Amphotericin B

Pronunciation: AM-foe-TER-i-sin
Class: Polyene antifungal Amphotericin B Cholesteryl Sulfate Complex

Trade Names

Amphotec
- Injection, lyophilized powder for solution 50 mg
- Injection, lyophilized powder for solution 100 mg

Amphotericin B Desoxycholate

Amphotericin B
- Injection, lyophilized powder for solution 50 mg

Amphotericin B Lipid Complex

Abelcet
- Injection, suspension 5 mg/mL

Amphotericin B Liposome

AmBisome
- Injection, lyophilized powder for suspension 50 mg

Pharmacology

Alters fungal cell membrane permeability by binding to the sterol component of the cell membrane.

Pharmacokinetics

Absorption

Amphotericin B cholesteryl sulfate complex

C _max is approximately 2.6 to 2.9 mcg/mL.

Amphotericin B desoxycholate

C _max is 0.5 to 2 mcg/mL.

Amphotericin B lipid complex

C _max is approximately 1.7 mcg/mL.

Amphotericin B liposome

C _max is approximately 7.3 to 83 mcg/mL (dosed at 1 to 5 mg/kg/day).

Distribution

Amphotericin B cholesteryl sulfate complex

Vd is approximately 3.8 to 4.1 L/kg; distribution half-life is approximately 3.5 min.

Amphotericin B desoxycholate

Plasma protein binding is more than 90%. Distributed to inflamed pleura, peritoneum, synovium, and aqueous humor.

Amphotericin B lipid complex

Vd is approximately 131 L/kg.

Amphotericin B liposome

Vd is approximately 0.1 to 0.44 L/kg (dosed at 1 to 5 mg/kg/day).

Metabolism

Not known.

Elimination

Amphotericin B cholesteryl sulfate complex

The half-life is approximately 27.5 to 28.2 h; Cl is approximately 0.105 to 0.112 L/h/kg.

Amphotericin B desoxycholate

Elimination half-life is approximately 15 days. Plasma half-life is about 24 h. Excreted slowly over a period of weeks to months by the kidneys, with approximately 40% appearing in the urine over a 7-day period.

Amphotericin B lipid complex

The half-life is approximately 173.4 h. Cl is approximately 436 mL/h/kg.

Amphotericin B liposome

The half-life is approximately 7 to 10 h (measured within 24-h dosing interval), and approximately 100 to 153 h (measured up to 49 days after dosing). Cl is approximately 11 to 51 mL/h/kg.

Special Populations

Renal Function Impairment
Amphotericin B cholesteryl sulfate complex

The pharmacokinetics were not related to baseline CrCl in patients with CrCl of 35 to 202 mL/min per 70 kg.

Amphotericin B lipid complex

The effect of renal impairment is not known; the effect of hemodialysis on elimination has not been studied.

Amphotericin B liposome

Pharmacokinetics have not been studied; however, amphotericin B liposome has been administered to patients with preexisting renal impairment.

Hepatic Function Impairment
Amphotericin B cholesteryl sulfate complex

The pharmacokinetics were not related to baseline liver function (mean values for AST and total bilirubin of 59.4 units/mL and 3.5 mg/dL, respectively, in population tested).

Amphotericin B lipid complex and amphotericin B liposome

The effect of hepatic impairment is not known.

Elderly
Amphotericin B cholesteryl sulfate complex

The pharmacokinetics were not related to age.

Amphotericin B lipid complex

The pharmacokinetics have not been studied in elderly patients.

Amphotericin B liposome

The pharmacokinetics in elderly patients have not been studied; however, amphotericin B liposome has been used in elderly patients.

Children
Amphotericin B cholesteryl sulfate complex

The pharmacokinetics were not related to age.

Amphotericin B lipid complex

The pharmacokinetics have not been studied in children 16 y of age and younger.

Amphotericin B liposome

The pharmacokinetics in children have not been studied; however, amphotericin B liposome has been used in children.

Gender
Amphotericin B lipid complex and amphotericin B liposome

The effect of gender on the pharmacokinetics has not been studied.

Race
Amphotericin B lipid complex and amphotericin B liposome

The effect of race on the pharmacokinetics has not been studied.

Indications and Usage

Amphotericin B cholesteryl sulfate complex

Treatment of invasive aspergillosis in patients for whom renal impairment or unacceptable toxicity precludes use of amphotericin B deoxycholate or in patients with invasive aspergillosis in whom amphotericin deoxycholate has failed.

