Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Fontus Health Ltd, 60 Lichfield Street, Walsall WS4 2BX, United Kingdom
Hypersensitivity to mercaptopurine or to any of the excipients listed in section 6.1.
In view of the seriousness of the indications there are no other absolute contraindications.
6-mercaptopurine is an active cytotoxic agent for use only under the direction of physician 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 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 6-mercaptopurine is not advised. Ribavirin may reduce efficacy and increase toxicity of 6-mercaptopurine (see section 4.5).
See section 6.6.
Since 6-mercaptopurine is strongly myelosuppressive full blood counts must be taken daily during remission induction. patients must be carefully monitored during therapy.
Treatment with 6-mercaptopurine causes bone marrow suppression leading to leukopenia and thrombocytopenia and, less frequently, anaemia. Full blood counts must be taken frequently during remission induction and careful monitoring of haematological parameters should be conducted during maintenance therapy and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present.
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Bone marrow suppression is reversible if 6-mercaptopurine is withdrawn early enough.
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 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression (see section 4.5).
Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations of mercaptopurine.
6-mercaptopurine is hepatotoxic and liver function tests should be monitored weekly during treatment. The level of gamma glutamyl transferase (GGT) in plasma will be especially important to determine if discontinuation is necessary 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 6-mercaptopurine 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 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6-mercaptopurine. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfazalazine. Also, 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).
About 0.3% (1: 300) of patients have low or no detectable enzyme activity. Approximately 10% of patients with low or intermediate TPMT activity, and 90% of patients have normal TPMT activity. There may also be a group of around 2% with a 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.
Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.
Patients suspected of having suffered a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, unless the patient has been confirmed to be hypersensitive to 6-mercaptopurine by allergological tests, and tested negative for azathioprine. As azathioprine is a pro-drug of 6-mercaptopurine, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to 6-mercapopurine prior to initiating treatment.
Caution is advised during the administration of 6-mercaptopurine 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 and section 5.2 Pharmacokinetic).
Patients receiving immunosuppressive therapy, including mercaptopurine are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and nonmelanoma), 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 hypernephroma patient who received an unstated dose of 6-mercaptopurine 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 6-mercaptopurine, in combination with other drugs, for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine 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 6-mercaptopurine played a causative role.
A patient with Hodgkin’s disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after 6-mercaptopurine treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine is used in combination with anti-TNF agents as unlicensed indication (see section 4.8).
Patients treated with 6-mercaptopurine monotherapy or in combination with other immunosuppressive drugs, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection and reactivation of the virus. Infectious disease and complications can be more serious in these patients than in patients who did not undergo treatment.
Prior exposure to or infection with the varicella zoster should be considered prior to initiation of therapy. Local guidelines may be taken into account, including prophylactic treatment if necessary. Serological tests for hepatitis B should be considered before starting treatment. Local guidelines may be taken into account, including prophylactic treatment in cases where serological tests are positive . If patients experience infection during treatment, appropriate measures, which may include antiviral therapy and supportive care.
Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine (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.
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.
Limited evidence suggests that neither the 6-mercaptopurine nor its pro-drug azathioprine are effective in patients with the rare inherited disease associated with complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of 6-mercaptopurine or azathioprine is not recommended in these patients.
Patients treated with 6-mercaptopurine is more sensitive to sunlight. Exposure to sunlight and UV light should be limited, and patients should be advised to wear protective clothing and use sunscreen with a high protection factor.
Patients with rare hereditary problems of galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.
When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine are administered concomitantly it is essential that only 25% of the usual dose of 6-mercaptopurine is given, since allopurinol decreases the rate of catabolism of 6-mercaptopurine (see section 4.2 and 4.5).
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine.
Vaccination with a live vaccine is not recommended in patients with impaired immune response (see section 4.4)
Taking 6-mercaptopurine with food may decrease systemic exposure slightly. 6-mercaptopurine can be taken with food or on an empty stomach, but patients should use a standard method of administration to avoid large variations in exposure. The dose must not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme that metabolizes 6-mercaptopurine and therefore may 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 6-mercaptopurine and ribavirin; therefore concomitant administration of ribavirin and 6-mercaptopurine is not advised (see section 4.4 and 5.2).
When 6-mercaptopurine is combined with other myelosuppressive agents caution should be used; dose reductions may be needed based on haematological monitoring (see section 4.4).
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 6-mercaptopurine are administered concomitantly it is essential that only 25% of the usual dose of 6-mercaptopurine is given (see section 4.2).
Other xanthine oxidase inhibitors, such as febuxostat, decrease metabolism of 6-mercaptopurine. Co-administration is not recommended, because data are insufficient to determine an adequate dose reduction.
There is in vitro and in vivo evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme. Therefore, lower doses of 6-mercaptopurine may need to be considered when administered concomitantly with aminosalicylate derivatives (see section 4.4).
Methotrexate (20 mg/m² orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m² intravenously) increased 6-mercaptopurine AUC by 69 and 93%, respectively. Therefore, when 6-mercaptopurine 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 and infliximab. Patients treated with azathioprine had transient increases in the levels of 6-TGN (6-tioguaninnukleotid, an active metabolite of azathioprine) and decreases in the average number of leukocytes in the first weeks after infusion of infliximab, which returned to previous levels after 3 months.
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with 6-mercaptopurine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with 6-mercaptopurine.
The effect of 6-mercaptopurine therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.
Transient oligospermia has been reported following exposure to 6-mercaptopurine.
Substantial transplacental and transamniotic transmission of 6-mercaptopurine and its metabolites from the mother to the foetus have been shown to occur.
The use of 6-mercaptopurine 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 6-mercaptopurine Tablets, during treatment and for at least three months after receiving the last dose.
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical safety data). The potential risk for humans is largely unknown.
Maternal exposure: Normal offspring have been born after 6-mercaptopurine 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 6-mercatopurine treatment in combination with other chemotherapy agents.
Paternal exposure: Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine.
6-mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with a pro-drug of 6-mercaptopurine. It is recommended that mothers receiving 6-mercaptopurine should not breast feed.
There is no data about the effects of 6-mercaptopurine on the ability to drive vehicles and use machines. A detrimental effect on these activities cannot be predicted from the pharmacology of mercaptopurine.
For 6-mercaptopurine 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 6-mercaptopurine 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).
| Organ system | Frequency | Adverse effect |
|---|---|---|
| Neoplasms benign, malignant and unspecified | Rare | Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and nonmelanomas), sarcomas (Kaposi’s and non-Kaposi’s) and uterine cervical cancer in situ (see section 4.4). |
| Very rare | Secondary Leukaemia and myelodysplasia (see section 4.4); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see section 4.4.) | |
| Blood and lymphatic system disorders | Very common | Myelosuppression: leukopenia and thrombocytopenia |
| Common | Anaemia | |
| Immune system disorders | 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 | |
| Metabolism and nutrition disorders | Uncommon | Anorexia |
| Not known | Hypoglycaemia* | |
| Gastrointestinal disorders | Common | Nausea; vomiting; pancreatitis in the IBD population (an unlicensed indication) |
| Rare | Oral ulceration, pancreatitis during treatment (in the licensed indications) | |
| Very rare | Intestinal ulceration. | |
| Hepatobiliary disorders | Common | Biliary stasis; hepatotoxicity |
| Rare | Hepatic necrosis | |
| Skin and subcutaneous tissue disorders | Rare | Alopecia. |
| Not known | Photosensitivity | |
| Reproductive system and breast disorders | Very rare | Temporary oligospermia. |
* In 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 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. 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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
Not applicable.
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