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Amphotericin B (Lipid Complex)

Pronunciation

(am foe TER i sin bee LIP id KOM pleks)

Index Terms

  • ABLC

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Intravenous:

Abelcet: 5 mg/mL (20 mL)

Brand Names: U.S.

  • Abelcet

Pharmacologic Category

  • Antifungal Agent, Parenteral

Pharmacology

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.

Distribution

High tissue concentration found in the liver, spleen, and lung; Vd: Increases with higher doses (likely reflects increased uptake by tissues); 131 L/kg with 5 mg/kg/day

Excretion

0.9% of dose excreted in urine over 24 hours; effects of hepatic and renal impairment on drug disposition are unknown

Half-Life Elimination

173 hours following multiple doses

Use: Labeled Indications

Treatment of invasive fungal infection in patients who are refractory to or intolerant of conventional amphotericin B (amphotericin B deoxycholate) therapy

Contraindications

Hypersensitivity to amphotericin or any component of the formulation

Dosing: Adult

Note: Lipid-based amphotericin formulations (Abelcet) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]) or with other lipid-based amphotericin formulations (amphotericin B liposomal [AmBisome]; amphotericin B cholesteryl sulfate complex [Amphotec]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.

Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal anti-inflammatory agent ± diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.

Usual dose: IV: 5 mg/kg once daily

Manufacturer’s labeling: Invasive fungal infections (when patients are intolerant or refractory to conventional amphotericin B): IV: 5 mg/kg/day

Indication-specific dosing:

Aspergillosis, invasive (alternative to preferred therapy): IV: 5 mg/kg/day; duration of treatment depends on site of infection, extent of disease and level of immunosuppression (Walsh 2008)

Aspergillosis (invasive) in HIV-infected patients (alternative to preferred therapy) (off-label use): 5 mg/kg/day; treat until infection appears to be resolved and CD4 count >200 cells/mm3 (HHS [OI adult 2015])

Blastomycosis, moderately severe to severe (off-label dose): IV: 3 to 5 mg/kg/day for 1 to 2 weeks or until improvement, followed by oral itraconazole (Chapman 2008)

Candidiasis (IDSA [Pappas 2016]): IV:

Candidemia (non-neutropenic patients) (off-label dose): 3 to 5 mg/kg/day; may transition to fluconazole (usually after 5 to 7 days) in clinically stable patients, with fluconazole-susceptible isolates and negative repeat cultures. Total duration of antifungal therapy is at least 2 weeks after the documented clearance of Candida from the bloodstream and resolution of candidemia-associated symptoms in patients without metastatic complications. Note: An amphotericin B lipid formation is considered a reasonable alternative agent if there is intolerance, limited availability, or resistance to other antifungals. In patients with suspected azole- and echinocandin-resistant infections, an amphotericin B lipid formulation is preferred.

Candidemia (neutropenic patients) (off-label dose): 3 to 5 mg/kg/day; may transition to fluconazole during persistent neutropenia in clinically stable patients, with fluconazole-susceptible isolates and negative repeat cultures. Total duration of antifungal therapy is at least 2 weeks after the documented clearance of Candida from the bloodstream and resolution of neutropenia and candidemia-associated symptoms in patients without metastatic complications. Note: An amphotericin B lipid formation is considered a potential alternative agent, but less attractive option due to its potential for toxicity. However, for infections due to C. krusei, an amphotericin B lipid formulation is a preferred agent.

Chronic disseminated (hepatosplenic) (off-label dose): 3 to 5 mg/kg/day for several weeks; transition to oral fluconazole in clinically stable patients unlikely to have a fluconazole-resistant isolate.

Empiric therapy (non-neutropenic ICU patients) (off-label use): 3 to 5 mg/kg/day; treatment should continue for 14 days in patients with clinical improvement. Consider discontinuing after 4 to 5 days in patients with no clinical response. Note: Considered an alternative to echinocandins.

Endocarditis (native or prosthetic valve) or infected implantable cardiac devices (eg, pacemaker, ICD, VAD) (off-label dose): 3 to 5 mg/kg/day (with or without flucytosine); for native or prosthetic valve endocarditis, therapy should continue for at least 6 weeks after valve replacement surgery (longer durations in patients with abscesses or other complications); for patients with implantable cardiac devices, therapy should continue for 4 to 6 weeks after surgery (4 weeks for infections limited to generator pockets and at least 6 weeks for infections involving the wires). Note: May transition to fluconazole if patient clinically stable with fluconazole-susceptible isolates in whom Candida has cleared from the bloodstream.

