1. Name of the medicinal product
Mercaptopurine Tablets USP 50mg TajPharma

2. Qualitative and quantitative composition
Each tablet contains:

Mercaptopurine USP         50mg
Excipients                            q.s.

3. Pharmaceutical form
Tablets
Pale yellow, round tablets, biconvex, scored on one side.

4. Clinical particulars

4.1 Therapeutic indications
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)).

4.2 Posology and method of administration
Posology
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).

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

Adults and paediatric population
For adults and children the usual dose is 2.5 mg/kg bodyweight per day, or 50 to 75 mg/mbody 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.

Older population
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
Consideration should be given to reducing the dosage in patients with impaired renal function (see section 5.2 Pharmacokinetic properties: Special patient populations; Renal impairment).

Hepatic impairment
Consideration should be given to reducing the dosage in patients with impaired hepatic function (see section 5.2 Pharmacokinetic properties: Special patient populations; Hepatic impairment).

Medicinal product interactions
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
Patients with inherited little or no 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. Most patients with heterozygous TPMT deficiency can tolerate recommended 6-mercaptopurine doses, but some may require dose reduction (see section 4.4 Special warnings and precautions for use: Monitoring and section 5.2 Pharmacokinetic properties).

Patients with NUDT15 variant
Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine 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 6-mercaptopurine therapy. In any case, close monitoring of blood counts is necessary.

4.3 Contraindications
Hypersensitivity to 6-mercaptopurine or to any other component of the preparation.

In view of the seriousness of the indications there are no other absolute contra-indications.

4.4 Special warnings and precautions for use
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 patients with ALL or AML. In all cases, patients in remission should not receive live organism vaccines until the patient is deemed to be able to respond to the vaccine. The interval between discontinuation of chemotherapy and restoration of the patient’s ability to respond to the vaccine depends on the intensity and type of immunosuppression-causing medications used, the underlying disease, and other factors.

Co-administration of ribavirin and 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).

Safe handling of 6-mercaptopurine Tablets
See section 6.6 Instructions for disposal; Safe handling

Monitoring:
Since 6-mercaptopurine is strongly myelosuppressive full blood counts must be taken daily during remission induction. Patients must be carefully monitored during therapy.

Bone marrow suppression
Treatment with 6-mercaptopurine causes bone marrow suppression leading to leukopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken frequently during remission induction. During maintenance therapy, complete blood counts, including platelets, should be regularly monitored and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present.

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

The leukocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately.

Bone marrow suppression is reversible if 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 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.

Tumour lysis syndrome
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.

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.

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.

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.

Renal and/or hepatic impairment
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 Posology and method of administration and section 5.2 Pharmacokinetic properties: Special populations).

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 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 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.

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 (unlicensed indication) have been received when 6-mercaptopurine is used in combination with anti-TNF agents (see section 4.8 Undesirable effects).

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.

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.

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.

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.

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

Xanthine oxidase inhibitors
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).

Anticoagulants
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 (see section 4.5).

 4.5 Interaction with other medicinal products and other forms of interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special warnings and precautions for use).

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.

Effect of concomitant medicinal products on 6-mercaptopurine

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).

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, 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 Posology and method of administration: Medicinal product interactions).

Other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of 6-mercaptopurine. 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 6-mercaptopurine 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 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.

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.

Effect of 6-mercaptopurine on other medicinal products

Anticoagulants
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.

 4.6 Fertility, pregnancy and lactation
Fertility
The effect of 6–mercaptopurine therapy on human fertility is unknown.

There are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence.

Transient oligospermia has been reported following exposure to 6–mercaptopurine.

Pregnancy
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 abortions have been reported after paternal exposure to 6-mercaptopurine.

Breast-feeding
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.

