AMPHOTERICIN B: 10,797 Adverse Event Reports & Safety Profile

DESCRIPTION Amphotericin B liposome for injection is a sterile, non-pyrogenic, yellow lyophilized product for intravenous infusion. Each vial contains amphotericin B, USP, 50 milligrams (mg), intercalated into a liposomal membrane consisting of alpha tocopherol, USP approximately 0.64 mg; cholesterol, NF, 52 mg; distearoyl phosphatidylglycerol sodium salt 86.48 mg; hydrogenated soy phosphatidylcholine 213 mg, together with disodium succinate hexahydrate, NF, 27 mg; and sucrose, NF, 900 mg. Amphotericin B liposome for injection may also contain hydrochloric acid and/or sodium hydroxide as pH adjusters.

Each

1 mL of reconstituted Amphotericin B liposome for injection contains 1 mg of sodium and less than 5 mg of phosphorus. Following reconstitution with Sterile Water for Injection, USP, the resulting pH of the suspension is between 5-6. 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-β-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 924.08. The structure of amphotericin B is shown below: schematic depiction of the liposome Chemical structure of amphotericin B

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 (1.5-6 mg/kg/day) compared with amphotericin B deoxycholate (0.3-1.2 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 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone. 294 (85.7%) 280 (81.4%) This therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors. The incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. Amphotericin B liposome for injection and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections.

Empirical

Therapy in Febrile Neutropenic Patients: Emergent Fungal Infections 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 Mycologically-confirmed fungal infection 11 (3.2%) 27 (7.8%) Clinically-diagnosed fungal infection 32 (9.3%) 16 (4.7%) Total emergent fungal infections 43 (12.5%) 43 (12.5%) Mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the amphotericin B liposome for injection group and 7 of 10 in the amphotericin B group.

Study

97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of amphotericin B liposome for injection (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six (166) patients received amphotericin B liposome for injection (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, Abelcet is not labeled for this indication. Two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of amphotericin B liposome for injection (1 and 3 mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease.

Study

104-10 enrolled adult patients (n = 134).

Study

104-14 enrolled pediatric patients (n = 214). Both studies support the efficacy equivalence of amphotericin B liposome for injection and amphotericin B as empirical therapy in febrile neutropenic patients. Treatment of Cryptococcal Meningitis in HIV-Infected Patients Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin B liposome for injection at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV-positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received amphotericin B liposome for injection 3 mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76 patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14 ± 4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for amphotericin B liposome for injection and amphotericin B deoxycholate are summarized in the following table: Success Rates at 2 Weeks (CSF Culture Conversion)

Study

94-0-013 Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success at Week 2 35/60 (58.3%) 97.5% CI 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B success rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection. = -9.4%, +31% 36/75 (48%) 97.5% CI = -18.8%, +19.8% 29/61 (47.5%) Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of amphotericin B liposome for injection 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that amphotericin B liposome for injection 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study.

Success

Rates and Survival Rates at Week 10, Study 94-0-013 (see text for definitions) Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success in patients with documented cryptococcal meningitis 27/73 (37%) 97.5% CI 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection. = -33.7%, +2.4% 42/85 (49%) 97.5% CI = -20.9%, +14.5% 40/76 (53%) Survival rates 74/86 (86%) 97.5% CI = -13.8%, +8.9% 85/94 (90%) 97.5% CI = -8.3%, +12.2% 77/87 (89%) The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving amphotericin B liposome for injection compared to amphotericin B deoxycholate (see ADVERSE REACTIONS section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen. Treatment of Patients with Aspergillus Species, Candida Species and/or Cryptococcus Species Infections Refractory to Amphotericin B Deoxycholate, or in Patients Where Renal Impairment or Unacceptable Toxicity Precludes the Use of Amphotericin B Deoxycholate Amphotericin B liposome for injection was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis. Treatment of Visceral Leishmaniasis Amphotericin B liposome for injection was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum . Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi . Amphotericin B liposome for injection achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12-30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30-40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV-infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients: Amphotericin B Liposome for Injection Efficacy in Visceral Leishmaniasis Immunocompetent Patients No. of Patients Parasite (%) Clearance at EOT Overall Success (%) at F/U 87 86/87 (98.9) 83/86 (96.5)

Immunocompromised Patients Regimen Total Dose

Parasite (%) Clearance at EOT Overall Success (%) at F/U 100 mg/day X 21 days 29 to 38.9 mg/kg 10/10 (100) 2/10 (20) 4 mg/kg/day, days 1 to 5, and 10, 17, 24, 31, 38 40 mg/kg 8/9 (88.9) 0/7 (0) TOTAL 18/19 (94.7) 2/17 (11.8) When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of amphotericin B liposome for injection or of maintenance therapy with this drug among immunocompromised patients.