Intra-abdominal candidiasis (off-label dose): 3 to 5 mg/kg/day; duration of therapy determined by clinical response and source control. Note: Considered an alternative to echinocandins.

Osteomyelitis or septic arthritis (alternative therapy) (off-label dose): 3 to 5 mg/kg/day for at least 2 weeks, followed by fluconazole.

Suppurative thrombophlebitis (off-label dose): 3 to 5 mg/kg/day; continue for at least 2 weeks after candidemia has cleared; consider transition to fluconazole in clinically stable patients with a fluconazole-susceptible isolate.

Coccidioidomycosis, progressive, disseminated (alternative to preferred therapy) (off-label dose): IV: 2 to 5 mg/kg/day (Galgiani 2005)

Coccidioidomycosis in HIV-infected patients with severe, nonmeningeal infection (ie, diffuse pulmonary or severely ill with extrathoracic disseminated disease) (off-label use): 4 to 6 mg/kg/day until clinical improvement, then switch to fluconazole or itraconazole (HHS [OI adult 2015])

Cryptococcosis: IV:

Cryptococcal meningitis in HIV-infected patients (alternative to preferred therapy) (off-label use): Induction therapy: 5 mg/kg/day with flucytosine for at least 2 weeks, followed by fluconazole for consolidation therapy (HHS [OI adult 2015]; Perfect 2010). Note: If flucytosine is not given due to intolerance, duration of amphotericin B lipid complex therapy should be 4 to 6 weeks (Perfect 2010).

Cryptococcal meningoencephalitis in HIV-negative patients and nontransplant patients (as an alternative to conventional amphotericin B): Induction therapy: 5 mg/kg/day (with flucytosine if possible) for ≥4 weeks followed by oral fluconazole. Note: If flucytosine is not given or treatment is interrupted, consider prolonging induction therapy for an additional 2 weeks (Perfect 2010).

Cryptococcal meningoencephalitis in transplant recipients: Induction therapy: 5 mg/kg/day (with flucytosine) for at least 2 weeks, followed by oral fluconazole Note: If flucytosine is not given, duration of amphotericin B lipid complex therapy should be 4 to 6 weeks (Perfect 2010).

Nonmeningeal cryptococcosis: Induction therapy: 5 mg/kg/day (with flucytosine if possible) for ≥4 weeks may be used for severe pulmonary cryptococcosis or for cryptococcemia with evidence of high fungal burden, followed by oral fluconazole. Note: If flucytosine is not given or treatment is interrupted, consider prolonging induction therapy for an additional 2 weeks (Perfect 2010).

Histoplasmosis: IV:

Acute pulmonary (moderately severe to severe): 5 mg/kg/day for 1 to 2 weeks, followed by oral itraconazole (Wheat 2007)

Moderate to severe disseminated disease in HIV-infected patients (alternative to preferred therapy) (off-label use): 3 mg/kg/day for at least 2 weeks, followed by itraconazole maintenance therapy (HHS [OI adult 2015])

Progressive disseminated (alternative to preferred therapy): 5 mg/kg/day for 1 to 2 weeks, followed by oral itraconazole (Wheat 2007)

Leishmaniasis (visceral) in HIV-infected patients (off-label use) (HHS [OI adult 2015]):

Chronic maintenance therapy (for patients with a CD4 count <200 cells/mm3: 3 mg/kg every 21 days (HHS [OI adult 2015])

Sporotrichosis (off-label dose): IV:

Meningeal: 5 mg/kg/day for 4 to 6 weeks, followed by oral itraconazole (Kauffman 2007)

Pulmonary, osteoarticular, and disseminated: 3 to 5 mg/kg/day, followed by oral itraconazole after a favorable response is seen with amphotericin initial therapy (Kauffman 2007)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Lipid-based amphotericin formulations (Abelcet) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]) or with other lipid-based amphotericin formulations (amphotericin B liposomal [AmBisome]; amphotericin B cholesteryl sulfate complex [Amphotec]). Lipid-based and conventional formulations are not interchangeable and have different dosing recommendations. Overdoses have occurred when conventional formulations were dispensed inadvertently for lipid-based products.

Note: Premedication: For patients who experience infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal anti-inflammatory agent ± diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.

Usual dose: 5 mg/kg once daily

Manufacturer’s labeling: Invasive fungal infections (when patients are intolerant or refractory to conventional amphotericin B): Children: IV: 5 mg/kg/day

Indication-specific dosing:

Aspergillosis (HIV-positive patients) (alternative to preferred therapy):

Infants and Children: IV: 5 mg/kg/day for ≥12 weeks (CDC [pediatric 2009])

Adolescents: Refer to adult dosing.

