Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Hypersensitivity to mercaptopurine monohydrate or to any other component of the preparation.
In view of the seriousness of the indications there are no other absolute contraindications.
Mercaptopurine monohydrate is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
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 patients with ALL or AML. 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.
Co-administration of ribavirin and mercaptopurine monohydrate is not advised. Ribavirin may reduce efficacy and increase toxicity of mercaptopurine monohydrate (see Section 4.5 Interaction with other medicinal products and other forms of interactions).
See Section 6.6 Special precautions for disposal; Safe handling h3. Monitoring
Since mercaptopurine monohydrate is strongly myelosuppressive full blood counts must be taken daily during remission induction. Patients must be carefully monitored during therapy.
Treatment with mercaptopurine monohydrate causes bone marrow suppression leading to leukopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken frequently during remission induction. During maintenance therapy, complete blood counts, including platelets, should be regularly monitored and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present.
Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations of mercaptopurine.
The leukocyte 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Bone marrow suppression is reversible if mercaptopurine monohydrate is withdrawn early enough.
During remission induction in acute myelogenous leukaemia, the patient may frequently have to survive a period of relative bone marrow aplasia and it is important that adequate supportive facilities are available.
The dosage of mercaptopurine monohydrate may need to be reduced when this agent is combined with other medicinal products whose primary or secondary toxicity is myelosuppression (see Section 4.5 Interaction with other medicinal products and other forms of interactions: Myelosuppressive agents).
Mercaptopurine monohydrate is hepatotoxic and liver function tests should be monitored weekly during treatment. Gamma glutamyl transferase (GGT) levels in plasma may be particularly predictive of withdrawal due to hepatotoxicity. 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 mercaptopurine monohydrate immediately if jaundice becomes apparent.
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.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of mercaptopurine monohydrate and prone to developing rapid bone marrow depression following the initiation of treatment with mercaptopurine monohydrate. This problem could be exacerbated by co-administration with medicinal products 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 mercaptopurine monohydrate in combination with other cytotoxics (see Section 4.8 Undesirable effects). Approximately 0.3% (1:300) of patients have little or no detectable enzyme activity. Approximately 10% of patients have low or intermediate TPMT activity and 90% of individuals have normal TPMT activity. There may also be a group of approximately 2% who have very high TPMT activity. 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 inherited mutated NUDT15 gene are at increased risk for severe mercaptopurine monohydrate 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.
Cross resistance usually exists between mercaptopurine monohydrate and 6‑thioguanine.
Patients suspected to have previously presented with a hypersensitivity reaction to mercaptopurine monohydrate should not be recommended to use its pro-drug azathioprine, unless the patient has been confirmed as hypersensitive to mercaptopurine monohydrate with allergological tests, and tested negative for azathioprine. As azathioprine is a pro-drug of mercaptopurine monohydrate, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to mercaptopurine monohydrate prior to initiating treatment.
Caution is advised during the administration of mercaptopurine monohydrate in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see Section 4.2 Posology and method of administration and Section 5.2 Pharmacokinetic properties: Special populations).
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of mercaptopurine monohydrate and in patients with chronic renal disease treated at doses of 0.4 to 1.0 mg/kg/day.
Two cases have been documented of the occurrence of acute non-lymphatic leukaemia in patients who received mercaptopurine monohydrate, in combination with other medicinal products, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with mercaptopurine monohydrate and later developed acute non-lymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the mercaptopurine monohydrate played a causative role.
A patient with Hodgkin’s disease treated with mercaptopurine monohydrate and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after mercaptopurine monohydrate treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T‑cell lymphoma in the inflammatory bowel disease (IBD) population ( unlicensed indication) have been received when mercaptopurine monohydrate is used in combination with anti-TNF agents (see Section 4.8 Undesirable effects).
Patients receiving immunosuppressive therapy, including mercaptopurine monohydrate 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.
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.
Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving mercaptopurine monohydrate (see Section 4.8 Undesirable Effects). The majority of reported cases were in children under the age of six or with a low body mass index.
Patients treated with mercaptopurine monohydrate 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 mercaptopurine monohydrate for ALL. If the patient is infected during treatment appropriate measures should be taken, which may include antiviral therapy and supportive care.
Limited evidence suggests that neither mercaptopurine monohydrate nor its pro-drug azathioprine are effective in patients with the rare inherited condition completehypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of mercaptopurine monohydrate or azathioprine is not recommended in these patients.
Patients treated with mercaptopurine monohydrate are more sensitive to the sun. Exposure to sunlight and UV light should be limited, and patients should be recommended to wear protective clothing and to use a sunscreen with a high protection factor.
Patients with rare hereditary problems of galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients treated with the xanthine oxidase inhibitors allopurinol, oxipurinol or thiopurinol, and mercaptopurine monohydrate should only receive 25% of the usual dose of mercaptopurine monohydrate since allopurinol decreases the rate of catabolism of mercaptopurine monohydrate (see Section 4.2 Posology and method of administration and Section 4.5 Interaction with other medicinal products and other forms of interaction).
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with mercaptopurine monohydrate; therefore higher doses of the anticoagulant may be needed (see section 4.5).
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special warnings and precautions for use).
