When Leflunomide isn't available, you still have options

If you've been trying to fill your Leflunomide prescription and keep hitting dead ends, it's natural to worry. Rheumatoid arthritis doesn't take a break just because your pharmacy is out of stock.

The good news is that Leflunomide isn't the only effective DMARD for RA. Your rheumatologist has several well-studied alternatives that may work for you — either as a temporary bridge while Leflunomide supply recovers, or as a longer-term switch if needed.

In this guide, we'll review what Leflunomide does, how it works, and the most common alternatives your doctor might consider. Important: Never switch medications on your own. Always work with your prescriber to find the right option for your specific situation.

What is Leflunomide and how does it work?

Leflunomide (brand name Arava) is a disease-modifying antirheumatic drug (DMARD) that's been used to treat rheumatoid arthritis since its FDA approval in 1998. Unlike NSAIDs or corticosteroids that primarily manage symptoms, Leflunomide works by actually slowing the underlying disease process.

Here's how it works at a cellular level: Leflunomide is a prodrug that gets converted in your body to its active form, called teriflunomide. This active metabolite inhibits an enzyme called dihydroorotate dehydrogenase (DHODH). This enzyme is crucial for producing pyrimidines — one of the building blocks that rapidly dividing immune cells need to multiply.

In rheumatoid arthritis, your immune system's T-cells and B-cells are overactive, attacking the lining of your joints. By blocking pyrimidine synthesis, Leflunomide reduces the proliferation of these overactive lymphocytes, calming the autoimmune response and slowing joint damage.

For a deeper dive, check out our guide on how Leflunomide works.

Alternative #1: Methotrexate

Methotrexate is often the first-line DMARD for rheumatoid arthritis and is the most widely used RA medication worldwide. If you're switching from Leflunomide, Methotrexate is likely the first alternative your doctor will consider.

How it works: Methotrexate inhibits folate metabolism, reducing the activity of rapidly dividing immune cells. It also has anti-inflammatory effects that help control RA symptoms.

Dosing: Typically 7.5 mg to 25 mg taken once weekly (oral or injectable), with daily folic acid supplementation to reduce side effects.

Pros:

• Decades of clinical evidence supporting its effectiveness
• Very affordable as a generic (often under $20/month)
• Available in oral tablets, oral solution, and injectable forms
• Can be combined with biologic DMARDs if needed
• Widely available — rarely faces supply issues

Cons:

• Requires regular liver function and blood count monitoring
• Can cause nausea, mouth sores, and fatigue (especially on dosing day)
• Also pregnancy Category X (must avoid pregnancy)
• Interacts with alcohol — patients should limit or avoid drinking

Important note: If you're switching from Leflunomide to Methotrexate, your doctor may recommend a cholestyramine washout procedure first, since combining the two increases hepatotoxicity risk. Leflunomide's active metabolite has a very long half-life (14-18 days) and can persist in your body for months without washout.

Alternative #2: Sulfasalazine

Sulfasalazine is another conventional DMARD that's been used for RA for decades. It's often used in combination with other DMARDs as part of "triple therapy" (Methotrexate + Sulfasalazine + Hydroxychloroquine).

How it works: The exact mechanism isn't fully understood, but Sulfasalazine has anti-inflammatory and immunomodulatory effects. It's broken down in the gut into sulfapyridine and 5-aminosalicylic acid, both of which contribute to its therapeutic effects.

Dosing: Typically started at 500 mg daily and gradually increased to 1,000 mg twice daily.

Pros:

• Well-established safety profile
• Affordable generic available
• Can be used in combination with other DMARDs
• Generally well-tolerated with gradual dose titration

Cons:

• May be less potent than Leflunomide or Methotrexate as monotherapy
• Can cause GI upset, headache, and skin rash
• Sulfa allergy is a contraindication
• Requires periodic blood monitoring

Alternative #3: Hydroxychloroquine (Plaquenil)

Hydroxychloroquine is a milder DMARD that's often used for early or mild RA, or as part of combination DMARD therapy.

How it works: Hydroxychloroquine modulates the immune system by interfering with antigen processing and reducing the production of inflammatory cytokines.

Dosing: Typically 200-400 mg daily.

Pros:

• Generally very well tolerated
• Doesn't require frequent blood work (beyond baseline eye exams)
• Affordable
• Safe to use in combination with other DMARDs

Cons:

• Milder effect — may not be sufficient as monotherapy for moderate-to-severe RA
• Takes 2-3 months to see full benefit
• Requires annual eye exams to monitor for rare retinal toxicity
• May not be a strong enough replacement for Leflunomide alone

Alternative #4: JAK inhibitors (Tofacitinib, Baricitinib, Upadacitinib)

Janus kinase (JAK) inhibitors are a newer class of targeted oral DMARDs. They represent a step up in treatment intensity and are typically reserved for patients who haven't responded adequately to conventional DMARDs.

How they work: JAK inhibitors block specific enzymes (JAK1, JAK2, JAK3) involved in the signaling pathways that drive inflammation and immune cell activation in RA.

Options include:

• Tofacitinib (Xeljanz): 5 mg twice daily or 11 mg extended-release once daily
• Baricitinib (Olumiant): 2 mg once daily
• Upadacitinib (Rinvoq): 15 mg once daily

Pros:

• Oral tablets (no injections or infusions)
• Fast onset of action compared to conventional DMARDs
• Effective in patients who've failed other treatments

Cons:

• Significantly more expensive than Leflunomide ($2,000-$5,000/month without insurance)
• Increased risk of serious infections, blood clots, and cardiovascular events (FDA boxed warning)
• Typically not first-line — reserved for patients who've tried other DMARDs first
• Requires regular monitoring of blood counts and lipid levels

Note: Your doctor will consider your disease severity, treatment history, and risk factors before recommending a JAK inhibitor. These aren't usually a direct swap for Leflunomide unless other conventional options have been exhausted.

Before you switch: try to find Leflunomide first

If Leflunomide has been working well for you, switching medications should be a last resort — not a first reaction to a temporary stock-out. Before committing to an alternative:

• Use Medfinder to find Leflunomide in stock near you
• Call independent and specialty pharmacies
• Ask your pharmacy to special-order it
• Consider mail-order options

Many patients find Leflunomide available within a few days once they broaden their search beyond their usual pharmacy.

Final thoughts

Running out of Leflunomide is stressful, but you're not without options. Methotrexate, Sulfasalazine, Hydroxychloroquine, and JAK inhibitors are all real alternatives that your rheumatologist can evaluate based on your individual needs.

The most important step is to talk to your doctor before making any changes. They can help you weigh the risks and benefits of each option and ensure a smooth transition that keeps your RA under control.

For more on managing your Leflunomide prescription, check out our shortage update for 2026, our guide to Leflunomide side effects, and tips on saving money on Leflunomide.