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 relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors. The incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. Amphotericin B liposome for injection and amphotericin B were found to be equivalent with respect to the total number of emergent fungal infections.

Empirical

Therapy in Febrile Neutropenic Patients: Emergent Fungal Infections 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 Mycologically-confirmed fungal infection 11 (3.2%) 27 (7.8%) Clinically-diagnosed fungal infection 32 (9.3%) 16 (4.7%) Total emergent fungal infections 43 (12.5%) 43 (12.5%) Mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the amphotericin B liposome for injection group and 7 of 10 in the amphotericin B group.

Study

97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of amphotericin B liposome for injection (3 and 5 mg/kg/day) compared with amphotericin B lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. One hundred and sixty-six (166) patients received amphotericin B liposome for injection (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin B lipid complex. The study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. The primary endpoint of this study was safety. The study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, Abelcet is not labeled for this indication. Two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of amphotericin B liposome for injection (1 and 3 mg/kg/day) compared to amphotericin B deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. These patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease.

Study

104-10 enrolled adult patients (n = 134).

Study

104-14 enrolled pediatric patients (n = 214). Both studies support the efficacy equivalence of amphotericin B liposome for injection and amphotericin B as empirical therapy in febrile neutropenic patients. Treatment of Cryptococcal Meningitis in HIV-Infected Patients Study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin B liposome for injection at doses (3 and 6 mg/kg/day) compared with amphotericin B deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric HIV-positive patients (the pediatric patient received amphotericin B deoxycholate). Of the 267 treated patients, 86 received amphotericin B liposome for injection 3 mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin B deoxycholate; cryptococcal meningitis was documented by a positive CSF culture at baseline in 73, 85 and 76 patients, respectively. Patients received study drug once daily for an induction period of 11 to 21 days. Following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. For mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline CSF culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14 ± 4 days), and was defined as CSF culture conversion. Success rates at 2 weeks for amphotericin B liposome for injection and amphotericin B deoxycholate are summarized in the following table: Success Rates at 2 Weeks (CSF Culture Conversion)

Study

94-0-013 Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success at Week 2 35/60 (58.3%) 97.5% CI * = -9.4%, +31% 36/75 (48%) 97.5% CI * = -18.8%, + 19.8% 29/61 (47.5%) * 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B success rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection. Success at 10 weeks was defined as clinical success at week 10 plus CSF culture conversion at or prior to week 10. Success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of amphotericin B liposome for injection 6 mg/kg/day approximates the efficacy of the amphotericin B deoxycholate regimen. These data do not support the conclusion that amphotericin B liposome for injection 3 mg/kg/day is comparable in efficacy to amphotericin B deoxycholate. The table also presents 10-week survival rates for patients treated in this study.

Success

Rates and Survival Rates at Week 10, Study 94-0-013 (see text for definitions) Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Success in patients with documented cryptococcal meningitis 27/73 (37%) 97.5% CI * = -33.7%, +2.4% 42/85 (49%) 97.5% CI * = -20.9%, +14.5% 40/76 (53%) Survival rates 74/86 (86%) 97.5% CI * = -13.8%, +8.9% 85/94 (90%) 97.5% CI * = -8.3%, +12.2% 77/87 (89%) * 97.5% Confidence Interval for the difference between amphotericin B liposome for injection and amphotericin B rates. A negative value is in favor of amphotericin B. A positive value is in favor of amphotericin B liposome for injection. The incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving amphotericin B liposome for injection compared to amphotericin B deoxycholate (see ADVERSE REACTIONS section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin B formulations should be taken into consideration when selecting a patient treatment regimen. Treatment of Patients with Aspergillus Species, Candida Species and/or Cryptococcus Species Infections Refractory to Amphotericin B Deoxycholate, or in Patients Where Renal Impairment or Unacceptable Toxicity Precludes the Use of Amphotericin B Deoxycholate Amphotericin B liposome for injection was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. These patients either had fungal infections refractory to amphotericin B deoxycholate, were intolerant to the use of amphotericin B deoxycholate, or had pre-existing renal insufficiency. Patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. Clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis. Treatment of Visceral Leishmaniasis Amphotericin B liposome for injection was studied in patients with visceral leishmaniasis who were infected in the Mediterranean basin with documented or presumed Leishmania infantum . Clinical studies have not provided conclusive data regarding efficacy against L. donovani or L. chagasi . Amphotericin B liposome for injection achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12 to 30 mg/kg were administered. Most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. While acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30 to 40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. Of the 21 immunocompromised patients studied, 17 were coinfected with HIV; approximately half of the HIV-infected patients had AIDS. The following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the Mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. Efficacy is expressed as both acute parasite clearance at the end of therapy (EOT) and as overall success (clearance with no relapse) during the follow-up period (F/U) of greater than 6 months for immunocompetent and immunocompromised patients: Amphotericin B Liposome for Injection Efficacy in Visceral Leishmaniasis Immunocompetent Patients No. of Patients Parasite (%) Clearance at EOT Overall Success (%) at F/U 87 86/87 (98.9) 83/86 (96.5)