Amphotericin B desoxycholate

Treatment of potentially life-threatening infections caused by certain fungal species. Amphotericin B for injection is specifically intended to treat potentially life-threatening fungal infections: aspergillosis, cryptococcosis (torulosis), North American blastomycosis, systemic candidiasis, coccidioidomycosis, histoplasmosis, zygomycosis including mucormycosis caused by susceptible species of the genera Absidia , Mucor , and Rhizopus , and infections caused by related susceptible species of Conidiobolus and Basidiobolos , and sporotrichosis.

Amphotericin B lipid complex

Treatment of invasive fungal infections in patients refractory to conventional amphotericin B therapy.

Amphotericin B liposome

Empirical treatment of febrile, neutropenic patients with presumed fungal infections; treatment of visceral leishmaniasis; treatment of cryptococcal meningitis in HIV-infected patients; treatment of Aspergillus species, Candida species, and Cryptococcus species refractory to amphotericin B deoxycholate, or in patients for whom renal impairment or unacceptable toxicity precludes use of amphotericin B deoxycholate.

Unlabeled Uses

Prophylaxis and treatment 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; intranasal or nebulized administration in immunocompromised patients at risk of aspergillosis.

Contraindications

Hypersensitivity.

Dosage and Administration

Amphotericin B Cholesteryl Sulfate Complex
Invasive Asperigillosis Adults and Children

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

Renal Function Impairment (CrCl less than 10 mL/min)

3 to 6 mg/kg every 24 to 36 h.

Amphotericin B Desoxycholate
Adults

IV Because individual tolerance varies greatly, consider administration of a single IV test dose (1 mg in 20 mL of dextrose 5% in water) administered over 20 to 30 min. Monitor the patient's temperature, pulse, respiration, and BP every 30 min for 2 to 4 h. In patients with healthy cardiorenal function, therapy is usually started with 0.25 mg/kg daily. However, in patients with a severe, rapidly progressing fungal infection, therapy may be started with a dose of 0.3 mg/kg daily. In patients with impaired cardiorenal function or severe reactions to the test dose, start therapy with lower daily doses. Depending on cardiorenal function, doses may be increased in increments of 5 to 10 mg/day to a final daily dose of 0.5 to 0.7 mg/kg. Total daily doses may range up to 1 mg/kg/day or 1.5 mg/kg given on alternate days.

Aspergillosis

Treatment has been for a period up to 11 mo with a total dose of up to 3.6 g.

Rhinocerebral phycomycosis

Because this fulminating disease generally occurs in association with diabetic ketoacidosis, it is imperative that diabetic control be restored for amphotericin B treatment to be successful. Although a total dose of 3 to 4 g will infrequently cause lasting renal function impairment, a cumulative dose of at least 3 g is recommended. This appears to be a reasonable minimum dose when there is evidence of deep tissue invasion.

Sporotrichosis

Treatment has been for a period of up to 9 mo with a total dose of up to 2.5 g.

Amphotericin B Lipid Complex
Systemic Fungal Infections Adults and Children

IV 5 mg/kg/day as a single infusion.

Renal Function Impairment (CrCl less than 10 mL/min)

5 mg/kg every 24 to 36 h.

Amphotericin B Liposome
Cryptococcal Meningitis in HIV Adults and Children 1 mo of age and older

IV 6 mg/kg/day.

Empirical Fungal Infections Adults and Children 1 mo of age and older

IV 3 mg/kg/day.

Leishmaniasis Adults and Children 1 mo of age and older

IV 3 mg/kg/day on days 1 through 5 and on days 14 and 21 for immunocompetent patients; administer 4 mg/kg/day on days 1 through 5 and on days 10, 17, 24, 31, and 38 for immunosuppressed patients. For immunocompetent patients who do not achieve parasitic Cl with the recommended dose, a repeat course may be useful.

Systemic Fungal Infections Adults and Children 1 mo of age and older

IV 3 to 5 mg/kg/day.

Renal Function Impairment (CrCl less than 10 mL/min)

3 mg/kg every 24 h.

General Advice

• Acute infusion-related reactions can be managed by pretreatment with antihistamines and corticosteroids and/or by reducing the rate of infusion and by prompt administration of antihistamines and corticosteroids.

