ossibly 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.

y of amphotericin b were conducted. this clinical program included both controlled and uncontrolled studies . these studies, which involved 2,171 patients, included patients with confirmed systemic mycoses, empirical therapy, and visceral leishmaniasis. nineteen hundred and forty-six (1,946) episodes were evaluable for efficacy, of which 1,280 (302 pediatric and 978 adults) were treated with amphotericin b. three controlled empirical therapy trials compared the efficacy and safety of amphotericin b liposome for injection to amphotericin b. one of these studies was conducted in a pediatric population, one in adults, and a third in patients aged 2 years or more. in addition, a controlled empirical therapy trial comparing the safety of amphotericin b liposome for injection to abelcet ® (amphotericin b lipid complex) was conducted in patients aged 2 years or more. one controlled trial compared the efficacy and safety of amphotericin b liposome for injection to amphotericin b in hiv patients with cryptococcal meningitis. one compassionate use study enrolled patients who had failed amphotericin b deoxycholate therapy or who were unable to receive amphotericin b deoxycholate because of renal insufficiency. empirical therapy in febrile neutropenic patients study 94-0-002, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin b liposome for injection (1.5 to 6 mg/kg/day) compared with amphotericin b deoxycholate (0.3 to 1.2 mg/kg/day) in the empirical treatment of 687 adult and pediatric neutropenic patients who were febrile despite having received at least 96 hours of broad spectrum antibacterial therapy. therapeutic success required (a) resolution of fever during the neutropenic period, (b) absence of an emergent fungal infection, (c) patient survival for at least 7 days post therapy, (d) no discontinuation of therapy due to toxicity or lack of efficacy, and (e) resolution of any study-entry fungal infection. the overall therapeutic success rates for amphotericin b liposome for injection and the amphotericin b deoxycholate were equivalent. results are summarized in the following table. note: the categories presented below are not mutually exclusive. empirical therapy in febrile neutropenic patients: randomized, double-blind study in 687 patients * 8 and 10 patients, respectively, were treated as failures due to premature discontinuation alone. amphotericin b liposome for injection 3 mg/kg/day amphotericin b 0.6 mg/kg/day number of patients receiving at least one dose of study drug 343 344 overall success 171 (49.9%) 169 (49.1%) fever resolution during neutropenic period 199 (58%) 200 (58.1%) no treatment-emergent fungal infection 300 (87.5%) 301 (87.7%) survival through 7 days post study drug 318 (92.7%) 308 (89.5%) study drug not prematurely discontinued due to toxicity or lack of efficacy* 294 (85.7%) 280 (81.4%) this therapeutic equivalence had no apparent relationship to the use of prestudy antifungal prophylaxis or concomitant granulocytic colony-stimulating factors. the incidence of mycologically-confirmed, and clinically-diagnosed, emergent fungal infections are presented in the following table. amphotericin b liposome for injection and amphotericin b were found to be equivalent with respect to the total number of emergent fungal infections. empirical therapy in febrile neutropenic patients: emergent fungal infections amphotericin b liposome for injection 3 mg/kg/day amphotericin b 0.6 mg/kg/day number of patients receiving at least one dose of study drug 343 344 mycologically-confirmed fungal infection 11 (3.2%) 27 (7.8%) clinically-diagnosed fungal infection 32 (9.3%) 16 (4.7%) total emergent fungal infections 43 (12.5%) 43 (12.5%) mycologically-confirmed fungal infections at study entry were cured in 8 of 11 patients in the amphotericin b liposome for injection group and 7 of 10 in the amphotericin b group. study 97-0-034, a randomized, double-blind, comparative multi-center trial, evaluated the safety of amphotericin b liposome for injection (3 and 5 mg/kg/day) compared with amphotericin b lipid complex (5 mg/kg/day) in the empirical treatment of 202 adult and 42 pediatric neutropenic patients. one hundred and sixty-six (166) patients received amphotericin b liposome for injection (85 patients received 3 mg/kg/day and 81 received 5 mg/kg/day) and 78 patients received amphotericin b lipid complex. the study patients were febrile despite having received at least 72 hours of broad spectrum antibacterial therapy. the primary endpoint of this study was safety. the study was not designed to draw statistically meaningful conclusions related to comparative efficacy and, in fact, abelcet is not labeled for this indication. two supportive, prospective, randomized, open-label, comparative multi-center studies examined the efficacy of two dosages of