Immunocompromised Patients Regimen Total Dose

Parasite (%) Clearance at EOT Overall Success (%) at F/U 100 mg/day X 21 days 29 to 38.9 mg/kg 10/10 (100) 2/10 (20) 4 mg/kg/day, days 1 to 5, and 10, 17, 24, 31, 38 40 mg/kg 8/9 (88.9) 0/7 (0) TOTAL 18/19 (94.7) 2/17 (11.8) When followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. While case reports have suggested there may be a role for long-term therapy to prevent relapses in HIV coinfected patients (Lopez-Dupla, et al. J Antimicrob Chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of amphotericin B liposome for injection or of maintenance therapy with this drug among immunocompromised patients.

DOSAGE & ADMINISTRATION ** VERIFY PRODUCT NAME AND DOSAGE. ** CAUTION: Under no circumstances should a total daily dose of 1.5 mg/kg be exceeded. Amphotericin B overdoses can result in potentially fatal cardiac or cardiopulmonary arrest (see WARNINGS and OVERDOSAGE ). Amphotericin B for Injection should be administered by slow intravenous infusion. Intravenous infusion should be given over a period of approximately 2 to 6 hours (depending on the dose) observing the usual precautions for intravenous therapy (see PRECAUTIONS: General ). The recommended concentration for intravenous infusion is 0.1 mg/mL (1mg/10mL). Since patient tolerance varies greatly, the dosage of amphotericin B must be individualized and adjusted according to the patient's clinical status (e.g., site and severity of infection, etiologic agent, cardio-renal function, etc.). A single intravenous test dose (1 mg in 20 mL of 5% dextrose solution) administered over 20 to 30 minutes may be preferred. The patient's temperature, pulse, respiration, and blood pressure should be recorded every 30 minutes for 2 to 4 hours. In patients with good cardio-renal function and a well tolerated test dose , therapy is usually initiated with a daily dose of 0.25 mg/kg of body weight. However, in those patients having severe and rapidly progressive fungal infection , therapy may be initiated with a daily dose of 0.3 mg/kg of body weight. In patients with impaired cardio-renal function or a severe reaction to the test dose , therapy should be initiated with smaller daily doses (i.e., 5 to 10 mg). Depending on the patient's cardio-renal status (see PRECAUTIONS: Laboratory Tests ), doses may gradually be increased by 5 to 10 mg per day to final daily dosage of 0.5 to 0.7 mg/kg. There are insufficient data presently available to define total dosage requirements and duration of treatment necessary for eradication of specific mycoses. The optimal dose is unknown. Total daily dosage may range up to 1.0 mg/kg per day or up to 1.5 mg/kg when given on alternate days. Sporotrichosis: Therapy with intravenous amphotericin B for sporotrichosis has ranged up to nine months with a total dose up to 2.5 g. Aspergillosis: Aspergillosis has been treated with amphotericin B intravenously for a period up to 11 months with a total dose up to 3.6 g. Rhinocerebral phycomycosis: This fulminating disease generally occurs in association with diabetic ketoacidosis. It is, therefore, imperative that diabetic control be restored in order for treatment with Amphotericin B for Injection to be successful. In contradistinction, pulmonary phycomycosis, which is more common in association with hematologic malignancies, is often an incidental finding at autopsy. A cumulative dose of at least 3 g of amphotericin B is recommended to treat rhinocerebral phycomycosis. Although a total dose of 3 to 4 g will infrequently cause lasting renal impairment, this would seem a reasonable minimum where there is clinical evidence of invasion of deep tissue. Since rhinocerebral phycomycosis usually follows a rapidly fatal course, the therapeutic approach must necessarily be more aggressive than that used in more indolent mycoses. Preparation of Solutions Reconstitute as follows: An initial concentrate of 5 mg amphotericin B per mL is first prepared by rapidly expressing 10 mL Sterile Water for Injection USP without a bacteriostatic agent directly into the lyophilized cake, using a sterile needle (minimum diameter: 20 gauge) and syringe. Shake the vial immediately until the colloidal solution is clear. The infusion solution, providing 0.1 mg amphotericin B per mL, is then obtained by further dilution (1:50) with 5% Dextrose Injection USP of pH above 4.2. The pH of each container of Dextrose Injection should be ascertained before use.

