITH HEPATICIMPAIRMENT BASED ON CLINICAL TRIAL DATAa
a These recommendations are based on dosages for patients without hepatic impairment of

135 mg/m2 over 24 hours or 175 mg/m2 over 3 hours; data are not available to make dose

adjustment recommendations for other regimens (eg, for AIDS-related Kaposi’s sarcoma).

b Differences in criteria for bilirubin levels between the 3- and 24-hour infusion are due to

differences in clinical trial design.

c Dosage recommendations are for the first course of therapy; further dose reduction in subsequent courses should be based on individual tolerance.
Degree of Hepatic Impairment Recommended Transaminase Levels         Bilirubin Levelsb Paclitaxel Injection Dosec    24-hour                                         infusion <2 × ULN and ≤1.5 mg/dL 135 mg/m2 2 to <10 × ULN and ≤1.5 mg/dL 100 mg/m2 <10 × ULN and 1.6–7.5 mg/dL 50 mg/m2 ≥10 × ULN or >7.5 mg/dL Not recommended 3-hour infusion <10 × ULN and ≤1.25 × ULN 175 mg/m2 <10 × ULN and 1.26–2.0 × ULN 135 mg/m2 <10 × ULN and 2.01–5.0 × ULN 90 mg/m2 ≥10 × ULN or >5.0 × 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. If paclitaxel injection 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 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 Injection must be diluted prior to infusion. Paclitaxel Injection should be diluted in 0.9% Sodium Chloride Injection, USP; 5% Dextrose Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; or 5% Dextrose in Ringer’s Injection to a final concentration of 0.3 to 1.2 mg/mL. The solutions are physically and chemically stable for up to 27 hours at ambient temperature (approximately 25° C) and room lighting conditions. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit.

Upon preparation, solutions may show haziness, which is attributed to the formulation vehicle. No significant losses in potency have been noted following simulated delivery of the solution through IV tubing containing an in-line (0.22 micron) filter.

Data collected for the presence of the extractable plasticizer DEHP [di-(2- ethylhexyl)phthalate] show that levels increase with time and concentration when dilutions are prepared in PVC containers. Consequently, the use of plasticized PVC containers and administration sets is not recommended. Paclitaxel Injection solutions should be prepared and stored in glass, polypropylene, or polyolefin containers. Non-PVC containing administration sets, such as those which are polyethylene-lined, should be used.

Paclitaxel Injection should be administered through an in-line filter with a microporous membrane not greater than 0.22 microns. Use of filter devices such as IVEX-2® filters which incorporate short inlet and outlet PVC-coated tubing has not resulted in significant leaching of DEHP.

The Chemo Dispensing Pin™ device or similar devices with spikes should not be used with vials of paclitaxel injection since they can cause the stopper to collapse resulting in loss of sterile integrity of the paclitaxel injection solution.

Chemo Dispensing Pin™ is a trademark of B. Braun Medical Incorporated.

Stability

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

Aspirin

2.1 Dosing Guidelines
• Dexmedetomidine hydrochloride injection dosing should be individualized and titrated to desired clinical response. • Dexmedetomidine hydrochloride injection is not indicated for infusions lasting longer than 24 hours. • Dexmedetomidine hydrochloride injection should be administered using a controlled infusion device.
2.2 Dosage Information
Table 1: Dosage Information
INDICATION

DOSAGE AND ADMINISTRATION

Initiation of Procedural Sedation

For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.

For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes.

For patients over 65 years of age: a loading infusion of 0.5 mcg/ kg over 10 minutes [see Use in Specific Populations (8.5)].

For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Maintenance of Procedural Sedation

For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.

For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.

For adult patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)].

For patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment

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

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

2.4 Preparation of Solution

Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride injection.

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

Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL)

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

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

2.5 Administration with Other Fluids

Dexmedetomidine hydrochloride injection infusion should not be coadministered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

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

Dexmedetomidine hydrochloride injection has been shown to be compatible when administered with the following intravenous fluids:
• 0.9% sodium chloride in water • 5% dextrose in water • 20% mannitol • Lactated Ringer's solution • 100 mg/mL magnesium sulfate solution • 0.3% potassium chloride solution
2.6 Compatibility with Natural Rubber

Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride to some types of natural rubber. Although dexmedetomidine hydrochloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
Zoledronic Acid

Zoledronic Acid

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

2.1 Hypercalcemia of Malignancy

The maximum recommended dose of zoledronic acid injection in hypercalcemia of malignancy (albumin-corrected serum calcium greater than or equal 12 mg/dL [3.0 mmol/L]) is 4 mg. The 4-mg dose must be given as a single-dose intravenous infusion over no less than 15 minutes. Patients who receive zoledronic acid injection should have serum creatinine assessed prior to each treatment.

Dose adjustments of zoledronic acid injection are not necessary in treating patients for hypercalcemia of malignancy presenting with mild-to-moderate renal impairment prior to initiation of therapy (serum creatinine less than 400 μmol/L or less than 4.5 mg/dL).

Patients should be adequately rehydrated prior to administration of zoledronic acid injection [see Warnings and Precautions (5.2)].

Consideration should be given to the severity of, as well as the symptoms of, tumor-induced hypercalcemia when considering use of zoledronic acid injection. Vigorous saline hydration, an integral part of hypercalcemia therapy, should be initiated promptly and an attempt should be made to restore the urine output to about 2 L/day throughout treatment. Mild or asymptomatic hypercalcemia may be treated with conservative measures (i.e., saline hydration, with or without loop diuretics). Patients should be hydrated adequately throughout the treatment, but overhydration, especially in those patients who have cardiac failure, must be avoided. Diuretic therapy should not be employed prior to correction of hypovolemia.

Retreatment with zoledronic acid injection 4 mg may be considered if serum calcium does not return to normal or remain normal after initial treatment. It is recommended that a minimum of 7 days elapse before retreatment, to allow for full response to the initial dose. Renal function must be carefully monitored in all patients receiving zoledronic acid injection and serum creatinine must be assessed prior to retreatment with zoledronic acid injection [see Warnings and Precautions (5.2)].

2.2 Multiple Myeloma and Metastatic Bone Lesions of Solid Tumors

The recommended dose of zoledronic acid injection in patients with multiple myeloma and metastatic bone lesions from solid tumors for patients with creatinine clearance greater than 60 mL/min is 4 mg infused over no less than 15 minutes every 3 to 4 weeks. The optimal duration of therapy is not known.

Upon treatment initiation, the recommended zoledronic acid injection doses for patients with reduced renal function (mild and moderate renal impairment) are listed in Table 1. These doses are calculated to achieve the same AUC as that achieved in patients with creatinine clearance of 75 mL/min. CrCl is calculated using the Cockcroft-Gault formula [see Warnings and Precautions (5.2)].
Table 1: Reduced Doses for Patients with Baseline CrCl Less Than or Equal to 60 mL/min * Doses calculated assuming target AUC of 0.66 (mg•hr/L) (CrCl = 75 mL/min) Baseline Creatinine Clearance (mL/min) Zoledronic Acid Injection Recommended Dose* greater than 60 4 mg 50 to 60 3.5 mg 40 to 49 3.3 mg 30 to 39 3 mg
During treatment, serum creatinine should be measured before each zoledronic acid injection dose and treatment should be withheld for renal deterioration. In the clinical studies, renal deterioration was defined as follows:

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

For patients with abnormal baseline creatinine, increase of 1.0 mg/dL

In the clinical studies, zoledronic acid injection treatment was resumed only when the creatinine returned to within 10% of the baseline value. Zoledronic acid injection should be reinitiated at the same dose as that prior to treatment interruption.

Patients should also be administered an oral calcium supplement of 500 mg and a multiple vitamin containing 400 international units of Vitamin D daily.

2.3 Preparation of Solution

Zoledronic acid injection must not be mixed with calcium or other divalent cation-containing infusion solutions, such as Lactated Ringer's solution, and should be administered as a single intravenous solution in a line separate from all other drugs.

4 mg per 5 mL Single-Use Vial

Vials of zoledronic acid injection concentrate for infusion contain overfill allowing for the withdrawal of 5 mL of concentrate (equivalent to 4 mg zoledronic acid). This concentrate should immediately be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP, following proper aseptic technique, and administered to the patient by infusion. Do not store undiluted concentrate in a syringe, to avoid inadvertent injection.

To prepare reduced doses for patients with baseline CrCl less than or equal to 60 mL/min, withdraw the specified volume of the zoledronic acid injection concentrate from the vial for the dose required (see Table 3).
Table 3: Preparation of Reduced Doses – Zoledronic Acid Injection concentrate Remove and Use Zoledronic Acid Injection Volume (mL) Dose (mg) 4.4 3.5 4.1 3.3 3.8 3
The withdrawn concentrate must be diluted in 100 mL of sterile 0.9% Sodium Chloride, USP, or 5% Dextrose Injection, USP.

If not used immediately after dilution with infusion media, for microbiological integrity, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F). The refrigerated solution should then be equilibrated to room temperature prior to administration. The total time between dilution, storage in the refrigerator, and end of administration must not exceed 24 hours.

2.4 Method of Administration

Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of zoledronic acid injection should not exceed 4 mg and the duration of infusion should be no less than 15 minutes [see Warnings and Precautions (5.3)]. In the trials and in postmarketing experience, renal deterioration, progression to renal failure and dialysis, have occurred in patients, including those treated with the approved dose of 4 mg infused over 15 minutes. There have been instances of this occurring after the initial zoledronic acid injection dose.
Doxycycline

Doxycycline

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

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

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

Adults

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

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

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

For Children Above Eight Years of Age

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

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

General

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

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

PREPARATION OF SOLUTION

To prepare a solution containing 10 mg/mL, the contents of the vial should be reconstituted with 10 mL (for the 100 mg/vial container) of Sterile Water for Injection or any of the 10 intravenous infusion solutions listed below. Each 100 mg of doxycycline for injection (i.e., withdraw entire solution from the 100 mg vial) is further diluted with 100 mL to 1000 mL of the intravenous solutions listed below.

1. Sodium Chloride Injection, USP

2. 5% Dextrose Injection, USP

3. Ringer's Injection, USP

4. Invert Sugar, 10% in Water

5. Lactated Ringer's Injection, USP

6. Dextrose 5% in Lactated Ringer's

7. Normosol-M® in D5-W (Abbott)

8. Normosol-R® in D5-W (Abbott)

9. Plasma-Lyte® 56 in 5% Dextrose (Baxter)

10. Plasma-Lyte® 148 in 5% Dextrose (Baxter)

This will result in desired concentrations of 0.1 to 1 mg/mL. Concentrations lower than 0.1 mg/mL or higher than 1 mg/mL are not recommended.

