Leflunomide

Approved Indications:

• Rheumatoid Arthritis (RA)
  For the treatment of active moderate-to-severe rheumatoid arthritis in adults to reduce signs and symptoms, inhibit structural damage, and improve physical function.
• Psoriatic Arthritis (PsA)
  Approved for adults with active psoriatic arthritis to alleviate symptoms and slow disease progression.

Clinically Accepted (Off-label) Uses:

• Lupus nephritis (in systemic lupus erythematosus)
• Juvenile idiopathic arthritis (JIA) in selected cases
• Sarcoidosis (refractory cases)
• Wegener’s granulomatosis (granulomatosis with polyangiitis)
• Graft-versus-host disease (GVHD) prevention post-hematopoietic stem cell transplantation
• Autoimmune uveitis

Formulation:

• Oral tablets: 10 mg, 20 mg

Route of Administration:

• Oral

A. Adults

• Loading dose can be skipped in patients with higher risk of adverse effects.

B. Pediatric Use

• Not FDA-approved for pediatric patients.
• Occasionally used off-label in juvenile idiopathic arthritis at 0.3 mg/kg/day (max 20 mg/day), under specialist supervision.

Special Populations:

• Renal Impairment:
  Use with caution; limited data. Avoid in severe renal impairment.
• Hepatic Impairment:
  Contraindicated in moderate to severe liver dysfunction (ALT or AST >2× ULN).
• Elderly:
  No specific dose adjustment, but monitor liver and hematologic parameters more frequently.

Leflunomide is a pyrimidine synthesis inhibitor that exerts immunomodulatory and anti-inflammatory effects by selectively inhibiting dihydroorotate dehydrogenase (DHODH), a key mitochondrial enzyme in de novo pyrimidine synthesis. This leads to a reduction in activated T and B lymphocyte proliferation, which rely heavily on this pathway for DNA and RNA synthesis. As a result, Leflunomide slows down the autoimmune-mediated joint destruction seen in rheumatoid and psoriatic arthritis, reducing inflammation and preventing structural damage.

• Absorption:
  Rapid and extensive absorption after oral administration. Bioavailability ~80–90%.
• Distribution:
  Volume of distribution: ~0.13 L/kg
  Protein binding: >99%
• Metabolism:
  Leflunomide is a prodrug, rapidly converted in the GI tract and liver to its active metabolite, teriflunomide (A77 1726).
• Elimination:
• Primarily via biliary excretion (major route)
• ~43% in feces, ~27% in urine (as metabolites)
• Half-life:
  15–18 days (long due to enterohepatic recycling)
• Time to steady-state:
  ~6–8 weeks without loading dose

• Pregnancy:
• Category X (Contraindicated): Teratogenic in animals; can cause birth defects in humans.
• Women of childbearing potential must use effective contraception during treatment and until drug levels are undetectable.
• Drug elimination procedure (with cholestyramine or activated charcoal) is required before pregnancy is attempted.
• Lactation:
• Excretion in human milk unknown; not recommended during breastfeeding due to potential serious adverse effects.

• Primary Class: Disease-Modifying Antirheumatic Drug (DMARD)
• Subclass: Pyrimidine synthesis inhibitor (non-biologic DMARD)

• Known hypersensitivity to leflunomide or its metabolites
• Pregnancy or women of childbearing potential not using effective contraception
• Severe hepatic impairment
• Pre-existing liver disease (ALT/AST >2× ULN)
• Severe immunodeficiency, bone marrow dysplasia, or severe uncontrolled infections

• Hepatotoxicity:
  Can cause fatal liver injury. Monitor ALT/AST monthly for the first 6 months, then every 6–8 weeks.
• Teratogenicity:
  Strictly contraindicated in pregnancy; use reliable contraception.
• Immunosuppression:
  Increases risk of infections including reactivation of TB and hepatitis B.
• Severe bone marrow suppression:
  Monitor CBC regularly; discontinue if pancytopenia or agranulocytosis develops.
• Interstitial lung disease:
  Rare but serious; monitor for dyspnea and cough.
• Peripheral neuropathy:
  Can occur; usually reversible upon discontinuation.
• Hypertension:
  Monitor blood pressure regularly.

Common (≥1%):

• Gastrointestinal: Diarrhea, nausea, abdominal pain
• Hepatic: Elevated ALT/AST
• Dermatologic: Rash, alopecia
• Respiratory: Bronchitis, cough
• Hematologic: Leukopenia

Less Common (<1%):

• Hypertension
• Headache, dizziness
• Weight loss
• Peripheral neuropathy
• Anemia or thrombocytopenia

Serious/Rare:

• Severe hepatotoxicity
• Bone marrow suppression (pancytopenia, agranulocytosis)
• Stevens-Johnson syndrome or toxic epidermal necrolysis
• Interstitial lung disease
• Opportunistic infections

Onset:
Most common side effects appear within the first 1–3 months of treatment.

• Methotrexate or other hepatotoxic drugs:
  ↑ Risk of hepatotoxicity; monitor LFTs closely.
• Warfarin:
  Leflunomide may ↑ INR — monitor coagulation parameters.
• Cholestyramine & Activated Charcoal:
  Accelerate elimination of teriflunomide; used in toxicity or before pregnancy.
• Live vaccines:
  Avoid during and after treatment until immune function recovers.
• CYP2C9 substrates (e.g., warfarin, phenytoin):
  Teriflunomide may inhibit metabolism — monitor levels/dose adjustment may be needed.

• ACR 2023 RA Guidelines:
  Leflunomide remains a first-line non-biologic DMARD option in RA alongside methotrexate.
• EULAR recommendations:
  Endorse use in RA and PsA; emphasize monitoring liver enzymes and pregnancy risk.
• Updated pregnancy guidelines:
  Women must undergo accelerated drug elimination procedure before attempting conception.
• Monitoring update:
  LFTs and CBC should be checked monthly for 6 months, then every 6–8 weeks.

• Storage Temperature:
  Store at 20°C to 25°C (68°F to 77°F)
  Permitted range: 15°C to 30°C (59°F to 86°F)
• Humidity & Light:
  Store in a dry place, protect from moisture and direct light.
• Handling Precautions:
  Tablets should be handled with care.
  Wash hands after handling; pregnant women or women planning pregnancy should not handle the tablets.
• No reconstitution or refrigeration required.