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Brand Name: Amphocin, Fungizone, AmBisome, Abelecet, Amphotec  |
Drug Class: Opportunistic Infection and Other Drugs
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Drug Description |
| Amphotericin B is an amphoteric polyene macrolide antibiotic produced by Streptomyces nodosus. Amphotericin B, formulated with sodium deoxycholate, was the first parenteral amphotericin B preparation available commercially. Because amphotericin B deoxycholate is associated with certain dose-limiting toxicities (principally nephrotoxicity), other parenteral amphotericin B preparations have been developed with lipid-based drug delivery systems. Amphotericin B is now commercially available as amphotericin B cholestryl sulfate complex (Amphotec), amphotericin B lipid complex (Abelcet), and amphotericin B liposomal (AmBisome).[1] |
HIV/AIDS-Related Uses |
Amphotericin B deoxycholate is indicated in the treatment of invasive fungal infections, including aspergillosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, and histoplasmosis, which are common opportunistic infections in HIV infected patients. Because of concern about nephrotoxicity and the availability of alternative treatments (voriconazole, caspofungin, and lipid amphotericin formulations), the indication for amphotericin B deoxycholate therapy is limited to patients who have normal renal function, will receive less than 2 weeks of therapy, and have conditions that cannot be treated with azole antifungals.[2]
Amphotericin B deoxycholate is used as an alternative agent for long-term suppressive therapy (i.e., secondary prophylaxis) or maintenance therapy to prevent recurrence or relapse of coccidioidomycosis, cryptococcosis, or histoplasmosis in HIV infected individuals who have received adequate treatment of these infections. Long-term suppressive or maintenance therapy is generally continued for life. The U.S. Public Health Service and Infectious Diseases Society of America make no recommendations for discontinuing therapy in patients receiving antiretroviral therapy who have CD4 cell counts greater than 100 cells/mm3. However, limited data suggest that discontinuing suppressive therapy in HIV infected adults and adolescents may be associated with low risk for recurrence of cryptococcosis. Individuals who consider discontinuing suppressive therapy should have successfully completed initial therapy for cryptococcosis, remained asymptomatic with respect to cryptococcosis, and have sustained (longer than 6 months) CD4 cell counts greater than 100 to 200 cells/mm3 in response to potent antiretroviral therapy.[3] |
Non HIV/AIDS-Related Uses |
Amphotericin B is indicated in the treatment of a variety of invasive fungal infections, including aspergillosis, blastomycosis, disseminated candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mucormycosis, and sporotrichosis. It is indicated for treatment of fungal endocarditis, intra-abdominal infections, meningitis, septicemia, and urinary tract infections. Because of its toxicity, amphotericin B deoxycholate is indicated primarily in patients with progressive, potentially fatal infections in whom the diagnosis is firmly established.[4]
Although some azole antifungal agents (e.g., itraconazole, fluconazole) are now also recognized as drugs of choice for the treatment of many systemic mycoses, amphotericin B deoxycholate remains the drug of first choice for the initial treatment of severe, life-threatening fungal infections, especially in immunocompromised patients. Because clinical experience with newer amphotericin B formulations is limited, these formulations have generally been reserved for second-line therapy in patients with invasive fungal infections that have not responded to amphotericin B deoxycholate or in patients who cannot tolerate amphotericin B deoxycholate.[5] Specific indications are listed below by formulation.
