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. DESCRIPTION OF CLINICAL STUDIES Eleven clinical studies supporting the efficacy and safety of amphotericin B liposome for injection were conducted. This clinical program included both controlled and uncontrolled studies. These studies, which involved 2,171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis. Nineteen hundred and forty-six (1946) episodes were evaluable for efficacy, of which 1,280 (302 pediatric and 978 adults) were treated with amphotericin B liposome for injection. Three controlled empirical therapy trials compared the efficacy and safety of amphotericin B liposome for injection to amphotericin B. One of these studies was conducted in a pediatric population, one in adults, and a third in patients aged 2 years or more. In addition, a controlled empirical therapy trial comparing the safety of amphotericin B liposome for injection to Abelcet ® (amphotericin B lipid complex) was conducted in patients aged 2 years or more. One controlled trial compared the efficacy and safety of amphotericin B liposome for injection to amphotericin B in HIV patients with cryptococcal meningitis. One compassionate use study enrolled patients who had failed amphotericin B deoxycholate therapy or who were unable to receive amphotericin B deoxycholate because of renal insufficiency. Empirical Therapy in Febrile Neutropenic Patients Study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin B liposome for injection (1.5 to 6 mg/kg/day) compared with amphotericin B deoxycholate (0.3 to 1.2 mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. Therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7 days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection. The overall therapeutic success rates for amphotericin B liposome for injection and the amphotericin B deoxycholate were equivalent. Results are summarized in the following table. Note: The categories presented below are not mutually exclusive. Empirical Therapy in Febrile Neutropenic Patients: Randomized, Double-Blind Study in 687 Patients Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Number of patients receiving at least one dose of study drug 343 344 Overall Success 171 (49.9%) 169 (49.1%) Fever resolution during neutropenic period 199 (58%) 200 (58.1%) No treatment-emergent fungal infection 300 (87.5%) 301 (87.7%) Survival through 7 days post study drug 318 (92.7%) 308 (89.5%) Study drug not prematurely discontinued due to toxicity or lack of efficacy* 294 (85.7%) 280 (81.4%) * 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone. This therapeutic equivalence had no apparent relati …

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 …

CONTRAINDICATIONS Amphotericin B liposome for injection is contraindicated in those patients who have demonstrated or have a known hypersensitivity to amphotericin B deoxycholate or any other constituents of the product unless, in the opinion of the treating physician, the benefit of therapy outweighs the risk.

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 …

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.

Mechanism of Action Amphotericin B, the active ingredient of amphotericin B liposome for injection, acts by binding to the sterol component, ergosterol, of the cell membrane of susceptible fungi. It forms transmembrane channels leading to alterations in cell permeability through which monovalent ions (Na + , K + , H + , and Cl - ) leak out of the cell resulting in cell death. While amphotericin B has a higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. Amphotericin B liposome for injection, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi.

DESCRIPTION Amphotericin B liposome for injection is a sterile, non-pyrogenic lyophilized product for intravenous infusion. Each vial contains amphotericin B, USP 50 milligrams (mg), intercalated into a liposomal membrane consisting of alpha tocopherol approximately 0.64 mg; cholesterol 52 mg; distearoylphosphatidylglycerol, sodium salt 84 mg; hydrogenated soy phosphatidylcholine 213 mg, together with disodium succinate hexahydrate 27 mg; and sucrose 900 mg. Amphotericin B liposome for injection may also contain hydrochloric acid and/or sodium hydroxide as pH adjusters. Following reconstitution with Sterile Water for Injection, the resulting pH of the suspension is between 5.0 to 6.0. Amphotericin B liposome for injection is a true single bilayer liposomal drug delivery system. Liposomes are closed, spherical vesicles created by mixing specific proportions of amphophilic substances such as phospholipids and cholesterol so that they arrange themselves into multiple concentric bilayer membranes when hydrated in aqueous solutions. Single bilayer liposomes are then formed by microemulsification of multilamellar vesicles using a homogenizer. Amphotericin B liposome for injection consists of these unilamellar bilayer liposomes with amphotericin B intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin B molecule, the drug is an integral part of the overall structure of the Amphotericin B liposomes. Amphotericin B liposome for injection contains true liposomes that are less than 100 nm in diameter. A schematic depiction of the liposome is presented below. Note: Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug’s functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with a common active ingredient may vary from one another in the chemical composition and physical form of the lipid component. Such differences may affect the functional properties of these drug products. Amphotericin B is a macrocyclic, polyene, antifungal antibiotic produced from a strain of Streptomyces nodosus . Amphotericin B is designated chemically as: [1R-(1R*,3S*,5R*,6R*,9R*,11R*,15S*,16R*,17R*,18S*, 19E,21E,23E,25E,27E,29E,31E,33R*,35S*,36R*,37S*)]-33-[(3-Amino-3,6-dideoxy-ß-D-mannopyranosyl)oxy]-1,3,5,6,9,11,17,37-octahydroxy-15,16,18-trimethyl-13-oxo-14,39-dioxabicyclo-[33.3.1]nonatriaconta-19,21,23,25,27,29,31-heptaene-36-carboxylic acid (CAS No.1397-89-3). Amphotericin B has a molecular formula of C 47 H 73 NO 17 and a molecular weight of 924.09 g/mol. The structure of amphotericin B is shown below: spl-ampho-lipo-structure spl-amphotercin-structure

OVERDOSAGE The toxicity of amphotericin B liposome for injection due to overdose has not been defined. Repeated daily doses up to 10 mg/kg in pediatric patients and 15 mg/kg in adult patients have been administered in clinical trials with no reported dose-related toxicity. Management If overdosage should occur, cease administration immediately. Symptomatic supportive measures should be instituted. Particular attention should be given to monitoring renal function. Hemodialysis or peritoneal dialysis do not appear to significantly affect the elimination of amphotericin B liposome for injection.

HOW SUPPLIED Amphotericin B liposome for injection, 50 mg/vial is supplied as yellow colored lyophilized mass, available in single carton (NDC 62756-954-01) and in packs of ten individual vial cartons (NDC 62756-954-02). Each carton contains one pre-packaged, disposable sterile 5 micron filter. Discard unused portion. * All trademarks are the property of their respective owners. PREMIERProRx® is a registered trademark of Premier Healthcare Alliance, L.P., used under license. Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 Manufactured by: Sun Pharmaceutical Industries Limited Baska Ujeti Road, Ujeti Halol-389350, Gujarat, India. ISS. 04/2026