6- mercaptopurine 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)).

General:

Puri-nethol treatment must be initiated and monitored under the supervision of a physician experienced in hematology.

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).

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

For adults and children the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/m ² 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 6-mercaptopurine.

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

6- mercaptopurine 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 6- mercaptopurine in the evening lowered the risk of relapse compared with morning administration.

Switching between tablet and oral suspension and vice versa

An oral suspension of 6-mercaptopurine is also available. The 6-mecaptopurine 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).

Method of administration

6 mercaptopurine 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). 6 mercaptopurine should be taken at least 1 hour before or 2 hours after milk or dairy products.

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 6-mercaptopurine dosage.

• Renal impairment

Since 6-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 6-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. Patients should be closely monitored for dose related adverse reactions (see sections 4.4 and 5.2)

• Combination with xanthine oxidase inhibitors

When the xanthine oxidase inhibitors, such as allopurinol, oxipurinol or thiopurinol and 6- mercaptopurine are administered concomitantly it is essential that only 25 % of the usual dose of 6- mercaptopurine is given since these agents decrease the rate of catabolism of 6-mercaptopurine. 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

6-Mercaptopurine is metabolised by the polymorphic TPMT enzyme. Patients with little or no inherited thiopurine S-methyltransferase (TPMT) activity are at increased risk for severe 6-mercaptopurine toxicity from conventional doses of 6-mercaptopurine 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 thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 5.2).

Method of Administration:

• Puri-nethol is a cytotoxic agent. Follow applicable special handling and disposal procedures (see section 6.6).

• Tablets should be swallowed whole.

• The tablets should not be broken or crushed, if possible. This might produce powder that can contaminate workplace surfaces.

• If tablet must be cut or crushed, this should be done by a professional trained personal experienced in safe handling of hazardous drugs using an appropriate equipment and safety procedures.

6-mercaptopurine is an active cytotoxic agent and should be use only under the direction of physician experienced in the administration of such agents.

Cytotoxicity and haematological monitoring

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 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 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).

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.

Co-administration of ribavirin and 6-mercaptopurine is not advised. Ribavirin may reduce efficacy and increase toxicity of 6-mercaptopurine (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 6-mercaptopurine 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

6-mercaptopurine 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 6-mercaptopurine 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.

Caution is advised during the administration of 6-mercaptopurine in patients with renal impairment and/or hepatic impairment (see section 4.2 and section 5.2).

 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 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.

 Two cases have been documented of the occurrence of acute non-lymphatic leukaemia in patients who received 6 mercaptopurine, 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 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.

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.

 Twelve and a half years after 6 mercaptopurine treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.

 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.

 Metabolism and nutrition disorders

Administration of purine analogues (azathioprine and mercaptopurine) may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency/pellagra. Few cases have been reported with the use of azathioprine, especially in patients with IBD (Crohn’s disease, colitis ulcerative). Diagnosis of pellagra should be considered in a patient presenting with localised pigmented rash (dermatitis); gastroenteritis (diarrhoea); and widespread neurologic deficits, including cognitive decline (dementia). Dose reduction or discontinuation of mercaptopurine treatment may not be required if appropriate medical care with niacin/nicotinamide supplementation is initiated. However, careful benefit-risk assessment is required on a case-by-case basis.

 Infections

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 NUDT15 variant

 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.

Paediatric population

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.

NUDT15 Mutation

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established. Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 5.2).

If the patient is infected during treatment appropriate measures should be taken, which may include antiviral therapy and supportive care.

Interactions

Patients treated with the xanthine oxidase inhibitors allopurinol, oxipurinol or thiopurinol, and 6- mercaptopurine should only receive 25 % of the usual dose of 6-mercaptopurine since allopurinol decreases the rate of catabolism of 6-mercaptopurine (see Section 4.2 Posology and method of administration and Section 4.5 Interaction with other medicinal products and other forms of interaction).

When oral anticoagulants are co-administered with 6-mercaptopurine, a reinforced monitoring of INR (International Normalised Ratio) is recommended (see section 4.5)

Excipients

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

 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 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 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 6-mercaptopurine and 6-thioguanine.

