Summary of the safety profile: The most frequently reported adverse effects with leflunomide are: mild increase in blood pressure, leucopenia, paresthesia, headache, dizziness, diarrhea, nausea, vomiting, oral mucosal disorders (e.g. aphthous stomatitis, mouth ulceration), abdominal pain, increased hair loss, eczema, rash (including maculo-papular rash), pruritus, dry skin, tenosynovitis, CPK increased, anorexia weight loss (usually insignificant), asthenia, mild allergic reactions and elevation of liver parameters (transaminases (especially ALT) less often gamma-GT alkaline phosphates, bilirubin)).
Classification of expected frequencies: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Infections and infestations: Rare: Severe infections including sepsis which may be fatal.
Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to infections, including opportunistic infections. Thus, the overall incidence of infections can increase (in particular of rhinitis, bronchitis and pneumonia).
Neoplasms benign, malignant and unspecified (incl. cysts and polyps): The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some immunosuppressive agents.
Blood and lymphatic system disorders: Common: Leucopenia (leucocytes >2 G/l).
Uncommon: Anaemia, mild thrombocytopenia (platelets <100 G/l).
Rare: Pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes <2 G/l)
Very rare: Agranulocytosis.
Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher risk of haematological effects.
Immune system disorders: Common: Mild allergic reactions.
Very rare: Severe anaphylactic/anaphylactoid reactions, vasculitis, including cutaneous necrotizing vasculitis.
Metabolism and nutrition disorders: Common: CPK increased.
Uncommon: Hypokalaemia, hyperlipidemia, hypophosphataemia.
Rare: LDH increased.
Not known: Hypouricemia.
Psychiatric disorders: Uncommon: Anxiety.
Nervous system disorders: Common: Paraesthesia, headache, dizziness, peripheral neuropathy.
Cardiac disorders: Common: Mild increase in blood pressure.
Rare: Severe increase in blood pressure.
Respiratory, thoracic and mediastinal disorders: Rare: interstitial lung disease (including interstitial pneumonitis), which may be fatal.
Gastrointestinal disorders: Common: diarrhoea, nausea, vomiting, oral mucosal disorders (e.g., aphthous stomatitis, mouth ulceration) abdominal pain.
Uncommon: Taste disturbances.
Very rare: Pancreatitis.
Hepatobiliary disorders: Common: Elevation of liver parameters (transaminases [especially ALT], less often gamma-GT, alkaline phosphatase, bilirubin).
Rare: Hepatitis jaundice/cholestasis.
Very rare: Severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal.
Skin and subcutaneous tissue disorders: Common: Increased hair loss, eczema, rash (including maculopapular rash), pruritus, dry skin.
Very rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Not known: Cutaneous lupus erythematosus, pustular psoriasis or worsening psoriasis, Drug Reactions with Eosinophilia and Systemic Symptoms (DRESS).
Musculoskeletal and connective tissue disorders: Common: Tenosynovitis.
Uncommon: Tendon rupture.
Renal and urinary disorders: Not known: renal failure.
Reproductive system and breast disorders: Not known: Marginal (reversible) decrease in sperm concentrations, told sperm count and rapid progressive motility.
General disorders and administration site conditions: Common: Anorexia, weight loss (usually insignificant), asthenia.