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 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 2 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) 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 3 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. 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 4 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 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 5 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, 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 6 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 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 7 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 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 8 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. 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 9 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 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 10 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 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 11 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 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 12 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.) 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 13 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. Contact: CCKM@uwhealth.org Last Revised: 03/2022 14 References 1. Widemann BC, Adamson PC. Understanding and managing methotrexate nephrotoxicity. Oncologist. Jun 2006;11(6):694-703. doi:10.1634/theoncologist.11-6-694 2. Wiczer T, Dotson E, Tuten A, Phillips G, Maddocks K. Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity. J Oncol Pharm Pract. Jul 6 2015;doi:10.1177/1078155215594417 3. 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 4. Frei E, 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. doi:10.1016/0002- 9343(80)90105-9 5. Mir O, Ropert S, Babinet A, et al. Hyper-alkalinization without hyper-hydration for the prevention of high-dose methotrexate acute nephrotoxicity in patients with osteosarcoma. Cancer Chemother Pharmacol. Nov 2010;66(6):1059-63. doi:10.1007/s00280-010-1259-3 6. Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19(6):453-6. 7. Shamash J, Earl H, Souhami R. Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol. 1991;28(2):150-1. 8. Ackland SP, Schilsky RL. High-dose methotrexate: a critical reappraisal. J Clin Oncol. Dec 1987;5(12):2017-31. 9. Treon SP, Chabner BA. Concepts in use of high-dose methotrexate therapy. Clin Chem. Aug 1996;42(8 Pt 2):1322-9. 10. Bleyer WA. Methotrexate: clinical pharmacology, current status and therapeutic guidelines. Cancer Treat Rev. Jun 1977;4(2):87-101. 11. Yasar Albushra Abdul Rahiem Ahmed YH. Prevention and Management of High Dose Methotrexate Toxicity. J Cancer Sci Ther. 2013;5(3):106-112. 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. May J, Carson KR, Butler S, Liu W, Bartlett NL, Wagner-Johnston ND. High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma. Jun 2014;55(6):1345-9. doi:10.3109/10428194.2013.840780 14. Buchen S, Ngampolo D, Melton RG, et al. Carboxypeptidase G2 rescue in patients with methotrexate intoxication and renal failure. Br J Cancer. Feb 14 2005;92(3):480-7. doi:6602337 [pii] 10.1038/sj.bjc.6602337 15. Fermiano M, Bergsbaken J, Kolesar JM. Glucarpidase for the management of elevated methotrexate levels in patients with impaired renal function. Am J Health Syst Pharm. May 15 2014;71(10):793-8. doi:10.2146/ajhp130483 16. Trifilio S, Ma S, Petrich A. Reduced-dose carboxypeptidase-G2 successfully lowers elevated methotrexate levels in an adult with acute methotrexate-induced renal failure. Clin Adv Hematol Oncol. May 2013;11(5):322-3. 17. Widemann BC, Schwartz S, Jayaprakash N, et al. Efficacy of glucarpidase (carboxypeptidase g2) in patients with acute kidney injury after high-dose methotrexate therapy. Pharmacotherapy. May 2014;34(5):427-39. doi:10.1002/phar.1360 18. Tuffaha HW, Al Omar S. Glucarpidase rescue in a patient with high-dose methotrexate-induced nephrotoxicity. J Oncol Pharm Pract. Jun 2011;17(2):136-40. doi:10.1177/1078155209348720 19. Methotrexate. [Package Insert]. Lake Forest, IL: Hospira, Inc.; 2013. 20. Voraxaze. [Package Insert]. West Conshohocken, PA: BTG International Inc.; 2012. 21. Karremann M, Sauerbier J, Meier C, et al. The impact of prehydration on the clearance and toxicity of high-dose methotrexate for pediatric patients. Leuk Lymphoma. Dec 2014;55(12):2874- 8. doi:10.3109/10428194.2014.898143 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 22. Ramsey LB, Balis FM, O'Brien MM, et al. Consensus Guideline for Use of Glucarpidase in Patients with High-Dose Methotrexate Induced Acute Kidney Injury and Delayed Methotrexate Clearance. Oncologist. 