4.1. Therapeutic indications

Mercaptopurine monohydrate is indicated for the treatment of acute leukaemia in adults, adolescents and children. It may be utilised in:

- Acute lymphoblastic leukaemia (ALL);

- Acute promyelocytic leukaemia (APL)/Acute myeloid leukaemia M3 (AML M3)).

4.2. Posology and method of administration

Mercaptopurine monohydrate treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with ALL and APL (AML M3).

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.

Depending on phase of treatment, starting or target doses should be lower in patients with reduced or absent Thiopurine Methyl Transferase (TPMT) enzyme activity (see section 4.4).

For adults and children the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/m2 body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic agents given in conjunction with mercaptopurine monohydrate.

The dosage should be carefully adjusted to suit the individual patient.

Mercaptopurine monohydrate has been used in various combination therapy schedules for acute leukaemia and the literature and current treatment guidelines should be consulted for details.

Studies carried out in children with acute lymphoblastic leukaemia suggested that administration of mercaptopurine monohydrate in the evening lowered the risk of relapse compared with morning administration.

Special populations

Elderly

It is advisable to monitor renal and hepatic function in these patients, and if there is impairment, consideration should be given to reducing the mercaptopurine monohydrate dosage.

Renal impairment

Since mercaptopurine monohydrate 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 monohydrate 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. Patients should be closely monitored for dose related adverse reactions (see sections 4.4 and 5.2)

Switching between tablet and oral suspension and vice versa

An oral suspension of mercaptopurine monohydrate is also available. The mercaptopurine oral suspension and tablet are not bioequivalent with respect to peak plasma concentration, and therefore intensified haematological monitoring of the patient is advised on switching formulations (see section 5.2).

Combination with xanthine oxidase inhibitors

When the xanthine oxidase inhibitors, such as allopurinol, oxipurinol or thiopurinol and mercaptopurine monohydrate are administered concomitantly it is essential that only 25 % of the usual dose of mercaptopurine monohydrate is given since these agents decrease the rate of catabolism of mercaptopurine monohydrate. Concomitant administration of other xanthine oxidase inhibitors, such as febuxostat, should be avoided (see section 4.5 Interaction with other medicinal products and other forms of interactions).

TPMT-deficient patients

Mercaptopurine monohydrate is metabolised by the polymorphic TPMT enzyme. Patients with little or no inherited thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe mercaptopurine monohydrate toxicity from conventional doses of mercaptopurine monohydrate and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established. 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 mercaptopurine. (see section 4.4 and section 5.2).

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe mercaptopurine monohydrate toxicity (see 4.4). These patients generally require dose reduction; particularly those being NUDT15 variant homozygotes (see 4.4). Genotypic testing of NUDT15 variants may be considered before initiating mercaptopurine monohydrate therapy. In any case, close monitoring of blood counts is necessary.

Method of administration

Mercaptopurine monohydrate 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 (see section 4.5). Mercaptopurine monohydrate should be taken at least 1 hour before or 2 hours after milk or dairy products.

Mercaptopurine monohydrate 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 mercaptopurine should be taken in the evening.

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

Mercaptopurine monohydrate is an active cytotoxic agent and should be used only under the direction of physician experienced in the administration of such agents.

Monitoring

Since mercaptopurine monohydrate is strongly myelosuppressive full blood counts must be taken daily during remission induction. Patients must be carefully monitored during therapy.

Cytotoxicity and haematological monitoring

Treatment with mercaptopurine monohydrate 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 monohydrate is withdrawn early enough.Cholestasis of pregnancy has occasionally been reported in association with mercaptopurine monohydrate therapy (see section 4.6). If cholestasis of pregnancy occurs, case by case assessment is necessary considering the risk-benefit profile of the product (potential withdrawal/dose reduction).

There are individuals with an inherited deficiency of the TPMT enzyme activity who are very 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 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 mercaptopurine monohydrate in combination with other cytotoxics (see section 4.8).

Increased haematological monitoring of the patient is advised when switching between different pharmaceutical formulations of mercaptopurine

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.

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).

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).

Hepatotoxicity

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 (see section 4.8).

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.

Renal and/or hepatic impairment

Caution is advised during the administration of mercaptopurine monohydrate in patients with renal impairment and/or hepatic impairment (see section 4.2 and section 5.2). Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored.

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.

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 mercaptopurine monohydrate 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) mercaptopurine monohydrate is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.

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.

Hepatosplenic T-cell lymphoma has been reported in patients with inflammatory bowel disease* treated with azathioprine (the prodrug to mercaptopurine monohydrate) or mercaptopurine monohydrate, 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

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.

Metabolic and nutritional disorders

Purine analogues (azathioprine and mercaptopurine) may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency (pellagra). Cases of pallagra have been reported with the use of analogues, particularly in patients with chronic inflammatory bowl disease. The diagnosis of pellagra should be considered in patients with a localised pigmented rash (dermatitis), gastroenteritis, or neurological deficits, including cognitive deterioration. Appropriate medical care with niacin/nicotinamide supplementation must be initiated.

Infections

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 appropriate antimicrobial therapy and supportive care.

Patients with NUDT15 variant

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.

Paediatric population

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.

Interactions

Xanthine oxidase inhibitors

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).

Anticoagulants

When oral anticoagulants are co-administered with mercaptopurine monohydrate, a reinforced monitoring of INR (International Normalised Ratio) is recommended (see section 4.5)

TPMT Deficiency

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 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 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.