The administration of mercaptopurine monohydrate with food may decrease systemic exposure slightly. Mercaptopurine monohydrate may be taken with food or on an empty stomach, but patients should standardise the method of administration to avoid large variability in exposure. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises mercaptopurine monohydrate and might therefore lead to reduced plasma concentrations of mercaptopurine.
Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of a pro-drug of mercaptopurine monohydrate and ribavirin; therefore concomitant administration of ribavirin and mercaptopurine monohydrate is not advised (see Section 4.4 Special warnings and precautions for use and Section 5.2 Pharmacokinetic properties: metabolism).
When mercaptopurine monohydrate is combined with other myelosuppressive agents caution should be used; dose reductions may be needed based on haematological monitoring (see Section 4.4 Special warnings and precautions for use).
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, oxipurinol and/or thiopurinol and mercaptopurine monohydrate are administered concomitantly it is essential that only 25% of the usual dose of mercaptopurine monohydrate is given (see Section 4.2 Posology and method of administration: Medicinal product interactions).
Other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of mercaptopurine monohydrate.
Concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction.
There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme. Therefore, lower doses of mercaptopurine monohydrate may need to be considered when administered concomitantly with aminosalicylate derivatives (see Section 4.4 Special warnings and precautions for use).
Methotrexate (20 mg/m² orally) increased mercaptopurine monohydrate AUC by approximately 31% and methotrexate (2 or 5 g/m² intravenously) increased mercaptopurine monohydrate AUC by 69 and 93%, respectively. Therefore, when mercaptopurine monohydrate is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.
Interactions have been observed between azathioprine, a pro-drug of mercaptopurine monohydrate, and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and decreases in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months.
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with mercaptopurine monohydrate; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with mercaptopurine monohydrate.
The effect of mercaptopurine monohydrate therapy on human fertility is unknown.
There are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Transient oligospermia has been reported following exposure to mercaptopurine monohydrate.
Substantial transplacental and transamniotic transmission of mercaptopurine monohydrate and its metabolites from the mother to the foetus have been shown to occur.
The use of mercaptopurine monohydrate should be avoided whenever possible during pregnancy, particularly during the first trimester. In any individual case the potential hazard to the foetus must be balanced against the expected benefit to the mother.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving mercaptopurine monohydrate tablets, during treatment and for at least three months after receiving the last dose.
Studies of mercaptopurine monohydrate in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data).
The potential risk for humans is largely unknown.
Normal offspring have been born after mercaptopurine monohydrate therapy administered as a single chemotherapy agent during human pregnancy, particularly when given prior to conception or after the first trimester.
Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal mercaptopurine monohydrate treatment in combination with other chemotherapy agents.
Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to mercaptopurine monohydrate.
Mercaptopurine monohydrate has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with a pro-drug of mercaptopurine monohydrate. It is recommended that mothers receiving mercaptopurine monohydrate should not breast feed.
There are no data on the effect of mercaptopurine monohydrate on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the medicinal product.
For mercaptopurine monohydrate, there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects. The frequency categories assigned to the adverse drug reactions below are estimates: for most reactions, suitable data for calculating incidence are not available. Undesirable effects may vary in their incidence depending on the dose received and also when given in combination with other therapeutic agents.
The main side effect of treatment with mercaptopurine monohydrate is bone marrow suppression leading to leucopenia and thrombocytopenia.
The following convention has been utilised for the classification of frequency: Very common ≥1/10, Common ≥1/100 and <1/10, Uncommon ≥1/1000 and <1/100, Rare ≥1/10,000 and <1/1000, Very rare <1/10,000, Not known (frequency cannot be estimated from the available data).
Uncommon: Bacterial and viral infections, infections associated with neutropenia
Very Rare: Secondary Leukaemia and myelodysplasia (see section 4.4 Special warnings and precautions for use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti‑TNF agents
(see section 4.4. Special warnings and precautions for use).
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 common: Bone marrow suppression; leucopenia and thrombocytopenia.
Common: Anaemia
Rare: Hypersensitivity reactions with the following manifestations have been
reported: Arthralgia; skin rash; drug fever.
Very Rare: Hypersensitivity reactions with the following manifestations have been reported: Facial oedema
Uncommon: Anorexia
Not known: Hypoglycaemia#
Common: Nausea; vomiting; pancreatitis in the IBD population (an unlicensed indication)
Rare: Oral ulceration; pancreatitis (in the licensed indications)
Very Rare: Intestinal ulceration
Common: Biliary stasis; hepatotoxicity
Rare: Hepatic necrosis
Rare: Alopecia
Not known: Photosensitivity
Very Rare: Transient oligospermia
# In the paediatric population
Mercaptopurine monohydrate 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 of 2.5 mg/kg bodyweight daily or 75 mg/m² body surface area per day is exceeded.
Monitoring of liver function tests may allow early detection of hepatotoxicity. Gamma glutamyl transferase (GGT) levels in plasma may be particularly predictive of withdrawal due to hepatotoxicity. Hepatotoxicity is usually reversible if mercaptopurine monohydrate 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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL-Dublin 2, Tel: +353 1 6764971, Fax: +353 1 6762517, Website: http://www.hpra.ie/, E-mail: medsafety@hpra.ie.
Not applicable.
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