4.7 Effects on ability to drive and use machines
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.

4.8 Undesirable effects
Summary of the safety profile
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.

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)

Body SystemSide effects
Infections and infestationsUncommonBacterial and viral infections, infections associated with neutropenia
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)RareNeoplasms 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 RareSecondary Leukaemia and myelodysplasia (see section 4.4 Special warnings and precautions for use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti-TNF agents (see section 4.4. Special warnings and precautions for use)
Blood and Lymphatic System DisordersVery commonBone marrow suppression; leucopenia and thrombocytopenia
CommonAnaemia
Immune System DisordersRareHypersensitivity reactions with the following manifestations have been reported: Arthralgia; skin rash; drug fever.
Very rareHypersensitivity reactions with the following manifestations have been reported: Facial oedema
Metabolism and nutrition disordersUncommonAnorexia
Not knownHypoglycaemia#
Gastrointestinal DisordersCommonNausea; vomiting; pancreatitis in the IBD population (an unlicensed indication)
RareOral ulceration; pancreatitis (in the licensed indications)
Very rareIntestinal ulceration
Hepatobiliary DisordersCommonBiliary stasis; hepatotoxicity
RareHepatic necrosis
Skin and Subcutaneous Tissue DisordersRareAlopecia
Not knownPhotosensitivity
Reproductive system and breast disordersVery RareTransient oligospermia

# 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 withdrawal due to hepatotoxicity. This is usually reversible if 6-mercaptopurine 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.

4.9 Overdose
Symptoms and signs
Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of 6-mercaptopurine. Liver dysfunction and gastroenteritis may also occur.

The risk of overdosage is also increased when allopurinol is being given concomitantly with6-mercaptopurine (see Section 4.5 Interactions with other medicinal products and other forms of interaction).

Treatment
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 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.

5. Pharmacological properties

5.1 Pharmacodynamic properties
Pharmacotherapeutic group: antineoplastic agents, antimetabolites, purine analogues

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 (TGNs) for cytotoxicity. The TGNs and other metabolites (e.g. 6-methyl-mecaptopurine ribonucleotides) inhibit de novo purine synthesis and purine nucleotide interconversions. The TGNs are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the medicinal product.

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

5.2 Pharmacokinetic properties
Pharmacokinectics
Absorption
The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability`. When administered at a dosage of 75 mg/mto seven paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%. The variable bioavailability probably results from the metabolism of a significant portion of 6-mercaptopurine during first-pass hepatic metabolism.

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
6-mercaptopurine is extensively metabolized by many multi-step pathways to active and inactive metabolites. Because of the complex metabolism, inhibition of one enzyme does not explain all cases of lack of efficacy and/or pronounced myelosuppression. The predominant enzymes responsible for the metabolism of 6-mercaptopurine or its downstream metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT), xanthine oxidase, inosine monophosphate dehydrogenase (IMPDH) and hypoxanthine guanine phosphribosyltransferase (HPRT). Additional enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which form TGNs) and inosine triphosphate pyrophosphatase (ITPase). There are also multiple inactive metabolites formed via other pathways.

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).

Elimination
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 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

  • Older population

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).

 5.3 Preclinical safety data

  • Carcinogenesis, mutagenesis:

6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and chromosome damage has been reported in mice, rats and man.

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.

  • Teratogenicity:

6-Mercaptopurine causes embryolethality and severe teratogenic effects in mice, rats, hamsters and rabbits 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.

6. Pharmaceutical particulars

6.1 List of excipients
Lactose
Maize Starch
Modified Maize StarchStearic Acid
Magnesium Stearate
Purified Water

6.2 Incompatibilities
None known

6.3 Shelf life
60 months

 6.4 Special precautions for storage
Store below 25°C. Keep the bottle tightly closed.

6.5 Nature and contents of container
Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.
Pack size: 25 tablets

6.6 Special precautions for disposal and other handling
Safe handling:
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.

Disposal
Any unused product or waste material should be disposed of in accordance with local requirements.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Mercaptopurine Tablets USP 50mg TajPharma

Package leaflet: Information for the patient

Mercaptopurine Tablets USP 50mg TajPharma

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.
– Keep this leaflet. You may need to read it again.
– If you have any further questions, ask your doctor or pharmacist.
– This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
– If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet.

