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High-Dose Methotrexate, Leucovorin and Glucarpidase Dosing, Administration, and Monitoring – Adult/Pediatric – Inpatient

High-Dose Methotrexate, Leucovorin and Glucarpidase Dosing, Administration, and Monitoring – Adult/Pediatric – Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Medications


1
High-Dose Methotrexate, Leucovorin and
Glucarpidase Dosing, Administration, and
Monitoring – Adult/Pediatric – Inpatient Clinical
Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ................................................................................................ 3
SCOPE ............................................................................................................................ 4
METHODOLOGY ............................................................................................................ 5
DEFINITIONS: ................................................................................................................ 6
INTRODUCTION ............................................................................................................. 6
RECOMMENDATIONS ................................................................................................... 7
UW HEALTH IMPLEMENTATION................................................................................ 13
REFERENCES .............................................................................................................. 14
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2
Contact for Content:
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:
Mike Fallon, PharmD, BCOP - Pharmacy
Erin McCreary, PharmD ± Pharmacy
Coordinating Team Members:
Mary Mably, RPh, BCOP ±Pharmacy
Mike Reed, RPh, BCOP ± Pharmacy
Review Individuals/Bodies:
Kenneth DeSantes, MD ± Pediatric Hematology/Oncology
Christopher Fletcher, MD ± Adult Hematology/Oncology
Committee Approvals/Dates:
Pharmacy Oncology Service Line: December 2015
Chemotherapy Review Council: January 2016
Pharmacy & Therapeutics Committee (Last Periodic Review: September 2015)
ξ Interim revisions: January 2016, September 2016
Release Date: September 2016 | Next Review Date: September 2018
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3
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 (Class 1 , Level of Evidence A)
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 (Class 1 , Level of Evidence B)
3. High-dose-methotrexate-induced nephrotoxicity treatment should include leucovorin dose-
adjustment and may include glucarpidase. 1,11,14- 18 (Class 1, Level of Evidence C)

Companion Documents
1. Drug Concentration Monitoring Delegation Protocol
2. Renal Function-Based Dose Adjustment Delegation Protocol
3. Renal Function-Based Dose Adjustments ± Adult ± Inpatient/Ambulatory Clinical Practice
Guideline
4. UWHC Guidelines for the Management of Extravasation of Chemotherapeutic Agents ±
Pediatric/Adult ± Inpatient/Ambulatory Clinical Practice Guideline
5. Intravenous Administration of Formulary Medications ± Adult ± Inpatient/Ambulatory
6. Intravenous Administration of Formulary Medications ± Neonatal/Pediatric ±
Inpatient/Ambulatory
7. Medications Defined as Chemotherapy at UWHC

Pertinent UW Health Policies & Procedures
1. UWMF Policy 102.081 : Methotrexate Injection

Patient Resources
1. Medication Fact Sheet: Methotrexate (pediatrics)
2. Medication Fact Sheet: Carboxypeptidase (Glucarpidase) (pediatrics)
3. Lexicomp: Methotrexate
4. Lexicomp: Glucarpidase
5. Lexicomp: Leucovorin











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4
Scope
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)

Guideline Metrics:
1. Adherence to guideline of recommendations
2. Incidence and severity of methotrexate toxicities as identified through voluntary reporting
and retrospective chart review

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5
Methodology
Methods used to analyze the Evidence:
Review of the following:
1. Standard drug databases including AHFS Drug Information ,Lexi-Comp On-line, Drug
Facts and Comparison and Micromedex;
2. FDA package inserts using Drugs@FDA website;
3. Existing UW Health Clinical Practice Guidelines; PubMed database and Google scholar
with the keywords: leucovorin, methotrexate, high-dose methotrexate, methotrexate
monitoring, glucarpidase, carboxypeptidase- G2

Methods Used to Formulate the Recommendations:
Review of standard drug databases, pertinent guidelines and literature with treatment effect size
and estimate of certainty of the treatment effect established according to the rating scheme (see
below)

Rolling Scheme for the Strength of the Recommendations:
A modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE)
system developed by the American Heart Association and the American College of Cardiology
Foundation has been used to assess the Quality and Strength of the evidence in this Clinical
Practice Guideline. 19

Figure 1: American Heart Association Grades of Recommendation19


Method of Guideline Validation:
Clinical experts from key clinical areas reviewed the final guideline.
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6
Definitions:
1. High-dose methotrexate: any dose of methotrexate • 500 mg/m 2 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�/ (for
additional information see UW Health Lab Test Directory ).



