Amphotericin B cholesteryl sulfate warnings and precautions

# Warnings
Anaphylaxis has been reported with amphotericin B deoxycholate and other amphotericin B-containing drugs. Immediate treatment of anaphylaxis or anaphylactoid reactions is required. Epinephrine, oxygen, intravenous steroids, and airway management should be administered as indicated. If severe respiratory distress occurs, the infusion should be immediately discontinued. The patient should not receive further infusions of AMPHOTEC.

# Precautions

## General
AMPHOTEC should be administered intravenously. Acute infusionrelated reactions including fever, chills, hypoxia, hypotension, nausea, or tachypnea, may occur 1 to 3 hours after starting intravenous infusion. These reactions are usually more severe or more frequent with the initial doses of AMPHOTEC and usually diminish with subsequent doses. Acute infusion-related reactions can be managed by pretreatment with antihistamines and corticosteroids and/or by reducing the rate of infusion and by prompt administration of antihistamines and corticosteroids.
Rapid intravenous infusion should be avoided.

## Laboratory Tests
Particularly tests of renal and hepatic function, serum electrolytes, complete blood count and prothrombin time should be monitored as medically indicated.

## Drug Interactions
No formal drug interaction studies have been conducted with AMPHOTEC. When administered concomitantly, the following drugs are known to interact with amphotericin B; therefore the following drugs may interact with AMPHOTEC.

## Antineoplastic Agents
Concurrent use of antineoplastic agents and amphotericin B may enhance the potential for renal toxicity, bronchospasm, and hypotension. Caution is urged when antineoplastic agents are given concomitantly with AMPHOTEC.

## 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 corticosteroids or corticotropin are used concomitantly with AMPHOTEC, serum electrolytes and cardiac function should be monitored.

## Cyclosporine and Tacrolimus
In the same randomized, double-blind, empiric trial to compare AMPHOTEC and amphotericin B deoxycholate, patients with normal baseline serum creatinine were prospectively enrolled into four strata: adults receiving cyclosporine or tacrolimus (n=89); or pediatric patients (< 16 years old) receiving cyclosporine or tacrolimus (n=15); adults not receiving cyclosporine or tacrolimus (n=75); or pediatric patients not receiving cyclosporine or tacrolimus (n=34). Patients were assessed for renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or  50% decrease from baseline calculated creatinine clearance. Adults and pediatric patients receiving cyclosporine or tacrolimus in addition to AMPHOTEC had a significantly lower rate of renal toxicity (31%, 16/51), compared to the amphotericin B deoxycholate patients receiving cyclosporine or tacrolimus (68%, 34/50). In the adults and pediatric patients not receiving cyclosporine or tacrolimus, only 8% (4/51) of the AMPHOTEC patients experienced renal toxicity compared to 35% (17/49) of the amphotericin B deoxycholate patients.

## Digitalis Glycosides
Concurrent use of amphotericin B may induce hypokalemia and may potentiate digitalis toxicity. If digitalis glycosides are administered concomitantly with AMPHOTEC, 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. Caution is urged when flucytosine is given concomitantly with AMPHOTEC.

## 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.

## Other Nephrotoxic Medications
Concurrent use of amphotericin B and agents such as aminoglycosides and pentamidine may enhance the potential for drug-induced renal toxicity. Caution is urged if aminoglycosides or pentamidine are used concomitantly with AMPHOTEC. 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. If skeletal muscle relaxants are administered concomitantly with AMPHOTEC, serum potassium levels should be closely monitored.

## Carcinogenesis, Mutagenesis and Impairment of Fertility
No long-term studies in animals have been performed with AMPHOTEC or amphotericin B deoxycholate to evaluate carcinogenic potential. AMPHOTEC and/or amphotericin B deoxycholate were not mutagenic in vitro with and without an exogenous mammalian microsomal metabolic activation system when assayed in the Salmonella reverse mutation assay, the CHO chromosomal aberration assay and the mouse lymphoma forward mutation assay. AMPHOTEC was also negative in vivo in the mouse bone marrow micronucleus assay. No studies have been conducted to determine if AMPHOTEC affects fertility or if it produces adverse effects when administered peri- or post-natally in animals. In multiple dose toxicity studies of up to 13 weeks in rats at doses up to 0.5 times the recommended human dose and in dogs at doses up to 0.4 times the recommended human dose (based on body surface area), ovarian and testicular histology were unaffected.

## Pregnancy
Teratogenic Effects. Pregnancy Category B:
There are no reports of pregnant women having been treated with AMPHOTEC. Reproductive studies with AMPHOTEC in rats at doses up to 0.4 times the recommended human dose and in rabbits at doses up to 1.1 times the recommended human dose have revealed no evidence of harm to the fetus due to treatment with AMPHOTEC. Because animal reproduction studies are not always predictive of human response and because adequate and well controlled studies have not been conducted in pregnant women, AMPHOTEC should be used during pregnancy only if the anticipated benefit to the patient outweighs the potential risk to the fetus.

## Nursing Mothers
It is not known whether AMPHOTEC is excreted in milk. Because of the potential for serious adverse reactions in nursing infants from amphotericin B, a decision should be made to discontinue nursing or discontinue treatment with AMPHOTEC, taking into account the importance of the drug to the mother.

## Pediatric Use
Ninety-seven pediatric patients with systemic fungal infections have been treated with AMPHOTEC, at daily doses (mg/kg) similar to those given to adults. No unexpected adverse events have been reported. In the same empiric, multicenter trial, pediatric patients (< 16 years) treated with AMPHOTEC had significantly less renal toxicity than amphotericin B deoxycholate patients. Only 12% (3/25) of pediatric patients treated with AMPHOTEC developed nephrotoxicity compared to 52% (11/21) of pediatric patients receiving amphotericin B deoxycholate. Renal toxicity defined as either a doubling or an increase of 1.0 mg/dL or more from baseline serum creatinine, or  50% decrease from baseline calculated creatinine clearance.

## Geriatric Use
Sixty-eight patients at least 65 years of age have been treated with AMPHOTEC. No unexpected adverse events have been reported.