Commercial Dextrose

Injection usually has a pH above 4.2; however, if it is below 4.2, then 1 or 2 mL of buffer should be added to the Dextrose Injection before it is used to dilute the concentrated solution of amphotericin B. The recommended buffer has the following composition: Dibasic sodium phosphate (anhydrous) 1.59 g Monobasic sodium phosphate (anhydrous) 0.96 g Water for Injection USP qs 100.0 mL The buffer should be sterilized before it is added to the Dextrose Injection, either by filtration through a bacterial retentive stone, mat, or membrane, or by autoclaving for 30 minutes at 15 lb pressure (121˚C). CAUTION: Aseptic technique must be strictly observed in all handling , since no preservative or bacteriostatic agent is present in the antibiotic or in the materials used to prepare it for administration. All entries into the vial or into the diluents must be made with a sterile needle. Do not reconstitute with saline solutions. The use of any diluent other than the ones recommended or the presence of a bacteriostatic agent (e.g., benzyl alcohol) in the diluent may cause precipitation of the antibiotic. Do not use the initial concentrate or the infusion solution if there is any evidence of precipitation or foreign matter in either one. An in-line membrane filter may be used for intravenous infusion of amphotericin B; however, the mean pore diameter of the filter should not be less than 1.0 micron in order to assure passage of the antibiotic dispersion.

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, multi-center 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, multi-center 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 adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with amphotericin B liposome for injection 3 mg/kg, 94 patients were treated with amphotericin B liposome for injection 6 mg/kg and 87 patients were treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV-positive patients. 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: Cryptococcal Meningitis Therapy Study 94-0-013 Common Adverse Events Adverse Event by Body System Amphotericin B Liposome for Injection 3 mg/kg/day N = 86 % Amphotericin B Liposome for Injection 6 mg/kg/day N = 94 % Amphotericin B 0.7 mg/kg/day N = 87 % Body as a Whole Abdominal pain 7 7.4

10.3 Infection 12.8 11.7

6.9 Procedural Complication 8.1 9.6

10.3 Cardiovascular System Phlebitis 9.3 10.6

25.3 Digestive System Anorexia 14 9.6

11.5 Constipation 15.1 14.9

20.7 Diarrhea 10.5 16

10.3 Nausea 16.3 21.3

25.3 Vomiting 10.5 21.3

20.7 Hemic and Lymphatic System Anemia 26.7 47.9

43.7 Leukopenia 15.1 17

17.2 Thrombocytopenia 5.8 12.8

6.9 Metabolic and Nutritional Disorders Bilirubinemia 0 8.5

12.6 BUN increased 9.3 7.4

10.3 Creatinine increased 18.6 39.4

43.7 Hyperglycemia 9.3 12.8

17.2 Hypocalcemia 12.8 17

13.8 Hypokalemia 31.4 51.1

48.3 Hypomagnesemia 29.1 48.9

40.2 Hyponatremia 11.6 8.5

9.2 Liver Function Tests Abnormal 12.8 4.3

9.2 Nervous System Dizziness 7 8.5

10.3 Insomnia 22.1 17

20.7 Respiratory System Cough Increased 8.1 2.1

10.3 Skin and Appendages Rash 4.7 11.7

4.6 Infusion-Related Reactions In Study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion-related reaction was administered prior to the first dose of study drug (Day 1). Amphotericin B liposome for injection-treated patients had a lower incidence of infusion-related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day 1 as compared to amphotericin B deoxycholate-treated patients. The incidence of infusion-related reactions on Day 1 in pediatric and adult patients is summarized in the following table: Incidence of Day 1 Infusion-Related Reactions (IRR)

