AmphotericinSnapshot(June2021)

Indication

• Treatment of progressive, potentially life-threatening fungal infections, including Mucormycosis.

• Liposomal amphotericin B is the treatment of choice for Mucormycosis and is preferred over conventional amphotericin B deoxycholate.

Dosage

• NOTE: Amphotericin B deoxycholate and amphotericin B liposome are dosed differently and are NOT interchangeable or substitutable on a mg per mg basis.

• Amphotericin B liposome (2)(6)

  • 5 mg/kg IV every 24 hours

  • 10 mg/kg IV every 24 hours in cases with CNS involvement

  • Initiate the full dose on treatment Day 1

• Amphotericin B deoxycholate

  • Test Dose: (1)

    • A single 1 mg test dose (in 20 mL of 5% dextrose solution) given over 20 to 30 minutes may be considered.

    • If used, test dose should be given 2 to 4 hours before the first therapeutic dose. 1 to 1.5 mg/kg/dose IV every 24 hours (3)(4)(6)

Administration:

• Amphotericin B liposome Reconstitution: (5) Add 12 mL of Sterile Water for Injection WITHOUT a bacteriostatic agent to each vial to yield a 4 mg/mL suspension. Shake vigorously for 30 seconds to completely disperse the product. Reconstituted suspension may be stored for up to 24 hours at 2 to 8 degrees C; DO NOT freeze. Dilution: (5) Withdraw the calculated amount of reconstituted suspension needed for the dose into a sterile syringe. Attach a 5-micron filter to the syringe; inject through the filter into an appropriate amount of 5% Dextrose Injection. Use only 1 filter per vial. Dilute with 5% Dextrose Injection to a final concentration of 1 to 2 mg/mL. For infants and small children, lower concentrations (i.e., 0.2 to 0.5 mg/mL) may be needed to provide sufficient infusion volume. Diluted product must be administered within 6 hours. Administration: Flush line with 5% Dextrose Injection before infusion. An in-line membrane filter may be used if the mean pore diameter is 1 micron or larger. (5) Administer by IV infusion over 2 to 3 hours. (6)

• Amphotericin B deoxycholate (1)

  • Patient management prior to treatment:

    • Pre-medication for fever, chills, or rigor: Aspirin, antipyretics (e.g. acetaminophen), antihistamines, antiemetics, meperidine, or small doses of steroids may decrease infusion-related reactions.

    • Pre-medication for nephrotoxicity prophylaxis: Hydration and sodium repletion may reduce the risk of nephrotoxicity. Also, supplemental alkali medication may decrease renal tubular acidosis.

  • Reconstitution:

    • Add 10 mL of Sterile Water for Injection WITHOUT a bacteriostatic agent to the vial.

    • Shake vial immediately until the colloidal solution is clear.

    • Concentration of the reconstituted solution is 5 mg/mL.

  • Dilution: Dilute the reconstituted solution to a concentration of 0.1 mg/mL (1 mg/10 mL) using 5% Dextrose Injection with a pH greater than 4.2,

  • Administration:

    • An in-line membrane filter may be used if the mean pore diameter is 1 micron or larger.

    • Administer by slow intravenous infusion over 2 to 6 hours.

    • Protect from light during the infusion.

• May consider step down to an oral antifungal agent with activity against Mucormycosis (i.e., posaconazole or isavuconazole) once favorable response is achieved and disease is stabilized.

• Antifungal therapy must be continued until clinical resolution of the infection, resolution of radiological signs of active disease, and elimination of predisposing factors (i.e., hyperglycemia, immunosuppression). (6)

Precautions

• Medication errors: (1)

  • Due to differences in dosing, there is a potential for accidental overdose with amphotericin B deoxycholate. This may result in fatal cardiac or cardiorespiratory arrest.

  • The dose of amphotericin B deoxycholate MUST NOT exceed 1.5 mg/kg.

  • Verify the product name and dose before administering.

• Infusion-related reactions: (1)

  • More frequent with amphotericin B deoxycholate then amphotericin B liposome.

  • Acute reactions often occur within 1 to 3 hours after beginning the infusion.

  • Most severe during the first few doses; but monitor patients during all infusions.

  • Slowing the infusion rate and pre-medicating patients may help.

  • Avoid rapid administration. Serious hypotension, hypokalemia, arrhythmias, and shock have occurred with rapid infusion rates.

• Renal impairment:

  • More frequent with amphotericin B deoxycholate then amphotericin B liposome.

  • Use cautiously in patients with preexisting renal disease because it can cause additional renal impairment.

  • Risk factors of nephrotoxicity include concurrent nephrotoxic medications, high daily dose, preexisting renal dysfunction, and bone marrow transplantation.

  • Hydration and sodium repletion prior to dose may reduce the risk. Supplemental alkali medication may decrease renal tubular acidosis complications. (1)

  • Monitor renal function during treatment. (6)

• Electrolyte imbalance:

  • Use cautiously in patients with hypokalemia, hypomagnesemia, hypocalcemia, and hyponatremia.

