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.

Patients with little or no inherited TPMT activity are at increased risk for severe toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity.

TPMT testing cannot substitute for haematological monitoring in patients receiving Xaluprine. 4). 4). 4). Genotypic testing of NUDT15 variants may be considered before initiating mercaptopurine therapy. In any case, close monitoring of blood counts is necessary.

Method of administration Xaluprine is for oral use and requires redispersing (by shaking vigorously at least for 30 seconds) prior to dosing. Two dosing syringes (a 1 ml and a 5 ml) are provided for accurate measurement of the prescribed dose of the oral suspension.

It is recommended that the healthcare professional advises the patient or carer which syringe to use to ensure that the correct volume is administered. Xaluprine may be taken with food or on an empty stomach, but patients should standardise the method of administration.

5). Xaluprine should be taken at least 1 hour before or 2 hours after milk or dairy products. Mercaptopurine displays diurnal variation in pharmacokinetics and efficacy. Administration in the evening compared to morning administration may lower the risk of relapse.

Therefore the daily dose of Xaluprine should be taken in the evening. 5 To assist accurate and consistent dose delivery to the stomach water should be taken after each dose of Xaluprine.

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.

Monitoring of liver function tests may allow early detection of hepatotoxicity. This is usually reversible if mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important.

It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

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.

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 discontinuation of chemotherapy and restoration of the patient's ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors.

5). 6 Hepatotoxicity Xaluprine is hepatotoxic and liver function tests should be monitored weekly during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy.

8). Renal toxicity During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy. Hydration and urine alkalinisation may minimize potential renal complications.

Pancreatitis in off-label treatment of patients with inflammatory bowel disease Pancreatitis has been reported to occur at a frequency of ≥ 1/100 to < 1/10 (“common”) in patients treated for the unlicensed indication inflammatory bowel disease.

Mutagenicity and carcinogenicity Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ.

The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder. A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities.

A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders. 0 mg/kg/day. In view of its action on cellular deoxyribonucleic acid (DNA) mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.

Hepatosplenic T-cell lymphoma has been reported in patients with inflammatory bowel disease* treated with azathioprine (the prodrug to mercaptopurine) or mercaptopurine, either with or without concomitant treatment with anti-TNF alpha antibody.

8). *inflammatory bowel disease (IBD) is an unlicensed indication. Macrophage activation syndrome Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD) (unlicensed indication), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine.

If MAS occurs, or is suspected, […]

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