Alternatives to Methotrexate If You Can't Fill Your Prescription

Methotrexate has been in shortage since March 2023, and for many patients, waiting isn't an option. Whether you're managing rheumatoid arthritis, psoriasis, or a cancer diagnosis, your treatment shouldn't be delayed. Here is a guide to the most established alternatives — broken down by condition — and how to approach the conversation with your provider.

Important: Always Consult Your Doctor Before Switching

Methotrexate has a specific place in your treatment plan, and switching medications — even to something in the same class — requires your provider's oversight. Some alternatives take weeks to become effective, some require different monitoring labs, and some are not appropriate for certain patients based on their medical history.

Alternatives for Rheumatoid Arthritis (RA) and Psoriatic Arthritis

Methotrexate is the first-line DMARD for RA. If it's unavailable, these alternatives have strong clinical evidence:

1. Leflunomide (Arava)

Leflunomide is the closest head-to-head competitor to methotrexate for RA. Like methotrexate, it is a DMARD that slows joint damage and reduces inflammation. It works differently — by inhibiting pyrimidine synthesis — but achieves comparable clinical outcomes in many patients.

Typical dose: 10–20 mg once daily (oral)

Key consideration: Also contraindicated in pregnancy and requires liver monitoring; long half-life means drug stays in system for months even after stopping

Cost: Generic leflunomide is affordable, typically $15–$50/month with a coupon

2. Hydroxychloroquine (Plaquenil)

Hydroxychloroquine is a milder DMARD frequently used for lupus and early or mild RA. It is not as powerful as methotrexate but has an excellent long-term safety profile. It's often used in combination with other DMARDs.

Key consideration: Requires annual eye exams (rare risk of retinal toxicity at high cumulative doses); safe in pregnancy

3. Sulfasalazine

Sulfasalazine is another first-line DMARD option for RA and psoriatic arthritis. It is also one of the few DMARDs considered safe in pregnancy, making it a key alternative for patients who are pregnant or planning to conceive.

4. Biologic DMARDs (TNF inhibitors and others)

If your disease is moderate to severe or has not responded to conventional DMARDs, biologic therapies are highly effective. Common options include:

Adalimumab (Humira, biosimilars): TNF inhibitor; wide biosimilar availability has reduced costs significantly

Etanercept (Enbrel): TNF inhibitor; subcutaneous injection weekly or twice weekly

Abatacept (Orencia), tocilizumab (Actemra): For patients who cannot tolerate TNF inhibitors

Note: Biologics require prior authorization from insurance and are significantly more expensive than methotrexate without assistance programs. They also come with their own monitoring requirements.

Alternatives for Psoriasis

For plaque psoriasis, methotrexate is a systemic treatment option. If unavailable, alternatives include:

Apremilast (Otezla): Oral PDE4 inhibitor; no lab monitoring required, but less potent for severe disease

IL-17 inhibitors (secukinumab/Cosentyx, ixekizumab/Taltz): Highly effective biologics for moderate-to-severe psoriasis

Acitretin: Oral retinoid; option for certain psoriasis types, but contraindicated in women of childbearing potential

Alternatives for Cancer Patients

For cancer patients, there is no universal substitute for methotrexate. The appropriate alternative depends on cancer type, stage, and treatment regimen. Your oncologist will lead this decision. In some cases, treatment regimens can be modified or other chemotherapy agents substituted. For leukemia patients requiring intrathecal administration, your institution's oncology team will follow ASHP guidelines for shortage management.

What to Tell Your Doctor

When calling your provider's office to discuss switching medications, have this ready:

Your current dose and how long you've been on methotrexate

Which pharmacies you've already checked (showing you've done the legwork)

Your insurance formulary (your pharmacist or insurer can give you this)

Whether cost or monitoring burden is a concern for you with potential alternatives

Before giving up on finding methotrexate, it may still be worth searching. Check out our guide on how to find methotrexate near you or let medfinder do the searching for you.