MECHANISM OF ACTION SECTION.

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

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS The following adverse events are based on the experience of 592 adult patients (295 treated with amphotericin liposome for injection and 297 treated with amphotericin deoxycholate) and 95 pediatric patients (48 treated with amphotericin liposome for injection and 47 treated with amphotericin deoxycholate) in Study 94-0-002, randomized double-blind, multi-center study in febrile, neutropenic patients. Amphotericin liposome for injection and amphotericin were infused over two hours. The incidence of common adverse events (incidence of 10% or greater) occurring with amphotericin liposome for injection compared to amphotericin deoxycholate, regardless of relationship to study drug, is shown in the following table: Empirical Therapy Study 94-0-002 Common Adverse EventsAdverse Event byBody SystemAmphotericin Liposome for InjectionN 343 %Amphotericin BN 344 %Body as Whole Abdominal pain19.821.8Asthenia13.110.8Back pain127.3Blood product transfusion reaction18.418.6Chills47.575.9Infection11.19.3Pain1412.8Sepsis1411.3Cardiovascular SystemChest pain1211.6Hypertension7.916.3Hypotension14.321.5Tachycardia13.420.9Digestive SystemDiarrhea30.327.3Gastrointestinal hemorrhage9.911.3Nausea39.738.7Vomiting31.843.9Metabolic and Nutritional DisordersAlkaline phosphatase increased22.219.2ALT (SGPT) increased14.614AST (SGOT) increased12.812.8Bilirubinemia18.119.2BUN increased2131.1Creatinine increased22.442.2Edema14.314.8Hyperglycemia2327.9Hypernatremia4.111Hypervolemia12.215.4Hypocalcemia18.420.9Hypokalemia42.950.6Hypomagnesemia20.425.6Peripheral edema14.617.2Nervous SystemAnxiety 13.711Confusion 11.413.4Headache 19.820.9Insomnia17.214.2Respiratory System Cough increased 17.821.8Dyspnea 2329.1Epistaxis 14.920.1Hypoxia 7.614.8Lung disorder 17.817.4Pleural effusion 12.59.6Rhinitis11.111Skin and AppendagesPruritus 10.810.2Rash 24.824.4Sweating710.8Urogenital SystemHematuria1414Amphotericin liposome for injection was well tolerated. Amphotericin liposome for injection had lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin deoxycholate. In pediatric patients (16 years of age or less) in this double-blind study, amphotericin liposome for injection compared to amphotericin deoxycholate, had lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). Similar trends, although with somewhat lower incidence, were observed in open-label, randomized Study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with amphotericin liposome for injection and 64 treated with amphotericin deoxycholate). Pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin 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 liposome for injection mg/kg, 81 patients were treated with amphotericin liposome for injection mg/kg and 78 patients were treated with amphotericin lipid complex mg/kg in Study 97-0-034, randomized, double-blind, multi-center study in febrile, neutropenic patients. Amphotericin liposome for injection and amphotericin 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 EventsAdverse Event byBody SystemAmphotericin Liposome for Injection3 mg/kg/dayN 85%Amphotericin Liposome for Injection5 mg/kg/dayN 81%Amphotericin Lipid Complex5 mg/kg/dayN 78%Body as WholeAbdominal pain 12.99.911.5Asthenia8.26.211.5Chills/rigors 4048.189.7Sepsis12.97.411.5Transfusion reaction10.68.65.1Cardiovascular SystemChest pain 8.211.16.4Hypertension 10.619.823.1Hypotension 10.67.419.2Tachycardia9.418.523.1Digestive SystemDiarrhea 15.317.314.1Nausea25.929.637.2Vomiting22.425.930.8Metabolic and Nutritional DisordersAlkaline phosphatase increased 7.18.612.8Bilirubinemia 16.511.111.5BUN increased 2018.528.2Creatinine increased 2018.548.7Edema 12.912.312.8Hyperglycemia 8.28.614.1Hypervolemia 8.211.114.1Hypocalcemia 10.64.95.1Hypokalemia 37.643.239.7Hypomagnesemia15.325.915.4Liver function tests abnormal10.67.411.5Nervous SystemAnxiety10.67.49Confusion 12.98.63.8Headache 9.417.310.3Respiratory SystemDyspnea 17.622.223.1Epistaxis10.68.614.1Hypoxia 7.16.220.5Lung disorder 14.113.615.4Skin and AppendagesRash 23.522.214.1The following adverse events are based on the experience