amphotericin b liposome for injection (1 and 3 mg/kg/day) compared to amphotericin b deoxycholate (1 mg/kg/day) in the treatment of neutropenic patients with presumed fungal infections. these patients were undergoing chemotherapy as part of a bone marrow transplant or had hematological disease. study 104-10 enrolled adult patients (n=134). study 104-14 enrolled pediatric patients (n=214). both studies support the efficacy equivalence of amphotericin b liposome for injection and amphotericin b as empirical therapy in febrile neutropenic patients. treatment of cryptococcal meningitis in hiv-infected patients study 94-0-013, a randomized, double-blind, comparative multi-center trial, evaluated the efficacy of amphotericin b liposome for injection at doses (3 and 6 mg/kg/day) compared with amphotericin b deoxycholate (0.7 mg/kg/day) for the treatment of cryptococcal meningitis in 266 adult and one pediatric hiv-positive patients (the pediatric patient received amphotericin b deoxycholate). of the 267 treated patients, 86 received amphotericin b liposome for injection 3 mg/kg/day, 94 received 6 mg/kg/day and 87 received amphotericin b deoxycholate; cryptococcal meningitis was documented by a positive csf culture at baseline in 73, 85 and 76 patients, respectively. patients received study drug once daily for an induction period of 11 to 21 days. following induction, all patients were switched to oral fluconazole at 400 mg/day for adults and 200 mg/day for patients less than 13 years of age to complete 10 weeks of protocol-directed therapy. for mycologically evaluable patients, defined as all randomized patients who received at least one dose of study drug, had a positive baseline csf culture, and had at least one follow-up culture, success was evaluated at week 2 (i.e., 14 ± 4 days), and was defined as csf culture conversion. success rates at 2 weeks for amphotericin b liposome for injection and amphotericin b deoxycholate are summarized in the following table: success rates at 2 weeks (csf culture conversion) study 94-0-013 * 97.5% confidence interval for the difference between amphotericin b liposome for injection and amphotericin b success rates. a negative value is in favor of amphotericin b. a positive value is in favor of amphotericin b liposome for injection. amphotericin b liposome for injection 3 mg/kg/day amphotericin b liposome for injection 6 mg/kg/day amphotericin b 0.7 mg/kg/day success at week 2 35/60 (58.3%) 97.5% ci * = -9.4%, +31% 36/75 (48%) 97.5% ci * = -18.8%, +19.8% 29/61 (47.5 %) success at 10 weeks was defined as clinical success at week 10 plus csf culture conversion at or prior to week 10. success rates at 10 weeks in patients with positive baseline culture for cryptococcus species are summarized in the following table and show that the efficacy of amphotericin b liposome for injection 6 mg/kg/day approximates the efficacy of the amphotericin b deoxycholate regimen. these data do not support the conclusion that amphotericin b liposome for injection 3 mg/kg/day is comparable in efficacy to amphotericin b deoxycholate. the table also presents 10-week survival rates for patients treated in this study. success rates and survival rates at week 10, study 94-0-013 (see text for definitions) amphotericin b liposome for injection 3 mg/kg/day amphotericin b liposome for injection 6 mg/kg/day amphotericin b 0.7 mg/kg/day * 97.5% confidence interval for the difference between amphotericin b liposome for injection and amphotericin b rates. a negative value is in favor of amphotericin b. a positive value is in favor of amphotericin b liposome for injection. success in patients with documented cryptococcal meningitis 27/73 (37%) 97.5% ci * = -33.7%, +2.4% 42/85 (49%) 97.5% ci * = -20.9%, +14.5% 40/76 (53%) survival rates 74/86 (86%) 97.5% ci * = -13.8%, +8.9% 85/94 (90%) 97.5% ci * = -8.3%, +12.2% 77/87 (89%) the incidence of infusion-related, cardiovascular and renal adverse events was lower in patients receiving amphotericin b liposome for injection compared to amphotericin b deoxycholate (see adverse reactions section for details); therefore, the risks and benefits (advantages and disadvantages) of the different amphotericin b formulations should be taken into consideration when selecting a patient treatment regimen. treatment of patients with aspergillus species, candida species and/or cryptococcus species infections refractory to amphotericin b deoxycholate, or in patients where renal impairment or unacceptable toxicity precludes the use of amphotericin b deoxycholate amphotericin b liposome for injection was evaluated in a compassionate use study in hospitalized patients with systemic fungal infections. these patients either had fungal infections refractory to amphotericin b deoxycholate, were intolerant to the use of amphotericin b deoxycholate, or had pre-existing renal insufficiency. patient