Amphotericin B (conventional)

MEDICATION SAFETY ISSUES
Safety issues:
Conventional amphotericin formulations (Amphocin®, Fungizone®) may be confused with lipid-based formulations (AmBisome®, Abelcet®, Amphotec®).
Large overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products. Single daily doses of conventional amphotericin formulation never exceed 1.5 mg/kg.

High alert medication: The Institute for Safe Medication Practices (ISMP) includes this medication (intrathecal administration) among its list of drugs which have a heightened risk of causing significant patient harm when used in error.

PHARMACOLOGIC CATEGORY
Antifungal Agent, Parenteral

DOSING: ADULTS — Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30-60 minutes prior to drug administration: NSAID (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.

Test dose: I.V.: 1 mg infused over 20-30 minutes. Many clinicians believe a test dose is unnecessary.

Susceptible fungal infections: I.V.: Adults: 0.05-1.5 mg/kg/day; 1-1.5 mg/kg over 4-6 hours every other day may be given once therapy is established; aspergillosis, rhinocerebral mucormycosis, often require 1-1.5 mg/kg/day; do not exceed 1.5 mg/kg/day
Aspergillosis, disseminated: I.V.: 0.6-0.7 mg/kg/day for 3-6 months
Bone marrow transplantation (prophylaxis): I.V.: Low-dose amphotericin B 0.1-0.25 mg/kg/day has been administered after bone marrow transplantation to reduce the risk of invasive fungal disease.
Candidemia (neutropenic or non-neutropenic): I.V.: 0.5-1 mg/kg/day until 14 days after last positive blood culture and resolution of signs and symptoms (Pappas, 2009)
Candidiasis, chronic, disseminated: I.V.: 0.5-0.7 mg/kg/day for 3-6 months and resolution of radiologic lesions (Pappas, 2009)
Dematiaceous fungi: I.V.: 0.7 mg/kg/day in combination with an azole
Endocarditis: I.V.: 0.6-1 mg/kg/day (with or without flucytosine) for 6 weeks after valve replacement; Note: If isolates susceptible and/or clearance demonstrated, guidelines recommend step-down to fluconazole; also for long-term suppression therapy if valve replacement is not possible (Pappas, 2009)
Endophthalmitis, fungal:
Intravitreal (unlabeled use): 10 mcg in 0.1 mL (in conjunction with systemic therapy)
I.V.: 0.7-1 mg/kg/day (with or without flucytosine) for at least 4-6 weeks (Pappas, 2009)
Esophageal: I.V.: 0.3-0.7 mg/kg/day for 14-21 days after clinical improvement
Histoplasmosis: Chronic, severe pulmonary or disseminated: I.V.: 0.5-1 mg/kg/day for 7 days, then 0.8 mg/kg every other day (or 3 times/week) until total dose of 10-15 mg/kg; may continue itraconazole as suppressive therapy (lifelong for immunocompromised patients)
Meningitis:
Candidal: I.V.: 0.7-1 mg/kg/day (with or without flucytosine) for at least 4 weeks; Note: Liposomal amphotericin favored by IDSA guidelines based on decreased risk of nephrotoxicity and potentially better CNS penetration (Pappas, 2009)
Cryptococcal or Coccidioides: I.T.: Initial: 25-300 mcg every 48-72 hours; increase to 500 mcg to 1 mg as tolerated; maximum total dose: 15 mg has been suggested
Histoplasma: I.V.: 0.5-1 mg/kg/day for 7 days, then 0.8 mg/kg every other day (or 3 times/week) for 3 months total duration; follow with fluconazole suppressive therapy for up to 12 months
Meningoencephalitis, cryptococcal: I.V.:
HIV positive: 0.7-1 mg/kg/day (plus flucytosine 100 mg/kg/day) for 2 weeks, then change to oral fluconazole for at least 10 weeks; alternatively, amphotericin and flucytosine may be continued uninterrupted for 6-10 weeks
HIV negative: 0.5-0.7 mg/kg/day (plus flucytosine) for 2 weeks
Oropharyngeal candidiasis: I.V.: 0.3 mg/kg/day for 7-14 days (Pappas, 2009)
Osteoarticular candidiasis: I.V.: 0.5-1 mg/kg/day for several weeks, followed by fluconazole for 6-12 months (osteomyelitis) or 6 weeks (septic arthritis)
Penicillium marneffei: I.V.: 0.6 mg/kg/day for 2 weeks
Pneumonia: Cryptococcal (mild-to-moderate): I.V.:
HIV positive: 0.5-1 mg/kg/day
HIV negative: 0.5-0.7 mg/kg/day (plus flucytosine) for 2 weeks
Sporotrichosis: Pulmonary, meningeal, osteoarticular or disseminated: I.V.: Total dose of 1-2 g, then change to oral itraconazole or fluconazole for suppressive therapy
Urinary tract candidiasis (Pappas, 2009):
Fungus balls: I.V.: 0.5-0.7 mg/kg/day with or without flucytosine 25 mg/kg 4 times daily
Pyelonephritis: I.V.: 0.5-0.7 mg/kg/day with or without flucytosine 25 mg/kg 4 times daily for 2 weeks
Symptomatic cystitis: I.V.: 0.3-0.6 mg/kg/day for 1-7 days
Bladder irrigation: Irrigate with 50 mcg/mL solution instilled periodically or continuously for 5-10 days or until cultures are clear for fluconazole-resistant Candida