of 267 patients (266 adult patients and pediatric patient) of whom 86 patients were treated with amphotericin liposome for injection mg/kg, 94 patients were treated with amphotericin liposome for injection mg/kg and 87 patients were treated with amphotericin deoxycholate 0.7 mg/kg in Study 94-0-013 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 EventsAdverse Event by BodySystem Amphotericin Liposome for Injection3 mg/kg/dayN 86%Amphotericin Liposome for Injection6 mg/kg/dayN 94%Amphotericin B0.7 mg/kg/dayN 87%Body as WholeAbdominal pain 77.410.3Infection 12.811.76.9Procedural Complication 8.19.610.3Cardiovascular SystemPhlebitis 9.310.625.3Digestive SystemAnorexia 149.611.5Constipation 15.114.920.7Diarrhea 10.51610.3Nausea 16.321.325.3Vomiting 10.521.320.7Hemic and Lymphatic SystemAnemia26.747.943.7Leukopenia 15.11717.2Thrombocytopenia 5.812.86.9Metabolic and Nutritional DisordersBilirubinemia 08.512.6BUN increased9.37.410.3Creatinine increased 18.639.443.7Hyperglycemia 9.312.817.2Hypocalcemia12.81713.8Hypokalemia 31.451.148.3Hypomagnesemia 29.148.940.2Hyponatremia 11.68.59.2Liver Function Tests Abnormal 12.84.39.2Nervous SystemDizziness 78.510.3Insomnia 22.11720.7Respiratory SystemCough Increased 8.12.110.3Skin and AppendagesRash 4.711.74.6 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 liposome for injection-treated patients had lower incidence of infusion-related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on Day as compared to amphotericin deoxycholate-treated patients.The incidence of infusion-related reactions on Day in pediatric and adult patients is summarized in the following table:Incidence of Day Infusion-Related Reactions (IRR) By Patient AgePediatric Patients(<=16 years of age)Adult Patients(>16 years of age)Amphotericin Liposome for Injection3 mg/kg/dayAmphotericin B0.6 mg/kg/dayAmphotericin Liposome for Injection3 mg/kg/dayAmphotericin B0.6 mg/kg/dayTotal number of patients receiving at least one dose of study drug4847295297Patients with feverDay body temperature increased above the temperature taken within hour prior to infusion (preinfusion temperature) or above the lowest infusion value (no preinfusion temperature recorded). increase >= 1.06 (13%)22 (47%)52 (18%)128 (43%)Patients with chills/rigors4 (8%)22 (47%)59 (20%)165 (56%)Patients with nausea4 (8%)4 (9%)38 (13%)31 (10%)Patients with vomiting2 (4%)7 (15%)19 (6%)21 (7%)Patients with other reactions10 (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 EventsEventAmphotericin Liposome for Injection3 mg/kg/dayN 343Amphotericin B0.6 mg/kg/dayN 344Hypotension 12 (3.5%) 28 (8.1%) Tachycardia (2.3%) 43 (12.5%) Hypertension (2.3%) 39 (11.3%) Vasodilatation 18 (5.2%) (0.6%) Dyspnea 16 (4.7%) 25 (7.3%) Hyperventilation (1.2%) 17 (4.9%) Hypoxia (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 liposome for injection-treated patients compared with amphotericin 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 liposome for injection compared with amphotericin lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each amphotericin liposome for injection group compared with the amphotericin lipid complex group. The infusion-related event hypoxia was reported for 11.5% of amphotericin lipid complex-treated patients compared with 0% of patients administered mg/kg per day amphotericin liposome for injection and 1.2% of patients treated with mg/kg per day amphotericin liposome for injection.Incidence of Day Infusion-Related Reactions (IRR) Chills/Rigors Empirical Therapy Study 97-0-034Amphotericin Liposome for InjectionAmphotericin lipid complex5 mg/kg/day3 mg/kg/day5 mg/kg/dayBOTHTotal 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 Hypoxia20 (23.5%)9 (10.6%)5 (5.9%)4 (4.7%)2 (2.4%)4 (4.7%)016 (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 body temperature increased above the temperature taken within 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 study drug infusion. In Study 94-0-013, randomized, double-blind, multicenter trial comparing amphotericin liposome for injection and amphotericin deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion-related reactions were permitted. Amphotericin liposome for injection-treated patients