What is in this leaflet
1. What Mercaptopurine Tablets are and what they are used for
2. What you need to know before you take Mercaptopurine Tablets
3. How to take Mercaptopurine Tablets
4. Possible side effects
5. How to store Mercaptopurine Tablets
6. Contents of the pack and other information

1. WHAT MERCAPTOPURINE TABLETS ARE AND WHAT THEY ARE USED FOR
Mercaptopurine tablets contain the active substance called 6-mercaptopurine. 6-mercaptopurine belongs to a group of medicines called cytotoxics (also called chemotherapy) and works by reducing the number of new blood cells your body makes.
Mercaptopurine is used to treat cancer of the blood (leukaemia) in adults, adolescents and children.

2. WHAT YOU NEED TO KNOW BEFORE YOU TAKE MERCAPTOPURINE TABLETS
Do not take Mercaptopurine:
• If you are allergic to 6-mercaptopurine or any of the other ingredients of this medicine (listed in section 6).

Warnings and precautions
Talk to your doctor or pharmacist before taking Mercaptopurine:
• If you have recently received, or are due to receive, a vaccination (vaccine). If you take Mercaptopurine, you should not have a live organism vaccine (for example; flu vaccine, measles vaccine, BCG vaccine, etc.) until advised it is safe to do so by your doctor. This is because some vaccines may give you an infection if you receive them while you are taking Mercaptopurine
• If you have reduced liver function or liver damage
• If you have a genetic condition called TPMT (thiopurine methyltransferase) deficiency
• If you have an inherited mutation in the NUDT15-gene (a gene which is involved in the breakdown of Mercaptopurine in the body), you have a higher risk of infections and hair loss and your doctor may in this case give you a lower dose.
• If you have an allergy to a medicine called azathioprine (also used to treat cancer)
• If you have a kidney problem.
• Tell your doctor whether you have, or have not, had chicken pox, shingles or hepatitis B (a liver disease caused by a virus).
• If you have a genetic condition called Lesch-Nyhan Syndrome If you are receiving immunosuppressive therapy, taking Mercaptopurine could put you at greater risk of:
• tumours, including skin cancer. Therefore, when taking Mercaptopurine, avoid excessive exposure to sunlight, wear protective clothing and use protective sunscreen with a high protection factor.
• lymphoproliferative disorders:
– treatment with Mercaptopurine increases your risk of getting a type of cancer called lymphoproliferative disorder. With treatment regimen containing multiple immunosuppressants (including thiopurines), this may lead to death.
– a combination of multiple immunosuppressants, given concomitantly increases the risk of disorders of the lymph system due to a viral infection (Epstein-Barr virus (EBV) – associated lymphoproliferative disorders).

Taking Mercaptopurine could put you at greater risk of:
• developing a serious condition called Macrophage Activation Syndrome (excessive activation of white blood cells associated with inflammation), which usually occurs in people who have certain types of arthritis.

Infections
When you are treated with Mercaptopurine the risk of viral, fungal and bacterial infections is increased and the infections may be more serious. See also section 4.
Tell your doctor before starting treatment whether or not you have had chickenpox, shingles or hepatitis B (a liver disease caused by a virus).

Blood tests
• Treatment with Mercaptopurine may affect your bone marrow. This means you may have a reduced number of white blood cells, platelets and (less commonly) red blood cells in your blood. Your doctor will carry out blood tests daily when you are at the beginning of your treatment (induction) and at least weekly when you are further along into your treatment (maintenance). This is in order to monitor the levels of these cells in your blood. If you stop treatment early enough, your blood cells will return to normal.

Other laboratory tests
• Additional laboratory tests (urine, blood, etc.) may also be carried out as directed by your doctor.