• Amphotericin B cholesteryl sulfate complex
• Administer by IV infusion rate of 1 mg/kg/h; avoid rapid infusion.
• 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.
• Administer diluted in dextrose 5% injection. For infusion, further dilute the reconstituted solution to a final concentration of approximately 0.6 mg/mL.
• Do not filter or use an in-line filter.
• Do not mix with other IV medications.
• Flush an existing IV line with dextrose 5% injection before infusion or use a separate infusion line.

• Amphotericin B desoxycholate
• Do not use a filter less than 1 micron.
• Whenever therapy is interrupted for more than 7 days, resume treatment by starting with the lowest dosage level and gradually increasing the dose.
• Under no circumstances should the daily dose exceed 1.5 mg/kg.
• Follow the manufacturer's instructions for reconstitution and administration. Reconstitute by using sterile water for injection without a bacteriostatic agent.
• Shake the vial immediately until the colloidal solution is clear.
• Use solution prepared for IV infusion (0.1 mg/mL or less) promptly after preparation and protect from light during administration.

• Amphotericin B lipid complex
• Shake the vial gently until there is no yellow sediment at the bottom.
• Administer by IV infusion at a rate of 2.5 mg/kg/h.
• Follow manufacturer's instructions for dilution and administration. Use dextrose 5% injection for dilution. Do not dilute with saline solutions or mix with other drugs or electrolytes because compatibility of lipid-based amphotericin B has not been established.
• Flush an existing IV line with dextrose 5% injection before infusion of lipid-based amphotericin B, or use a separate infusion line.
• Do not use an in-line filter.
• If the infusion exceeds 2 h, mix the contents by shaking the infusion bag every 2 h.
• Do not use the admixture after dilution with dextrose 5% injection if there is any evidence of foreign matter. Vials are for single use.
• Final concentration before infusion is 1 mg/mL (2 mg/mL for pediatric and CV patients). Before infusion, shake the bag until the contents are thoroughly mixed.

• Amphotericin B liposome
• Amphotericin B liposome must be reconstituted using sterile water for injection (without a bacteriostatic agent).
• Do not reconstitute with saline or add saline to the reconstituted concentration, or mix with other drugs. The use of solutions other than those recommended may cause precipitation.
• Calculate the amount of reconstituted amphotericin B liposome (4 mg/mL) to be further diluted to yield a final concentration of 1 to 2 mg/mL for administration. Lower concentrations of 0.2 to 0.5 mg/mL may be more appropriate for infants and small children.
• Administer using a controlled infusion device over approximately 120 min; infusion time may be reduced to 60 min if well tolerated or increased if patient experiences discomfort.
• Flush an existing IV line with dextrose 5% for injection prior to and following infusion; otherwise, administer via a separate line.
• Do not use an in-line membrane filter less than 1 micron for administration.

Storage/Stability

Amphotericin B cholesteryl sulfate complex

Store unopened vials between 59° and 86°F. After reconstitution, store refrigerated between 36° and 46°F and use within 24 h. Do not freeze. After further dilution with dextrose 5% in water for injection, store refrigerated between 36° and 46°F and use within 24 h. Discard unused portion.

Amphotericin B desoxycholate

Store refrigerated between 36° and 46°F. Protect from light. The concentrate after reconstitution may be stored in the dark at room temperature for 24 h or refrigerated for 1 wk. Discard any unused portion. Use solution prepared for IV infusion (0.1 mg/mL or less) promptly after preparation and protect from light during administration.

Amphotericin B lipid complex

Store refrigerated between 36° and 46°F. Protect from light. Do not freeze. After reconstitution, store up to 48 h between 36° and 46°F and an additional 6 h at room temperature. Discard any unused portion.

Amphotericin B liposome

Store unopened vials at 77°F. Store reconstituted product concentrate refrigerated between 36° and 46°F. Do not freeze. Inject within 6 h of dilution with dextrose 5% injection in water.

Drug Interactions

Antineoplastic agents

Concurrent use may enhance potential for bronchospasm, hypotension, and renal toxicity. Coadminister with caution.

Azole antifungal agents (eg, fluconazole, ketoconazole)

Antagonism between amphotericin B and the antifungal agent may occur. Coadminister with caution, especially in immunocompromised patients.

