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amphotericin b, dimyristoylphosphatidylcholine, dl- and dimyristoylphosphatidylglycerol, dl-
Overview
What is ABELCET?
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 . 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 CHNO. The structural formula is:
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 (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 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 and
ABELCET shows in vitro activity against sp. (n=3) and sp. (n=10), with MICs generally <1 μg/mL. Depending upon the species and strain of and tested, significant differences in susceptibility to amphotericin B have been reported (MICs ranging from 0.1 to >10 μg/mL). However, standardized techniques for susceptibility testing for antifungal agents have not been established, and results of susceptibility studies do not necessarily correlate with clinical outcome.
ABELCET is active in animal models against , and sp., sp., sp., and 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.
What does ABELCET look like?
What are the available doses of ABELCET?
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What should I talk to my health care provider before I take ABELCET?
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How should I use ABELCET?
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.
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:
[ ]= 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.
[ ]= 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.
The recommended daily dosage for adults and children is 5 mg/kg given as a single infusion. ABELCET should be administered by intravenous infusion at a rate of 2.5 mg/kg/h. If the infusion time exceeds 2 hours, mix the contents by shaking the infusion bag every 2 hours.
Renal toxicity of ABELCET, as measured by serum creatinine levels, has been shown to be dose dependent. Decisions about dose adjustments should be made only after taking into account the overall clinical condition of the patient.
Preparation of Admixture for Infusion:
DO NOT DILUTE WITH SALINE SOLUTIONS OR MIX WITH OTHER DRUGS OR ELECTROLYTES as the compatibility of ABELCET with these materials has not been established. An existing intravenous line should be flushed with 5% Dextrose Injection before infusion of ABELCET, or a separate infusion line should be used. DO NOT USE AN IN-LINE FILTER.
The diluted ready-for-use admixture is stable for up to 48 hours at 2° to 8°C (36° to 46°F) and an additional 6 hours at room temperature.
What interacts with ABELCET?
ABELCET is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.
What are the warnings of ABELCET?
The glucocorticoid activity of Megestrol Acetate Oral Suspension USP has not been fully evaluated. Clinical cases of new onset diabetes mellitus, exacerbation of pre-existing diabetes mellitus, and overt Cushing's syndrome have been reported in association with the chronic use of megestrol acetate. In addition, clinical cases of adrenal insufficiency have been observed in patients receiving or being withdrawn from chronic megestrol acetate therapy in the stressed and non-stressed state. Furthermore, adrenocorticotropin (ACTH) stimulation testing has revealed the frequent occurrence of asymptomatic pituitary-adrenal suppression in patients treated with chronic megestrol acetate therapy. Therefore, the possibility of adrenal insufficiency should be considered in any patient receiving or being withdrawn from chronic megestrol acetate therapy who presents with symptoms and/or signs suggestive of hypoadrenalism (e.g., hypotension, nausea, vomiting, dizziness, or weakness) in either the stressed or non-stressed state. Laboratory evaluation for adrenal insufficiency and consideration of replacement or stress doses of a rapidly acting glucocorticoid are strongly recommended in such patients. Failure to recognize inhibition of the hypothalamic-pituitary-adrenal axis may result in death. Finally, in patients who are receiving or being withdrawn from chronic megestrol acetate therapy, consideration should be given to the use of empiric therapy with stress doses of a rapidly acting glucocorticoid in conditions of stress or serious intercurrent illness (e.g., surgery, infection).
What are the precautions of ABELCET?
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:
Corticosteroids and corticotropin (ACTH):
Cyclosporin A:
Digitalis glycosides:
Flucytosine
Imidazoles (e.g., ketoconazole, miconazole, clotrimazole, fluconazole, etc.):
Leukocyte transfusions:
Other nephrotoxic medications
Skeletal muscle relaxants:
Zidovudine:
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
No long-term studies in animals have been performed to evaluate the carcinogenic potential of ABELCET. The following (with and without metabolic activation) and 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 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).
Pregnancy:
There are no reports of pregnant women having been treated with ABELCET. Teratogenic Effects. 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.
What are the side effects of ABELCET?
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.
The causal association between these adverse events and ABELCET is uncertain.
The following adverse events have also been reported in patients using ABELCET in open-label, uncontrolled clinical studies. The causal association between these adverse events and ABELCET is uncertain.
Body as a whole:
Allergic:
Cardiopulmonary:
Dermatological:
Gastrointestinal:
Hematologic:
Musculoskeletal:
Neurologic:
Urogenital:
Serum electrolyte abnormalities:
Liver function test abnormalities:
Renal function test abnormalities:
Other test abnormalities:
To report SUSPECTED ADVERSE REACTIONS, contact Leadiant Biosciences, Inc. at 1-888-393-4584 or by email at drugsafety@leadiant.com or contact the FDA at 1-800-FDA-1088 or www.fda.gov/safety/medwatch.
| Adverse Events with an Incidence of ≥3% (N=556) | |
| Chills | 18 |
| Fever | 14 |
| Increased Serum Creatinine | 11 |
| Multiple Organ Failure | 11 |
| Nausea | 9 |
| Hypotension | 8 |
| Respiratory Failure | 8 |
| Vomiting | 8 |
| Dyspnea | 7 |
| Sepsis | 7 |
| Diarrhea | 6 |
| Headache | 6 |
| Cardiac Arrest | 6 |
| Hypertension | 5 |
| Hypokalemia | 5 |
| Infection | 5 |
| Kidney Failure | 5 |
| Pain | 5 |
| Thrombocytopenia | 5 |
| Anemia | 4 |
| Hyperbilirubinemia | 4 |
| Gastrointestinal Hemorrhage | 4 |
| Leukopenia | 4 |
| Rash | 4 |
| Respiratory Disorder | 4 |
| Chest Pain | 3 |
| Nausea and Vomiting | 3 |
What should I look out for while using ABELCET?
ABELCET is contraindicated in patients who have shown hypersensitivity to amphotericin B or any other component in the formulation.
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.
What might happen if I take too much ABELCET?
Amphotericin B desoxycholate overdose has been reported to result in cardio-respiratory arrest. Fifteen patients have been reported to have received one or more doses of ABELCET between 7-13 mg/kg. None of these patients had a serious acute reaction to ABELCET. If an overdose is suspected, discontinue therapy, monitor the patient’s clinical status, and administer supportive therapy as required. ABELCET is not hemodialyzable.
How should I store and handle ABELCET?
Single-use vials along with 5-micron filter needles are individually packaged. 100 mg of ABELCET in 20 mL of suspension NDC 57665-101-41Single-use vials along with 5-micron filter needles are individually packaged. 100 mg of ABELCET in 20 mL of suspension NDC 57665-101-41
