Puri-Nethol 50 mg Tablet.

PURI-NETHOL is indicated in combination with other medicines for the treatment of acute leukaemia in adults, adolescents and children. PURI-NETHOL is indicated for:

• Acute lymphoblastic leukaemia (ALL)
• Acute promyelocytic leukaemia (APL) / Acute myeloid leukaemia M3 (AML M3).

Posology

PURI-NETHOL treatment should be supervised by a medical practitioner experienced in the management of patients with ALL and APL (AML M3) (see section 4.4). The dosage should be carefully adjusted to suit the individual patient. PURI-NETHOL 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). PURI-NETHOL should be taken at least one hour before or two hours after milk or dairy products (see section 5.1).

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/m2 body surface area per day, but the dose and duration of administration depend on the nature and dosage of other cytotoxic medicines given in conjunction with PURI-NETHOL. The dosage should be adjusted according to individual response and tolerance. PURI-NETHOL has been used in various combination therapy schedules for acute leukaemia and the literature and current treatment guidelines should be consulted for details. PURI-NETHOL should be administered to children with ALL in the evening to lower the risk of relapse.

Elderly population

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

Renal impairment

Consideration should be given to reducing the dose in renal impairment.

Hepatic impairment

Consideration should be given to reducing the dose in hepatic impairment.

PURI-NETHOL is contraindicated in:

• Patients with hypersensitivity to 6-mercaptopurine, azathioprine or to any of the excipients in PURI-NETHOL (see section 6.1).

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

PURI-NETHOL IS AN ACTIVE CYTOTOXIC MEDICINE FOR USE ONLY UNDER THE DIRECTION OF MEDICAL PRACTITIONERS EXPERIENCED IN THE ADMINISTRATION OF SUCH MEDICINES.

Monitoring

SINCE PURI-NETHOL IS STRONGLY MYELOSUPPRESSIVE FULL BLOOD COUNTS MUST BE TAKEN DAILY DURING REMISSION INDUCTION. PATIENTS MUST BE CAREFULLY MONITORED DURING THERAPY.

Hypersensitivity

Patients suspected to have previously presented with a hypersensitivity reaction to PURI-NETHOL 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 (see section 4.3).

Immunisation

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 APL (AML M3). 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 medicines used, the underlying disease, and other factors.

The interval between cessation of PURI-NETHOL and immunisation should be at least three months.

Ribavirin

Co-administration of ribavirin and PURI-NETHOL is not advised. Ribavirin may reduce efficacy and increase toxicity of PURI-NETHOL (see section 4.5).

Safe handling of PURI-NETHOL

For the safe handling of PURI-NETHOL tablets, refer to section 4.2. It is advisable to take care when handling or halving these tablets not to contaminate hands or inhale the medicine.

Bone marrow suppression

The main side effect of treatment with PURI-NETHOL is 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 platelet counts, should be regularly monitored and more frequently if high dosage is used or if severe renal and/or hepatic disorder is present. Bone marrow suppression is usually reversible if PURI-NETHOL is withdrawn early enough. During remission induction in APL (AML M3) the patient may frequently have to survive a period of relative bone marrow aplasia, and it is important that adequate support facilities are available.

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. The dosage of PURI-NETHOL may need to be reduced when this medicine is combined with other medicines whose primary or secondary toxicity is myelosuppression (see sections 4.2 and 4.5).

Renal impairment

Caution is advised during the administration of PURI-NETHOL in patients with renal impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored.

Tumour lysis syndrome

During remission induction when rapid cell lysis occurs, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria and acute gout may develop, with the risk of uric acid nephropathy.

Hepatotoxicity

PURI-NETHOL 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 PURI-NETHOL immediately if jaundice becomes apparent. This may be reversible if 6-mercaptopurine therapy is stopped soon enough, but fatal liver damage has occurred.

Thiopurine methyltransferase (TPMT) deficiency

Individuals with an inherited deficiency of the enzyme TPMT may be unusually sensitive to the myelosuppressive effect of PURI-NETHOL and prone to developing rapid bone marrow depression following the initiation of PURI-NETHOL treatment. This problem could be exacerbated by co-administration with medicines that inhibit TPMT such as olsalazine, mesalazine or sulphasalazine. There is an association between decreased TPMT activity and secondary leukaemias and myelodysplasia in individuals receiving PURI-NETHOL in combination with other cytotoxics (see section 4.8). 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 almost 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.

NUDT15 Mutation

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from 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.

When the xanthine oxidase inhibitors, such as allopurinol and PURI-NETHOL are administered concomitantly it is essential that only a quarter (25 %) of the usual dose of PURI-NETHOL is given since these medicines decreases the rate of catabolism of PURI-NETHOL. Concomitant administration of other xanthine oxidase inhibitors, such as febuxostat, should be avoided (see section 4.5).

