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4.2 Posology and method of administration

 

•           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.

 

 

4.4       Special warnings and precautions for use

 

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.

 

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 sections 4.2 and 5.2).

 

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. 

 

 

4.8       Undesirable effects

 

Body System				Side effects
Infections and infestations	Uncommon		Bacterial and viral infections, infections associated with neutropenia

 

10        DATE OF REVISION OF THE TEXT

 

June 2017  Feb 2016

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4.4       Special warnings and precautions for use

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.

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.

4.8       Undesirable Effects

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).

 

1         DATE OF REVISION OF THE TEXT

 

May 2016 December 2015

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Safe handling of 6-mercaptopurine tablets

See 6.6 Special precautions 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 and after therapy.

Bone marrow suppression

Treatment with 6-mercaptopurine causes bone marrow suppression leading to leukopenia and thrombocytopenia and less frequently, anaemia. Full blood counts must be taken frequently  during remission induction. 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.

 

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 drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. 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 cytototoxics (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.

 

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

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.

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).

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.

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 since allopurinol decreases the rate of catabolism of 6-mercaptopurine (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.

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.

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.

5.1       Pharmacodynamic properties

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

  Mechanism of action

6-Mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic anti-metabolite

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 thioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.

 

            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.

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).

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2           Qualitative and Quantitative composition

 

Each tablet contains 50mg of the active substance 6-mercaptopurine.

 

Excipients with known effect:

 

Each tablet also contains 59mg of the excipient lactose monohydrate

 

For thea full list of excipients, see section 6.1.

4.1     Therapeutic iIndications

 

Puri-Nethol6-mercaptopurine is indicated for the treatment of acute leukaemia.  It may be utilised in remission induction and is particularly indicated for maintenance therapy in:

-          aAcute lymphoblastic leukaemia (ALL);

-          aAcute myelogenous leukaemia (AML).

 

Puri-Nethol may be used in the treatment of chronic granulocytic leukaemia.

 

4.2       Posology and Method of Administration

 

Posology

6‑mercaptopurine should be administered at least 1 hour before or 3 hours after food or milk (see section 5.2 Pharmacokinetic properties: Absorption).

 

Populations

 

Dosage in aAdults and children:

For adults and children the usual dose is 2.5 mg/kg bodyweight per day, or 50 to- 75mg/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 Puri-Nethol6-mercaptopurine.

 

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

 

       Puri-Nethol6-mercaptopurine has been used in various combination therapy schedules for acute leukaemia and the literature 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.

 

Children considered to be overweight may require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended (see section 5.2 Pharmacokinetic properties: Special patient populations; Overweight children).

 

Dosage in the eElderly:

       No specific studies have been carried out in the elderly. However, iIt is advisable to monitor renal and hepatic function in these patients, and if there is any impairment, consideration should be given to reducing the 6-mercaptopurinePuri-Nethol dosage.

 

Dosage inRrenal 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).

 

       Dosage in hHepatic 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).

 

In generalMedicinal product interaction:

When xanthine oxidase inhibitors, such as allopurinol, and 6-mercaptopurine are administered concomitantly it is essential that only a quarter25 % of the usual dose of 6-mercaptopurine is given since allopurinol decreases the rate of catabolism of 6-mercaptopurine (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 (see section 4.4 Special warnings and precautions for use: Monitoring and section 5.2 Pharmacokinetic properties).

 

Most patients with heterozygous TPMT deficiency can tolerate recommended 6-mercaptopurine doses, but some may require dose reduction.  Genotypic and phenotypic tests of TPMT are available (see section 4.4 Special warnings and precautions for use: Monitoring and section 5.2 Pharmacokinetic properties).

 

 

4.4       Special Wwarnings and Pprecautions for uUse

 

PURI-NETHOL6-MERCAPTOPURINE IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF SPECIALIST ONCOLOGISTSPHYSICIANS EXPERIENCED IN THE ADMINISTRATION OF SUCH AGENTS.

