Source: European Medicines Agency (EU) Revision Year: 2019 Publisher: Nova Laboratories Ireland Limited, 3<sup>rd</sup> Floor, Ulysses House, Foley Street, Dublin 1, D01 W2T2, Ireland
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).
Treatment with 6-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 Bone marrow suppression is reversible if 6-mercaptopurine is withdrawn early enough..
There are individuals with an inherited deficiency of the TPMT enzyme activity who are very sensitive to the myelosuppresive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6-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 6-mercaptopurine in combination with other cytotoxics (see section 4.8).
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
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. The patient should be instructed to discontinue Xaluprine immediately if jaundice becomes apparent (see section 4.8).
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 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.
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.
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a renal cell carcinoma patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4-1.0 mg/kg/day.
In view of its action on cellular deoxyribonucleic acid (DNA) 6-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 6-mercaptopurine) or 6-mercaptopurine, either with or without concomitant treatment with anti-TNF alpha antibody. This rare type of T cell lymphoma has an aggressive disease course and is usually fatal (see also section 4.8).
* inflammatory bowel disease (IBD) is an unlicensed indication
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, evaluation and treatment should be started as early as possible, and treatment with mercaptopurine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
Patients treated with 6-mercaptopurine alone or in combination with other immunosuppressive agents, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection, and viral reactivation. The infectious disease and complications may be more severe in these patients than in non-treated patients.
Prior exposure to or infection with varicella zoster virus should be taken into consideration prior to starting treatment. Local guidelines may be considered, including prophylactic therapy if necessary. Serologic testing prior to starting treatment should be considered with respect to hepatitis B. Local guidelines may be considered, including prophylactic therapy for cases which have been confirmed positive by serologic testing. Cases of neutropenic sepsis have been reported in patients receiving 6-mercaptopurine for ALL.
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-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 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.
Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine (see section 4.8). The majority of reported cases were in children under the age of six or with a low body mass index.
When oral anticoagulants are coadministered with 6-mercaptopurine, a reinforced monitoring of INR (International Normalised Ratio) is recommended (see section 4.5).
This medicinal product contains aspartame (E951), a source of phenylalanine. May be harmful for people with phenylketonuria.
It also contains sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate which may cause allergic reaction (possibly delayed).
As this medicine contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Long term use increases the risk of dental caries and it is essential that adequate dental hygiene is maintained.
Parents and care givers should avoid Xaluprine contact with skin or mucous membrane. If the suspension comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water (see section 6.6).
The administration of 6-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 6-mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine.
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).
Inhibition of the anticoagulant effect of warfarin, when given with 6-mercaptopurine, has been reported. Monitoring of the INR (International Normalised Ratio) value is recommended during concomitant administration with oral anticoagulants.
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.
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 6-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.
As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, which metabolises 6-mercaptopurine, they should be administered with caution to patients receiving concurrent Xaluprine therapy (see section 4.4).
Evidence of the teratogenicity of 6-mercaptopurine in humans is equivocal. Both sexually active men and women should use effective methods of contraception during treatment and for at least three months after receiving the last dose. Animal studies indicate embryotoxic and embryolethal effects (see section 5.3).
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 6-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 6-mercatopurine 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.
6-mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment and thus women receiving Xaluprine should not breast-feed.
The effect of 6-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 6-mercaptopurine in combination with corticosteroids.
No studies on the effect on the ability to drive and use machines have been performed. A detrimental effect on these activities cannot be predicted from the pharmacology of the active substance.
The main adverse reaction of treatment with 6-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.
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) and very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Bacterial and viral infections, infections associated with neutropenia
Rare: Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ (see section 4.4).
Very rare: Secondary leukaemia and myelodysplasia
Unknown: Hepatosplenic T-cell lymphoma* (see section 4.4)
Very common: Bone marrow suppression; leucopenia and thrombocytopenia
Common: Anaemia
Uncommon: Arthralgia, skin rash, drug fever
Rare: Facial oedema
Common: Anorexia
Unknown: Hypoglycaemia†
Common: Stomatitis, diarrhoea, vomiting, nausea
Uncommon: Pancreatitis, oral ulceration
Very rare: Intestinal ulceration
Common: Biliary stasis, hepatotoxicity
Uncommon: Hepatic necrosis
Rare: Alopecia
Unknown: Photosensitivity reaction
Rare: Transient oligospermia
* In patients with inflammatory bowel disease (IBD), an unlicensed indication.
† In the paediatric population.
6-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 6-mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred.
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.
Not applicable.
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