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Urine Alkalinization and Methotrexate Clearance: Are These Key to Safe Administration of High-Dose Methotrexate?

JHOP - October 2021 Vol 11, No 5 - Editorial, Chemotherapy, Oncology Pharmacy Protocols
Joseph Bubalo, PharmD, BCPS, BCOP
Assistant Professor of Medicine, Division of Hematology and Medical Oncology, and Oncology Clinical Pharmacy Specialist, Oregon Health and Science Hospital, OHSU Hospital and Clinics, Portland, OR
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With intermittent shortages of intravenous (IV) sodium bicarbonate and sodium acetate, we have witnessed increased interest in the use of sodium bicarbonate tablets, sometimes concurrent with acetazolamide, to achieve urine alkalinization to facilitate the delivery of high-dose methotrexate, which is an integral part of therapies for lymphoma and osteosarcoma.

In this issue of the Journal, Sinoimeri and colleagues compared the safety and efficacy of an alternative non-IV sodium bicarbonate–based urine alkalinization protocol versus the current standard-of-care protocol for their center in patients with cancer who received high-dose methotrexate during a period of sodium bicarbonate shortage.1 Their study showed no difference in adverse events between patients who received the standard alkalinization protocol and those who received the alternative protocol.1

Additional recent peer-reviewed articles have further made it clear that oral alkalinization regimens can be provided to patients safely and effectively.2-6 However, the question arises whether patients who are receiving alkalinization regimens are ready to receive high-dose methotrexate.

Recently, a patient arrived at our institution to receive a course of high-dose methotrexate. The patient had taken an oral sodium bicarbonate and his first urine test result showed a pH of 7.5. The staffing physician ordered the patient’s methotrexate chemotherapy to proceed, although his baseline laboratory values showed a slightly elevated serum creatinine level and blood urea nitrogen compared with that seen in previous chemotherapy cycles. As the pharmacist in this case—should you hold up this high dose of methotrexate, or is an alkaline pH level adequate to ensure the patient’s safety while receiving methotrexate?

Of note, among several retrospective reviews of protocols for the use of oral sodium bicarbonate, the primary end point is the time to methotrexate clearance, and the overall safety of each protocol is implied by the results.1,3,4,6 In these articles, the authors highlight other aspects of pharmaceutical care that are essential for the safe delivery of high-dose methotrexate. These practices include:

  1. Adequate hydration and an associated urine output.
  2. Careful monitoring for drug interactions, including pharmacokinetic interactions that would diminish methotrexate clearance, and medications that may increase the risk for renal adverse events, either each drug alone or in combination with methotrexate.
  3. A cycle-by-cycle evaluation to assess if the time to methotrexate clearance is changing because of cumulative renal effects from methotrexate itself or from a concomitant agent, such as cisplatin.

These clinical messages are important when evaluating a patient for the use of high-dose methotrexate. As in the patient case mentioned earlier, there is a tendency by multiple types of clinicians to equate alkaline urine with readiness to receive methotrexate. This assumption understates the significant component of the patient’s renal readiness to receive therapy, which is provided by the aggressive hydration that is often used for safe delivery of methotrexate.

Administering high-dose methotrexate to a dehydrated or marginally hydrated patient, despite the presence of alkaline urine, is potentially harmful. Thus, minimum standards of hydration and urine output should be set and achieved at each institution before the initiation of a high-dose methotrexate infusion.

