Amphotericin B

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.

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.

Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs, including amphotericin B liposome for injection. If a severe anaphylactic reaction occurs, the infusion should be immediately discontinued and the patient should not receive further infusions of amphotericin B liposome for injection.

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 mg/kg and 15 mg/kg, doses equivalent to human doses of 1.6 mg/kg 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 mg/kg 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 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.

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 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 multicenter 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. […]

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.

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 mg/kg 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.

Many drugs are excreted in human milk; however, it is not known whether amphotericin B 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 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.