Can leflunomide cause diarrhea? Understanding the Link and Management

October 8, 2025 •

4 min read

Diarrhea is the most common side effect of leflunomide, affecting approximately 17% to 27% of patients in clinical trials [1.2.1, 1.2.3]. Understanding why this occurs and how to manage it is crucial for patients undergoing treatment for conditions like rheumatoid arthritis.

Quick Summary

Yes, leflunomide frequently causes diarrhea. This side effect can range from mild and transient to severe and chronic, sometimes leading to colitis. Management involves dose adjustments, dietary changes, and in some cases, medication to control symptoms.

Key Points

Diarrhea is Common: Diarrhea is the most frequently reported side effect of leflunomide, affecting up to 27% of users [1.2.3].
Acute vs. Chronic: The diarrhea is often acute and transient, appearing in the first few weeks, but can become chronic or signal a more serious issue like colitis [1.3.6, 1.2.1].
Management Strategies: Management options include dose reduction, taking the medication with food, staying hydrated, and using approved OTC medications [1.3.2, 1.2.3, 1.3.3].
Medical Consultation is Key: Never stop or change your leflunomide dose without consulting your doctor, especially if diarrhea is severe or persistent [1.8.1].
Long Half-Life: Leflunomide stays in the body for up to two years after stopping, sometimes requiring a "washout" procedure with cholestyramine to clear it faster if serious side effects occur [1.8.2].
Serious Complications are Rare: Although common, simple diarrhea can rarely progress to drug-induced colitis, which requires stopping the medication [1.2.5].
Regular Monitoring: While on leflunomide, regular blood tests are necessary to monitor liver function and blood counts due to potential serious side effects [1.7.1].

What is Leflunomide?

Leflunomide, sold under the brand name Arava, is a disease-modifying antirheumatic drug (DMARD) used primarily to treat rheumatoid arthritis (RA) and psoriatic arthritis [1.4.3, 1.4.6]. It works by suppressing the immune system to reduce inflammation, which in turn helps to decrease pain, swelling, and joint damage [1.3.2, 1.4.4]. Leflunomide is an immunomodulatory agent that inhibits an enzyme called dihydroorotate dehydrogenase, a key step in pyrimidine synthesis. This action hampers the proliferation of activated T-cells, which are crucial drivers of the autoimmune response in RA [1.2.2, 1.4.5].

The Link Between Leflunomide and Diarrhea

Diarrhea is not just a possible side effect of leflunomide; it is the most common one reported [1.2.4]. Studies show that between 17% and 27% of users experience it [1.2.1, 1.2.3].

Acute vs. Chronic Diarrhea

For many patients, the diarrhea is acute, typically starting within the first few weeks of treatment. This initial phase is often transient and may resolve on its own as the body adjusts to the medication [1.2.2, 1.3.6].

However, for some individuals, the diarrhea can be more persistent or even chronic. In rare instances, long-term leflunomide use can lead to more serious gastrointestinal issues, including different forms of colitis (inflammation of the colon), such as microscopic colitis, collagenous colitis, or lymphocytic colitis [1.2.1, 1.2.7]. The onset of leflunomide-induced colitis can be delayed, sometimes appearing months or even years after starting the medication [1.2.1, 1.2.2].

Why Does It Happen?

While the exact mechanism for leflunomide-induced diarrhea isn't fully understood, it is related to how the drug works and is processed in the gastrointestinal tract [1.3.6]. Leflunomide is a prodrug that is converted into its active metabolite, A77 1726 (also known as teriflunomide), within the intestinal mucosa and plasma [1.2.2]. This process and the drug's effect on rapidly dividing cells, including those in the gut lining, can lead to gastrointestinal upset.