Corticosteroids (eg, prednisone) and corticotropin

Increased potential for hypokalemia, which may predispose patients to cardiac dysfunction. If coadministration is necessary to manage adverse reactions, closely monitor serum electrolytes and cardiac function.

Cyclosporine, tacrolimus

Concomitant use of cyclosporine or tacrolimus and amphotericin B may increase the risk of nephrotoxicity. Also, the risk of cyclosporine neurotoxicity may be increased. Closely monitor patients and renal function when coadministering cyclosporine or tacrolimus and amphotericin B. If renal function declines or neurotoxicity occurs, decrease the dosage or stop one or both drugs.

Digitalis glycosides

Amphotericin B–induced hypokalemia may potentiate digitalis toxicity. Closely monitor serum potassium concentrations and promptly correct potassium deficits.

Flucytosine

Increased risk of flucytosine toxicity. Use with caution.

Foscarnet

Because of additive or synergistic effects, the risk of renal toxicity may be increased. If the use of amphotericin B and foscarnet cannot be avoided, aggressive hydration and close clinical monitoring of renal function are indicated.

Leukocyte transfusions

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

Nephrotoxic agents (eg, aminoglycosides, pentamidine)

Possible synergistic nephrotoxicity. Use caution when coadministering and monitor renal function intensively.

Skeletal muscle relaxants (eg, tubocurarine)

Amphotericin B–induced hypokalemia may enhance curariform effect of skeletal muscle relaxant. Closely monitor serum potassium concentrations.

Adverse Reactions

Cardiovascular

Phlebitis (25%); hypertension, tachycardia (23%); hypotension (22%); chest pain (12%); cardiac arrest (6%); vasodilatation (5%); atrial fibrillation, bradycardia, cardiac arrest, cardiomegaly, hemorrhage, postural hypotension, valvular heart disease, vascular disorder (2% to 10%); cardiovascular disorder (at least 5%); CHF, shock, supraventricular tachycardia, syncope, ventricular extrasystoles (1% to less than 5%); MI, shock, tachypnea.

CNS

Insomnia (22%); headache (21%); anxiety (14%); asthenia, confusion (13%); dizziness (10%); abnormal thinking, agitation, coma, convulsions, depression, dysesthesia, hallucinations, malaise, nervousness, paresthesia, somnolence, tremor (2% to 10%); hypertonia, neuropathy, psychosis, speech disorder, stupor (1% to less than 5%); cerebral vascular accident, diplopia, encephalopathy, extrapyramidal syndrome, peripheral neuropathy, transient vertigo.

Dermatologic

Rash (25%); pruritus, sweating (11%); alopecia, dry skin, herpes simplex, maculopapular rash, purpura, skin discoloration, skin disorder, skin ulcer, urticaria, vesiculobullous rash (2% to 10%); acne, petechial rash, skin nodule (1% to less than 5%); erythema, erythema multiforme, exfoliative dermatitis, flushing.

EENT

Conjunctivitis, dry eyes, eye hemorrhage, pharyngitis (2% to 10%); amblyopia, deafness, ear disorder, tinnitus (1% to less than 5%); visual impairment.

GI

Vomiting (44%); nausea (40%); diarrhea (30%); abdominal pain (22%); constipation (21%); anorexia (14%); GI hemorrhage, nausea and vomiting (11%); abdomen enlarged, dry mouth/nose, dyspepsia, dysphagia, eructation, fecal incontinence, flatulence, hemorrhoids, gum/oral hemorrhage, hematemesis, ileus, mucositis, rectal disorder, stomatitis, ulcerative stomatitis (2% to 10%); bloody diarrhea, GI disorder, gingivitis, glossitis, increased GGT, melena, mouth ulceration, oral moniliasis, rectal disorder (1% to less than 5%); cramping, epigastric pain.

Genitourinary

Nephrotoxicity (63%); hematuria (14%); kidney failure (5%); abnormal renal function, acute kidney failure, acute renal failure, dysuria, toxic nephropathy, urinary incontinence, vaginal hemorrhage (2% to 10%); albuminuria, glucosuria, oliguria, urinary retention, urinary tract disorder (1% to less than 5%); anuria, azotemia, decreased renal function, hemorrhagic cystitis, hyposthenuria, impotence, nephrocalcinosis, renal tubular acidosis.

