Puri-nethol Valeant

Puri-nethol Valeant is indicated for the treatment of acute lymphoblastic leukaemia (ALL) in adults, adolescents and children.

Puri-nethol Valeant treatment should be supervised by a physician or other healthcare professionals experienced in the management of patients with ALL.

Posology

The dose is governed by cautiously monitored haematotoxicity and the dose should be carefully adjusted to suit the individual patient in accordance with the employed treatment protocol. Depending on phase of treatment, starting or target doses generally vary between 25-75 mg/m² body surface area (BSA) per day, but should be lower in patients with reduced or absent Thiopurine Methyl Transferase (TPMT) enzyme activity.

6-mercaptopurine is metabolised by the polymorphic TPMT enzyme. Patients with little or no inherited TPMT activity are at increased risk for severe toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. TPMT testing cannot substitute for haematological monitoring in patients receiving Puri-nethol Valeant. The optimal starting dose for homozygous deficient patients has not been established.

Special populations

Elderly

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 Valeant dose.

Renal impairment

Since 6-mercaptopurine pharmacokinetics has not been formally studied in renal impairment, no specific dose recommendations can be given. Since impaired renal function may result in slower elimination of mercaptopurine and its metabolites and therefore a greater cumulative effect, consideration should be given to reduced starting doses in patients with impaired renal function. Patients should be closely monitored for dose related adverse reactions.

Hepatic impairment

Since 6-mercaptopurine pharmacokinetics has not been formally studied in hepatic impairment, no specific dose recommendations can be given. Since there is a potential for reduced elimination of mercaptopurine, consideration should be given to reduced starting doses in patients with impaired hepatic function. Patients should be closely monitored for dose related adverse reactions.

Switching between tablet and oral suspension and vice versa

A tablet form of 6-mercaptopurine is also available. The 6-mecaptopurine oral suspension and tablet are not bioequivalent with respect to peak plasma concentration, and therefore intensified haematological monitoring of the patient is advised on switching formulations.

Combination with xanthine oxidase inhibitors

Allopurinol and other xanthine oxidase inhibitors decrease the rate of catabolism of 6-mercaptopurine. When allopurinol and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given. Other xanthine oxidase inhibitors should be avoided.

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 substantial 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.

Method of administration

Puri-nethol Valeant is for oral use and requires redispersing (by shaking vigorously at least for 30 seconds) prior to dosing.

Two dosing syringes (a purple syringe graduated to 1 ml and a white syringe graduated to 5 ml) are provided for accurate measurement of the prescribed dose of the oral suspension. It is recommended that the healthcare professional advises the patient or carer which syringe to use to ensure that the correct volume is administered.

Puri-nethol Valeant 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. Puri-nethol Valeant should be taken at least 1 hour before or 2 hours after milk or dairy products.

6-mercaptopurine displays diurnal variation in pharmacokinetics and efficacy. Administration in the evening compared to morning administration may lower the risk of relapse. Therefore the daily dose of Puri-nethol Valeant should be taken in the evening.

To assist accurate and consistent dose delivery to the stomach water should be taken after each dose of Puri-nethol Valeant.

Concomitant use with yellow fever vaccine

Cytotoxicity and haematological monitoring

Treatment with 6-mercaptopurine causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Careful monitoring of haematological parameters should be conducted during therapy. The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of an abnormally large fall in the counts, treatment should be interrupted immediately. Bone marrow suppression is reversible if 6-mercaptopurine is withdrawn early enough..

There are individuals with an inherited deficiency of the TPMT enzyme activity who are very sensitive to the myelosuppresive effect of 6-mercaptopurine and prone to developing rapid bone marrow depression following the initiation of treatment with 6-mercaptopurine. This problem could be exacerbated by coadministration with active substances that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is necessary. Substantial dose reductions are generally required for homozygous-TPMT deficiency patients to avoid the development of life threatening bone marrow suppression.

A possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine in combination with other cytotoxics.

Immunosuppression

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.

Hepatotoxicity

Puri-nethol Valeant 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 Puri-nethol Valeant immediately if jaundice becomes apparent.

Renal toxicity

During remission induction when rapid cell lysis is occurring, uric acid levels in blood and urine should be monitored as hyperuricaemia and/or hyperuricosuria may develop, with the risk of uric acid nephropathy. Hydration and urine alkalinisation may minimize potential renal complications.

Pancreatitis in off-label treatment of patients with inflammatory bowel disease

Pancreatitis has been reported to occur at a frequency of > 1/100 to < 1/10 (“common”) in patients treated for the unlicensed indication inflammatory bowel disease.

Mutagenicity and carcinogenicity

Patients receiving immunosuppressive therapy, including mercaptopurine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.

A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.

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

In view of its action on cellular deoxyribonucleic acid (DNA) 6-mercaptopurine is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment.

Hepatosplenic T-cell lymphoma has been reported in patients with inflammatory bowel disease* treated with azathioprine (the prodrug to 6-mercaptopurine) or 6-mercaptopurine, either with or without concomitant treatment with anti-TNF alpha antibody.).