recruitment involved 140 infectious episodes in 133 patients, with 53 episodes evaluable for mycological response and 91 episodes evaluable for clinical outcome. clinical success and mycological eradication occurred in some patients with documented aspergillosis, candidiasis, and cryptococcosis. treatment of visceral leishmaniasis amphotericin b was studied in patients with visceral leishmaniasis who were infected in the mediterranean basin with documented or presumed leishmania infantum . clinical studies have not provided conclusive data regarding efficacy against l. donovani or l. chagasi . amphotericin b achieved high rates of acute parasite clearance in immunocompetent patients when total doses of 12 to 30 mg/kg were administered. most of these immunocompetent patients remained relapse-free during follow-up periods of 6 months or longer. while acute parasite clearance was achieved in most of the immunocompromised patients who received total doses of 30 to 40 mg/kg, the majority of these patients were observed to relapse in the 6 months following the completion of therapy. of the 21 immunocompromised patients studied, 17 were coinfected with hiv; approximately half of the hiv-infected patients had aids. the following table presents a comparison of efficacy rates among immunocompetent and immunocompromised patients infected in the mediterranean basin who had no prior treatment or remote prior treatment for visceral leishmaniasis. efficacy is expressed as both acute parasite clearance at the end of therapy (eot) and as overall success (clearance with no relapse) during the follow-up period (f/u) of greater than 6 months for immunocompetent and immunocompromised patients: amphotericin b liposome for injection efficacy in visceral leishmaniasis immunocompetent patients no. of patients parasite (%) clearance at eot overall success (%) at f/u 87 86/87 (98.9) 83/86 (96.5) immunocompromised patients regimen total dose parasite (%) clearance at eot overall success (%) at f/u 100 mg/day x 21 days 29 to 38.9 mg/kg 10/10 (100) 2/10 (20) 4 mg/kg/day, days 1 to 5, and 10, 17, 24, 31, 38 40 mg/kg 8/9 (88.9) 0/7 (0) total 18/19 (94.7) 2/17 (11.8) when followed for 6 months or more after treatment, the overall success rate among immunocompetent patients was 96.5% and the overall success rate among immunocompromised patients was 11.8% due to relapse in the majority of patients. while case reports have suggested there may be a role for long-term therapy to prevent relapses in hiv coinfected patients (lopez-dupla, et al. j antimicrob chemother 1993; 32: 657-659), there are no data to date documenting the efficacy or safety of repeat courses of amphotericin b or of maintenance therapy with this drug among immunocompromised patients.

periences discomfort during infusion, the duration of infusion may be increased. the recommended initial dose of amphotericin b liposome for injection 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 to 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 to 5) and 3 on days 14, 21 immunocompromised patients 4 (days 1 to 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 amphotericin b liposome for injection must be reconstituted using sterile water for injection, usp (without a bacteriostatic agent). vials of amphotericin b liposome for injection containing 50 mg of amphotericin b are prepared as follows: reconstitution 1. aseptically add 12 ml of sterile water for injection, usp to each amphotericin b liposome for injection 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 amphotericin b liposome for injection. 2. immediately after the addition of water, shake the vial vigorously for 30 seconds to completely disperse the amphotericin b liposome for injection. amphotericin b liposome for injection 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) amphotericin b liposome for injection to be further diluted. 4. withdraw this amount of reconstituted amphotericin b liposome for injection 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 amphotericin b liposome for injection). 6. amphotericin b liposome for injection 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 . storage of amphotericin b liposome for injection unopened vials of lyophilized material are to be stored at temperatures up to 25° c (77° f). storage of reconstituted product concentrate the reconstituted product concentrate may be stored for up to 24 hours at 2° to 8°c (36° to 46°f) following reconstitution with sterile water for injection, usp. do not freeze. storage of diluted product injection of amphotericin b liposome for injection should commence within 6 hours of dilution with 5% dextrose injection. as with all parenteral drug products, the reconstituted amphotericin b 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 b liposome for injection or in the materials specified for reconstitution and dilution.