By Patient Age Pediatric

Patients (≤16 years of age)

Adult

Patients (>16 years of age) Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Total number of patients receiving at least one dose of study drug 48 47 295 297 Patients with fever Day 1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). increase ≥ 1.0℃ 6 (13%) 22 (47%) 52 (18%) 128 (43%) Patients with chills/rigors 4 (8%) 22 (47%) 59 (20%) 165 (56%) Patients with nausea 4 (8%) 4 (9%) 38 (13%) 31 (10%) Patients with vomiting 2 (4%) 7 (15%) 19 (6%) 21 (7%) Patients with other reactions 10 (21%) 13 (28%) 47 (16%) 69 (23%) Cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin B-treated patients as summarized in the following table: Incidence of Infusion-Related Cardiorespiratory Events Event Amphotericin B Liposome for Injection 3 mg/kg/day N = 343 Amphotericin B 0.6 mg/kg/day N = 344 Hypotension 12 (3.5%) 28 (8.1%)

Tachycardia

8 (2.3%) 43 (12.5%)

Hypertension

8 (2.3%) 39 (11.3%)

Vasodilatation

18 (5.2%) 2 (0.6%)

Dyspnea

16 (4.7%) 25 (7.3%)

Hyperventilation

4 (1.2%) 17 (4.9%)

Hypoxia

1 (0.3%) 22 (6.4%) The percentage of patients who received drugs either for the treatment or prevention of infusion-related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in amphotericin B liposome for injection-treated patients compared with amphotericin B deoxycholate-treated patients. In the empirical therapy study 97-0-034, on Day 1, where no premedication was administered, the overall incidence of infusion-related events of chills/rigors was significantly lower for patients administered amphotericin B liposome for injection compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each amphotericin B liposome for injection group compared with the amphotericin B lipid complex group. The infusion-related event hypoxia was reported for 11.5% of amphotericin B lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day amphotericin B liposome for injection and 1.2% of patients treated with 5 mg/kg per day amphotericin B liposome for injection. Incidence of Day 1 Infusion-Related Reactions (IRR)

Chills/Rigors

Empirical Therapy Study 97-0-034 Amphotericin B Liposome for Injection Amphotericin B lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day BOTH Total number of patients 85 81 166 78 Patients with Chills/Rigors (Day 1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%) Patients with other notable reactions: Fever (≥1.0℃ increase in temperature)

Nausea Vomiting Hypertension Tachycardia Dyspnea

Hypoxia 20 (23.5%) 9 (10.6%) 5 (5.9%) 4 (4.7%) 2 (2.4%) 4 (4.7%) 0 16 (19.8%) 7 (8.6%) 5 (6.2%) 7 (8.6%) 8 (9.9%) 8 (9.9%) 1 (1.2%) 36 (21.7%) 16 (9.6%) 10 (6%) 11 (6.6%) 10 (6%) 12 (7.2%) 1 (< 1%) 45 (57.7%) 9 (11.5%) 11 (14.1%) 12 (15.4%) 14 (17.9%) 8 (10.3%) 9 (11.5%)

Day

1 body temperature increased above the temperature taken within 1 hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). Patients were not administered premedications to prevent infusion-related reactions prior to the Day 1 study drug infusion.

In Study

94-0-013, a randomized, double-blind, multicenter trial comparing amphotericin B liposome for injection and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion-related reactions were permitted. Amphotericin B liposome for injection-treated patients had a lower incidence of fever, chills/rigors and respiratory adverse events as summarized in the following table: Incidence of Infusion-Related Reactions Study 94-0-013 Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Patients with fever increase of >1°C 6 (7%) 8 (9%) 24 (28%) Patients with chills/rigors 5 (6%) 8 (9%) 42 (48%) Patients with nausea 11 (13%) 13 (14%) 18 (20%) Patients with vomiting 14 (16%) 13 (14%) 16 (18%) Respiratory adverse events 0 1 (1%) 8 (9%) There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with amphotericin B liposome for injection administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within a few minutes after the start of infusion and disappeared rapidly when the infusion was stopped. The symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed. Toxicity and Discontinuation of Dosing In Study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the amphotericin B liposome for injection group compared with the amphotericin B group. In addition, nearly three times as many patients administered amphotericin B required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion-related reaction compared with those administered amphotericin B liposome for injection. In empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin B lipid complex group discontinued the study drug due to an adverse event than in the amphotericin B liposome for injection groups.

