1. Clinical Overview
Leflunomide is a disease-modifying anti-rheumatic drug (DMARD) with immunomodulatory and anti-inflammatory properties. It is a prodrug whose active metabolite, teriflunomide, inhibits dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in the de novo pyrimidine synthesis pathway, leading to a cytostatic effect on rapidly dividing lymphocytes. It is indicated for the treatment of active rheumatoid arthritis (RA) in adults to reduce signs and symptoms, inhibit structural damage, and improve physical function.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical improvement in RA symptoms is typically observed within 4-8 weeks of initiating therapy. | The active metabolite has a very long half-life (approximately 2 weeks). Effects can persist for several months after discontinuation due to enterohepatic recycling and slow elimination. | Approximately 80% following oral administration. |
2. Mechanism of Action
Leflunomide is a prodrug. Its active metabolite, teriflunomide, is a reversible inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). DHODH is a key enzyme in the de novo synthesis pathway of pyrimidine ribonucleotides. By inhibiting DHODH, teriflunomide decreases the intracellular pool of pyrimidines (specifically uridine monophosphate - UMP), which are essential for DNA and RNA synthesis. This has a selective antiproliferative effect on activated lymphocytes (T-cells and B-cells), which rely heavily on the de novo pathway during rapid division. This leads to a reduction in the population of autoimmune lymphocytes, thereby suppressing the inflammatory process in rheumatoid arthritis.
3. Indications & Uses
- Active Rheumatoid Arthritis (RA) in adults
- Psoriatic Arthritis (as a DMARD option)
4. Dosage & Administration
Adult Dosage: For Rheumatoid Arthritis: 10mg to 20mg once daily. In India, 10mg once daily is a common maintenance dose, especially for long-term therapy and to improve tolerability. A loading dose of 100mg once daily for 3 days was historically used but is now often omitted due to increased risk of side effects (e.g., diarrhea, hepatotoxicity).
Administration: Administer orally once daily, with or without food. Tablets should be swallowed whole with a glass of water. Consistency in timing is recommended.
5. Side Effects
Common side effects may include:
- Diarrhea
- Nausea
- Abdominal pain
- Dyspepsia
- Headache
- Dizziness
- Alopecia (hair thinning)
- Hypertension
- Rash
- Elevated liver enzymes (ALT/AST)
6. Drug Interactions
| Drug | Effect | Severity |
|---|---|---|
| Methotrexate | Increased risk of hepatotoxicity and pancytopenia. Requires extremely close monitoring of LFTs and CBC. | Major |
| Warfarin | Leflunomide may increase INR; monitor INR closely upon initiation and discontinuation. | Moderate |
| Rifampicin | Significantly increases teriflunomide levels (by up to 40%). Increased risk of toxicity. | Major |
| Live Vaccines (e.g., MMR, Varicella, Yellow Fever) | Risk of disseminated infection due to immunosuppression. Contraindicated. | Major |
| Cholestyramine / Activated Charcoal | Markedly accelerates elimination of teriflunomide (used in washout procedures). | Moderate |
| NSAIDs (e.g., Diclofenac, Ibuprofen) | Increased risk of gastrointestinal ulceration and hepatotoxicity. Use with caution. | Moderate |
| Tolbutamide | Leflunomide may increase tolbutamide levels. Monitor blood glucose. | Moderate |
7. Patient Counselling
- Do take the medicine exactly as prescribed, usually once daily.
- Do not stop taking the medicine abruptly without consulting your doctor.
- Do inform all your doctors and dentists that you are taking leflunomide before any surgery or new prescription.
- Do not receive live vaccines while on this medication.
- Do report any signs of infection (fever, sore throat), unusual bleeding/bruising, or yellowing of skin/eyes immediately.
8. Toxicology & Storage
Overdose: Expected symptoms would be an exaggeration of its known adverse effects: severe diarrhea, abdominal pain, leukopenia, anemia, elevated liver enzymes, and rash. Single doses up to 100mg have been tolerated.
Storage: Store below 30°C. Protect from light and moisture. Keep the container tightly closed. Keep out of reach of children.