uct transfusion reaction 18.4 18.6 chills 47.5 75.9 infection 11.1 9.3 pain 14 12.8 sepsis 14 11.3 cardiovascular system chest pain 12 11.6 hypertension 7.9 16.3 hypotension 14.3 21.5 tachycardia 13.4 20.9 digestive system diarrhea 30.3 27.3 gastrointestinal hemorrhage 9.9 11.3 nausea 39.7 38.7 vomiting 31.8 43.9 metabolic and nutritional disorders alkaline phosphatase increased 22.2 19.2 alt (sgpt) increased 14.6 14 ast (sgot) increased 12.8 12.8 bilirubinemia 18.1 19.2 bun increased 21 31.1 creatinine increased 22.4 42.2 edema 14.3 14.8 hyperglycemia 23 27.9 hypernatremia 4.1 11 hypervolemia 12.2 15.4 hypocalcemia 18.4 20.9 hypokalemia 42.9 50.6 hypomagnesemia 20.4 25.6 peripheral edema 14.6 17.2 nervous system anxiety 13.7 11 confusion 11.4 13.4 headache 19.8 20.9 insomnia 17.2 14.2 respiratory system cough increased 17.8 21.8 dyspnea 23 29.1 epistaxis 14.9 20.1 hypoxia 7.6 14.8 lung disorder 17.8 17.4 pleural effusion 12.5 9.6 rhinitis 11.1 11 skin and appendages pruritus 10.8 10.2 rash 24.8 24.4 sweating 7 10.8 urogenital system hematuria 14 14 amphotericin b liposome for injection was well tolerated. amphotericin b liposome for injection had a lower incidence of chills, hypertension, hypotension, tachycardia, hypoxia, hypokalemia, and various events related to decreased kidney function as compared to amphotericin b deoxycholate. in pediatric patients (16 years of age or less) in this double-blind study, amphotericin b liposome for injection compared to amphotericin b deoxycholate, had a lower incidence of hypokalemia (37% versus 55%), chills (29% versus 68%), vomiting (27% versus 55%), and hypertension (10% versus 21%). similar trends, although with a somewhat lower incidence, were observed in open-label, randomized study 104-14 involving 205 febrile neutropenic pediatric patients (141 treated with amphotericin b liposome for injection and 64 treated with amphotericin b deoxycholate). pediatric patients appear to have more tolerance than older individuals for the nephrotoxic effects of amphotericin b deoxycholate. the following adverse events are based on the experience of 244 patients (202 adult and 42 pediatric patients) of whom 85 patients were treated with amphotericin b liposome for injection 3 mg/kg, 81 patients were treated with amphotericin b liposome for injection 5 mg/kg and 78 patients were treated with amphotericin b lipid complex 5 mg/kg in study 97-0-034, a randomized, double-blind, multi-center study in febrile, neutropenic patients. amphotericin b liposome for injection and amphotericin b lipid complex were infused over two hours. the incidence of adverse events occurring in more than 10% of subjects in one or more arms, regardless of relationship to study drug, are summarized in the following table: empirical therapy study 97-0-034 common adverse events adverse event by body system amphotericin b liposome for injection 3 mg/kg/day n = 85 % amphotericin b liposome for injection 5 mg/kg/day n = 81 % amphotericin b lipid complex 5 mg/kg/day n = 78 % body as a whole abdominal pain 12.9 9.9 11.5 asthenia 8.2 6.2 11.5 chills/rigors 40 48.1 89.7 sepsis 12.9 7.4 11.5 transfusion reaction 10.6 8.6 5.1 cardiovascular system chest pain 8.2 11.1 6.4 hypertension 10.6 19.8 23.1 hypotension 10.6 7.4 19.2 tachycardia 9.4 18.5 23.1 digestive system diarrhea 15.3 17.3 14.1 nausea 25.9 29.6 37.2 vomiting 22.4 25.9 30.8 metabolic and nutritional disorders alkaline phosphatase increased 7.1 8.6 12.8 bilirubinemia 16.5 11.1 11.5 bun increased 20 18.5 28.2 creatinine increased 20 18.5 48.7 edema 12.9 12.3 12.8 hyperglycemia 8.2 8.6 14.1 hypervolemia 8.2 11.1 14.1 hypocalcemia 10.6 4.9 5.1 hypokalemia 37.6 43.2 39.7 hypomagnesemia 15.3 25.9 15.4 liver function tests abnormal 10.6 7.4 11.5 nervous system anxiety 10.6 7.4 9 confusion 12.9 8.6 3.8 headache 9.4 17.3 10.3 respiratory system dyspnea 17.6 22.2 23.1 epistaxis 10.6 8.6 14.1 hypoxia 7.1 6.2 20.5 lung disorder 14.1 13.6 15.4 skin and appendages rash 23.5 22.2 14.1 the following adverse events are based on the experience of 267 patients (266 adult patients and 1 pediatric patient) of whom 86 patients were treated with amphotericin b liposome for injection 3 mg/kg, 94 patients were treated with amphotericin b liposome for injection 6 mg/kg and 87 patients were treated with amphotericin b deoxycholate 0.7 mg/kg in study 94-0-013 a randomized, double-blind, comparative