amphotericin B
Amphocin, Fungizone

Available forms
Available by prescription only
Cream: 3%
Lotion: 3%
Ointment: 3%
Oral suspension: 100 mg/ml
Powder for injection: 50 mg

Indications and dosages
 Systemic (potentially fatal) fungal infections caused by susceptible organisms, fungal endocarditis, fungal septicemia. Adults and children: Some clinicians recommend an initial dose of 1 mg I.V. in 20 ml D₅W infused over 20 minutes. If test dose is tolerated, then give daily doses of 0.25 to 0.30 mg/kg, gradually increasing by 5 to 10 mg daily until daily dose is 1 mg/kg or 1.5 mg/kg q alternate day. Duration of therapy depends on the severity and nature of infection.
 For sporotrichosis, give 0.4 to 0.5 mg/kg amphotericin B daily I.V. for up to 9 months. Total I.V. dosage of 2.5 g over 9 months.
 For aspergillosis, give 0.5 to 0.6 mg/kg daily initially and a total I.V. dosage of 1.5 to 4 g over 11 months.
 Fungal meningitis ◇. Adults: Intrathecal injection of 25 mcg/0.1 ml diluted with 10 to 20 ml of CSF and administered by barbotage two or three times weekly. Initial dose shouldn’t exceed 50 mcg.
 Candidal cystitis ◇. Adults: Bladder irrigations in concentrations of 5 to 50 mcg/ml instilled periodically or continuously for 5 to 7 days.
 Oropharyngeal candidiasis. Adults and children: 100 mg/ml oral suspension q.i.d. swish and swallow.
 Topical fungal infections (3% cream, lotion, ointment). Adults and children: Apply liberally and rub well into affected area b.i.d. to q.i.d.
 Cutaneous or mucocutaneous candidal infections. Adults and children: Apply topical product b.i.d., t.i.d., or q.i.d. for 1 to 3 weeks; apply up to several months for interdigital or paronychial lesions.
 Histoplasmal pulmonary and intrapleural effusion ◇. Adults: 15 to 20 mg with 25 mg hydrocortisone sodium succinate.
 Pulmonary coccidioidomycosis ◇. Adults: Via intermittent positive pressure breathing device, 5 to 10 mg q.i.d.
 Ophthalmic candidal infection ◇. Adults: 0.1 to 1 mg/ml drop suspension q 30 minutes.
 Empiric therapy of presumed fungal infections in febrile, neutropenic patients including cancer patients and bone marrow transplant ◇. Adults: 0.1 mg/kg daily.
 Mucocutaneous leishmaniasis. Adults and children: 0.25 to 0.5 mg/kg/day I.V., increased gradually to 0.5 to 1 mg/kg/day, then give on alternate days. Treat for 3 to 12 weeks.
 Visceral leishmaniasis. Adults and children: 0.5 to 1 mg/kg/day I.V. on alternate days for 14 to 20 doses.

Pharmacodynamics
Antifungal action: Amphotericin B is fungistatic or fungicidal, depending on the concentrations available in body fluids and on the susceptibility of the fungus. It binds to sterols in the fungal cell membrane, increasing membrane permeability of fungal cells, causing subsequent leakage of intracellular components; it also may interfere with some human cell membranes that contain sterols.
 Spectrum of activity includes Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neoformans, Candida species, Aspergillus fumigatus, Mucor, Rhizopus species, Absidia species, Entomophthora species, Basidiobolus species, Paracoccidioides brasiliensis, Sporothrix schenckii, and Rhodotorula species.

Pharmacokinetics
Absorption: Absorbed poorly from the GI tract.
Distribution: Distributed well into inflamed pleural cavities and joints; in low levels into aqueous humor, bronchial secretions, pancreas, bone, muscle, and parotids. CSF levels reach about 3% of serum levels. Drug is 90% to 95% bound to plasma proteins; it reportedly crosses the placental barrier.
Metabolism: Not well defined.
Excretion: Elimination is biphasic: initial serum half-life of 24 hours, followed by a second phase half-life of about 15 days. About 2% to 5% of drug is excreted unchanged in urine. Amphotericin B isn’t readily removed by hemodialysis.

Contraindications and precautions
Contraindicated in patients hypersensitive to drug. Use cautiously in patients with renal impairment.

Interactions
Drug-drug. Aminoglycosides, cisplatin, pentamidine, other nephrotoxic drugs: Cause additive nephrotoxic effects. Avoid use together.
Clotrimazole, fluconazole, itraconazole, ketoconazole, miconazole: May antagonize amphotericin B. Monitor patient closely.
Corticosteroids, corticotropin: Cause electrolyte imbalances. Carefully monitor serum electrolyte levels and cardiac function.
Digoxin: Increases risk of digitalis toxicity. Monitor serum digoxin level if used together.
Flucytosine, other antibiotics: Potentiate effects. Use together cautiously.
Skeletal muscle relaxants: Amphotericin B-induced hypokalemia may enhance effects of skeletal muscle relaxants. Use together cautiously.
Zidovudine: Increases myelotoxicity and nephrotoxicity. Monitor renal and hematologic function.
Drug-herb. Gossypol: May increase risk of renal toxicity. Discourage use together.

