Related | High-Dose Methotrexate, Leucovorin, and Glucarpidase Dosing, Administration, and Monitoring - Adult/Pediatric - Inpatient
1
High-Dose Methotrexate, Leucovorin and
Glucarpidase Dosing, Administration, and Monitoring
- Adult/Pediatric - Inpatient
Consensus Care Guideline
Note: Active Table of Contents – Click to follow link
TABLE OF CONTENTS
EXECUTIVE SUMMARY ............................................................................ 2
DEFINITIONS ............................................................................................. 3
INTRODUCTION ........................................................................................ 3
RECOMMENDATIONS .............................................................................. 4
COLLATERAL TOOLS & RESOURCES ................................................. 13
REFERENCES ......................................................................................... 14
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Executive Summary
Guideline Overview
These guidelines provide recommendations for the prevention, monitoring, and treatment of
methotrexate toxicity in adult and pediatric patients receiving high-dose methotrexate therapy.
Key Practice Recommendations
1. Prevention of toxicity for patients receiving high-dose methotrexate should include
hyperhydration, urine alkalization, pharmacokinetically guided leucovorin rescue, and
monitoring for drug interactions.1-11 (UW Health GRADE High Quality Evidence, Strong
Recommendation)
2. Monitoring of toxicity for patients receiving high-dose methotrexate should begin 24 hours
after the start of the methotrexate infusion and include methotrexate blood concentration,
serum creatinine, urine output, and urine pH.1, 2, 11-13 (UW Health GRADE High Quality
Evidence, Conditional Recommendation)
3. High-dose-methotrexate-induced nephrotoxicity treatment should include leucovorin and
intravenous fluid dose adjustment and may include glucarpidase.1, 11, 14-18 (UW Health GRADE
Moderate Quality Evidence, Conditional Recommendation)
Population/Problem
Disease/Condition(s):
Hematologic and solid tumor malignancies requiring utilization of high-dose methotrexate
Clinical Specialty:
Bone Marrow Transplant, Hematology, Nursing, Oncology, Pediatrics, Pharmacy
Intended Users:
Advanced Practice Providers, Pharmacists, Physicians, Registered Nurses
Objectives:
To maximize outcomes and minimize toxicity associated with high-dose methotrexate regimens.
In addition, this guideline aims to avoid inappropriate use of glucarpidase.
Target Population:
1. Adult and pediatric inpatients receiving high-dose methotrexate
Interventions and Practices Considered:
1. This guideline recommends appropriate use of enteral sodium bicarbonate, intravenous
sodium bicarbonate, leucovorin, and glucarpidase as preventative supportive care for
and the treatment of high-dose methotrexate toxicity
2. This guideline provides recommendations for the appropriate monitoring of high-dose
methotrexate treatment utilizing methotrexate blood concentration, serum creatinine,
urine output, and urine pH
Major Outcomes Considered:
1. Renal clearance of high-dose methotrexate to below detectable levels in the absence of
toxicity
2. Prevention and resolution of toxic reactions to methotrexate (i.e. myelosuppression, oral
mucositis, acute kidney injury, acute hepatic dysfunction, and acute dermatitis)
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Guideline Metrics:
1. Adherence to guideline of recommendations
2. Incidence and severity of methotrexate toxicities as identified through voluntary reporting
and retrospective chart review
Definitions
1. High-dose methotrexate: any dose of methotrexate ≥500 mg/m2 15
2. Creatinine clearance (CrCl): measure of the rate in which creatinine, a byproduct of
protein metabolism, is cleared from the blood by the kidneys
3. Below detection methotrexate blood concentration: Laboratory result ≤0.05 µM/L (for
additional information see UW Health Lab Test Directory).
