Pharmacology of Leflunomide

Leflunomide is an important immunosuppressant and disease-modifying antirheumatic drug (DMARD). Here, we learn more about what leflunomide is used to treat, how it works, and what side effects and drug interactions the medicine is linked to. We also review its major clinical considerations.

Let’s review, then, the fundamental facts about leflunomide you need to know!


Currently, there are only two indications that leflunomide has received FDA regulatory approval for:

  • Rheumatoid arthritis
  • Psoriatic arthritis

Investigations are ongoing to determine the usefulness of leflunomide in other conditions such as lupus, ankylosing spondylitis, Crohn’s disease and other inflammatory disorders.

  • Adult Dose (rheumatoid arthritis)

Loading dose: 100 mg orally once daily for 3 days

Maintenance: 20 mg orally once daily

Mechanism of action

At the most fundamental level, leflunomide works as a pyrimidine synthesis inhibitor.

More specifically, leflunomide works by inhibiting the enzyme dihydroorotate dehydrogenase – a mitochondrial enzyme used in the de novo manufacture of uridine monophosphate (rUMP). Of course, rUMP is important; it is needed for the synthesis of both RNA and DNA. By these means, leflunomide works to inhibit replication of actively dividing cells (for example – lymphocytes).

The active metabolite of leflunomide is teriflunomide – itself an approved medicine. Approximately 70 percent of leflunomide is converted into the active ingredient, teriflunomide.

Teriflunomide is not only effective at reducing the immune response to rheumatoid arthritis, but it has also shown activity against several viruses. It inhibits viral assembly and, by extension, viral replication.

Side effects

Leflunomide is associated with its own range of potential side effects:

  • GI effects: nausea, diarrhea, abdominal pain
  • Hepatotoxicity – elevated liver enzymes
  • Hair thinning / loss
  • Fatigue, weakness
  • Hypertension
  • Back pain
  • Numbness in hands / feet

More seriously, leflunomide is – due to its immunosuppressant powers – linked to onset of serious infections.

Clinical considerations

When it comes to the clinical pharmacology of leflunomide, here are some of the key factors you must consider:

  • Due to the risk of enhanced immunosuppression, caution is warranted with other drugs that also suppress the immune response.
  • Due to immunosuppression, avoid live vaccines; it increases the risk of severe infection.
  • Severe hepatotoxicity may result if leflunomide is taken with methotrexate.
  • Patients taking leflunomide should avoid persons who have colds or flu or other active infections.
  • Due to the risk of hepatotoxicity, liver function tests are often performed regularly. Similarly, blood pressure may also undergo frequent testing.
  • Leflunomide should be avoided in pregnancy. Birth control should be deployed by patients taking this medicine.
  • Leflunomide should be avoided in severe liver disease.
  • Hepatotoxicity risk increases when leflunomide is taken with NSAIDs, antibiotics, cholesterol-lowering medicines or hormone replacement therapy. Certain antifungal and antiseizure medicines (carbamazepine, valproic acid and phenytoin) also increase this risk.

Leflunomide is an important anti-rheumatic medicine. However, as an immunosuppressant, it comes with its own range of potentially serious side effects and drug interactions. Here, we’ve detailed the fundamental challenges with leflunomide use; a drug with remarkable clinical potential, but also a drug saddled with significant clinical risk.

For even more facts and pharmacology quiz questions on leflunomide pharmacology, register with PharmaFactz today. Check back to our pharmacy blog soon for even more great learning tips and tricks on leflunomide and many other immunosuppressant drugs.