had lower incidence of fever, chills/rigors and respiratory adverse events as summarized in the following table:Incidence of Infusion-Related Reactions Study 94-0-013Amphotericin BLiposome forInjection3 mg/kg/dayAmphotericin BLiposome for Injection6 mg/kg/dayAmphotericin B0.7 mg/kg/dayTotal number of patients receiving at least one dose of study drug 869487Patients with fever increase of >1C (7%)8 (9%)24 (28%)Patients with chills/rigors (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 01 (1%)8 (9%)There have been few reports of flushing, back pain with or without chest tightness, and chest pain associated with amphotericin liposome for injection administration; on occasion this has been severe. Where these symptoms were noted, the reaction developed within 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, significantly lower incidence of grade or toxicity was observed in the amphotericin liposome for injection group compared with the amphotericin group. In addition, nearly three times as many patients administered amphotericin required reduction in dose due to toxicity or discontinuation of study drug due to an infusion-related reaction compared with those administered amphotericin liposome for injection. In empirical therapy study 97-0-034, greater proportion of patients in the amphotericin lipid complex group discontinued the study drug due to an adverse event than in the amphotericin liposome for injection groups. Less Common Adverse Events The following adverse events also have been reported in 2% to 10% of amphotericin liposome for injection-treated patients receiving chemotherapy or bone marrow transplantation, or who had HIV disease in six comparative, clinical trials: Body as WholeAbdomen enlarged, allergic reaction, cellulitis, cell-mediated immunological reaction, face edema, graft-versus-host disease, malaise, neck pain, and procedural complication. Cardiovascular SystemArrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing). Digestive SystemAnorexia, 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 SystemAnemia, 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 SystemArthralgia, bone pain, dystonia, myalgia, and rigors. Nervous SystemAgitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor. Respiratory SystemAsthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis. Skin AppendagesAlopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash. Special SensesConjunctivitis, dry eyes, and eye hemorrhage. Urogenital SystemAbnormal 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 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 liposome for injection and amphotericin 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 liposome for injection group as summarized in the following table:Study 94-0-002 Laboratory Evidence of NephrotoxicityAmphotericin Liposomefor Injection mg/kg/dayAmphotericin B0.6 mg/kg/dayTotal number of patients receiving at least one dose of study drug 343344Nephrotoxicity 64 (18.7%)116 (33.7%)Mean peak creatinine 1.24 mg/dL1.52 mg/dLMean change from baseline in creatinine 0.48 mg/dL0.77 mg/dLHypokalemia 23 (6.7%)40 (11.6%)The effect of amphotericin liposome for injection (3 mg/kg/day) vs. amphotericin (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 liposome for injection (individual dose groups and combined) compared with amphotericin lipid complex.Incidence of Nephrotoxicity Empirical Therapy Study 97-0-034Amphotericin Liposome for InjectionAmphotericin Blipid complex5 mg/kg/day3 mg/kg/day5 mg/kg/dayBOTHTotal number of patients 858116678Number with nephrotoxicity1.5X 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 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 liposome for injection groups as shown in the following table:Laboratory Evidence of Nephrotoxicity Study 94-0-013Amphotericin BLiposome forInjection3 mg/kg/dayAmphotericin BLiposome forInjection6 mg/kg/dayAmphotericin B0.7 mg/kg/dayTotal number of patients receiving at least one dose of study drug 869487Number 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 Renal Function in Adult Patients Figure average serum creatinine concentrations.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