*inflammatory bowel disease (IBD) is an unlicensed indication

Macrophage activation syndrome

Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD) (unlicensed indication), and there could potentially be an increased susceptibility for developing the condition with the use of mercaptopurine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with mercaptopurine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

Infections

Patients treated with 6-mercaptopurine alone or in combination with other immunosuppressive agents, including corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection, and viral reactivation. The infectious disease and complications may be more severe in these patients than in non-treated patients.

Prior exposure to or infection with varicella zoster virus should be taken into consideration prior to starting treatment. Local guidelines may be considered, including prophylactic therapy if necessary. Serologic testing prior to starting treatment should be considered with respect to hepatitis B. Local guidelines may be considered, including prophylactic therapy for cases which have been confirmed positive by serologic testing. Cases of neutropenic sepsis have been reported in patients receiving 6-mercaptopurine for ALL.

Patients with NUDT15 variant

Patients with inherited mutated NUDT15 gene are at increased risk for severe 6-mercaptopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy. They generally require substantial dose reduction, particularly those being NUDT15 variant homozygotes (see 4.2). The frequency of NUDT15 c.415C>T has an ethnic variability of approximately 10 % in East Asians, 4 % in Hispanics, 0.2 % in Europeans and 0 % in Africans. In any case, close monitoring of blood counts is necessary.

Paediatric population

Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine. The majority of reported cases were in children under the age of six or with a low body mass index.

Interactions

When oral anticoagulants are coadministered with 6-mercaptopurine, a reinforced monitoring of INR (International Normalised Ratio) is recommended.

Excipients

This medicinal product contains aspartame (E951), a source of phenylalanine. May be harmful for people with phenylketonuria.

It also contains sodium methyl parahydroxybenzoate and sodium ethyl parahydroxybenzoate which may cause allergic reaction (possibly delayed).

As this medicine contains sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. Long term use increases the risk of dental caries and it is essential that adequate dental hygiene is maintained.

Safe handling of the suspension

Parents and care givers should avoid Puri-nethol Valeant contact with skin or mucous membrane. If the suspension comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water.

No studies on the effect on the ability to drive and use machines have been performed. A detrimental effect on these activities cannot be predicted from the pharmacology of the active substance.

Summary of the safety profile

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

For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of adverse reactions.

Tabulated list of adverse reactions

The following events have been identified as adverse reactions. The adverse reactions are displayed by system organ class and frequency: very common (>1/10), common (>1/100 to < 1/10), uncommon (>1/1000 to < 1/100), rare (>1/10,000 to < 1/1000) and very rare (< 1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

* In patients with inflammatory bowel disease (IBD), an unlicensed indication.

^†In the paediatric population.

Description of selected adverse reactions

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 is exceeded.

Monitoring of liver function tests may allow early detection of 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. Healthcare professionals are asked to report any suspected adverse reactions via:

Ireland

HPRA Pharmacovigilance

Earlsfort Terrace

IRL - Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: [email protected]

Malta

ADR Reporting

Website: www.medicinesauthority.gov.mt/adrportal

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

Symptoms and signs

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

The risk of overdose is also increased when xanthine oxidase inhibitors is being given concomitantly with 6-mercaptopurine.

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 the use of activated charcoal or gastric lavage) may not be effective in the event of 6-mercaptopurine overdose unless the procedure can be undertaken within 60 minutes of ingestion.

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

Mechanism of action

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

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

Absorption

The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability, which probably results from its first-pass metabolism. When administered orally at a dosage of 75 mg/m² to 7 paediatric patients, the bioavailability averaged 16% of the administered dose, with a range of 5 to 37%.

In a comparative bioavailability study in healthy adult volunteers (n=60), 50mg of Puri-nethol Valeant oral suspension was demonstrated to be bioequivalent to the reference 50mg tablet for AUC, but not C_max. The mean (90% CI) C_max with the oral suspension was 39% (22% - 58%) higher than the tablet although there was less between-subject variability (%C.V) with the oral suspension (46%) than the tablet (69%).

Biotransformation

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

Elimination

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

The main route of elimination for 6-mercaptopurine is by metabolism.

Genotoxicity

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

Carcinogenicity

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

Teratogenicity

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

Not applicable.

Safe handling

Anyone handling Puri-nethol Valeant should wash their hands before and after administering a dose. To decrease the risk of exposure, parents and care givers should wear disposable gloves when handling Puri-nethol Valeant.

Puri-nethol Valeant contact with skin or mucous membrane must be avoided. If Puri-nethol Valeant comes into contact with skin or mucosa, it should be washed immediately and thoroughly with soap and water. Spillages must be wiped immediately.

Women who are pregnant, planning to be or breast-feeding should not handle Puri-nethol Valeant.

Parents / care givers and patients should be advised to keep Puri-nethol Valeant out of the reach and sight of children, preferably in a locked cupboard. Accidental ingestion can be lethal for children.

Keep the bottle tightly closed to protect the integrity of the product and minimise the risk of accidental spillage.

The bottle should be shaken vigorously for at least 30 seconds to ensure the oral suspension is well mixed.

Disposal

Puri-nethol Valeant is cytotoxic. Any unused product or waste material should be disposed of in accordance with local requirements.