What are the routes of administration and side effects of Methotrexate (MTX)?

From the Guidelines

Methotrexate should be administered orally, starting with 15 mg/week, and escalating with 5 mg/month to 25–30 mg/week, or the highest tolerable dose, with a subsequent switch to subcutaneous administration in the case of an insufficient response, as recommended by the 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis 1. The choice of route depends on the condition being treated and dosage required. Common side effects of methotrexate include:

• Nausea
• Vomiting
• Mouth sores
• Fatigue
• Headache More serious side effects include:
• Bone marrow suppression (leading to decreased blood cell counts)
• Liver toxicity (hepatotoxicity)
• Lung inflammation (pneumonitis)
• Kidney damage Patients taking methotrexate should have regular blood tests to monitor liver function, kidney function, and blood counts. Folic acid supplementation (typically 1mg daily or 5mg weekly, taken on non-methotrexate days) is recommended to reduce side effects, as it has been shown to decrease gastrointestinal and liver toxicity without reducing efficacy 1. Methotrexate works by inhibiting dihydrofolate reductase, an enzyme needed for DNA synthesis and cell division, which explains both its therapeutic effects and many of its side effects. It also has anti-inflammatory properties through multiple mechanisms including inhibition of adenosine metabolism. Methotrexate is contraindicated in pregnancy due to teratogenic effects, and both men and women should use effective contraception during treatment and for some time after discontinuation. The most recent and highest quality study, the 2021 American College of Rheumatology guideline, provides the best evidence for the optimal dosage and route of administration of methotrexate in rheumatoid arthritis 1.

From the FDA Drug Label

DOSAGE AND ADMINISTRATION: Neoplastic Diseases For intrathecal and high-dose methotrexate therapy, use the preservative-free formulation of methotrexate. Do not use the preserved formulation of methotrexate for intrathecal or high-dose therapy because it contains benzyl alcohol Oral administration in tablet form is often preferred when low doses are being administered since absorption is rapid and effective serum levels are obtained. Methotrexate for Injection may be given by the intramuscular, intravenous, intra-arterial or intrathecal route Methotrexate is administered orally or intramuscularly in doses of 15 to 30 mg daily for a five-day course Methotrexate in combination with other agents appears to be the drug of choice for securing maintenance of drug-induced remissions When remission is achieved and supportive care has produced general clinical improvement, maintenance therapy is initiated, as follows: Methotrexate is administered 2 times weekly either by mouth or intramuscularly in total weekly doses of 30 mg/m2. The routes of administration for methotrexate are:

• Intramuscular
• Intravenous
• Intra-arterial
• Intrathecal
• Oral The side effects of methotrexate are not directly stated in the provided drug label, however, it is mentioned that toxic symptoms may subside after rest periods of one or more weeks interposed between courses 2.

From the Research

Methotrexate Routes

• Methotrexate (MTX) can be administered weekly by different routes: oral, subcutaneous, or intramuscular 3
• The subcutaneous route seems to be more effective than the oral route for MTX administration based on the results of several studies, and this route may be preferred because of better usability and absence of pain at the infusion site 3
• Parenteral administration of MTX is indicated in those patients with poor compliance toward the oral form 3

Methotrexate Side Effects

• Many patients treated with MTX experience mucosal, gastrointestinal, hepatic or haematologic side effects 4
• Supplementation with folic or folinic acid during treatment with MTX may ameliorate these side effects 4, 5
• Folic and folinic acid appear to be protective against abnormal serum transaminase elevation caused by MTX, with a 76.9% relative risk reduction 4
• Folic and folinic acid also reduce the incidence of GI side effects, such as nausea, vomiting or abdominal pain, with a 26% relative risk reduction 4
• Folate supplementation can reduce patient withdrawal from MTX treatment, with a 60.8% relative risk reduction 4, 5

Folate Supplementation

• Folate supplementation can reduce the incidence of hepatotoxicity and gastrointestinal side-effects of MTX in patients with RA 5
• Folate supplementation can also reduce patient withdrawal from MTX treatment 5
• There is no significant difference between high-dose folate and low-dose folate on MTX efficacy or toxicity 5, 6
• FA supplementation of 5 mg per week and 30 mg per week was associated with similar tolerability of methotrexate in RA patients 6