  • Significant renal electrolyte loss (especially potassium) may occur.

  • If possible, correct electrolyte imbalances prior to starting treatment. (1) Monitor serum electrolytes during treatment. (6)

• Hematologic disease: (1)

  • Use cautiously in patients with preexisting anemia, leukopenia, or thrombocytopenia.

  • Treatment may worsen preexisting blood cell count abnormalities.

  • Monitor CBC and platelets.

• Infusion-related reactions: headache, chills, fever, tachypnea, flushing, decreased blood pressure, decreased appetite, nausea, vomiting, inflammation and pain at the infusion site, phlebitis or thrombophlebitis, and irritation due to extravasation

• Nephrotoxicity: azotemia, hyposthenuria, nephrolithiasis (specifically nephrocalcinosis), renal tubular acidosis, acute or frank renal failure, anuria, elevated serum creatinine, oliguria, and nephrogenic diabetes insipidus

• Electrolyte Imbalance: hypokalemia, hypomagnesemia, hypocalcemia, and hyperkalemia.

• Hematologic: anemia, agranulocytosis, coagulopathy, bleeding, decreased and increased prothrombin times, ecchymosis, petechiae, eosinophilia, leukopenia, leukocytosis, and thrombocytopenia

• Cardiovascular: cardiac arrest (primarily with rapid infusion), arrhythmia exacerbation (including ventricular fibrillation), heart failure, hypertension, and hypotension

• Gastrointestinal: anorexia, cramping, diarrhea, dyspepsia, epigastric or abdominal pain, hemorrhagic gastroenteritis, melena, nausea, vomiting, and weight loss

• Hepatic: elevated hepatic enzymes, hyperbilirubinemia, increased alkaline phosphatase and gamma-glutamyl transpeptidase, acute hepatic failure, hepatitis, and jaundice

• Neurologic: diplopia, encephalopathy, hearing loss, leukoencephalopathy, malaise, peripheral neuropathy, seizures or convulsions, tinnitus, transient vertigo, and visual impairment

• Hypersensitivity: anaphylaxis, bronchospasm, dyspnea, wheezing, hypersensitivity pneumonitis, pulmonary edema, and shock

• Dermatologic: rash, maculopapular rash, pruritus, skin exfoliation, Stevens-Johnson syndrome, and toxic epidermal necrolysis

• Musculoskeletal: generalized pain, arthralgia, and myalgia

• Antineoplastic agents:

  • May increase the risk for renal toxicity, bronchospasms, and hypotension.

• Corticosteroids and Corticotropin (ACTH):

  • May increase amphotericin-induced hypokalemia.

  • If used together, closely monitor serum electrolytes and cardiac function.

• Digoxin:

  • Amphotericin-induced hypokalemia may increase the risk for digitalis toxicity.

  • If used together, closely monitor serum potassium and cardiac function.

• Flucytosine:

  • May increase flucytosine toxicity by increasing cellular uptake and decreasing renal excretion.

• Imidazole antifungals:

  • Imidazoles may induce fungal resistance to amphotericin B.

• Nephrotoxic medications:

  • May increase the risk for drug-induced renal toxicity.

  • oIf used together, closely monitor renal function.

• Skeletal muscle relaxants:

  • Amphotericin-induced hypokalemia may increase the curariform effect of skeletal muscle relaxants.

  • If use together, closely monitor serum potassium.

• Leukocyte transfusions:

  • Acute pulmonary toxicity has been reported in patients receiving these drugs together.

References:

1. Amphotericin B injection package insert. Big Flats, NY: X-Gen Pharmaceuticals, Inc.; 2009 Dec.

2. Cornely OA, Alastruey-Izquierdo A, Arenz D, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Conference of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Retrieved May 17, 2021. Available at on the World Wide Web at: http://dx.doi.org/10.1016/S1473-3099(19)30312-3.

3. Shah A, Lagvankar S, Shah A. Cutaneous mucormycosis in children. Indian Pediatr 2006;43:167-170.

4. Morales-Aguirre JJ, Aguero-Echeverria WM, Ornelas-Carsolio ME, et al. Successful treatment of a primary cutaneous zygomycosis caused by Absidia corymbifera in a premature newborn. Pediatr Infect Dis J 2004;23:470-472.

5. AmBisome (amphotericin B liposome for injection) package insert. Northbrook, IL: Astellas Pharma US, Inc; 2020 May.

6. Directorate General of Health Services, MoHFW, GOI. Comprehensive Guidelines for Management of COVID-19 patients. Retrieved June 7, 2021. Available on the World Wide Web at: https://dghs.gov.in/WriteReadData/News/202105270436027770348ComprehensiveGuidelinesforManagementofCOVID-1927May2021DteGHS.pdf