4. Delayed methotrexate clearance: the need for any escalation in fluid rate or leucovorin
dose based upon serum creatinine increase or methotrexate level above expected at
any time following high-dose methotrexate administration
5. Evidence of impaired renal function: CrCl <60 mL/min OR serum creatinine (SCr) ≥150%
of baseline
Introduction
Methotrexate is one of the most widely used anti-cancer agents and has application where
immunosuppression is required (rheumatoid arthritis, psoriasis and after bone marrow
transplant).1, 10, 19 Methotrexate blood concentration monitoring is useful because both drug
concentration and exposure time have been correlated with toxicity. The severity of toxicity is
directly proportional to the duration at which the extracellular concentration remains above
threshold. The critical threshold varies from organ to organ. The most common toxic reactions
to methotrexate are myelosuppression, oral mucositis, acute kidney injury, acute hepatic
dysfunction, and acute dermatitis. Intestinal mucositis, diarrhea, vomiting, vaginal mucositis,
conjunctivitis, vasculitis, immunosuppression, and acute neurotoxicity may also occur. High
doses of methotrexate (>500 mg/m2) are used for a wide variety of hematologic and solid tumor
malignancies. High-dose methotrexate is considered lethal unless appropriately reversed by
leucovorin rescue in a timely manner.
The etiology of methotrexate-induced nephrotoxicity is mediated by the precipitation of
methotrexate and its metabolites in the renal tubules. Because methotrexate is primarily excreted
via the kidneys, elimination of the drug becomes problematic once nephrotoxicity has occurred.
Current recommendations for the prevention of methotrexate nephrotoxicity are routine
monitoring of creatinine and methotrexate blood concentration, dose-adjusted leucovorin rescue,
aggressive hydration, and urine alkalinization. The utilization of these prophylactic strategies has
decreased the incidence of severe and life-threatening toxicities from 10% to less than 1%.
However, nephrotoxicity potentially leading to death still occurs in a fraction of patients, especially
in adult patients with poor performance status.1, 2, 13
Glucarpidase (Voraxaze®) is a recombinant carboxypeptidase enzyme that degrades folic acid
and methotrexate into inactive metabolites. Thus, it provides an alternate non-renal pathway for
methotrexate elimination in patients with renal dysfunction during high-dose methotrexate
treatment.12, 17, 20 It is FDA approved for the treatment of toxic methotrexate blood concentrations
in patients with delayed methotrexate clearance due to impaired renal function. Glucarpidase has
no impact on intracellular concentrations of methotrexate or on reversing methotrexate-induced
renal toxicity. Protection of cells from intracellular methotrexate still requires the administration
of high-dose leucovorin.
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Recommendations
1. Prevention of toxicity for patients receiving high-dose methotrexate
1.1 Patients should receive adequate hydration per specific chemotherapy protocol (UW
Health GRADE Moderate Quality Evidence, Conditional Recommendation)1, 2, 8, 11, 19, 21
1.1.1 A minimum of four hours of pre-hydration is reasonable. (UW Health GRADE
Moderate Quality Evidence, Conditional Recommendation)
1.1.2 It is reasonable to titrate pre-hydration to maintain urine output
>2.5 L/m2/day until methotrexate blood concentration is below detection (UW
Health GRADE Moderate Quality Evidence, Conditional Recommendation)1, 22
1.1.3 It is recommended that patients receive 2.5-3.5 L/m2 per 24 hours of fluid,
starting 12 hours before the start of the MTX infusion and continuing for 24 to
48 hours. (UW Health GRADE Moderate Quality Evidence, Conditional
Recommendation)11
1.2 Urine alkalization with a goal urine pH >7 should be achieved prior to initiation of high-
dose methotrexate and continued until methotrexate blood concentration is below
detection (UW Health GRADE High Quality Evidence, Strong Recommendation)1, 19, 21-
23
1.2.1 Medications or fluids that may acidify the urine (e.g. folic acid, vitamin C, normal
saline, cranberry juice, soda etc.) should be avoided. (UW Health GRADE High
Quality Evidence, Strong Recommendation) 1, 2, 13, 19
1.2.2 Adult patients
1.2.2.1 Prior to admission for high-dose methotrexate it may be useful for
patients take oral sodium bicarbonate to support rapid urinary
alkalization (UW Health GRADE Moderate Quality Evidence,
Conditional Recommendation)3, 24, 25
1.2.2.1.1 It is reasonable to consider instructing patients to take ½ tsp
baking soda by mouth every 4-6 hours for 5 doses, starting
the day before high-dose methotrexate treatment is initiated.
