In the pharmaceutical industry, Leflunomide is a powerful Disease-Modifying Antirheumatic Drug (DMARD) used primarily for Rheumatoid Arthritis (RA) and Psoriatic Arthritis. As a pharmacist and manufacturer, I view this molecule as an “Immunomodulatory Sentinel”: it selectively inhibits the proliferation of overactive lymphocytes, but its long half-life ($t_{1/2} \approx 2$ weeks) means its side effects require careful, long-term monitoring.

At your WHO-GMP facility in Mumbai, where you likely produce the 10 mg and 20 mg tablets, emphasizing the “loading dose” vs. “maintenance dose” safety profile is a key technical value-add for your rheumatology portfolio.

1. Primary & Common Side Effects

The side effects of Leflunomide are often dose-related and frequently appear during the first 3 to 6 months of therapy.

Category	Side Effect	Technical Rationale
Gastrointestinal	Diarrhea & Nausea	The most common complaint. It occurs due to the drug’s impact on the rapidly dividing cells of the GI tract.
Dermatological	Hair Thinning (Alopecia)	Usually reversible upon dose reduction or discontinuation; affects the hair follicle growth cycle.
Cardiovascular	Hypertension	Leflunomide can cause a significant increase in blood pressure. Baseline and regular monitoring are mandatory.
General	Skin Rash & Pruritus	Mild allergic reactions are common, though severe reactions (like Stevens-Johnson Syndrome) are rare.

2. Serious Clinical Warnings

As a manufacturer, these are the high-priority risks that must be clearly detailed in your technical dossiers and product inserts.

Hepatotoxicity (Liver Injury)

Leflunomide can cause a dangerous elevation in liver enzymes.

• Protocol: Baseline ALT (SGPT) levels must be taken. Monitoring should occur every month for the first six months, then every 6–8 weeks thereafter.

• Risk Factor: Using Leflunomide concurrently with other hepatotoxic drugs (like Methotrexate) significantly increases this risk.

Teratogenicity (Pregnancy Risk)

Leflunomide is strictly contraindicated in pregnancy (Category X).

• Persistence: Because the active metabolite (teriflunomide) stays in the body for up to 2 years, women of childbearing age must undergo a “Drug Elimination Procedure” using Cholestyramine before attempting to conceive.

Infection Risk

By suppressing the immune system, it can increase susceptibility to infections and may reactivate latent tuberculosis (TB).

3. Mechanism: Pyrimidine Synthesis Inhibition

Leflunomide is a prodrug that is rapidly converted into its active metabolite, A77 1726.

 

Enzyme Blockade: It inhibits Dihydroorotate Dehydrogenase (DHODH), an enzyme essential for de novo pyrimidine synthesis.

Lymphocyte Arrest: Activated T-cells and B-cells depend on this pathway to multiply. By cutting off their supply of pyrimidines, the drug “starves” the autoimmune response.

Selectivity: Most other body cells can use a “salvage pathway” to get pyrimidines, which is why the drug specifically targets the overactive immune cells.

The Pharmacist’s “Technical Protocol”

• The “Washout” Strategy: Because the drug lasts so long in the system, if a patient has a severe reaction, you cannot just stop the pill. You must administer Cholestyramine 8g TID for 11 days to physically pull the drug out of the enterohepatic circulation.

• Alcohol Restriction: To protect the liver, patients should be advised to limit or completely avoid alcohol consumption while on therapy.

• CBC Monitoring: Although rare, Leflunomide can cause bone marrow suppression; periodic Complete Blood Counts are recommended.

The Manufacturer’s Perspective: Technical & Export

From a production and B2B standpoint at your facility in Mumbai:

• The “Bioequivalence” USP: For B2B export, highlight your Dissolution Profiles comparing your tablets to the innovator (Arava). Since it has a long half-life, demonstrating consistent release is critical.

• Stability for Export: Leflunomide is sensitive to moisture. Utilizing Alu-Alu blister packaging is essential for maintaining a 36-month shelf life in Zone IVb tropical regions.

• Dossier Support: We provide full WHO-standard CTD/eCTD Dossiers with updated safety data to support your firm’s registration in international orthopedic and rheumatology tenders.