Carcinogenesis, Mutagenesis, Impairment of Fertility No long-term studies in animals have been performed to evaluate carcinogenic potential of amphotericin liposome for injection. Amphotericin liposome for injection has not been tested to determine its mutagenic potential. Segment 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 liposome for injection did not affect fertility or days to copulation. There were no effects on male reproductive function.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY Pharmacokinetics The assay used to measure amphotericin in the serum after administration of amphotericin liposome for injection does not distinguish amphotericin that is complexed with the phospholipids of amphotericin liposome for injection from amphotericin that is uncomplexed. The pharmacokinetic profile of amphotericin after administration of amphotericin liposome for injection is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of to mg/kg/day amphotericin liposome for injection for to 20 days. The pharmacokinetics of amphotericin after administration of amphotericin liposome for injection is nonlinear such that there is greater than proportional increase in serum concentrations with an increase in dose from to mg/kg/day. The pharmacokinetic parameters of total amphotericin (mean +- SD) after the first dose and at steady state are shown in the table below.Pharmacokinetic Parameters of Amphotericin Liposome for InjectionDose1 mg/kg/day2.5 mg/kg/day5 mg/kg/dayDay1n 8Lastn 71n 7Lastn 71n 12Lastn 9ParametersCmax (mcg/mL)7.3 +- 3.812.2 +- 4.917.2 +- 7.131.4 +- 17.857.6 +- 2183 +- 35.2AUC0-24 (mcgohr/mL)27 +- 1460 +- 2065 +- 33197 +- 183269 +- 96555 +- 311t 1/2 (hr)10.7 +- 6.47 +- 2.18.1 +- 2.36.3 +- 26.4 +- 2.16.8 +- 2.1Vss (L/kg)0.44 +- 0.270.14 +- 0.050.40 +- 0.370.16 +- 0.090.16 +- 0.100.10 +- 0.07Cl (mL/hr/kg)39 +- 2217 +- 651 +- 4422 +- 1521 +- 1411 +- . Distribution. Based on total amphotericin concentrations measured within dosing interval (24 hours) after administration of amphotericin liposome for injection, the mean half-life was 7-10 hours. However, based on total amphotericin concentration measured up to 49 days after dosing of amphotericin liposome for injection, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably slow redistribution from tissues. Steady state concentrations were generally achieved within days of dosing. Although variable, mean trough concentrations of amphotericin remained relatively constant with repeated administration of the same dose over the range of to mg/kg/day, indicating no significant drug accumulation in the serum. Metabolism. The metabolic pathways of amphotericin after administration of amphotericin liposome for injection are not known. Excretion. The mean clearance at steady state was independent of dose. The excretion of amphotericin after administration of amphotericin liposome for injection has not been studied. Pharmacokinetics in Special Populations Renal Impairment. The effect of renal impairment on the disposition of amphotericin after administration of amphotericin liposome for injection has not been studied. However, amphotericin liposome for injection has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES). Hepatic Impairment. The effect of hepatic impairment on the disposition of amphotericin after administration of amphotericin liposome for injection is not known. Pediatric and Elderly Patients. The pharmacokinetics of amphotericin after administration of amphotericin liposome for injection in pediatric and elderly patients has not been studied; however, amphotericin liposome for injection has been used in pediatric and elderly patients (see DESCRIPTION OF CLINICAL STUDIES). Gender and Ethnicity. The effect of gender or ethnicity on the pharmacokinetics of amphotericin after administration of amphotericin liposome for injection is not known.