(UW Health GRADE Moderate Quality Evidence, Conditional
Recommendation)3, 5, 24-26
1.2.2.2 Intravenous maintenance fluids should be sterile water or dextrose 5%
solution with 100 mEq of sodium bicarbonate per liter. (UW Health
GRADE High Quality Evidence, Conditional Recommendation)1, 19, 25
1.2.2.3 If urine pH is less than or equal to 7.0 while on appropriate intravenous
fluids, a sodium bicarbonate IV 50 mEq bolus is indicated as often as
every 2 hours. (UW Health GRADE High Quality Evidence, Conditional
Recommendation)1, 19, 22
1.2.3 Pediatric patients
1.2.3.1 Sodium bicarbonate 1 mEq/mL intravenously may be infused at a rate
of 0.15 mEq/kg/hr, titrated up by 2 mEq/hr or down by 1 mEq/hr to keep
urine pH between 7 and 8. (UW Health GRADE Moderate Quality
Evidence, Conditional Recommendation)3
1.2.3.2 Maintenance fluids of dextrose 5% or sodium chloride 0.45% should be
infused at a rate of 125 mL/m2/hr until the methotrexate blood
concentration is below detection. (UW Health GRADE High Quality
Evidence, Conditional Recommendation)1, 19
1.3 Specific protocols should be followed to guide starting time, dose, and frequency of
leucovorin rescue following high-dose methotrexate administration (UW Health GRADE
High Quality Evidence, Conditional Recommendation)1, 19, 27
1.3.1 Adult patients
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1.3.1.1 Leucovorin should be started 24 hours following the initiation of
therapy. (UW Health GRADE High Quality Evidence, Conditional
Recommendation)1, 2, 4, 12, 19, 28, 29
1.3.1.2 An initial intravenous dose of 50 mg/m2 may be considered to ensure
adequate and rapid absorption (UW Health GRADE Moderate Quality
Evidence, Conditional Recommendation)1, 8, 11
1.3.1.2.1 It is reasonable for subsequent doses of leucovorin to be 15
mg/m2 intravenously until the methotrexate blood
concentration is ≤0.5 µM/L in patients without increased risk
factors for methotrexate toxicity (UW Health GRADE
Moderate Quality Evidence, Conditional Recommendation)1,
19
1.3.1.2.2 It is reasonable for 15 mg leucovorin to be given orally
every 6 hours once the methotrexate blood concentration is
≤0.5 µM/L and continued until the methotrexate blood
concentration is ≤0.1 µM/L in patients without increased risk
factors for methotrexate toxicity. (UW Health GRADE
Moderate Quality Evidence, Conditional Recommendation)1,
19
1.3.1.2.3 Adult patients can be considered for discharge when the
methotrexate blood concentration is ≤0.1 µM/L. If concern
for third spacing or potential toxicity it is reasonable to
discharge patients with a prescription for 15 mg oral
leucovorin tablets to be taken every 6 hours along with ½
tsp baking soda every 6 hours until a follow-up
methotrexate blood concentration is confirmed to be ≤0.05
µM/L. (UW Health GRADE Moderate Quality Evidence,
Conditional Recommendation)1, 19
1.3.1.3 Intravenous route should be used for doses of leucovorin greater than
25 mg and for patients at risk of decreased oral absorption (UW Health
GRADE High Quality Evidence, Conditional Recommendation)9, 19
1.3.2 Pediatric patients
1.3.2.1 Individual protocols should be followed for dosing of leucovorin (UW
Health GRADE High Quality Evidence, Conditional
Recommendation)4
1.4 Drug-drug interactions with methotrexate have potential to initiate or worsen toxicity and
should be avoided (UW Health GRADE High Quality Evidence, Conditional
Recommendation)2-6
1.4.1 Medications that displace methotrexate from binding sites on plasma proteins,
resulting in increased methotrexate blood concentrations (e.g. sulfonamides,