 Hypersensitivity

Patients suspected to have previously presented with a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, unless the patient has been confirmed as hypersensitive to 6-mercaptopurine with 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.

Lesch-Nyhan syndrome

Limited evidence suggests that neither 6-mercaptopurine 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 6-mercaptopurine or azathioprine is not recommended in these patients.

UV exposure

Patients treated with 6-mercaptopurine 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.

Safe handling of 6- mercaptopurine tablets – See section 6.6

The administration of 6–mercaptopurine with food may decrease systemic exposure slightly. 6- mercaptopurine 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 and acenocoumarol, 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 6-mercaptopurine, making dose adjustments as necessary.

Effects of other medicinal products on 6-mercaptopurine

When allopurinol and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine 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 6-mercaptopurine therapy (see section 4.4).’

Methotrexate

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 and white blood cell counts should be very closely monitored.

Infliximab 

Interactions have been observed between azathioprine, a pro-drug of 6-mercaptopurine, 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.

Therefore close monitoring of haematological parameters is necessary if Puri-nethol is administered with concomitant Infliximab therapy.

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 6-mercaptopurine and ribavirin; therefore concomitant administration of ribavirin and 6-mercaptopurine is not advised (see section 4.4 Special warnings and precautions for use and section 5.2 Pharmacokinetic properties: metabolism).

 Myelosuppressive agents

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 Special warnings and precautions for use).

Contraception in males and females

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).

Pregnancy

6-mercaptopurine 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.

An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy. Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine and for 3 months after the last dose.

It is recommended that newborns of women exposed to mercaptopurine during pregnancy are monitored for haematological and immune system disturbances. Verify the pregnancy status in females of reproductive potential prior to initiating mercaptopurine.

Breast-feeding

6-mercaptopurine 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.

An increased incidence of miscarriage has been reported in women who received mercaptopurine in the first trimester of pregnancy. Adverse embryo-fetal findings, including miscarriage and stillbirth, have been reported in women who received mercaptopurine after the first trimester of pregnancy. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with mercaptopurine and for 6 months after the last dose. Advise males with female partners of reproductive potential to use effective contraception during treatment with mercaptopurine and for 3 months after the last dose

It is recommended that newborns of women exposed to mercaptopurine during pregnancy are monitored for haematological and immune system disturbances. Verify the pregnancy status in females of reproductive potential prior to initiating mercaptopurine.

Contraception in males and females

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).

There are no data on the effect of 6-mercaptopurine 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.

 Summary of the safety profile

The main side effect of treatment with 6 mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia.

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.

Tabulated list of adverse reactions

 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)

# In the paediatric population

Description of selected adverse reactions:

Hepatobiliary disorders

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 withdraw al due to hepatotoxicity. This is usually reversible if 6-mercaptopurine therapy is stopped soon enough but fatal liver damage has occurred.

Please report adverse drug events to:

• Saudi Arabia:

-      Other GCC States:

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 6-mercaptopurine. Liver dysfunction and gastroenteritis may also occur.

The risk of overdose is also increased when xanthine oxidase inhibitors are being given concomitantly with 6- mercaptopurine (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 or gastric lavage) may not be effective in the event of 6-mercaptopurine 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.

Pharmacotherapeutic group: antineoplastic agents, antimetabolites, purine analogues, ATC Code: L01BB02

Mechanism of action 

6-Mercaptopurine is sulphydryl analogue of the purine bases, adenine and hypoxanthine and acts as a cytotoxic antimetabolite.

6-Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to thioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the active substance.

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

Pharmacodynamic effects

The cytotoxic effect of 6-mercaptopurine can be related to the levels of red blood cell 6- mercaptopurine derived thioguanine nucleotides, but not to the plasma 6-mercaptopurine concentration

Absorption

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism`. When administered orally at a dosage of 75 mg/m² to seven paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%.

After oral administration of 6-mercaptopurine 75 mg/m² to 14 children with acute lymphoblastic leukaemia, the mean Cmax was 0.89µM, with a range of 0.29 - 1.82µM and Tmax was 2.2 hours with a range of 0.5 - 4 hours.

The mean relative bioavailability of 6-mercaptopurine was approximately 26 % lower following administration with food and milk compared to an overnight fast. 6-mercaptopurine is not stable in milk due to the presence of xanthine oxidase (30 % degradation within 30 minutes) (see Section 4.2 Posology and method of administration).