Stability

Doxycycline is stable for 48 hours in solution when diluted with Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP, to concentrations between 1 mg/mL and 0.1 mg/mL and stored at 25oC. Doxycycline in these solutions is stable under fluorescent light for 48 hours, but must be protected from direct sunlight during storage and infusion. Reconstituted solutions (1 to 0.1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded.

Doxycycline, when diluted with Ringer's Injection, USP, or Invert Sugar, 10% in Water, to a concentration between 1 mg/mL and 0.1 mg/mL, must be completely infused within 12 hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Reconstituted solutions (1 to 0.1 mg/mL) may be stored up to 72 hours prior to start of infusion if refrigerated and protected from sunlight and artificial light. Infusion must then be completed within 12 hours. Solutions must be used within these time periods or discarded.

Diluted solutions (0.1 to 1 mg/mL) prepared using Normosol-M® in D5-W (Abbott); Normosol-R® in D5-W (Abbott); Plasma-Lyte® 56 in 5% Dextrose (Baxter); or Plasma-Lyte® 148 in 5% Dextrose (Baxter) may also be stored up to 12 hours prior to start of infusion, if refrigerated and protected from sunlight and artificial light. The infusion must be completed within 12 hours. Solutions must be used within these time periods or discarded.

When diluted with Lactated Ringer's Injection, USP, or Dextrose 5% in Lactated Ringer's, infusion of the solution (ca. 1 mg/mL) or lower concentrations (not less than 0.1 mg/mL) must be completed within six hours after reconstitution to ensure adequate stability. During infusion, the solution must be protected from direct sunlight. Solutions must be used within this time period or discarded.

Solutions of doxycycline for injection, at a concentration of 10 mg/mL in Sterile Water for Injection, when frozen immediately after reconstitution are stable for eight weeks when stored at -20oC. If the product is warmed, care should be taken to avoid heating it after the thawing is complete. Once thawed the solution should not be refrozen.

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

Oxaliplatin

Oxaliplatin for Injection, USP should be administered under the supervision of a qualified physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of therapy and complications is possible only when adequate diagnostic and treatment facilities are readily available.

2.1 Dosage

Administer Oxaliplatin for Injection, USP in combination with 5- fluorouracil/leucovorin every 2 weeks. For advanced disease, treatment is recommended until disease progression or unacceptable toxicity. For adjuvant use, treatment is recommended for a total of 6 months (12 cycles):

Day 1: Oxaliplatin for Injection, USP 85 mg/m2 intravenous infusion in 250-500 mL 5% Dextrose injection, USP and leucovorin 200 mg/m2 intravenous infusion in 5% Dextrose injection, USP both given over 120 minutes at the same time in separate bags using a Y-line, followed by 5- fluorouracil 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5- fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose injection, USP (recommended) as a 22-hour continuous infusion.

Day 2: Leucovorin 200 mg/m2 intravenous infusion over 120 minutes, followed by 5- fluorouracil 400 mg/m2 intravenous bolus given over 2-4 minutes, followed by 5- fluorouracil 600 mg/m2 intravenous infusion in 500 mL 5% Dextrose injection, USP (recommended) as a 22-hour continuous infusion.

Figure 1

The administration of Oxaliplatin for Injection, USP does not require prehydration. Premedication with antiemetics, including 5-HT3 blockers with or without dexamethasone, is recommended.

For information on 5-fluorouracil and leucovorin, see the respective package inserts.

2.2 Dose Modification Recommendations

Prior to subsequent therapy cycles, patients should be evaluated for clinical toxicities and recommended laboratory tests [see Warnings and Precautions (5.6)]. Prolongation of infusion time for Oxaliplatin for Injection, USP from 2 hours to 6 hours may mitigate acute toxicities. The infusion times for 5- fluorouracil and leucovorin do not need to be changed.

Adjuvant Therapy in Patients with Stage III Colon Cancer

Neuropathy and other toxicities were graded using the NCI CTC scale version 1 [see Warnings and Precautions (5.2)].

For patients who experience persistent Grade 2 neurosensory events that do not resolve, a dose reduction of Oxaliplatin for Injection, USP 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 for Injection, USP to 75 mg/m2 and infusional 5- fluorouracil to 300 mg/m2 bolus and 500 mg/m2 22 hour infusion is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy in Previously Untreated and Previously Treated Patients with Advanced Colorectal 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 for Injection, USP to 65 mg/m2 should be considered. For patients with persistent Grade 3 neurosensory events, discontinuing therapy should be considered. The 5- fluorouracil/leucovorin regimen need not be altered.

A dose reduction of Oxaliplatin for Injection, USP to 65 mg/m2 and 5- fluorouracil by 20% (300 mg/m2 bolus and 500 mg/m2 22-hour infusion) is recommended for patients after recovery from grade 3/4 gastrointestinal (despite prophylactic treatment) or grade 4 neutropenia or grade 3/4 thrombocytopenia. The next dose should be delayed until: neutrophils ≥1.5 x 109/L and platelets ≥75 x 109/L.

Dose Modifications in Therapy for Patients with Renal Impairment

In patients with normal renal function or mild to moderate renal impairment, the recommended dose of Oxaliplatin for Injection, USP is 85 mg/m2. In patients with severe renal impairment, the initial recommended Oxaliplatin for Injection, USP dose should be reduced to 65 mg/m2 [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

2.3 Preparation of Infusion Solution

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 250-500 mL of 5% Dextrose Injection, USP.

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

Oxaliplatin for Injection, USP is not light sensitive.

Oxaliplatin for Injection, USP is incompatible in solution with alkaline medications or media (such as basic solutions of 5-fluorouracil) and must not be mixed with these or administered simultaneously through the same infusion line. The infusion line should be flushed with 5% Dextrose injection, USP prior to administration of any concomitant medication.

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

Needles or intravenous administration sets containing aluminum parts that may come in contact with Oxaliplatin for Injection, USP should not be used for the preparation or mixing of the drug. Aluminum has been reported to cause degradation of platinum compounds.
Topotecan Hydrochloride...

Topotecan Hydrochloride

Verify dose using body surface area prior to dispensing. Recommended dosage should generally not exceed 4 mg intravenously [see Overdosage (10)].

Prior to administration of the first course of Topotecan Hydrochloride for Injection, patients must have a baseline neutrophil count of >1,500 cells/mm3 and a platelet count of >100,000 cells/mm3.

2.1 Ovarian Cancer and Small Cell Lung Cancer

Recommended Dosage:
The recommended dose of Topotecan Hydrochloride for Injection 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 3 ovarian clinical trials was 9 to 12 weeks, and 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 for Injection 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 for Injection 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 <1000 cells/mm3 with temperature of 38.0°C or 100.4°F), reduce the dose of Topotecan Hydrochloride for Injection to 0.60 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 for Injection). If febrile neutropenia occurs despite the use of G-CSF, reduce the dose of Topotecan Hydrochloride for Injection to 0.45 mg/m2 for subsequent courses. In the event the platelet count falls below 25,000 cells/mm3, reduce doses to 0.60 mg/m2 for subsequent courses.
2.3 Dosage Adjustment in Specific Populations

Renal Impairment:

No dosage adjustment of Topotecan Hydrochloride for Injection appears to be required for patients with mild renal impairment (Clcr 40 to 60 mL/min). Dosage adjustment of Topotecan Hydrochloride for Injection 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 for Injection [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Topotecan Hydrochloride for Injection 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 for Injection after cisplatin discontinuation in patients with cervical cancer.

2.4 Instructions for Handling, Preparation and Intravenous Administration

Handling

Topotecan Hydrochloride for Injection is a cytotoxic anticancer drug. Prepare Topotecan Hydrochloride for Injection under a vertical laminar flow hood while wearing gloves and protective clothing. If Topotecan Hydrochloride for Injection solution contacts the skin, wash the skin immediately and thoroughly with soap and water. If Topotecan Hydrochloride for Injection 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 for Injection 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 for Injection are stable until the date indicated on the package when stored between 20° and 25°C (68° and 77°F) [see USP] 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 for Injection diluted for infusion are stable at approximately 20° to 25°C (68° to 77°F) and ambient lighting conditions for 24 hours.
Doxorubicin Hydrochlori...

Doxorubicin Hydrochloride

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin hydrochloride, USP is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles [see Clinical Studies (14)].

Metastatic Disease, Leukemia, or Lymphoma
The recommended dose of doxorubicin hydrochloride, USP when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days. The recommended dose of doxorubicin hydrochloride, USP, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days. Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].
2.2 Dose Modifications

Cardiac Impairment

Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Doxorubicin hydrochloride, USP is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4)].

Decrease the dose of doxorubicin hydrochloride, USP in patients with elevated serum total bilirubin concentrations as follows:
Table Serum bilirubin concentration Doxorubicin hydrochloride, USP Dose reduction 1.2 to 3 mg/dL 50 % 3.1 to 5 mg/dL 75 % greater than 5 mg/dL Do not initiate doxorubicin hydrochloride, USP Discontinue doxorubicin hydrochloride, USP
[see Warnings and Precautions (5.5) and Use in Specific Populations (8.7)]

2.3 Preparation and Administration

Preparation for Continuous Intravenous Infusion

Dilute doxorubicin hydrochloride, USP solution or reconstituted solution in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Protect from light following preparation until completion of infusion.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of Doxorubicin hydrochloride injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [15 to 30 C (59 to 86 F)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by Intravenous Injection
Administer doxorubicin hydrochloride, USP as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Administer doxorubicin hydrochloride, USP intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
Administration by Continuous Intravenous Infusion:
Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Protect from light from preparation for infusion until completion of infusion.
Management of Suspected Extravasation

Discontinue doxorubicin hydrochloride, USP for burning or stinging sensation or other evidence indicating peri venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:
Do not remove the needle until attempts are made to aspirate extravasated fluid. Do not flush the line. Avoid applying pressure to the site. Apply ice to the site intermittently for 15 min 4 times a day for 3 days. If the extravasation is in an extremity, elevate the extremity. In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)] .
Incompatibility with Other Drugs

Do not admix doxorubicin hydrochloride, USP with other drugs. If doxorubicin hydrochloride, USP is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride, USP.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin hydrochloride, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.
Doxorubicin Hydrochlori...

Doxorubicin Hydrochloride

2.1 Recommended Dose

Adjuvant Breast Cancer

The recommended dose of doxorubicin hydrochloride, USP is 60 mg/m2 administered as an intravenous bolus on day 1 of each 21-day treatment cycle, in combination with cyclophosphamide, for a total of four cycles [see Clinical Studies (14)].

