Jayempi · 4.6 Fertility, pregnancy and lactation · 1

HOS-287687 · has-adverse-reaction-information · PDF-Seite 13

Summary of the safety profile The most frequently reported adverse reactions include bone marrow depression, most frequently expressed as leukopenia and thrombocytopenia as well as viral, fungal and bacterial infections after using azathioprine in combination with other immunosuppressants. The most serious adverse reactions are usually rare to very rare and include life-threatening liver injury , neoplasms including hepatosplenic T-cell lymphoma, hypersensitivity, Stevens-Johnson syndrome and toxic epidermal necrolysis. Tabulated list of adverse reactions The adverse reactions are listed below according to system organ class and frequency. The frequencies are defined as follows: 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 the order of decreasing seriousness. 13 System organ class Frequency Adverse reactions Infections and infestations Very common Viral, fungal and bacterial infections (in transplant recipients who are treated with azathioprine in combination with other immunosuppressants) Uncommon Viral, fungal and bacterial infections (in other patients) Very rare Cases of progressive multifocal leukoencephalopathy (PML) caused by the JC virus have been reported after using azathioprine in combination with other immunosuppressants (see section 4.4) Neoplasms benign, malignant Rare Neoplasms including and unspecified (incl. cysts and lymphoproliferative disorders, skin polyps) cancers (malignant melanomas and non- melanomas), sarcomas (Kaposi

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HOS-287683 · has-contraindication-information · PDF-Seite 7

- Hypersensitivity to the active substance azathioprine, 6-mercaptopurine (metabolite of azathioprine) or to any of the excipients listed in section 6.1. - Any live vaccine, especially Bacillus Calmette-Guérin (BCG), measles, mumps and rubella (MMR), smallpox, yellow fever (see section 4.5). - Lactation (see section 4.6).

HOS-287682 · has-indication-information · PDF-Seite 2

Transplantation Jayempi is indicated in combination with other immunosuppressive agents for the prophylaxis of transplant rejection in patients receiving allogenic kidney, liver, heart, lung or pancreas transplants. Azathioprine is indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basis immunosuppression). Jayempi is used as an immunosuppressant antimetabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and/ or procedures which influence the immune response. Chronic inflammatory bowel disease (IBD) Jayempi is used for the treatment of moderately severe to severe forms of chronic inflammatory bowel disease (IBD) (Crohn’s disease or ulcerative colitis) in patients in whom glucocorticosteroid therapy is necessary, but where glucocorticosteroids are not tolerated, or in whom the disease is untreatable with other common means of first choice. Multiple sclerosis (adults only) It is also indicated in adult patients in relapsing multiple sclerosis, if an immunomodulatory therapy is indicated but beta interferon therapy is not possible, or a stable course has been achieved with previous treatment with azathioprine. Myasthenia gravis Jayempi is indicated for the treatment of generalised myasthenia gravis. Depending on the severity of the disease, Jayempi should be given in combination with glucocorticosteroids because of slow onset of action at the beginning of treatment and the glucocorticosteroid dose should be gradually reduced after several months of treatment. 2 Other conditions Jayempi is indicated in patients who are intolerant to glucocorticosteroids or if the therapeutic response is inadequate despite treatment with high doses of glucocorticosteroids, in the following diseases: - severe active rheumatoid arthritis (chronic polyarthritis) that cannot be kept under control by less toxic agents (disease-modifying anti-rheumatic -medicinal products – DMARDs) - auto-immune hepatitis - systemic lupus erythematosus - dermatomyositis - polyarteritis nodosa - pemphigus vulgaris and bullous pemphigoid - Behçet’s disease - refractory auto-immune haemolytic anaemia, caused by warm IgG antibodies - chronic refractory idiopathic thrombocytopenic purpura