Amphotericin B cholestryl sulfate complex is indicated for the treatment of invasive aspergillosis in cases where renal impairment or unacceptable toxicity precludes the use of amphotericin B deoxycholate in effective doses and in cases where prior amphotericin B deoxycholate therapy has failed.[6]
Amphotericin B lipid complex is indicated for the treatment of invasive fungal infections in patients who are refractory to or intolerant of amphotericin B deoxycholate therapy.[7]
Amphotericin B liposomal is indicated as empiric therapy for presumed fungal infections in febrile, neutropenic patients; treatment of cryptococcal meningitis in HIV infected patients; treatment of aspergillosis, candidiasis, or cryptococcosis in patients refractory to amphotericin B deoxycholate or with renal impairment that precludes the use of amphotericin B deoxycholate; and the treatment of leishmaniasis.[8]
Amphotericin B deoxycholate may be the preferred agent for pregnant women with invasive fungal infections due to concerns regarding the use of azole antifungal agents during pregnancy. Intravenous amphotericin B has also been used for empiric therapy in febrile neutropenic patients and for prophylaxis in certain immunosuppressed individuals (e.g., cancer patients and bone marrow or solid organ transplant patients.[9]
Amphotericin B is also used for the treatment of certain protozoal infections, including leishmaniasis and amebic meningoencephalitis. Amphotericin B is not effective against bacteria, rickettsiae, or viruses.[10] |
Dosing Information |
Mode of Delivery |
Intravenous (IV) infusion.[11]
May also be given intrathecally, intra-articularly, intrapleurally, and by local instillation or irrigation.[12] |
Dosage Form |
Vials containing amphotericin B powder 50 mg each.[13]
The maximum recommended IV total daily dose for adults should not exceed 1.5mg/kg. Prior to initiation of conventional IV amphotericin B therapy, a single test dose of the drug (1 mg in 20 ml of 5% dextrose injection) should be administered IV over 20 to 30 minutes and the patient carefully monitored every 30 minutes for 2 hours. Depending on the patient's cardio-renal status, dosage may gradually be increased by 5 to 10 mg daily to a final daily dosage of 0.5 to 0.7 mg/kg.[14]
The recommended IV dose of amphotericin B for infants and small children is 0.2 to 0.5 mg/ml (base) per kg of body weight per day and is administered in 5% dextrose injection over a period of 6 hours.[15] |
Storage |
| Prior to reconstitution, store powder between 2 C and 8 C (36 F and 46 F). Protect from light.[16] |
Pharmacology |
Amphotericin B is fungistatic or fungicidal, depending upon the susceptibility of the fungus and the concentration obtained in body fluids. Amphotericin binds to sterols in the fungal cell membrane, changing the membrane permeability and causing leakage of intracellular components.[17] Cell death occurs in part because of these permeability changes, but other mechanisms may also contribute to amphotericin's antifungal activity. Amphotericin B is not active in vitro against organisms that do not contain sterols in their cell membranes (e.g., bacteria). Binding to sterols in mammalian cells (e.g., certain kidney cells, erythrocytes) may be responsible for the toxicities associated with amphotericin B therapy.[18]
Amphotericin B is poorly absorbed from the gastrointestinal (GI) tract and must be given parenterally to treat systemic fungal infections.[19] After completion of IV infusion of amphotericin B 50 mg, the average peak serum concentration was approximately 2 mcg/ml.([20]
Amphotericin B distributes into lungs, liver, spleen, kidneys, adrenal glands, muscle, and other tissues in potentially therapeutic concentrations. The volume of distribution is approximately 4 l/kg in adults. Concentrations attained in inflamed pleural, peritoneal, and synovial fluids and in aqueous humor are reportedly about 60% of concurrent plasma concentrations.[21] Concentrations in cerebrospinal fluid (CSF) are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, amphotericin B must be administered intrathecally.[22]
Amphotericin B is in FDA Pregnancy Category B. Amphotericin B reportedly crosses the placenta, and low concentrations are attained in amniotic fluid. Safe use of amphotericin B during pregnancy has not been established. Animal studies have not revealed evidence of harm to the fetus. It is not known if amphotericin B is distributed into breast milk.[23][24]
Amphotericin B is highly protein bound (greater than 90%). Metabolism of amphotericin B has not been fully elucidated. The initial plasma elimination half-life is 24 hours and the terminal elimination half-life is approximately 15 days. Amphotericin B is eliminated very slowly (weeks to months) by the kidneys; only about 40% of an administered dose is excreted over 7 days. Only 3% of a dose is excreted in the urine unchanged. Amphotericin B is not removed by hemodialysis.[25]
Resistance to amphotericin B has been produced in vitro, and resistant strains have been isolated from patients who have received long-term therapy with amphotericin B deoxycholate. Fluconazole-resistant strains of Candida albicans that were cross resistant to amphotericin B have been isolated from a few immunocompromised patients. Cryptococcus neoformans isolates resistant to fluconazole and amphotericin B have also been documented. Fungi resistant to amphotericin B deoxycholate may also be resistant to amphotericin B cholestryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal.[26] |