DOSING: PEDIATRIC — Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30-60 minutes prior to drug administration: NSAID (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.

(For additional information see "Amphotericin B (conventional): Pediatric drug information")

Test dose: I.V.: Infants and Children: 0.1 mg/kg/dose to a maximum of 1 mg; infuse over 30-60 minutes. Many clinicians believe a test dose is unnecessary.

Susceptible fungal infections: I.V.: Infants and Children: Maintenance dose: 0.25-1 mg/kg/day given once daily; infuse over 2-6 hours. Once therapy has been established, amphotericin B can be administered on an every-other-day basis at 1-1.5 mg/kg/dose; cumulative dose: 1.5-2 g over 6-10 weeks
Note: Duration of therapy varies with nature of infection: Usual duration is 4-12 weeks or cumulative dose of 1-4 g.

Meningitis, coccidioidal or cryptococcal: I.T.: Children: 25-100 mcg every 48-72 hours; increase to 500 mcg as tolerated

DOSING: ELDERLY — Refer to adult dosing.

DOSING: RENAL IMPAIRMENT
If renal dysfunction is due to the drug, the daily total can be decreased by 50% or the dose can be given every other day. I.V. therapy may take several months.

Poorly dialyzed; no supplemental dose is necessary when using hemo- or peritoneal dialysis or continuous renal replacement therapy (CRRT).

Administration in dialysate: 1-2 mg/L of peritoneal dialysis fluid either with or without low-dose I.V. amphotericin B (a total dose of 2-10 mg/kg given over 7-14 days). Precipitate may form in ionic dialysate solutions.

DOSAGE FORMS — Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Injection, powder for reconstitution, as desoxycholate: 50 mg

DOSAGE FORMS: CONCISE
Injection, powder for reconstitution: 50 mg

GENERIC EQUIVALENT AVAILABLE — Yes

ADMINISTRATION — May be infused over 4-6 hours. For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related 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. Bolus infusion of normal saline immediately preceding, or immediately preceding and following amphotericin B may reduce drug-induced nephrotoxicity. Risk of nephrotoxicity increases with amphotericin B doses >1 mg/kg/day. Infusion of admixtures more concentrated than 0.25 mg/mL should be limited to patients absolutely requiring volume contraction.

COMPATIBILITY
Solution compatibility:
Compatible: Heparin sodium, hydrocortisone, sodium bicarbonate.
Incompatible: Ampicillin, calcium gluconate, carbenicillin, cimetidine, dopamine, gentamicin, lidocaine, potassium chloride, sodium chloride, tetracycline, verapamil.

USE — Treatment of severe systemic and central nervous system infections caused by susceptible fungi such as Candida species, Histoplasma capsulatum, Cryptococcus neoformans, Aspergillus species, Blastomyces dermatitidis, Torulopsis glabrata, and Coccidioides immitis; fungal peritonitis; irrigant for bladder fungal infections; used in fungal infection in patients with bone marrow transplantation, amebic meningoencephalitis, ocular aspergillosis (intraocular injection), candidal cystitis (bladder irrigation), chemoprophylaxis (low-dose I.V.), immunocompromised patients at risk of aspergillosis (intranasal/nebulized), refractory meningitis (intrathecal), coccidioidal arthritis (intra-articular/I.M.).

