Xaluprine (Previously Mercaptopurine Nova Laboratories)

Xaluprine treatment should be supervised by a physician or other healthcare professionals experienced in the management of patients with ALL. Posology The dose is governed by cautiously monitored haematotoxicity and the dose should be carefully adjusted to suit the individual patient in accordance with the employed treatment protocol.

4). 4 Special populations Elderly No specific studies have been carried out in the elderly. However, it is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the Xaluprine dose.

4 Renal impairment Since mercaptopurine pharmacokinetics has not been formally studied in renal impairment, no specific dose recommendations can be given. Since impaired renal function may result in slower elimination of mercaptopurine and its metabolites and therefore a greater cumulative effect, consideration should be given to reduced starting doses in patients with impaired renal function.

Patients should be closely monitored for dose related adverse reactions. Hepatic impairment Since mercaptopurine pharmacokinetics has not been formally studied in hepatic impairment, no specific dose recommendations can be given. Since there is a potential for reduced elimination of mercaptopurine, consideration should be given to reduced starting doses in patients with impaired hepatic function.

4). Switching between tablet and oral suspension and vice versa A tablet form of mercaptopurine is also available. 2). Combination with xanthine oxidase inhibitors Allopurinol and other xanthine oxidase inhibitors decrease the rate of catabolism of mercaptopurine.

When allopurinol and mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of mercaptopurine is given. 5). Patients with TPMT variant Mercaptopurine is metabolised by the polymorphic TPMT enzyme.

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.

10 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. 4) Gastrointestinal disorders Common Diarrhoea, vomiting, nausea, pancreatitis* Uncommon Oral ulceration Rare Pancreatitis Very rare Intestinal ulceration Not known Stomatitis, cheilitis Hepatobiliary disorders Common Biliary stasis, hepatotoxicity Uncommon Hepatic necrosis Not known Portal hypertension*, nodular regenerative hyperplasia*, sinusoidal obstruction syndrome* Skin and subcutaneous tissue disorders Rare Alopecia Not known Photosensitivity reaction, erythema nodosum Reproductive system and breast disorders Rare Transient oligospermia General disorders and administration site conditions Not known Mucosal inflammation Investigations Not known Coagulation factors decreased * In patients with inflammatory bowel disease (IBD), an unlicensed indication.

† In the paediatric population. 11 Description of selected adverse reactions Mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary stasis. The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended dose is exceeded.

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. 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.

2). 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.

1. 5).