Amphotericin B (Conventional)

Pronunciation

(am foe TER i sin bee con VEN sha nal)

U.S. Brand Names

Amphocin®; Fungizone®

Synonyms

Amphotericin B Desoxycholate

Generic Available

Yes: Powder for reconstitution

Canadian Brand Names

Fungizone®

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; and topically for cutaneous and mucocutaneous candidal 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 0.1-0.25 mg/kg/day has been administered after bone marrow transplantation to reduce the risk of invasive fungal disease. Alternative routes of administration and extemporaneous preparations have been used when standard antifungal therapy is not available (eg, inhalation, intraocular injection, subconjunctival application, intracavitary administration into various joints and the pleural space).

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to amphotericin or any component of the formulation

Warnings/Precautions

Anaphylaxis has been reported with other amphotericin B-containing drugs. During the initial dosing, the drug should be administered under close clinical observation. Avoid additive toxicity with other nephrotoxic drugs; drug-induced renal toxicity usually improves with interrupting therapy, decreasing dosage, or increasing dosing interval. I.V. amphotericin is used primarily for the treatment of patients with progressive and potentially fatal fungal infections; topical preparations may stain clothing. Infusion reactions are most common 1-3 hours after starting the infusion and diminish with continued therapy. Use amphotericin B with caution in patients with decreased renal function. Pulmonary reactions may occur in neutropenic patients receiving leukocyte transfusions; separation of the infusions as much as possible is advised.

Adverse Reactions

>10%:

Central nervous system: Fever, chills, headache, malaise, generalized pain

Endocrine & metabolic: Hypokalemia, hypomagnesemia

Gastrointestinal: Anorexia

Hematologic: Anemia

Renal: Nephrotoxicity

1% to 10%:

Cardiovascular: Hypotension, hypertension, flushing

Central nervous system: Delirium, arachnoiditis, pain along lumbar nerves

Gastrointestinal: Nausea, vomiting

Genitourinary: Urinary retention

Hematologic: Leukocytosis

Local: Thrombophlebitis

Neuromuscular & skeletal: Paresthesia (especially with I.T. therapy)

Renal: Renal tubular acidosis, renal failure

<1%: Cardiac arrest, bone marrow suppression, convulsions, maculopapular rash, coagulation defects, thrombocytopenia, agranulocytosis, leukopenia, acute liver failure, vision changes, hearing loss, anuria, dyspnea

Overdosage/Toxicology

Symptoms of overdose include renal dysfunction, cardiac arrest, anemia, thrombocytopenia, granulocytopenia, fever, nausea, and vomiting. Treatment is supportive.

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

Reconstitute only with sterile water without preservatives, not bacteriostatic water. Benzyl alcohol, sodium chloride, or other electrolyte solutions may cause precipitation.

Short-term exposure (<24 hours) to light during I.V. infusion does not appreciably affect potency

Reconstituted solutions with sterile water for injection and kept in the dark remain stable for 24 hours at room temperature and 1 week when refrigerated

Stability of parenteral admixture at room temperature (25°C): 24 hours; at refrigeration (4°C): 2 days

Standard diluent: Dose/250-500 mL D5W

Compatibility

Admixtures are compatible with glass or plastic containers, including polyvinyl chloride, although some sterile evacuated glass containers have small amounts of ionic liquid buffer that may cause precipitation.

Solution compatibility:

Compatible: Heparin sodium, hydrocortisone, sodium bicarbonate

Incompatible: Ampicillin, calcium gluconate, carbenicillin, cimetidine, dopamine, gentamicin, lidocaine, potassium chloride, tetracycline, verapamil

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 use

Dosage

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.

Infants and Children:

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

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 week.

Adults:

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

Maintenance dose: Usual: 0.25-1.5 mg/kg/day; 1-1.5 mg/kg over 4-6 hours every other day may be given once therapy is established; aspergillosis, mucormycosis, rhinocerebral phycomycosis often require 1-1.5 mg/kg/day; do not exceed 1.5 mg/kg/day

Duration of therapy varies with nature of infection: Usual duration is 4-12 weeks or cumulative dose of 1-4 g

I.T.: Meningitis, coccidioidal or cryptococcal:

Children.: 25-100 mcg every 48-72 hours; increase to 500 mcg as tolerated

Adults: 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

Oral: 1 mL (100 mg) 4 times/day

Topical: Apply to affected areas 2-4 times/day for 1-4 weeks of therapy depending on nature and severity of infection

Bladder irrigation: Candidal cystitis: Irrigate with 50 mcg/mL solution instilled periodically or continuously for 5-10 days or until cultures are clear

Dosing adjustment in 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

Dialysis: Poorly dialyzed; no supplemental dosage necessary when using hemo- or peritoneal dialysis or continuous arteriovenous or venovenous hemodiafiltration effects

Administration in dialysate: Children and Adults: 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.

