Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Suspension Reconstituted, Intravenous:
Amphotec: 50 mg (1 ea [DSC]); 100 mg (1 ea [DSC]) [contains edetate disodium, hydrochloric acid, lactose, sodium cholesteryl sulfate, tromethamine]
Pharmacology
Mechanism of Action
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 (Lyman, 1992).
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: Total volume increases with higher doses, reflects increasing uptake by tissues (with 4 mg/kg/day = 4 L/kg); predominantly distributed in the liver; concentrations in kidneys and other tissues are lower than observed with conventional amphotericin B (Walsh 2008)
Half-Life Elimination
~28 hours; prolonged with higher doses
Use: Labeled Indications
Treatment of invasive aspergillosis in patients who have failed amphotericin B deoxycholate treatment, or who have renal impairment or experience unacceptable toxicity which precludes treatment with amphotericin B deoxycholate in effective doses.
Use: Off Label
Candida species infections (serious)yes
Based on the Infectious Diseases Society of America (IDSA) clinical practice guidelines for the management of candidiasis, a lipid formulation of amphotericin B (eg, amphotericin B cholesteryl sulfate complex) is effective and recommended for the treatment of serious Candida species infections.
Contraindications
Hypersensitivity to amphotericin B or any component of the formulation (unless the benefits outweigh the possible risk to the patient)
Dosage and Administration
Dosing: Adult
Note: Amphotec has been discontinued in the US for more than 1 year.
Note: Lipid-based amphotericin formulations (Amphotec) may be confused with conventional formulations (desoxycholate [Amphocin, Fungizone]). 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.
Aspergillosis (invasive), treatment: Usual dosage range: 3 to 4 mg/kg/day. Note: 6 mg/kg/day has been used for treatment of life-threatening invasive aspergillosis in immunocompromised patients (Bowden, 2002).
Premedication: For patients who experience chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions, premedicate with the following drugs 30 to 60 minutes prior to drug administration: A nonsteroidal with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50 to 100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008).
Test dose: For patients receiving their first dose in a new treatment course, a small amount (10 mL of the final preparation, containing between 1.6 to 8.3 mg) infused over 15 to 30 minutes is recommended. The patient should then be observed for an additional 30 minutes.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Pediatric
Note: Amphotec has been discontinued in the US for more than 1 year.
Medication errors, including deaths, have resulted from confusion between lipid-based forms of amphotericin (Abelcet, Amphotec, AmBisome) and conventional amphotericin B for injection. 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 fever, chills, hypotension, nausea, or other nonanaphylactic infusion-related immediate reactions may be given 30 to 60 minutes prior to drug administration: NSAIDs (with or without diphenhydramine) or acetaminophen with diphenhydramine or hydrocortisone may be given (Paterson 2008); if patient experiences rigors during infusion, meperidine may be administered. The manufacturer’s labeling advises a test dose be administered immediately preceding the first dose when a new course of treatment occurs. A small amount of drug (eg, 10 mL of final preparation containing between 1.6 and 8.3 mg of drug) should be infused over 15 to 30 minutes and patient should be carefully observed for the next 30 minutes.
Aspergillosis, treatment:
Invasive: Infants, Children, and Adolescents: IV: Usual dose range: 3 to 4 mg/kg/dose once daily; doses as high as 7.5 mg/kg/dose have been described in open label studies (Sandler 2000)
Endocarditis: Children and Adolescents: IV: 3 to 5 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015])
Candidiasis, treatment: Infants, Children, and Adolescents:
Invasive: IV: 3 to 5 mg/kg/dose once daily (IDSA [Pappas 2016])
Endocarditis: Infants, Children, and Adolescents: IV: 3 to 5 mg/kg/dose once daily with or without flucytosine (AHA [Baltimore 2015]; IDSA [Pappas 2016])
Esophageal (HIV-exposed/-positive): Adolescents: IV: 3 to 4 mg/kg/dose once daily for 14 to 21 days (HHS [OI adult 2016])
Coccidiodomycosis, disseminated (non-CNS) or diffuse pulmonary disease: HIV-exposed/-infected:
Infants and Children: IV: 5 mg/kg/dose once daily until clinical improvement; dose may be increased as high as 10 mg/kg/dose once daily for life-threatening infection (HHS [OI pediatric 2013])
Adolescents: IV: 3 to 5 mg/kg/dose once daily until clinical improvement, then change to fluconazole or itraconazole (HHS [OI adult 2016])
Histoplasmosis, disseminated disease (moderately severe to severe): HIV-exposed/-positive: Adolescents: IV: 3 mg/kg/dose once daily for at least 2 week induction, followed by oral itraconazole (HHS [OI adult 2016])
Reconstitution
Reconstitute 50 mg and 100 mg vials with 10 mL and 20 mL of SWI, respectively. The reconstituted vials contain 5 mg/mL of amphotericin B. Shake the vial gently by hand until all solid particles have dissolved. Further dilute amphotericin B colloidal dispersion with D5W.