Distribution

Concentrations of 6-mercaptopurine in cerebrospinal fluid (CSF) are low or negligible after IV or oral administration (CSF: plasma ratios of 0.05 to 0.27). Concentrations in the CSF are higher after intrathecal administration.

Biotransformation

The intracellular anabolism of 6-merpactopurine is catalysed by several enzymes to eventually form 6-thioguanine nucleotides (TGNs), but a variety of intermediary TGNs are formed en route to the TGNs. The first step is catalysed by hypoxanthine-guanine phosphoribosyl transferase yielding thioinosine monophosphate (TIMP). 6-mercaptopurine is also subject to S-methylation by the enzyme thiopurine S-methyltransferase (TPMT), yielding methylmercaptopurine, which is inactive. However, TPMT also catalyses the S-methylation of the principle nucleotide metabolite, TIMP, to form methylthioinosine monophosphate (mTIMP). Both TIMP and mTIMP are inhibitors of phosphoribosyl pyrophosphate amidotransferase, an enzyme which is important in de novo purine synthesis. Xanthine oxidase is the main catabolic enzyme and it converts the 6-mercaptopurine into the inactive metabolite, 6-thiouric acid. This is excreted in the urine. Approximately 7% of an oral dose is excreted as unchanged 6-mercaptopurine within 12 hours after administration.

There is evidence that polymorphisms in the genes encoding the different enzyme systems involved with metabolism of 6-mercaptopurine may predict adverse drug reactions to 6-mercaptopurine therapy. For example, individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations (see Section 4.4).

Recent studies indicate that a strong association exists between the NUDT15 variant NUDT15 c.415C>T [p.Arg139Cys] (also known as NUDT15 R139C [rs116855232]), which is thought to lead to a loss of function of the NUDT15 enzyme, and thiopurine-mediated toxicity such as leukopenia and alopecia. The frequency of NUDT15 c.415C>T has an ethnic variability of 9.8 % in East Asians, 3.9

% in Hispanics, 0.2 % in Europeans and 0.0 % in Africans, indicating an increased risk for the Asian population. Patients who are NUDT15 variant homozygotes (NUDT15 T risk alleles) are at an excessive risk of thiopurine toxicity compared with the C homozygotes.

Reduced thiopurine doses for patients who carry the NUDT15 variants may decrease their risk of toxicity. Therefore, genotypic analysis determining NUDT15 genotype should be determined for all patients, including paediatric patients, prior to initiating thiopurine treatment (see section 4.2). The prescribing physician is advised to establish whether dose reduction is required based on patient response to treatment as well as their genetic profile.

Patients with variants in both the NUDT15 and TPMT enzymes are significantly less tolerant of thiopurines than those with risk alleles in only one of these two genes.

The precise mechanism of NUDT15-associated thiopurine-related toxicity is not understood.

Elimination

The elimination half-life of 6-mercaptopurine is 90 ± 30 minutes, but the active metabolites have a longer half-life (approximately 5 hours) than the parent compound. The apparent body clearance is 4832 ± 2562 ml/min/m2. There is low entry of 6-mercaptopurine into the cerebrospinal fluid. The main route of elimination for 6-mercaptopurine is by metabolism.

In a study with 22 adult patients the mean 6-mercaptopurine clearance and half-life after IV infusion was 864 mL/min/m² and 0.9 hours respectively. The mean renal clearance reported in 16 of these patients was 191 mL/min/m². Only about 20 % of the dose was excreted in the urine as intact drug medicinal product after IV administration. In a study with 7 children patients the mean 6- mercaptopurine clearance and half-life after IV infusion was 719 (+/-610) ml/min/m² and 0.9 (+/-0.3) hours respectively.

Special patient populations

•  Elderly

No specific studies have been carried out in the elderly (see Section 4.2 Posology and method of administration).

• Renal impairment

Studies with a pro-drug of 6-mercaptopurine have shown no difference in 6-mercaptourine pharmacokinetics in uremic patients compared to renal transplant patients. Since little is known about the active metabolites of 6-mercaptopurine in renal impairment (see Section 4.2 Posology and method of administration).

