Amphotericin B Lipid Complex (Systemic)
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VA CLASSIFICATION
Primary: AM700
Commonly used brand name(s): ABELCET.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antifungal (systemic)—
Indications
Accepted
Fungal infections, invasive (treatment)—Amphotericin B lipid complex is indicated in the treatment of invasive fungal infections in patients who are refractory to or intolerant of conventional amphotericin B therapy. {01}
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Chemistry
A suspension of amphotericin B complexed with two phospholipids, L-alpha-dimyristoylphosphatidylcholine (DMPC) and L-alpha-dimyristoylphosphatidylglycerol (DMPG), in a 1:1 drug-to-lipid molar ratio {01}.
Molecular weight—
Amphotericin B: 924.1 {02}
Mechanism of action/Effect:
Amphotericin B acts by binding to sterols in the cell membrane of susceptible fungi, with a resultant change in the permeability of the membrane. {01}
Distribution:
High concentrations are found in the spleen, lung, and liver; also found in lymph node, kidney, heart, and brain tissues. {01}
Apparent Vol D—Approximately 131 L per kg. {01}
Biotransformation:
Metabolic pathways unknown. {01}
Half-life:
Terminal—Approximately 7.2 days. {01}
Peak plasma concentration
After 5 mg per kg of body weight per day for 5 to 7 days—Approximately 1.7 micrograms per mL (1.8 micromoles per liter). {01}
Elimination:
Renal; approximately 0.9% is excreted in the urine over 24 hours after administration of the last dose. {01}
In dialysis—Amphotericin B lipid complex is not hemodialyzable. {01}
Precautions to Consider
Carcinogenicity
Long-term studies in animals to evaluate the carcinogenic potential of amphotericin B lipid complex have not been done. {01}
Mutagenicity
No mutagenic effects were found in the bacterial reverse mutation assay, mouse lymphoma forward mutation assay, chromosomal aberration assay in CHO cells, or the in vivo mouse micronucleus assay. {01}
Pregnancy/Reproduction
Fertility—
No impact on fertility was found in studies done in male and female rats at doses of up to 0.32 times the recommended human dose, based on body surface area. {01}
Pregnancy—
Adequate and well-controlled studies in humans have not been done.
Studies in rats and rabbits at doses of up to 0.64 times the recommended human dose, based on body surface area, revealed no harm to the fetus. {01}
FDA Pregnancy Category B.
Breast-feeding
It is not known whether amphotericin B lipid complex is distributed into breast milk. Because of the potential for serious side effects in nursing infants, a decision should be made to either stop breast-feeding or discontinue taking amphotericin B lipid complex. {01}
Pediatrics
One hundred eleven children 16 years of age and younger have been treated with amphotericin B lipid complex. No serious or unexpected adverse events have been reported. {01}
Geriatrics
Forty-nine patients 65 years of age and older have been treated with amphotericin B lipid complex. No serious or unexpected adverse events have been reported. {01}
Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Antifungals, azole (azole antifungals have been reported to be antagonistic with amphotericin B in in vitro and in vivo animal studies {01})
Blood dyscrasia-causing medications (See Appendix II ) or
» Bone marrow depressants (See Appendix II ) or
» Radiation therapy (concurrent use of these medications or radiation therapy with amphotericin B may increase the chance of renal toxicity, bronchospasm, and hypotension; these medications should be used with amphotericin B lipid complex with caution {01})
» Corticosteroids, glucocorticoid, especially with significant mineralocorticoid activity or
» Corticosteroids, mineralocorticoid or
» Corticotropin (ACTH), especially with long-term use (concurrent use of these medications with amphotericin B lipid complex may result in hypokalemia, which could predispose the patient to cardiac arrhythmias; serum electrolytes and cardiac function should be monitored {01})
» Cyclosporin A or
» Nephrotoxic medications, other (See Appendix II ) (concurrent use of these medications may increase the chance for medication-induced renal toxicity; these medications should be used with amphotericin B lipid complex with caution {01})
» Digitalis glycosides or
Neuromuscular blocking agents, nondepolarizing (amphotericin B may induce hypokalemia, which may increase the potential for digitalis toxicity or enhance the blockade of nondepolarizing neuromuscular blocking agents; serum potassium determinations and correction of hypokalemia may be necessary prior to administration of nondepolarizing neuromuscular blocking agents or at frequent intervals during concurrent therapy with digitalis glycosides {01})
Flucytosine (concurrent use may increase flucytosine toxicity, possibly by increasing its cellular intake and/or impairing its renal excretion {01})
Zidovudine (increased myelotoxicity and nephrotoxicity were seen in dogs that were administered either amphotericin B lipid complex at doses 0.16 or 0.5 times the recommended human dose or amphotericin B desoxycholate concurrently with zidovudine for 30 days; renal and hematologic functions should be monitored closely {01})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Alkaline phosphatase and
Amylase and
Aspartate aminotransferase (AST [SGOT]) (serum values may be increased {01})
Blood urea nitrogen (BUN) and
Creatinine, serum and
Potassium, serum (concentrations may be increased {01})
Calcium, serum and
Magnesium, serum (concentrations may be decreased {01})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
Except under special circumstances, this medication should not be used when the following medical problem exists:
» Leukocyte transfusions (acute pulmonary toxicity has been reported in patients receiving amphotericin B lipid complex and leukocyte transfusions; leukocyte transfusions and amphotericin B lipid complex should not be given concurrently {01})
Risk-benefit should be considered when the following medical problems exist
Hypersensitivity to amphotericin B
» Renal function impairment (amphotericin B lipid complex can produce dose-dependent nephrotoxicity; however, some patients with a serum creatinine above 2.5 mg per deciliter being treated for aspergillosis with amphotericin B lipid complex experienced a decline in serum creatinine during treatment {01})
Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):
Complete blood count (CBC) (counts should be monitored frequently {01})
Creatinine, serum and
Magnesium, serum and
Potassium, serum (concentrations should be monitored frequently {01})
Liver function tests (values should be monitored frequently {01})
Side/Adverse Effects
Note: One case of anaphylaxis has been reported. {01}
Acute reactions, including fever and chills, may occur 1 to 2 hours after initiation of an infusion of amphotericin B lipid complex. These reactions are more likely to occur with the first few doses and generally diminish with subsequent doses. Amphotericin B lipid complex has rarely been associated with hypotension, bronchospasm, arrhythmias, and shock. {01}
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence more frequent
Infusion-related reaction (fever and chills; headache; nausea and vomiting){01}
Incidence less frequent
Anemia (unusual tiredness and weakness){01}
leukopenia (sore throat and fever){01}
respiratory distress (difficulty in breathing){01}
thrombocytopenia (unusual bleeding or bruising){01}
Incidence rare
Renal function impairment (increased or decreased urination){01}
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Gastrointestinal disturbance (diarrhea; loss of appetite; nausea; stomach pain; vomiting){01}
Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).
Clinical effects of overdose
Amphotericin B desoxycholate overdose has resulted in cardiopulmonary arrest. {01} Fifteen patients have been reported to have received one or more doses of 7 to 13 mg per kg of body weight of amphotericin B lipid complex. None of these patients had a serious acute reaction. Amphotericin B lipid complex is not hemodialyzable. {01}
Treatment of overdose
Supportive care—Patients in whom intentional overdose is confirmed or suspected should be referred for psychiatric consultation.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Amphotericin B Lipid Complex (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
» Conditions affecting use, especially:
Hypersensitivity to amphotericin B
Breast-feeding—Not recommended, due to potential serious side effects in the nursing infant
Other medications, especially bone marrow depressants, corticosteroids, corticotropin, cyclosporin A, digitalis glycosides, other nephrotoxic medications, or radiation therapy
Other medical problems, especially leukocyte transfusions or renal function impairment
Side/adverse effects
Signs of potential side effects, especially infusion-related reactions, anemia, leukopenia, respiratory distress, thrombocytopenia, or renal function impairment
General Dosing Information
Renal toxicity has been shown to be dose-dependent. There are no firm guidelines for adjusting the dose based on laboratory test results. {01}
The infusion should be administered at a rate of 2.5 mg per kg of body weight per hour. If the infusion time exceeds 2 hours, the contents of the infusion bag should be shaken every 2 hours. {01}
Parenteral Dosage Forms
AMPHOTERICIN B LIPID COMPLEX INJECTION
Usual adult and adolescent dose
Fungal infections, invasive—Intravenous infusion, 5 mg per kg of body weight per day, administered at a rate of 2.5 mg per kg of body weight per hour. {01}
Usual pediatric dose
See Usual adult and adolescent dose . {01}
Usual geriatric dose
See Usual adult and adolescent dose . {01}
Size(s) usually available:
U.S.—
100 mg in 20 mL (Rx) [ABELCET (L-alpha-dimyristoylphosphatidylcholine [DMPC]) (L-alpha-dimyristoylphosphatidylglycerol [DMPG])]{01}
Packaging and storage:
Prior to admixing, store between 2 and 8 °C (36 and 46 °F). Protect from light. Do not freeze. {01}
After dilution with 5% dextrose injection, the admixture may be stored for up to 48 hours at 2 to 8 °C (36 to 46 °F) and an additional 6 hours at room temperature. Do not freeze. {01}
Preparation of dosage form:
The vial should be shaken gently until there is no evidence of any yellow sediment at the bottom. The appropriate dose of amphotericin B lipid complex should be withdrawn from the required number of vials into one or more 20-mL syringes using an 18-gauge needle. The needle is then replaced with the 5-micron filter needle supplied with each vial. Empty the contents of the syringe into a bag of 5% dextrose injection so that the final concentration is 1 mg per mL. For pediatric patients and patients with cardiovascular disease, the final infusion concentration may be 2 mg per mL. Before infusion, the bag should be shaken until the contents are thoroughly mixed. {01}
Incompatibilities:
Compatibility has not been established with sodium chloride injection or with other medications or electrolytes. An existing intravenous line should be flushed with 5% dextrose injection before infusion of amphotericin B lipid complex, or a separate infusion line should be used. In-line filters should not be used. {01}
Developed: 05/28/1996
References
- ABELCET package insert (Liposome—US), New 11/95, Rec 1/96; Rev 10/96, Rec 3/98.
- Canada JR, editor. USP dictionary of USAN and international drug names 1998. Rockville, MD: The United States Pharmacopeial Convention Inc; 1997. p. 52.
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