 

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).

 

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp galactoase deficiency or glucose-galactose malabsorption should not take this medicinal producte.

 

Safe handling of Puri-Nethol tablets:

See 6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal products and other handling of the product.

 

Monitoring:

SINCEince  6-MERCAPTOPURINE IS Puri-Nethol is STRONGLY MYELOSUPPRESSIVE FULL BLOOD COUNTS MUST BE TAKEN DAILY DURING REMISSION INDUCTIONstrongly myelosuppressive full blood counts must be taken daily during remission induction. PATIENTS MUST BE CAREFULLY MONITORED DURING AND AFTER THERAPYPatients must be carefully monitored during and after therapy.

 Bone marrow suppression is reversible if 6-mercaptopurinePuri-Nethol is withdrawn early enough.

 

6-mercaptopurinePuri-Nethol is hepatotoxic and liver function tests should be monitored weekly during treatment. 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-mercaptopurinePuri-Nethol immediately if jaundice becomes apparent.

 

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressiveon effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6-mercaptopurinePuri-Nethol. This problem could be exacerbated by co-administration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphfasalazine. 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 Ccytototoxics (see section 4.8 Undesirable eEffects). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.

 

Cross-resistance usually exists between 6-mercaptopurine and 6-thioguanine (Lanvis).

 

The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other medicinal productsdrugs whose primary or secondary toxicity is myelosuppression (see section 4.5 Interaction with other medicinal products and other forms of interactions: Myelosuppressive agents).

 

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 Ccarcinogenicity: 

Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients, in a hypernephroma patient who received an unstated dose of 6-mercaptopurine and in patients with chronic renal disease treated at doses of 0.4 to– 1.0 mg/kg/day.

 

Two cases have been documented of the occurrence of acute non-lymphatic leukaemia in patients who received 6-mercaptopurine, in combination with other drugs for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with 6-mercaptopurine and later developed acute non-lymphatic leukaemia, but it is not clear whether this was part of the natural history of the disease or if the 6-mercaptopurine played a causative role.

 

 

4.5   Interaction with Oother mMedicinal pProducts and Oother Fforms of Iinteraction

 

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see section 4.4 Special Wwarnings and Pprecautions for use).

 

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

 

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 a quarter25 % of the usual dose of 6-mercaptopurine is given since allopurinol decreases the rate of catabolism of 6-mercaptopurine (see section 4.2 Posology and method of administration: Medicinal product interactions).

 

Inhibition of the anticoagulant effect of warfarin, when given with 6-mercaptopurine, has been reported.

 

Aminosalicylates

 

As tThere is in-vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, meslazine or sulphfasalazine) inhibit the TPMT enzyme. Therefore, lower doses of 6-mercaptopurine may need to be considered when, they should be administered concomitantly with aminosalicylate derivativescaution to patients receiving concurrent Puri-Nethol therapy (see section 4.4 Special Wwarnings and Special Pprecautions for Uuse).

 

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.

 

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, Ppregnancy and Llactation

 

Fertility:

 

No text.

 

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-mercaptopurinePuri-Nethol 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-mercaptopurinePuri-Nethol tablets.

 

Studies of 6-mercaptopurine in animals have shown reproductive toxicity (See section 5.3). 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.

 

 

Normal offspring have been born after 6-mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy.

 

Paternal exposure:

Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to 6-mercaptopurine.

 

Studies of 6-mercaptopurine in animals have shown reproductive toxicity (See section 5.3). The potential risk for humans is largely unknown.

 

Breast-feedingLactation:

6-Mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine. It is recommended and thus, that mothers receiving 6-mercaptopurinePuri-Nethol should not be used during breast-feeding should not breast-feed.

 

Fertility:

 

No text.

 

 

4.7       Effect on Aability to Ddrive and uUse Mmachines

 

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 productdrug.

 

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.

