INDICATIONS

FDA

  • AmBisome, Abelcet, and Amphotec: Aspergillosis (in pts refractory to or intolerant of amphotericin B deoxycholate)
  • AmBisome: Candidiasis (in pts refractory to or intolerant of amphotericin B deoxycholate)
  • AmBisome: Cryptococcosis, including cryptococcal meningitis (in pts refractory to or intolerant of amphotericin B deoxycholate)
  • AmBisome: Empiric therapy for presumed fungal infection in pts with febrile neutropenia
  • AmBisome: Visceral leishmaniasis

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

AmBisome

Amphotericin B liposomal

Fujisawa

IV

vial

50 mg

$188.40

Abelcet

Amphotericin B lipid complex (ABLC)

Enzon Inc.

IV

vial

100 mg

$240

Amphotec

Amphotericin B cholesteryl sulfate complex (ABCD)

Intermune pharmaceutical

IV

vial

50 mg and 100 mg

$93.33; $160.00

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

AmBisome: 3-5 mg/kd/d (generally 5 mg/kg/d for most systemic fungal infections). Abelcet: 5 mg/kg/d. Amphotec: 3-4 mg/kg.

  • Cryptococcal meningitis: AmBisome 3-4 mg/kg once-daily + 5FC x ≥2 wks followed by fluconazole (FDA labeled dose for cryptococcal meningitis 6 mg/kg/d) OR Abelcet 5 mg/kg + 5FC x ≥2 wks followed by fluconazole (more limited data). Amphotec: no data in the treatment of cryptococcal meningitis and not recommended.
  • Empiric treatment of fever in neutropenic pts not responding to antibiotics: AmBisome 3 mg/kg once-daily. Higher doses (5 mg/kg/d) should be considered with neutropenia >10 days, clinically unstable, and/or evidence of fungal infection.
  • Higher doses (up to 10-15 mg/kg/d ) have been employed in refractory zygomycotic infections. Limited data support this dosing. Posaconazole may be considered in refractory cases.
  • Invasive aspergillosis: 5 mg/kg once-daily. Lower doses (3 mg/kg/d) may be considered in clinically stable patients.
  • Invasive candidiasis: 5 mg/kg once-daily

RENAL DOSING

DOSING FOR GLOMERULAR FILTRATION OF 50-80

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF 10-50

Usual dose

DOSING FOR GLOMERULAR FILTRATION OF <10 ML/MIN

No data, use with close monitoring of worsening renal function.

DOSING IN HEMODIALYSIS

No data. Usual dose likely

DOSING IN PERITONEAL DIALYSIS

No data. Usual dose likely

DOSING IN HEMOFILTRATION

No data

ADVERSE DRUG REACTIONS

OCCASIONAL

  • Chills: 18% in AmBisome treated pts compared to 50% in amphotericin B treated pts. 53% in Amphotec treated pts compared to 30% amphotericin treated pts. Infusion related ADR was higher with abelcet compared to amphotericin.
  • Fever (>38): 27% in amphotec treated pts compared to 16% in amphotericin B treated pts. 8% in ambisome treated pts and 10-20% in Abelcet treated pts compared to up to 40% in amphotericin treated pts.
  • Phlebitis and pain at injection site
  • Creatinine elevation (>2x baseline) observed in up to 19% in AmBisome, 25% in Amphotec, 8% in low dose Abelcet treated pts compared to 30-50% in amphotericin B treated pts.
  • Hypokalemia, hypomagnesemia, hypocalcemia
  • Nausea, vomiting, diarrhea, abdominal pain, metallic taste
  • Hypotension
  • Headache and insomnia
  • Transaminase elevation (>2 x ULN with cumulative dose >2000 mg)
  • Increased in bilirubin (>1.5x baseline)
  • Anemia

RARE

  • Rash and pruritis

DRUG INTERACTIONS

  • Digoxin: potential increase in digitalis toxicity secondary to amphotericin-induced potassium depletion. Monitor potassium closely with co-administration.
  • Nephrotoxic agents (aminoglycosides, cidofovir, foscarnet, and potentially TDF): may result in additive nephrotoxicity.
  • Skeletal muscle relaxant: may enhance curariform effect of skeletal muscle relaxants (e.g. tubocurarine) due to hypokalemia. Monitor potassium closely with co-administration.

SPECTRUM

Aspergillus spp (A. fumigatus, A. flavus), Candida spp (C. albicans, C. krusei, C. lusitaniae, C. parapsilosis, C.tropicalis), Cryptococcus neoformans, and Blastomyces dermatitidis. Active against most fungi with the notable exceptions of Candida lusitaniae, Trichosporon beigelii, Aspergillus terreus (some isolates), Pseudallescheria boydii, Malassezia furfur and Fusarium spp.

PHARMACOLOGY

MECHANISM

Polyene agent binds to ergosterol resulting in the disruption of the fungal cell membrane causing leakage of intracellular contents. Lipid formulation designed to reduce binding of amphotericin to mammalian cell membranes, therefore reducing toxicities.