HOS-287685 · has-interaction-information · PDF-Seite 11

Vaccines The immunosuppressive activity of azathioprine can lead to an atypical and possibly harmful response to live vaccines. Therefore, it is recommended that patients do not receive live vaccines until at least 3 months after the end of treatment with azathioprine (see section 4.4). Immunosuppressed patients must not be vaccinated with live vaccines, since they are at risk of infection from the live vaccine (see section 4.4). A decreased immune response to inactivated or toxoid vaccines is likely. This has been observed with hepatitis B vaccine among patients treated with a combination of azathioprine and corticosteroids. Therefore, the vaccination success should always be checked with a titre determination. A small clinical study has indicated that standard therapeutic doses of azathioprine do not deleteriously affect the immune response to a polyvalent pneumococcal vaccine (as assessed on the basis of mean anti-capsular specific antibody concentration). Effects of concomitantly administered medicinal products on azathioprine Ribavirin Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to lower production of active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore, co-administration is not advised (see sections 4.4 and 5.2). Cytostatic/myelosuppressive agents Where possible, concomitant administration of cytostatic medicinal products, or medicinal products which may have a myelosuppressive effect, such as penicillamine, should be avoided (see section 4.4). There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between azathioprine and trimethoprim/sulfamethoxazole. There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and angiotensin-converting enzyme (ACE) inhibitors. It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of azathioprine. Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxipurinol and/or thiopurinol are given concomitantly with 6-mercaptop

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HOS-287686 · has-pregnancy-information · PDF-Seite 12

Men and women of childbearing potential Both male and female patients of reproductive age should use contraceptive methods while using azathioprine (see section 4.4). Men should not father children during and up to 6 months after the end of treatment. This also applies to patients with reduced fertility due to chronic uraemia, as fertility generally returns to normal after a transplant. Case reports indicate that intrauterine devices (IUD) (coil or T-shaped ‘copper coil’) can fail under azathioprine therapy. Therefore, other or additional contraceptive methods should be recommended. Pregnancy Malformations occurred in animal experiments due to azathioprine. In animal studies azathioprine was teratogenic and embryotoxic (see section 5.3). There are conflicting findings on the teratogenic potential of azathioprine in humans. Azathioprine must only be used during pregnancy after a careful benefit/risk analysis. It is known that considerable amounts of azathioprine and its metabolites pass through the placenta and amniotic sac, and are thereby transferred from the mother to the foetus. Blood count changes (leukopenia and/or thrombocytopenia) have been reported in a number of neonates whose mothers received azathioprine during pregnancy. Extra care in haematological monitoring of the mother is advised during pregnancy. 12 Temporary impairment of the immune response was detected in neonates from intrauterine exposure to a combination of azathioprine with prednisone. There have been reports of intrauterine growth retardation, premature births and low birth weights vis-à-vis azathioprine, in particular in combination with corticosteroids. Moreover, data is available on spontaneous abortions after both maternal and paternal exposure. Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes of the offspring of patients treated with azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine. Cholestasis of pregnancy has occasionally been reported in association with azathioprine therapy. Early diagnosis and discontinuation of azathioprine may minimise the effects on the foetus. However, the maternal benefit and the effects on the foetus should be carefully assessed if cholestasis of pregnancy is confirmed. Breast-feeding 6-Mercaptopurine, the active metabolite of azat

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HOS-287684 · has-warning-information · PDF-Seite 7

Monitoring Therapy with Jayempi in pre-existing, severe infections, in severe disorders of the liver and bone marrow function and in the presence of pancreatitis should only be initiated subject to a careful benefit/risk analysis and the precautions specified below. Special attention should be given to monitoring the blood count. If necessary, the maintenance dose should be reduced as much as possible, provided there is clinical response. Azathioprine should only be prescribed if the patient can be adequately monitored for haematological and hepatic effects throughout the duration of therapy. During the first 8 weeks of treatment, a complete blood count, including platelet count must be performed at least once weekly. It should be controlled more frequently: - if high doses are used - in elderly patients - if renal function is impaired. If haematological toxicity occurs, the dose must be reduced (see also sections 4.2 and 5.2) - if hepatic function is impaired. In this case, liver function should be monitored regularly and if hepatic or haematological toxicity occur, the dose must be reduced (see also sections 4.2 and 5.2). In particular, patients with impaired liver function require special monitoring when using azathioprine, as life-threatening liver damages have been reported (see section 4.8). This is particularly important in patients with severe impaired liver function and azathioprine should only be used after a careful benefit/risk analysis. Azathioprine is hepatotoxic and liver function tests should be routinely monitored during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. Cases of non-cirrhotic portal hypertension/portosinusoidal vascular disease have been reported. Early clinical signs include liver enzyme abnormalities, mild jaundice, thrombocytopenia, and splenomegaly (see section 4.8). The patients should be informed about the symptoms of liver injury and advised to contact their doctor immediately if these occur. The frequency of blood counts may be reduced after 8 weeks and be repeated monthly or at least at intervals of no longer than 3 months (maximum quarterly). At the first sign of an abnormal change in the blood count, treatment should be discontinued immediately because the number of leucocytes and platelets may continue to decrease after the end of treatment. Patients receiving azathioprine mu

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