Amphotericin b

INDICATIONS AND USAGE Amphotericin B liposome for injection is indicated for the following: Empirical therapy for presumed fungal infection in febrile, neutropenic patients. Treatment of Cryptococcal Meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES) . Treatment of patients with Aspergillus species, Candida species and/or Cryptococcus species infections (see above for the treatment of Cryptococcal Meningitis) refractory to amphotericin B deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate. Treatment of visceral leishmaniasis. In immunocompromised patients with visceral leishmaniasis treated with amphotericin B liposome for injection, relapse rates were high following initial clearance of parasites (see DESCRIPTION OF CLINICAL STUDIES) . See DOSAGE AND ADMINISTRATION for recommended doses by indication.

DOSAGE AND ADMINISTRATION Amphotericin B liposome for injection is not interchangeable or substitutable on a mg per mg basis with other amphotericin B products. Different amphotericin B products are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing. Amphotericin B liposome for injection should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes. An in-line membrane filter may be used for the intravenous infusion of amphotericin B liposome for injection, provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON. NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of amphotericin B liposome for injection. If this is not feasible, amphotericin B liposome for injection must be administered through a separate line. Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended initial dose of amphotericin B liposome for injection for each indication for adult and pediatric patients is as follows: Indication Dose (mg/kg/day) Empirical therapy 3 Systemic fungal infections: Aspergillus Candida Cryptococcus 3 to 5 Cryptococcal meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES ) 6 Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events. Doses recommended for visceral leishmaniasis are presented below: Visceral Leishmaniasis Dose (mg/kg/day) Immunocompetent patients 3 (days 1 to 5) and 3 on days 14, 21 Immunocompromised patients 4 (days 1 to 5) and 4 on days 10, 17, 24, 31, 38 For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful. For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information, see DESCRIPTION OF CLINICAL STUDIES. Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution Amphotericin B liposome for injection must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of amphotericin B liposome for injection containing 50 mg of amphotericin B are prepared as follows: Reconstitution 1. Aseptically add 12 mL of Sterile Water for Injection, USP to each amphotericin B liposome for injection vial to yield a preparation containing 4 mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of amphotericin B liposome for injection. 2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the amphotericin B liposome for injection. Amphotericin B liposome for injection forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. Filtration and Dilution 3. Calculate the amount of reconstituted (4 mg/mL) amphotericin B liposome for injection to be further diluted. 4. Withdraw this amount of reconstituted amphotericin B liposome for injection into a sterile syringe. 5. Attach the 5-micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection (use only one filter per vial of amphotericin B liposome for injection). 6. Amphotericin B liposome for injection must be diluted with 5% Dextrose Injection to a final concentration of 1 mg/mL to 2 mg/mL prior to administration. Lower concentrations (0.2 mg/mL to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS. STORAGE OF AMPHOTERICIN B LIPOSOME FOR INJECTION Unopened vials of lyophilized material are to be stored at temperatures 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Storage of Reconstituted Product Concentrate The reconstituted product concentrate may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) following reconstitution with Sterile Water for Injection, USP. Do not freeze. Storage of Diluted Product Amphotericin B liposome for injection should commence within 6 hours of dilution with 5% Dextrose Injection. As with all parenteral drug products, the reconstituted amphotericin B liposome for injection should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if the

