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Current Drug Metabolism

Editor-in-Chief

ISSN (Print): 1389-2002
ISSN (Online): 1875-5453

Review Article

Methotrexate overdose in clinical practice

Author(s): Ashok Kumar Pannu*

Volume 20, Issue 9, 2019

Page: [714 - 719] Pages: 6

DOI: 10.2174/1389200220666190806140844

Price: $65

Abstract

Background: A folic-acid antagonist, methotrexate, is one of the most commonly prescribed drugs with its expanding use in clinical practice. The drug requires regular monitoring given its wide range of adverse effects including bone marrow suppression, hepatic or renal dysfunction, gastrointestinal distress, mucocutaneous damage, and neurotoxicity. The toxicity usually occurs rapidly and leads to severe neutropenia, sepsis, and advanced renal failure that are difficult to manage.

Methods: This review is an update for the clinicians to understand the pharmacology, clinical features, laboratory evaluation, and treatment of patients with methotrexate overdose. High-quality literature of the past six decades was collected and reviewed in this article. Several landmark articles were reviewed using PubMed, EMBASE Ovid, and the Cochrane Library, that have important implications in current clinical practice.

Results: Methotrexate overdose has complex toxicokinetic and produces myriad clinical features mimicking conditions of lesser severity. Organ dysfunction related to bone marrow, kidney or central nervous system is lifethreatening. The management should focus on high-quality supportive care, antidotal therapy (folinic acid and carboxypeptidase- G2) and plasma alkalization.

Conclusion: In accordance with the dictum “prevention is better than cure”, the author emphasizes on the role of patient education, regular clinical observation, and laboratory monitoring for prompt recognition and diagnosis of methotrexate overdosing at the earliest stage.

Keywords: Methotrexate, poisoning, toxicity, overdose, folinic acid, leucovorin, glucarpidase, carboxypeptidase-G2.

