1. NAME OF THE MEDICINAL PRODUCT Azathioprin Orifarm 50 mg film-coated tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Azathioprine 50 mg For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Film-coated tablet Light yellow, film-coated, circular, biconvex tablet engraved ”A50”and score line on one side and plain on the other side. The score line is not intended for breaking the tablet. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Azathioprine 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 usually indicated in immunosuppressive regimens as an adjunct to immunosuppressive agents that form the mainstay of treatment (basis immunosuppression). Azathioprine is indicated in severe cases of systemic lupus erythematosus, in patients who are intolerant to steroids or who are dependent on steroids and in whom the therapeutic response is inadequate despite treatment with high doses of steroids. 4.2 Posology and method of administration Posology Transplantation Depending on the immunosuppressive regime selected, a loading dose of up to 5mg/kg/body weight/day orally is usually given. The maintenance dose can range from 1-4 mg/kg body weight/day and should be adjusted according to the clinical response and haematological tolerance. To enhance the survival and function of the transplant organ azathioprine is often given in combination with corticosteroids. Withdrawal of treatment with azathioprine after several years of therapy entail a high risk of graft rejection. Systemic lupus erytematosus In general, the starting dosage is 1-3mg/kg/body weight/day and should be adjusted according to the clinical response (which may not be evident for weeks or months) and haematological tolerance. The maintenance dose is usually 2-2,5 mg/kg body weight/day and should be adjusted according to the clinical response and haematological tolerance. Clinical response is expected within a few days or weeks after starting treatment with azathioprine. If a clinical effect is not reached within three months, discontinuation should be considered. Otherwise it may be continued as a long term treatment if tolerated. Since the treatment effects can have a delayed onset of action it is important to without delay adjust dosing in case of rapid fall of leukocyte counts or other signs of myelosuppression Use in patients with renal and/ or hepatic impairment: In patients with impaired renal and/or hepatic function, it should be considered to reduce the dosage (see section 4.4). Azathioprine is contra-indicated in severe hepatic impairment. (See section 4.3). Paediatric population There are insufficient data to recommend the use of azathioprine for the treatment of systemic lupus erythematosus (in children and adolescents < 18 years). Concerning the other indication the given dose recommendations apply for children and adolescents as well as for adults. Use in the elderly: There is limited experience of the administration of azathioprine in elderly patients. It is advisable to monitor renal and hepatic function, and to consider dosage reduction if there is impairment (see section 4.2 – Renal and/or hepatic impairment). Interaction with other medicinal products When allopurinol, oxipurinol or thiopurinol is given concomitantly with azathioprine, the dose of azathioprine must be reduced to a quarter of the original dose (see sections 4.4 and 4.5). It can take weeks or months before therapeutic effect is seen. The medicinal product may be given over the long term unless the patient cannot tolerate the preparation. Withdrawal of azathioprine should always be a gradual process performed under close monitoring. Treatment with azathioprine should be initiated or supervised by a physician with great experience of immunosuppressive treatment. Azathioprine should only be prescribed if sufficient follow-up concerning toxic effects can be provided throughout the treatment period. TPMT-deficient patients Patients with inherited little or no thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe azathioprine toxicity from conventional doses of azathioprine and generally requires substantial dose reduction. The optimal starting dose for homozygous patients with TPMT deficiency has not been established (see section 4.4 and 5.2). Most patients with heterozygous TPMT deficiency tolerate recommended azathioprine doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available (see section 4.4 and 5.2). Patients with NUDT15 variant Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity (see section 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see section 4.4). Genotypic testing of NUDT15 variants may be considered before initiating azathioprine therapy. In any case, close monitoring of blood counts is necessary. Method of administration Azathioprin Orifarm is supplied for oral administration. The tablet should be taken with at least a glass of liquid (200 ml). Azathioprin Orifarm should be taken following a meal in order to reduce the risk of nausea. Halving of the film-coated tablet should be avoided. The score line is not intended to divide the tablet into equal doses. 4.3 Contraindications Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 Hypersensitivity to 6-mercaptopurine (6-MP) Severe infections Seriously impaired hepatic function or bone marrow function Pancreatitis Any live vaccine, especially BCG, smallpox or yellow fever Lactation (see section 4.6) 4.4 Special warnings and special precautions for use Immunisation using a live vaccine is not recommended as it has the potential to cause infection in immunocompromised hosts (see section 4.5). Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine (see section 4.5). Monitoring There are potential dangers in the use of azathioprine; it should therefore not be prescribed unless the patient can be adequately monitored for toxic effects throughout the duration of therapy. Especially the haematological toxicity should be closely monitored and the maintenance dose must be reduced to the lowest dose required for a clinically response. During the first eight 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 hepatic function is mildly to moderately impaired (see also sections 4.2 and 5.2) - if bone marrow function is mildly to moderately impaired (see also section 4.2) - in patients with hypersplenism The frequency of the blood count controls may be reduced after 8 weeks. It is recommended that complete blood counts be repeated monthly, or at least at intervals of no longer than 3 months. At the first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped. S-alkaline phosphatase, S-transaminase and S-bilirubin should be monitored. Increase in these parameters may necessitate dose reduction or temporary discontinuation. Patients must be advised to inform their doctor immediately about ulcerations of the throat, fever, infections, bruising, bleeding or other signs of myelosuppression. Myelosuppression is reversible if azathioprine is stopped early enough. 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. The patient should be instructed to discontinue azathioprine immediately if jaundice becomes apparent. There are individuals with an inherited deficiency of the enzyme thiopurine methyl transferase (TPMT) who may be unusually sensitive to the myelosuppression effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co- administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6– mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see section 4.8). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary. Patients with NUDT15 variant Patients with inherited mutated NUDT15 gene are at increased risk for severe azathioprine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require dose reduction, particularly those being NUDT15 variant homozygotes (see section 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10% in East Asians, 4% in Hispanics, 0.2% in Europeans and 0% in Africans. In any case, close monitoring of blood counts is necessary. The dosage of azathioprine may need to be reduced when this agent is combined with other drugs