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Amphotericin B

Pronouncation: (am-foe-TER-i-sin B)
Class: Polyene antifungal Amphotericin B Cholesteryl

Trade Names:
Amphotec
- Powder for injection 50 mg (as cholesteryl)
- Powder for injection 100 mg (as cholesteryl)

Amphotericin B, Lipid-Based

Trade Names:
Abelcet
- Suspension for injection 100 mg per 20ߙmL (as lipid complex)

Trade Names:
AmBisome
- Powder for injection 50 mg (as liposomal)

Pharmacology

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Compare with other drugs.

Alters fungal cell membrane permeability.

Pharmacokinetics

Absorption

Amphotericin B cholesteryl

C _max is approximately 2.6ߙto 2.9ߙmcg/mL.

Amphotericin B lipid-based

C _max is approximately 1.7ߙmcg/mL ( Abelcet ) and approximately 7.3 to 83 mcg/mL ( Ambisome ; 1 to 5 mg/kg/day).

Distribution

Amphotericin B cholesteryl

Vd is approximately 3.8 to 4.1ߙL/kg; distribution t _½ is approximately 3.5ߙmin.

Amphotericin B lipid-based

Vd is approximately 131 L/kg ( Abelcet ) and 0.1 to 0.44 L/kg ( Ambisome ; 1 to 5 mg/kg/day).

Metabolism

Not known.

Elimination

Amphotericin B cholesteryl

The t _½ is approximately 27.5 to 28.2 h; Cl is approximately 0.105 to 0.112 L/h/kg.

Amphotericin B lipid-based

The t _½ is approximately 173.4 h ( Abelcet ), approximately 7 to 10 h ( Ambisome ; measured within 24-h dosing interval), and approximately 100 to 153 h ( Ambisome ; measured up to 49 days after dosing). Cl is approximately 436ߙmL/h/kg ( Abelcet ) and 11 to 51 mL/h/kg ( Ambisome ).

Indications and Usage

Treatment of progressive, potentially fatal infections caused by certain fungal species.

Amphotericin B cholesteryl

Treatment of invasive aspergillosis.

Amphotericin B lipid-based

Treatment of invasive fungal infections in patients refractory to conventional amphotericin B (lipid complex); empirical treatment of febrile, neutropenic patients with presumed fungal infections (liposomal); treatment of visceral leishmaniasis (liposomal).

Unlabeled Uses

Prophylaxis of fungal infections in patients with bone marrow transplantation; treatment of primary amoebic meningoencephalitis caused by Naegleria fowleri ; subconjunctival or intravitreal treatment of ocular aspergillosis; bladder irrigation for candidal cystitis; chemoprophylaxis of aspergillosis; intrathecal treatment of severe meningitis unresponsive to IV therapy; intra-articular or IM treatment of coccidioidal arthritis.

Contraindications

Standard considerations.

Dosage and Administration

Amphotericin B Cholesteryl
Systemic Fungal Infections Adults and Children

IV Test dose advisable (eg, 10ߙmL containing 1.6 to 8.3 mg infused over 15 to 30 min); recommended treatment dose is 3 to 4 mg/kg/day.

Amphotericin B Lipid Complex
Systemic Fungal Infections Adults and Children

IV 5 mg/kg/day as a single infusion at a rate of 2.5 mg/kg/h. If infusion time exceeds 2 h, mix contents of infusion bag by shaking every 2 h. Dilute to 2 mg/mL for patients with CV disease.

Amphotericin B Liposomal
Empirical Fungal Infections Adults

IV 3 mg/kg/day.

Systemic Fungal Infections Adults

IV 3 to 5 mg/kg/day as a 1 to 2ߙmg/mL dilution.

Children

IV 3 to 5ߙmg/kg/day as a 0.2 to 0.5 mg/mL dilution.

Cryptococcal Meningitis Adults

IV 6 mg/kg/day.

Leishmaniasis Adults

IV 3 mg/kg/day on days 1 through 5 (days 14ߙand 21 for immunocompetent patients); administer 4 mg/kg/day on days 1 through 5 (days 10, 17, 24, 31, and 38 for immunosuppressed patients).