Hematologic-Lymphatic

Anemia (48%); leukopenia (17%); thrombocytopenia (13%); coagulation disorder, decreased or increased prothrombin, ecchymosis, fluid overload, petechiae (2% to 10%); decreased thromboplastin, hypochromic anemia, increased fibrinogen, leukocytosis (1% to less than 5%); blood dyscrasias including coagulation defects, eosinophilia, normochromic or normocytic anemia; agranulocytosis (postmarketing).

Hepatic

Bilirubinemia (19%); increased ALT (15%); abnormal LFTs, increased AST (13%); hepatocellular damage, hepatomegaly, veno-occlusive liver disease (2% to 10%); jaundice (at least 5%); liver failure (1% to less than 5%); cholangitis, cholecystitis, hepatitis.

Hypersensitivity

Allergic reaction (2% to 10%); anaphylactic and anaphylactoid reactions, bronchospasm, hypersensitivity pneumonitis, wheezing.

Local

Injection-site inflammation (2% to 10%); injection-site pain, injection-site reaction (1% to less than 5%); thrombophlebitis.

Metabolic-Nutritional

Hypokalemia (51%); hypomagnesemia, increased creatinine (49%); increased BUN (31%); hyperglycemia (28%); increased alkaline phosphatase (22%); hypocalcemia (21%); peripheral edema (17%); edema, hypervolemia (15%); hyponatremia (12%); hypernatremia (11%); acidosis, hyperchloremia, hyperkalemia, hypermagnesemia, hyperphosphatemia, hypophosphatemia, hypoproteinemia, increased amylase, increased LDH, increased nonprotein nitrogen, respiratory alkalosis (2% to 10%); weight gain (at least 5%); dehydration, hyperlipidemia, hypoglycemia, weight loss (1% to less than 5%); hyperamylasemia, hyperuricemia.

Musculoskeletal

Back pain (12%); arthralgia, bone pain, dystonia, myalgia, neck pain, rigors (2% to 10%); myasthenia including bone, joint, and muscle pain.

Respiratory

Dyspnea (29%); increased cough (22%); hypoxia (21%); epistaxis (20%); lung disorder (18%); pleural effusion (13%); rhinitis (11%); respiratory failure (8%); apnea (at least 5%); hyperventilation (5%); asthma, atelectasis, hemoptysis, hiccup, lung edema, pneumonia, respiratory insufficiency, sinusitis (2% to 10%); respiratory disorder (1% to less than 5%); bronchospasm, cyanosis/hypoventilation, pulmonary edema (postmarketing).

Miscellaneous

Chills/rigors (90%); chills (77%); fever (58%); blood product transfusion reaction (19%); pain, sepsis (14%); infection (13%); multiple organ failure (11%); procedural complications (10%); cell-mediated immunological reaction, cellulitis, face edema, graft-versus-host disease, influenza-like symptoms (2% to 10%); chills/fever (7%); mucous membrane disorder (at least 5%); death, hypothermia, immune system disorder (1% to less than 5%); angioedema (postmarketing).

Precautions

Warnings Do not use amphotericin B desoxycholate to treat noninvasive forms of fungal diseases (eg, esophageal candidiasis, oral thrush, vaginal candidiasis) in patients with normal neutrophil counts. Exercise caution to prevent inadvertent overdose. Use primarily for the treatment of progressive and potentially life-threatening fungal infections.

Monitor Monitor pulmonary function in patients receiving leukocyte transfusions. 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, antihistamine, 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 serum electrolytes (particularly magnesium and potassium levels), during therapy.

Pregnancy

Category B .

Lactation

Undetermined.

Children

Amphotericin B cholesteryl sulfate complex and amphotericin B lipid complex

Safety and efficacy have been established.

Amphotericin B desoxycholate

Safety and efficacy not established. Carefully monitor elderly patients receiving amphotericin B.

Amphotericin B liposome

Safety and efficacy in children younger than 1 mo of age not established.

Elderly

No serious unexpected adverse reactions have been reported.

Hypersensitivity

Anaphylaxis has been reported.

Nephrotoxicity

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

Rapid infusion

Rapid IV infusion has been associated with arrhythmias, hypokalemia, hypotension, and shock.

Overdosage

Symptoms

Cardiorespiratory arrest.

Patient Information

• Explain the 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, difficulty breathing or swallowing, fever, or malaise.

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