Metastatic Disease, Leukemia, or Lymphoma
The recommended dose of doxorubicin hydrochloride, USP when used as a single agent is 60 to 75 mg/m2 intravenously every 21 days. The recommended dose of doxorubicin hydrochloride, USP, when administered in combination with other chemotherapy drugs, is 40 to 75 mg/m2 intravenously every 21 to 28 days. Consider use of the lower doxorubicin dose in the recommended dose range or longer intervals between cycles for heavily pretreated patients, elderly patients, or obese patients. Cumulative doses above 550 mg/m2 are associated with an increased risk of cardiomyopathy [see Warnings and Precautions (5.1)].
2.2 Dose Modifications

Cardiac Impairment

Discontinue doxorubicin in patients who develop signs or symptoms of cardiomyopathy.

Hepatic Impairment

Doxorubicin hydrochloride, USP is contraindicated in patients with severe hepatic impairment (Child-Pugh Class C or serum bilirubin >5.0 mg/dL) [see Contraindications (4)].

Decrease the dose of doxorubicin hydrochloride, USP in patients with elevated serum total bilirubin concentrations as follows:
Serum bilirubin concentration Doxorubicin hydrochloride, USP Dose reduction 1.2 to 3 mg/dL 50 % 3.1 to 5 mg/dL 75 % greater than 5 mg/dL Do not initiate doxorubicin hydrochloride, USPDiscontinue doxorubicin hydrochloride, USP
[see Warnings and Precautions (5.5) and Use in Specific Populations (8.7)]

2.3 Preparation and Administration

Preparation of Doxorubicin Hydrochloride for injection, USP

Reconstitute doxorubicin hydrochloride for injection, USP with 0.9% Sodium Chloride Injection, USP to obtain a final concentration of 2 mg per mL as follows:
5 mL 0.9% Sodium Chloride Injection, USP to reconstitute 10 mg doxorubicin hydrochloride, USP vial. 25 mL 0.9% Sodium Chloride Injection, USP to reconstitute 50 mg doxorubicin hydrochloride, USP vial.
Gently shake vial until the contents have dissolved.

Protect reconstituted solution from light.

Administration

Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Discard if the solution is discolored, cloudy, or contains particulate matter.

Storage of vials of Doxorubicin hydrochloride for injection, USP following reconstitution under refrigerated conditions can result in the formation of a gelled product. Place gelled product at room temperature [150 to 300 C (590 to 860F)] for 2 to 4 hours to return the product to a slightly viscous, mobile solution.

Administration by Intravenous Injection:
Administer doxorubicin hydrochloride, USP as an intravenous injection through a central intravenous line or a secure and free-flowing peripheral venous line containing 0.9% Sodium Chloride Injection, USP, 0.45% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Administer doxorubicin hydrochloride, USP intravenously over 3 to 10 minutes. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.
Administration by Continuous Intravenous Infusion:

Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur.

Protect from light from preparation for infusion until completion of infusion.
Infuse only through a central catheter. Decrease the rate of doxorubicin hydrochloride, USP administration if erythematous streaking along the vein proximal to the site of infusion or facial flushing occur. Protect from light from preparation for infusion until completion of infusion.
Management of Suspected Extravasation

Discontinue doxorubicin hydrochloride, USP for burning or stinging sensation or other evidence indicating peri venous infiltration or extravasation. Manage confirmed or suspected extravasation as follows:
Do not remove the needle until attempts are made to aspirate extravasated fluid. Do not flush the line. Avoid applying pressure to the site. Apply ice to the site intermittently for 15 min 4 times a day for 3 days. If the extravasation is in an extremity, elevate the extremity. In adults, consider administration of dexrazoxane [see Warnings and Precautions (5.3)] .
Incompatibility with Other Drugs

Do not admix doxorubicin hydrochloride, USP with other drugs. If doxorubicin hydrochloride, USP is mixed with heparin or fluorouracil a precipitate may form. Avoid contact with alkaline solutions which can lead to hydrolysis of doxorubicin hydrochloride, USP.

2.4 Procedures for Proper Handling and Disposal

Handle and dispose of doxorubicin hydrochloride, USP consistent with recommendations for the handling and disposal of hazardous drugs.1

Treat accidental contact with the skin or eyes immediately by copious lavage with water, or soap and water, or sodium bicarbonate solution. Do not abrade the skin by using a scrub brush. Seek medical attention.
Vinorelbine

Vinorelbine

2.1 Recommended Dose

In Combination with Cisplatin 100 mg/m2
The recommended dose of Vinorelbine Injection, USP is 25 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes on days 1, 8, 15 and 21 of a 28 day cycle in combination with cisplatin 100 mg/m2 on day 1 only of each 28 day cycle.
In Combination with Cisplatin 120 mg/m2
The recommended dose of Vinorelbine Injection, USP is 30 mg/m2 administered as an intravenous injection or infusion over 6 to 10 minutes once a week in combination with cisplatin 120 mg/m2 on days 1 and 29, then every 6 weeks.
Single-Agent
The recommended dose of Vinorelbine Injection, USP is 30 mg/m2 administered intravenously over 6 to 10 minutes once a week.
2.2 Dose Modifications

Hematologic Toxicity

[see Warnings and Precautions (5.1)]

Hold or decrease the dose of Vinorelbine Injection, USP in patients with decreased neutrophil counts using the following schema.
Neutrophils on Day of Treatment (Cells/mm3) Percentage of Starting Dose of Vinorelbine Injection, USP ≥ 1,500 100% 1,000 to 1,499 50% < 1,000 Do not administer Vinorelbine Injection USP.Repeat neutrophil count in one week.If three consecutive weekly doses are held because Neutrophil count is < 1,000 cells/mm3, discontinue Vinorelbine Injection, USP Note : For patients who experience fever and/or sepsis while neutrophil count is < 1,500 or had 2 consecutive weekly doses held due to neutropenia, subsequent doses of Vinorelbine Injection, USP should be: > 1,500 75% 1,000 to 1,499 37.5% < 1,000 Do not administer Vinorelbine Injection, USP.Repeat neutrophil count in one week.
Hepatic Impairment/Toxicity

[see Warnings and Precautions (5.2) and Use in Specific Populations (8.6)]

Reduce Vinorelbine Injection, USP dose in patients with elevated serum total bilirubin concentration according to the following schema:
Serum total bilirubin concentration (mg/dl) Percentage of Starting Dose of Vinorelbine Injection, USP ≤ 2.0 100% 2.1 to 3.0 50% > 3.0 25%
Concurrent Hematologic Toxicity and Hepatic Impairment

In patients with both hematologic toxicity and hepatic impairment, administer the lower of the doses based on the corresponding starting dose of Vinorelbine Injection, USP determined from the above schemas.

Neurologic Toxicity

[see Warnings and Precautions (5.5) ]

Discontinue Vinorelbine Injection, USP for NCI CTCAE Grade 2 or higher peripheral neuropathy or autonomic neuropathy causing constipation.

2.3 Preparation and Administration

Preparation of Vinorelbine Injection, USP

Dilute Vinorelbine Injection, USP in either a syringe or intravenous bag using one of the recommended solutions.

Syringe

Dilute to a concentration between 1.5 and 3 mg/mL. The following solutions may be used for dilution:
5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP
Intravenous Bag

Dilute to a concentration between 0.5 and 2 mg/mL. The following solutions may be used for dilution:
5% Dextrose Injection, USP 0.9% Sodium Chloride Injection, USP 0.45% Sodium Chloride Injection, USP 5% Dextrose and 0.45% Sodium Chloride Injection, USP Ringer's Injection, USP Lactated Ringer's Injection, USP
Stabiliy

Diluted Vinorelbine Injection, USP may be used for up to 24 hours under normal room light when stored in polypropylene syringes or polyvinyl chloride bags at 5° to 30°C (41° to 86°F).

Administration

Administer diluted Vinorelbine Injection, USP over 6 to 10 minutes into the side port of a free-flowing intravenous line followed by flushing with at least 75 to 125 mL of one of the solutions.

Vinorelbine Injection, USP must only be administered intravenously. It is extremely important that the intravenous needle or catheter be properly positioned before any Vinorelbine Injection, USP is injected.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If particulate matter is seen, Vinorelbine Injection, USP should not be administered.

Management of Suspected Extravasation
If Vinorelbine Injection, USP leakage into surrounding tissue occurs or is suspected, immediately stop administration of Vinorelbine Injection, USP and initiate appropriate management measures in accordance with institutional policies. [see Warnings and Precautions (5.4)]
2.4 Procedures for Proper Handling and Disposal

Handle and dispose Vinorelbine Injection, USP consistent with recommendations for the handling and disposal of hazardous drugs2.

Exercise caution in handling and preparing the solution of Vinorelbine Injection, USP. The use of gloves is recommended. If the solution of Vinorelbine Injection, USP contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Avoid contamination of the eye with Vinorelbine Injection, USP. If exposure occurs, flush the eyes with water immediately and thoroughly.
Nicardipine Hydrochlori...

Nicardipine Hydrochloride

Nicardipine hydrochloride injection is intended for intravenous use. Titrate dose to achieve the desired blood pressure reduction. Individualize dosage depending on the blood pressure to be obtained and the response of the patient.

The time course of blood pressure decrease is dependent on the initial rate of infusion and the frequency of dosage adjustment. With constant infusion, blood pressure begins to fall within minutes. It reaches about 50% of its ultimate decrease in about 45 minutes.

Preparation

WARNING: VIALS MUST BE DILUTED BEFORE INFUSION.

Dilution

Nicardipine hydrochloride injection is administered by slow continuous infusion at a CONCENTRATION OF 0.1 mg/mL. Each vial (25 mg) should be diluted with 240 mL of compatible intravenous fluid (see below), resulting in 250 mL of solution at a concentration of 0.1 mg/mL.

Nicardipine hydrochloride injection has been found to be compatible and stable in glass or polyvinyl chloride containers for 24 hours at controlled room temperature with:

Dextrose (5%) Injection, USP

Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP

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

Dextrose (5%) with 40 mEq Potassium, USP

Sodium Chloride (0.45%) Injection, USP

Sodium Chloride (0.9%) Injection, USP

Nicardipine hydrochloride injection is NOT compatible with Sodium Bicarbonate (5%) Injection, USP or Lactated Ringer’s Injection, USP.

THE DILUTED SOLUTION IS STABLE FOR 24 HOURS AT ROOM TEMPERATURE.

Inspection

As with all parenteral drugs, nicardipine hydrochloride injection should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Nicardipine hydrochloride injection is normally light yellow in color.

