Stanford Antimicrobial Safety and Sustainability Program Revision date 11/2019

Stanford Medication Usage Guide Amphotericin B - Liposomal (AmBisome) Usage • Liposomal amphotericin B is FDA approved for the treatment of cryptococcal in HIV-infected patients, empiric therapy for febrile neutropenia, invasive or pulmonary , , , and visceral . • Off-label uses o , , and . o Amphotericin B may be given via other routes. . For intrathecal, bladder irrigations, use conventional formulation. Use L-AmB inhalation per lung and heart transplant protocol. • Note: intrinsic resistance common for , Fusarium spp., Scedosporium spp., Trichosporon asahii. lusitaniae: phenotypic switching to amphotericin-resistant isolates when exposed to drug. Dosing CrCl Liposomal Amphotericin B (L-AmB) Dosing Regimen (typical duration 2-12 weeks) All General: 3-6 mg/kg/day IV + hydration ± premeds if infusion reaction Mucormycosis: 5mg/kg q24h is standard. High doses (7.5-10mg/kg q24h) are suggested in some settings, e.g. for CNS disease, 2, 14 however clinical studies show that 10mg/kg/day is no more effective compared to prior studies & associated with high rate (up to 40%) of kidney injury.12 Long term use: less frequent dosing, e.g. 3x a week, may be an option for some patients (usually in outpatient setting) • Use total body weight (TBW); consider using fixed dose (e.g. 500mg rather than 5mg/kg)13 or adjusted BW in obese. Lung and/or heart transplant fungal prophylaxis: inhaled L-AmB 25mg q 1-2 weeks

ESRD on IHD, CRRT Poorly dialyzed; no dosage adjustment or supplemental doses necessary ESRD=end stage renal disease; IHD=intermittent hemodialysis; CRRT=continuous renal replacement therapy

Pharmacokinetics/Pharmacodynamics Liposomal Amphotericin B (L-AMB) 100% (IV route) Kinetics Exhibits nonlinear kinetics; greater than proportional increase in serum concentration with an increase in dose. Distribution Vd 0.1 – 0.16 L/kg, > 90% protein binding Metabolism Not metabolized

Half-life elimination 7-10 hours (following a single 24-hour dosing interval) Terminal half-life: 100 – 153 hours (following multiple dosing up to 49 days) Time to steady state Steady state generally achieved within 4 days of dosing. Excretion Mean clearance at steady state was shown to be independent of dose. ~43% in feces, ~33% in urine (unchanged)

Stanford Antimicrobial Safety and Sustainability Program Revision date 11/2019

Administration • Administer 1st dose over 2 hours o 1 hour in patients who tolerate treatment well o 4 hours if patient experiences infusion reaction • Not compatible in normal (systemic preparations prepared in D5W and topical irrigations prepared in sterile water) • Hydration: 500 mL -1L NS pre infusion. o If fluid overloaded, use 500 mL pre hydration o If hyperchloremic or hypernatremic, may use Normosol or LR instead of NS. D5W is not considered an appropriate fluid for this purpose, as salt loading is generally desirable to decrease AmB’s nephrotoxic effects. • Pre-medication (for patients that experience non-anaphylactic infusion reaction): o Give 30-60 min prior to each L-AmB dose o APAP 650–1000 mg x 1 + 25–50 mg x 1 o Misc supportive meds: . Meperidine 25 mg IV q15min PRN x 4 doses for rigors . 25 mg PO/IV x 1 PRN (usually for deoxycholate formulation) • Do not filter for intrathecal route. In-line filters may be used for amphotericin deoxycholate and Ambisome (not Abelcet): pore size must be > 1 µm • Continuous infusions have been associated with less , however the efficacy is unknown, as it exhibits concentration-dependent killing.

