AMBISOME

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

Am B isome 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 Am B isome, relapse rates were high following initial clearance of parasites (see DESCRIPTION OF CLINICAL STUDIES ). See DOSAGE AND ADMINISTRATION for recommended doses by indication.

AmBisome is not interchangeable or substitutable on a mg per mg basis with other amphotericin B products. Different amphotericin B products are not equivalent in terms of pharmacodynamics, pharmacokinetics and dosing. Am B isome should be administered by intravenous infusion, using a controlled infusion device, over a period of approximately 120 minutes. An in-line membrane filter may be used for the intravenous infusion of Am B isome, 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 AmBisome. If this is not feasible, AmBisome must be administered through a separate line. Infusion time may be reduced to approximately 60 minutes in patients in whom the treatment is well-tolerated. If the patient experiences discomfort during infusion, the duration of infusion may be increased. The recommended initial dose of Am B isome for each indication for adult and pediatric patients is as follows: Indication Dose (mg/kg/day) Empirical therapy 3 Systemic fungal infections: Aspergillus Candida Cryptococcus 3 - 5 Cryptococcal meningitis in HIV-infected patients (see DESCRIPTION OF CLINICAL STUDIES ) 6 Dosing and rate of infusion should be individualized to the needs of the specific patient to ensure maximum efficacy while minimizing systemic toxicities or adverse events. Doses recommended for visceral leishmaniasis are presented below: Visceral Leishmaniasis Dose (mg/kg/day) Immunocompetent patients 3 (days 1 - 5) and 3 on days 14, 21 Immunocompromised patients 4 (days 1 - 5) and 4 on days 10, 17, 24, 31, 38 For immunocompetent patients who do not achieve parasitic clearance with the recommended dose, a repeat course of therapy may be useful. For immunocompromised patients who do not clear parasites or who experience relapses, expert advice regarding further treatment is recommended. For additional information, see DESCRIPTION OF CLINICAL STUDIES . Directions for Reconstitution, Filtration and Dilution Read This Entire Section Carefully Before Beginning Reconstitution Am B isome must be reconstituted using Sterile Water for Injection, USP (without a bacteriostatic agent). Vials of Am B isome containing 50 mg of amphotericin B are prepared as follows: Reconstitution 1. Aseptically add 12 mL of Sterile Water for Injection, USP to each Am B isome vial to yield a preparation containing 4 mg amphotericin B/mL. CAUTION: DO NOT RECONSTITUTE WITH SALINE OR ADD SALINE TO THE RECONSTITUTED CONCENTRATION, OR MIX WITH OTHER DRUGS. The use of any solution other than those recommended, or the presence of a bacteriostatic agent in the solution, may cause precipitation of Am B isome. 2. Immediately after the addition of water, SHAKE THE VIAL VIGOROUSLY for 30 seconds to completely disperse the Am B isome. Am B isome forms a yellow, translucent suspension. Visually inspect the vial for particulate matter and continue shaking until completely dispersed. Filtration and Dilution 3. Calculate the amount of reconstituted (4 mg/mL) Am B isome to be further diluted. 4. Withdraw this amount of reconstituted Am B isome into a sterile syringe. 5. Attach the 5 micron filter provided to the syringe. Inject the syringe contents through the filter, into the appropriate amount of 5% Dextrose Injection (use only one filter per vial of Am B isome). 6. Am B isome must be diluted with 5% Dextrose Injection to a final concentration of 1 to 2 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 .

Am B isome 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.

