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 Table of Contents  
Year : 2017  |  Volume : 12  |  Issue : 2  |  Page : 114-115

Splitting dose of methotrexate in the management of rheumatoid arthritis: Making a mountain out of a molehill?

1 Department of Rheumatology, National Hospital, Kozhikode, Kerala, India
2 Department of Rheumatology, National Hospital; Centre for Rheumatology, Kozhikode, Kerala, India

Date of Web Publication26-May-2017

Correspondence Address:
Vinod Ravindran
Centre for Rheumatology, Kozhikode - 673 009, Kerala
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_42_17

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How to cite this article:
Mohamedali NK, Ravindran V. Splitting dose of methotrexate in the management of rheumatoid arthritis: Making a mountain out of a molehill?. Indian J Rheumatol 2017;12:114-5

How to cite this URL:
Mohamedali NK, Ravindran V. Splitting dose of methotrexate in the management of rheumatoid arthritis: Making a mountain out of a molehill?. Indian J Rheumatol [serial online] 2017 [cited 2023 Feb 5];12:114-5. Available from:

Dear Editor,

Methotrexate (MTX) is universally regarded as the key to the cost-effective management of rheumatoid arthritis (RA) and is usually given orally once weekly.[1] The doses used are considered low, the range usually being between 7.5 mg and 25 mg once weekly.[2] At higher doses, however, many patients experience troublesome nausea and vomiting, resulting in poor treatment adherence.[3] To avoid this, sometimes, splitting the dose of MTX is contemplated. The conventional posology of MTX, however, is that the split should not extend over a period of <24 h once a week (Professor Joel Kremer; personal communication), and it is recommended that, if patients are on a weekly dose of MTX of at least 12.5 mg, it would be best to split the dose to improve its bioavailability with two doses taken no more than 12 h apart. On the other hand, the half-life of its active compound, the polyglutamate MTX, is 3 days,[4] implying that MTX doses spread over a week should not necessarily be toxic. The main argument against splitting the MTX over the course of a week is of enhanced bone marrow toxicity. It is thought that, when used in such fashion, rapidly dividing cells in the bone marrow will be subject to therapeutic doses of MTX with a frequency which will exceed their ability to overcome its effects. As our patients also realize that MTX is indeed the “anchor” of RA treatment, when faced mainly with gastrointestinal intolerance, they also try their best to overcome it by splitting the doses, and we looked at this particular aspect of MTX use among our patients.

From the department database, all patients who were splitting the dose of MTX over a week (i.e., twice in two different weekdays) were identified and their diseases and other relevant parameters were recorded.

A total of 29 such patients (18 females) were identified [Table 1]. The long-term “splitting” was patient initiated and was necessitated by well-known adverse effects (AEs) of MTX (i.e., nausea and vomiting) and was facilitated by the lack of availability of single 20 mg or 25 mg of MTX tablets (these formulations have since become available in the Indian formulary). The dose split was mostly 3 days apart but five patients took them 4 days apart. They all took folic acid 5 mg on a different weekday. The efficacy of MTX was maintained and there were no significant AEs [Table 1]. In this cohort, therefore, potential use of glucocorticoids was also avoided, and by not using the antiemetics, further costs were saved.
Table 1: Impact of splitting the dose of methotrexate

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Potential ways of overcoming gastrointestinal intolerance due to MTX include increased use of folic acid, switching to subcutaneous or intramuscular routes, concomitant use of caffeine, and/or even anecdotal concomitant use of glucocorticoids; none of them are however universally popular or effective.[1],[5],[6],[7] Contrary to the popular notion, splitting of MTX in patients with RA was safe and without loss of efficacy in our small cohort. Few studies have addressed safety issue directly but did indeed provide evidence that splitting oral MTX over the course of a week was no less efficacious.[8],[9] Recent evidence indicates that mere unique pharmacokinetics and pharmacodynamics of MTX do not fully explain its toxicity which is probably governed by genetic polymorphism much more than previously thought.[10] The conventional posology of MTX, therefore, needs a rethink but the evidence is lacking, and our “real-life” observations highlight the need for well-designed trials looking into this particular aspect.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Cipriani P, Ruscitti P, Carubbi F, Liakouli V, Giacomelli R. Methotrexate in rheumatoid arthritis: Optimizing therapy among different formulations. Current and emerging paradigms. Clin Ther 2014;36:427-35.  Back to cited text no. 1
Cronstein BN. Low-dose methotrexate: A mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev 2005;57:163-72.  Back to cited text no. 2
Calasan MB, van den Bosch OF, Creemers MC, Custers M, Heurkens AH, van Woerkom JM, et al. Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis. Arthritis Res Ther 2013;15:R217.  Back to cited text no. 3
Tian H, Cronstein BN. Understanding the mechanisms of action of methotrexate: Implications for the treatment of rheumatoid arthritis. Bull NYU Hosp Jt Dis 2007;65:168-73.  Back to cited text no. 4
Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol 2001;30:129-34.  Back to cited text no. 5
Li D, Yang Z, Kang P, Xie X. Subcutaneous administration of methotrexate at high doses makes a better performance in the treatment of rheumatoid arthritis compared with oral administration of methotrexate: A systematic review and meta-analysis. Semin Arthritis Rheum 2016;45:656-62.  Back to cited text no. 6
Malaviya AN. Methotrexate intolerance in the treatment of rheumatoid arthritis (RA): Effect of adding caffeine to the management regimen. Clin Rheumatol 2017;36:279-85.  Back to cited text no. 7
Dhaon P, Das SK, Srivastava R, Agarwal G, Asthana A. Oral Methotrexate in split dose weekly versus oral or parenteral Methotrexate once weekly in Rheumatoid Arthritis: A short-term study. Int J Rheum Dis 2017. doi: 10.1111/1756-185X.12910.  Back to cited text no. 8
Pandya S, Aggarwal A, Misra R. Methotrexate twice weekly vs. once weekly in rheumatoid arthritis: A pilot double-blind, controlled study. Rheumatol Int 2002;22:1-4.  Back to cited text no. 9
Wessels JA, de Vries-Bouwstra JK, Heijmans BT, Slagboom PE, Goekoop-Ruiterman YP, Allaart CF, et al. Efficacy and toxicity of methotrexate in early rheumatoid arthritis are associated with single-nucleotide polymorphisms in genes coding for folate pathway enzymes. Arthritis Rheum 2006;54:1087-95.  Back to cited text no. 10


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