Cross Resistance

Cross resistance usually exists between mercaptopurine monohydrate and 6-thioguanine.

Hypersensitivity

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.

Lesch-Nyhan syndrome

Limited evidence suggests that neither mercaptopurine monohydrate nor its pro-drug azathioprine are effective in patients with the rare inherited condition complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of mercaptopurine monohydrate or azathioprine is not recommended in these patients.

UV exposure

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.

Excipients

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Safe handling of mercaptopurine monohydratetablets – See section 6.6

4.5. Interaction with other medicinal products and other forms of interaction

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 6–mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine.

Effects of mercaptopurine on other medicinal products

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).

Anticoagulants

Inhibition of the anticoagulant effect of warfarin, when given with mercaptopurine monohydrate has been reported. Monitoring of the INR (International Normalised Ratio) value is recommended during concomitant administration with oral anticoagulants.

Antiepileptics

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 mercaptopurine monohydrate, making dose adjustments as necessary.

Effects of other medicinal products on mercaptopurine monohydrate

Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors

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 and mercaptopurine monohydrate are administered concomitantly it is essential that only a quarter of the usual dose of mercaptopurine monohydrate is given since allopurinol decreases the rate of metabolism of mercaptopurine monohydrate 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.

Aminosalicylates

There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfazalazine) 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

Methotrexate (20 mg/m2 orally) increased mercaptopurine monohydrate exposure (area under curve, AUC) by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased mercaptopurine monohydrate AUC by 69% and 93%, respectively. When administered concomitantly with high dose methotrexate, the mercaptopurine dose may need adjustment.

Infliximab

Interactions have been observed between azathioprine, a pro-drug of mercaptopurine monohydrate, and infliximab. Patients receiving 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.

Ribavirin

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).

Myelosuppressive agents

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).

4.6. Fertility pregnancy and lactation

Contraception in males and females

Evidence of the teratogenicity of mercaptopurine monohydrate 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).

Pregnancy

Mercaptopurine monohydrate should not be given to patients who are pregnant or likely to become pregnant without careful assessment of risk versus benefit.

Substantial transplacental and transamniotic transmission of mercaptopurine monohydrate and its metabolites from the mother to the foetus have been shown to occur.

There have been reports of premature birth and low birth weight following maternal exposure to mercaptopurine monohydrate. 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 mercaptopurine monohydrate 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.

Cholestasis of pregnancy has occasionally been reported in association with azathioprine (a prodrug of mercaptopurine monohydrate) therapy. Early diagnosis and discontinuation of mercaptopurine monohydrate may minimise impact on the foetus. However, acareful assessment of benefit to the mother and impact on the foetus should be performed, if cholestasis of pregnancy is confirmed.

Breast-feeding

Mercaptopurine monohydrate has been identified in the colostrum and breast milk of women receiving azathioprine treatment and thus women receiving 6 mercaptopurine should not breast-feed.

Fertility

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.

Maternal exposure:

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.

Paternal exposure

Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to mercaptopurine monohydrate.

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

Summary of the safety profile

The main side effect of treatment with mercaptopurine monohydrate is bone marrow suppression leading to leucopenia and thrombocytopenia.

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 when given in combination with other therapeutic agents.

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 (frequency cannot be estimated from the available data)

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Body System

Side effects

Infections and infestations

Uncommon

Bacterial and viral infections, infections associated with neutropenia

Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)

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

Not known

Hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease (IBD) (an unlicensed indication) when used in combination with anti TNF agents (see Section 4.4.).

Blood and Lymphatic System Disorders

Very common

Bone marrow suppression; leucopenia and thrombocytopenia

Common

Anaemia

Immune System Disorders

Uncommon

Hypersensitivity reactions with the following manifestations have been reported: Arthralgia; skin rash; drug fever.

Rare

Hypersensitivity reactions with the following manifestations have been reported: Facial oedema

Metabolism and nutrition disorders

Common

Anorexia

Not known

Hypoglycaemia#

Pellagra (see section 4.4)

Gastrointestinal Disorders

Common

Nausea; vomiting; pancreatitis in the IBD population (an unlicensed indication)

Rare

Oral ulceration; pancreatitis (in the licensed indications)

Very rare

Intestinal ulceration

Not known

Stomatitis, chelitis

Hepatobiliary Disorders

Common

Biliary stasis; hepatotoxicity

Uncommon

Hepatic necrosis, cholestasis of pregnancy

Skin and Subcutaneous Tissue Disorders

Rare

Alopecia

Not known

Photosensitivity, 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 the paediatric population

Description of selected adverse reactions:

Hepatobiliary disorders

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. This is usually reversible if mercaptopurine monohydrate 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 Yellow Card Scheme:

Website: www.mhra.gov.uk/yellowcard

4.9. Overdose

Symptoms and signs

Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdose having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdose than with a single ingestion of mercaptopurine monohydrate. Liver dysfunction and gastroenteritis may also occur.

The risk of overdose is also increased when xanthine oxidase inhibitors are being given concomitantly with mercaptopurine monohydrate (see Section 4.5).

Management

As there is no known antidote, blood counts should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as the use of activated charcoal) may not be effective in the event of mercaptopurine monohydrate overdose unless the procedure can be undertaken within 60 minutes of ingestion.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.