Dosage

Dosage as a Substitute for Oral Nicardipine Therapy

The intravenous infusion rate required to produce an average plasma concentration equivalent to a given oral dose at steady state is shown in the following table:

Oral Nicardipine Dose

Equivalent I.V. Infusion Rate

20 mg q8h

0.5 mg/hr = 5 mL/hr

30 mg q8h

1.2 mg/hr = 12 mL/hr

40 mg q8h

2.2 mg/hr = 22 mL/hr

Dosage for Initiation of Therapy in a Patient Not Receiving Oral Nicardipine

Initiate therapy at 50 mL/hr (5 mg/hr). If desired blood pressure reduction is not achieved at this dose, the infusion rate may be increased by 25 mL/hr (2.5 mg/hr) every 5 minutes (for rapid titration) to 15 minutes (for gradual titration) up to a maximum of 150 mL/hr (15 mg/hr), until desired blood pressure reduction is achieved. Following achievement of the blood pressure goal utilizing rapid titration, decrease the infusion rate to 30 mL/hr (3 mg/hr).

Drug Discontinuation and Transfer to Oral Antihypertensive Agents

Discontinuation of infusion is followed by a 50% offset action in about 30 minutes.

If treatment includes transfer to an oral antihypertensive agent other than oral nicardipine, initiate therapy upon discontinuation of nicardipine hydrochloride injection.

If oral nicardipine is to be used, administer the first dose one hour prior to discontinuation of the infusion.
Aloprim

Aloprim

Children and Adults

The dosage of ALOPRIM (allopurinol sodium) for Injection to lower serum uric acid to normal or near-normal varies with the severity of the disease. The amount and frequency of dosage for maintaining the serum uric acid just within the normal range is best determined by using the serum uric acid level as an index. In adults, in one clinical trial, doses over 600 mg a day did not appear to be more effective. The recommended daily dose of ALOPRIM (allopurinol sodium) for Injection is as follows:
Recommended Daily Dose
Adult:

200 to 400 mg/m2/day Maximum 600 mg/day

Child:

Starting Dose 200 mg/m2/day

Hydration

A fluid intake sufficient to yield a daily urinary output of at least two liters in adults and the maintenance of a neutral or, preferably, slightly alkaline urine are desirable.

Impaired Renal Function

The dose of ALOPRIM (allopurinol sodium) for Injection should be reduced in patients with impaired renal function to avoid accumulation of allopurinol and its metabolites:
Creatinine Clearance Recommended Daily Dose
10 to 20 mL/min

200 mg/day

3 to 10 mL/min

100 mg/day

<3 mL/min

100 mg/day at extended intervals

Administration

In both adults and children, the daily dose can be given as single infusion or in equally divided infusions at 6-, 8-, or 12- hour intervals at the recommended final concentration of not greater than 6 mg/mL (see Preparation of Solution). The rate of infusion depends on the volume of infusate. Whenever possible, therapy with ALOPRIM (allopurinol sodium) for Injection should be initiated 24 to 48 hours before the start of chemotherapy known to cause tumor cell lysis (including adrenocortical steroids).

ALOPRIM (allopurinol sodium) for Injection should not be mixed with or administered through the same intravenous port with agents which are incompatible in solution with ALOPRIM (allopurinol sodium) for Injection (see Preparation of Solution).

Preparation of Solution

ALOPRIM (allopurinol sodium) for Injection must be reconstituted and diluted. The contents of each 30 mL vial should be dissolved with 25 mL of Sterile Water for Injection. Reconstitution yields a clear, almost colorless solution with no more than a slight opalescence. This concentrated solution has a pH of 11.1 to 11.8. It should be diluted to the desired concentration with 0.9% Sodium Chloride Injection or 5% Dextrose for Injection. Sodium bicarbonate-containing solutions should not be used. A final concentration of no greater than 6 mg/mL is recommended. The solution should be stored at 20° to 25°C (68° to 77°F) and administration should begin within 10 hours after reconstitution. Do not refrigerate the reconstituted and/or diluted product.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use this product if particulate matter or discoloration is present.

The following table lists drugs that are physically incompatible in solution with ALOPRIM (allopurinol sodium) for Injection.
Drugs That Are Physically Incompatible in Solution with ALOPRIM® (allopurinol sodium) for Injection
Amikacin sulfate

Hydroxyzine HCl

Amphotericin B

Idarubicin HCl

Carmustine

Imipenem-cilastatin sodium

Cefotaxime sodium

Mechlorethamine HCl

Chlorpromazine HCl

Meperidine HCl

Cimetidine HCl

Metoclopramide HCl

Clindamycin phosphate

Methylprednisolone sodium succinate

Cytarabine

Minocycline HCl

Dacarbazine

Nalbuphine HCl

Daunorubicin HCl

Netilmicin sulfate

Diphenhydramine HCl

Ondansetron HCl

Doxorubicin HCl

Prochlorperazine edisylate

Doxycycline hyclate

Promethazine HCl

Droperidol

Sodium bicarbonate

Floxuridine

Streptozocin

Gentamicin sulfate

Tobramycin sulfate

Haloperidol lactate

Vinorelbine tartrate
Chlorothiazide Sodium

Chlorothiazide Sodium

Chlorothiazide sodium for injection, USP 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, USP 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, USP 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 chlorothiazide sodium for injection, USP 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.
Dexmedetomidine Hydroch...

Dexmedetomidine Hydrochloride

2.1 Dosing Guidelines
• Dexmedetomidine hydrochloride injection dosing should be individualized and titrated to desired clinical response. • Dexmedetomidine hydrochloride injection is not indicated for infusions lasting longer than 24 hours. • Dexmedetomidine hydrochloride injection should be administered using a controlled infusion device.
2.2 Dosage Information
Table 1: Dosage Information
INDICATION

DOSAGE AND ADMINISTRATION

Initiation of Procedural Sedation

For adult patients: a loading infusion of one mcg/kg over 10 minutes. For less invasive procedures such as ophthalmic surgery, a loading infusion of 0.5 mcg/kg given over 10 minutes may be suitable.

For awake fiberoptic intubation in adult patients: a loading infusion of one mcg/kg over 10 minutes.

For patients over 65 years of age: a loading infusion of 0.5 mcg/ kg over 10 minutes[see Use in Specific Populations (8.5)].

For adult patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

Maintenance of Procedural Sedation

For adult patients: the maintenance infusion is generally initiated at 0.6 mcg/kg/hour and titrated to achieve desired clinical effect with doses ranging from 0.2 to 1 mcg/kg/hour. The rate of the maintenance infusion should be adjusted to achieve the targeted level of sedation.

For awake fiberoptic intubation in adult patients: a maintenance infusion of 0.7 mcg/kg/hour is recommended until the endotracheal tube is secured.

For adult patients over 65 years of age: a dose reduction should be considered [see Use in Specific Populations (8.5)].

For patients with impaired hepatic function: a dose reduction should be considered [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].

2.3 Dosage Adjustment

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

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

2.4 Preparation of Solution

Strict aseptic technique must always be maintained during handling of dexmedetomidine hydrochloride injection.

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

Dexmedetomidine Hydrochloride Injection, 200 mcg/2 mL (100 mcg/mL)

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

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

2.5 Administration with Other Fluids

Dexmedetomidine hydrochloride injection infusion should not be coadministered through the same intravenous catheter with blood or plasma because physical compatibility has not been established.

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

Dexmedetomidine hydrochloride injection has been shown to be compatible when administered with the following intravenous fluids:
• 0.9% sodium chloride in water • 5% dextrose in water • 20% mannitol • Lactated Ringer's solution • 100 mg/mL magnesium sulfate solution • 0.3% potassium chloride solution
2.6 Compatibility with Natural Rubber

Compatibility studies have demonstrated the potential for absorption of dexmedetomidine hydrochloride to some types of natural rubber. Although dexmedetomidine hydrochloride injection is dosed to effect, it is advisable to use administration components made with synthetic or coated natural rubber gaskets.
Dexrazoxane Hydrochlori...

Dexrazoxane Hydrochloride

2.1 Recommended Dose

Administer dexrazoxane for injection by slow I.V. push or rapid drip intravenous infusion from a bag.

The recommended dosage ratio of dexrazoxane for injection to doxorubicin is 10:1 (e.g., 500 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin). Do not administer doxorubicin before dexrazoxane for injection. Administer doxorubicin within 30 minutes after the completion of dexrazoxane for injection infusion.

2.2 Dose Modifications

Dosing in Patients with Renal Impairment

Reduce dexrazoxane for injection dosage in patients with moderate to severe renal impairment (creatinine clearance values less than 40 mL/min) by 50% (dexrazoxane for injection to doxorubicin ratio reduced to 5:1; such as 250 mg/m2 dexrazoxane for injection to 50 mg/m2 doxorubicin) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Dosing in Patients with Hepatic Impairment

Since a doxorubicin dose reduction is recommended in the presence of hyperbilirubinemia, reduce the dexrazoxane for injection dosage proportionately (maintaining the 10:1 ratio) in patients with hepatic impairment.

2.3 Preparation and Administration

Preparation and Handling of Infusion Solution

Dexrazoxane for injection must be reconstituted with 0.167 Molar (M/6) sodium lactate injection, USP, to give a concentration of 10 mg dexrazoxane for injection for each mL of sodium lactate. The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given.

Reconstituted dexrazoxane for injection, when transferred to an empty infusion bag, is stable for 6 hours from the time of reconstitution when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

The reconstituted dexrazoxane for injection solution may be diluted with either 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP to a concentration range of 1.3 to 5 mg/mL in intravenous infusion bags. The resultant solutions are stable for 6 hours when stored at controlled room temperature, 20° to 25°C (68° to 77°F) or under refrigeration, 2° to 8°C (36° to 46°F). DISCARD UNUSED SOLUTIONS.

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

Use caution when handling and preparing the reconstituted solution. The use of gloves is recommended. If dexrazoxane for injection powder or solutions contact the skin or mucosae, wash exposed area immediately and thoroughly with soap and water. Follow special handling and disposal procedures.1

Administration

Do not mix dexrazoxane for injection with other drugs.

The reconstituted solution should be given by slow I.V. push or rapid drip intravenous infusion from a bag. After completing the infusion of dexrazoxane for injection, and prior to a total elapsed time of 30 minutes (from the beginning of the dexrazoxane for injection infusion), the intravenous injection of doxorubicin should be given.
Ibandronate Sodium

Ibandronate Sodium

2.1 Important Administration Instructions

Ibandronate injection must be administered intravenously only by a health care professional.

