Low-dose Methotrexate

Indications

Unlike its use for treatment of cancer, methotrexate is administered as long-term, low-dose therapy, usually 7.5 to 25 mg weekly in rheumatoid arthritis and other disorders.

  • Sometimes, it might be a good idea to have a discussion with patients to select a day for them to take this medication.
  • It could be a Monday, since methotrexate starts with a "M", or it could be a Sunday, since patient is going to church in the morning.



Method of Administration

In terms of prandial advice, methotrexate should be taken with an empty stomach.

  • Milk-rich foods may decrease its absorption. However, under management, Lexicomp did suggest to administer without regards to food, which is interesting to be take note of.

Being an antineoplastic agent, methotrexate is categorized under NIOSH List of Antineoplastic and Other Hazardous Drugs in Healthcare Settings, 2016 Group 1.

  • The 2.5 mg methotrexate tablet should not be cut or crushed in an unprotected environment.

If a weekly dose is missed, it can be taken as soon as it is remembered if this is within 2 days.

  • However, if the dose is three or more days late then a doctor or the rheumatology clinic should be contacted for advice.
  • A double dose should not be taken to make up for a missed dose.
  • It is unlikely that a disease flare-up would occur as result of single missed dose.



Dosage and Bioavailability

The doses used for the treatment of RA typically range from 7.5 to 20 mg weekly. Doses exceeding 20 mg weekly can increase the risk for toxicities.

  • At doses higher than 15 mg weekly, oral methotrexate may not have significant added clinical benefit; changing to subcutaneous methotrexate may increase bioavailability and clinical benefit.

The absorption of oral methotrexate is highly variable.

  • At low doses (≤30 mg/m2), oral bioavailability is about 60%, and this decreases at higher doses.
Injectable methotrexate has a higher bioavailability compared with oral methotrexate and thus provides superior clinical efficacy.

  • Injectable methotrexate is typically better tolerated and has less potential to cause gastrointestinal side effects as well.



Folic Acid Supplementation

It is not uncommon to see patients are being told to take folic acid 5mg six days a week, except the days patient is taking methotrexate. Otherwise, they may even be advised to take folic acid supplementation on certain days of the week only.

So, the two big questions here are:

  • What is the reason of folic acid supplementation?
  • Why is it not advisable to take folic acid on the methotrexate day?

The first question is straightforward. Folic acid supplementation helps to reduce the gastrointestinal adverse effects of methotrexate, such as stomatitis, nausea, diarrhoea. This is achieved without significant loss of efficacy. With reduced gastrointestinal symptoms, fewer patients on folic acid supplementation will discontinue methotrexate therapy.

According to UpToDate, folic acid can be taken daily, including the day on which methotrexate is administered, because it is passively taken up by the cell and does not compete with methotrexate for uptake by the reduced folate carrier. However, some data have suggested that daily folate may reduce the efficacy of methotrexate for rheumatoid arthritis. This was illustrated in a post-hoc analysis of the outcomes of two control groups in 2 separate randomized controlled trials that compared leflunomide with methotrexate.



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