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). 1,10,20 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/m 2) 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.12,17,21 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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7
Recommendations
1. Prevention of toxicity for patients receiving high-dose methotrexate
1.1 Patients should receive adequate hydration per specific chemotherapy protocol (Class
I, Level B) 1,2,8,11,20,22
1.1.1 A minimum of four hours of pre-hydration is reasonable. (Class IIa, Level C) 4
6,22,23

1.1.2 It is reasonable to titrate pre-hydration to PDLQWDLQ�XULQH�RXWSXW�DW�•�����P/�KU�
until methotrexate blood concentration is below detection (Class IIa, Level C) 1
1.1.3 It is recommended that patients receive 2.5-3.5 L/m 2 per 24 hours of fluid,
starting 12 hours before the start of the MTX infusion and continuing for 24 to
48 hours. (Class IIa, Level C) 11

1.2 8ULQH�DONDOL]DWLRQ�ZLWK�D�JRDO�XULQH�S+�•���VKRXOG�EH�DFKLHYHG�SULRU�WR�LQLWLDWLRQ�RI�KLJK-
dose methotrexate and continued until methotrexate blood concentration is below
detection (Class 1, Level A) 1,20,22,24
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. (Class I, Level B )
1,2,13,20


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 (Class IIb, Level B) 3
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. (Class IIb, Level C) 3,5,25
1.2.2.2 Intravenous maintenance fluids should be sterile water or dextrose
5% solution with100 mEq of sodium bicarbonate per liter. (Class I ,
Level B) 1,20,23
1.2.2.3 If urine pH is less than 7 while on appropriate intravenous fluids, a
sodium bicarbonate IV 50mEq bolus is indicated as often as every 2
hours. (Class I, Level B) 1,20

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. (Class IIb, Level C) 3
1.2.3.2 Maintenance fluids of dextrose 5% or sodium chloride 0.45% should
be infused at a rate of 125 mL/m 2/hr until the methotrexate blood
concentration is below detection. (Class I, Level B) 1,20

1.3 Specific protocols should be followed to guide starting time, dose, and frequency of
leucovorin rescue following high-dose methotrexate administration (Class I, Level B) 1,20
1.3.1 Adult patients
1.3.1.1 Leucovorin should be started 24 hours following the initiation of
therapy. (Class 1, Level B) 1,2,4,12,20,26,27
1.3.1.2 An initial intravenous dose of 50 mg/m 2 may be considered to ensure
adequate and rapid absorption (Class IIb, Level C) 1,8,11
1.3.1.2.1 It is reasonable for subsequent doses of leucovorin to be 15 mg/m 2
intravenously until the methotrexate blood concentration LV�”�����—0�/�
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8
in patients without increased risk factors for methotrexate toxicity
(Class IIb, Level C) 1,20
1.3.1.2.2 It is reasonable for 15 mg leucovorin to be given orally every 6 hours
once the methotrexate blood concentration LV� ”� ���� —0�/� DQG�
continued until the methotrexate blood concentration is undetectable
�”� ����� —0�/� in patients without increased risk factors for
methotrexate toxicity. (Class IIb, Level C) 1,20
1.3.1.2.3 Adult patients can be considered for discharge when the methotrexate
blood concentration LV� ”� ���� —0�/ but is not yet undetectable. 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 FRQILUPHG�WR�EH�”������—0�/� (Class IIb, Level C) 1,20
1.3.1.2.3.1 A follow-up methotrexate blood concentrati on should be drawn
no later than 48 hours after discharge.
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 (Class 1,
Level B) 9,20

1.3.2 Pediatric patients
1.3.2.1 Individual protocols should be followed for dosing of leucovorin (Class
1, Level B) 4

1.4 Drug-drug interactions with methotrexate have potential to initiate or worsen toxicity
and should be avoided (Class I, Level B) 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. (Class I, Level B) 3-
6

1.4.2 Medications that re duce 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. (Class I, Level B) 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,
amiodarone, doxycycline, simvastatin) should be avoided. (Class I, Level B) 3-
6, 11,28

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 (Class I, Level A) 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 (Class IIa,
Level B) 3,6,11,29
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1.5.1 ,W� LV� UHDVRQDEOH� WR�HYDOXDWH�SDWLHQWV�ZLWK�ZHLJKW�JDLQ�•���NJ�IURP�DGPLVVLRQ�IRU�
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, urine output <
����P/�GD\��ZHLJKW�JDLQ�•���NJ�IURP�DGPLVVLRQ��GLDUUKHD��YRPLWLQJ��SUH-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 (Class I, Level A). 1,8,10-12,22