Liver function
• Mercaptopurine is toxic to your liver. Therefore, your doctor will carry out weekly liver function tests when you are taking Mercaptopurine. If you already have liver disease, or if you are taking other medications which may affect your liver, your doctor will carry out more frequent tests. If you notice the whites of your eyes or your skin turn yellow (jaundice) tell your doctor immediately as you may need to stop your treatment immediately.

Children and adolescents
Low blood sugar levels (sweating more than usual, nausea, dizziness, confusion, etc.) have been reported in some children receiving Mercaptopurine; however, most of the children were under the age of six years old and had a low body weight.

If you are not sure if any of the above applies to you, talk to your doctor or pharmacist before taking Mercaptopurine.

Other medicines and Mercaptopurine
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

In particular, tell your doctor or pharmacist if you are taking any of the following:
• Ribavirin (used to treat viruses)
• Other cytotoxic medicines (chemotherapy – used to treat cancer)
• Allopurinol, thiopurinol, oxipurinol or febuxostat (used to treat gout)
• Olsalazine (used to treat a bowel problem called ulcerative colitis)
• Mesalazine (used to treat Crohn’s Disease and ulcerative colitis)
• Sulfasalazine (used to treat rheumatoid arthritis or ulcerative colitis)
• Methotrexate (used to treat rheumatoid arthritis or severe psoriasis)
• Infliximab (used to treat Crohn’s Disease and ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis or severe psoriasis)
• Warfarin or acenocoumarol (used to ‘thin’ the blood)

Having vaccines while you are taking Mercaptopurine
If you are going to have a vaccination speak to your doctor or nurse before you have it. If you take Mercaptopurine, you should not have a live vaccine (for example; flu vaccine, measles vaccine, BCG vaccine, etc.) until advised it is safe to do so by your doctor. This is because some vaccines may give you an infection if you have them whilst you are taking Mercaptopurine.

Mercaptopurine with food and drink
You can take Mercaptopurine with food or on an empty stomach but the choice of method should be consistent from day to day. You should take your medicine at least 1 hour before or 2 hours after having milk or dairy products.

Pregnancy and breast-feeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor for advice before taking this medicine.

Pregnancy
Treatment with Mercaptopurine is not recommended during pregnancy, particularly in the first trimester (three months) because it may cause damage to the foetus.

If you are pregnant your doctor will consider the risks and benefits to you and your baby before prescribing Mercaptopurine for you. If you or your partner are taking Mercaptopurine, you must use a reliable form of contraception to avoid pregnancy for the whole course of Mercaptopurine treatment and for at least 3 months after receiving the last dose of Mercaptopurine. This applies to both men and women.

Breast-feeding
It is recommended that you do not breast-feed when you are taking Mercaptopurine.

Driving and using machines
It is not expected that Mercaptopurine will affect your ability to drive or use machines, but no studies have been done to confirm this.

Mercaptopurine tablets contain lactose
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before you take Mercaptopurine tablets.

3. HOW TO TAKE MERCAPTOPURINE TABLETS
Mercaptopurine should only be prescribed to you by a specialist doctor who is experienced in treating cancers of the blood.

  • When you take Mercaptopurine, your doctor will take regular blood tests. This is to check the number and type of cells in your blood, and to ensure your liver is working correctly
    • Your doctor may also ask for other blood and urine tests to monitor how your kidneys are working and to measure uric acid levels. Uric acid is a natural substance made in your body and levels of uric acid can rise while you are taking Mercaptopurine. High levels of uric acid may damage your kidneys
    • Your doctor may sometimes change your dose of Mercaptopurine as a result of these tests.

Always take Mercaptopurine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure. It is important to take your medicine at the right times. The label on your pack will tell you how many tablets to take and how often to take them. If the label does not say or if you are not sure, ask your doctor, nurse or pharmacist.

The usual dose for adults and children is 2.5 mg per kilogram of your body weight each day (or alternatively 50 to 75 mg per m2 of your body surface area each day). Your doctor will calculate and adjust your dose based on your body weight, results of your blood tests, whether or not you are taking other chemotherapy medicines and your kidney and liver function.