Adverse Events/Toxicity |
Most patients on amphotericin B deoxycholate therapy experience adverse effects. Acute infusion reactions and nephrotoxicity are the two most common adverse effects.[27]
The majority of patients receiving amphotericin B deoxycholate (50% to 90%) experience some degree of intolerance to initial doses. Acute infusion reactions of fever, shaking chills, hypotension, anorexia, nausea, vomiting, headache, dyspnea, and tachypnea may occur 1 to 3 hours after initiation of IV infusions. Lipid-based amphotericin B preparations are also associated with acute infusion reactions, although to a lesser degree. Administration of an antipyretic, an antihistamine, meperidine, or a corticosteroid just before the start of the infusion may reduce the incidence or severity of the reaction.[28]
Rapid infusion of amphotericin B deoxycholate has been associated with a more severe reaction consisting of hypotension, bronchospasm, hypokalemia, arrhythmias, and shock. It may be difficult to determine whether these severe reactions indicate intolerance or hypersensitivity to amphotericin B. Anaphylaxis and anaphylactoid reactions have been reported in people taking all formulations of amphotericin B.[29]
Nephrotoxicity is the major dose-limiting toxicity reported with amphotericin B deoxycholate, and nephrotoxicity occurs to some degree in the majority of patients receiving the drug. Adverse renal effects include decreased renal function, azotemia, hypokalemia, hyposthenuria, renal tubular acidosis, and nephrocalcinosis. Increased blood urea nitrogen (BUN) and serum creatinine concentrations and decreased creatinine clearance, glomerular filtration rate, and renal plasma flow occur in most patients. Nephrotoxicity associated with amphotericin B deoxycholate appears to involve several mechanisms, including direct vasoconstrictive effects on renal arterioles and lytic action on renal tubular cell membranes. Renal function usually improves within a few months of discontinuing therapy, but some impairment may remain. Lipid-based amphotericin B formulations are generally associated with a lower risk of nephrotoxicity than amphotericin B deoxycholate. However, abnormal renal lab values have been reported in patients using alternate formulations.[30]
Amphotericin B intravenous infusion has also been associated with anemia, headache, thrombophlebitis, and GI effects (indigestion, loss of appetite, nausea, vomiting, diarrhea, stomach pain). Less frequently, blurred or double vision, cardiac arrhythmias, leukopenia, peripheral neuropathy, seizures, and thrombocytopenia have been reported.[31] |
Drug And Food Interactions |
Because nephrotoxic effects may be additive, the concurrent or sequential use of amphotericin B and other drugs with similar nephrotoxic effects (e.g., aminoglycosides, capreomycin, colistin, cisplatin, methoxyflurane, polymyxin B, vancomycin, cyclosporine, pentamidine) should be avoided. Intensive monitoring is recommended in patients requiring concomitant administration of any nephrotoxic medications.[32]
Concomitant administration of zidovudine and amphotericin B may be associated with increased myelotoxicity and nephrotoxicity.[33]
Concomitant administration of flucytosine and amphotericin B may have additive or slightly synergistic effects. Amphotericin B-induced renal dysfunction may decrease the clearance of flucytosine and result in flucytosine adverse effects, such as bone marrow toxicity.[34] |
Contraindications |
| Amphotericin B deoxycholate and alternative formulations of amphotericin B are contraindicated in patients allergic to amphotericin B or any of the formulation components. Extreme caution should be exercised when using amphotericin B deoxycholate in patients with renal impairment.[35] |
Clinical Trials |
| Click here to search ClinicalTrials.gov for trials that use Amphotericin B. |
Chemistry |
CAS Name |
| (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-beta-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[36] |
CAS Number |
| 1397-89-3[37] |
Molecular Formula |
| C47-H73-N-O17[38] |
Elemental Composition |
| C61.09%, H7.96%, N1.52%, O29.43%[39] |
Molecular Weight |
| 924.08[40] |
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Physical Description |
| Yellow to orange, odorless or practically odorless powder.[41] |
Stability |
| Concentrated solutions (5 mg/ml) in sterile water retain their potency for 24 hours at room temperature if protected from light, or for 1 week if refrigerated. Diluted solutions (0.1 mg/ml) in 5% dextrose should be used promptly after dilution.[42] |
Solubility |
| Crystalline amphotericin B is insoluble in water. It is solubilized by the addition of sodium deoxycholate to form a mixture, which creates a colloidal dispersion.[43] |
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Further Reading |
Prescribing Information from the FDA Web site. More current versions may be available on the manufacturer's Web site.
PMID/17554704 Bicanic T, Meintjes G, Wood R, Hayes M, Rebe K, Bekker LG, Harrison T. Fungal burden, early fungicidal activity, and outcome in cryptococcal meningitis in antiretroviral-naive or antiretroviral-experienced patients treated with amphotericin B or fluconazole. Clin Infect Dis. 2007 Jul 1;45(1):76-80. Epub 2007 May 25. Erratum in: Clin Infect Dis. 2007 Aug 15;45(4):526.
