ARAVA (Leflunomide) is indicated for the treatment of adult patients with: active rheumatoid arthritis as a "disease-modifying antirheumatic drug" (DMARD). Active psoriatic arthritis Recent or concurrent treatment with hepatotoxic or haematotoxic DMARDs (e.g.methotrexate) may result in an increased risk of serious adverse reactions; therefore, the initiation of leflunomide treatment has to be carefully considered regarding these benefit/risk aspects. Moreover, switching from leflunomide to another DMARD without following the washout procedure may also increase the risk of serious adverse reactions even for a long time after the switching. Arava must not be used in patients with hypersensitivity to leflunomide (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) or to any of the excipients in the tablets. Leflunomide is contraindicated in: - patients with impairment of liver function, - patients with severe immunodeficiency states, e.g. AIDS, - patients with significantly impaired bone marrow function or significant anaemia, leukopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis, - patients with serious infections, - patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group, - patients with severe hypoproteinaemia, e.g. in nephrotic syndrome, - pregnant women, or women of childbearing potential who are not using reliable contraception during treatment with leflunomide and thereafter as long as the plasma levels of the active metabolite are above 0.02 mg/l (see also section 4.6). Pregnancy must be excluded before start of treatment with leflunomide. Women must not breast-feed while they are receiving leflunomide. See also section 4.6. Male patients should be aware of the possible male-mediated foetal toxicity. Reliable contraception during treatment with leflunomide should also be guaranteed. Arava is not recommended for use in patients under 18 years as its safety and efficacy have not been studied in this age group.

ALT (SGPT) and a complete blood cell count, including differential white blood cell count and a platelet count, must be checked simultaneously and with the same frequency: • Before initiation of leflunomide • every two weeks during the first six months of treatment and • every 8 weeks thereafter (see also section 4.4). Leflunomide therapy is started with a loading dose of 100 mg once daily for 3 days. The recommended maintenance dose for rheumatoid arthritis is leflunomide 10 mg to 20 mg once daily and is 20mg once daily for psoriatic arthritis (see section 5.1). The therapeutic effect usually starts after 4 to 6 weeks and may further improve up to 4 to 6 months. There is no dose adjustment recommended in patients with mild renal insufficiency. No dosage adjustment is required in patients above 65 years of age. The product should be prescribed by specialists experienced in the treatment of rheumatoid arthritis and psoriatic arthritis.

Cardiac disorders Common: mild increase in blood pressure Rare: severe increase in blood pressure Gastrointestinal disorders Common: diarrhoea, nausea, vomiting, anorexia, oral mucosal disorders (e.g., aphthous stomatitis, mouth ulceration), abdominal pain Hepato-biliary disorders Common: elevation of liver parameters (transaminases [especially ALT], less often gamma-GT, alkaline phosphatase, bilirubin) Rare: hepatitis, jaundice/cholestasis and very rarely, severe liver injury such as hepatic failure and acute hepatic necrosis that may be fatal Very rare: pancreatitis Infections and infestations Very rare: severe infections, including sepsis which may be fatal Like other agents with immunosuppressive potential, leflunomide may increase susceptibility to infections, including opportunistic infections (see also section 4.4). Thus, the overall incidence of infections can increase (in particular of rhinitis, bronchitis and pneumonia) Metabolism and nutrition disorders Common: weight loss (usually insignificant) Uncommon: hypokalaemia Nervous system disorders Common: headache, dizziness, asthenia, paraesthesia Uncommon: taste disturbances, anxiety Very rare: peripheral neuropathy Musculoskeletal and connective tissue disorders Common: tenosynovitis Uncommon: tendon rupture Skin and subcutaneous tissue disorders Common: increased hair loss, eczema, dry skin Uncommon: urticaria Very rare: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme Immune system disorders Common: mild allergic reactions, rash (including maculopapular rash), pruritus Very rare: severe anaphylactic/anaphylactoid reactions Respiratory, thoracic and mediastinal disorders Rare: interstitial lung disease (including interstitial pneumonitis), which may be fatal. Blood and lymphatic system disorders Common: leukopenia (leukocytes>2 G/l) Uncommon: anaemia, mild thrombocytopenia (platelets <100 G/l) Rare: eosinophilia, leukopenia (leukocytes <2 G/l), pancytopenia (probably by antiproliferative mechanism) Very rare: agranulocytosis, vasculitis Recent, concomitant or consecutive use of potentially myelotoxic agents may be associated with a higher risk of haematological effects. The risk of malignancy, particularly lymphoproliferative disorders, is increased with use of some immunosuppressive agents. Mild hyperlipidaemia may occur. Uric acid levels usually decrease. Laboratory findings for which a clinical relevance could not be established include small increases in LDH and CK. Mild hypophosphataemia is uncommon. Marginal (reversible) decreases in sperm concentration, total sperm count and rapid progressive motility cannot be excluded. The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. If a severe undesirable effect of leflunomide occurs, or if for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure described in section 4.4 has to be followed. The procedure may be repeated as clinically necessary. For suspected severe immunological/allergic reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis, a complete washout is essential.