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Abelcet Injection (Enzon)

Abelcet Injection (Enzon)

DESCRIPTION

ABELCET ® is a sterile, pyrogen-free suspension for intravenous infusion. ABELCET ® consists of amphotericin B complexed with two phospholipids in a 1:1 drug-to-lipid molar ratio. The two phospholipids, L-(alpha)-dimyristoylphosphatidylcholine (DMPC) and L-(alpha)-dimyristoylphosphatidylglycerol (DMPG), are present in a 7:3 molar ratio. ABELCET ® is yellow and opaque in appearance, with a pH of 5-7.

NOTE: Liposomal encapsulation or incorporation in a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated or nonlipid-associated drug. In addition, different liposomal or lipid-complexed 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 functional properties of these drug products.

Amphotericin B is a 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-(beta)-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.

INDICATIONS AND USAGE

ABELCET ® indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. This is based on open-label treatment of patients judged by their physicians to be intolerant to or failing conventional amphotericin B therapy (See DESCRIPTION OF CLINICAL STUDIES ).

DESCRIPTION OF CLINICAL STUDIES

Fungal infections

Data from 473 patients were pooled from three open-label studies in which ABELCET ® was provided for the treatment of patients with invasive fungal infections who were judged by their physicians to be refractory to or intolerant of conventional amphotericin B, or who had preexisting nephrotoxicity. Results of these studies demonstrated effectiveness of ABELCET ® in the treatment of invasive fungal infections as a second line therapy. Patients were defined by their individual physician as being refractory to or falling conventional amphotericin B therapy based on overall clinical judgement after receiving a minimum total dose of 500 mg of amphotericin B. Nephrotoxicity was defined as a serum creatinine that had increased to >2.5 mg/dL in adults and >1.5 mg/dL in pediatric patients, or a creatinine clearance of <25 mL/min while receiving conventional amphotericin B therapy. Of the 473 patients, four were enrolled more than once; each enrollment contributed separately to the denominator. The median age was 39 years (range of <1 to 93 years); 307 patients were male and 166 female. Patients were Caucasian (381, 81%), African-American (41, 9%), Hispanic (27, 6%), Asian (10, 2%), and various other races (14, 3%). The median baseline neutrophil count was 4,000 PMN/mm 3 of these, 101 (21%) had a baseline neutrophil count <500/mm 3 .

Two-hundred eighty-two patients of the 473 patients were considered evaluable for response to therapy; the other 191 patients were excluded on the basis of unconfirmed diagnosis, confounding factors, concomitant systemic antifungal therapy, or receiving 4 doses or less of ABELCET ® . For evaluable patients, the following fungal infections were treated (n=282): aspergillosis (n=111), candidiasis (n=87), zygomycosis (n=25), cryptococcosis (n=16), and fusariosis (n=11). There were fewer than 10 evaluable patients for each of several other fungal species treated.

For each type of fungal infection listed above there were some patients successfully treated. However, in the absence of controlled studies it is unknown how response would have compared to either continuing conventional amphotericin B therapy or the use of alternative antifungal agents.

Renal Function: Patients with aspergillosis who initiated treatment with ABELCET ® when serum creatinine was above 2.5 mg/dL experienced a decline in serum creatinine during treatment (Figure 1). Serum creatinine levels were also lower during treatment with ABELCET ® when compared to the serum creatinine levels of patients treated with conventional amphotericin B in a retrospective historical control study. Meaningful statistical testing of the differences between these two groups in precluded since these data were obtained from two separate studies.

In a randomized study of ABELCET ® for the treatment of invasive candidiasis in patients with normal baseline renal function, the incidence of nephrotoxicity was significantly less for ABELCET ® at a dose of 5 mg/kg/day than for conventional amphotericin B at a dose of 0.7 mg/kg/day.

Despite generally less nephrotoxicity of ABELCET ® observed at a dose of 5 mg/kg/day compared with conventional amphotericin B therapy at a dose range of 0.6-1 mg/kg/day, dose-limiting renal toxicity may still be observed with ABELCET ® . Renal toxicity of doses greater than 5 mg/kg/day of ABELCET ® has not been formally studied.

CONTRAINDICATIONS

ABELCET ® is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.

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. ABELCET ® was 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).

ADVERSE REACTIONS

The total safety data base is composed of 921 patients treated with ABELCET ® (5 patients were enrolled twice and counted as separate patients), of whom 775 were treated with 5 mg/kg/day. Of these 775 patients, 194 patients were treated in four comparative studies; 25 were treated in open-label, non-comparative studies; and 556 patients were treated in an open-label, emergency-use program. Most had underlying hematologic neoplasms, and many were receiving multiple concomitant medications. Of the 556 patients treated with ABELCET ® , 9% discontinued treatment due to adverse events regardless of presumed relationship to study drug. In general, the adverse events most commonly reported with ABELCET ® were transient chills and/or fever during infusion of the drug.

HOW SUPPLIED

Single-use vials along with 5-micron filter needles are individually packaged. 100 mg of ABELCET ® in 20 mL of suspension NDC 57665-101-41