PMID/18035917 Chamilos G, Luna M, Lewis RE, Chemaly R, Raad II, Kontoyiannis DP. Effects of liposomal amphotericin B versus an amphotericin B lipid complex on liver histopathology in patients with hematologic malignancies and invasive fungal infections: a retrospective, nonrandomized autopsy study. Clin Ther. 2007 Sep;29(9):1980-6.
PMID/12877636 Herbrecht R, Natarajan-Ame S, Nivoix Y, Letscher-Bru V. The lipid formulations of amphotericin B. Expert Opin Pharmacother. 2003 Aug;4(8):1277-87.
PMID/17852947 Techapornroong M, Suankratay C. Alternate-day versus once-daily administration of amphotericin B in the treatment of cryptococcal meningitis: a randomized controlled trial.Scand J Infect Dis. 2007;39(10):896-901.
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Manufacturer Information |
Fungizone
Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
(800) 321-1335
Amphotericin B
Bristol - Myers Squibb Co
PO Box 4500
Princeton, NJ 08543-4500
(800) 321-1335
Amphocin
Pfizer Inc
235 East 42nd Street
New York, NY 10017-5755
(800) 438-1985
Abelecet
Enzon, Inc.
20 Kingsbridge Road
Piscataway, NJ 08854-3969
(908) 541-8600
Amphotec
Oryx Pharmaceuticals Inc.
6500 Kitimat Road
Mississauga, Ontario, Canada
AmBisome
Fujisawa Healthcare Inc
Parkway Center North / 3 Parkway North
Deerfield, IL 60015-2548
(800) 727-7003
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References |
[1] AHFS Drug Information - 2007; p. 527
[2] Medical Management of HIV Infection - Bartlett JG, Gallant JE. 2006; p. 147
[3] AHFS Drug Information - 2007; pp. 519-20
[4] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[5] AHFS Drug Information - 2007; p. 517
[6] AHFS Drug Information - 2007; p. 517
[7] Enzon, Inc. - Abelcet Prescribing Information, November 2002, p. 1. Available at: http://www.enzon.com/company/AbelcetPI.pdf. Accessed 03/20/08.
[8] Fujisawa Healthcare Inc - AmBisome Prescribing Information, July 2005, p. 5. Available at: http://www.astellas.us/docs/ambisome.pdf. Accessed 03/20/08.
[9] USP DI - 2005; p. 124
[10] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[11] AHFS Drug Information - 2007; p. 521
[12] AHFS Drug Information - 2007; p. 521
[13] AHFS Drug Information - 2007; p. 527
[14] AHFS Drug Information - 2007; p. 521
[15] Fujisawa Healthcare Inc - AmBisome Prescribing Information, July 2005, p. 27. Available at: http://www.astellas.us/docs/ambisome.pdf. Accessed 03/20/08.
[16] AHFS Drug Information - 2007; p. 527
[17] AHFS Drug Information - 2007; p. 525
[18] AHFS Drug Information - 2007; p. 525
[19] AHFS Drug Information - 2007; p. 526
[20] AHFS Drug Information - 2007; p. 526
[21] AHFS Drug Information - 2007; p. 526
[22] AHFS Drug Information - 2007; p. 526
[23] AHFS Drug Information - 2007; p. 524
[24] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[25] AHFS Drug Information - 2007; p. 527
[26] AHFS Drug Information - 2007; p. 526
[27] AHFS Drug Information - 2007; p. 522
[28] AHFS Drug Information - 2007; pp. 522-3
[29] AHFS Drug Information - 2007; pp. 522-3
[30] AHFS Drug Information - 2007; p. 523
[31] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[32] AHFS Drug Information - 2007; pp. 524-5
[33] AHFS Drug Information - 2007; p. 525
[34] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[35] AHFS Drug Information - 2007; p. 524
[36] ChemIDplus. - Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/20/08.
[37] ChemIDplus - http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/16/07.
[38] ChemIDplus - http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 03/20/08.
[39] Merck Index - 2006; p. 585
[40] Merck Index - 2006; p. 585
[41] AHFS Drug Information - 2007; p. 527
[42] Wolters Kluwer Health, Inc. - Amphotericin B, Facts and Comparisons 4.0. Available at: http://online.factsandcomparisons.com. Accessed 03/20/08.
[43] Pfizer - Amphocin Prescribing Information, September 2003, p. 1; Available at: http://media.pfizer.com/files/products/uspi_amphocin.pdf. Accessed 03/20/08..
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Updated March 20, 2008
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