Candidiasis, invasive (HIV-positive patients) (alternative to preferred therapy): Infants and Children: IV: 5 mg/kg/day; treatment duration based on clinical response, treat until 2 to 3 weeks after last positive blood culture (CDC [pediatric 2009])

Coccidioidomycosis in HIV-infected patients with severe, nonmeningeal infection (ie, diffuse pulmonary or severely ill with extrathoracic disseminated disease) (off-label use): Adolescents: Refer to adult dosing.

Cryptococcosis:

Cryptococcus neoformans, disseminated disease (non-CNS disease) (HIV-positive patients): Infants and Children: IV: 5 mg/kg/day (with or without flucytosine); treatment duration of non-CNS disease varies by clinical response and site/severity of infection (CDC [pediatric 2009])

Cryptococcal meningitis in HIV-infected patients (as an alternative to preferred therapy) (off-label use): Adolescents: Refer to adult dosing.

Histoplasmosis in HIV-infected patients with moderate to severe disseminated disease (alternative to preferred therapy): Adolescents: Refer to adult dosing.

Leishmaniasis (visceral), chronic maintenance therapy in HIV-infected patients (off-label use): Adolescents: Refer to adult dosing.

Dosing: Renal Impairment

Manufacturer's labeling: No dosage adjustment provided in manufacturer's labeling (has not been studied).

Alternate recommendations (Aronoff 2007):

Intermittent hemodialysis: Not hemodialyzable; no supplemental dosage necessary.

Peritoneal dialysis: No supplemental dosage necessary.

Continuous renal replacement therapy (CRRT): No supplemental dosage necessary.

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer's labeling (has not been studied).

Reconstitution

Shake the vial gently until there is no evidence of any yellow sediment at the bottom. Withdraw the appropriate dose from the vial using an 18-gauge needle. Remove the 18-gauge needle and attach the provided 5-micron filter needle to filter, and dilute the dose with D5W to a final concentration of 1 mg/mL. Limited data suggests D10W and D15W may also be used for dilution (data on file [Sigma-Tau Pharmaceuticals 2014]). Each filter needle may be used to filter up to four 100 mg vials. A final concentration of 2 mg/mL may be used for pediatric patients and patients with cardiovascular disease.

Do not dilute with saline solutions or mix with other drugs or electrolytes - compatibility has not been established

Administration

For patients who experience nonanaphylactic infusion-related reactions, premedicate 30-60 minutes prior to drug administration with a nonsteroidal anti-inflammatory agent ± diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone. If the patient experiences rigors during the infusion, meperidine may be administered.

Administer at an infusion rate of 2.5 mg/kg/hour (eg, over 2 hours for 5 mg/kg). Invert infusion container several times prior to administration and every 2 hours during infusion if it exceeds 2 hours. Do not use an in-line filter during administration. Flush line with dextrose; normal saline may cause precipitate.

Dietary Considerations

If on parenteral nutrition, may need to adjust the amount of lipid infused. The lipid portion of amphotericin B (lipid complex) formulation contains 0.045 kcal per 5 mg (Sacks 1997).

Compatibility

Stable in D5W; incompatible with NS or other electrolyte solutions.

Y-site administration: Incompatible with caspofungin.

Storage

Intact vials should be stored at 2°C to 8°C (35°F to 46°F); do not freeze. Protect intact vials from exposure to light. Solutions in D5W for infusion are stable for 48 hours under refrigeration and for an additional 6 hours at room temperature.

Drug Interactions

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminoglycosides: Amphotericin B may enhance the nephrotoxic effect of Aminoglycosides. Monitor therapy

Antifungal Agents (Azole Derivatives, Systemic): May diminish the therapeutic effect of Amphotericin B. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Cardiac Glycosides: Amphotericin B may enhance the adverse/toxic effect of Cardiac Glycosides. Monitor therapy

Colistimethate: Amphotericin B may enhance the nephrotoxic effect of Colistimethate. Consider therapy modification

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Amphotericin B. Monitor therapy

CycloSPORINE (Systemic): Amphotericin B may enhance the nephrotoxic effect of CycloSPORINE (Systemic). Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dronabinol: May increase the serum concentration of Amphotericin B. Specifically, dronabinol may displace amphotericin B from its protein-binding sites, leading to an increased concentration of active, unbound drug. Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Flucytosine: Amphotericin B may enhance the adverse/toxic effect of Flucytosine. This may be related to the adverse effects of amphotericin B on renal function. Monitor therapy

Foscarnet: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Saccharomyces boulardii: Antifungal Agents (Systemic, Oral) may diminish the therapeutic effect of Saccharomyces boulardii. Avoid combination

Sodium Stibogluconate [INT]: Amphotericin B may enhance the cardiotoxic effect of Sodium Stibogluconate [INT]. Consider therapy modification

Adverse Reactions

Nephrotoxicity and infusion-related hyperpyrexia, rigor, and chilling are reduced relative to amphotericin deoxycholate.