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. (Class I, Level C) 20
2.2.1 It is reasonable to monitor methotrexat e 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. (Class IIa, Level C) 1

2.4 To assess for alkalosis, it is reasonable to monitor urine pH and respiratory rate every
8 hours and serum bicarbonate daily. (Class IIa, Level C) 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 (Class I, Level B) 1,20
3.1.1 It may be reasonable to adjust leucovorin dose to 100 mg/m 2 IV every 6 hours
if serum creatinine incrHDVHV�•����IURP�EDVHOLQH�RU� WR��00 mg/m 2 IV every 3
KRXUV�LI�VHUXP�FUHDWLQLQH�LQFUHDVHV�•�����IURP�EDVHOLQH. (Class IIb, Level C) 9
3.1.2 If methotrexate blood concentration LV� •�� µmol/L at 24 hours, it may be
reasonable to increase leucovorin dose to 100 mg/m 2 IV every 3 hours. (Class
IIb, Level C) 4
3.1.3 The dosing algorithm in Table 1 should be used to guide leucovorin dose
adjustments. (Class I, Level B) 1,10,20








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Table 1: Leucovorin Dosing Algorithm 2, 4 ,1,3,4,8,10-12,24,27,30- 32
1. This table may only be utilized to consider dose adjustments in adult inpatients

24-hour Concentration Action
< 10 µM/L
< 20 µM/L for Hyper-CVAD*
No change; Draw next AM concentration
≥ 10 µM/L and/or SCr ≥ 125% baseline
≥ 20 µM/L for Hyper-CVAD*
Increase fluids to 175 mL/hr
Adjust leucovorin to 30mg/m2 IV Q6H
Draw 36 hour concentration
≥ 10 µM/L and/or SCr ≥ 150% baseline
≥ 20 µM/L for Hyper-CVAD*
Increase fluids to 200 mL/hr
Adjust leucovorin to 100mg/m2 IV Q6H
Draw 36 hour concentration
> 50 µM/L and/or SCr ≥ 200% baseline
≥ 20 µM/L for Hyper-CVAD*
Increase fluids to 200 mL/hr
Adjust leucovorin to 100mg/m2 IV Q3H
Draw 36 hour concentration
Consider glucarpidase use**
Conditional 36-hour Concentration Action
≥ 3 µM/L Increase fluids to 200mL/hr if not already there
Increase leucovorin to 30 mg/m2 IV Q6H
≥ 10 µM/L and/or SCr ≥ 125% baseline Increase fluids to 200mL/hr if not already there
Increase leucovorin to 100mg/m2 IV Q6H
42-48 hour “next AM” Concentration Action
≤ 0.5 µM/L
Transition to PO leucovorin
0.51 – 1 µM/L
No change; Draw next AM concentration
1.01-5 µM/L and/or SCr ≥ 125% baseline Increase fluids to 200mL/hr if not already there
Increase leucovorin to 30 mg/m2 IV Q6H
5.01 – 9.99 µM/L and/or SCr ≥ 150% baseline Increase fluids to 200mL/hr if not already there
Increase leucovorin to 30 mg/m2 IV Q3H
Consider glucarpidase use**
10-49.99 µM/L and/or SCr ≥ 200% baseline Increase fluids to 200mL/hr if not already there
Increase leucovorin to 100mg/m2 Q3H
Consider glucarpidase use**
≥ 50 µM/L Increase fluids to 200mL/hr if not already there
Increase leucovorin to 1000 mg/m2 Q6H
Consider glucarpidase use**
*For HyperCVAD, increase the fluids immediately per the algorithm if 24 hour concentration 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.

3.2 Treatment with glucarpidase
3.2.1 To be eligible for glucarpidase treatment patients should meet BOTH the
methotrexate concentration outlined in Table 2 AND have evidence of impaired
renal function (CrCl < 60 mL/min 25�6&U� •� ����� EDVHOLQH ). (Class I, Level
A) 15,17,21,33
3.2.1.1 Glucarpidase should not be given if the methotrexate blood
FRQFHQWUDWLRQ�LV�”��� µM /L. (Class I, Level A) 15,17,21,33
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11
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 .
(Class IIa, Level A) 7,9

Table 2: Methotrexate concentration eligibility criteria for glucarpidase administration. 7 , 9




Note: Methotrexate concentrations [MTX] are measured from the START of the infusion