CONTRAINDICATIONS SECTION.

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

DESCRIPTION SECTION.

DESCRIPTION Amphotericin liposome for injection is sterile, non-pyrogenic, yellow lyophilized product for intravenous infusion. Each vial contains amphotericin B, USP, 50 milligrams (mg), intercalated into 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 liposome for injection may also contain hydrochloric acid and/or sodium hydroxide as pH adjusters. Each mL of reconstituted Amphotericin liposome for injection contains mg of sodium and less than mg of phosphorus. Following reconstitution with Sterile Water for Injection, USP, the resulting pH of the suspension is between 5-6.Amphotericin liposome for injection is 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 homogenizer. Amphotericin liposome for injection consists of these unilamellar bilayer liposomes with amphotericin intercalated within the membrane. Due to the nature and quantity of amphophilic substances used, and the lipophilic moiety in the amphotericin molecule, the drug is an integral part of the overall structure of the amphotericin liposomes. Amphotericin liposome for injection contains true liposomes that are less than 100 nm in diameter. schematic depiction of the liposome is presented below.Note: Liposomal encapsulation or incorporation into lipid complex can substantially affect drugs functional properties relative to those of the unencapsulated drug or non-lipid associated drug. In addition, different liposomal or lipid-complex products with 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 is macrocyclic, polyene, antifungal antibiotic produced from strain of Streptomyces nodosus. Amphotericin 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--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 has molecular formula of C47H73NO17 and molecular weight of 924.08. The structure of amphotericin is shown below:. schematic depiction of the liposome. Chemical structure of amphotericin B.

DOSAGE & ADMINISTRATION SECTION.

DOSAGE AND ADMINISTRATION Amphotericin liposome for injection is not interchangeable or substitutable on mg per mg basis with other amphotericin products. Different amphotericin products are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing. Amphotericin liposome for injection should be administered by intravenous infusion, using controlled infusion device, over period of approximately 120 minutes. An in-line membrane filter may be used for the intravenous infusion of amphotericin liposome for injection, provided THE MEAN PORE DIAMETER OF THE FILTER IS NOT LESS THAN 1.0 MICRON. NOTE: An existing intravenous line must be flushed with 5% Dextrose Injection prior to infusion of amphotericin liposome for injection. If this is not feasible, amphotericin liposome for injection must be administered through separate line. Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended initial dose of amphotericin liposome for injection for each indication for adult and pediatric patients is as follows:Indication Dose (mg/kg/day)Empirical therapy 3Systemic fungal infections: Aspergillus Candida Cryptococcus3 to 5Cryptococcal meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES)6Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events. Doses recommended for visceral leishmaniasis are presented below:Visceral LeishmaniasisDose (mg/kg/day)Immunocompetent patients (days to 5) and3 on days 14, 21Immunocompromised patients (days to 5) and4 on days 10, 17, 24, 31, 38For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, repeat course of therapy may be useful. For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information, see DESCRIPTION OF CLINICAL STUDIES. Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning ReconstitutionAmphotericin liposome for injection must be reconstituted using Sterile Water for Injection, USP (without bacteriostatic agent). Vials of amphotericin liposome for injection containing 50 mg of amphotericin are prepared as follows: Reconstitution 1.Aseptically add 12 mL of Sterile Water for Injection, USP to each amphotericin liposome for injection vial to yield preparation containing mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of bacteriostatic agent in the solution, may cause precipitation of amphotericin liposome for injection. 2.Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the amphotericin liposome for injection. Amphotericin liposome for injection forms yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. Filtration and Dilution 3.Calculate the amount of reconstituted (4 mg/mL) amphotericin liposome for injection to be further diluted. 4.Withdraw this amount of reconstituted amphotericin liposome for injection into sterile syringe. 5.Attach the micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection (use only one filter per vial of amphotericin liposome for injection). 6.Amphotericin liposome for injection must be diluted with 5% Dextrose Injection to final concentration of to mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.STORAGE OF AMPHOTERICIN LIPOSOME FOR INJECTIONUnopened vials of lyophilized material are to be stored at temperatures up to 25C (77F). Storage of Reconstituted Product ConcentrateThe reconstituted product concentrate may be stored for up to 24 hours at to 8C (36 to 46F) following reconstitution with Sterile Water for Injection, USP. Do not freeze. Storage of Diluted ProductInjection of amphotericin liposome for injection should commence within hours of dilution with 5% Dextrose Injection. As with all parenteral drug products, the reconstituted amphotericin liposome for injection should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use material if there is any evidence of precipitation or foreign matter. Aseptic technique must be strictly observed in all handling, since no preservative or bacteriostatic agent is present in amphotericin liposome for injection or in the materials specified for reconstitution and dilution.. 1.Aseptically add 12 mL of Sterile Water for Injection, USP to each amphotericin liposome for injection vial to yield preparation containing mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of bacteriostatic agent in the solution, may cause precipitation of amphotericin liposome for injection. 2.Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the amphotericin liposome for injection. Amphotericin liposome for injection forms yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. 3.Calculate the amount of reconstituted (4 mg/mL) amphotericin liposome for injection to be further diluted. 4.Withdraw this amount of reconstituted amphotericin liposome for injection into sterile syringe. 5.Attach the micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection (use only one filter per vial of amphotericin liposome for injection). 6.Amphotericin liposome for injection must be diluted with 5% Dextrose Injection to final concentration of to mg/mL prior to administration. Lower concentrations (0.2 to 0.5 mg/mL) may be appropriate for infants and small children to provide sufficient volume for infusion. DISCARD PARTIALLY USED VIALS.

