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Investigational

Amphotericin B  Audio icon

Other Names: ABLC, Abelcet, AmBisome, Amphotec, amphotericin B deoxycholate, liposomal amphotericin B
Drug Class: Opportunistic Infections and Coinfections
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amphotericin B
amphotericin B
Molecular Weight: 924.0837
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Drug Description


Amphotericin B is an amphoteric polyene macrolide antibiotic produced by Streptomyces nodosus. Amphotericin B, formulated with sodium desoxycholate, was the first parenteral amphotericin B preparation available commercially. Because amphotericin B desoxycholate 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] Liposomal encapsulation or incorporation into a lipid complex can substantially affect a drug's functional properties relative to those of the unencapsulated drug or non-lipid associated drug. [2]


References

[1] AHFS Drug Information 2008; p. 545

[2] Fujisawa Healthcare Inc AmBisome Prescribing Information, October 2008, p. 2. Available at: http://www.astellas.us/docs/ambisome.pdf. Accessed 05/13/09.

HIV/AIDS-Related Uses


Amphotericin B desoxycholate 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 desoxycholate 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. [1]

Amphotericin B desoxycholate 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. [2]


References

[1] Medical Management of HIV Infection Bartlett JG, Gallant JE. 2006; p. 147

[2] AHFS Drug Information 2008; pp. 536-7

Dosing Information


Mode of Delivery

Intravenous (IV) infusion. [1]

May also be given intrathecally, intra-articularly, intrapleurally, and by local instillation or irrigation. [2]

Dosage Form

Vials containing amphotericin B powder 50 mg each. [3]

The maximum recommended IV total daily dose of Amphoterixin B desoxycholate 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. [4]

Conventional amphotericin B for injection when administered to pediatric patients should be limited to the smallest dose compatibile with an effective therapeutic regimen. [5]

The recommended IV dose of liposomal 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. [6]

Storage

Prior to reconstitution, store powder between 2 C to 8 C (36 F to 46 F). Protect from light. [7]


References

[1] AHFS Drug Information 2008; p. 546

[2] AHFS Drug Information 2008; p. 546

[3] AHFS Drug Information 2008; p. 546

[4] AHFS Drug Information 2008; p. 540

[5] X-Gen Pharmaceuticals Inc Amphotericin B for Injection USP Package Insert, April 2007, p. 1. Available at: http://www.x-gen.us/Injectables/Amphotericin%20B/Amphotericin_files/insert/Amphotericin_pi.pdf. Accessed 05/13/09.

[6] Fujisawa Healthcare Inc AmBisome Prescribing Information, October 2008, p. 27. Available at: http://www.astellas.us/docs/ambisome.pdf. Accessed 05/13/09.

[7] AHFS Drug Information 2008; p. 546

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. [1] 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. [2]

Amphotericin B is poorly absorbed from the gastrointestinal (GI) tract and must be given parenterally to treat systemic fungal infections. [3] After completion of IV infusion of amphotericin B 50 mg, the average peak serum concentration was approximately 2 mcg/mL. [4]

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. [5] Concentrations in cerebrospinal fluid (CSF) are approximately 3% of concurrent serum concentrations. To achieve fungistatic CSF concentrations, amphotericin B must be administered intrathecally. [6]

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. [7] [8]

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. [9]

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 desoxycholate. 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 desoxycholate may also be resistant to amphotericin B cholestryl sulfate complex, amphotericin B lipid complex, and amphotericin B liposomal. [10]


References

[1] AHFS Drug Information 2008; p. 544

[2] AHFS Drug Information 2008; p. 544

[3] AHFS Drug Information 2008; p. 545

[4] AHFS Drug Information 2008; p. 545

[5] AHFS Drug Information 2008; p. 545

[6] AHFS Drug Information 2008; p. 545

[7] AHFS Drug Information 2008; p. 543

[8] Wolters Kluwer Health, Inc. Amphotericin B, Facts and Comparisons 4.0 [online]. Available at: http://online.factsandcomparisons.com. Accessed 05/13/09.

[9] AHFS Drug Information 2008; p. 545

[10] AHFS Drug Information 2008; p. 544

Adverse Events/Toxicity


Most patients on amphotericin B desoxycholate therapy experience adverse effects. Acute infusion reactions and nephrotoxicity are the two most common adverse effects. [1]

The majority of patients receiving amphotericin B desoxycholate (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. [2]

Rapid infusion of amphotericin B desoxycholate 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. [3]

Nephrotoxicity is the major dose-limiting toxicity reported with amphotericin B desoxycholate, 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 desoxycholate 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 desoxycholate. However, abnormal renal lab values have been reported in patients using alternate formulations. [4]

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. [5]


References

[1] AHFS Drug Information 2008; p. 541

[2] AHFS Drug Information 2008; p. 541

[3] AHFS Drug Information 2008; p. 541

[4] AHFS Drug Information 2008; pp. 541-2

[5] Wolters Kluwer Health, Inc. Amphotericin B, Facts and Comparisons 4.0 [online]. Available at: http://online.factsandcomparisons.com. Accessed 05/13/09.

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. [1]

Concomitant administration of zidovudine and amphotericin B may be associated with increased myelotoxicity and nephrotoxicity. [2]

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. [3]


References

[1] AHFS Drug Information 2008; p. 543

[2] AHFS Drug Information 2008; p. 543

[3] Wolters Kluwer Health, Inc. Amphotericin B, Facts and Comparisons 4.0 [online]. Available at: http://online.factsandcomparisons.com. Accessed 05/13/09.

Contraindications


Amphotericin B desoxycholate 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 desoxycholate in patients with renal impairment. [1]


References

[1] AHFS Drug Information 2008; p. 542

Clinical Trials


Click here to search ClinicalTrials.gov for trials that use Anfotericina 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 [1]

CAS Number

1397-89-3 [2]

Elemental Composition

C61.09%, H7.96%, N1.52%, O29.43%

Molecular Weight

924.08

Physical Description

Yellow to orange, odorless or practically odorless powder. [3]

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. [4]

Solubility

Crystalline amphotericin B is insoluble in water. It is solubilized by the addition of sodium desoxycholate to form a mixture, which creates a colloidal dispersion. [5]


References

[1] ChemIDplus. Available at: http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 05/13/09.

[2] ChemIDplus http://chem.sis.nlm.nih.gov/chemidplus/chemidlite.jsp. Accessed 05/13/09.

[3] AHFS Drug Information 2008; p. 545

[4] Wolters Kluwer Health, Inc. Amphotericin B, Facts and Comparisons 4.0 [online]. Available at: http://online.factsandcomparisons.com. Accessed 05/13/09.

[5] Pfizer Amphocin Prescribing Information, September 2003, p. 1; Available at: http://media.pfizer.com/files/products/uspi_amphocin.pdf. Accessed 05/13/09.

Further Reading



Prescribing Information from the
FDA Web site. More current versions may be available on the manufacturer's Web site.
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.
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.
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.
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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