Nordimet · 4.1 Therapeutic indications · 1

HOS-217023 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile Most serious adverse reactions of methotrexate include bone marrow suppression, pulmonary toxicity, hepatotoxicity, renal toxicity, neurotoxicity, thromboembolic events, anaphylactic shock and Stevens-Johnson syndrome. Most frequently (very common) observed adverse reactions of methotrexate include gastrointestinal disorders (e.g. stomatitis, dyspepsia, abdominal pain, nausea, loss of appetite) and abnormal liver function tests (e.g. increased Alanine aminotransferase (ALAT), Aspartate aminotransferase (ASAT), bilirubin, alkaline phosphatase). Other frequently (common) occurring adverse reactions are leukopenia, anaemia, thrombopenia, headache, tiredness, drowsiness, pneumonia, interstitial alveolitis/pneumonitis often associated with eosinophilia, oral ulcers, diarrhoea, exanthema, erythema and pruritus. The most relevant adverse reaction is suppression of the haematopoietic system and gastrointestinal disorders. List of adverse reactions 12 Frequencies are defined using the following convention: 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, adverse reactions are presented in order of decreasing seriousness. Infections and infestations Uncommon: Pharyngitis. Rare: Infection (incl. reactivation of inactive chronic infection), sepsis, conjunctivitis. Neoplasms benign, malignant and unspecified (including cysts and polyps) Very rare: lymphoma (see “description” below) Blood and lymphatic system disorders Common: Leukopenia, anaemia, thrombopenia. Uncommon: Pancytopenia. Very rare: Agranulocytosis, severe courses of bone marrow depression, lymphoproliferative disorders (see “description below”). Not known: Eosinophilia Immune system disorders Rare: Allergic reactions, anaphylactic shock, hypogammaglobulinaemia. Metabolism and nutrition disorders Uncommon: Precipitation of diabetes mellitus. Psychiatric disorders Uncommon: Depression, confusion. Rare: Mood alterations. Nervous system disorders Common: Headache, tiredness, drowsiness. Uncommon: Dizziness. Very rare: Pain, muscular asthenia, paraesthesia/hypoaesthesia, changes in sense of taste (metallic taste), convulsions, meningism, acute aseptic meningitis, paralysis. Not known: Encephalopathy/ Leukoencephalopathy. Eye disorders Rare: Vis

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HOS-217019 · has-contraindication-information · PDF-Seite 5

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. - Severe hepatic impairment if serum if bilirubin is > 5 mg/dl (85.5 µmol/l) (see section 4.2). - Alcohol abuse. - Severe renal impairment (creatinine clearance less than 30 ml/min) (see sections 4.2 and 4.4). - Pre-existing blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia. - Immunodeficiency. - Serious, acute or chronic infections such as tuberculosis and HIV. - Stomatitis, ulcers of the oral cavity and known active gastrointestinal ulcer disease. 5 - Pregnancy and breast-feeding (see section 4.6). - Concurrent vaccination with live vaccines.

HOS-217018 · has-indication-information · PDF-Seite 3

Nordimet is indicated for the treatment of: - active rheumatoid arthritis in adult patients, - polyarthritic forms of severe, active juvenile idiopathic arthritis (JIA), when the response to nonsteroidal anti-inflammatory drugs (NSAIDs) has been inadequate, - moderate to severe plaque psoriasis in adults who are candidates for systemic therapy, and severe psoriatic arthritis in adult patients, - induction of remission in moderate steroid-dependent Crohn's disease in adult patients, in combination with corticosteroids and for maintenance of remission, as monotherapy, in patients who have responded to methotrexate.

HOS-217021 · has-interaction-information · PDF-Seite 9

NSAIDs including salicylic acid In animal experiments NSAIDs including salicylic acid caused reduction of tubular methotrexate secretion and consequently increased its toxic effects. However, in clinical studies, where NSAIDs and salicylic acid were given as concomitant medicinal products to patients with rheumatoid arthritis, no increase of adverse reactions was observed. Treatment of rheumatoid arthritis with such medicinal products can be continued during low-dose methotrexate therapy but only under close medical supervision. Hepatotoxicity Regular alcohol consumption and administration of additional hepatotoxic medicinal products increase the probability of hepatotoxic effects of methotrexate. Alcohol consumption must be avoided during treatment with methotrexate. Patients taking potentially hepatotoxic and haematoxic medicinal products during methotrexate therapy (e.g. leflunomide, azathioprine, sulphasalazine, and retinoids) should be closely monitored for possibly increased hepatotoxicity. Haematotoxic medicinal products Administration of additional haematotoxic medicinal products increases the likelihood of severe haematoxic adverse reactions to methotrexate. Concurrent administration of metamizole and methotrexate can increase the haematotoxic effect of methotrexate, especially in elderly patients. 9 Therefore, coadministration should be avoided. Pharmacokinetic interactions One should be aware of pharmacokinetic interactions between methotrexate, anticonvulsant medicinal products (reduced methotrexate blood levels), and 5-fluorouracil (increased t½ of 5--fluorouracil). Alterations in bioavailability of methotrexate Salicylates, phenylbutazone, phenytoin, barbiturates, tranquillisers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides and p-aminobenzoic acid displace methotrexate from serum albumin binding and thus increase bioavailability (indirect dose increase). Probenecid and mild organic acids may also reduce tubular methotrexate secretion, and thus cause indirect dose elevations, too. Antibiotics, like penicillin, glycopeptides, sulfonamides, ciprofloxacin and cefalotin can, in individual cases, reduce the renal clearance of methotrexate, so that increased serum concentrations of methotrexate with simultaneous haematological and gastro-intestinal toxicity may occur. Oral antibiotics such as tetracyclines, chloramphenicol and non-absorbable broad-spectrum antib