DRUG INTERACTIONS SECTION.

Drug Interactions No formal clinical studies of drug interactions have been conducted with amphotericin liposome for injection; however, the following drugs are known to interact with amphotericin and may interact with amphotericin 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 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 and leukocyte transfusions. Other Nephrotoxic Medications. Concurrent use of amphotericin 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.

GENERAL PRECAUTIONS SECTION.

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 liposome for injection has been shown to be significantly less toxic than amphotericin deoxycholate; however, adverse events may still occur.

GERIATRIC USE SECTION.

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

HEPATIC IMPAIRMENT SUBSECTION.

Hepatic Impairment. The effect of hepatic impairment on the disposition of amphotericin after administration of amphotericin liposome for injection is not known.

HOW SUPPLIED SECTION.

HOW SUPPLIED Amphotericin liposome for injection is sterile, non-pyrogenic, yellow lyophilized product for intravenous infusion and is available as an individual carton (NDC 67457-926-50) and in packs of ten individual cartons (NDC 67457-926-99). Each individual carton contains one pre-packaged, disposable sterile micron filter. All other trademarks and registered trademarks are the property of their respective owners.Rx only Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A.Manufactured by: Mylan Laboratories Limited Bangalore, India50105038JUNE 2025.

INDICATIONS & USAGE SECTION.

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

LABORATORY TESTS SECTION.

Laboratory Tests Patient management should include laboratory evaluation of renal, hepatic and hematopoietic function, and serum electrolytes (particularly magnesium and potassium).

MICROBIOLOGY SECTION.