The following adverse events are based on the experience of 592 adult patients (295 treated with Am B isome and 297 treated with amphotericin B deoxycholate) and 95 pediatric patients (48 treated with Am B isome and 47 treated with amphotericin B deoxycholate) in Study 94-0-002, a randomized double-blind, multi-center study in febrile, neutropenic patients. Am B isome and amphotericin B were infused over two hours. The incidence of common adverse events (incidence of 10% or greater) occurring with Am B isome 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 AmBisome N = 343 % Amphotericin B N = 344 % Body as a Whole Abdominal pain Asthenia Back pain Blood product transfusion reaction Chills Infection Pain Sepsis 19.8 13.1 12 18.4 47.5 11.1 14 14 21.8 10.8 7.3 18.6 75.9 9.3 12.8 11.3 Cardiovascular System Chest pain Hypertension Hypotension Tachycardia 12 7.9 14.3 13.4 11.6 16.3 21.5 20.9 Digestive System Diarrhea Gastrointestinal hemorrhage Nausea Vomiting 30.3 9.9 39.7 31.8 27.3 11.3 38.7 43.9 Metabolic and Nutritional Disorders Alkaline phosphatase increased ALT (SGPT) increased AST (SGOT) increased Bilirubinemia BUN increased Creatinine increased Edema Hyperglycemia Hypernatremia Hypervolemia Hypocalcemia Hypokalemia Hypomagnesemia Peripheral edema 22.2 14.6 12.8 18.1 21 22.4 14.3 23 4.1 12.2 18.4 42.9 20.4 14.6 19.2 14 12.8 19.2 31.1 42.2 14.8 27.9 11 15.4 20.9 50.6 25.6 17.2 Nervous System Anxiety Confusion Headache Insomnia 13.7 11.4 19.8 17.2 11 13.4 20.9 14.2 Respiratory System Cough increased Dyspnea Epistaxis Hypoxia Lung disorder Pleural effusion Rhinitis 17.8 23 14.9 7.6 17.8 12.5 11.1 21.8 29.1 20.1 14.8 17.4 9.6 11 Skin and Appendages Pruritus Rash Sweating 10.8 24.8 7 10.2 24.4 10.8 Urogenital System Hematuria 14 14 Am B isome was well tolerated. Am B isome 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, Am B isome 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 Am B isome 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 Am B isome 3 mg/kg, 81 patients were treated with Am B isome 5 mg/kg and 78 patients were treated with amphotericin B lipid complex 5 mg/kg in Study 97-0-034, a randomized, double-blind, multi-center study in febrile, neutropenic patients. Am B isome 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 AmBisome 3 mg/kg/day N = 85 % AmBisome 5 mg/kg/day N = 81 % Amphotericin B Lipid Complex 5 mg/kg/day N = 78 % Body as a Whole Abdominal pain Asthenia Chills/rigors Sepsis Transfusion reaction 12.9 8.2 40 12.9 10.6 9.9 6.2 48.1 7.4 8.6 11.5 11.5 89.7 11.5 5.1 Cardiovascular System Chest pain Hypertension Hypotension Tachycardia 8.2 10.6 10.6 9.4 11.1 19.8 7.4 18.5 6.4 23.1 19.2 23.1 Digestive System Diarrhea Nausea Vomiting 15.3 25.9 22.4 17.3 29.6 25.9 14.1 37.2 30.8 Metabolic and Nutritional Disorders Alkaline phosphatase increased Bilirubinemia BUN increased Creatinine increased Edema Hyperglycemia Hypervolemia Hypocalcemia Hypokalemia Hypomagnesemia Liver function tests abnormal 7.1 16.5 20 20 12.9 8.2 8.2 10.6 37.6 15.3 10.6 8.6 11.1 18.5 18.5 12.3 8.6 11.1 4.9 43.2 25.9 7.4 12.8 11.5 28.2 48.7 12.8 14.1 14.1 5.1 39.7 15.4 11.5 Nervous System Anxiety Confusion Headache 10.6 12.9 9.4 7.4 8.6 17.3 9 3.8 10.3 Respiratory System Dyspnea Epistaxis Hypoxia Lung disorder 17.6 10.6 7.1 14.1 22.2 8.6 6.2 13.6 23.1 14.1 20.5 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 Am B isome 3 mg/kg, 94 patients were treated with Am B isome 6 mg/kg and 87 patients were treated with amphotericin B deoxycholate 0.7 mg/kg in Study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in HIV-positive patients. The incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table: Cryptococcal Meningitis Therapy Study 94-0-013 Common Adverse Events Adverse Event by Body System AmBisome 3 mg/kg/day N = 86 % AmBisome 6 mg/kg/day N = 94 % Amphotericin B 0.7 mg/kg/day N = 87 % Body as a Whole Abdominal pain Infection Procedural Complication 7 12.8 8.1 7.4 11.7 9.6 10.3 6.9 10.3 Cardiovascular System Phlebitis 9.3 10.6 25.3 Digestive System Anorexia Constipation Diarrhea Nausea Vomiting 14 15.1 10.5 16.3 10.5 9.6 14.9 16 21.3 21.3 11.5 20.7 10.3 25.3 20.7 Hemic and Lymphatic System Anemia Leukopenia Thrombocytopenia 26.7 15.1 5.8 47.9 17 12.8 43.7 17.2 6.9 Metabolic and Nutritional Disorders Bilirubinemia BUN increased Creatinine increased Hyperglycemia Hypocalcemia Hypokalemia Hypomagnesemia Hyponatremia Liver Function Tests Abnormal 0 9.3 18.6 9.3 12.8 31.4 29.1 11.6 12.8 8.5 7.4 39.4 12.8 17 51.1 48.9 8.5 4.3 12.6 10.3 43.7 17.2 13.8 48.3 40.2 9.2 9.2 Nervous System Dizziness Insomnia 7 22.1 8.5 17 10.3 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). Am B isome-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) AmBisome 3 mg/kg/day Amphotericin B 