Low-dose amphotericin B has been administered after bone marrow transplantation to reduce the risk of invasive fungal disease.

ADVERSE REACTIONS SIGNIFICANT
Systemic:

>10%:
Cardiovascular: Hypotension, tachypnea
Central nervous system: Fever, chills, headache (less frequent with I.T.), malaise
Endocrine & metabolic: Hypokalemia, hypomagnesemia
Gastrointestinal: Anorexia, nausea (less frequent with I.T.), vomiting (less frequent with I.T.), diarrhea, heartburn, cramping epigastric pain
Hematologic: Normochromic-normocytic anemia
Local: Pain at injection site with or without phlebitis or thrombophlebitis (incidence may increase with peripheral infusion of admixtures)
Neuromuscular & skeletal: Generalized pain, including muscle and joint pains (less frequent with I.T.)
Renal: Decreased renal function and renal function abnormalities including azotemia, renal tubular acidosis, nephrocalcinosis (>0.1 mg/mL)

1% to 10%:
Cardiovascular: Hypertension, flushing
Central nervous system: Delirium, arachnoiditis, pain along lumbar nerves (especially I.T. therapy)
Genitourinary: Urinary retention
Hematologic: Leukocytosis
Neuromuscular & skeletal: Paresthesia (especially with I.T. therapy)

<1% (Limited to important or life-threatening): Acute liver failure, agranulocytosis, anuria, bone marrow suppression, cardiac arrest, coagulation defects, convulsions, dyspnea, hearing loss, leukopenia, maculopapular rash, renal failure, renal tubular acidosis, thrombocytopenia, vision changes

CONTRAINDICATIONS — Hypersensitivity to amphotericin or any component of the formulation

WARNINGS / PRECAUTIONS
Boxed warnings: Error prevention: See "Other warnings/precautions" below. Fungal infections: See "Disease-related concerns" below.

Concerns related to adverse effects: Anaphylaxis: Has been reported with 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. Infusion reactions: Acute reactions (including fever and chills) may occur 1-3 hours after starting an intravenous infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses.

Disease-related concerns: Fungal infections: [U.S. Boxed Warning]: Should be used primarily for treatment of progressive, potentially life-threatening fungal infections, not noninvasive forms of infection. Renal impairment: Use with caution in patients with renal impairment.

Concurrent drug therapy issues: Nephrotoxic drugs: Avoid use with other nephrotoxic drugs; drug-induced renal toxicity usually improves with interrupting therapy, decreasing dosage, or increasing dosing interval.

Special populations: Neutropenic patients: Pulmonary reactions may occur in neutropenic patients receiving leukocyte transfusions; separation of the infusions as much as possible is advised.

Other warnings/precautions: Error prevention: [U.S. Boxed warning]: Verify the product name and dosage if dose exceeds 1.5 mg/kg.

DRUG INTERACTIONS
Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Risk C: Monitor therapy

Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Risk D: Consider therapy modification

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Risk C: Monitor therapy

CycloSPORINE: Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE. Risk C: Monitor therapy

Flucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Risk C: Monitor therapy

Gallium Nitrate: Amphotericin B may enhance the nephrotoxic effect of Gallium Nitrate. Risk X: Avoid combination

Saccharomyces boulardii: Antifungal Agents may diminish the therapeutic effect of Saccharomyces boulardii. Risk D: Consider therapy modification

PREGNANCY RISK FACTOR — B (show table)

LACTATION — Excretion in breast milk unknown/contraindicated

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)

REFERENCE RANGE — Therapeutic: 1-2 mcg/mL (SI: 1-2.2 µmol/L)

CANADIAN BRAND NAMES — Fungizone®

INTERNATIONAL BRAND NAMES — Amphocil (MX); Fungizone (PL); Terix (MX)

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: Minimal amounts enter the aqueous humor, bile, CSF (inflamed or noninflamed meninges), amniotic fluid, pericardial fluid, pleural fluid, and synovial fluid

Protein binding, plasma: 90%

Half-life elimination: Biphasic: Initial: 15-48 hours; Terminal: 15 days

Time to peak: Within 1 hour following a 4- to 6-hour dose

Excretion: Urine (2% to 5% as biologically active form); ~40% eliminated over a 7-day period and may be detected in urine for at least 7 weeks after discontinued उसे.