Managing Leflunomide-Induced Diarrhea

If you experience diarrhea while taking leflunomide, it's essential to communicate with your healthcare provider. Do not stop taking the medication without consulting them first [1.8.1]. Several strategies can help manage this side effect:

Dose Adjustment: Your doctor may recommend reducing the dose of leflunomide. For example, a patient on a 20 mg daily dose might be moved to 10 mg daily to see if the symptoms improve [1.3.2].
Taking with Food: Administering leflunomide with food can sometimes help prevent or ease stomach upset and diarrhea [1.2.3].
Hydration: It's crucial to stay hydrated by drinking plenty of water or electrolyte-containing sports drinks to replace lost fluids [1.3.3].
Over-the-Counter (OTC) Medications: For mild cases, your doctor may approve the use of OTC anti-diarrheal medications like loperamide (Imodium) or kaopectate [1.3.1]. Always consult your doctor or pharmacist before taking new medications.
Medical Evaluation: If diarrhea is severe, persistent, or accompanied by blood, severe abdominal pain, or significant weight loss, it requires immediate medical attention. Your doctor will need to rule out other causes, such as infection or drug-induced colitis [1.2.5].

When Discontinuation is Necessary

In cases of severe or intolerable side effects, or if drug-induced colitis is diagnosed, discontinuing leflunomide may be necessary [1.2.5]. Because leflunomide's active metabolite has a very long half-life and can stay in the body for up to two years, a special "washout" procedure may be required to eliminate it from your system more quickly. This typically involves an 11-day course of cholestyramine or activated charcoal [1.3.5, 1.8.2]. This procedure is also essential for women who plan to become pregnant, as leflunomide can cause severe birth defects [1.3.2].

Leflunomide vs. Other DMARDs: A Side Effect Comparison

Leflunomide is often compared to methotrexate, another common DMARD for RA. Both have similar efficacy, but their side effect profiles differ.


Side Effect	Leflunomide	Methotrexate
Gastrointestinal	Diarrhea and nausea are very common [1.2.3].	Nausea and GI complaints are common [1.5.6].
Liver Enzymes	Can cause elevated liver enzymes [1.4.6].	Higher risk of elevated liver enzymes [1.5.2].
Hair Loss	Hair loss or thinning is a known side effect [1.2.3].	Hair loss can also occur [1.5.4].
Lung Issues	Rare but serious risk of interstitial lung disease [1.6.2].	Can also cause pulmonary issues [1.5.2].
Blood Counts	Can cause decreased blood cell counts [1.3.2].	Risk of bone marrow suppression [1.5.4].

Overall, the choice between leflunomide and methotrexate often depends on the individual patient's tolerance and pre-existing conditions [1.5.5].

Conclusion

Yes, leflunomide can, and frequently does, cause diarrhea. For many, this side effect is mild and temporary, but for others, it can be a persistent and challenging issue. Open communication with your rheumatologist is key to managing this side effect effectively, whether through dose adjustments, supportive care, or, if necessary, discontinuing the drug. Regular monitoring of blood tests for liver function and blood counts is also a critical part of staying safe while on leflunomide therapy [1.7.1].

For more information from an authoritative source, you can visit the American College of Rheumatology's patient information page: Leflunomide (Arava)

Frequently Asked Questions

Diarrhea is the most common side effect of leflunomide, occurring in approximately 17-27% of patients who take it [1.2.1, 1.2.3].

In many cases, diarrhea is mild and transient, improving over time as your body adjusts to the medication. However, if it persists or is severe, you should contact your doctor [1.3.2, 1.2.2].

Your doctor may approve over-the-counter medications like loperamide (Imodium). It is also important to stay hydrated. Always consult your healthcare provider before starting any new medication [1.3.1, 1.3.3].

No, you should not stop taking leflunomide without first talking to your doctor. They can recommend strategies to manage the side effect or may adjust your dose. Stopping abruptly could cause your arthritis symptoms to return [1.8.1, 1.8.2].

While rare, long-term use of leflunomide can lead to a more serious condition called colitis (inflammation of the colon), which can present as chronic diarrhea. This requires medical evaluation and discontinuation of the drug [1.2.1, 1.2.5].

Leflunomide has a very long half-life and can remain in the body for up to two years. Side effects can persist during this time unless a 'washout procedure' using cholestyramine or activated charcoal is performed to speed up its elimination [1.8.2].

While both medications can cause gastrointestinal issues, diarrhea is more commonly associated with leflunomide. Studies have shown that GI complaints are frequent with both, but diarrhea is a hallmark side effect of leflunomide [1.2.3, 1.5.1].