Administration
IV: Initially infuse at 1 mg/kg/hour. Rate of infusion may be increased with subsequent doses as patient tolerance allows (minimum infusion time: 2 hours). For a patient who experiences chills, fever, hypotension, nausea, or other nonanaphylactic infusion-related reactions, premedicate with the following drugs 30-60 minutes prior to drug administration: A nonsteroidal with or without diphenhydramine or acetaminophen with diphenhydramine or hydrocortisone 50-100 mg with or without a nonsteroidal and diphenhydramine (Paterson, 2008). If the patient experiences rigors during the infusion, meperidine may be administered. If severe respiratory distress occurs, the infusion should be immediately discontinued.
Storage
Store intact vials at 15°C to 30°C (59°F to 86°F). After reconstitution, the solution should be refrigerated at 2°C to 8°C (36°F to 46°F) and used within 24 hours. Concentrations of 0.1-2 mg/mL in D5W are stable for 24 hours at 2°C to 8°C (36°F to 46°F).
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
Benperidol: 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
Bromperidol: Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Bromperidol may diminish the hypotensive effect of Blood Pressure Lowering Agents. Avoid combination
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
Dichlorphenamide: Amphotericin B may enhance the hypokalemic effect of Dichlorphenamide. 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
Fexinidazole [INT]: Amphotericin B may enhance the arrhythmogenic effect of Fexinidazole [INT]. Avoid combination
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
Ganciclovir-Valganciclovir: May enhance the nephrotoxic effect of Amphotericin B. Monitor therapy
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-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy
Methoxyflurane: May enhance the nephrotoxic effect of Amphotericin B. Avoid combination
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
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. 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: Amphotericin B may enhance the cardiotoxic effect of Sodium Stibogluconate. Consider therapy modification
Adverse Reactions
Amphotericin B colloidal dispersion has an improved therapeutic index compared to conventional amphotericin B, and has been used safely in patients with amphotericin B-related nephrotoxicity; however, continued decline of renal function has occurred in some patients.
>10%:
Cardiovascular: Hypotension, tachycardia
Central nervous system: Chills
Endocrine & metabolic: Hypokalemia
Gastrointestinal: Vomiting
Hepatic: Hyperbilirubinemia
Renal: Increased serum creatinine
Miscellaneous: Fever
5% to 10%:
Cardiovascular: Chest pain, facial edema, hypertension
Central nervous system: Abnormality in thinking, drowsiness, headache, insomnia
Dermatologic: Diaphoresis, pruritus, skin rash
Endocrine & metabolic: Hyperglycemia, hypocalcemia, hypomagnesemia, hypophosphatemia
Gastrointestinal: Abdominal pain, diarrhea, enlargement of abdomen, hematemesis, nausea, stomatitis, xerostomia
Hematologic & oncologic: Anemia, hemorrhage, thrombocytopenia
Hepatic: Abnormal hepatic function tests, increased serum alkaline phosphatase, jaundice
Neuromuscular & skeletal: Back pain, muscle rigidity, tremor
Respiratory: Dyspnea, epistaxis, hypoxia, increased cough, rhinitis
<5%, postmarketing, and/or case reports: Acidosis, atrial arrhythmia, cardiac arrest, cardiac failure, gastrointestinal hemorrhage, hepatic failure, injection site reaction, oliguria, pain at injection site, pleural effusion, renal failure, seizure, syncope, ventricular arrhythmia
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; the patient should not receive further infusions. During the initial dosing, the drug should be administered under close clinical observation.
- Infusion reactions: Acute infusion reactions, sometimes severe, may occur 1-3 hours after starting infusion. These reactions are usually more common with the first few doses and generally diminish with subsequent doses. Pretreatment with antihistamines/corticosteroids and/or decreasing the rate of infusion can be used to manage reactions. Avoid rapid infusion.
Disease-related concerns:
- Heart failure: In a scientific statement from the American Heart Association, amphotericin has been determined to be an agent that may cause direct myocardial toxicity (magnitude: moderate/major) (AHA [Page 2016]).
Monitoring Parameters
Liver function tests, serum electrolytes (especially potassium and magnesium), BUN, serum creatinine, CBC, prothrombin time; temperature, I/O; signs of hypokalemia (muscle weakness, cramping, drowsiness, ECG changes)
Pregnancy
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; Pilmis 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, diarrhea, lack of appetite, weight loss, muscle pain, joint pain, or abdominal pain. Have patient report immediately to prescriber signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin), signs of kidney problems (unable to pass urine, blood in the urine, 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, fast heartbeat, increased thirst, seizures, loss of strength and energy, lack of appetite, unable to pass urine or change in amount of urine passed, dry mouth, dry eyes, or nausea or vomiting), shortness of breath, chills, severe dizziness, passing out, fast breathing, fast heartbeat, 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.
