amphotericin B cholesteryl sulfate

amphotericin B cholesteryl sulfate Warning - High-alert drug!

Amphocil (UK), Amphotec

Pharmacologic class: Systemic polyene antifungal

Therapeutic class: Antifungal

Pregnancy risk category B

FDA Boxed Warning

• Amphotericin B desoxycholate should be used mainly to treat progressive and potentially life-threatening fungal infections. It shouldn't be used to treat noninvasive forms of fungal disease (such as oral thrush, vaginal candidiasis, or esophageal candidiasis) in patients with normal neutrophil counts.

Action

Binds to sterols in fungal cell membrane, increasing permeability. This allows potassium to exit the cell, causing fungal impairment or death.

Availability

Amphotericin B cholesteryl sulfate -

Injection: 50 mg, 100 mg

Amphotericin B desoxycholate -

Injection: 50-mg vial

Oral suspension: 100 mg/ml in 24-ml bottles

Amphotericin B lipid complex -

Suspension for injection: 100 mg/20-ml vials

Amphotericin B liposome -

Injection: 50 mg

⊘Indications and dosages

➣ Invasive aspergillosis

Adults: Amphotericin B desoxycholate - For patients with good cardiorenal function who tolerate test dose, give 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours). Gradually increase to 0.5 to 0.6 mg/kg daily. Patients with neutropenia or rapidly progressing, potentially fatal infections may require higher dosages (1 to 1.5 mg/kg daily).

Adults and children ages 1 month and older: Amphotericin B liposome - 3 to 5 mg/kg I.V. daily

➣ Invasive aspergillosis in patients with renal impairment or unacceptable toxicity who can't tolerate or don't respond to amphotericin B desoxycholate in effective doses

Adults and children: Amphotericin B cholesteryl sulfate - 3 to 4 mg/kg daily I.V. Dilute in dextrose 5% in water (D₅W) and give by continuous infusion at 1 mg/kg/hour. Amphotericin B lipid complex - 5 mg/kg daily I.V. prepared as 1-mg/ml infusion and delivered at a rate of 2.5 mg/kg/hour.

➣ Systemic histoplasmosis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.5 to 0.6 mg/kg daily I.V. for 4 to 8 weeks; higher dosages (0.7 to 1 mg) may be necessary for rapidly progressing, potentially fatal infections.

➣ Systemic coccidioidomycosis and blastomycosis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.5 to 1 mg/kg daily I.V. for 4 to 12 weeks.

➣ Systemic cryptococcosis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.3 to 1 mg/kg daily I.V. (with or without flucytosine) for 2 weeks to several months. For patients with human immunodeficiency virus (HIV) infection, usual dosage is 0.7 mg/kg daily I.V. for 4 weeks, followed by 0.7 mg/kg I.V. given on alternate days for 4 additional weeks. If patient can't tolerate or doesn't respond to amphotericin B desoxycholate, give amphotericin B cholesteryl sulfate at a dosage of 3 to 6 mg/kg daily I.V.

Adults and children ages 1 month and older: Amphotericin B liposome - 3 to 5 mg/kg daily I.V.

➣ Cryptococcal meningitis in HIV-infected patients

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.3 to 1 mg/kg daily I.V. (with or without flucytosine) for 2 weeks to several months. Amphotericin B lipid complex - 5 mg/kg I.V. infusion daily for 6 weeks, followed by 12 weeks of oral fluconazole therapy. Amphotericin B liposome - 6 mg/kg I.V. infusion daily.

➣ Disseminated candidiasis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.4 to 0.6 mg/kg daily by slow I.V. infusion for 7 to 14 days (low-risk patients) or for 6 weeks (high-risk patients). For hepatosplenic candidiasis, 1 mg/kg daily I.V. given with oral flucytosine; for severe or refractory esophageal candidiasis in HIV-infected patients, 0.3 mg/kg daily I.V. for at least 5 to 7 days; for candiduria, 0.3 mg/kg daily I.V. for 3 to 5 days.