Graphical Abstract
[1]
Wood, P.R.; Caplan, L. Drug-induced gastrointestinal and hepatic disease associated with biologics and nonbiologic disease-modifying antirheumatic drugs. Rheum. Dis. Clin. North Am., 2018, 44(1), 29-43.
[http://dx.doi.org/10.1016/j.rdc.2017.09.003] [PMID: 29149926]
[2]
Chan, E.S.; Cronstein, B.N. Methotrexate-how does it really work? Nat. Rev. Rheumatol., 2010, 6(3), 175-178.
[http://dx.doi.org/10.1038/nrrheum.2010.5] [PMID: 20197777]
[3]
Nelson, L.S.; Howland, M.A.; Lewin, N.A.; Smith, S.W.; Goldfrank, L.R.; Hoffman, R.S. Goldfrank’s Toxicological Emergencies, 11th ed; McGraw Hill Education: New York, 2019.
[4]
Wellstein, A.; Giaccone, G.; Michael, B. Atkins, M.B.; Sausville, E.A. Cytotoxic Drugs. Goodman & Gilman’s The Pharmacological Basis of Therapeutics; Brunton, L.L.; Hilal-Dandan, R; Knollmann, B.C., Ed.; McGraw-Hill Education: New York, 2018, pp. 1177-1180.
[5]
Gugelmann, H. Methotrexate. Poisoning & Drug Overdose; Olson, K.R.; Anderson, I.B.; Benowitz, N.L.; Blanc, P.D.; Clark, R.F.; Kearney, T.E.; Kim-Katz, S.Y; Wu, A.H.B., Ed.; McGraw-Hill Education: New York, 2018, pp. 319-321.
[6]
Chu, E. Cancer Chemotherapy.Basic & Clinical Pharmacology; Katzung, B.G., Ed.; McGraw-Hill Education: New York, 2018, p. 957.
[7]
Ceacareanu, A.C.; Wintrob, Z.A.P. Pharmacokinetic Consideration in Oncology.Casebook in Clinical Pharmacokinetics and Drug Dosing; Cohen, H., Ed.; McGraw-Hill Education: New York, 2015, pp. 264-267.
[8]
Municio, C.; Soler Palacios, B.; Estrada-Capetillo, L.; Benguria, A.; Dopazo, A.; García-Lorenzo, E.; Fernández-Arroyo, S.; Joven, J.; Miranda-Carús, M.E.; González-Álvaro, I.; Puig-Kröger, A. Methotrexate selectively targets human proinflammatory macrophages through a thymidylate synthase/p53 axis. Ann. Rheum. Dis., 2016, 75(12), 2157-2165.
[http://dx.doi.org/10.1136/annrheumdis-2015-208736] [PMID: 26920997]
[9]
Joerger, M.; Huitema, A.D.; van den Bongard, H.J.; Baas, P.; Schornagel, J.H.; Schellens, J.H.; Beijnen, J.H. Determinants of the elimination of methotrexate and 7-hydroxy-methotrexate following high-dose infusional therapy to cancer patients. Br. J. Clin. Pharmacol., 2006, 62(1), 71-80.
[http://dx.doi.org/10.1111/j.1365-2125.2005.02513.x] [PMID: 16842380]
[10]
Saland, J.M.; Leavey, P.J.; Bash, R.O.; Hansch, E.; Arbus, G.S.; Quigley, R. Effective removal of methotrexate by high-flux hemodialysis. Pediatr. Nephrol., 2002, 17(10), 825-829.
[http://dx.doi.org/10.1007/s00467-002-0946-7] [PMID: 12376811]
[11]
Kolesar, J.; Vermeulen, L. Top 300 Pharmacy Drug Cards-2016/2017; McGraw-Hill Education: New York, 2016, p. 180.
[12]
Morgan, S.L.; Baggott, J.E.; Vaughn, W.H.; Austin, J.S.; Veitch, T.A.; Lee, J.Y.; Koopman, W.J.; Krumdieck, C.L.; Alarcón, G.S. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebo-controlled trial. Ann. Intern. Med., 1994, 121(11), 833-841.
[http://dx.doi.org/10.7326/0003-4819-121-11-199412010-00002] [PMID: 7978695]
[13]
Dhir, V.; Sandhu, A.; Kaur, J.; Pinto, B.; Kumar, P.; Kaur, P.; Gupta, N.; Sood, A.; Sharma, A.; Sharma, S. Comparison of two different folic acid doses with methotrexate-a randomized controlled trial (FOLVARI Study). Arthritis Res. Ther., 2015, 17, 156.
[http://dx.doi.org/10.1186/s13075-015-0668-4] [PMID: 26063325]
[14]
Young, J.S.; Simmons, J.W. Chemotherapeutic medications and their emergent complications. Hematol. Oncol. Clin. North Am., 2017, 31(6), 995-1010.
[http://dx.doi.org/10.1016/j.hoc.2017.08.005] [PMID: 29078934]
[15]
Livshits, Z.; Rao, R.B.; Smith, S.W. An approach to chemotherapy-associated toxicity. Emerg. Med. Clin. North Am., 2014, 32(1), 167-203.
[http://dx.doi.org/10.1016/j.emc.2013.09.002] [PMID: 24275174]
[16]
Adelberg, D.E.; Bishop, M.R. Emergencies related to cancer chemotherapy and hematopoietic stem cell transplantation. Emerg. Med. Clin. North Am., 2009, 27(2), 311-331.
[http://dx.doi.org/10.1016/j.emc.2009.01.005] [PMID: 19447314]
[17]
Klastersky, J.; de Naurois, J.; Rolston, K.; Rapoport, B.; Maschmeyer, G.; Aapro, M.; Herrstedt, J. Management of febrile neutropaenia. Ann. Oncol., 2016, 27(Suppl. 5), v111-v118.
[http://dx.doi.org/10.1093/annonc/mdw325] [PMID: 27664247]
[18]
Thatishetty, A.V.; Agresti, N.; O’Brien, C.B. Chemotherapy-induced hepatotoxicity. Clin. Liver Dis., 2013, 17(4), 671-686.
[http://dx.doi.org/10.1016/j.cld.2013.07.010] [PMID: 24099024]
[19]
Lopez, A.M.; Hendrickson, R.G. Toxin-induced hepatic injury. Emerg. Med. Clin. North Am., 2014, 32(1), 103-125.
[http://dx.doi.org/10.1016/j.emc.2013.09.005] [PMID: 24275171]
[20]
Dye, L.R.; Murphy, C.; Calello, D.P.; Levine, M.; Skolnik, A. Case Studies in Medical Toxicology, 1st ed; Springer International Publishing AG: Cham, Switzerland, 2017, pp. 173-179.
[http://dx.doi.org/10.1007/978-3-319-56449-4]
[21]