salicylates, phenytoin, and tetracycline), should be avoided. (UW Health GRADE
High Quality Evidence, Conditional Recommendation)3-6
1.4.2 Medications that reduce renal tubular transport as a result of decreased urine pH
(increased acidity), resulting in increased methotrexate blood concentrations
(e.g. folic acid, salicylates, ascorbic acid, multiple vitamins containing vitamin C),
should be avoided. (UW Health GRADE High Quality Evidence, Conditional
Recommendation)3-6
1.4.3 Medications that compete for P-glycoprotein transport, CYP450 metabolism, or
renal excretion of methotrexate, resulting in increased methotrexate blood
concentrations and toxicities (e.g. non-steroidal anti-inflammatory drugs
[NSAIDs], penicillins, probenecid, gemfibrozil, cyclosporine, ciprofloxacin,
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amiodarone, doxycycline, simvastatin) should be avoided. (UW Health GRADE
High Quality Evidence, Conditional Recommendation) 3-6,11,30
1.4.4 Concomitant use of proton pump inhibitors, such as omeprazole, esomeprazole,
and pantoprazole, with methotrexate (primarily at high doses), should be
avoided, as they may elevate and prolong blood concentrations of methotrexate
and/or its metabolite hydroxymethotrexate (UW Health GRADE High Quality
Evidence, Strong Recommendation) 3,5
1.5 Patients with third-space fluids such as pleural effusions, significant edema, or ascites,
may have altered volume of distribution and extended terminal half-life of methotrexate,
causing delayed elimination of the drug that is not likely correctable with hemodialysis.
For this reason, it is reasonable to examine patients to identify potential sites of third-
spacing prior to administration of high-dose methotrexate and to consider holding
treatment in those patients with significant third-spacing present (UW Health GRADE
Moderate Quality Evidence, Conditional Recommendation)3, 6, 11, 31
1.5.1 It is reasonable to evaluate patients with weight gain ≥ 2 kg from admission for
third-spacing and fluid retention and consider these patients at risk for delayed
methotrexate clearance
1.5.2 Use of furosemide within 48 hours of the initiation of high-dose methotrexate can
delay methotrexate clearance. It is reasonable to consider furosemide use within
48 hours of high-dose methotrexate for patients with signs and symptoms of fluid
overload where the benefit of use outweighs the risk.
1.5.2.1 It is not appropriate to utilize furosemide within 48 hours of high-dose
methotrexate initiation to increase urine output in the absence of
symptoms
2. Monitoring of toxicity for patients receiving high-dose methotrexate
2.1 Patients with pleural effusions, pericardial effusions, ascites, edema, age >65 years,
urine output <500 mL/day, BSA ≥2.2 m2, weight gain ≥2 kg from admission, diarrhea,
vomiting, pre-existing renal dysfunction, urinary tract obstruction, and significant
changes in serum creatinine and/or calculated creatinine clearance during treatment
with high-dose methotrexate are at increased risk for toxicity (UW Health GRADE High
Quality Evidence, Strong Recommendation).1, 8, 10-12, 21, 32
2.2 Methotrexate blood concentration and serum creatinine should be monitored 24 hours
after the start of the methotrexate infusion and then at least once daily until elimination
to below detection. (UW Health GRADE High Quality Evidence, Conditional
Recommendation)19
2.2.1 It is reasonable to monitor methotrexate blood concentration and serum
creatinine at 36-hours of treatment in patients with increased risk factors for
methotrexate toxicity (Table 1).