Monitoring Parameters • Acute infusion reactions o May occur 1 – 3h after starting infusion, though usually within first 5 min. Infusion reactions o More common in the first few doses, generally diminish with subsequent , chills, rigors doses. chest pain • Frequently monitor renal function, electrolytes (especially potassium and dyspnea severe pain in abdomen, magnesium), signs of , LFTs, temperature, CBC, and cardiac function (if back, flank, leg on ) during therapy. flushing • Limit use of concomitant nephrotoxic drugs urticaria N/V Special Circumstances tachycardia • Amphotericin B formulations are not interchangeable and have different dosing recommendations. • FDA risk category B.

Comparison to other formulations Conventional Amphotericin B Deoxycholate (AMB-D) Clinical Use Topical (inhalation, bladder irrigation, etc.), intraperitoneal, intrathecal, intravitreal Dose 0.1 – 1.5 mg/kg/day IV + hydration + pre-medication Penetration Brain/CSF AMB-D ≈ L-AMB

Kidney/Urine AMB-D > L-AMB; consistent with reduced nephrotoxicity with L-

AMB

Eye ; higher in inflamed eyes AMB-D ≈ L-AMB Lung AMB-D < L-AMB Heart AMB-D ≈ L-AMB Liver AMB-D ≈ L-AMB Bone ; both still have high penetration AMB-D < L-AMB *AMB-D=amphotericin B deoxycholate; L-AMB=liposomal amphotericin B

Adverse Effects More nephrotoxicity and higher incidence of infusion-related reactions compared to AmBisome and other lipid-based formulations

Stanford Antimicrobial Safety and Sustainability Program Revision date 11/2019

References: 1. https://www.astellas.us/docs/ambisome.pdf 2. Farmakiotis D, Kontoyiannis DP. Mucormycoses. Infectious Disease Clinics. 2016 Mar 1;30(1):143-63. 3. Felton T, Troke PF, Hope WW. Tissue penetration of antifungal agents. Clin Microbiol Rev. 2014;27(1):68-88. 4. Gigliotti F, Shenep JL, Lott L, Thornton D. Induction of synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B. J Infect Dis. 1987;156(5):784-9. 5. Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin Infect Dis. 1995;20(4):755-61. 6. Groll AH, Giri N, Petraitis V, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental of the central nervous system. J Infect Dis. 2000;182(1):274-82. 7. Heinemann V, Bosse D, Jehn U, et al. Pharmacokinetics of liposomal amphotericin B (Ambisome) in critically ill patients. Antimicrob Agents Chemother. 1997;41(6):1275-80. 8. Lexi-comp 9. Eriksson U, Seifert B, Schaffner A. Comparison of effects of amphotericin B deoxycholate infused over 4 or 24 hours: randomised controlled trial. BMJ. 2001 Mar 10;322(7286):579-82. 10. Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013 Jun 1;73(9):919-34. 11. Guidelines for Prevention and Treatment of Opportunistic in HIV-Infected Adults and Adolescents [accessed 4/1/2019, page 165, M-5] https://aidsinfo.nih.gov/guidelines 12. Lanternier F, Poiree S, Elie C, et al; French Study Group. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother 2015; 70:3116–23. 13. Wasmann RE et al, Fixed Dosing of Liposomal Amphotericin B in Morbidly Obese Individuals. Clin Infect Dis. 2019 Sep 7. pii: ciz885. doi: 10.1093/cid/ciz885. [Epub ahead of print] 14. Cornely OA et al, Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium, Lancet ID 2019 http://dx.doi.org/10.1016/S1473-3099(19)30312-3

Document Information: A. Original Author/Date: Riti Gupta, PharmD, 8/25/2017, SASS team B. Gatekeeper: Antimicrobial Stewardship Program C. Review and Renewal Requirement This document will be reviewed every three years and as required by change of law or practice D. Revision/Review History: 11/19/2019: Lina Meng PharmD, William Alegria PharmD, Emily Mui PharmD, David Ha PharmD, David Epstein MD E. Approvals 1. Antimicrobial Subcommittee: 11/2017, 1/30/2020 2. P&T: 12/2017, 2/2020

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