Woodell, T.; Avasare, R.S. Nephrotoxicity of select rheumatologic drugs. Rheum. Dis. Clin. North Am., 2018, 44(4), 605-617.
[http://dx.doi.org/10.1016/j.rdc.2018.06.005] [PMID: 30274626]
[22]
Sandoval, C.; Kutscher, M.; Jayabose, S.; Tenner, M. Neurotoxicity of intrathecal methotrexate: MR imaging findings. AJNR Am. J. Neuroradiol., 2003, 24(9), 1887-1890.
[PMID: 14561622]
[23]
Conway, R.; Low, C.; Coughlan, R.J.; O’Donnell, M.J.; Carey, J.J. Methotrexate and lung disease in rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheumatol., 2014, 66(4), 803-812.
[http://dx.doi.org/10.1002/art.38322] [PMID: 24757133]
[24]
Conway, R.; Low, C.; Coughlan, R.J.; O’Donnell, M.J.; Carey, J.J. Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: Systematic literature review and meta-analysis of randomised controlled trials. BMJ, 2015, 350, h1269.
[http://dx.doi.org/10.1136/bmj.h1269] [PMID: 25770113]
[25]
Stoller, R.G.; Hande, K.R.; Jacobs, S.A.; Rosenberg, S.A.; Chabner, B.A. Use of plasma pharmacokinetics to predict and prevent methotrexate toxicity. N. Engl. J. Med., 1977, 297(12), 630-634.
[http://dx.doi.org/10.1056/NEJM197709222971203] [PMID: 302412]
[26]
O’Marcaigh, A.S.; Johnson, C.M.; Smithson, W.A.; Patterson, M.C.; Widemann, B.C.; Adamson, P.C.; McManus, M.J. Successful treatment of intrathecal methotrexate overdose by using ventriculolumbar perfusion and intrathecal instillation of carboxypeptidase G2. Mayo Clin. Proc., 1996, 71(2), 161-165.
[http://dx.doi.org/10.4065/71.2.161] [PMID: 8577190]
[27]
Chan, B.S.; Dawson, A.H.; Buckley, N.A. What can clinicians learn from therapeutic studies about the treatment of acute oral methotrexate poisoning? Clin. Toxicol. (Phila.), 2017, 55(2), 88-96.
[http://dx.doi.org/10.1080/15563650.2016.1271126] [PMID: 28084171]
[28]
Gadgil, S.D.; Damle, S.R.; Advani, S.H.; Vaidya, A.B. Effect of activated charcoal on the pharmacokinetics of high-dose methotrexate. Cancer Treat. Rep., 1982, 66(5), 1169-1171.
[PMID: 7083219]
[29]
Smith, S.W.; Nelson, L.S. Case files of the New York City Poison Control Center: Antidotal strategies for the management of methotrexate toxicity. J. Med. Toxicol., 2008, 4(2), 132-140.
[http://dx.doi.org/10.1007/BF03160968] [PMID: 18570175]
[30]
Flombaum, C.D.; Meyers, P.A. High-dose leucovorin as sole therapy for methotrexate toxicity. J. Clin. Oncol., 1999, 17(5), 1589-1594.
[http://dx.doi.org/10.1200/JCO.1999.17.5.1589] [PMID: 10334548]
[31]
Gahart, B.L.; Nazareno, A.R.; Ortega, M.G. Gahart’s 2019 Intravenous medications; Elsevier: St. Louis, 2019, pp. 806-807.
[32]
Jardine, L.F.; Ingram, L.C.; Bleyer, W.A. Intrathecal leucovorin after intrathecal methotrexate overdose. J. Pediatr. Hematol. Oncol., 1996, 18(3), 302-304.
[http://dx.doi.org/10.1097/00043426-199608000-00014] [PMID: 8689347]
[33]
Florit-Sureda, M.; Conde-Estévez, D.; Vidal, J.; Montagut, C. Hypersensitivity reaction caused by folinic acid administration: A case report and literature review. J. Chemother., 2016, 28(6), 500-505.
[http://dx.doi.org/10.1179/1973947815Y.0000000048] [PMID: 26042586]
[34]
Howard, S.C.; McCormick, J.; Pui, C.H.; Buddington, R.K.; Harvey, R.D. Preventing and managing toxicities of high-dose methotrexate. Oncologist, 2016, 21(12), 1471-1482.
[http://dx.doi.org/10.1634/theoncologist.2015-0164] [PMID: 27496039]
[35]
Gibson, T.P.; Reich, S.D.; Krumlovsky, F.A.; Ivanovich, P.; Gonczy, C. Hemoperfusion for methotrexate removal. Clin. Pharmacol. Ther., 1978, 23(3), 351-355.
[http://dx.doi.org/10.1002/cpt1978233351] [PMID: 627142]
[36]
Diskin, C.J.; Stokes, T.J.; Dansby, L.M.; Radcliff, L.; Carter, T.B. Removal of methotrexate by peritoneal dialysis and hemodialysis in a single patient with end-stage renal disease. Am. J. Med. Sci., 2006, 332(3), 156-158.
[http://dx.doi.org/10.1097/00000441-200609000-00013] [PMID: 16969149]
[37]
Bénézet, S.; Chatelut, E.; Bagheri, H.; Rigal-Huguet, F.; Nguyen, L.; Pourrat, J.; Robert, A.; Montastruc, J.L.; Canal, P. Inefficacy of exchange-transfusion in case of a methotrexate poisoning. Bull. Cancer, 1997, 84(8), 788-790.
[PMID: 9339182]
[38]
Addiego, J.E., Jr; Ridgway, D.; Bleyer, W.A. The acute management of intrathecal methotrexate overdose: Pharmacologic rationale and guidelines. J. Pediatr., 1981, 98(5), 825-828.
[http://dx.doi.org/10.1016/S0022-3476(81)80859-1] [PMID: 6971923]
[39]
Finkelstein, Y.; Zevin, S.; Heyd, J.; Bentur, Y.; Zigelman, Y.; Hersch, M. Emergency treatment of life-threatening intrathecal methotrexate overdose. Neurotoxicology, 2004, 25(3), 407-410.
[http://dx.doi.org/10.1016/j.neuro.2003.10.004] [PMID: 15019303]
[40]
Chen, H.Y.; Albertson, T.E.; Olson, K.R. Treatment of drug-induced seizures. Br. J. Clin. Pharmacol., 2016, 81(3), 412-419.
[http://dx.doi.org/10.1111/bcp.12720] [PMID: 26174744]

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