6- mercaptopurine and/or its metabolites are eliminated by haemodialysis, with approximately 45 % of radioactive metabolites eliminated during dialysis of 8 hours.

• Hepatic impairment

A study with a pro-drug of 6-mercaptopurine was performed in three groups of renal transplant patients: those without liver disease, those with hepatic impairment (but no cirrhosis) and those with hepatic impairment and cirrhosis. The study demonstrated that 6-mercaptopurine exposure was 1.6 times higher in patients with hepatic impairment (but no cirrhosis) and 6 times higher in patients with hepatic impairment and cirrhosis, compared to patients without liver disease (see Section 4.2 Posology and method of administration).

Genotoxicity

6-mercaptopurine, in common with other antimetabolites, is mutagenic and causes chromosomal aberrations in vitro and in vivo in mice and rats.

 Carcinogenicity

Given its genotoxic potential, 6-mercaptopurine is potentially carcinogenic.

 Teratogenicity

6-mercaptopurine causes embryolethality and severe teratogenic effects in the mouse, rat, hamster and rabbit at doses that are non-toxic to the mother. In all species, the degree of embryotoxicity and the type of malformations are dependent on the dose and stage of the gestation at the time of administration

Lactose monohydrate

Maize Starch

Modified Maize Starch

Stearic Acid

Magnesium Stearate

Purified Water

None known

Do not store above 30°C. Protect from light and Keep dry.

Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.

Pack size: 25 tablets

It is recommended that 6-mercaptopurine tablets should be handled following the prevailing local recommendations and/or regulations for the handling and disposal of cytotoxic agents.

Handling:

•  Puri-nethol is a cytotoxic drug. Considered as potentially carcinogenic
• In healthcare settings, use designated area for medication storage and restrict access to only authorized personal
• To minimize the risk of dermal exposure, wear chemotherapy gloves and sleeve covers when handling Puri-Nethol. This includes all handling activities in clinical settings, pharmacies, storerooms and home healthcare settings, including receiving, unpacking and, and storing within a facility.
• For transportation of intact tablet within the facility, wear single chemotherapy gloves and place in double bag or in a sealed container.
• The tablets should not be divided, broken or crushed. This might produce powder that can contaminate workplace surfaces.
• Caution should be observed in handling broken or crushed tablets; wear double chemotherapy gloves and place in double bag or in a sealed container. Avoid direct contact with skin or mucous membranes. If such contact occurs, wash thoroughly with soap and water, rinse eyes thoroughly with sterile water, or plain water if sterile water is unavailable.
• When manipulations are necessary such as compounding, crushing, cutting, or splitting; should be performed within a ventilated engineering enclosure and/ or augment the control of generated aerosols using supplementary controls such as glove bags or pill pouches that contain the hazardous drug during and after the crushing process.
• Wear double chemotherapy gloves, protective gown and sleeve covers. Add eye/face protection and respiratory protection [N95] if compounding is done outside of the ventilated engineering control. Hair and shoe covers should be worn.
• When clinically appropriate, add liquid or moist products to crushed hazardous drug product as soon as possible after crushing, to avoid the potential of subsequent aerosol dissemination.
• For medication administration, wear single chemotherapy gloves with intact and coated tablets and double chemotherapy gloves with cut or crushed tablets. Add eye and face protection if there is the potential to contact vomit or if patient may resist or is pre-disposed to spitting out.
• Personnel who are pregnant should avoid exposure to crushed or broken coated tablets.

Disposal

• Wear double chemotherapy gloves and protective gown for any disposal or cleaning activity of medication contaminated waste.
• Avoid creating dusts. Place in sealed bags for disposal. Use caution when closing bags as pushing waste down may force hazardous drug dusts up into the user’s face.
• For disposal of drugs and metabolites in body fluids, wear chemotherapy gloves and protective gown. Fold soft materials (sheets, hygiene care products) inward to prevent leakage and place in sealed bags.
• In case of spill, limit access to area, use wet wiping method (absorbent pads for liquid spills). Place in sealed bags for disposal. Disinfection, deactivation or decontamination agents may be necessary.
• Any unused medicinal product or waste material should be disposed of in accordance with local requirements.