1 Appendix. Table 1: Adult Inpatient Leucovorin and Intravenous Fluids Dosing Algorithm*1-15 From: High-Dose Methotrexate, Leucovorin and Glucarpidase Dosing, Administration, and Monitoring - Adult/Pediatric - Inpatient Consensus Care Guideline Contact for Content: Sara Shull, PharmD Methotrexate 24-hour Level Action ≤10 µM/L (≤20 µM/L if dose given as 24-hour infusion**) AND SCr <125% of baseline No change; Draw next AM level >10-50 µM/L (>20-120 µM/L if dose given as 24-hour infusion**) OR SCr 125%-150% of baseline Increase fluids to 175 mL/hr Increase leucovorin to 30 mg/m2 IV Q6H*** Draw 36-hour level SCr >150% of baseline with MTX ≤50 µM/L (≤120 µM/L if dose given as 24-hour infusion**) Increase fluids to 200 mL/hr Increase leucovorin to 100 mg/m2 IV Q6H Draw 36-hour level >50 µM/L (>120 µM/L if dose given as 24-hour infusion**) Increase fluids to 200 mL/hr Increase leucovorin to 100 mg/m2 IV Q3H Draw 36-hour level Consider glucarpidase use if dose given over ≤6 hours+ Methotrexate Conditional 36-hour Level Action ≤3 µM/L No change; Draw next AM level >3-10 µM/L Increase fluids to 200 mL/hr if not already there Increase leucovorin to 30 mg/m2 IV Q6H*** >10-30 µM/L OR SCr ≥125% baseline Increase fluids to 200 mL/hr if not already there Increase leucovorin to 100 mg/m2 IV Q6H >30 µM/L Increase fluids to 200 mL/hr if not already there Increase leucovorin to 100 mg/m2 IV Q3H Consider glucarpidase use+ Methotrexate 42-hour “next AM” or 48-hour Level Action ≤0.5 µM/L Transition to PO leucovorin± >0.5-1 µM/L No change; Draw next AM level >1-5 µM/L OR SCr 125%-150% baseline Increase fluids to 200 mL/hr if not already there Increase leucovorin to 30 mg/m2 IV Q6H*** >5-10 µM/L OR SCr >150%-200% baseline Increase fluids to 200 mL/hr if not already there Increase leucovorin to 30 mg/m2 IV Q3H*** Consider glucarpidase use if 48-hour level+ >10-50 µM/L OR SCr >200% baseline Increase fluids to 200 mL/hr if not already there Increase leucovorin to 100 mg/m2 IV Q3H Consider glucarpidase use+ >50 µM/L Increase fluids to 200 mL/hr if not already there Increase leucovorin to 1000 mg/m2 Q6H Consider glucarpidase use+ *Methotrexate levels [MTX] are measured from the START of the infusion **If dose given as 24-hour infusion (i.e. HyperCVAD), increase the fluids immediately per the algorithm if 24-hour level or SCr is elevated. Increase the leucovorin dose per the algorithm as well, but do not start these changes until hour 36. If the escalation requires 100 mg/m2 dosing, discontinue the 50 mg/m2 leucovorin bolus order and start with 100 mg/m2 at hour 36. ***If initial leucovorin supportive care dose is 100 mg/m2 IV Q6H (i.e., MT-R regimen #5296) do not decrease the leucovorin dose to 30 mg/m2 +To consider glucarpidase use there must be evidence of impaired renal function, defined as CrCl <60 mL/min OR SCr ≥150% baseline. The pharmacokinetic modeling tool at mtxpk.org may be used to evaluate trends in methotrexate level and serum creatinine to aid in the decision regarding glucarpidase use. ±Patients who experience delayed methotrexate clearance, defined as the need for any escalation in fluid rate or leucovorin dose per this algorithm, should receive intravenous leucovorin until methotrexate level is ≤0.1 µM/L and the patient is safe to discharge. Effective 3/8/2022. Contact CCKM@uwhealth.org for previous versions Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 03/2022 Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 03/2022 2 References 1. Yasar Albushra Abdul Rahiem Ahmed YH. Prevention and Management of High Dose Methotrexate Toxicity. J Cancer Sci Ther. 2013;5(3):106-112. 2. Methotrexate [prescribing information]. Hospira, Inc.; Lake Forest, IL. 2013. 3. Ackland SP, Schilsky RL. High-dose methotrexate: a critical reappraisal. J Clin Oncol. Dec 1987;5(12):2017-31. 4. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol. Mar 10 2006;24(8):1281-8. doi:10.1200/jco.2005.04.8819 5. Bleyer WA. Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev. Jun 1977;4(2):87-101. 6. Flombaum CD, Meyers PA. High-dose leucovorin as sole therapy for methotrexate toxicity. J Clin Oncol. May 1999;17(5):1589-94. 7. Frei E, 3rd, Blum RH, Pitman SW, et al. High dose methotrexate with leucovorin rescue. Rationale and spectrum of antitumor activity. Am J Med. Mar 1980;68(3):370-6. 8. Kintzel PE, Campbell AD, Yost KJ, et al. Reduced time for urinary alkalinization before high-dose methotrexate with preadmission oral bicarbonate. J Oncol Pharm Pract. Jun 2012;18(2):239-44. doi:10.1177/1078155211426913 9. Monjanel S, Rigault JP, Cano JP, Carcassonne Y, Favre R. High-dose methotrexate: preliminary evaluation of a pharmacokinetic approach. Cancer Chemother Pharmacol. 1979;3(3):189-96. 10. Stoller RG, Hande KR, Jacobs SA, Rosenberg SA, Chabner BA. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med. Sep 22 1977;297(12):630-4. doi:10.1056/nejm197709222971203 11. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. Jun 2006;11(6):694-703. doi:10.1634/theoncologist.11-6-694 12. Widemann BC, Balis FM, Kim A, et al. Glucarpidase, leucovorin, and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome. J Clin Oncol. Sep 1 2010;28(25):3979-86. doi:10.1200/JCO.2009.25.4540 13. Howard SC, McCormick J, Pui CH, Buddington RK, Harvey RD. Preventing and Managing Toxicities of High-Dose Methotrexate. Oncologist. Dec 2016;21(12):1471-1482. doi:10.1634/theoncologist.2015-0164 14. Nowak TJ, Lorge AH, Rein LE, et al. Implementation and evaluation of high-dose methotrexate administration guidelines. J Oncol Pharm Pract. Oct 2019;25(7):1675-1681. doi:10.1177/1078155218808866 15. Taylor ZL, Mizuno T, Punt NC, et al. MTXPK.org: A Clinical Decision Support Tool Evaluating High-Dose Methotrexate Pharmacokinetics to Inform Post-Infusion Care and Use of Glucarpidase. Clin Pharmacol Ther. Sep 2020;108(3):635-643. doi:10.1002/cpt.1957 Effective 3/8/2022. Contact CCKM@uwhealth.org for previous versions Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 03/2022 Copyright © 2022 University of Wisconsin Hospitals and Clinics Authority. All Rights Reserved. Printed with Permission. Contact: CCKM@uwhealth.org Last Revised: 03/2022