Tabulated list of adverse reactions

The following convention has been utilised for the classification of undesirable effectsfrequency:-

Very common ( ³1/10), c

Common (³1/100 and < 1/10), u

Uncommon (³1/1000 and <1/100), r

Rare (³1/10,000 and <1/1000), v

Very rare (<1/10,000).

Body System		Side effects
Neoplasms Benign, Malignant and Unspecified (including cysts and polyps)	Very Rare	Secondary Leukaemia and myelodysplasia (see section 4.4 Special warnings and precautions for use); hepatosplenic T-cell lymphoma in patients with IBD (an unlicensed indication) when used in combination with anti‑TNF agents (see section 4.4. Special warnings and precautions for use).
Blood and Lymphatic System Disorders	Very common	Bone marrow suppression; leucopenia and thrombocytopenia.
Immune System Disorders	Rare	Hypersensitivity reactions with the following manifestations have been reported: Arthralgia; skin rash; drug fever.
	Very rare	Hypersensitivity reactions with the following manifestations have been reported: Facial oedema
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
Hepatobiliary Disorders	Common	Biliary stasis; hepatotoxicity
	Rare	Hepatic necrosis
Skin and Subcutaneous Tissue Disorders	Rare	Alopecia
-          Metabolism and nutrition disorders	Uncommon	Anorexia
-          Reproductive system and breast disorders	Very Rare	Transient oligospermia

 

 

 

Description of selected adverse reactions:

 

Blood and lymphatic system disorders

 

Very common : Bone marrow suppression; leucopenia and thrombocytopenia.

 

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

 

 

Metabolism and nutrition disorders

 

Uncommon: Anorexia

 

Gastrointestinal disorders

 

Common:  Nausea; vomiting; pancreatitis in the inflammatory bowel disease (IBD) population (an unlicensed indication)

 

Rare: Oral ulceration; pancreatitis (in the licensed indications)

 

Very rare:   Intestinal ulceration

Hepato-biliary disorders

 

Common: Biliary stasis; hepatotoxicity

 

Rare: Hepatic necrosis

6-mercaptopurine is hepatotoxic in animals and man. The histological findings in man have shown hepatic necrosis and biliary stasis.

 

 

Skin and subcutaneous tissue disorders

 

Rare:  alopecia

 

Reproductive system and breast disorders

 

           Very Rare: Transient oligospermia

-    

            Immune System Disorders

            Hypersensitivity reactions with the following manifestations have been reported:

           

            Rare                 Arthralgia; skin rash; drug fever

 

            Very Rare        Facial Oedema

 

Neoplasms benign, malignant and unspecified (including cysts and polyps)

 

Very rare            Secondary Leukaemia and myelodysplasia (see Warnings and Precautions);

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 Special Warnings and

Precautions for Use).

 

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

 

HPRA Pharmacovigilance,

Earlsfort Terrace,

IRL - Dublin 2

 

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

 E-mail: medsafety@hpra.ie

 

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 national reporting system:

 

Pharmacovigilance Section

Irish Medicines Board

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.imb.ie

e-mail: imbpharmacovigilance@imb.ie

 

4.9       Overdose

 

Symptoms and signs:

 

Gastro-intestinal 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-mercaptopurinePuri-Nethol. Liver dysfunction and gastroenteritis may also occur.

 

The risk of overdosage is also increased when allopurinol is being given concomitantly with Puri-Nethol6-mercaptopurine (see 4.5 Interactions with Oother Mmedicinal productsaments and Oother Fforms of Iinteraction).

 

ManagementTreatment:Management

 

As there is no known antidote, the blood countspicture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as activated charcoal) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

2           Pharmacological Properties

 

 

5.2         Pharmacokinetic properties

 

Absorption

 

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability. When administered 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 %. 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 0.89 μM, with a range of 0.29-1.82 μM 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 Pharmacokinetics: Metabolism). 6-Mercaptopurine should be administered at least 1 hour before or 3 hours after food or milk (see Dosage and Administration).

