Can Higher-Dose Oral Methotrexate Be Split?

Joanna M. Pangilinan, PharmD, BCOP


June 03, 2009


When using oral methotrexate (MTX) to treat rheumatoid arthritis (RA), it's my understanding that MTX absorption decreases as the dose increases. At what dose of MTX should oral administration be converted to parenteral administration? Does splitting the dose improve oral absorption?

Response from Joanna Maudlin Pangilinan, PharmD, BCOP
Pharmacist, Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor, Michigan

MTX is a dihydrofolate reductase inhibitor[1] that is effective in low doses as a disease-modifying antirheumatic drug for treatment of RA.[2] A typical starting dose of MTX for RA is 7.5 mg once weekly with titration upwards to clinical effect or development of adverse effects (eg, gastrointestinal intolerance, bone marrow toxicity).[1] MTX is frequently given orally for RA but may also be administered parenterally, usually via subcutaneous (SC) or intramuscular (IM) injection.[2]

Oral MTX is rapidly but incompletely absorbed, with a bioavailability of about 60%.[1] The extent of absorption is subject to intra- and interindividual variability.[3] While a dose of 7.5 mg given orally or IM has similar bioavailability,[4] the bioavailability of single oral doses of 25-40 mg is about two thirds compared with the same dose given IM or SC.[2,5] Parenteral administration of MTX may be more effective than the same dose given orally due to factors such as improved bioavailability, decreased side effects, and improved patient adherence.[2] It has been suggested that patients who require more than 25 mg of MTX be changed to IM or SC administration.[3] However, oral administration is preferable for most patients in part due to convenience and lack of injections and resulting injection site reactions.

Weekly oral MTX administered as a split dose has been evaluated. Hoekstra and colleagues[6] studied the bioavailability of MTX in 10 patients receiving a stable MTX dose (median 30 mg weekly). Pharmacokinetic analysis was used to evaluate the bioavailability of a single oral dose vs an equal but divided dose separated by 8 hours. The split-dose regimen had 28% higher bioavailability compared with single-dose therapy (P = .007). The authors concluded that splitting a higher oral dose of MTX (25-35 mg weekly) results in bioavailability similar to SC administration and may be an alternative to SC or IM administration.

Further research with larger studies is necessary to confirm these findings, as well as to study the efficacy, tolerability, and adverse effects of such a regimen. Therefore, the patient should be monitored closely if such administration is ordered. As medication error has occurred due to confusion with split dosing,[7] the clinician should ensure that clear and precise instructions are communicated to the pharmacist and patient.


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