multi-center trial, in the treatment of cryptococcal meningitis in hiv-positive patients. the incidence of adverse events occurring in more than 10% of subjects in one or more arms regardless of relationship to study drug are summarized in the following table: cryptococcal meningitis therapy study 94-0-013 common adverse events adverse event by body system amphotericin b liposome for injection 3 mg/kg/day n = 86 % amphotericin b liposome for injection 6 mg/kg/day n = 94 % amphotericin b 0.7 mg/kg/day n = 87 % body as a whole abdominal pain 7 7.4 10.3 infection 12.8 11.7 6.9 procedural complication 8.1 9.6 10.3 cardiovascular system phlebitis 9.3 10.6 25.3 digestive system anorexia 14 9.6 11.5 constipation 15.1 14.9 20.7 diarrhea 10.5 16 10.3 nausea 16.3 21.3 25.3 vomiting 10.5 21.3 20.7 hemic and lymphatic system anemia 26.7 47.9 43.7 leukopenia 15.1 17 17.2 thrombocytopenia 5.8 12.8 6.9 metabolic and nutritional disorders bilirubinemia 0 8.5 12.6 bun increased 9.3 7.4 10.3 creatinine increased 18.6 39.4 43.7 hyperglycemia 9.3 12.8 17.2 hypocalcemia 12.8 17 13.8 hypokalemia 31.4 51.1 48.3 hypomagnesemia 29.1 48.9 40.2 hyponatremia 11.6 8.5 9.2 liver function tests abnormal 12.8 4.3 9.2 nervous system dizziness 7 8.5 10.3 insomnia 22.1 17 20.7 respiratory system cough increased 8.1 2.1 10.3 skin and appendages rash 4.7 11.7 4.6 infusion-related reactions in study 94-0-002, the large, double-blind study of pediatric and adult febrile neutropenic patients, no premedication to prevent infusion-related reaction was administered prior to the first dose of study drug (day 1). amphotericin b liposome for injection-treated patients had a lower incidence of infusion-related fever (17% versus 44%), chills/rigors (18% versus 54%) and vomiting (6% versus 8%) on day 1 as compared to amphotericin b deoxycholate-treated patients. the incidence of infusion-related reactions on day 1 in pediatric and adult patients is summarized in the following table: incidence of day 1 infusion-related reactions (irr) by patient age * 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). 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%) cardiorespiratory events, except for vasodilatation (flushing), during all study drug infusions were more frequent in amphotericin b-treated patients as summarized in the following table: incidence of infusion-related cardiorespiratory events event amphotericin b liposome for injection 3 mg/kg/day n = 343 amphotericin b 0.6 mg/kg/day n = 344 hypotension 12 (3.5%) 28 (8.1%) tachycardia 8 (2.3%) 43 (12.5%) hypertension 8 (2.3%) 39 (11.3%) vasodilatation 18 (5.2%) 2 (0.6%) dyspnea 16 (4.7%) 25 (7.3%) hyperventilation 4 (1.2%) 17 (4.9%) hypoxia 1 (0.3%) 22 (6.4%) the percentage of patients who received drugs either for the treatment or prevention of infusion-related reactions (e.g., acetaminophen, diphenhydramine, meperidine and hydrocortisone) was lower in amphotericin b liposome for injection-treated patients compared with amphotericin b deoxycholate-treated patients. in the empirical therapy study 97-0-034, on day 1, where no premedication was administered, the overall incidence of infusion-related events of chills/rigors was significantly lower for patients administered amphotericin b liposome for injection compared with amphotericin b lipid complex. fever, chills/rigors and hypoxia were significantly lower for each amphotericin b liposome for injection group compared with the amphotericin b lipid complex group. the infusion-related event hypoxia was reported for 11.5% of amphotericin b lipid complex-treated patients compared with 0% of patients administered 3 mg/kg per day amphotericin b liposome for injection and 1.2% of patients treated with 5 mg/kg per day amphotericin b liposome for injection. incidence of day 1 infusion-related reactions (irr) chills/rigors empirical therapy study 97-0-034 amphotericin b liposome for injection amphotericin b lipid complex 5 mg/kg/day 3 mg/kg/day 5 mg/kg/day both total number of patients 85 81 166 78 patients with chills/rigors (day 1) 16 (18.8%) 19 (23.5%) 35 (21.1%) 62 (79.5%) patients with other notable reactions: fever (≥1.0ºc 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, chills/rigors and respiratory adverse events as summarized in the following table: incidence of infusion-related reactions study 94-0-013 amphotericin b liposome