Amphotericin B lipid complex warnings and precautions

# Warnings
Anaphylaxis has been reported with amphotericin B desoxycholate and other amphotericin B-containing drugs. Anaphylaxis has been reported with ABELCET with an incidence rate of <0.1%. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of ABELCET.

# Precautions

### General
As with any amphotericin B-containing product, during the initial dosing of ABELCET, the drug should be administered under close clinical observation by medically trained personnel.
Acute reactions including fever and chills may occur 1 to 2 hours after starting an intravenous infusion of ABELCET. These reactions are usually more common with the first few doses of ABELCET and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.

### Laboratory Tests
Serum creatinine should be monitored frequently during ABELCET therapy (see ADVERSE REACTIONS). It is also advisable to regularly monitor liver function, serum electrolytes (particularly magnesium and potassium), and complete blood counts.

### Drug Interactions
No formal clinical studies of drug interactions have been conducted with ABELCET. However, when administered concomitantly, the following drugs are known to interact with amphotericin B; therefore, the following drugs may interact with ABELCET:
Antineoplastic agents: Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Antineoplastic agents should be given concomitantly with ABELCET with great caution.
Corticosteroids and corticotropin (ACTH): Concurrent use of corticosteroids and corticotropin (ACTH) with amphotericin B may potentiate hypokalemia which could predispose the patient to cardiac dysfunction. If used concomitantly with ABELCET, serum electrolytes and cardiac function should be closely monitored.
Cyclosporin A: Data from a prospective study of prophylactic ABELCET in 22 patients undergoing bone marrow transplantation suggested that concurrent initiation of cyclosporin A and ABELCET within several days of bone marrow ablation may be associated with increased nephrotoxicity.
Digitalis glycosides: Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. When administered concomitantly with ABELCET, serum potassium levels should be closely monitored.
Flucytosine: Concurrent use of flucytosine with amphotericin B-containing preparations may increase the toxicity of flucytosine by possibly increasing its cellular uptake and/or impairing its renal excretion. Flucytosine should be given concomitantly with ABELCET with caution.
Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.): Antagonism between amphotericin B and imidazole derivatives such as miconazole and ketoconazole, which inhibit ergosterol synthesis, has been reported in both in vitro and in vivo animal studies. The clinical significance of these findings has not been determined.
Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving intravenous amphotericin B and leukocyte transfusions. Leukocyte transfusions and ABELCET should not be given concurrently.
Other nephrotoxic medications: Concurrent use of amphotericin B and agents such as aminoglcosides and pentamidine may enhance the potential for drug-induced renal toxicity. Aminoglycosides and pentamidine should be used concomitantly with ABELCET only with great caution. 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 with ABELCET, serum potassium levels should be closely monitored.
Zidovudine: Increased myelotoxicity and nephrotoxicity were observed in dogs when either ABELCET (at doses 0.16 or 0.5 times the recommended human dose) or amphotericin B desoxycholate (at 0.5 times the recommended human dose) were administered concomitantly with zidovudine for 30 days. If zidovudine is used concomitantly with ABELCET, renal and hematologic function should be closely monitored.

### Carcinogenesis, Mutagenesis, and Impairment of Fertility
No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCET. The following in vitro (with and without metabolic activation) and in vivo studies to assess ABELCET for mutagenic potential were conducted: bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, and in vivo mouse micronucleus assay. ABELCETwas found to be without mutagenic effects in all assay systems. Studies demonstrated that ABELCET had no impact on fertility in male and female rats at doses up to 0.32 times the recommended human dose (based on body surface area considerations).

### Pregnancy
There are no reports of pregnant women having been treated with ABELCET. Teratogenic Effects. Pregnancy Category B: Reproductive studies in rats and rabbits at doses of ABELCET up to 0.64 times the human dose revealed no harm to the fetus. Because animal reproductive studies are not always predictive of human response, and adequate and well-controlled studies have not been conducted in pregnant women, ABELCET should be used during pregnancy only after taking into account the importance of the drug to the mother.

### Nursing Mothers
It is not known whether ABELCET is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in breast-fed infants from ABELCET, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

### Pediatric Use
One hundred eleven children (2 were enrolled twice and counted as separate patients), age 16 years and under, of whom 11 were less than 1 year, have been treated with ABELCET at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. In one single-center study, 5 children with hepatosplenic candidiasis were effectively treated with 2.5 mg/kg/day of ABELCET. No serious unexpected adverse events have been reported.

### Geriatric Use
Forty-nine elderly patients, age 65 years or over, have been treated with ABELCET at 5 mg/kg/day in two open-label studies and one small, prospective, single-arm study. No serious unexpected adverse events have been reported.