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HOS-217022 · has-pregnancy-information · PDF-Seite 11

Women of childbearing potential / contraception in females Women must not get pregnant during methotrexate therapy, and effective contraception must be used during treatment with methotrexate and at least 6 months thereafter (see section 4.4). Prior to initiating therapy, women of childbearing potential must be informed of the risk of malformations associated with methotrexate and any existing pregnancy must be excluded with certainty by taking appropriate measures, e.g. a pregnancy test. During treatment pregnancy tests should be repeated as clinically required (e.g. after any gap of contraception). Female patients of reproductive potential must be counselled regarding pregnancy prevention and planning. Contraception in males It is not known if methotrexate is present in semen. Methotrexate has been shown to be genotoxic in animal studies, such that the risk of genotoxic effects on sperm cells cannot completely be excluded. Limited clinical evidence does not indicate an increased risk of malformations or miscarriage following paternal exposure to low-dose methotrexate (less than 30 mg/week). For higher doses, there is insufficient data to estimate the risks of malformations or miscarriage following paternal exposure. As precautionary measures, sexually active male patients or their female partners are recommended to use reliable contraception during treatment of the male patient and for at least 3 months after cessation of methotrexate. Men should not donate semen during therapy or for 3 months following discontinuation of methotrexate. Pregnancy Methotrexate is contraindicated during pregnancy in non-oncological indications (see section 4.3). If pregnancy occurs during treatment with methotrexate and up to six months thereafter, medical advice should be given regarding the risk of harmful effects on the child associated with treatment 11 and ultrasonography examinations should be performed to confirm normal foetal development. In animal studies, methotrexate has shown reproductive toxicity, especially during the first trimester (see section 5.3). Methotrexate has been shown to have a teratogenic effect in humans; it has been reported to cause foetal death and/or congenital abnormalities (e.g. craniofacial, cardiovascular, central nervous system and extremity-related). Methotrexate is a powerful human teratogen, with an increased risk of spontaneous abortions, intrauterine growth restriction and cong

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HOS-217020 · has-warning-information · PDF-Seite 6

Patients must be clearly advised that the therapy is to be administered once a week, and not every day. Incorrect administration of methotrexate can lead to severe, including potentially lethal adverse reactions. Healthcare professionals and patients should be clearly instructed. Patients receiving therapy should be appropriately monitored, so that signs of possible toxic effects or adverse reactions can be recognised and assessed without delay. Hence, methotrexate should be only administered by, or under the supervision of, doctors whose knowledge and experience include the use of antimetabolite therapy. Due to the risk of severe or even fatal toxic reactions, patients should be thoroughly informed by the doctor about the risks (including early signs and symptoms of toxicity) and recommended safety measures. They are to be informed about the necessity to immediately consult the physician if symptoms of intoxication occur, as well as about the subsequent necessary monitoring of symptoms of intoxication (including regular laboratory tests). Doses exceeding 20 mg/week can be associated with significant increase in toxicity, especially bone marrow suppression. Skin and mucosal contact with methotrexate is to be avoided. In the case of contamination, the parts concerned should be rinsed with plenty of water. Fertility and reproduction Fertility Methotrexate has been reported to cause oligospermia, menstrual dysfunction and amenorrhoea in humans, during and for a short period after cessation of therapy, and to cause impaired fertility, affecting spermatogenesis and oogenesis during the period of its administration. These effects appear to be reversible on discontinuing therapy. Teratogenicity – reproductive risk Methotrexate causes embryotoxicity, abortion and foetal defects in humans. Therefore, the possible risks of effects on reproduction, pregnancy loss and congenital malformations should be discussed with female patients of childbearing potential (see section 4.6). The absence of pregnancy must be confirmed before Nordimet is used. If women of child bearing potential are treated, effective contraception must be used during treatment and for at least six months after. For contraception advice for men, see section 4.6. Recommended examinations and safety measures Before initiating therapy or upon resuming therapy after a rest period Complete blood count with differential blood count and platelets, liver enzymes, bilirubin, serum albumin, chest X-ra

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