INFORMATION FOR HEALTH PROFESSIONALS
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Purinethol 50mg Tablets: Each tablet contains 50mg mercaptopurine BP.
Pale, yellow, round tablets, biconvex, scored on one side, engraved GX above the score and EX2 below the score and plain on the other side.
PURI-NETHOL is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and is particularly indicated for maintenance therapy in:
acute lymphoblastic leukaemia;
acute myelogenous leukaemia.
PURI-NETHOL may be used in the treatment of chronic granulocytic leukaemia.
For adults and children the usual dose is 2.5mg/kg bodyweight per day, or 50-75mg/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-NETHOL.
The dosage should be carefully adjusted to suit the individual patient.
PURI-NETHOL 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 leukemia suggested that administration of mercaptopurine in the evening lowered the risk of relapse compared with morning administration.
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.
Consideration should be given to reducing the dosage in patients with impaired renal function.
Consideration should be given to reducing the dosage in patients with impaired hepatic function.
When allopurinol and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given since allopurinol decreases the rate of catabolism of 6-mercaptopurine.
Hypersensitivity to any component of the preparation
In view of the seriousness of the indications there are no other absolute contra-indications.
PURI-NETHOL IS AN ACTIVE CYTOTOXIC AGENT FOR USE ONLY UNDER THE DIRECTION OF PHYSICIANS 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.
See Instructions for Use/Handling.
SINCE PURI-NETHOL IS STRONGLY MYELOSUPPRESSIVE FULL BLOOD COUNTS MUST BE TAKEN DAILY DURING REMISSION INDUCTION. PATIENTS MUST BE CAREFULLY MONITORED DURING THERAPY.
Treatment with 6-mercaptopurine causes bone marrow suppression leading to leucopenia and thrombocytopenia and, less frequently, to anaemia. Full blood counts must be taken daily during remission induction and careful monitoring of haematological parameters should be conducted during maintenance 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 PURI-NETHOL 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.
PURI-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 PURI-NETHOL immediately if jaundice becomes apparent.
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.
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 PURI-NETHOL. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. 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 Undesirable Effects). 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
The dosage of 6-mercaptopurine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
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 0.4-1.0mg/kg/day.
Two cases have been documented of the occurrence of acute nonlymphatic 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 nonlymphatic 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.
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Special Warnings and Special Precautions for Use).
When allopurinol and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of mercaptopurine is given since allopurinol decreases the rate of catabolism of mercaptopurine.
Inhibition of the anticoagulant effect of warfarin, when given with 6-mercaptopurine, has been reported. As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent PURI-NETHOL therapy (see Special Warnings and Special Precautions for Use).
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.
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. Multiple congenital abnormalities have been reported following maternal 6-mercaptopurine treatment in combination with other chemotherapy agents.
Paternal exposure Congenital abnormalities and spontaneous abortions have been reported exposure to 6-mercaptopurine.
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Preclinical safety data). The potential risk for humans is largely unknown.
6-mercaptopurine has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of 6-mercaptopurine and thus mothers receiving PURI-NETHOL should not breast feed.
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 drug.
For mercaptopurine there is a lack of modern clinical documentation which can serve as support for accurately determining the frequency of undesirable effects.
The following convention has been utilised for the classification of undesirable effects:- Very common ≥1/10, common ≥1/100, <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000.
| Neoplasms benign, malignant and unspecified (including cysts and polyps) | |
|---|---|
| Very rare: | Secondary Leukaemia and myelodysplasia (see Special Warnings and Special Precautions for Use) |
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. | |
Immune system disorders |
|
| Hypersensitivity reactions with the following manifestations have been reported | |
| Rare: | Arthralgia; skin rash; drug fever |
| Very rare: | Facial oedema |
Metabolism and nutrition disorders |
|
| Uncommon: | Anorexia |
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 |
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 The incidence of hepatotoxicity varies considerably and can occur with any dose but more frequently when the recommended dose of 2.5mg/kg bodyweight daily or 75mg/m2 body surface area per day 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. |
|
Skin and subcutaneous tissue disorders |
|
| Rare: | Alopecia |
Reproductive system and breast disorders |
|
| Very rare: | Transient oligospermia |
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 PURI-NETHOL. Liver dysfunction and gastroenteritis may also occur.
The risk of overdosage is also increased when allopurinol is being given concomitantly with PURI-NETHOL (see Interaction with Other Medicinal Products and Other Forms of Interaction).
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.
6-mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite.
6-mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to thioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The thioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.
6-mercaptopurine is converted into the active thioguanine nucleotides by the enzyme hypoxanthineguanine phosphoribosyltransferase. The conversion of 6-mercaptopurine into its active thioguanine nucleotides is a stepwise process, via thioinosinic acid. 6-mercaptopurine can also undergo methylation by the enzyme thiopurine methyltransferase to form S-methylated nucleotides, which are also cytotoxic.
The bioavailability of oral 6-mercaptopurine shows considerable inter-individual variability. When administered at a dosage of 75mg/m2 to 7 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.
The mean time to peak plasma concentration in 14 pediatric patients was 2.2 hours with a range of 0.5 to 4 hours. In 7 paediatric patients the elimination half-life of 6-mercaptopurine was 90 ± 30 minutes, but the active metabolites have a longer half life (approximately 5 hours), and the total clearance is 719 ± 610 mL/min/m2. One to four hours after an intravenous infusion of 6-mercaptopurine (100mg/m2/h) cerebrospinal fluid levels are between 10 and 25% of the corresponding plasma levels. After oral administration of between 50 and 165mg/m2 levels in the cerebrospinal fluid were not detectable ((0.18 micromol/L). There is a low entry of 6-mercaptopurine into the cerebrospinal fluid. There is low entry of 6-mercaptopurine into the cerebrospinal fluid.
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.
The main method of elimination for 6-mercaptopurine is by metabolic alteration (see also Pharmacodynamic Properties). The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase catalyses the conversion of 6-mercaptopurine into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.
Mutagenicity and Carcinogenicity
6-mercaptopurine in common with other antimetabolites is potentially mutagenic in man and chromosome damage has been reported in mice and 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.
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 type of malformations is dependent on the dose and the stage of gestation at the time of administration.
Lactose
Maize starch
Hydrolysed starch
Stearic acid
Magnesium stearate
None known.
5 years.
Store at 25°C. Protect from light. Keep dry.
Bottles of 25 tablets
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.
PURI-NETHOL tablets surplus to requirements should be destroyed in a manner appropriate to the prevailing local regulations for the destruction of dangerous substances.
Prescription Only Medicine
GlaxoSmithKline NZ Limited
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown Auckland
NEW ZEALAND
Phone: (09) 367 2900
Facsimile: (09) 367 2506
Issue number: 7
Issue date: 25 October 2004
PURINETHOL™ is a trade mark of the GlaxoSmithKline group of companies.
© This Data Sheet is copyrighted to GlaxoSmithKline and may be reproduced but not altered in any way.