Adults and children ages 1 month and older: Amphotericin B liposome - 3 to 5 mg/kg/day I.V. for 5 to 7 days

➣ Systemic zygomycosis, including mucormycosis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 1 to 1.5 mg/kg daily I.V. for 2 to 3 months. For rhinocerebral phycomycosis form, total dosage is 3 g I.V.

➣ Systemic disseminated sporotrichosis

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.4 to 0.5 mg/kg daily I.V. for 2 to 3 months.

➣ Cutaneous leishmaniasis

Adults and children: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.5 mg/kg/day given by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) until 0.5 to 1 mg/kg/day is reached; then give every other day. Usual duration is 3 to 12 weeks.

➣ Visceral leishmaniasis in immunocompetent patients

Adults and children ages 1 month and older: Amphotericin B liposome - 3 mg/kg given I.V. over 2 hours on days 1 through 5, 14, and 21. Repeat course if initial treatment fails to clear parasites.

➣ Visceral leishmaniasis in immunocompromised patients

Adults and children ages 1 month and older: Amphotericin B liposome - 4 mg/kg given I.V. over 2 hours on days 1 through 5, 10, 17, 24, 31, and 38

➣ Empiric therapy for presumed fungal infection in febrile, neutropenic patients

Adults: Amphotericin B desoxycholate - If patient tolerates test dose, gradually increase from initial recommended dosage of 0.25 to 0.3 mg/kg daily by slow I.V. infusion (0.1 mg/ml over 2 to 6 hours) to usual dosage of 0.25 to 1 mg/kg daily I.V. Amphotericin B liposome - 3 mg/kg daily given I.V. over 120 minutes for 2 weeks

Off-label uses

• Chemoprophylaxis in immunocompromised patients
• Coccidioidal arthritis
• Prophylaxis of fungal infections in bone-marrow transplant recipients, patients with primary amoebic meningoencephalitis caused by Naegleria fowleri, and patients with ocular aspergillosis

Contraindications

• Hypersensitivity to drug and its components
• Severe respiratory distress

Precautions

Use cautiously in:
• renal impairment, electrolyte abnormalities
• pregnant or breastfeeding patients
• children.

Administration

• Know that amphotericin B should be given only by health care professionals thoroughly familiar with drug, its administration, and adverse reactions.
☞ Before giving first dose of conventional amphotericin B (desoxycholate form), test dose may be ordered (due to widely varying tolerance and clinical status) as follows: 1 mg in 20 ml of D₅W over 20 to 30 minutes; monitor vital signs every 30 minutes for next 2 hours.
• Know that if desoxycholate form is discontinued for 1 week or longer, drug should be restarted at 0.25 mg/kg daily, with dosage then increased gradually.
• Pretreat with antihistamines, antipyretics, or corticosteroids, as prescribed.
• Give through separate I.V. line, using infusion pump and in-line filter with pores larger than 1 micron.
• Choose distal vein for I.V. site. Alternate sites regularly.
• Mix with 10 ml of sterile water to reconstitute. Don't mix with sodium chloride, other electrolytes, or bacteriostatic products.
• Flush I.V. line with 5% dextrose injection before and after infusion.
• Keep dry form of drug away from light. Once mixed with fluid, solution can be kept in light for up to 8 hours.
☞ Know that total daily dosage of amphotericin B desoxycholate form should never exceed 1.5 mg/kg.

