ABELCET: Package Insert and Label Information

ABELCET- amphotericin b, dimyristoylphosphatidylcholine, dl- and dimyristoylphosphatidylglycerol, dl- injection
Leadiant Biosciences, Inc.

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-α-dimyristoylphosphatidylcholine (DMPC) and l-α-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- 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.

It has a molecular weight of 924.09 and a molecular formula of C 47 H 73 NO 17 . The structural formula is:

chemical image
(click image for full-size original)

ABELCET ® is provided as a sterile, opaque suspension in 20 mL glass, single-use vials. Each 20 mL vial contains 100 mg of amphotericin B in 20 mL of suspension (see DOSAGE AND ADMINISTRATION), and each mL of ABELCET ® contains:

Amphotericin B USP 5.0 mg

l-α-dimyristoylphosphatidylcholine (DMPC) 3.4 mg

l-α-dimyristoylphosphatidylglycerol (DMPG) 1.5 mg

Sodium Chloride USP 9.0 mg

Water for Injection USP, q.s. 1.0 mL

MICROBIOLOGY

Mechanism of Action

The active component of ABELCET ® , amphotericin B, acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. Mammalian cell membranes also contain sterols, and damage to human cells is believed to occur through the same mechanism of action.

Activity in vitro and in vivo

ABELCET ® shows in vitro activity against Aspergillus sp. (n=3) and Candida sp. (n=10), with MICs generally <1 μg/mL. Depending upon the species and strain of Aspergillus and Candida tested, significant in vitro differences in susceptibility to amphotericin B have been reported (MICs ranging from 0.1 to >10 μg/mL).

ABELCET ® is active in animal models against Aspergillus fumigatus, Candida albicans, C. guillermondii, C. stellatoideae , and C. tropicalis, Cryptococcus sp., Coccidioidomyces sp., Histoplasma sp., and Blastomyces sp. in which end-points were clearance of microorganisms from target organ(s) and/or prolonged survival of infected animals.

Drug Resistance

Fungal species with decreased susceptibility to amphotericin B have been isolated after serial passage in culture media containing the drug, and from some patients receiving prolonged therapy. Although the relevance of drug resistance to clinical outcome has not been established, fungal species which are resistant to amphotericin B may also be resistant to ABELCET ®.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria, and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL PHARMACOLOGY

Pharmacokinetics

The assay used to measure amphotericin B in the blood after the administration of ABELCET ® does not distinguish amphotericin B that is complexed with the phospholipids of ABELCET ® from amphotericin B that is uncomplexed.

The pharmacokinetics of amphotericin B after the administration of ABELCET ® are nonlinear. Volume of distribution and clearance from blood increase with increasing dose of ABELCET ® , resulting in less than proportional increases in blood concentrations of amphotericin B over a dose range of 0.6-5 mg/kg/day. The pharmacokinetics of amphotericin B in whole blood after the administration of ABELCET ® and amphotericin B desoxycholate are:

Pharmacokinetic Parameters of Amphotericin B in Whole Blood

in Patients Administered Multiple Doses of ABELCET ® or Amphotericin B Desoxycholate

Pharmacokinetic Parameter

ABELCET ® 5 mg/kg/day for 5-7 days Mean ± SD

Amphotericin B 0.6 mg/kg/day for 42 days a Mean ± SD

Peak Concentration ( μg/mL)

1.7 ± 0.8 (n=10) b

1.1 ± 0.2 (n=5)

Concentration at End of Dosing Interval (μg/mL)

0.6 ± 0.3 (n=10 b

0.4 ± 0.2 (n=5)

Area Under Blood Concentration-Time Curve (AUC 0-24h ) (μg*h/mL)

14.0 ± 7.0 (n=14) b,c

17.1 ± 5 (n=5)

Clearance (mL/h*kg)

436.0.± 188.5 (n=14) b,c

38.0 ± 15 (n=5)

Apparent Volume of Distribution (Vd area ) (L/kg)

131.0.± 57.7 (n=8) c

5.0.± 2.8 (n=5)

Terminal Elimination Half-Life (h)

173.4 ± 78.0 (n=8) c

91.1 ± 40.9 (n=5)

Amount Excreted in Urine Over 24 h After Last Dose (% of dose) d

0.9 ± 0.4 (n=8) c

9.6 ± 2.5 (n=8)

a Data from patients with mucocutaneous leishmaniasis. Infusion rate was 0.25 mg/kg/h.

b Data from studies in patients with cytologically proven cancer being treated with chemotherapy or neutropenic patients with presumed or proven fungal infection. Infusion rate was 2.5 mg/kg/h.

c Data from patients with mucocutaneous leishmaniasis. Infusion rate was 4 mg/kg/h.

d Percentage of dose excreted in 24 hours after last dose.

The large volume of distribution and high clearance from blood of amphotericin B after the admistration of ABELCET ® probably reflect uptake by tissues. The long terminal elimination half-life probably reflects a slow redistribution from tissues. Although amphotericin B is excreted slowly, there is little accumulation in the blood after repeated dosing. AUC of amphotericin B increased approximately 34% from day 1 after the administration of ABELCET ® 5 mg/kg/day for 7 days. The effect of gender or ethnicity on the pharmacokinetics of ABELCET ® has not been studied.

Tissue concentrations of amphotericin B have been obtained at autopsy from one heart transplant patient who received three doses of ABELCET ® at 5.3 mg/kg/day:

Concentration in Human Tissues

Organ

Amphotericin B

Tissue Concentration (µg/g)

Spleen

290.0

Lung

222.0

Liver

196.0

Lymph Node

7.6

Kidney

6.9

Heart 0

5.

Brain

1.6

This pattern of distribution is consistent with that observed in preclinical studies in dogs in which greatest concentrations of amphotericin B after ABELCET ® administration were observed in the liver, spleen, and lung; however, the relationship of tissue concentrations of amphotericin B to its biological activity when administered as ABELCET ® is unknown.

Special Populations

Hepatic Impairment: The effect of hepatic impairment on the disposition of ABELCET ® is not known.

Renal Impairment: The effect of renal impairment on the disposition of ABELCET ® is not known. The effect of dialysis on the elimination of ABELCET ® has not been studied; however, amphotericin B is not removed by hemodialysis when administered as amphotericin B desoxycholate.

Pediatric and Elderly Patients: The pharmacokinetics and pharmacodynamics of pediatric patients (≤16 years of age) and elderly patients (≥65 years of age) have not been studied.

INDICATIONS AND USAGE

ABELCET ® is 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 failing 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/mm3; 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 is precluded since these data were obtained from two separate studies.

figure 1
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[ ]= Number of patients at each time point.

Note: These curves do not represent the clinical course of a given patient, but that of an open-label cohort of patients.

figure 2
(click image for full-size original)

[ ]= Number of patients at each time point.

Note: These curves do not represent the clinical course of a given patient, but that of an open-label cohort of patients.

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 ®.

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