 

Distribution

 

The mean (± SD) apparent volume of distribution of 6-mercaptopurine is 0.9 (± 0.8) L/kg, although this may be an underestimate because 6-mercaptopurine is cleared throughout the body (and not just in the liver).

 

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.

 

Metabolism

 

6-mercaptopurine is extensively metabolized by many multi-step pathways to active and inactive metabolites, with no one enzyme predominating. 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) (see Warnings and Precautions: Monitoring and Interactions: Aminosalicylates), xanthine oxidase (see Interactions: Allopurinol/oxipurinol/thiopurinol and Pharmacokinetics: Absorption), inosine monophosphate dehydrogenase (IMPDH) (see Interactions: Ribavirin), 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.

 

Thiopurine S-Methyl Transferase (TPMT)

 

TPMT activity is inversely related to red blood cell 6-mercaptopurine derived thioguanine nucleotide concentration, with higher thioguanine nucleotide concentrations resulting in greater reductions in white blood cell and neutrophil counts. Individuals with TPMT deficiency develop very high cytotoxic thioguanine nucleotide concentrations. 

 

Genotypic testing can determine the allelic pattern of a patient. Currently, 3 alleles—TPMT*2, TPMT*3A and TPMT*3C—account for about 95 % of individuals with reduced levels of TPMT activity. Approximately 0.3 % (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10 % of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90 % of individuals have normal TPMT activity with two functional alleles. There may also be a group of approximately 2 % who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in red blood cells and can also be informative (see Warnings and Precautions).

 

Elimination

 

In a study with 22 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 after IV administration.

 

Special Patient Populations

 

Elderly

 

No specific studies have been carried out in the elderly (see Posology and Method of AdministrationDosage and Administration).

 

Overweight children

 

In a US clinical study, 18 children (aged 3 to 14 years) were evenly divided into two groups; either a weight to height ratio above or below the 75th percentile. Each child was on maintenance treatment of 6-mercaptopurine and the dosage was calculated based on their body surface area. The mean AUC (0 - ) of 6-mercaptopurine in the group above the 75th percentile was 2.4 times lower than that for the group below the 75th percentile. Therefore, children considered to be overweight may require 6-mercaptopurine doses at the higher end of the dose range and close monitoring of response to treatment is recommended (see Posology and Method of AdministrationDosage and 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, consideration should be given to reducing the dosage in patients with impaired renal function (see Dosage and 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.

 

Therefore, consideration should be given to reducing the dosage in patients with impaired hepatic function (see Posology and Method of AdministrationDosage and Administration).

6.6     Special precautions for disposal of a used medicinal product or waste material derived from such a medicinal products and other handling of the product

 

-              Safe handling:

 

1.     If halving of a tablet is required, care should be taken not to contaminate the hands or inhale the drug. 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 6-mercaptopurine tablets surplus to requirements should be destroyed in a manner appropriate to the prevailing local regulations for the destruction of dangerous substances.

 

10           Date of Revision of The Text

 

Feb 2011Dec2013

 

Text in red = new text
Text strikethrough = deleted text

7. Marketing Authorisation Holder
Aspen Pharma Trading Limited
12/13 Exchange Place

I.F.S.C, Dublin 1,

Ireland

 

3016 Lake Drive

Citywest Business Campus

Dublin 24

Ireland

10 Date of Revision of Text
February 2011
December 2013

 

The following  text (underlined in green) has been inserted or deleted (in red) into section 3 and section 4.4.
3.    pharmaceutical form

 

Tablet.

 

Pale yellow, round tablets, biconvex, scored on one side, engraved GX and EX2 on either side of the scoreline and plain on the other side.

 

The scoreline is only to facilitate breaking of the tablets for ease of swallowing and not to divide into equal doses.

4.4       Special Warnings and Precautions for Use

4.4       Special Warnings and Precautions for Use

 

PURI-NETHOL IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF SPECIALIST ONCOLOGISTS 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.