Care must be taken not to administer intra-arterially or paravenously as this could lead to tissue damage [see Warnings and Precautions (5.4)].
Appropriate medical support and monitoring measures should be readily available when ibandronate injection is administered. If anaphylactic or other severe hypersensitivity/allergic reactions occur, immediately discontinue the injection and initiate appropriate treatment [see Warnings and Precautions (5.2) ]. Visually inspect the liquid in the prefilled syringe for particulate matter and discoloration before administration. Do not use prefilled syringes with particulate matter or discoloration. Administer only with 25-gauge, 3/4 inch needle attached with 9 cm plastic tubing. Discard any unused portion. Do not mix with calcium-containing solutions or other intravenously administered drugs. Prefilled syringes are for single use only.
2.2 Dosage Information

The recommended dose of ibandronate injection for the treatment of postmenopausal osteoporosis is 3 mg every 3 months administered intravenously over a period of 15 to 30 seconds. Do not administer more frequently than once every 3 months.

2.3 Laboratory Testing and Oral Examination Prior to Administration

Prior to administration of each dose obtain a serum creatinine [see Warnings and Precautions (5.3)]. Given that bisphosphonates have been associated with osteonecrosis of the jaw (ONJ), perform a routine oral examination prior to administration of ibandronate injection.

2.4 Calcium and Vitamin D Supplementation

Instruct patients to take supplemental calcium and vitamin D if their dietary intake is inadequate. [see Warnings and Precautions (5.1)].

2.5 Dosing After Missed Dose

If the dose is missed, administer as soon as it can be re-scheduled. Thereafter, ibandronate injection should be scheduled every 3 months from the date of the last injection.

2.6 Dosage Modifications in Patients with Renal Impairment

Do not administer to patients with severe renal impairment (creatinine clearance less than 30 mL/minute) [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)]. No dose adjustment is necessary for patients with mild or moderate renal impairment (creatinine clearance greater than or equal to 30 mL/min) [see Clinical Pharmacology (12.3)].
Methotrexate

Methotrexate

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal (Only preservative free) route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and similar trophoblastic diseases

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

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

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

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

Leukemia

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

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.

When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days.

If and when relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

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

Meningeal Leukemia

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

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

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
AGE (years) DOSE (mg) <1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

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

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

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

Lymphomas

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

Mycosis fungoides (cutaneous T cell lymphoma)

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

Osteosarcoma

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

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

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

When these higher doses of methotrexate are to be administered, the following safety guidelines should be closely observed.
Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 15 mg orally every six hours for Leucovorin 10 doses starting at 24 hours after - - - start of methotrexate infusion Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42
Methotrexate

Methotrexate

Neoplastic Diseases

Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal (Only preservative free) route. However, the preserved formulation contains Benzyl Alcohol and must not be used for intrathecal or high dose therapy. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Choriocarcinoma and similar trophoblastic diseases

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

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

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

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

Leukemia

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

Methotrexate alone or in combination with steroids was used initially for induction of remission in acute lymphoblastic leukemias. More recently corticosteroid therapy, in combination with other antileukemic drugs or in cyclic combinations with methotrexate included, has appeared to produce rapid and effective remissions.

When used for induction, methotrexate in doses of 3.3 mg/m2 in combination with 60 mg/m2 of prednisone, given daily, produced remissions in 50% of patients treated, usually within a period of 4 to 6 weeks. Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions. When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. It has also been given in doses of 2.5 mg/kg intravenously every 14 days. If and when

relapse does occur, reinduction of remission can again usually be obtained by repeating the initial induction regimen.

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

Meningeal Leukemia

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

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

Intrathecal methotrexate administration at a dose of 12 mg/m2 (maximum 15 mg) has been reported to result in low CSF methotrexate concentrations and reduced efficacy in pediatric patients and high concentrations and neurotoxicity in adults. The following dosage regimen is based on age instead of body surface area:
AGE (years) DOSE (mg) <1 6 1 8 2 10 3 or older 12
In one study in patients under the age of 40, this dosage regimen appeared to result in more consistent CSF methotrexate concentrations and less neurotoxicity. Another study in pediatric patients with acute lymphocytic leukemia compared this regimen to a dose of 12 mg/m2 (maximum 15 mg), a significant reduction in the rate of CNS relapse was observed in the group whose dose was based on age.

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

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

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

Lymphomas

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

Mycosis fungoides (cutaneous T cell lymphoma)

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

Osteosarcoma

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

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

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

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

closely observed.
Drug* Dose* Treatment Week After Surgery Methotrexate 12 g/m2 IV as 4 hour infusion (starting dose) 4,5,6,7,11,12,15,16,29,30,44,45 15 mg orally every six hours for Leucovorin 10 doses starting at 24 hours after - - - start of methotrexate infusion Doxorubicin† as a single drug 30 mg/m2 day IV x 3 days 8,17 Doxorubicin† 50 mg/m2 IV 20,23,33,36 Cisplatin† 100 mg/m2 IV 20,23,33,36 Bleomycin† 15 units/m2 IV x 2 days 2,13,26,39,42 Cyclophosphamide† 600 mg/m2 IV x 2 days 2,13,26,39,42 Dactinomycin† 0.6 mg/m2 IV x 2 days 2,13,26,39,42
Cytarabine

Cytarabine

Cytarabine Injection (non-preserved) can be administered by intravenous injection or infusion, subcutaneously, or intrathecally. However, the intent of this Pharmacy Bulk Package is for the preparation of solutions for IV infusion only. Intrathecal use of cytarabine requires the use of single-dose, unpreserved solutions only.

Cytarabine Injection is not active orally. The schedule and method of administration varies with the program of therapy to be used. While Cytarabine Injection may be given by intravenous infusion or injection or subcutaneously, or intrathecally, THE PURPOSE OF THE PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF INTRAVENOUS INFUSIONS. 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 anti-cancer drugs is 100 mg/m2/day by continuous IV infusion (Days 1-7) or 100 mg/ m2 IV every 12 hours (Days 1-7).

The literature should be consulted for the current recommendations for use in acute lymphocytic leukemia.

Intrathecal Use in Meningeal Leukemia

Cytarabine 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.

If used intrathecally, do not use a solution containing benzyl alcohol. This pharmacy bulk package is not intended to be used for the preparation of intrathecal doses.

Cytarabine given intrathecally may cause systemic toxicity and careful monitoring of the hemopoietic 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.

When cytarabine 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 is left to the discretion of the treating physician.

Focal leukemic involvement of the central nervous system may not respond to intrathecal cytarabine and may be better treated with radiotherapy.

Chemical Stability in Infusion Solutions

Chemical stability studies were performed by a stability indicating HPLC assay on Cytarabine Injection in infusion solutions. These studies showed that when Cytarabine Injection was diluted with Water for Injection, 5% Dextrose Injection or Sodium Chloride Injection, in both glass and plastic infusion bags, 97-100% of the cytarabine was present after 8 days storage at room temperature.

This chemical stability information in no way indicates that it would be acceptable practice to infuse a cytarabine admixture well after the preparation time. Good professional practice suggests that administration of an admixture should be as soon after preparation as feasible.

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

Handling and Disposal

Procedures for proper handling and disposal of anti-cancer drugs should be considered. Several guidelines on this subject have been published.1-7 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Direction for Proper Use of Pharmacy Bulk Package

The 50 mL Pharmacy Bulk Package is for use in the Pharmacy Admixtures Service only. The vials should be inserted into the plastic handling device provided, suspended as a unit in the laminar flow hood.

A single entry through the vial closure should be made with a sterile dispensing set or transfer device. Transfer individual doses to appropriate intravenous infusion solutions. Use of a syringe with needle is not recommended. Multiple entries will increase the potential of microbial and particulate contamination.

The above process should be carried out under a laminar flow hood using aseptic technique. Care should be exercised to protect personnel from aerosolized drug (see DOSAGE AND ADMINISTRATION, REFERENCES). Discard any unused portion within 4 hours after initial closure entry.
Melphalan Hydrochloride...

Melphalan Hydrochloride Kit

The usual IV dose is 16 mg/m2. Dosage reduction of up to 50% should be considered in patients with renal insufficiency (BUN ≥30 mg/dL) (see PRECAUTIONS: General). The drug is administered as a single infusion over 15 to 20 minutes. Melphalan is administered at 2-week intervals for 4 doses, then, after adequate recovery from toxicity, at 4-week intervals. Available evidence suggests about one third to one half of the patients with multiple myeloma show a favorable response to the drug. Experience with oral melphalan suggests that repeated courses should be given since improvement may continue slowly over many months, and the maximum benefit may be missed if treatment is abandoned prematurely. Dose adjustment on the basis of blood cell counts at the nadir and day of treatment should be considered.

Administration Precautions

As with other toxic compounds, caution should be exercised in handling and preparing the solution of Melphalan Hydrochloride. Skin reactions associated with accidental exposure may occur. The use of gloves is recommended. If the solution of Melphalan Hydrochloride contacts the skin or mucosa, immediately wash the skin or mucosa thoroughly with soap and water.

Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. 1-4 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration whenever solution and container permit. If either occurs, do not use this product.

Care should be taken to avoid possible extravasation of melphalan and in cases of poor peripheral venous access, consideration should be given to use of a central venous line (see WARNINGS).

Preparation for Administration/Stability
1. Melphalan Hydrochloride for Injection must be reconstituted by rapidly injecting 10 mL of the supplied diluent directly into the vial of lyophilized powder using a sterile needle (20-gauge or larger needle diameter) and syringe. Immediately shake vial vigorously until a clear solution is obtained. This provides a 5-mg/mL solution of melphalan. Rapid addition of the diluent followed by immediate vigorous shaking is important for proper dissolution. 2. Immediately dilute the dose to be administered in 0.9% Sodium Chloride Injection, USP, to a concentration not greater than 0.45 mg/mL. 3. Administer the diluted product over a minimum of 15 minutes. 4. Complete administration within 60 minutes of reconstitution.
The time between reconstitution/dilution and administration of Melphalan Hydrochloride for Injection should be kept to a minimum because reconstituted and diluted solutions of Melphalan Hydrochloride for Injection are unstable. Over as short a time as 30 minutes, a citrate derivative of melphalan has been detected in reconstituted material from the reaction of Melphalan Hydrochloride with Sterile Diluent for Melphalan Hydrochloride for Injection. Upon further dilution with saline, nearly 1% label strength of melphalan hydrolyzes every 10 minutes.

A precipitate forms if the reconstituted solution is stored at 5°C. DO NOT REFRIGERATE THE RECONSTITUTED PRODUCT.
Etomidate

Etomidate

Etomidate injection is intended for administration only by the intravenous route (see CLINICAL PHARMACOLOGY). The dose for induction of anesthesia in adult patients and in children above the age of ten (10) years will vary between 0.2 and 0.6 mg/kg of body weight, and it must be individualized in each case. The usual dose for induction in these patients is 0.3 mg/kg, injected over a period of 30 to 60 seconds. There are inadequate data to make dosage recommendations for induction of anesthesia in patients below the age of ten (10) years; therefore, such use is not recommended. Geriatric patients may require reduced doses of etomidate.