TPMT-deficient patients

Patients with inherited little or no thiopurine S-methyltransferase TPMT activity are at increased risk for severe PURI-NETHOL toxicity from conventional doses of PURI-NETHOL 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 PURI-NETHOL doses, but some may require dose reduction. The optimal starting dose for homozygous deficient patients has not been established (see section 4.4).

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established.

Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine-related severe leukocytopenia and alopecia, especially in Asian populations (see section 5.1).

Method of administration

For oral administration. Instructions for use/handling It is recommended that the handling of PURI-NETHOL tablets follows the u201cGuidelines for the Handling of Cytotoxic Drugsu201d according to prevailing local recommendations and/or regulations. Surplus PURI-NETHOL tablets should be destroyed in a manner appropriate to the prevailing local recommendations for the destruction of dangerous substances (see section 6.6).

Women of childbearing potential / Contraception in males and females

As with all cytotoxic treatments, female patients who use 6-mercaptopurine, as in PURI-NETHOL, should use adequate contraceptive methods during the treatment and for a period of six months following the cessation of treatment. Male patients who use 6-mercaptopurine, as in PURI-NETHOL, should also use adequate contraceptive methods during the treatment and for a period of three months following the cessation of treatment. The final decision regarding the additional time period on contraception should be taken by the doctor.

It is recommended to have a consultation on sperm cryopreservation and/or individual genetic counselling for male and female patients intending to have a child after treatment with PURI-NETHOL.

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. Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal PURI-NETHOL treatment in combination with other chemotherapy medicines. Substantial transplacental and transamniotic transmission of 6-mercaptopurine as found in PURI-NETHOL and its metabolites from the mother to the foetus have been shown to occur. In utero exposure to thiopurines has not been associated with negative effects on long-term childhood development or susceptibility for infectious disease. Normal offspring with normal Apgar scores directly after birth in most cases, have been born after 6-mercaptopurine therapy administered during pregnancy. Pregnancy may affect thiopurine metabolism, which may increase the risk of toxicity. Pregnant women on thiopurine, as in PURI-NETHOL, therapy should be closely monitored.

There have been case reports of cholestasis in pregnancy reported in association with thiopurine, as in PURI-NETHOL, therapy (see section 4.4).

Paternal exposure

Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to PURI-NETHOL (see section 4.4).

Breastfeeding

PURI-NETHOL is excreted into breast milk. Mothers receiving PURI-NETHOL should not breastfeed.

Fertility

The effect of PURI-NETHOL therapy on human fertility is unknown. Oligospermia has been reported following exposure to 6 u2013 mercaptopurine as found in PURI-NETHOL (see section 4.8).

PURI-NETHOL has no or negligible influence on the ability to drive and use machines.

a) 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 medicines 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 medicines.

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

b) Tabulated list of adverse reactions

System organ class

• Frequent
• Less frequent
• Frequency unknown (cannot be estimated from the available data)

Infections and infestations

• Bacterial and viral infections, infections associated with neutropenia

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

• Neoplasms including lymphoproliferative disorders, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ, secondary leukaemia, myelodysplasia, hepatosplenic T-cell lymphoma in patients with IBD (when used in combination with anti-TNF medicines)

Blood and the lymphatic system disorders

• Bone marrow depression/failure, leukopenia, thrombocytopenia, anaemia

Immune system disorders

• Hypersensitivity, arthralgia, rash, pyrexia, facial oedema

Metabolism and nutrition disorders

• Anorexia

Hypoglycaemia (In the paediatric population), pellagra (see section 4.4)

Gastrointestinal disorders

• Pancreatitis, nausea, vomiting, stomatitis

Mouth ulceration, intestinal ulcer, mild diarrhoea, sprue-like symptoms

Hepato-biliary disorders

• Cholestasis, hepatotoxicity

Hepatic necrosis

Cholestasis of pregnancy

Skin and subcutaneous tissue disorders

• Alopecia, photosensitivity reaction

Erythema nodosum

Reproductive system and breast disorder

• Transient oligospermia

General disorders and administration site conditions

• Mucosal inflammation

c) Description of selected adverse reactions

The incidence of hepatoxicity varies considerably and can occur with any dose but more frequently when the recommended dose of 2,5 mg/kg bodyweight daily is exceeded.

d) Paediatric population

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 medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare providers are asked to report any suspected adverse reactions to SAHPRA via the Med Safety APP (Medsafety X SAHPRA) and eReporting platform (who-umc.org) found on SAHPRA website. Aspen Pharmacare: E-mail: [email protected] Tel: 0800 118 088

Symptoms

Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of an overdose. The principal toxic effect is bone marrow suppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of PURI-NETHOL. Liver dysfunction and gastro-enteritis may also occur. The risk of overdosage is also increased when allopurinol is being given concomitantly with PURI-NETHOL (see section 4.5).

Treatment

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 the use of activated charcoal) may not be effective in the event of PURI-NETHOL overdose unless the procedure can be undertaken within 60 minutes of ingestion.