0.6 mg/kg/day AmBisome 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 ≥ 1.0 o C 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 AmBisome 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 Am B isome-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 Am B isome compared with amphotericin B lipid complex. Fever, chills/rigors and hypoxia were significantly lower for each Am B isome 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 Am B isome and 1.2% of patients treated with 5 mg/kg per day Am B isome. Incidence of Day 1 Infusion-Related Reactions (IRR) Chills/Rigors Empirical Therapy Study 97-0-034 AmBisome Amphotericin B lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day BOTH Total number of patients 85 81 166 78 Patients with Chills/Rigors (Day 1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%) Patients with other notable reactions: Fever ( > 1.0 o C 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 Am B isome and amphotericin B deoxycholate as initial therapy for cryptococcal meningitis, premedications to prevent infusion-related reactions were permitted. Am B isome-treated patients had a lower incidence of fever, chills/rigors and respiratory adverse events as summarized in the following table: Incidence of Infusion-Related Reactions Study 94-0-013 AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Patients with fever increase of >1°C 6 (7%) 8 (9%) 24 (28%) Patients with chills/rigors 5 (6%) 8 (9%) 42 (48%) Patients with nausea 11 (13%) 13 (14%) 18 (20%) Patients with vomiting 14 (16%) 13 (14%) 16 (18%) Respiratory adverse events 0 1 (1%) 8 (9%) There have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with Am B isome 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 Am B isome 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 Am B isome. 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 Am B isome groups. Less Common Adverse Events The following adverse events also have been reported in 2% to 10% of Am B isome-treated patients receiving chemotherapy or bone marrow transplantation, or who had HIV disease in six comparative, clinical trials: Body as a Whole Abdomen enlarged, allergic reaction, cellulitis, cell-mediated immunological reaction, face edema, graft-versus-host disease, malaise, neck pain, and procedural complication. Cardiovascular System Arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing). Digestive System Anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease. Hemic & Lymphatic System Anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia. Metabolic & Nutritional Disorders Acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (NPN) increased, and respiratory alkalosis. Musculoskeletal System Arthralgia, bone pain, dystonia, myalgia, and rigors. Nervous System Agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor. Respiratory System Asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis. Skin & Appendages Alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash. Special Senses Conjunctivitis, dry eyes, and eye hemorrhage. Urogenital System Abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage. Post-marketing Experience The following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis. Clinical Laboratory Values The effect of Am B isome 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 Am B isome 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 Am B isome group as summarized in the following table: Study 94-0-002 Laboratory Evidence of Nephrotoxicity AmBisome 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 Am B isome (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: 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 Am B isome (individual dose groups and combined) compared with amphotericin B lipid complex. Incidence of Nephrotoxicity Empirical Therapy Study 97-0-034 AmBisome 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. The incidence of nephrotoxicity in Study 94-0-013 comparative trial in cryptococcal meningitis was lower in the Am B isome groups as shown in the following table: Laboratory Evidence of Nephrotoxicity Study 94-0-013 AmBisome 3 mg/kg/day AmBisome 6 mg/kg/day Amphotericin B 0.7 mg/kg/day Total number of patients receiving at least one dose of study drug 86 94 87 Number with Nephrotoxicity (%) 1.5X baseline serum creatinine 30 (35%) 44 (47%) 52 (60%) 2X baseline serum creatinine 12 (14%) 20 (21%) 29 (33%) Mean Change in Creatinine Over Time in Study 94-0-002 Mean Creatine Concentrations Over Time

No formal clinical studies of drug interactions have been conducted with Am B isome; however, the following drugs are known to interact with amphotericin B and may interact with Am B isome: 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.