  • Swallow your tablets whole. Do not chew the tablets. The tablets should not be broken or crushed. If you or your caregiver does handle broken tablets, wash the hands immediately.

You can take your medicine with food or on an empty stomach but the choice of method should be consistent from day to day. You should take your medicine at least 1 hour before or 2 hours after having milk or dairy products.

If you take more Mercaptopurine than you should
If you take more Mercaptopurine than you should, tell your doctor immediately or go to a hospital straight away. Take the medicine pack with you.

If you forget to take Mercaptopurine
Tell your doctor. Do not take a double dose to make up for a forgotten dose.

If you stop taking Mercaptopurine
If you stop taking Mercaptopurine, tell your doctor immediately.

If you have any further questions on the use of this medicine, ask your doctor, nurse or pharmacist.

4. POSSIBLE SIDE EFFECTS
Like all medicines, this medicine can cause side effects, although not everybody gets them.

If you get any of the following side effects, talk to your specialist doctor or go to hospital immediately:
• An allergic reaction with swelling of the face and sometimes mouth and throat (this is a very rare side effect).
• An allergic reaction with joint pain, skin rashes, high temperature (fever) (this is a rare side effect).
• Yellowing of the skin and whites of the eyes. If you get such symptoms, you should stop taking Mercaptopurine.
• Any signs of fever or infection (sore throat, sore mouth or urinary problems) or any unexplained bruising or bleeding. Treatment with Mercaptopurine affects your bone marrow and will cause a reduction in your white blood cells and platelets (this is a very common side effect).

Talk to your doctor if you have any of the following side effects, which may also happen with this medicine:

Common (may affect up to 1 in 10 people)
• Nausea (you feel sick) or vomiting (being sick)
• Low red blood cell count (anaemia)

Uncommon (may affect up to 1 in 100 people)
• Loss of appetite

Rare (may affect up to 1 in 1,000 people)
• Mouth ulcers
• Inflammation of the pancreas (pancreatitis); symptoms may include abdominal pain or feeling or being sick
• Damage to your liver (hepatic necrosis)
• Hair loss
• Various types of cancers including blood, lymph and skin cancers

Very rare (may affect up to 1 in 10,000 people)
• Blood cancer
• Cancer of the spleen and liver (in patients with a condition called Inflammatory Bowel Disease)
• Ulcers in the intestines; symptoms may include abdominal pain and bleeding
• Low sperm count in men

Not known (frequency cannot be estimated from the available data)
• Increased sensitivity to sunlight and UV light

Additional side effects in children
Low blood sugar levels (sweating more than usual, nausea, dizziness, confusion, etc.) have been reported in some children receiving Mercaptopurine; however, most of the children were under the age of six years old and had a low body weight.

Reporting of side effects
If you get any side effects, talk to your doctor, nurse or pharmacist. This includes any possible side effects not listed in this leaflet. By reporting side effects you can help provide more information on the safety of this medicine.

5. HOW TO STORE MERCAPTOPURINE TABLETS
• Keep this medicine out of the sight and reach of children.
• Do not use this medicine after the expiry date which is stated on the pack after ‘Exp’.
• Do not store your Mercaptopurine tablets above 25°C. Keep the bottle tightly closed.
• If your doctor tells you to stop taking the tablets, it is important to return any which are left over to your pharmacist, who will destroy them according to disposal of dangerous substance guidelines. Only keep the tablets if your doctor tells you to.

6. Further Information

What Mercaptopurine Soluble Tablets contain
The active substance is 6-mercaptopurine.
Each tablet contains:Mercaptopurine USP         50mg
The other ingredients are lactose, maize starch, modified maize starch, stearic acid and magnesium stearate.

What Mercaptopurine Tablets look like and contents of the pack
Mercaptopurine tablets are a pale yellow coloured. Your Mercaptopurine tablets are in bottles of 25 tablets.

7. Manufactured In India By:
TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com