2.3 It is reasonable to measure urine output continuously and document output at least every
8 hours. (UW Health GRADE Moderate Quality Evidence, Conditional
Recommendation)1
2.4 To assess for alkalosis, it is reasonable to monitor urine pH and respiratory rate every 8
hours and serum bicarbonate daily. (UW Health GRADE Moderate Quality Evidence,
Conditional Recommendation)2
3. Treatment of high-dose-methotrexate-induced nephrotoxicity or delayed clearance
3.1 Leucovorin dosing should be evaluated for potential adjustment starting 24 hours after
start of methotrexate (UW Health GRADE High Quality Evidence, Conditional
Recommendation)1, 19
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3.1.1 It may be reasonable to adjust leucovorin dose to 100 mg/m2 IV every 6 hours if
serum creatinine is ≥150% of baseline or to 100 mg/m2 IV every 3 hours if serum
creatinine is ≥200% of baseline at 24 hours after start of methotrexate. (UW
Health GRADE Moderate Quality Evidence, Conditional Recommendation)9
3.1.2 If methotrexate blood concentration is ≥50 µmol/L at 24 hours, it may be
reasonable to increase leucovorin dose to 100 mg/m2 IV every 3 hours. (UW
Health GRADE Moderate Quality Evidence, Conditional Recommendation)4
3.1.3 The dosing algorithm in Table 1 should be used to guide leucovorin dose
adjustments. (UW Health GRADE High Quality Evidence, Conditional
Recommendation)1, 10, 19
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Table 1: Adult Inpatient Leucovorin and Intravenous Fluids Dosing Algorithm*1, 3, 4, 8, 10-12, 23, 27, 29, 33-37
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 #5269) 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.
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3.2 Treatment with glucarpidase
3.2.1 To be eligible for glucarpidase treatment patients should meet BOTH the
methotrexate concentration outlined in Table 1 AND have evidence of impaired
renal function (CrCl <60 mL/min OR SCr ≥150% baseline). (UW Health GRADE
High Quality Evidence, Strong Recommendation)15, 17, 20, 38
3.2.1.1 Glucarpidase should not be given if the methotrexate blood
concentration is ≤1 µM/L. (UW Health GRADE High Quality Evidence,
Strong Recommendation)15, 17, 20, 38, 39
3.2.1.2 It is reasonable to consider toxicities other than renal dysfunction (e.g.
central nervous system, mucositis) in the use of glucarpidase. (UW
Health GRADE Moderate Quality Evidence, Strong Recommendation)8,
9
3.2.2 Leucovorin rescue dosing should be monitored closely with glucarpidase
administration (UW Health GRADE High Quality Evidence, Strong
Recommendation)17, 20
3.2.2.1 Glucarpidase has no impact on intracellular concentrations of
methotrexate. Leucovorin should still be administered to protect cells
from intracellular methotrexate, which will be released into the vascular
space following glucarpidase administration. (UW Health GRADE High
Quality Evidence, Strong Recommendation) 8, 9, 15, 17, 38
3.2.2.2 To allow glucarpidase to optimally metabolize methotrexate rather than
leucovorin, which is also metabolized by glucarpidase, leucovorin
should not be administered within 2 hours before or 2 hours after a dose
of glucarpidase. (UW Health GRADE High Quality Evidence, Strong
Recommendation)15, 17, 20
3.2.2.3 Starting at least 2 hours after glucarpidase injection, the SAME dose of
leucovorin as given prior to glucarpidase should be administered for at
least 48 hours following the dose (UW Health GRADE High Quality
Evidence, Strong Recommendation)15, 17, 20
3.2.2.4 Beyond 48 hours after administration of glucarpidase, leucovorin doses
should be adjusted based on methotrexate concentrations per Table 1.