 

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

 

Safe handling of Puri-Nethol tablets:

See 6.6 Instructions for use and handlingSpecial precautions for disposal of a used medicinal product or waste materials derived from such medicinal products and other handling of the product.

 

Improved presentation

Product ownership changed from GSK to Aspen

Puri-Nethol Summary of SPC changes

Renewal & GDS version 18

 

 

 

2          qualitative and QUantitative composition

 

Each tablet contains 50mg of mercaptopurine.

Each tablet also contains 59mg of the excipient lactose monohydrate

 

For a full list of excipients, see 6.1.

 

3        pharmaceutical form

 

Tablet.

 

Pale yellow, round tablets, biconvex, scored on one side, engraved GX above the score and EX2 on either side of the scoreline and plain on the other side.  The scoreline is only to facilitate breaking of the tablets for ease of swallowing and not to divide into equal doses.

 

………………………..

 

4.3       Contra-indications

 

Hypersensitivity to any component of the preparation.

 

Use in patients with acute untreated infections.

 

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

 

 

4.4       Special Warnings and Precautions for Use

 

PURI-NETHOL IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF SPECIALIST ONCOLOGISTS 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.

 

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

 

Safe handling of Puri-Nethol tablets:

See 6.6 Instructions for Use and Handling Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal products and other handling of the product

 

…………………………….

 

 

A patient with Hodgkin’s disease treated with 6-mercaptopurine and multiple additional cytotoxic agents developed acute myelogenous leukaemia.

 

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

 

Reports of hepatosplenic T‑cell lymphoma in the inflammatory bowel disease (IBD) population have been received when 6-mercaptopurine is used in combination with anti-TNF agents (see section 4.8 Undesirable Effects).

 

………………………

 

 

4.6       Pregnancy and Lactation

 

Pregnancy:

The use of Puri-Nethol 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 Puri-Nethol tablets.

 

Maternal exposure:

 

The effect of 6-mercaptopurine on human fertility is largely unknown; however 6-mercarptopurine can cause fetal harm when administered to a pregnant woman.

 

………………………….

 

 

4.8       Undesirable Effects

 

……………………………

 

 

Gastrointestinal disorders

 

Common:  Nausea; vomiting; pancreatitis in the inflammatory bowel disease (IBD) population (an unlicensed indication)

 

Rare: Oral ulceration; pancreatitis (in the licensed indications)

 

Very rare:   Intestinal ulceration

 

……………………………….

 

Neoplasms benign, malignant and unspecified (including cysts and polyps)

 

Very rare            Secondary Leukaemia and myelodysplasia (see Warnings and Precautions); 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 Special Warnings and Precautions for Use).

 

 

4.9       Overdose

 

……………………………….

 

 

Management:

As there is no known antidote the blood picture should be closely monitored and general supportive measures, together with appropriate blood transfusion, instituted if necessary. Active measures (such as 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.

 

……………………………….

 

6.4          Special Precautions for Storage

 

Do not store above 25°C. 

Store in the original container, in order to protect from light.

Keep the container tightly closed in order to protect from moisture.

 

 

6.6       Instructions for Use and Handling Special precautions for disposal of a used medicinal product or waste material derived from such a medicinal products and other handling of the product

 

Safe handling:

It is recommended that the handling of Puri-Nethol tablets follows the "Guidelines for the Handling of Cytotoxic Drugs" according to prevailing local recommendations and/or regulations.

 

If halving of a tablet is required, care should be taken not to contaminate the hands or inhale the drug.

 

Disposal:

 

Puri-Nethol tablets surplus to requirements should be destroyed in a manner appropriate to the prevailing local regulations for the destruction of dangerous substances.

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

10        Date of (Partial) Revision of the Text

 

October 2004

 

March 2010

Section 10

Date change from Oct 22nd 2004 to Dec 2004