Adverse reactions
CNS: fever, generalized pain,malaise, headache, peripheral neuropathy, seizures.
CV: phlebitis, thrombophlebitis, flushing, hypotension, arrhythmias, asystole, hypertension.
EENT: hearing loss, tinnitus, transient vertigo, blurred vision, diplopia.
GI: anorexia, nausea, vomiting, dyspepsia, diarrhea, epigastric pain, cramping, melena, hemorrhagic gastroenteritis.
GU: abnormal renal function with hypokalemia, azotemia, hyposthenuria, renal tubular acidosis, nephrocalcinosis; with large doses, permanent renal impairment, anuria, oliguria.
Hematologic: normochromic, normocytic anemia, thrombocytopenia, leukopenia, agranulocytosis, eosinophilia, leukocytosis.
Hepatic: hepatitis, jaundice, acute liver failure.
Metabolic: hypokalemia, hypomagnesemia, weight loss.
Musculoskeletal: arthralgia, myalgia.
Respiratory: dyspnea, tachypnea, bronchospasm, wheezing.
Skin: pain at injection site, maculopapular rash, pruritus without rash (with systemic form); dryness, contact sensitivity, erythema, burning, pruritus (with topical administration).
Other: tissue damage with extravasation, chills, anaphylactoid reactions.

Effects on lab test results
• May increase nitrogenous compounds (urea), uric acid, BUN, creatinine, alkaline phosphatase, ALT, AST, GGT, LDH, and bilirubin levels. May decrease potassium and magnesium levels. May increase or decrease glucose levels.
• May decrease hemoglobin and platelet and granulocyte counts. May increase or decrease WBC and eosinophil counts.

Overdose and treatment
Overdose may affect CV and respiratory function.
 Treatment is largely supportive. Hemodialysis isn’t effective. Correction of electrolyte imbalances is usually necessary.

Special considerations
 ALERT Amphotericin B preparations aren’t interchangeable and dosages will vary.
• Cultures and histologic and sensitivity testing must be completed and diagnosis confirmed before starting therapy in nonimmunocompromised patient.
• Severity of some adverse reactions can be reduced by premedication with aspirin or acetaminophen, antihistamines, antiemetics, meperidine, or small doses of corticosteroids; by addition of phosphate buffer to the solution; and by alternate-day dosing. If reactions are severe, drug may have to be discontinued for varying periods.
• Prepare infusion as manufacturer directs, with strict aseptic technique, using only 10 ml of sterile water to reconstitute. To avoid precipitation, don’t mix with solutions containing sodium chloride, other electrolytes, or bacteriostatic agents such as benzyl alcohol.
• Don’t use if reconstituted solution contains a precipitate or other foreign particles. Store the dry form at 36° to 46° F (2° to 8° C). Protect drug from light, and check expiration date.
• Don’t mix or piggyback antibiotics with amphotericin B infusion; the I.V. solution appears compatible with small amounts of heparin sodium, hydrocortisone sodium succinate, and methylprednisolone sodium succinate.
• For I.V. infusion, use an in-line membrane with a mean pore diameter larger than 1 micron.
• Give drug in distal veins and infuse slowly; rapid infusion may cause CV collapse.
• Check vital signs every 30 minutes for at least 4 hours after start of I.V. infusion; fever may appear in 1 to 2 hours but should subside within 4 hours of discontinuing drug.
• Watch for first-dose acute infusion reactions, which include fever, chills, hypotension, nausea, vomiting, headache, dyspnea, and tachycardia. Reaction may occur in 1 to 3 hours.
• Monitor site for discomfort or thrombosis; if thrombosis occurs, consider alternate-day therapy.
• Monitor intake and output, and check for changes in urine appearance or volume; renal damage may be reversible if drug is stopped at earliest sign of dysfunction.
• Monitor potassium and magnesium levels closely. Monitor calcium and magnesium levels twice weekly. Perform liver and renal function studies and CBC regularly (usually twice weekly).
• Use topical products for folds of groin, neck, or armpit; avoid occlusive dressing with ointment, and discontinue if signs of hypersensitivity develop.
• Store at room temperature. Solution is stable at room temperature and in indoor light for 24 hours or in the refrigerator for 1 week.
• Intrathecal and intra-articular uses are unapproved.
Pregnant patients
• Safety during pregnancy hasn’t been established, but the drug has been used without obvious adverse effects to the fetus.
Breast-feeding patients
• Safety hasn’t been established in breast-feeding women.

Patient education
• Teach patient signs and symptoms of hypersensitivity and other adverse reactions, especially those that occur with I.V. therapy. Warn that fever and chills are likely to occur and can be severe when therapy begins. These symptoms usually subside with repeated doses. Encourage patient feedback during infusion.
• Warn patient that therapy may take several months; recommend personal hygiene and other measures to prevent spread and recurrence of lesions.
• Urge patient to adhere to regimen and to return, as instructed, for follow-up.
• Tell patient that topical products may stain skin and clothing; cream or lotion may be removed from clothing with soap and water.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use