for injection 3 mg/kg/day amphotericin b liposome for injection 6 mg/kg/day amphotericin b 0.7 mg/kg/day total number of patients receiving at least one dose of study drug 86 94 87 patients with fever increase of >1°c 6 (7%) 8 (9%) 24 (28%) patients with chills/rigors 5 (6%) 8 (9%) 42 (48%) patients with nausea 11 (13%) 13 (14%) 18 (20%) patients with vomiting 14 (16%) 13 (14%) 16 (18%) respiratory adverse events 0 1 (1%) 8 (9%) there have been a few reports of flushing, back pain with or without chest tightness, and chest pain associated with amphotericin b liposome for injection administration; on occasion this has been severe. where these symptoms were noted, the reaction developed within a few minutes after the start of infusion and disappeared rapidly when the infusion was stopped. the symptoms do not occur with every dose and usually do not recur on subsequent administrations when the infusion rate is slowed. toxicity and discontinuation of dosing in study 94-0-002, a significantly lower incidence of grade 3 or 4 toxicity was observed in the amphotericin b liposome for injection group compared with the amphotericin b group. in addition, nearly three times as many patients administered amphotericin b required a reduction in dose due to toxicity or discontinuation of study drug due to an infusion-related reaction compared with those administered amphotericin b liposome for injection. in empirical therapy study 97-0-034, a greater proportion of patients in the amphotericin b lipid complex group discontinued the study drug due to an adverse event than in the amphotericin b liposome for injection groups. less common adverse events the following adverse events also have been reported in 2% to 10% of amphotericin b liposome for injection-treated patients receiving chemotherapy or bone marrow transplantation, or who had hiv disease in six comparative, clinical trials: body as a whole abdomen enlarged, allergic reaction, cellulitis, cell-mediated immunological reaction, face edema, graft-versus-host disease, malaise, neck pain, and procedural complication. cardiovascular system arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder, and vasodilatation (flushing). digestive system anorexia, constipation, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, hepatocellular damage, hepatomegaly, liver function test abnormal, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis, and veno-occlusive liver disease. hemic & lymphatic system anemia, coagulation disorder, ecchymosis, fluid overload, petechia, prothrombin decreased, prothrombin increased, and thrombocytopenia. metabolic & nutritional disorders acidosis, amylase increased, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hyponatremia, hypophosphatemia, hypoproteinemia, lactate dehydrogenase increased, nonprotein nitrogen (npn) increased, and respiratory alkalosis. musculoskeletal system arthralgia, bone pain, dystonia, myalgia, and rigors. nervous system agitation, coma, convulsion, cough, depression, dysesthesia, dizziness, hallucinations, nervousness, paresthesia, somnolence, thinking abnormality, and tremor. respiratory system asthma, atelectasis, hemoptysis, hiccup, hyperventilation, influenza-like symptoms, lung edema, pharyngitis, pneumonia, respiratory insufficiency, respiratory failure, and sinusitis. skin & appendages alopecia, dry skin, herpes simplex, injection site inflammation, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, and vesiculobullous rash. special senses conjunctivitis, dry eyes, and eye hemorrhage. urogenital system abnormal renal function, acute kidney failure, acute renal failure, dysuria, kidney failure, toxic nephropathy, urinary incontinence, and vaginal hemorrhage. post-marketing experience the following infrequent adverse experiences have been reported in post-marketing surveillance, in addition to those mentioned above: angioedema, erythema, urticaria, bronchospasm, cyanosis/hypoventilation, pulmonary edema, agranulocytosis, hemorrhagic cystitis, and rhabdomyolysis. clinical laboratory values the effect of amphotericin b liposome for injection on renal and hepatic function and on serum electrolytes was assessed from laboratory values measured repeatedly in study 94-0-002. the frequency and magnitude of hepatic test abnormalities were similar in the amphotericin b liposome for injection and amphotericin b