Smaller increments of intravenous etomidate may be administered to adult patients during short operative procedures to supplement subpotent anesthetic agents, such as nitrous oxide. The dosage employed under these circumstances, although usually smaller than the original induction dose, must be individualized. There are insufficient data to support this use of etomidate for longer adult procedures or for any procedures in pediatric patients; therefore, such use is not recommended. The use of intravenous fentanyl and other neuroactive drugs employed during the conduct of anesthesia may alter the etomidate dosage requirements. Consult the prescribing information for all other such drugs before using.

Premedication:

Etomidate injection is compatible with commonly administered pre-anesthetic medications, which may be employed as indicated. See also CLINICAL PHARMACOLOGY, ADVERSE REACTIONS, and dosage recommendations for maintenance of anesthesia.

Etomidate hypnosis does not significantly alter the usual dosage requirements of neuromuscular blocking agents employed for endotracheal intubation or other purposes shortly after induction of anesthesia.

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

To prevent needle-stick injuries, needles should not be recapped, purposely bent, or broken by hand.
Rocuronium Bromide

Rocuronium Bromide

Rocuronium bromide injection is for intravenous use only. This drug should only be administered by experienced clinicians or trained individuals supervised by an experienced clinician familiar with the use, actions, characteristics, and complications of neuromuscular blocking agents. Doses of rocuronium bromide injection should be individualized and a peripheral nerve stimulator should be used to monitor drug effect, need for additional doses, adequacy of spontaneous recovery or antagonism, and to decrease the complications of overdosage if additional doses are administered.

The dosage information which follows is derived from studies based upon units of drug per unit of body weight. It is intended to serve as an initial guide to clinicians familiar with other neuromuscular blocking agents to acquire experience with rocuronium bromide.

In patients in whom potentiation of, or resistance to, neuromuscular block is anticipated, a dose adjustment should be considered [see Dosage and Administration (2.5), Warnings and Precautions (5.9, 5.12), Drug Interactions (7.2, 7.3, 7.4, 7.5, 7.6, 7.8, 7.10), and Use in Specific Populations (8.6)].

2.1 Dose for Tracheal Intubation

The recommended initial dose of rocuronium bromide, regardless of anesthetic technique, is 0.6 mg/kg. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1 (0.4 to 6) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 3 minutes. This dose may be expected to provide 31 (15 to 85) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Under halothane, isoflurane, and enflurane anesthesia, some extension of the period of clinical relaxation should be expected [see Drug Interactions (7.3)].

A lower dose of rocuronium bromide (0.45 mg/kg) may be used. Neuromuscular block sufficient for intubation (80% block or greater) is attained in a median (range) time of 1.3 (0.8 to 6.2) minute(s) and most patients have intubation completed within 2 minutes. Maximum blockade is achieved in most patients in less than 4 minutes. This dose may be expected to provide 22 (12 to 31) minutes of clinical relaxation under opioid/nitrous oxide/oxygen anesthesia. Patients receiving this low dose of 0.45 mg/kg who achieve less than 90% block (about 16% of these patients) may have a more rapid time to 25% recovery, 12 to 15 minutes.

A large bolus dose of 0.9 or 1.2 mg/kg can be administered under opioid/nitrous oxide/oxygen anesthesia without adverse effects to the cardiovascular system [see Clinical Pharmacology (12.2)].

2.2 Rapid Sequence Intubation

In appropriately premedicated and adequately anesthetized patients, rocuronium bromide 0.6 to 1.2 mg/kg will provide excellent or good intubating conditions in most patients in less than 2 minutes [see Clinical Studies (14.1)].

2.3 Maintenance Dosing

Maintenance doses of 0.1, 0.15, and 0.2 mg/kg rocuronium bromide, administered at 25% recovery of control T1 (defined as 3 twitches of train-of-four), provide a median (range) of 12 (2 to 31), 17 (6 to 50) and 24 (7 to 69) minutes of clinical duration under opioid/nitrous oxide/oxygen anesthesia [see Clinical Pharmacology (12.2)]. In all cases, dosing should be guided based on the clinical duration following initial dose or prior maintenance dose and not administered until recovery of neuromuscular function is evident. A clinically insignificant cumulation of effect with repetitive maintenance dosing has been observed [see Clinical Pharmacology (12.2)].

2.4 Use by Continuous Infusion

Infusion at an initial rate of 10 to 12 mcg/kg/min of rocuronium bromide should be initiated only after early evidence of spontaneous recovery from an intubating dose. Due to rapid redistribution [see Clinical Pharmacology (12.3)] and the associated rapid spontaneous recovery, initiation of the infusion after substantial return of neuromuscular function (more than 10% of control T1) may necessitate additional bolus doses to maintain adequate block for surgery.

Upon reaching the desired level of neuromuscular block, the infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. In clinical trials, infusion rates have ranged from 4 to 16 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane, may enhance the neuromuscular blocking action of non-depolarizing muscle relaxants. In the presence of steady-state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion by 30% to 50%, at 45 to 60 minutes after the intubating dose.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following comparable total doses administered by repetitive bolus injections [see Clinical Pharmacology (12.2)].

Infusion solutions of rocuronium bromide can be prepared by mixing rocuronium bromide injection with an appropriate infusion solution such as 5% glucose in water or lactated Ringers [see Dosage and Administration (2.6)]. These infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Infusion rates of rocuronium bromide can be individualized for each patient using the following tables for three different concentrations of rocuronium bromide solution as guidelines:
Table 1: Infusion Rates Using Rocuronium Bromide Injection (0.5 mg/mL)* * 50 mg rocuronium bromide in 100 mL solution.
Patient Weight

Drug Delivery Rate (mcg/kg/min)

(kg)

(lbs)

4

5

6

7

8

9

10

12

14

16

Infusion Delivery Rate (mL/hr)

10

22

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

15

33

7.2

9

10.8

12.6

14.4

16.2

18

21.6

25.2

28.8

20

44

9.6

12

14.4

16.8

19.2

21.6

24

28.8

33.6

38.4

25

55

12

15

18

21

24

27

30

36

42

48

35

77

16.8

21

25.2

29.4

33.6

37.8

42

50.4

58.8

67.2

50

110

24

30

36

42

48

54

60

72

84

96

60

132

28.8

36

43.2

50.4

57.6

64.8

72

86.4

100.8

115.2

70

154

33.6

42

50.4

58.8

67.2

75.6

84

100.8

117.6

134.4

80

176

38.4

48

57.6

67.2

76.8

86.4

96

115.2

134.4

153.6

90

198

43.2

54

64.8

75.6

86.4

97.2

108

129.6

151.2

172.8

100

220

48

60

72

84

96

108

120

144

168

192
Table 2: Infusion Rates Using Rocuronium Bromide Injection (1 mg/mL)* * 100 mg rocuronium bromide in 100 mL solution.
Patient Weight

Drug Delivery Rate (mcg/kg/min)

(kg)

(lbs)

4

5

6

7

8

9

10

12

14

16

Infusion Delivery Rate (mL/hr)

10

22

2.4

3

3.6

4.2

4.8

5.4

6

7.2

8.4

9.6

15

33

3.6

4.5

5.4

6.3

7.2

8.1

9

10.8

12.6

14.4

20

44

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

25

55

6

7.5

9

10.5

12

13.5

15

18

21

24

35

77

8.4

10.5

12.6

14.7

16.8

18.9

21

25.2

29.4

33.6

50

110

12

15

18

21

24

27

30

36

42

48

60

132

14.4

18

21.6

25.2

28.8

32.4

36

43.2

50.4

57.6

70

154

16.8

21

25.2

29.4

33.6

37.8

42

50.4

58.8

67.2

80

176

19.2

24

28.8

33.6

38.4

43.2

48

57.6

67.2

76.8

90

198

21.6

27

32.4

37.8

43.2

48.6

54

64.8

75.6

86.4

100

220

24

30

36

42

48

54

60

72

84

96
Table 3: Infusion Rates Using Rocuronium Bromide Injection (5 mg/mL)* * 500 mg rocuronium bromide in 100 mL solution.
Patient Weight

Drug Delivery Rate (mcg/kg/min)

(kg)

(lbs)

4

5

6

7

8

9

10

12

14

16

Infusion Delivery Rate (mL/hr)

10

22

0.5

0.6

0.7

0.8

1

1.1

1.2

1.4

1.7

1.9

15

33

0.7

0.9

1.1

1.3

1.4

1.6

1.8

2.2

2.5

2.9

20

44

1

1.2

1.4

1.7

1.9

2.2

2.4

2.9

3.4

3.8

25

55

1.2

1.5

1.8

2.1

2.4

2.7

3

3.6

4.2

4.8

35

77

1.7

2.1

2.5

2.9

3.4

3.8

4.2

5

5.9

6.7

50

110

2.4

3

3.6

4.2

4.8

5.4

6

7.2

8.4

9.6

60

132

2.9

3.6

4.3

5

5.8

6.5

7.2

8.6

10.1

11.5

70

154

3.4

4.2

5

5.9

6.7

7.6

8.4

10.1

11.8

13.4

80

176

3.8

4.8

5.8

6.7

7.7

8.6

9.6

11.5

13.4

15.4

90

198

4.3

5.4

6.5

7.6

8.6

9.7

10.8

13

15.1

17.3

100

220

4.8

6

7.2

8.4

9.6

10.8

12

14.4

16.8

19.2

2.5 Dosage in Specific Populations

Pediatric Patients

The recommended initial intubation dose of rocuronium bromide is 0.6 mg/kg; however, a lower dose of 0.45 mg/kg may be used depending on anesthetic technique and the age of the patient.

For sevoflurane (induction) rocuronium bromide doses of 0.45 mg/kg and 0.6 mg/kg in general produce excellent to good intubating conditions within 75 seconds. When halothane is used, a 0.6 mg/kg dose of rocuronium bromide resulted in excellent to good intubating conditions within 60 seconds.

The time to maximum block for an intubating dose was shortest in infants (28 days up to 3 months) and longest in neonates (birth to less than 28 days). The duration of clinical relaxation following an intubating dose is shortest in children (greater than 2 years up to 11 years) and longest in infants.