(UW Health GRADE High Quality Evidence, Strong
Recommendation)15, 17, 20
3.2.2.5 It is reasonable to continue oral leucovorin for a minimum of 3 days
after methotrexate blood concentration is first undetectable. (UW
Health GRADE Moderate Quality Evidence, Conditional
Recommendation)17, 20
3.2.3 Glucarpidase dosing
3.2.3.1 A dose of 50 units/kg IV is recommended (UW Health GRADE High
Quality Evidence, Strong Recommendation)15, 17, 20, 40
3.2.3.1.1 It may be reasonable to round glucarpidase doses to the
nearest 1000-unit vial size. (UW Health GRADE Moderate
Quality Evidence, Conditional Recommendation)20, 38, 41-46
3.2.3.1.2 It may be reasonable to cap the dose of glucarpidase at
2000 units (2 vials) (UW Health GRADE Low Quality
Evidence, Conditional Recommendation)14, 16, 17, 20, 38, 41-46
3.2.3.2 Glucarpidase should be administered intravenously as a bolus injection
over 5 minutes (UW Health GRADE High Quality Evidence, Strong
Recommendation)12, 15, 17, 20
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3.2.3.3 Second and third doses of glucarpidase are NOT recommended, as
they have not shown clinical benefit and may increase risk of
immunogenicity. (UW Health GRADE High Quality Evidence, Strong
Recommendation)15, 17
3.2.4 Monitoring patients following glucarpidase administration
3.2.4.1 Methotrexate blood concentration should be monitored daily until below
detection, as for 48 hours after a glucarpidase dose, methotrexate
blood concentration will be artificially elevated. This is due to the fact
that glucarpidase metabolizes methotrexate into an inactive metabolite
(4-deoxy-4-amino-N10-methylpteroic acid), which is detected, along
with active methotrexate, in the immunoassay; thus, accurate
methotrexate blood concentration can only be obtained ≥48 hours after
glucarpidase administration. (UW Health GRADE High Quality
Evidence, Strong Recommendation)12, 14
3.2.4.2 Urine output should be monitored at least every 8 hours until stable,
then every 24 hours. (UW Health GRADE High Quality Evidence,
Strong Recommendation)
3.2.4.3 Following glucarpidase administration SCr is likely to continue to
gradually rise for three days prior to declining; thus serum creatinine
should be monitored every 12 hours until stable, then every 24 hours.
(UW Health GRADE High Quality Evidence, Strong
Recommendation)17, 20
3.2.5 Dialysis-based methods have not been shown to reduce methotrexate toxicity
and are not recommended (UW Health GRADE Moderate Quality Evidence,
Conditional Recommendation)1, 11, 31
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Disclaimer
Consensus care models assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.
Content Expert(s):
Name: Sara Shull, PharmD, MBA, BCPS
Phone Number: (608) 262-1817
Email Address: ssmith-shull@uwhealth.org
Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS
Phone Number: (608) 263-1308
Email Address: ptrapskin@uwhealth.org
Guideline Author(s):
Mike Fallon, PharmD, BCOP - Pharmacy
Mikala Hillis, PharmD – Pharmacy
Workgroup Members:
Mary Mably, RPh, BCOP –Pharmacy
Mike Reed, RPh, BCOP – Pharmacy
Reviewer(s):
Kenneth DeSantes, MD – Pediatric Hematology/Oncology
Christopher Fletcher, MD – Adult Hematology/Oncology
Committee Approvals/Dates:
Chemotherapy Review Council: January 2016, April 2021
Pharmacy & Therapeutics Committee: January 2016, September 2016, May 2021,
December 2021
Release Date: December 2021 | Next Review Date: May 2024
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Table 1. GRADE Ranking of Evidence47
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.
Table 2. GRADE Ratings for Recommendations for or Against Practice
Strong (S)
Generally, should be performed (i.e., the net benefit of the treatment
is clear, patient values and circumstances are unlikely to affect the
decision.)
Conditional (C)
May be reasonable to perform (i.e., may be conditional upon patient
values and preferences, the resources available, or the setting in
which the intervention will be implemented.)