ADVERSE REACTIONS The following adverse events are based on the experience of 592 adult patients (295 treated with amphotericin B liposome for injection and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with amphotericin B liposome for injection and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multicenter study in febrile, neutropenic patients. Amphotericin B liposome for injection and amphotericin B were infused over two hours. The incidence of common adverse events (incidence of 10% or greater) occurring with amphotericin B liposome for injection compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table: Empirical Therapy Study 94-0-002 Common Adverse Events Adverse Event by Body System Amphotericin B Liposome for Injection N=343 % Amphotericin B N=344 % Body as a Whole Abdominal pain 19.8 21.8 Asthenia 13.1 10.8 Back pain 12 7.3 Blood product transfusion reaction 18.4 18.6 Chills 47.5 75.9 Infection 11.1 9.3 Pain 14 12.8 Sepsis 14 11.3 Cardiovascular System Chest pain 12 11.6 Hypertension 7.9 16.3 Hypotension 14.3 21.5 Tachycardia 13.4 20.9 Digestive System Diarrhea 30.3 27.3 Gastrointestinal hemorrhage 9.9 11.3 Nausea 39.7 38.7 Vomiting 31.8 43.9 Metabolic and Nutritional Disorders Alkaline phosphatase increased 22.2 19.2 ALT (SGPT) increased 14.6 14 AST (SGOT) increased 12.8 12.8 Bilirubinemia 18.1 19.2 BUN increased 21 31.1 Creatinine increased 22.4 42.2 Edema 14.3 14.8 Hyperglycemia 23 27.9 Hypernatremia 4.1 11 Hypervolemia 12.2 15.4 Hypocalcemia 18.4 20.9 Hypokalemia 42.9 50.6 Hypomagnesemia 20.4 25.6 Peripheral edema 14.6 17.2 Nervous System Anxiety 13.7 11 Confusion 11.4 13.4 Headache 19.8 20.9 Insomnia 17.2 14.2 Respiratory System Cough increased 17.8 21.8 Dyspnea 23 29.1 Epistaxis 14.9 20.1 Hypoxia 7.6 14.8 Lung disorder 17.8 17.4 Pleural effusion 12.5 9.6 Rhinitis 11.1 11 Skin and Appendages Pruritus 10.8 10.2 Rash 24.8 24.4 Sweating 7 10.8 Urogenital System Hematuria 14 14 Amphotericin B liposome for injection was well tolerated. Amphotericin B liposome for injection had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate. In pediatric patients (16 years of age or less) in this double-blind study, amphotericin B liposome for injection compared to amphotericin B deoxycholate, had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with amphotericin B liposome for injection and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate. The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with amphotericin B liposome for injection 3 mg/kg, 81 patients were treated with amphotericin B liposome for injection 5 mg/kg and 78 patients were treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized, double-blind, multicenter study in febrile, neutropenic patients. Amphotericin B liposome for injection and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms, regardless of relationship to study drug, are summarized in the following table: Empirical Therapy Study 97-0-034 Common Adverse Events Adverse Event by Body System Amphotericin B Liposome for Injection 3 mg/kg/day N=85 % Amphotericin B Liposome for Injection 5 mg/kg/day N=81 % Amphotericin B Lipid Complex 5 mg/kg/day N=78 % Body as a Whole Abdominal pain 12.9 9.9 11.5 Asthenia 8.2 6.2 11.5 Chills/rigors 40 48.1 89.7 Sepsis 12.9 7.4 11.5 Transfusion reaction 10.6 8.6 5.1 Cardiovascular System Chest pain 8.2 11.1 6.4 Hypertension 10.6 19.8 23.1 Hypotension 10.6 7.4 19.2 Tachycardia 9.4 18.5 23.1 Digestive System Diarrhea 15.3 17.3 14.1 Nausea 25.9 29.6 37.2 Vomiting 22.4 25.9 30.8 Metabolic and Nutritional Disorders Alkaline phosphatase increased 7.1 8.6 12.8 Bilirubinemia 16.5 11.1 11.5 BUN increased 20 18.5 28.2 Creatinine increased 20 18.5 48.7 Edema 12.9 12.3 12.8 Hyperglycemia 8.2 8.6 14.1 Hypervolemia 8.2 11.1 14.1 Hypocalcemia 10.6 4.9 5.1 Hypokalemia 37.6 43.2 39.7 Hypomagnesemia 15.3 25.9 15.4 Liver function tests abnormal 10.6 7.4 11.5 Nervous System Anxiety 10.6 7.4 9 Confusion 12.9 8.6 3.8 Headache 9.4 17.3 10.3 Respiratory System Dyspnea 17.6 22.2 23.1 Epistaxis 10.6 8.6 14.1 Hypoxia 7.1 6.2 20.5 Lung disorder 14.1 13.6 15.4 Skin and Appendages Rash 23.5 22.2 14.1 The following adve

Drug Interactions No formal clinical studies of drug interactions have been conducted with amphotericin B liposome for injection; however, the following drugs are known to interact with amphotericin B and may interact with amphotericin B liposome for injection: Antineoplastic Agents Concurrent use of antineoplastic agents may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with caution. Corticosteroids and Corticotropin (ACTH) Concurrent use of corticosteroids and ACTH may potentiate hypokalemia, which could predispose the patient to cardiac dysfunction. If used concomitantly, serum electrolytes and cardiac function should be closely monitored. Digitalis Glycosides Concurrent use may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly, serum potassium levels should be closely monitored. Flucytosine Concurrent use of flucytosine may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Azoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.) In vitro and in vivo animal studies of the combination of amphotericin B and imidazoles suggest that imidazoles may induce fungal resistance to amphotericin B. Combination therapy should be administered with caution, especially in immunocompromised patients. Leukocyte Transfusions Acute pulmonary toxicity has been reported in patients simultaneously receiving intravenous amphotericin B and leukocyte transfusions. Other Nephrotoxic Medications Concurrent use of amphotericin B and other nephrotoxic medications may enhance the potential for drug-induced renal toxicity. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications. Skeletal Muscle Relaxants Amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g. tubocurarine) due to hypokalemia. When administered concomitantly, serum potassium levels should be closely monitored.