Leflunomide ratiopharm

HOS-155097 · has-adverse-reaction-information · PDF-Seite 11

Summary of the safety profile The most frequently reported adverse effects with leflunomide are: mild increase in blood pressure, leucopenia, paraesthesia, headache, dizziness, diarrhoea, 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 phosphatise, 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 (see also section 4.4). 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) 11 Rare: pancytopenia (probably by antiproliferative mechanism), leucopenia (leucocytes <2 G/L), eosinophilia 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: hypou

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HOS-155093 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity (especially previous Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme) to the active substance, to the principal active metabolite teriflunomide, to peanut or soya or to any of the excipients listed in section 6.1. • Patients with impairment of liver function. • Patients with severe immunodeficiency states, e.g. AIDS. • Patients with significantly impaired bone marrow function or significant anaemia, leucopenia, neutropenia or thrombocytopenia due to causes other than rheumatoid or psoriatic arthritis. • Patients with serious infections (see section 4.4). • Patients with moderate to severe renal insufficiency, because insufficient clinical experience is available in this patient group. 3 • 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 section 4.6). Pregnancy must be excluded before start of treatment with leflunomide. • Breast-feeding women (see section 4.6).

HOS-155092 · has-indication-information · PDF-Seite 2

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 (see section 4.4) may also increase the risk of serious adverse reactions even for a long time after the switching.

HOS-155095 · has-interaction-information · PDF-Seite 7

Interactions studies have only been performed in adults. 7 Increased side effects may occur in case of recent or concomitant use of hepatotoxic or haematotoxic medicinal products or when leflunomide treatment is followed by such medicinal products without a washout period (see also guidance concerning combination with other treatments, section 4.4). Therefore, closer monitoring of liver enzymes and haematological parameters is recommended in the initial phase after switching. Methotrexate In a small (n=30) study with co-administration of leflunomide (10 to 20 mg per day) with methotrexate (10 to 25 mg per week) a 2- to 3-fold elevation in liver enzymes was seen on 5 of 30 patients. All elevations resolved, 2 with continuation of both medicinal products and 3 after discontinuation of leflunomide. A more than 3-fold increase was seen in another 5 patients. All of these also resolved, 2 with continuation of both medicinal products and 3 after discontinuation of leflunomide. In patients with rheumatoid arthritis, no pharmacokinetic interaction between the leflunomide (10 to 20 mg per day) and methotrexate (10 to 25 mg per week) was demonstrated. Vaccinations No clinical data are available on the efficacy and safety of vaccinations under leflunomide treatment. Vaccination with live attenuated vaccines is, however, not recommended. The long half-life of leflunomide should be considered when contemplating administration of a live attenuated vaccine after stopping Leflunomide ratiopharm. Warfarin and other coumarine anticoagulants There have been case reports of increased prothrombin time, when leflunomide and warfarin were co-administered. A pharmacodynamics interaction with warfarin was observed with A771726 in a clinical pharmacology study (see below). Therefore, when warfarin or another coumarin anticoagulant is co-administered, close international normalised ratio (INR) follow-up and monitoring is recommended. NSAIDS/Corticosteroids If the patient is already receiving nonsteroidal anti-inflammatory drugs (NSAIDs) and/or corticosteroids, these may be continued after starting leflunomide. Effect of other medicinal products on leflunomide: Cholestyramine or activated charcoal It is recommended that patients receiving leflunomide are not treated with colestyramine or activated powdered charcoal because this leads to a rapid and significant decrease in plasma A771726 (the active metabolite of leflun

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HOS-155096 · has-pregnancy-information · PDF-Seite 10

Pregnancy The active metabolite of leflunomide, A771726 is suspected to cause serious birth defects when administered during pregnancy. Leflunomide ratiopharm is contraindicated in pregnancy (see section 4.3). Women of childbearing potential have to use effective contraception during and up to 2 years after treatment (see “waiting period” below) or up to 11 days after treatment (see abbreviated “washout period” below). The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing, and if positive, the physician and patient must discuss the risk to the pregnancy. It is possible that rapidly lowering the blood level of the active metabolite, by instituting the drug elimination procedure described below, at the first delay of menses may decrease the risk to the foetus from leflunomide. In a small prospective study in women (n=64) who became inadvertently pregnant while taking leflunomide for no more than three weeks after conception and followed by a drug elimination procedure, no significant differences (p=0.13) were observed in the overall rate of major structural defects (5.4%) compared to either of the comparison groups (4.2% in the disease matched group [n=108] and 4.2% in healthy pregnant women [n=78]). For women receiving leflunomide treatment and who wish to become pregnant, one of the following procedures is recommended in order to ascertain that the foetus is not exposed to toxic concentrations of A771726 (target concentration below 0.02 mg/L): Waiting period A771726 plasma levels can be expected to be above 0.02 mg/L for a prolonged period. The concentration may be expected to decrease below 0.02 mg/L about 2 years after stopping the treatment with leflunomide. After a 2-year waiting period, the A771726 plasma concentration is measured for the first time. Thereafter, the A771726 plasma concentration must be determined again after an interval of at least 14 days. If both plasma concentrations are below 0.02 mg/L no teratogenic risk is to be expected. For further information on the sample testing please contact the marketing authorisation holder or its local representative (see section 7). Washout procedure After stopping treatment with leflunomide: • colestyramine 8 g is administered 3 times daily for a period of 11 days, • alternatively, 50 g of activated powdered charcoal is administered 4 times dail

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HOS-155094 · has-warning-information · PDF-Seite 4

Concomitant administration of hepatotoxic or haematotoxic DMARDs (e.g. methotrexate) is not advisable. The active metabolite of leflunomide, A771726, has a long half-life, usually 1 to 4 weeks. Serious undesirable effects might occur (e.g. hepatotoxicity, haematotoxicity or allergic reactions, see below), even if the treatment with leflunomide has been stopped. Therefore, when such toxicities occur or if for any other reason A771726 needs to be cleared rapidly from the body, the washout procedure has to be followed. The procedure may be repeated as clinically necessary. For washout procedures and other recommended actions in case of desired or unintended pregnancy, see section 4.6. Liver reactions Rare cases of severe liver injury, including cases with fatal outcome, have been reported during treatment with leflunomide. Most of the cases occurred within the first 6 months of treatment. Co- treatment with other hepatotoxic medicinal products was frequently present. It is considered essential that monitoring recommendations are strictly adhered to. ALT (SGPT) must be checked before initiation of leflunomide and at the same frequency as the complete blood cell count (every two weeks) during the first six months of treatment and every 8 weeks thereafter. For ALT (SGPT) elevations between 2- and 3-fold the upper limit of normal, dose reduction from 20 mg to 10 mg may be considered and monitoring must be performed weekly. If ALT (SGPT) elevations of more than 2-fold the upper limit of normal persist or if ALT elevations of more than 3- fold the upper limit of normal are present, leflunomide must be discontinued and wash-out procedures initiated. It is recommended that monitoring of liver enzymes be maintained after discontinuation of leflunomide treatment, until liver enzyme levels have normalised. Due to a potential for additive hepatotoxic effects, it is recommended that alcohol consumption be avoided during treatment with leflunomide. Since the active metabolite of leflunomide, A771726, is highly protein bound and cleared via hepatic metabolism and biliary secretion, plasma levels of A771726 are expected to be increased in patients with hypoproteinaemia. Leflunomide ratiopharm is contraindicated in patients with severe hypoproteinaemia or impairment of liver function (see section 4.3). Haematological reactions Together with ALT, a complete blood cell count, including differential white blood cell count and platelets, must be performed before start o

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