Less Common Adverse Events

The following adverse events also have been reported in 2% to 10% of amphotericin B liposome for injection-treated patients receiving chemotherapy or bone marrow transplantation, or who had HIV disease in six comparative, clinical trials: Body as a Whole Abdomen enlarged, allergic reaction, cellulitis, cell-mediated immunological reaction, face edema, graft-versus-host disease, malaise, neck pain, and procedural complication.

Cardiovascular System

Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing).

Digestive System

Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease. Hemic & Lymphatic System Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia. Metabolic & Nutritional Disorders Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis.

Musculoskeletal System

Arthralgia, bone pain, dystonia, myalgia, and rigors.

Nervous System

Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor.

Respiratory System

Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis. Skin & Appendages Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash.

Special Senses

Conjunctivitis, dry eyes, and eye hemorrhage.

Urogenital System

Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage. Post-marketing Experience The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis.

Clinical Laboratory Values

The effect of amphotericin B liposome for injection on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in Study 94-0-002. The frequency and magnitude of hepatic test abnormalities were similar in the amphotericin B liposome for injection and amphotericin B groups. Nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients, provided the peak creatinine concentration was >1.2 mg/dL. Hypokalemia was defined as potassium levels ≤2.5 mmol/L any time during treatment. Incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and incidence of hypokalemia in the double-blind, randomized study were lower in the amphotericin B liposome for injection group as summarized in the following table: Study 94-0-002 Laboratory Evidence of Nephrotoxicity Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B 0.6 mg/kg/day Total number of patients receiving at least one dose of study drug 343 344 Nephrotoxicity 64 (18.7%) 116 (33.7%) Mean peak creatinine 1.24 mg/dL 1.52 mg/dL Mean change from baseline in creatinine 0.48 mg/dL 0.77 mg/dL Hypokalemia 23 (6.7%) 40 (11.6%) The effect of amphotericin B liposome for injection (3 mg/kg/day) vs. amphotericin B (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure: Mean Change in Creatinine Over Time Study 94-0-002 In empirical therapy study 97-0-034, the incidence of nephrotoxicity as measured by increases of serum creatinine from baseline was significantly lower for patients administered amphotericin B liposome for injection (individual dose groups and combined) compared with amphotericin B lipid complex. Incidence of Nephrotoxicity Empirical Therapy Study 97-0-034 Amphotericin B Liposome for Injection Amphotericin B lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day BOTH Total number of patients 85 81 166 78 Number with nephrotoxicity 1.5X baseline serum creatinine value 25 (29.4%) 21 (25.9%) 46 (27.7%) 49 (62.8%) 2X baseline serum creatinine value 12 (14.1%) 12 (14.8%) 24 (14.5%) 33 (42.3%) The following graph shows the average serum creatinine concentrations in the compassionate use study and shows that there is a drop from pretreatment concentrations for all patients, especially those with elevated (greater than 1.7 mg/dL) pretreatment creatinine concentrations.

Mean Creatinine Concentrations Over Time

The incidence of nephrotoxicity in Study 94-0-013 comparative trial in cryptococcal meningitis was lower in the amphotericin B liposome for injection groups as shown in the following table: Laboratory Evidence of Nephrotoxicity Study 94-0-013 Amphotericin B Liposome for Injection 3 mg/kg/day Amphotericin B Liposome for Injection 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Number with Nephrotoxicity (%) 1.5X baseline serum creatinine 30 (35%) 44 (47%) 52 (60%) 2X baseline serum creatinine 12 (14%) 20 (21%) 29 (33%) To report SUSPECTED ADVERSE REACTIONS, contact Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Figure

1 Renal Function in Adult Patients Figure 2 average serum creatinine concentrations

WARNINGS Amphotericin B is frequently the only effective treatment available for potentially life-threatening fungal disease. In each case, its possible life-saving benefit must be balanced against its untoward and dangerous side effects. EXERCISE CAUTION to prevent inadvertent Amphotericin B for Injection overdose, which can result in potentially fatal cardiac or cardiopulmonary arrest. Verify the product name and dosage dosage pre-administration, especially if dose exceeds 1.5 mg/kg. (see OVERDOSAGE and DOSAGE AND ADMINISTRATION )

PRECAUTIONS General As with any amphotericin B-containing product the drug should be administered by medically trained personnel. During the initial dosing period, patients should be under close clinical observation. Amphotericin B liposome for injection has been shown to be significantly less toxic than amphotericin B deoxycholate; however, adverse events may still occur.

