Xaluprine (previously Mercaptopurine Nova Laboratories) · 4.1 Therapeutic indications · 1

HOS-155075 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile The main adverse reaction of treatment with mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia. For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of adverse reactions. 9 Tabulated list of adverse reactions The following events have been identified as adverse reactions. The adverse reactions are displayed by system organ class and frequency: very common (≥1/10), common (≥1/100 to < 1/10), uncommon (≥1/1000 to < 1/100), rare (≥1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. System organ class Frequency Adverse reaction Bacterial and viral infections, Infections and infestations Uncommon infections associated with neutropenia Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and Rare non-melanomas), sarcomas Neoplasms benign, malignant (Kaposi's and non-Kaposi's) and unspecified (including and uterine cervical cancer in cysts and polyps) situ (see section 4.4) Secondary leukaemia and Very rare myelodysplasia Hepatosplenic T-cell Not known lymphoma* (see section 4.4) Bone marrow suppression; Blood and lymphatic system Very common

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HOS-155071 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Concomitant use with yellow fever vaccine (see section 4.5).

HOS-155070 · has-indication-information · PDF-Seite 2

Xaluprine is indicated for the treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children.

HOS-155073 · has-interaction-information · PDF-Seite 7

Effects of food on mercaptopurine The administration of mercaptopurine with food may decrease systemic exposure slightly but this is unlikely to be of clinical significance. Therefore, Xaluprine may be taken with food or on an empty stomach, but patients should standardise the method of administration. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine. 7 Effects of mercaptopurine on other medicinal products Vaccines Concomitant administration of yellow fever vaccine is contraindicated, due to the risk of fatal disease in immunocompromised patients (see section 4.3). Vaccinations with other live organism vaccines are not recommended in immunocompromised individuals (see section 4.4). Anticoagulants Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine, has been reported. Monitoring of the INR (International Normalised Ratio) value is recommended during concomitant administration with oral anticoagulants. Antiepileptics Cytotoxic agents may decrease the intestinal absorption of phenytoin. Careful monitoring of the phenytoin serum levels is recommended. It is possible that the levels of other anti-epileptic medicinal products may also be altered. Serum antiepileptic levels should be closely monitored during treatment with Xaluprine, making dose adjustments as necessary. Effects of other medicinal products on mercaptopurine 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 and Xaluprine are administered concomitantly it is essential that only a quarter of the usual dose of Xaluprine is given since allopurinol decreases the rate of metabolism of mercaptopurine via xanthine oxidase. Also other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of mercaptopurine and concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction. Aminosalicylates As there is in vitro evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, which metabolises mercapt

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HOS-155074 · has-pregnancy-information · PDF-Seite 9

Contraception in males and females Evidence of the teratogenicity of mercaptopurine in humans is equivocal. Both sexually active men and women should use effective methods of contraception during treatment and for at least three or six months respectively after receiving the last dose. Animal studies indicate embryotoxic and embryolethal effects (see section 5.3). Pregnancy Xaluprine should not be given to patients who are pregnant or likely to become pregnant without careful assessment of risk versus benefit. There have been reports of premature birth and low birth weight following maternal exposure to mercaptopurine. There have also been reports of congenital abnormalities and spontaneous abortion following either maternal or paternal exposure. Multiple congenital abnormalities have been reported following maternal mercaptopurine treatment in combination with other chemotherapy agents. A more recent epidemiological report suggests that there is no increased risk of preterm births, low birth weight at term, or congenital abnormalities in women exposed to mercaptopurine during pregnancy. It is recommended that newborns of women exposed to mercaptopurine during pregnancy are monitored for haematological and immune system disturbances. Cholestasis of pregnancy has occasionally been reported in association with azathioprine (a prodrug of mercaptopurine) therapy. A careful assessment of benefit to the mother and impact on the foetus should be performed, if cholestasis of pregnancy is confirmed. Breast-feeding Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment and thus women receiving Xaluprine should not breast-feed. Fertility The effect of mercaptopurine therapy on human fertility is unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence. Transient profound oligospermia has been reported following exposure to mercaptopurine in combination with corticosteroids.

HOS-155072 · has-warning-information · PDF-Seite 5

Cytotoxicity and haematological monitoring Treatment with mercaptopurine causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Careful monitoring of haematological parameters should be conducted during therapy. The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately. Bone marrow suppression is reversible if mercaptopurine is withdrawn early enough. Patients with TPMT variant Patients with inherited variant in the TPMT gene resulting in a deficiency or absence of the TPMT enzyme, are very sensitive to the myelosuppressive effect of mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with mercaptopurine. This problem could be exacerbated by coadministration with active substances that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. 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 necessary. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients to avoid the development of life threatening bone marrow suppression. A possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving mercaptopurine in combination with other cytotoxics (see section 4.8). Patients with NUDT15 variant Patients with inherited variant in the NUDT15 gene are at increased risk for severe mercaptopurine 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. Immunosuppression Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended. In all cases, patients in remission should not receive live organism vaccines until the patient is deemed to be able to respond to the vaccine. The interval between discontin

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