When sevoflurane is used for induction and isoflurane/nitrous oxide for maintenance of general anesthesia, maintenance dosing of rocuronium bromide can be administered as bolus doses of 0.15 mg/kg at reappearance of T3 in all pediatric age groups. Maintenance dosing can also be administered at the reappearance of T2 at a rate of 7 to 10 mcg/kg/min, with the lowest dose requirement for neonates (birth to less than 28 days) and the highest dose requirement for children (greater than 2 years up to 11 years).

When halothane is used for general anesthesia, patients ranging from 3 months old through adolescence can be administered rocuronium bromide maintenance doses of 0.075 to 0.125 mg/kg upon return of T1 to 0.25% to provide clinical relaxation for 7 to 10 minutes. Alternatively, a continuous infusion of rocuronium bromide initiated at a rate of 12 mcg/kg/min upon return of T1 to 10% (one twitch present in train-of-four), may also be used to maintain neuromuscular blockade in pediatric patients.

Additional information for administration to pediatric patients of all age groups is presented elsewhere in the label [see Clinical Pharmacology (12.2)].

The infusion of rocuronium bromide must be individualized for each patient. The rate of administration should be adjusted according to the patient’s twitch response as monitored with the use of a peripheral nerve stimulator. Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of rocuronium bromide infusion may be expected to proceed at rates comparable to that following similar total exposure to single bolus doses [see Clinical Pharmacology (12.2)].

Rocuronium bromide is not recommended for rapid sequence intubation in pediatric patients.

Geriatric Patients

Geriatric patients (65 years or older) exhibited a slightly prolonged median (range) clinical duration of 46 (22 to 73), 62 (49 to 75), and 94 (64 to 138) minutes under opioid/nitrous oxide/oxygen anesthesia following doses of 0.6, 0.9, and 1.2 mg/kg, respectively. No differences in duration of neuromuscular blockade following maintenance doses of rocuronium bromide were observed between these subjects and younger subjects, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.2) and Clinical Studies (14.2)]. [See also Warnings and Precautions (5.4).]

Patients with Renal or Hepatic Impairment

No differences from patients with normal hepatic and kidney function were observed for onset time at a dose of 0.6 mg/kg rocuronium bromide. When compared to patients with normal renal and hepatic function, the mean clinical duration is similar in patients with end-stage renal disease undergoing renal transplant, and is about 1.5 times longer in patients with hepatic disease. Patients with renal failure may have a greater variation in duration of effect [see Use in Specific Populations (8.6, 8.7) and Clinical Pharmacology (12.3)].

Obese Patients

In obese patients, the initial dose of rocuronium bromide 0.6 mg/kg should be based upon the patient’s actual body weight [see Clinical Studies (14.1)].

An analysis across all U.S. controlled clinical studies indicates that the pharmacodynamics of rocuronium bromide are not different between obese and non-obese patients when dosed based upon their actual body weight.

Patients with Reduced Plasma Cholinesterase Activity

Rocuronium metabolism does not depend on plasma cholinesterase so dosing adjustments are not needed in patients with reduced plasma cholinesterase activity.

Patients with Prolonged Circulation Time

Because higher doses of rocuronium bromide produce a longer duration of action, the initial dosage should usually not be increased in these patients to reduce onset time; instead, in these situations, when feasible, more time should be allowed for the drug to achieve onset of effect [see Warnings and Precautions (5.7)].

Patients with Drugs or Conditions Causing Potentiation of Neuromuscular Block

The neuromuscular blocking action of rocuronium bromide is potentiated by isoflurane and enflurane anesthesia. Potentiation is minimal when administration of the recommended dose of rocuronium bromide occurs prior to the administration of these potent inhalation agents. The median clinical duration of a dose of 0.57 to 0.85 mg/kg was 34, 38, and 42 minutes under opioid/nitrous oxide/oxygen, enflurane and isoflurane maintenance anesthesia, respectively. During 1 to 2 hours of infusion, the infusion rate of rocuronium bromide required to maintain about 95% block was decreased by as much as 40% under enflurane and isoflurane anesthesia [see Drug Interactions (7.3)].

2.6 Preparation for Administration of Rocuronium Bromide Injection

Diluent Compatibility: Rocuronium bromide injection is compatible in solution with:

0.9% NaCl solution

sterile water for injection

5% glucose in water

lactated Ringers

5% glucose in saline

Rocuronium bromide injection is compatible in the above solutions at concentrations up to 5 mg/mL for 24 hours at room temperature in plastic bags, glass bottles, and plastic syringe pumps.

Drug Admixture Incompatibility: Rocuronium bromide injection is physically incompatible when mixed with the following drugs:

amphotericin

hydrocortisone sodium succinate

amoxicillin

insulin

azathioprine

Intralipid

cefazolin

ketorolac

cloxacillin

lorazepam

dexamethasone

methohexital

diazepam

methylprednisolone

erythromycin

thiopental

famotidine

trimethoprim

furosemide

vancomycin

If rocuronium bromide injection is administered via the same infusion line that is also used for other drugs, it is important that this infusion line is adequately flushed between administration of rocuronium bromide and drugs for which incompatibility with rocuronium bromide has been demonstrated or for which compatibility with rocuronium bromide has not been established.

Infusion solutions should be used within 24 hours of mixing. Unused portions of infusion solutions should be discarded.

Rocuronium bromide injection should not be mixed with alkaline solutions [see Warnings and Precautions (5.10)].

Visual Inspection: Parenteral drug products should be inspected visually for particulate matter and clarity prior to administration whenever solution and container permit. Do not use solution if particulate matter is present.
Sotalol Hydrochloride

Sotalol Hydrochloride

2.1 General Rules and Safety Measures of Intravenous Sotalol Therapy

For the safety of the patient, the safety measures required of oral sotalol administration must also be applied for intravenous route. To minimize the risk of induced arrhythmia, patients initiated or re-initiated on sotalol should be hospitalized for at least three days or until steady state drug levels are achieved, in a facility that can provide cardiac resuscitation and continuous electrocardiographic monitoring. Initiate intravenous sotalol therapy in the presence of personnel trained in the management of serious ventricular arrhythmias. Perform a baseline ECG to determine the QT interval and measure and normalize serum potassium and magnesium levels before initiating therapy with starting sotalol injection. Measure serum creatinine and calculate an estimated creatinine clearance in order to establish the appropriate dosing interval for sotalol.

If the baseline QT is greater than 450 ms (JT >330 ms if QRS over 100 ms), sotalol is not recommended.

The patient's creatinine clearance should be calculated using the one of several formulas. The Cockcroft-Gault formula to determine creatinine clearance is:

Creatinine clearance (male) =

(140-age) × body weight in kg

72 × serum creatinine (mg/dL)

Creatinine clearance (female) =

(140-age) × body weight in kg ×0.85

72 × serum creatinine (mg/dL)

When serum creatinine is given in µmol/L, divide the value by 88.4 (1 mg/dL = 88.4 µmol/L).

Start sotalol therapy only if the baseline QT interval is <450 ms. During initiation and titration, monitor the QT interval after the completion of each infusion If the QT interval prolongs to 500 ms or greater, reduce the dose, decrease the infusion rate, or discontinue the drug.

Administer sotalol twice daily in patients with a creatinine clearance >60 mL/min or once daily) in patients with a creatinine clearance between 40 and 60 mL/min. Sotalol is not recommended in patients with a creatinine clearance <40 mL/min. The recommended initial IV dose of sotalol is 75 mg (once or twice daily) and is initiated as shown in the dosing algorithm described below. The 75 mg dose can be titrated upward to 112.5 or 150 mg after at least 3 days [see Dosage and Administration (2.5)].

2.2 Dose of Intravenous Sotalol

The bioavailability of oral sotalol is between 90% and 100%. The corresponding dose of intravenous sotalol is, therefore, slightly less than that of the oral dose. The effects of the initial intravenous dose must be monitored and the dose titrated either upward or downward, if needed, based on clinical effect, QT interval, or adverse reactions.
Table 1: Conversion from Oral Sotalol to Intravenous Sotalol Oral dose Once or twice daily Intravenous dose Once or twice daily Administered over 5 hours
80 mg

75 mg (5 mL sotalol injection)

120 mg

112.5 mg (7.5 mL sotalol injection)

160 mg

150 mg (10 mL sotalol injection)

2.3 Preparation of Sotalol Infusion

Intravenous sotalol must be diluted for infusion. Appropriate diluents are saline, 5% dextrose in water (D5W), or Ringer's lactate. Usually, prepare in a volume of 100-250 mL. Use a volumetric infusion pump to infuse intravenous sotalol at a constant rate. The following table compensates for dead space in the infusion set.
Table 2: Sotalol Infusion Preparation to Compensate for Dead Space in Infusion Set Target Dose Sotalol Injection Diluent Volume Prepared Volume to Infuse
75 mg

6 mL

114 mL

120 mL

100 mL

112.5 mg

9 mL

111 mL

100 mL

150 mg

12 mL

108 mL

100 mL

75 mg

6 mL

294 mL

300 mL

250 mL

112.5 mg

9 mL

291 mL

250 mL

150 mg

12 mL

288 mL

250 mL

2.4 Initiation of Intravenous Sotalol Therapy

The starting dose of intravenous sotalol is 75 mg infused over 5 hours once or twice daily based on the creatinine clearance. Monitor ECG for excessive increase in QTc.

2.5 Upward Titration of Dose

If the 75 mg dose of intravenous sotalol does not reduce the frequency of relapses of life threatening ventricular arrhythmias or symptomatic AFIB/AFL and is tolerated without excessive (i.e., to >500 ms) QTc prolongation, increase the dose to 112.5 mg infused over 5 hours, once or twice daily depending upon the creatinine clearance. Continue to monitor QTc during dose escalations.

2.6 Dose for Ventricular Arrhythmias

The recommended initial dose of intravenous sotalol is 75 mg infused over 5 hours, once or twice daily based on creatinine clearance. The dose may be increased in increments of 75 mg/day every 3 days. The usual therapeutic effect is observed with oral doses of 80 to 160 mg once or twice a day (corresponding to 75 to 150 mg intravenous sotalol). Oral doses as high as 240-320 mg once or twice a day (corresponding to 225 to 300 mg intravenous sotalol) have been utilized in patients with refractory life-threatening arrhythmias.

2.7 Dose for Symptomatic AFIB/AFL

In the U.S. multicenter dose-response study, 120 mg orally once or twice a day (corresponding to 112.5 mg intravenous sotalol) was found to be the most effective dose in prolonging the time to ECG-documented symptomatic recurrence of AFIB/AFL. If that dose level, at steady state, does not reduce the frequency of early relapse of arrhythmia and is tolerated without excessive QTc prolongation (>520 ms), increase the dose to 160 mg orally once or twice a day (corresponding to 150 mg intravenous sotalol).