01 2018;23(1):52-61. doi:10.1634/theoncologist.2017-0243 23. Batchelor T, Loeffler JS. Primary CNS lymphoma. J Clin Oncol. Mar 10 2006;24(8):1281-8. doi:10.1200/jco.2005.04.8819 24. Reed DR, Pierce EJ, Sen JM, Keng MK. A prospective study on urine alkalization with an oral regimen consisting of sodium bicarbonate and acetazolamide in patients receiving high-dose methotrexate. Cancer Manag Res. 2019;11:8065-8072. doi:10.2147/CMAR.S190084 25. Rouch JA, Burton B, Dabb A, et al. Comparison of enteral and parenteral methods of urine alkalinization in patients receiving high-dose methotrexate. J Oncol Pharm Pract. Jan 2017;23(1):3-9. doi:10.1177/1078155215610914 26. Zelcer S, Kellick M, Wexler LH, Gorlick R, Meyers PA. The Memorial Sloan Kettering Cancer Center experience with outpatient administration of high dose methotrexate with leucovorin rescue. Pediatr Blood Cancer. Jun 2008;50(6):1176-80. doi:10.1002/pbc.21419 27. 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 28. Pitman SW, Frei E, 3rd. Weekly methotrexate-calcium leucovorin rescue: effect of alkalinization on nephrotoxicity; pharmacokinetics in the CNS; and use in CNS non-Hodgkin's lymphoma. Cancer Treat Rep. Jul 1977;61(4):695-701. 29. Flombaum CD, Meyers PA. High-dose leucovorin as sole therapy for methotrexate toxicity. J Clin Oncol. May 1999;17(5):1589-94. 30. Korstanje MJ, van Breda Vriesman CJ, van de Staak WJ. Cyclosporine and methotrexate: a dangerous combination. J Am Acad Dermatol. Aug 1990;23(2 Pt 1):320-1. 31. Kawabata K, Makino H, Nagake Y, et al. A case of methotrexate-induced acute renal failure successfully treated with plasma perfusion and sequential hemodialysis. Nephron. 1995;71(2):233-4. 32. Orgel E, Nabais T, Douglas C, Mittelman SD, Neely M. Effect of Body Fat on Population Pharmacokinetics of High-Dose Methotrexate in Pediatric Patients With Acute Lymphoblastic Leukemia. J Clin Pharmacol. Dec 2020;doi:10.1002/jcph.1799 33. Methotrexate [prescribing information]. Hospira, Inc.; Lake Forest, IL. 2013. 34. 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. 35. 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 36. 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 37. 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 38. Schwartz S, Borner K, Muller K, et al. Glucarpidase (carboxypeptidase g2) intervention in adult and elderly cancer patients with renal dysfunction and delayed methotrexate elimination after high-dose methotrexate therapy. Oncologist. Nov 2007;12(11):1299-308. doi:10.1634/theoncologist.12-11-1299 39. Young A, Beriault D, Jung B, et al. DAMPAned Methotrexate: A Case Report and Review of the Management of Acute Methotrexate Toxicity. Can J Kidney Health Dis. 2019;6:2054358119895078. doi:10.1177/2054358119895078 40. Boelens AD, Mathôt RAA, Vlaar APJ, Bouman CSC. Glucarpidase treatment for methotrexate intoxication: a case report and review of the literature. Neth J Med. 01 2018;76(1):36-39. 41. Awad D, Nguyen M, Espinosa G, Tahir M. Flat-Dose Glucarpidase Rescue Following Accumulation of High-Dose Methotrexate in a Patient with Diffuse B-Cell Lymphoma Amy Spigelmyer, PharmD; David Awad, PharmD; Melissa Nguyen, PharmD; Gloria Espinosa, PharmD; Maria Tahir. presented at: ASHP Midyear 2019; 2019; Las Vegas, Nevada. Session Resident Posters. 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 16 42. Gulley S, Franco K, Elder J. Monitoring methotrexate levels in a patient after glucarpidase administration: a case report. Journal of Hematology Oncology Pharmacy; 2020. p. 154-7. 43. Scott JR, Zhou Y, Cheng C, et al. Comparable efficacy with varying dosages of glucarpidase in pediatric oncology patients. Pediatr Blood Cancer. Sep 2015;62(9):1518-22. doi:10.1002/pbc.25395 44. Truong H, Leung N. Fixed-Dose Glucarpidase for Toxic Methotrexate Levels and Acute Kidney Injury in Adult Lymphoma Patients: Case Series. Clin Lymphoma Myeloma Leuk. Jan 2021;doi:10.1016/j.clml.2021.01.006 45. Widemann BC. Practical considerations for the administration of glucarpidase in high-dose methotrexate (HDMTX) induced renal dysfunction. Pediatr Blood Cancer. Sep 2015;62(9):1512-3. doi:10.1002/pbc.25577 46. Widemann BC. Using a lower dose of glucarpidase to reduce plasma levels of methotrexate. Clin Adv Hematol Oncol. May 2013;11(5):324-5. 47. Guyatt G, Oxman AD, Akl EA, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. Apr 2011;64(4):383-94. doi:10.1016/j.jclinepi.2010.04.026 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