Amphotericin B (Lipid Complex)

Pronunciation

(am foe TER i sin bee LIP id KOM pleks)

U.S. Brand Names

Abelcet®

Synonyms

ABLC

Generic Available

Canadian Brand Names

Abelcet®

Use

Treatment of aspergillosis or any type of progressive fungal infection in patients who are refractory to or intolerant of conventional amphotericin B therapy

Use - Unlabeled/Investigational

Effective in patients with serious Candida species infections

Pregnancy Risk Factor

Lactation

Enters breast milk/contraindicated

Contraindications

Hypersensitivity to amphotericin or any component of the formulation

Warnings/Precautions

Anaphylaxis has been reported with other amphotericin B-containing drugs. Facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If severe respiratory distress occurs, the infusion should be immediately discontinued. During the initial dosing, the drug should be administered under close clinical observation. Acute reactions (including fever and chills) may occur 1-2 hours after starting an intravenous infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Pulmonary reactions may occur in neutropenic patients receiving leukocyte transfusions; separation of the infusions as much as possible is advised.

Adverse Reactions

Nephrotoxicity and infusion-related hyperpyrexia, rigor, and chilling are reduced relative to amphotericin deoxycholate.

>10%:

Central nervous system: Chills, fever

Renal: Increased serum creatinine

1% to 10%:

Cardiovascular: Hypotension, cardiac arrest

Central nervous system: Headache, pain

Dermatologic: Rash

Endocrine & metabolic: Bilirubinemia, hypokalemia, acidosis

Gastrointestinal: Nausea, vomiting, diarrhea, gastrointestinal hemorrhage, abdominal pain

Renal: Renal failure

Respiratory: Respiratory failure, dyspnea, pneumonia

Drug Interactions

Increased nephrotoxicity: Aminoglycosides, cyclosporine, other nephrotoxic drugs

Potentiation of hypokalemia: Corticosteroids, corticotropin

Increased digitalis and neuromuscular-blocking agent toxicity due to hypokalemia

Decreased effect: Pharmacologic antagonism may occur with azole antifungal agents (eg, miconazole, ketoconazole)

Pulmonary toxicity has occurred with concomitant administration of amphotericin B and leukocyte transfusions

Stability

100 mg vials in 20 mL of suspension in single-use vials (no preservative is present). Intact vials should be stored at 2°C to 8°C (35°F to 46°F) and protected from exposure to light; do not freeze intact vials. Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose and filter the contents (5 micron filter) prior to dilution. Dilute into D5W to a final concentration of 1 mg/mL. For pediatric patients and patients with cardiovascular disease, the drug may be diluted with D5W to a final concentration of 2 mg/mL.

Do not dilute with saline solutions or mix with other drugs or electrolytes - compatibility has not been established

Do not use an in-line filter during administration.

Diluted solution is stable for up to 48 hours at 2°C to 8°C (38°F to 46°F) and an additional 6 hours at room temperature

Compatibility

Do not admix or Y-site with any blood products, intravenous drugs, or intravenous fluids other than D5W.

Mechanism of Action

Binds to ergosterol altering cell membrane permeability in susceptible fungi and causing leakage of cell components with subsequent cell death. Proposed mechanism suggests that amphotericin causes an oxidation-dependent stimulation of macrophages (Lyman, 1992).

Pharmacodynamics/Kinetics

Distribution: Vd: Increases with higher doses; reflects increased uptake by tissues (131 L/kg with 5 mg/kg/day)

Half-life elimination: ~24 hours

Excretion: Clearance: Increases with higher doses (5 mg/kg/day): 400 mL/hour/kg

Dosage

Children and Adults: I.V.:

Premedication: For patients who experience chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions, premedicate with the following drugs, 30-60 minutes prior to drug administration: a nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) with or without diphenhydramine; or acetaminophen with diphenhydramine; or hydrocortisone 50-100 mg. If the patient experiences rigors during the infusion, meperidine may be administered.

Range: 2.5-5 mg/kg/day as a single infusion

Dosing adjustment in renal impairment: None necessary; effects of renal impairment are not currently known

Hemodialysis: No supplemental dosage necessary

Peritoneal dialysis: No supplemental dosage necessary

Continuous arteriovenous or venovenous hemofiltration: No supplemental dosage necessary

Administration

For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related reactions, premedication with the following drugs, 30-60 minutes prior to drug administration: A nonsteroidal (eg, ibuprofen, choline magnesium trisalicylate) with or without diphenhydramine; or acetaminophen with diphenhydramine, or hydrocortisone 50-100 mg. If the patient experiences rigors during the infusion, meperidine may be administered. If infusion time exceeds 2 hours, mix contents by shaking infusion bag every 2 hours.

Monitoring Parameters

Renal function (monitor frequently during therapy), electrolytes (especially potassium and magnesium), liver function tests, temperature, PT/PTT, CBC; monitor input and output; monitor for signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes, etc)

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. This medication can only be administered by infusion and therapy may last several weeks. Maintain good personal hygiene to reduce spread and recurrence of lesions. Maintain adequate hydration (2-3 L/day of fluids) unless instructed to restrict fluid intake. May cause postural hypotension (use caution when changing from lying or sitting position to standing or when climbing stairs); or nausea or vomiting (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help). Report chest pain or palpitations; CNS disturbances; skin rash; chills or fever; persistent nausea, vomiting, or abdominal pain; sore throat; excessive fatigue; swelling of extremities or unusual weight gain; respiratory difficulty; pain at infusion site; muscle cramping or weakness; or other adverse reactions. Breast-feeding precaution: Do not breast-feed.