>10%:

Central nervous system: Chills (18%)

Renal: Increased serum creatinine (11%)

Miscellaneous: Fever (14%), multi-organ failure (11%)

1% to 10%:

Cardiovascular: Hypotension (8%), cardiac arrest (6%), hypertension (5%), chest pain (3%)

Central nervous system: Headache (6%), pain (5%)

Dermatologic: Skin rash (4%)

Endocrine & metabolic: Hypokalemia (5%)

Gastrointestinal: Nausea (9%), vomiting (8%), diarrhea (6%), abdominal pain (4%), gastrointestinal hemorrhage (4%)

Hematologic & oncologic: Thrombocytopenia (5%), anemia (4%), leukopenia (4%)

Hepatic: Hyperbilirubinemia (4%)

Infection: Sepsis (7%), infection (5%)

Renal: Renal failure (5%)

Respiratory: Respiratory failure (8%), dyspnea (6%), respiratory tract disease (4%)

<1% (Limited to important or life-threatening): Acute hepatic failure, anaphylactoid reaction, anuria, asthma, blood coagulation disorder, brain disease, bronchospasm, cardiac arrhythmia, cardiomyopathy, cerebrovascular accident, cholangitis, cholecystitis, deafness, dysuria, eosinophilia, erythema multiforme, exfoliative dermatitis, extrapyramidal reaction, hearing loss, hematologic disease, hemoptysis, hepatic veno-occlusive disease, hepatitis, hepatomegaly, hepatotoxicity, hypercalcemia, hyperkalemia, hypersensitivity reaction, hypocalcemia, hypomagnesemia, increased blood urea nitrogen, increased serum transaminases, injection site reaction, jaundice, leukocytosis, myasthenia, myocardial infarction, oliguria, peripheral neuropathy, pleural effusion, pulmonary edema, pulmonary embolism, renal insufficiency, renal tubular acidosis, seizure, shock, tachycardia, thrombophlebitis, ventricular fibrillation, vertigo (transient), visual impairment

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis: Has been reported with amphotericin B-containing drugs; facilities for cardiopulmonary resuscitation should be available during administration due to the possibility of anaphylactic reaction. If severe respiratory distress occurs, the infusion should be immediately discontinued; during the initial dosing, the drug should be administered under close clinical observation.

• Infusion reactions: Acute reactions (including fever and chills) may occur 1-2 hours after starting an intravenous infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Infusion has been rarely associated with hypotension, bronchospasm, arrhythmias, and shock.

Concurrent drug therapy issues:

• Antineoplastics: Concurrent use with antineoplastic agents may enhance the potential for renal toxicity, bronchospasm or hypotension; use with caution.

• Nephrotoxic drugs: Concurrent use of amphotericin B with other nephrotoxic drugs may enhance the potential for drug-induced renal toxicity.

Other warnings/precautions:

• Leukocyte transfusions: Acute pulmonary toxicity has been reported in patients receiving leukocyte transfusions and amphotericin B; amphotericin B lipid complex and concurrent leukocyte transfusions are not recommended.

Monitoring Parameters

BUN and serum creatinine levels should be determined every other day while therapy is increased and at least weekly thereafter. 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)

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not observed in animal reproduction studies. Amphotericin crosses the placenta and enters the fetal circulation. Amphotericin B is recommended for the treatment of serious, systemic fungal diseases in pregnant women, refer to current guidelines (IDSA [Pappas 2016]; King 1998; Pilmus 2015).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience nausea, vomiting, or diarrhea. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice); signs of kidney problems (urinary retention, hematuria, change in amount of urine passed, or weight gain); signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, severe dizziness or passing out, tachycardia, increased thirst, seizures, loss of strength and energy, lack of appetite, urinary retention or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting); shortness of breath; chills; severe dizziness; passing out; abnormal heartbeat; angina; black, tarry, or bloody stools; vomiting blood; severe loss of strength and energy; severe headache; bruising; or bleeding (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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