3.2.2 Leucovorin rescue dosing should be monitored closely with glucarpidase
administration (Class 1, Level A) 17,21
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. (Class I, Level
A) 7,9,15,17,33
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. (Class I, Level A) 15,17,21
3.2.2.3 Starting 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 (Class I, Level A) 15,17,21
3.2.2.4 Beyond 48 hours after administration of glucarpidase, leucovorin
doses should be adjusted based on methotrexate concentrations per
Table 1. (Class 1, Level A) 15,17,21
3.2.2.5 It is reasonable to continue leucovorin for a minimum of 3 days after
methotrexate blood concentration is first undetectable. (Class IIa,
Level C) 17,21

3.2.3 Glucarpidase dosing
3.2.3.1 A dose of 50 units/kg IV is recommended (Class 1, Level A) 15,17,21
3.2.3.1.1 It may be reasonable to round glucarpidase doses to the
nearest 1000 unit vial size . (Class IIb, Level C) 7
3.2.3.2 Glucarpidase should be administered intravenously as a bolus
injection over 5 minutes (Class I, Level A) 7
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. (Class III, Level A) 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 FDQ�RQO\�EH�REWDLQHG�•���
hours after glucarpidase administration. (Class 1, Level A) 7, 9
[MTX] (µM /L ) at 24
hours
[MTX] (µM /L ) at
42hours
[MTX] (µM /L ) at 48
hours
>50 >5 >3
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12
3.2.4.2 Urine output should be monitored at least every 8 hours until stable,
then every 24 hours. (Class I, level A)
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.
(Class 1, Level A) 17,21

3.2.5 Dialysis-based methods have not been shown to reduce methotrexate toxicity
and are not recommended (Class III, Level B) 1,11,29

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13
UW Health Implementation
Benefits/Harms of Implementation
This guideline is intended to provide a resource for making decisions regarding the prevention,
monitoring, and treatment of methotrexate toxicity in adult and pediatric patients receiving high-
dose methotrexate therapy. Use of the guideline is expected to improve the safety and
efficiency of the high-dose methotrexate treatment process.

Qualifying Statements:
1. This guideline must be used in conjunction with clinical evaluation, and adjustments must be
made to account for the individual patient. Factors to consider include age, body weight, drug
interactions, renal insufficiency, hepatic insufficiency, and other concurrent disease states.

Potential Benefits:
1. Delineate appropriate supportive care and monitoring for patients receiving high-dose
methotrexate
2. Standardize starting and escalation dosing of leucovorin rescue following administration of
high-dose methotrexate
3. Define criteria and dosing of glucarpidase in patients experiencing high-dose methotrexate
toxicity

Potential Harms:
1. Patients must be monitored for laboratory and clinical signs and symptoms of metabolic
alkalosis. Iatrogenic metabolic alkalosis can be seen by monitoring CO 2 (serum CO 2 > 34),
anion gap and pH on serum chemistry. Clinically, metabolic alkalosis results in changes in
mental status, muscle spasms, and decreased respiratory drive that can be life threatening
(respiratory rate >30 is a sign that the patient may not be able to compensate for increased
CO 2).
2. Serious allergic reactions, including anaphylaxis, are possible with glucarpidase
administration
3. Development of anti-glucarpidase antibodies is possible following administration of a single
dose of glucarpidase

Implementation Strategy
1. This guideline will be housed on U-Connect in a dedicated folder for clinical practice
guidelines.
2. Pharmacists will be educated about the guideline at staff and team meetings.
3. Nurses and physicians will be educated about the guideline and through in-service education
sessions.

Implementation Tools/Plan
1. Health link will be used to implement the clinical practice guideline. Beacon treatment plans
containing high-dose methotrexate will be updated and maintained to reflect
recommendations in this guideline.
2. A standardized pharmacokinetic monitoring note will be utilized by clinical pharmacists to
ensure recommendations are followed.
3. The dose button for glucarpidase will be locked at 50 units/kg.
4. Evaluation of guideline: A retrospective medication-use evaluation of high-dose
methotrexate and each dose of glucarpidase will be completed to assess utility of the
guideline. A prospective evaluation will occur for one year from guideline approval to assess
the safety and efficacy of leucovorin dose-adjustments.
Copyright © 201� University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 09/2016CCKM@uwhealth.org



14
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and
treatment of patients. This Clinical Practice Guideline outlines the preferred evidence-based
approach for PRVW�SDWLHQWV���,W�LV�QRW�LQWHQGHG�WR�UHSODFH�D�FOLQLFLDQ¶V�MXGJPHQW�RU�WR�HVWDEOLVK�D�
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.

References
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Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 09/2016CCKM@uwhealth.org



15
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Copyright © 201� University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 09/2016CCKM@uwhealth.org