Laboratory Tests

Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium). Drug-Laboratory Interactions: Serum phosphate false elevation False elevations of serum phosphate may occur when samples from patients receiving amphotericin B liposome for injection are analyzed using the PHOSm assay (e.g. used in Beckman Coulter analyzers including the Synchron LX20). This assay is intended for the quantitative determination of inorganic phosphorus in human serum, plasma or urine samples.

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. Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of amphotericin B liposome for injection. Amphotericin B liposome for injection has not been tested to determine its mutagenic potential. A Segment I Reproductive Study in rats found an abnormal estrous cycle (prolonged diestrus) and decreased number of corpora lutea in the high-dose groups (10 and 15 mg/kg, doses equivalent to human doses of 1.6 and 2.4 mg/kg based on body surface area considerations). Amphotericin B liposome for injection did not affect fertility or days to copulation. There were no effects on male reproductive function.

Pregnancy

There have been no adequate and well-controlled studies of amphotericin B liposome for injection in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin B deoxycholate, but the number of cases reported has been small. Segment II studies in both rats and rabbits have concluded that amphotericin B liposome for injection had no teratogenic potential in these species. In rats, the maternal non-toxic dose of amphotericin B liposome for injection was estimated to be 5 mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of 1 to 5 mg/kg) and in rabbits, 3 mg/kg (equivalent to 0.2 to 1 times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to 2 times the recommended human dose) of amphotericin B liposome for injection experienced a higher rate of spontaneous abortions than did the control groups. Amphotericin B liposome for injection should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.

Nursing Mothers

Many drugs are excreted in human milk; however, it is not known whether amphotericin B liposome for injection is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, a decision should be made whether to discontinue nursing or whether to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Pediatric patients, age 1 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with amphotericin B liposome for injection. In studies which included 302 pediatric patients administered amphotericin B liposome for injection, there was no evidence of any differences in efficacy or safety of amphotericin B liposome for injection compared to adults. Since pediatric patients have received amphotericin B liposome for injection at doses comparable to those used in adults on a per kilogram body weight basis, no dosage adjustment is required in this population. Safety and effectiveness in pediatric patients below the age of one month have not been established (See DESCRIPTION OF CLINICAL STUDIES - Empirical Therapy in Febrile Neutropenic Patients and DOSAGE AND ADMINISTRATION ).

Elderly Patients

Experience with amphotericin B liposome for injection in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of amphotericin B liposome for injection for this population. As with most other drugs, elderly patients receiving amphotericin B liposome for injection should be carefully monitored.

Drug Interactions When administered concurrently, the following drugs may interact with amphotericin B: Antineoplastic agents: may enhance the potential for renal toxicity, bronchospasm and hypotension. Antineoplastic agents (e.g., nitrogen mustard, etc.) should be given concomitantly only with great caution. Corticosteroids and Corticotropin (ACTH): may potentiate amphotericin B-induced hypokalemia which may predispose the patient to cardiac dysfunction. Avoid concomitant use unless necessary to control side effects of amphotericin B. If used concomitantly, closely monitor serum electrolytes and cardiac function (see ADVERSE REACTIONS ). Digitalis glycosides: amphotericin B-induced hypokalemia may potentiate digitalis toxicity. Serum potassium levels and cardiac function should be closely monitored and any deficit promptly corrected. Flucytosine: while a synergistic relationship with amphotericin B has been reported, concomitant use may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): in vitro and animal studies with 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. Other nephrotoxic medications: agents such as aminoglycosides, cyclosporine, and pentamidine may enhance the potential for drug-induced renal toxicity, and should be used concomitantly only with great caution. Intensive monitoring of renal function is recommended in patients requiring any combination of nephrotoxic medications (see PRECAUTIONS: Laboratory Tests ). Skeletal muscle relaxants: amphotericin B-induced hypokalemia may enhance the curariform effect of skeletal muscle relaxants (e.g., tubocurarine). Serum potassium levels should be monitored and deficiencies corrected. Leukocyte transfusions: acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions (see PRECAUTIONS: General ).