PHARMACOKINETIC PARAMETERS

Absorption

Not absorbed from the GI tract

Metabolism and Excretion

Unknown metabolic pathway with up to 10% renal excretion. Increased uptake by the liver and spleen and decreased renal concentration

Protein Binding

No data

Cmax, Cmin, and AUC

Cmax: 3.1 mcg/ml (Amphotec); 1.7mcg/ml (Abelcet); 83mcg/ml (Ambisome)

T1/2

Ambisome: 100-153 hrs; Abelcet: 7.2 d; Amphotec: 25 hrs

Distribution

Greater Vd compared to conventional amphotericin. Increased uptake by the liver and spleen and decreased kidney concentration

DOSING FOR DECREASED HEPATIC FUNCTION

No data

PREGNANCY RISK

Category B (for all lipid formulation): Limited data on use of lipid amphotericin in pregnancy; use should be limited tosituations in which benefits outweighs risks.

BREAST FEEDING COMPATIBILITY

No data

COMMENTS

AmBisome is most expensive formulation. Randomized trials showing equivalence with reduced toxicity compared to conventional amphotericin B for aspergillosis, febrile neutropenia, and cryptococcal meningitis. AmBisome superior to amphotericin B in treatment of histoplasmosis. For treatment of cryptococcal meningitis liposomal amphotericin B resulted in faster CSF sterilization with less nephrotoxicity vs. standard amphotericin B, but this did not result in improved clinical outcomes. Despite high cost of lipid amphotericin formulations, they may be more cost effective due to reduced rates of renal failure and dialysis [2] [5].

Basis for recommendation

  1. Perfect JR et al: Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america. Clin Infect Dis 50:291, 2010  [PMID:20047480]

    Comment: Flucytosine plus amphotericin B, liposomal amphotericin, or amphotericin lipid complex (x ≥2 wks) is recommended for treatment of cryptococcal meningitis. Without 5FC, recommended lipid amphotericin treatment duration is 4-6 wks.

References

  1. Bates DW et al: Mortality and costs of acute renal failure associated with amphotericin B therapy. Clin Infect Dis 32:686, 2001  [PMID:11229835]
  2. Sharkey PK et al: Amphotericin B lipid complex compared with amphotericin B in the treatment of cryptococcal meningitis in patients with AIDS. Clin Infect Dis 22:315, 1996  [PMID:8838189]

    Comment: Clinical improvement occurred in 86% of pts treated with Abelcet even though CSF sterilization was achieved in 42% after 2 wks of therapy. This small study suggests that there may be a role for Abelcet in the treatment of cryptococcal meningitis, however larger trials need to be conducted.

  3. Sobel JD: Practice guidelines for the treatment of fungal infections. For the Mycoses Study Group. Infectious Diseases Society of America. Clin Infect Dis 30:, 2000  [PMID:10770725]

    Comment: IDSA guidelines for treatment of fungal infections. ID expert recommendations concerning lipid formulation are 1) serum creatinine >2.5 mg/dl. 2) Most pts with candidiasis, cryptococcosis and endemic mycosis should not be treated initially with lipid-based amphotericin B preparations. 3) immunocompromised pts with life-threatening infections with aspergillus or zygomycosis - some authorities recommend initiating treatment with lipid-based amphotericin B and others with with conventional amphotericin B and switch according to criteria summarized.

  4. Ostrosky-Zeichner L et al: Amphotericin B: time for a new "gold standard". Clin Infect Dis 37:415, 2003  [PMID:12884167]
  5. Johnson PC et al: Safety and efficacy of liposomal amphotericin B compared with conventional amphotericin B for induction therapy of histoplasmosis in patients with AIDS. Ann Intern Med 137:105, 2002  [PMID:12118965]

    Comment: Randomized, double-blind trial that compared liposomal amphotericin 3 mg/kg/d to conventional amphotericin 0.7 mg/kg/d for the treatment of moderate to severe histoplasmosis in 83 HIV+ pts. Clinical success achieved in 14/22 pts (64%) treated with conventional amphotericin B compared with 45/51 pts (88%) receiving liposomal amphotericin B (p=0.014).

  6. Leenders AC et al: Liposomal amphotericin B (AmBisome) compared with amphotericin B both followed by oral fluconazole in the treatment of AIDS-associated cryptococcal meningitis. AIDS 11:1463, 1997  [PMID:9342068]

    Comment: This randomized trial in cryptococcal meningitis demonstrated that liposomal amphotericin B resulted in faster CSF sterilization compared to standard conventional amphotericin B, but this did not result in improved clinical outcomes. Liposomal amphotericin B was clinically equivalent to standard amphotericin and resulted in less nephrotoxicity.

  7. Leenders AC et al: Liposomal amphotericin B compared with amphotericin B deoxycholate in the treatment of documented and suspected neutropenia-associated invasive fungal infections. Br J Haematol 103:205, 1998  [PMID:9792309]

    Comment: This trial concluded that liposomal amphotericin B was superior to conventional amphotericin B in treatment of invasive fungal infection in neutropenic host. Although most authorities agree that AmBisome is at least equivalent in efficacy to standard amphotericin and shows less nephrotoxicity, the dispute regarding preferential use is based on cost implications.

  8. Walsh TJ et al: Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327, 2008  [PMID:18177225]

    Comment: The IDSA guidelines recommend AmBisome (3 - 5 mg/kg/day IV) or Abelcet (5 mg/ kg/day IV) as alternatives to voriconazole for treatment of invasive aspergillosis.

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Last updated: November 7, 2011