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

mol/L)

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. Take entire prescription, even if you are feeling better. Most skin lesions may take 1-3 weeks of therapy; 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 nausea, vomiting, or anorexia (small, frequent meals, frequent mouth care, sucking lozenges, or chewing gum may help); generalized muscle or joint paint (consult prescriber for approved analgesic); or hypotension (use caution when rising from sitting or lying position or when climbing stairs). Report severe muscle cramping or weakness; chest pain or palpitations; CNS disturbances; skin rash; change in urinary patterns or difficulty voiding; black stool; unusual bruising or bleeding; or pain, redness, swelling at infusion site.

Topical: Amphotericin cream may slightly discolor skin and stain clothing; use gloves when applying. Avoid covering topical application with occlusive bandages. Most skin lesions require 1-3 weeks of therapy. Maintain good personal hygiene to reduce the spread and recurrence of lesions.

Breast-feeding precaution: Do not breast-feed.

Additional Information

Premedication with diphenhydramine and acetaminophen may reduce the severity of acute infusion-related reactions. Meperidine reduces the duration of amphotericin B-induced rigors and chilling. Hydrocortisone may be used in patients with severe or refractory infusion-related reactions. 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 restriction. Amphotericin B does not have a bacteriostatic constituent, subsequently admixture expiration is determined by sterility more than chemical stability.

Anesthesia and Critical Care Concerns/Other Considerations

Patients may be premedicated with acetaminophen and diphenhydramine 30 minutes prior to the amphotericin infusion. Meperidine (Demerol®) may help to reduce rigors. Avoid rapid injection (usually 4- to 6-hour infusion required). Dosage adjustments are not necessary with renal impairment. If decreased renal function is due to amphotericin, the daily dose can be decreased by 50% or the dose can be given every other day.

Hydrocortisone may be used in patients with severe or refractory infusion-related reactions. 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 restriction. Amphotericin B does not have a bacteriostatic constituent, subsequently admixture expiration is determined by sterility more than chemical stability.

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

Cream (Fungizone®): 3% (20 g)

Injection, powder for reconstitution, as desoxycholate (Amphocin®; Fungizone®): 50 mg

Lotion (Fungizone®): 3% (30 mL)

References

Anderson RP and Clark DA, "Amphotericin B Toxicity Reduced by Administration in Fat Emulsion," Ann Pharmacother , 1995, 29(5):496-500.

Arning M, Heer-Sonderhoff A, and Schneider W, "Cardiopulmonary Toxicity After Liposomal Amphotericin B (AmBisome®) in Neutropenic Patients With Acute Leukemia," Onkologie , 1994, 17:4.

Arsura EL, Ismail Y, Freedman S, et al, "Amphotericin B-Induced Dilated Cardiomyopathy," Am J Med , 1994, 97(6):560-2.

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Bianco JA, Almgren J, Kern DL, et al, "Evidence That Oral Pentoxifylline Reverses Acute Renal Dysfunction in Bone Marrow Transplant Recipients Receiving Amphotericin B and Cyclosporine," Transplantation , 1991, 51(4):925-7.

Branch RA, "Prevention of Amphotericin B-Induced Renal Impairment. A Review on the Use of Sodium Supplementation," Arch Intern Med , 1988, 148(11):2389-94.

Brent J, Hunt M, Kulig K, et al, "Amphotericin B Overdoses in Infants: Is There a Role for Exchange Transfusion?" Vet Hum Toxicol , 1990, 32(2):124-5.

Cruz JM, Peacock JE Jr, Loomer L, et al, "Rapid Intravenous Infusion of Amphotericin B: A Pilot Study," Am J Med , 1992, 93:123-30.

Devuyst O, Goffin E, and Van Ypersele de Strihou C, "Recurrent Hemiparesis Under Amphotericin B for Candida albicans Peritonitis," Nephrol Dial Transplant , 1995, 10(5):699-701.

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.

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Jeffery GM, Beard ME, Ikram RB, et al, "Intranasal Amphotericin B Reduces the Frequency of Invasive Aspergillosis in Neutropenic Patients," Am J Med , 1991, 90(6):685-92.

Jones RS, Barman A, Suh B, et al, "Successful Treatment of Aspergillus vertebral Osteomyelitis With Amphotericin B Lipid Complex," Infect Dis Clin Pract , 1995, 4:237-9.

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International Brand Names

Fungizone® (CA)

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