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.

ADVERSE REACTIONS The following adverse events are based on the experience of 592 adult patients (295 treated with amphotericin B liposome for injection and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with amphotericin B liposome for injection and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multicenter study in febrile, neutropenic patients. Amphotericin B liposome for injection and amphotericin B were infused over two hours. The incidence of common adverse events (incidence of 10% or greater) occurring with amphotericin B liposome for injection compared to amphotericin B deoxycholate, regardless of relationship to study drug, is shown in the following table: Empirical Therapy Study 94-0-002 Common Adverse Events Adverse Event by Body System Amphotericin B Liposome for Injection N=343 % Amphotericin B N=344 % Body as a Whole Abdominal pain 19.8 21.8 Asthenia 13.1 10.8 Back pain 12 7.3 Blood product transfusion reaction 18.4 18.6 Chills 47.5 75.9 Infection 11.1 9.3 Pain 14 12.8 Sepsis 14 11.3 Cardiovascular System Chest pain 12 11.6 Hypertension 7.9 16.3 Hypotension 14.3 21.5 Tachycardia 13.4 20.9 Digestive System Diarrhea 30.3 27.3 Gastrointestinal hemorrhage 9.9 11.3 Nausea 39.7 38.7 Vomiting 31.8 43.9 Metabolic and Nutritional Disorders Alkaline phosphatase increased 22.2 19.2 ALT (SGPT) increased 14.6 14 AST (SGOT) increased 12.8 12.8 Bilirubinemia 18.1 19.2 BUN increased 21 31.1 Creatinine increased 22.4 42.2 Edema 14.3 14.8 Hyperglycemia 23 27.9 Hypernatremia 4.1 11 Hypervolemia 12.2 15.4 Hypocalcemia 18.4 20.9 Hypokalemia 42.9 50.6 Hypomagnesemia 20.4 25.6 Peripheral edema 14.6 17.2 Nervous System Anxiety 13.7 11 Confusion 11.4 13.4 Headache 19.8 20.9 Insomnia 17.2 14.2 Respiratory System Cough increased 17.8 21.8 Dyspnea 23 29.1 Epistaxis 14.9 20.1 Hypoxia 7.6 14.8 Lung disorder 17.8 17.4 Pleural effusion 12.5 9.6 Rhinitis 11.1 11 Skin and Appendages Pruritus 10.8 10.2 Rash 24.8 24.4 Sweating 7 10.8 Urogenital System Hematuria 14 14 Amphotericin B liposome for injection was well tolerated. Amphotericin B liposome for injection had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin B deoxycholate. In pediatric patients (16 years of age or less) in this double-blind study, amphotericin B liposome for injection compared to amphotericin B deoxycholate, had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with a somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with amphotericin B liposome for injection and 64 treated with amphotericin B deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin B deoxycholate. The following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with amphotericin B liposome for injection 3 mg/kg, 81 patients were treated with amphotericin B liposome for injection 5 mg/kg and 78 patients were treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized, double-blind, multicenter study in febrile, neutropenic patients. Amphotericin B liposome for injection and amphotericin B lipid complex were infused over two hours. The incidence of adverse events occurring in more than 10% of subjects in one or more arms, regardless of relationship to study drug, are summarized in the following table: Empirical Therapy Study 97-0-034 Common Adverse Events Adverse Event by Body System Amphotericin B Liposome for Injection 3 mg/kg/day N=85 % Amphotericin B Liposome for Injection 5 mg/kg/day N=81 % Amphotericin B Lipid Complex 5 mg/kg/day N=78 % Body as a Whole Abdominal pain 12.9 9.9 11.5 Asthenia 8.2 6.2 11.5 Chills/rigors 40 48.1 89.7 Sepsis 12.9 7.4 11.5 Transfusion reaction 10.6 8.6 5.1 Cardiovascular System Chest pain 8.2 11.1 6.4 Hypertension 10.6 19.8 23.1 Hypotension 10.6 7.4 19.2 Tachycardia 9.4 18.5 23.1 Digestive System Diarrhea 15.3 17.3 14.1 Nausea 25.9 29.6 37.2 Vomiting 22.4 25.9 30.8 Metabolic and Nutritional Disorders Alkaline phosphatase increased 7.1 8.6 12.8 Bilirubinemia 16.5 11.1 11.5 BUN increased 20 18.5 28.2 Creatinine increased 20 18.5 48.7 Edema 12.9 12.3 12.8 Hyperglycemia 8.2 8.6 14.1 Hypervolemia 8.2 11.1 14.1 Hypocalcemia 10.6 4.9 5.1 Hypokalemia 37.6 43.2 39.7 Hypomagnesemia 15.3 25.9 15.4 Liver function tests abnormal 10.6 7.4 11.5 Nervous System Anxiety 10.6 7.4 9 Confusion 12.9 8.6 3.8 Headache 9.4 17.3 10.3 Respiratory System Dyspnea 17.6 22.2 23.1 Epistaxis 10.6 8.6 14.1 Hypoxia 7.1 6.2 20.5 Lung disorder 14.1 13.6 15.4 Skin and Appendages Rash 23.5 22.2 14.1 The following 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. 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† Increase ≥1.0ºC 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%) †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). 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 (Day1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%) Patients with other notable reactions: Fever (>1.0ºC increase in temperature) 20 (23.5%) 16 (19.8%) 36 (21.7%) 45 (57.7%) Nausea 9 (10.6%) 7 (8.6%) 16 (9.6%) 9 (11.5%) Vomiting 5 (5.9%) 5 (6.2%) 10 (6%) 11 (14.1%) Hypertension 4 (4.7%) 7 (8.6%) 11 (6.6%) 12 (15.4%) Tachycardia 2 (2.4%) 8 (9.9%) 10 (6%) 14 (17.9%) Dyspnea 4 (4.7%) 8 (9.9%) 12 (7.2%) 8 (10.3%) Hypoxia 0 1 (1.2%) 1 (<1%) 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, chill/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 >1ºC 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. Postmarketing Experience The following infrequent adverse experiences have been reported in postmarketing 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 in 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%) 2 X baseline serum creatinine 12 (14%) 20 (21%) 29 (33%) spl-figure1 spl-figure2