1. Clinical Overview
Leflunomide is a synthetic disease-modifying antirheumatic 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 a cornerstone in the management of active rheumatoid arthritis in the Indian context, often used after failure of methotrexate or as part of combination therapy.
| Onset | Duration | Bioavailability |
|---|---|---|
| Clinical improvement in rheumatoid arthritis symptoms typically begins within 4-8 weeks of starting therapy, with maximum benefit observed after 12-16 weeks of continuous treatment. | The active metabolite has a very long half-life, resulting in a prolonged pharmacodynamic effect. Clinical effects can persist for several weeks to months after discontinuation, necessitating a washout procedure with cholestyramine. | Approximately 80% following oral administration. Food does not significantly affect the extent of absorption but may slow the rate. |
2. Mechanism of Action
Leflunomide is a prodrug. Its active metabolite, teriflunomide, is a reversible, non-competitive inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH). DHODH is a key enzyme in the de novo synthesis pathway of pyrimidine ribonucleotides, specifically converting dihydroorotate to orotate. Inhibition of DHODH leads to a depletion of the intracellular pyrimidine pool (UTP, CTP), which is crucial for DNA and RNA synthesis. This has a selective antiproliferative effect on activated lymphocytes (T-cells and B-cells) that rely heavily on de novo synthesis during rapid clonal expansion, while resting cells and other cell types can utilize salvage pathways. This results in a cytostatic reduction in autoimmune lymphocyte proliferation.
3. Indications & Uses
- Active Rheumatoid Arthritis (moderate to severe) in adults
- Psoriatic Arthritis
4. Dosage & Administration
Adult Dosage: For Rheumatoid/Psoriatic Arthritis: A loading dose of 100 mg once daily for 3 days, followed by a maintenance dose of 10 mg to 20 mg once daily. In India, 20 mg once daily is the standard maintenance dose. Dose may be reduced to 10 mg daily for tolerability.
Administration: Administer orally, with or without food. Tablet should be swallowed whole with a glass of water. Consistent daily timing is recommended. If a dose is missed, it should be taken as soon as remembered on the same day. Do not double the dose the next day.
5. Side Effects
Common side effects may include:
- Diarrhea
- Nausea
- Dyspepsia
- Abdominal pain
- Headache
- Dizziness
- Alopecia (hair thinning)
- Rash
- Elevated liver enzymes (ALT/AST)
- Hypertension
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 and risk of bleeding. Monitor INR closely when starting or stopping leflunomide. | Major |
| Rifampicin | Significantly increases teriflunomide levels, increasing toxicity risk. Contraindicated. | Major |
| Live Vaccines (MMR, Varicella, Yellow Fever) | Risk of disseminated vaccine-induced infection. Contraindicated. | Major |
| Cholestyramine / Activated Charcoal | Markedly accelerates elimination of teriflunomide (used for washout). | Moderate |
| NSAIDs (e.g., Diclofenac, Ibuprofen) | Increased risk of GI ulceration/bleeding. Use with caution. | Moderate |
| Tolbutamide | Leflunomide may increase tolbutamide levels. | Moderate |
| Repaglinide | May increase repaglinide levels, risk of hypoglycemia. | Moderate |
7. Patient Counselling
- Do take the medicine exactly as prescribed, at the same time each day.
- Do not get pregnant or father a child while on this medicine. Discuss contraception with your doctor.
- Do not receive live vaccines (MMR, chickenpox, nasal flu) without consulting your doctor.
- Do not start any new medicine, including OTC drugs and herbal supplements, without informing your doctor.
- Do report for all scheduled blood tests (LFT, CBC).
- Do not skip the loading dose if prescribed, unless advised by your doctor.
8. Toxicology & Storage
Overdose: Symptoms may include abdominal pain, diarrhea, nausea, vomiting, leukopenia, anemia, thrombocytopenia, elevated liver enzymes, and rash. There is no specific clinical picture due to the long half-life.
Storage: Store below 30°C in a cool, dry place, protected from light and moisture. Keep the bottle tightly closed. Keep out of reach of children. Do not use after the expiry date printed on the pack.