General Advice

Amphotericin B cholesteryl
Administer diluted in dextrose 5% injection by IV infusion rate of 1ߙmg/kg/h.
Follow manufacturer's instructions for reconstitution and administration. Reconstitute by using sterile water for injection. Do not reconstitute with saline or dextrose solutions or admix with saline or electrolytes.
Do not filter or use an in-line filter.
Do not mix with other IV medications.

Amphotericin B lipid-based
Administer IV at a rate of 2.5 mg/kg/h. If infusion time exceeds 2 h, mix contents by shaking the infusion bag every 2ߙh.
Follow manufacturer's instructions for reconstitution and administration. Use dextrose 5% injection for reconstitution. Do not reconstitute with other drugs or electrolytes because compatibility of liposomal amphotericin B has not been established. Flush an existing IV line with dextrose 5% injection before infusion of liposomal amphotericin B, or use a separate infusion line.
Shake the vial gently until there is no yellow sediment at the bottom.
Do not use an in-line filter less than 5ߙmicrons.

Storage/Stability

Amphotericin B lipid-based

Do not freeze. Retain in the carton until time of use.
May be stored for 15 h if refrigerated or 6ߙh at room temperature.
Discard any unused material.

Amphotericin B cholesteryl

Use within 24 h after reconstitution.
Store unopened vials at 59° to 86°F.
Refrigerate after reconstitution.

Drug Interactions

Antineoplastic agents

Concurrent use may enhance potential for arrhythmias, bronchospasm, renal toxicity, and shock.

Azole antifungal agents (eg, fluconazole, ketoconazole)

Antagonism between amphotericin B and the antifungal agent may occur.

Corticosteroids and corticotropin

Increased potential for hypokalemia.

Cyclosporine, tacrolimus

May increase nephrotoxic effects.

Digitalis glycosides

Amphotericin B–induced hypokalemia may potentiate digitalis toxicity.

Flucytosine

Increased risk of flucytosine toxicity.

Leukocyte transfusions

Acute pulmonary toxicity has been reported in patients receiving IV amphotericin B and leukocyte transfusions. Do not give concurrently.

Nephrotoxic agents (eg, aminoglycosides)

Possible synergistic nephrotoxicity.

Skeletal muscle relaxants (eg, tubocurarine)

Amphotericin B–induced hypokalemia may enhance curariform effect of skeletal muscle relaxant.

Zidovudine

Closely monitor renal and hematologic function if used with amphotericin B.

Incompatibility

Do not mix with other IV medications.

Laboratory Test Interactions

None well documented.

Adverse Reactions

Cardiovascular

Hypotension, tachycardia (10%); hypertension (9%); hemorrhage, postural hypotension (at least 5%); arrhythmia, atrial fibrillation, bradycardia, cardiac arrest, CHF, phlebitis, shock, supraventricular tachycardia, syncope, vasodilation, venoocclusive liver disease, ventricular extrasystoles (1% to less than 5%); ventricular fibrillation.

CNS

Headache (8%); abnormal thinking, confusion, dizziness, insomnia, somnolence, tremor (at least 5%); asthenia (1% to less than 5%); agitation, anxiety, convulsion, depression, hallucinations, hypertonia, nervousness, neuropathy, paresthesia, psychosis, speech disorder, stupor (1% to less than 5%); malaise, peripheral nephropathy.

Dermatologic

Maculopapular rash, pruritus, rash, sweating (at least 5%); acne, alopecia, petechial rash, skin discoloration, skin disorder, skin nodule, skin ulcer, urticaria, vesiculobullous rash (1% to less than 5%).

EENT

Eye hemorrhage (at least 5%); amblyopia, deafness, ear disorder, pharyngitis, tinnitus (1% to less than 5%).

