Related | Leucovorin and Intravenous Fluids Dosing Algorithm
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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
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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