groups. nephrotoxicity was defined as creatinine values increasing 100% or more over pretreatment levels in pediatric patients, and creatinine values increasing 100% or more over pretreatment levels in adult patients, provided the peak creatinine concentration was >1.2 mg/dl. hypokalemia was defined as potassium levels ≤ 2.5 mmol/l any time during treatment. incidence of nephrotoxicity, mean peak serum creatinine concentration, mean change from baseline in serum creatinine, and incidence of hypokalemia in the double-blind, randomized study were lower in the amphotericin b liposome for injection group as summarized in the following table: study 94-0-002 laboratory evidence of nephrotoxicity amphotericin b liposome for injection 3 mg/kg/day amphotericin b 0.6 mg/kg/day total number of patients receiving at least one dose of study drug 343 344 nephrotoxicity 64 (18.7%) 116 (33.7%) mean peak creatinine 1.24 mg/dl 1.52 mg/dl mean change from baseline in creatinine 0.48 mg/dl 0.77 mg/dl hypokalemia 23 (6.7%) 40 (11.6%) the effect of amphotericin b liposome for injection (3 mg/kg/day) vs. amphotericin b (0.6 mg/kg/day) on renal function in adult patients enrolled in this study is illustrated in the following figure: mean change in creatinine over time 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%) 2x baseline serum creatinine 12 (14%) 20 (21%) 29 (33%) mean change in creatinine over time in study 94-0-002 mean creatinine concentrations over time

ossibly 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.

iposome for injection should only be used during pregnancy if the possible benefits to be derived outweigh the potential risks involved.

5 years or older) comprised 72 patients. it has not been necessary to alter the dose of amphotericin b liposome for injection for this population. as with most other drugs, elderly patients receiving amphotericin b liposome for injection should be carefully monitored.

l amphotericin b (mean ± sd) after the first dose and at steady state are shown in the table below. pharmacokinetic parameters of amphotericin b liposome for injection dose 1 mg/kg/day 2.5 mg/kg/day 5 mg/kg/day day 1 n = 8 last n = 7 1 n =7 last n = 7 1 n = 12 last n = 9 parameters c max (mcg/ml) 7.3 ± 3.8 12.2 ± 4.9 17.2 ± 7.1 31.4 ± 17.8 57.6 ± 21 83 ± 35.2 auc 0-24 (mcg·hr/ml) 27 ± 14 60 ± 20 65 ± 33 197 ± 183 269 ± 96 555 ± 311 t ½ (hr) 10.7 ± 6.4 7 ± 2.1 8.1 ± 2.3 6.3 ± 2 6.4 ± 2.1 6.8 ± 2.1 v ss (l/kg) 0.44 ± 0.27 0.14 ± 0.05 0.40 ± 0.37 0.16 ± 0.09 0.16 ± 0.10 0.10 ± 0.07 cl (ml/hr/kg) 39 ± 22 17 ± 6 51 ± 44 22 ± 15 21 ± 14 11 ± 6 distribution based on total amphotericin b concentrations measured within a dosing interval (24 hours) after administration of amphotericin b liposome for injection, the mean half-life was 7 to 10 hours. however, based on total amphotericin b concentration measured up to 49 days after dosing of amphotericin b liposome for injection, the mean half-life was 100 to 153 hours. the long terminal elimination half-life is probably a slow redistribution from tissues. steady state concentrations were generally achieved within 4 days of dosing. although variable, mean trough concentrations of amphotericin b remained relatively constant with repeated administration of the same dose over the range of 1 to 5 mg/kg/day, indicating no significant drug accumulation in the serum. metabolism the metabolic pathways of amphotericin b after administration of amphotericin b liposome for injection are not known. excretion the mean clearance at steady state was independent of dose. the excretion of amphotericin b after administration of amphotericin b liposome for injection has not been studied. pharmacokinetics in special populations renal impairment the effect of renal impairment on the disposition of amphotericin b after administration of amphotericin b liposome for injection has not been studied. however, amphotericin b 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 b after administration of amphotericin b liposome for injection is not known. pediatric and elderly patients the pharmacokinetics of amphotericin b after administration of amphotericin b liposome for injection in pediatric and elderly patients has not been studied; however, amphotericin b 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 b after administration of amphotericin b liposome for injection is not known.