Route	Onset	Peak	Duration
P.O.	Unknown	Unknown	Unknown
I.V.	Rapid	End of infusion	24 hr

Adverse reactions

CNS: anxiety, confusion, headache, insomnia, weakness, depression, dizziness, drowsiness, hallucinations, speech difficulty, ataxia, vertigo, stupor, psychosis, seizures

CV: hypotension, hypertension, tachycardia, phlebitis, chest pain, orthostatic hypotension, vasodilation, asystole, atrial fibrillation, bradycardia, cardiac arrest, shock, supraventricular tachycardia

EENT: double or blurred vision, amblyopia, eye hemorrhage, hearing loss, tinnitus, epistaxis, rhinitis, sinusitis, pharyngitis

GI: nausea, vomiting, diarrhea, melena, abdominal pain, abdominal distention, dry mouth, oral inflammation, oral candidiasis, anorexia, GI hemorrhage

GU: painful urination, hematuria, albuminuria, glycosuria, excessive urea buildup, urine of low specific gravity, nephrocalcinosis, renal failure, renal tubular acidosis, oliguria, anuria

Hematologic: eosinophilia; normochromic, normocytic, or hypochromic anemia; leukocytosis; thrombocytopenia; leukopenia; agranulocytosis; coagulation disorders

Hepatic: jaundice, acute hepatic failure, hepatitis

Metabolic: hypomagnesemia, hypokalemia, hypocalcemia, hypernatremia, hyperglycemia, dehydration, hypoproteinemia, hypervolemia, hyperlipidemia, acidosis

Musculoskeletal: muscle, joint, neck, or back pain

Respiratory: increased cough, hypoxia, lung disorders, hyperventilation, wheezing, dyspnea, hemoptysis, tachypnea, asthma, bronchospasm, respiratory failure, pulmonary edema, pleural effusion

Skin: discoloration, bruising, flushing, pruritus, urticaria, acne, rash, sweating, nodules, skin ulcers, alopecia, maculopapular rash

Other: gingivitis, fever, infection, peripheral or facial edema, weight changes, pain or reaction at injection site, tissue damage with extravasation, hypersensitivity reactions including anaphylaxis

Interactions

Drug-drug. Antineoplastics (such as mechlorethamine): renal toxicity, bronchospasm, hypotension

Cardiac glycosides: increased risk of digitalis toxicity (in potassium-depleted patients)

Corticosteroids: increased potassium depletion

Cyclosporine, tacrolimus: increased creatinine levels

Flucytosine: increased flucytosine toxicity

Imidazoles (clotrimazole, fluconazole, ketoconazole, miconazole): antagonism of amphotericin B effects

Leukocyte transfusion: pulmonary reactions

Nephrotoxic drugs (such as antibiotics, pentamidine): increased risk of renal toxicity

Thiazides: increased electrolyte depletion

Skeletal muscle relaxants: increased skeletal muscle relaxation

Zidovudine: increased myelotoxicity and nephrotoxicity

Drug-diagnostic tests. Alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, bilirubin, blood urea nitrogen, creatinine, gamma-glutamyltransferase, lactate dehydrogenase, nitrogenous compounds (urea), uric acid: increased levels

Calcium, hemoglobin, magnesium, platelets, potassium, protein: decreased levels

Eosinophils, glucose, white blood cells: increased or decreased levels

Liver function tests: abnormal results

Prothrombin time: prolonged

Drug-herbs. Gossypol: increased risk of renal toxicity

Patient monitoring

☞ Monitor for infusion-related reactions (fever, chills, hypotension, GI symptoms, breathing difficulties, and headache). Stop infusion and notify prescriber immediately if reaction occurs.
☞ After giving test dose, monitor vital signs and temperature every 30 minutes for 2 to 4 hours, as ordered.
• Assess fluid intake and output.
• Monitor kidney and liver function test results and serum electrolyte levels.
• Assess for signs and symptoms of ototoxicity (hearing loss, tinnitus, ataxia, and vertigo).

Patient teaching

☞ Advise patient to contact prescriber immediately if he has fever, chills, headache, vomiting, diarrhea, cough, or breathing problems.
• Instruct patient to report hearing loss, dizziness, or unsteady gait.
• Caution patient to avoid driving and other hazardous activities until he knows how drug affects concentration, alertness, and vision.
• Instruct patient to drink plenty of fluids.
• Tell patient to monitor urine output and report significant changes.
• Advise patient to minimize GI upset by eating small, frequent servings of food and drinking plenty of fluids.
• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs, tests, and herbs mentioned above.