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Collateral Tools & Resources
Companion Documents
1. High-Dose Methotrexate Monitoring, Leucovorin and Sodium Bicarbonate Intravenous Fluids Dosing -
Adult - Inpatient Delegation Protocol [261]
2. Renal Function-Based Dose Adjustments - Adult - Inpatient/Ambulatory Consensus Care Mode
3. Management of Extravasation of Chemotherapeutic Agents Adult/Pediatric- Inpatient/Ambulatory
Consensus Care Model
4. Intravenous Administration of Formulary Medications - Adult - Inpatient/Ambulatory
5. Intravenous Administration of Formulary Medications - Neonatal/Pediatric - Inpatient/Ambulatory
6. Medications Defined as Chemotherapy at UW Health
7. High-Dose Methotrexate Inpatient RN Workflow
Pertinent UW Health Policies & Procedures
1. Glucarpidase Prescribing and Procurement Procedure
Beacon Protocols
1. CSC HEM INPT HIGH DOSE METHOTREXATE FOR CNS LYMPHOMA [3086]
2. CSC HEM INPT/OUTPT CHOEP WITH HIGH DOSE METHOTREXATE [4400]
3. CSC HEM INPT/OUTPT CHOP WITH HIGH DOSE METHOTREXATE [4395]
4. CSC HEM INPT/OUTPT R-CHOP WITH HIGH DOSE METHOTREXATE [4401]
5. CSC HEM INPT/OUTPT PCNSL INDUCTION METHOTREXATE/RITUXIMAB/TEMOZOLOMIDE
[5296]
6. CSC HEM INPT/OUTPT DEXAMETHASONE/ETOPOSIDE/IFOSFAMIDE/
METHOTREXATE/PEGASPARGASE [4390]
7. CSC SARCOMA INPT CISPLATIN(35D:1)/DOXORUBICIN(35D:1-3)/ METHOTREXATE(35D:21,28)
[975]
8. CSC HEM INPT/OUTPT CYTARABINE/DASATINIB/DEXAMETHASONE/
MERCAPTOPURINE/METHOTREXATE/PREDNISONE/RITUXIMAB CD20-POSITIVE [6614]
9. CSC HEM INPT/OUTPT CYTARABINE/DASATINIB/DEXAMETHASONE/
MERCAPTOPURINE/METHOTREXATE/PREDNISONE/VINCRISTINE CD20-NEGATIVE [7788]
10. CSC HEM INPT MODIFIED MAGRATH HIGH RISK (A-B-A-B) WITH RITUXIMAB [3187]
11. CSC HEM RITUXIMAB-MBVP [6245]
12. CSC HEM INPT/OUTPT HYPER-CVAD PART (A) AND (B) – LYMPHOMA [3171]
13. CSC HEM INPT MODIFIED MAGRATH LOW RISK WITH RITUXIMAB (A-A-A) [3038]
14. CSC HEM INPT/OUTPT HYPER-CVAD PART (A) and (B) – LEUKEMIA [3087]
15. CSC HEM INPT/OUTPT CYCLOPHOSPHAMIDE/CYTARABINE IV+IT/
DEXAMETHASONE/DOXORUBICIN/ETOPOSIDE/IFOSFAMIDE/METHOTREXATE
IV+IT/PREDNISONE/RITUXIMAB/VINCRISTINE [6500]
Best Practice Alerts (BPA)
1. Glucarpidase Verification BPA
Patient Resources
1. Medication Fact Sheet: Methotrexate (pediatrics)
2. Medication Fact Sheet: Carboxypeptidase (Glucarpidase) (pediatrics)
3. Lexicomp: Methotrexate
4. Lexicomp: Glucarpidase
5. Lexicomp: Leucovorin
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.
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14
References
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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
15
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Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate
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Resident Posters.
Effective 3/8/2022. Contact CCKM@uwhealth.org for previous versions
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16
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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
Definitions
Introduction
Recommendations
Collateral Tools & Resources
References