MICROBIOLOGY Mechanism of Action Amphotericin B, the active ingredient of amphotericin liposome for injection, acts by binding to the sterol component, ergosterol, of the cell membrane of susceptible fungi. It forms transmembrane channels leading to alterations in cell permeability through which monovalent ions (NA+, K+, H+, and Cl-) leak out of the cell resulting in cell death. While amphotericin has higher affinity for the ergosterol component of the fungal cell membrane, it can also bind to the cholesterol component of the mammalian cell leading to cytotoxicity. Amphotericin liposome for injection, the liposomal preparation of amphotericin B, has been shown to penetrate the cell wall of both extracellular and intracellular forms of susceptible fungi. Resistance Mutants with decreased susceptibility to amphotericin have been isolated from several fungal species after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Drug combination studies in vitro and in vivo suggest that imidazoles may induce resistance to amphotericin B; however, the clinical relevance of drug resistance has not been established. Antimicrobial Activity Amphotericin liposome for injection has shown in vitro activity comparable to amphotericin against the following organisms: Aspergillus fumigatus, Aspergillus flavus, Candida albicans, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans, and Blastomyces dermatitidis. Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

NURSING MOTHERS SECTION.

Nursing Mothers. Many drugs are excreted in human milk; however, it is not known whether amphotericin liposome for injection is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, 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.

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 50 mg/vial NDC 67457-926-50Amphotericin BLiposomefor Injection50 mg/vialMust be reconstituted andfurther dilutedFor Intravenous Infusion OnlyAmphotericin Liposome for Injection isNot Interchangeable or Substitutable on amg per mg Basis with other Amphotericin Products.Rx only Single-Dose VialSterile, nonpyrogenic.Each vial contains amphotericin B, USP,50 milligrams (mg), intercalated into liposomalmembrane consisting of alpha tocopherol, USPapproximately 0.64 mg; cholesterol, NF, 52 mg;distearoyl phosphatidylglycerol sodium salt86.48 mg; hydrogenated soy phosphatidylcholine213 mg, together with disodium succinatehexahydrate, NF, 27 mg; and sucrose, NF, 900 mg.Amphotericin Liposome for Injection may alsocontain hydrochloric acid and/or sodiumhydroxide as pH adjusters.Preservative-free. Discard unused portion.Usual dosage: See package insert. For Intravenous use: See package insert.Contents:One-single-dose vialOne-5 micron filterOne-package insertStore at temperature up to 25C (77F).Manufactured for: Mylan Institutional LLC Morgantown, WV 26505 U.S.A.Made in IndiaCode No.: TN/DRUGS/TN00003234Mylan.com. Amphotericin Liposome for Injection 50 mg/vial Carton Label.

PEDIATRIC USE SECTION.

Pediatric Use Pediatric patients, age month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with amphotericin liposome for injection. In studies which included 302 pediatric patients administered amphotericin liposome for injection, there was no evidence of any differences in efficacy or safety of amphotericin liposome for injection compared to adults. Since pediatric patients have received amphotericin liposome for injection at doses comparable to those used in adults on 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).

PHARMACOKINETICS SECTION.

Pharmacokinetics The assay used to measure amphotericin in the serum after administration of amphotericin liposome for injection does not distinguish amphotericin that is complexed with the phospholipids of amphotericin liposome for injection from amphotericin that is uncomplexed. The pharmacokinetic profile of amphotericin after administration of amphotericin liposome for injection is based upon total serum concentrations of amphotericin B. The pharmacokinetic profile of amphotericin was determined in febrile neutropenic cancer and bone marrow transplant patients who received 1-2 hour infusions of to mg/kg/day amphotericin liposome for injection for to 20 days. The pharmacokinetics of amphotericin after administration of amphotericin liposome for injection is nonlinear such that there is greater than proportional increase in serum concentrations with an increase in dose from to mg/kg/day. The pharmacokinetic parameters of total amphotericin (mean +- SD) after the first dose and at steady state are shown in the table below.Pharmacokinetic Parameters of Amphotericin Liposome for InjectionDose1 mg/kg/day2.5 mg/kg/day5 mg/kg/dayDay1n 8Lastn 71n 7Lastn 71n 12Lastn 9ParametersCmax (mcg/mL)7.3 +- 3.812.2 +- 4.917.2 +- 7.131.4 +- 17.857.6 +- 2183 +- 35.2AUC0-24 (mcgohr/mL)27 +- 1460 +- 2065 +- 33197 +- 183269 +- 96555 +- 311t 1/2 (hr)10.7 +- 6.47 +- 2.18.1 +- 2.36.3 +- 26.4 +- 2.16.8 +- 2.1Vss (L/kg)0.44 +- 0.270.14 +- 0.050.40 +- 0.370.16 +- 0.090.16 +- 0.100.10 +- 0.07Cl (mL/hr/kg)39 +- 2217 +- 651 +- 4422 +- 1521 +- 1411 +- . Distribution. Based on total amphotericin concentrations measured within dosing interval (24 hours) after administration of amphotericin liposome for injection, the mean half-life was 7-10 hours. However, based on total amphotericin concentration measured up to 49 days after dosing of amphotericin liposome for injection, the mean half-life was 100-153 hours. The long terminal elimination half-life is probably slow redistribution from tissues. Steady state concentrations were generally achieved within days of dosing. Although variable, mean trough concentrations of amphotericin remained relatively constant with repeated administration of the same dose over the range of to mg/kg/day, indicating no significant drug accumulation in the serum. Metabolism. The metabolic pathways of amphotericin after administration of amphotericin liposome for injection are not known. Excretion. The mean clearance at steady state was independent of dose. The excretion of amphotericin after administration of amphotericin liposome for injection has not been studied.