Additional Information

As a modification of dimyristoyl phosphatidylcholine:dimyristoyl phosphatidylglycerol 7:3 (DMPC:DMPG) liposome, amphotericin B lipid-complex has a higher drug to lipid ratio and the concentration of amphotericin B is 33 M. ABLC is a ribbon-like structure, not a liposome.

Controlled trials which compare the original formulation of amphotericin B to the newer liposomal formulations (ie, Abelcet®) are lacking. Thus, comparative data discussing differences among the formulations should be interpreted cautiously. Although the risk of nephrotoxicity and infusion-related adverse effects may be less with Abelcet®, the efficacy profiles of Abelcet® and the original amphotericin formulation are comparable. Consequently, Abelcet® should be restricted to those patients who cannot tolerate or fail a standard amphotericin B formulation.

Anesthesia and Critical Care Concerns/Other Considerations

This product is significantly more expensive than conventional amphotericin B. The incidence of nephrotoxicity of ABLC appears to be less when compared to conventional amphotericin B. The incidence of infusion-related reactions does not appear to be decreased with ABLC, but tolerance usually develops. Premedication may be considered to prevent/attenuate infusion-related adverse events. To prevent aggregation of the lipid products, it is important to shake the bag before hanging and once every 2 hours. In vitro experiments confirm that liposomal amphotericin B is at least as active as amphotericin B against clinical isolates of Candida, Cryptococcus, Blastomyces, and Aspergillus. Their activities also have appeared to be equal against Fusarium. Abelcet® may be restricted to patients who cannot tolerate or fail a standard amphotericin B formulation.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Sedation is common; may cause delirium

Mental Health: Effects on Psychiatric Treatment

May cause bone marrow suppression; use caution with clozapine and carbamazepine

Oncology: Emetic Potential

Very low (<10%)

Oncology: Vesicant

Dosage Forms

Injection, suspension: 5 mg/mL (20 mL)

References

De Marie S, "Clinical Use of Liposomal and Lipid-Complexed Amphotericin B," J Antimicrob Chemother , 1994, 33(5):907-16.

Edwards JE Jr, Bodey GP, Bowden RA, et al, "International Conference for the Development of a Consensus on the Management and Prevention of Severe Candidal Infections," Clin Infect Dis , 1997, 25(1):43-59.

Eggimann P, Francioli P, Bille J, et al, "Fluconazole Prophylaxis Prevents Intra-Abdominal Candidiasis in High-Risk Surgical Patients," Crit Care Med , 1999, 27(6):1066-72.

Fichtenbaum CJ, Zackin R, Rajicic N, et al, "Amphotericin B Oral Suspension for Fluconazole-Refractory Oral Candidiasis in Persons With HIV Infection. Adult AIDS Clinical Trials Group Study Team 295," AIDS , 2000, 14(7):845-52.

Hiemenz JW and Walsh TJ, "Lipid Formulations of Amphotericin B: Recent Progress and Future Directions," Clin Infect Dis , 1996, 22(Suppl 2):133-44.

Kline S, Larsen TA, Fieber L, et al, "Limited Toxicity of Prolonged Therapy With High Doses of Amphotericin B Lipid Complex," Clin Infect Dis , 1995, 21(5):1154-8.

Lyman CA and Walsh TJ, "Systemically Administered Antifungal Agents. A Review of Their Clinical Pharmacology and Therapeutic Applications," Drugs , 1992, 44(1):9-35.

Mora-Duarte J, Betts R, Rotstein C, et al, "Comparison of Caspofungin and Amphotericin B for Invasive Candidiasis," N Engl J Med , 2002, 347(25):2020-9.

Patel R, "Antifungal Agents. Part I. Amphotericin B Preparations and Flucytosine," Mayo Clin Proc , 1998, 73(12):1205-25.

Rapp RP, Gubbins PO, and Evans ME, "Amphotericin B Lipid Complex," Ann Pharmacother , 1997, 31(10):1174-86.

Rex JH, Bennett JE, Sugar AM, "A Randomized Trial Comparing Fluconazole With Amphotericin B for the Treatment of Candidemia in Patients Without Neutropenia. Candidemia Study Group and the National Institute," N Engl J Med , 1994, 331(20):1325-30.

Rex JH, Pappas PG, Karchmer AW, et al, "A Randomized and Blinded Multicenter Trial of High-Dose Fluconazole Plus Placebo Versus Fluconazole Plus Amphotericin B as Therapy for Candidemia and Its Consequences in Nonneutropenic Subjects," Clin Infect Dis , 2003, 36(10):1221-8.

Rex JH, Walsh TJ, Sobel JD, et al, "Practice Guidelines for the Treatment of Candidiasis. Infectious Diseases Society of America," Clin Infect Dis , 2000, 30(4):662-78.

Slain D, "Lipid-Based Amphotericin B for the Treatment of Fungal Infections," Pharmacotherapy , 1999, 19(3):306-23.

International Brand Names

Abelcet® (CA)

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