2.8 Dosing and Administration in Children

Intravenous sotalol has not been studied in children. As in adults the following precautionary measures should be considered when initiating sotalol treatment in children: initiation of treatment in the hospital after appropriate clinical assessment; individualized regimen as appropriate; gradual increase of doses if required; careful assessment of therapeutic response and tolerability; and frequent monitoring of the QTc interval and heart rate.

For children aged about 2 years and greater, with normal renal function, doses normalized for body surface area are appropriate for both initial and incremental dosing. Since the Class III potency in children [see Clinical Pharmacology (12.2)] is not very different from that in adults, reaching plasma concentrations that occur within the adult dose range is an appropriate guide. From pediatric pharmacokinetic data the following is recommended. For initiation of treatment, 30 mg/m2 three times a day (90 mg/m2 total daily dose) is approximately equivalent to the initial 160 mg total oral daily dose for adults. Subsequent titration to a maximum of 60 mg/m2 (approximately equivalent to the 360 mg total daily dose for adults) can then occur. Titration should be guided by clinical response, heart rate and QTc, with increased dosing being carried out in-hospital. At least 36 hours should be allowed between dose increments to attain steady-state plasma concentrations of sotalol in patients with age-adjusted normal renal function.

For children about 2 years or younger the above pediatric dosage should be reduced by a factor that depends heavily upon age, as shown in the following graph which shows age plotted on a logarithmic scale in months.

For a child aged 20 months, the dosing suggested for children with normal renal function aged 2 years or greater should be multiplied by about 0.97; the initial starting dose would be (30 × 0.97) = 29.1 mg/m2, administered orally three times daily. For a child aged 1 month, the starting dose should be multiplied by 0.68; the initial starting dose would be (30 × 0.68) = 20 mg/m2, administered orally three times daily. For a child aged 1 week, the initial starting oral dose should be multiplied by 0.3; the starting dose would be (30 × 0.3) = 9 mg/m2. Similar calculations should be made for increased doses as titration proceeds. Since the half-life of sotalol decreases with decreasing age (below about 2 years), time to steady-state will also increase. Thus, in neonates the time to steady-state may be as long as a week or longer.

In all children, individualization of dosage is required. As in adults sotalol should be used with particular caution in children if the QTc is greater than 500 ms on therapy and serious consideration should be given to reducing the dose or discontinuing therapy when QTc exceeds 550 ms.

The use of oral sotalol in children with renal impairment has not been investigated. Sotalol elimination is predominantly via the kidney in the unchanged form. Use of sotalol in any age group with decreased renal function should be at lower doses or at increased intervals between doses. Monitoring of heart rate and QTc is most important. It will take much longer to reach steady-state with any dose and/or frequency of administration in these children.
Salicylic Acid

Salicylic Acid

Vecuronium bromide for injection is for intravenous use only.

This drug should be administered by or under the supervision of experienced clinicians familiar with the use of neuromuscular blocking agents. Dosage must be individualized in each case. The dosage information which follows is derived from studies based upon units of drug per unit of body weight and is intended to serve as a guide only, especially regarding enhancement of neuromuscular blockade of vecuronium bromide by volatile anesthetics and by prior use of succinylcholine (see PRECAUTIONS, Drug Interactions).

To obtain maximum clinical benefits of vecuronium bromide and to minimize the possibility of overdosage, the monitoring of muscle twitch response to peripheral nerve stimulation is advised.

The recommended initial dose of vecuronium bromide is 0.08 to 0.1 mg/kg (1.4 to 1.75 times the ED90) given as an intravenous bolus injection. This dose can be expected to produce good or excellent non-emergency intubation conditions in 2.5 to 3 minutes after injection. Under balanced anesthesia, clinically required neuromuscular blockade lasts approximately 25 to 30 minutes, with recovery to 25% of control achieved approximately 25 to 40 minutes after injection and recovery to 95% of control achieved approximately 45 to 65 minutes after injection. In the presence of potent inhalation anesthetics, the neuromuscular blocking effect of vecuronium bromide is enhanced. If vecuronium bromide is first administered more than 5 minutes after the start of inhalation agent or when steady-state has been achieved, the initial vecuronium bromide dose may be reduced by approximately 15%, i.e., 0.06 to 0.085 mg/kg.

Prior administration of succinylcholine may enhance the neuromuscular blocking effect and duration of action of vecuronium bromide. If intubation is performed using succinylcholine, a reduction of initial dose of vecuronium bromide to 0.04 to 0.06 mg/kg with inhalation anesthesia and 0.05 to 0.06 mg/kg with balanced anesthesia may be required.

During prolonged surgical procedures, maintenance doses of 0.01 to 0.015 mg/kg of vecuronium bromide are recommended; after the initial vecuronium bromide injection, the first maintenance dose will generally be required within 25 to 40 minutes. However, clinical criteria should be used to determine the need for maintenance doses.

Since vecuronium bromide lacks clinically important cumulative effects, subsequent maintenance doses, if required, may be administered at relatively regular intervals for each patient, ranging approximately from 12 to 15 minutes under balanced anesthesia, slightly longer under inhalation agents. (If less frequent administration is desired, higher maintenance doses may be administered.)

Should there be reason for the selection of larger doses in individual patients, initial doses ranging from 0.15 mg/kg up to 0.28 mg/kg have been administered during surgery under halothane anesthesia without ill effects to the cardiovascular system being noted as long as ventilation is properly maintained (see CLINICAL PHARMACOLOGY, Pharmacokinetics).

Use by Continuous Infusion

After an intubating dose of 80 to 100 mcg/kg, a continuous infusion of 1 mcg/kg/min can be initiated approximately 20 to 40 minutes later. Infusion of vecuronium bromide should be initiated only after early evidence of spontaneous recovery from the bolus dose. Long-term intravenous infusion to support mechanical ventilation in the intensive care unit has not been studied sufficiently to support dosage recommendations. (See PRECAUTIONS, Long Term Use in ICU.)

The infusion of vecuronium bromide should be individualized for each patient. The rate of administration should be adjusted according to the patient's twitch response as determined by peripheral nerve stimulation. An initial rate of 1 mcg/kg/min is recommended, with the rate of the infusion adjusted thereafter to maintain a 90% suppression of twitch response. Average infusion rates may range from 0.8 to 1.2 mcg/kg/min.

Inhalation anesthetics, particularly enflurane and isoflurane may enhance the neuromuscular blocking action of nondepolarizing muscle relaxants. In the presence of steady state concentrations of enflurane or isoflurane, it may be necessary to reduce the rate of infusion 25 to 60 percent, 45 to 60 minutes after the intubating dose. Under halothane anesthesia it may not be necessary to reduce the rate of infusion.

Spontaneous recovery and reversal of neuromuscular blockade following discontinuation of vecuronium bromide infusion may be expected to proceed at rates comparable to that following a single bolus dose (see CLINICAL PHARMACOLOGY).

Infusion solutions of vecuronium bromide can be prepared by adding vecuronium bromide with an appropriate infusion solution such as Dextrose 5% Injection, Sodium Chloride 0.9% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, or Lactated Ringer's Injection.

Unused portions of infusion solutions should be discarded.

Infusion rates of vecuronium bromide can be individualized for each patient using the following table:
*10 mg of Vecuronium bromide in 100 mL solution ‡20 mg of Vecuronium bromide in 100 mL solution
Drug Delivery Rate(mcg/kg/min)

Infusion Delivery Rate

(mL/kg/min)

0.1 mg/mL*

0.2 mg/mL‡

0.7

0.007

0.0035

0.8

0.008

0.0040

0.9

0.009

0.0045

1.0

0.010

0.0050

1.1

0.011

0.0055

1.2

0.012

0.0060

1.3

0.013

0.0065

The following table is a guideline for mL/min delivery for a solution of 0.1 mg/mL (10 mg in 100 mL) with an infusion pump.
VECURONIUM BROMIDE INFUSION RATE - mL/min NOTE: If a concentration of 0.2 mg/mL is used (20 mg in 100 mL), the rate should be decreased by one half.
Amount of Drugmcg/kg/min

Patient Weight - kg

40

50

60

70

80

90

100

0.7

0.28

0.35

0.42

0.49

0.56

0.63

0.70

0.8

0.32

0.40

0.48

0.56

0.64

0.72

0.80

0.9

0.36

0.45

0.54

0.63

0.72

0.81

0.90

1.0

0.40

0.50

0.60

0.70

0.80

0.90

1.00

1.1

0.44

0.55

0.66

0.77

0.88

0.99

1.10

1.2

0.48

0.60

0.72

0.84

0.96

1.08

1.20

1.3

0.52

0.65

0.78

0.91

1.04

1.17

1.30

Use in Pediatrics

Pediatric patients (10 to 16 years of age) have approximately the same dosage requirements (mg/kg) as adults and may be managed the same way. Younger pediatric patients (1 to 10 years of age) may require a slightly higher initial dose and may also require supplementation slightly more often than adults.

Infants under 1 year of age but older than 7 weeks are moderately more sensitive to vecuronium bromide on a mg/kg basis than adults and take about 1 1/2 times as long to recover. See also subsection of PRECAUTIONS titled Pediatric Use. Information presently available does not permit recommendation on usage in pediatric patients less then 7 weeks of age (see PRECAUTIONS - Pediatric Use). There are insufficient data concerning continuous infusion of vecuronium in pediatric patients, therefore, no dosing recommendations can be made.

COMPATIBILITY

Vecuronium bromide is compatible in solution with:

Sodium Chloride 0.9% Injection

Dextrose 5% Injection

Sterile Water for Injection

Dextrose 5% in Sodium Chloride 0.9% Injection

Lactated Ringer's Injection

Use within 24 hours of mixing with the above solutions.

Vecuronium bromide is also compatible in solution with:

Bacteriostatic Water for Injection (NOT FOR USE IN NEWBORNS)

Use within 5 days of mixing with the above solution.

Reconstituted vecuronium bromide, which has an acid pH, should not be mixed with alkaline solutions (e.g., barbiturate solutions such as thiopental) in the same syringe or administered simultaneously during intravenous infusion through the same needle or through the same intravenous line.

After Reconstitution

See DOSAGE AND ADMINISTRATION-COMPATIBILITY for diluents compatible with Vecuronium Bromide for Injection.

Single-Dose Use

When reconstituted with compatible IV solutions not containing an antimicrobial preservative (e.g., Sterile Water for Injection), refrigerate and use within 24 hours. Discard unused portion.

Multi-Dose Use (NOT FOR USE IN NEWBORNS)

When reconstituted with bacteriostatic Water for Injection, use within 5 days. The reconstituted solution may be stored at room temperature or refrigerated.

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

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