PRECAUTIONS SECTION.

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 liposome for injection has been shown to be significantly less toxic than amphotericin 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 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 liposome for injection; however, the following drugs are known to interact with amphotericin and may interact with amphotericin 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 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 and leukocyte transfusions. Other Nephrotoxic Medications. Concurrent use of amphotericin 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 liposome for injection. Amphotericin liposome for injection has not been tested to determine its mutagenic potential. Segment 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 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 liposome for injection in pregnant women. Systemic fungal infections have been successfully treated in pregnant women with amphotericin deoxycholate, but the number of cases reported has been small. Segment II studies in both rats and rabbits have concluded that amphotericin liposome for injection had no teratogenic potential in these species. In rats, the maternal non-toxic dose of amphotericin liposome for injection was estimated to be mg/kg (equivalent to 0.16 to 0.8 times the recommended human clinical dose range of to mg/kg) and in rabbits, mg/kg (equivalent to 0.2 to times the recommended human clinical dose range), based on body surface area correction. Rabbits receiving the higher doses, (equivalent to 0.5 to times the recommended human dose) of amphotericin liposome for injection experienced higher rate of spontaneous abortions than did the control groups. Amphotericin 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 liposome for injection is excreted in human milk. Due to the potential for serious adverse reactions in breastfed infants, 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 month to 16 years, with presumed fungal infection (empirical therapy), confirmed systemic fungal infections or with visceral leishmaniasis have been successfully treated with amphotericin liposome for injection. In studies which included 302 pediatric patients administered amphotericin liposome for injection, there was no evidence of any differences in efficacy or safety of amphotericin liposome for injection compared to adults. Since pediatric patients have received amphotericin liposome for injection at doses comparable to those used in adults on 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 liposome for injection in the elderly (65 years or older) comprised 72 patients. It has not been necessary to alter the dose of amphotericin liposome for injection for this population. As with most other drugs, elderly patients receiving amphotericin liposome for injection should be carefully monitored.

PREGNANCY SECTION.

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

RENAL IMPAIRMENT SUBSECTION.

Renal Impairment. The effect of renal impairment on the disposition of amphotericin after administration of amphotericin liposome for injection has not been studied. However, amphotericin liposome for injection has been successfully administered to patients with pre-existing renal impairment (see DESCRIPTION OF CLINICAL STUDIES).

SPL UNCLASSIFIED SECTION.

Resistance Mutants with decreased susceptibility to amphotericin have been isolated from several fungal species after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Drug combination studies in vitro and in vivo suggest that imidazoles may induce resistance to amphotericin B; however, the clinical relevance of drug resistance has not been established.

WARNINGS SECTION.

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