GI

Nausea (12%); nausea and vomiting, vomiting (11%); diarrhea, dry mouth, hematemesis, stomatitis (at least 5%); anorexia, bloody diarrhea, constipation, dyspepsia, fecal incontinence, GI disorder, GI hemorrhage, gingivitis, glossitis, increased gamma glutamyl transpeptidase, melena, mouth ulceration, oral moniliasis, rectal disorder (1% to less than 5%); cramping, epigastric pain.

Genitourinary

Hematuria (at least 5%); albuminuria, dysuria, glycosuria, kidney failure, oliguria, urinary incontinence, urinary retention, urinary tract disorder (1% to less than 5%); anuria, azotemia, hematuria, hypostenuria, nephrocalcinosis, renal tubular acidosis.

Hematologic-Lymphatic

Thrombocytopenia (7%); anemia, coagulation disorder, decreased prothrombin (at least 5%); decreased thromboplastin, ecchymosis, hypochromic anemia, increased fibrinogen, leukocytosis, leukopenia, petechiae (1% to less than 5%); agranulocytosis, eosinophilia, normochromic anemia, normocytic anemia.

Hepatic

Abnormal LFTs (11%); jaundice (at least 5%).

Local

Injection-site inflammation (at least 5%); injection-site pain with phlebitis and thrombophlebitis.

Metabolic-Nutritional

Increased creatinine (34%); hypokalemia (29%); hyperbilirubinemia (19%); hypomagnesemia (11%); hyperglycemia (9%); increased alkaline phosphatase (8%); hypophosphatemia, peripheral edema, weight gain (at least 5%); acidosis, dehydration, hyperkalemia, hyperlipemia, hypernatremia, hypervolemia, hypoglycemia, hyponatremia, hypoproteinemia, increased ALT and AST, increased BUN, increased lactic dehydrogenase, weight loss (1% to less than 5%).

Musculoskeletal

Back pain (at least 5%); arthralgia, myalgia, neck pain (1% to less than 5%); joint pain, muscle pain.

Respiratory

Dyspnea, hypoxia (9%); apnea, asthma, epistaxis, hyperventilation, increased cough, lung disorder, rhinitis (at least 5%); hemoptysis, lung edema, pleural effusion, respiratory disorder, sinusitis (1% to less than 5%); respiratory failure.

Miscellaneous

Chills (77%); fever (55%); abdominal pain, chest pain, enlarged abdomen, face edema, mucous membrane disorder, pain, sepsis (at least 5%); accidental injury, allergic reaction (including anaphylactoid reactions and anaphylaxis), death, hypothermia, immune system disorder, infection (1% to less than 5%).

Precautions

Warnings

Do not use to treat noninvasive forms of fungal diseases (eg, oral thrush, vaginal candidiasis, esophageal candidiasis) in patients with normal neutrophil counts. Exercise caution to prevent inadvertent overdose.

Monitor

Fungal culture

Ensure that fungal culture (blood or urine, as appropriate) of organism has been obtained before beginning therapy.

Infusion-related symptoms

If the patient experiences infusion-related symptoms (eg, chills, fever, hypotension, joint pain), an NSAID, corticosteroid, or other antipyretic may be given before administering drug.

Injection site

Monitor IV injection site closely during administration for signs of infiltration.

Lab values

Monitor laboratory values, including LFTs, CBC, renal function tests, and magnesium and potassium levels, during therapy.

Pregnancy

Category B .

Lactation

Undetermined.

Children

Safety and efficacy in children younger than 1 mo of age not established (amphotericin B lipid-based, amphotericin B cholesteryl).

Nephrotoxicity

Drug is toxic and should be used with caution under close supervision. Renal damage is most important toxic effect. Despite its dangerous adverse reactions, amphotericin B frequently is the only effective treatment for potentially fatal fungal diseases.

Overdosage

Symptoms

Cardiorespiratory arrest.

Patient Information

Explain need for prolonged therapy and for close monitoring during course of therapy.
Encourage patient to increase fluid intake to 2,000 to 3,000 mL/day, if allowed.
Inform patient to report any discomfort at injection site immediately.
Instruct patient to report symptoms of chills, malaise, or fever.