Pediatric protocols frequently highlight the need for hyperhydration, and in general begin with hydration of 125 mL/m2 to 200 mL/m2 per hour, with accompanying urine output goals that ensure a brisk diuresis and a well-hydrated patient.7 An assessment of adequate hydration can be determined by urine output or by urine-specific gravity, to ensure that the patient can receive methotrexate safely, and that hydration can occur rapidly in some sites of care to decrease the treatment time and thus the patient’s length of hospital stay.8

Hydration is much easier to achieve in pediatric patients than in adults, because adults may require more balancing of overall volume status to manage the fluids that are needed to support normal methotrexate clearance safely. With different reports of fluid rates and volumes infused in the literature, no standard is available for the infusion of fluids in adults.6,9-11 Some reports simply state that fluids were infused based on the institutional standard of care, whereas others omit infusion rates completely, because they focus on reaching the patient’s urine pH goals.12,13

In addition, a recent investigation of the role of sodium in the hydration fluids on clearance of methotrexate showed that exposure to a higher sodium dose may increase the clearance of methotrexate.7 This may benefit a patient whose ability to clear methotrexate is marginal, but it can potentially decrease the patient’s clinical benefit if diminished methotrexate plasma levels are achieved. This issue is relevant to 24-hour infusions that target a specific steady-state methotrexate concentration.7

Although the answer to the effects of different fluids on methotrexate clearance remains unclear, we should be cautious as we adjust our hydration process during drug shortages, or as institution protocols change. We need to apply the best evidence available to each decision.

Given that the role of urinary alkalinization is to increase the solubility of methotrexate in urine and to reduce the risk for the crystallization of methotrexate in urine as the urine supersaturates, the goal of this editorial is not to diminish the important work of the professionals who develop these protocols, such as reported in the study by Sinoimeri and colleagues. Rather, the goal is to highlight the need for concomitant best practices that make high-dose methotrexate safe for patients. It is also an invitation for oncology hematology pharmacists to review the literature carefully before applying the information to patient care.


  1. Sinoimeri C, Lei M, Monaco S, Lou U. Efficacy of an enteral urine alkalinization strategy during intravenous sodium bicarbonate shortage in patients with cancer receiving high-dose methotrexate. J Hematol Oncol Pharm. 2021;11(5):248-255.
  2. Clemmons AB, Chase A, Duong P, et al. Assessing the impact of adding acetazolamide to oral or intravenous sodium bicarbonate as compared with intravenous bicarbonate monotherapy as urinary alkalinization in adults receiving high-dose methotrexate. Support Care Cancer. 2021;29:1527-1534.
  3. Heisler RD, Kelly JJ, Abedinzadegan Abdi S, et al. Evaluation of an oral sodium bicarbonate protocol for high-dose methotrexate urine alkalinization. Support Care Cancer. 2021 Sep 1. Epub ahead of print.
  4. Kramer E, Filtz M, Pace M. Evaluation of methotrexate clearance with an enteral urine alkalinization protocol for patients receiving high-dose methotrexate. J Oncol Pharm Pract. 2021;27:26-32.
  5. 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.
  6. Roy AM, Lei M, Lou U. Safety and efficacy of a urine alkalinization protocol developed for high-dose methotrexate patients during intravenous bicarbonate shortage. J Oncol Pharm Pract. 2019;25:1860-1866.
  7. Mangum R, Bernhardt MB, Cheng WS, et al. Do intravenous fluid substitutions influence methotrexate clearance? An unanticipated impact of an intravenous sodium bicarbonate drug shortage. Pediatr Blood Cancer. 2020;67:e28334. doi: 10.1002/pbc.28334.
  8. Meredith S, Hilliard J, Vaillancourt R. Evaluation of a rapid hydration protocol: safety and effectiveness. J Oncol Pharm Pract. 2017;23:249-254.
  9. Cohen IJ. Acute renal injury after high-dose methotrexate is independent of folinic acid dose. Support Care Cancer. 2021;29:5557-5558.
  10. Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19:453-456.
  11. Stoller RG, Hande KR, Jacobs SA, et al. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N Engl J Med. 1977;297:630-634.
  12. Cerminara Z, Duffy A, Nishioka J, et al. A single center retrospective analysis of a protocol for high-dose methotrexate and leucovorin rescue administration. J Oncol Pharm Pract. 2019;25:76-84.
  13. 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. 2017;23:3-9.
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