1. Name Of The Medicinal Product
Puri-Nethol® 50 mg tablets
2. Qualitative And Quantitative Composition
Each tablet contains 50 mg of 6-mercaptopurine.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Tablets
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
4. Clinical Particulars
4.1 Therapeutic Indications
Cytotoxic agent.
Puri-Nethol is indicated for the treatment of acute leukaemia. It may be utilised in remission induction and it 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.
4.2 Posology And Method Of Administration
For oral administration
Dosage in adults and children:
For adults and children the usual starting dose is 2.5 mg/kg bodyweight per day, or 50-75 mg/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.
Dosage in the 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 dosage.
Dosage in renal impairment:
Consideration should be given to reducing the dosage in patients with impaired renal function.
Dosage in hepatic function:
Consideration should be given to reducing the dosage in patients with impaired hepatic function.
In general:
When Zyloric (allopurinol) and 6-mercaptopurine are administered concomitantly it is essential that only a quarter of the usual dose of 6-mercaptopurine is given since Zyloric (allopurinol) decreases the rate of catabolism of 6-mercaptopurine.
4.3 Contraindications
Hypersensitivity to any component of the preparation.
In view of the seriousness of the indications there are no other absolute contra-indications.
4.4 Special Warnings And Precautions For Use
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.
Safe handling of Puri-Nethol Tablets:
See section 6.6 Instructions for Use/Handling
Monitoring:
Treatment with Puri-Nethol 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.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppresive 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 sulfazalazine. Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6–mercaptopurine in combination with other cytotoxics (see Section 4.8 Undesirable Effects). 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.
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.
Cross resistance usually exists between 6-mercaptopurine and 6-tioguanine.
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.
Mutagenicity and carcinogenicity:
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 – 1.0 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 carcinogenisis with this treatment.
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 Hodgkins 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 (an unlicensed indication) in combination with anti-TNF agents (see section 4.8 Undesirable Effects).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).
When Zyloric (allopurinol) and Puri-Nethol are administered concomitantly it is essential that only a quarter of the usual dose of Puri-Nethol is given since Zyloric decreases the rate of catabolism of Puri-Nethol.
Inhibition of the anticoagulant effect of warfarin, when given with Puri-Nethol, has been reported.
As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfazalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Puri-Nethol therapy (see Section 4.4 Special Warnings and Precautions for Use).
4.6 Pregnancy And Lactation
Pregnancy:
6-mercaptopurine is potentially teratogenic. The use of Puri-Nethol should be avoided whenever possible during pregnancy. 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:
Studies of 6-mercaptopurine in animals have shown reproductive toxicity (see Section 5.3 Preclinical Safety Data). The potential risk for humans is unclear.
Normal offspring have been born after mercaptopurine therapy administered as a single chemotherapy agent during human pregnancy. Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal 6-mercatopurine treatment in combination with other chemotherapy agents.
Paternal Exposure:
Congenital abnormalities and spontaneous abortion have been reported after paternal exposure to 6-mercaptopurine.
Effects on fertility:
The effect of Puri-Nethol therapy on human fertility is largely unknown but there are reports of successful fatherhood/motherhood after receiving treatment during childhood or adolescence. Transient profound oligospermia was observed in a young man who received 6-mercaptopurine 150 mg/day plus prednisone 80 mg/day for acute leukaemia. Two years after cessation of the chemotherapy, he had a normal sperm count and he fathered a normal child.
Lactation:
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.
4.7 Effects On Ability To Drive And Use Machines
There are no data on the effect of 6-mercaptopurine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
4.8 Undesirable Effects
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
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. |
The main side effect of treatment with 6-mercaptopurine is bone marrow suppression leading to leucopenia and thrombocytopenia. | |
Uncommon | anaemia |
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 2.5 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. 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 |
4.9 Overdose
Symptoms and signs:
Gastrointestinal effects, including nausea, vomiting and diarrhoea and anorexia may be early symptoms of overdosage having occurred. The principal toxic effect is on the bone marrow, resulting in myelosuppression. Haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Puri-Nethol. Liver dysfunction and gastroenteritis may also occur.
The risk of overdosage is also increased when Zyloric is being given concomitantly with Puri-Nethol (see Section 4.5 Interactions with other Medicaments and other forms of Interaction).
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) 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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
ATC Code: L01BB02
Pharmacotherapeutic group:
6-Mercaptopurine is sulphydryl analogue of the purine base hypoxanthine and acts as a cytotoxic antimetabolite.
Mode of Action:
6-Mercaptopurine is an inactive pro-drug which acts as a purine antagonist but requires cellular uptake and intracellular anabolism to tioguanine nucleotides for cytotoxicity. The 6-mercaptopurine metabolites inhibit de novo purine synthesis and purine nucleotide interconversions. The tioguanine nucleotides are also incorporated into nucleic acids and this contributes to the cytotoxic effects of the drug.
5.2 Pharmacokinetic Properties
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%).
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 drug. The apparent body clearance is 4832 ± 2562 ml/min/m2. There is low entry of 6-mercaptopurine into the cerebrospinal fluid.
The main method of elimination for 6-mercaptopurine is by metabolic alteration. The kidneys eliminate approximately 7% of 6-mercaptopurine unaltered within 12 hours of the drug being administered. Xanthine oxidase is the main catabolic enzyme of 6-mercaptopurine and it converts the drug into the inactive metabolite, 6-thiouric acid. This is excreted in the urine.
5.3 Preclinical Safety Data
6-Mercaptopurine, in common with other antimetabolites, is potentially mutagenic in man and chromosome damage has been reported in mice, rats and man.
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.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Lactose
Maize Starch
Hydrolysed Starch
Stearic Acid
Magnesium Stearate
Purified Water
6.2 Incompatibilities
None known
6.3 Shelf Life
60 months
6.4 Special Precautions For Storage
Store below 25ºC. Keep the bottle tightly closed.
6.5 Nature And Contents Of Container
Amber glass bottles with child resistant high density polyethylene closures with induction heat seal liners.
Pack size: 25 tablets
6.6 Special Precautions For Disposal And Other Handling
Safe handling and disposal:
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 drugs.
Administrative Data
7. Marketing Authorisation Holder
ALKOPHARMA SARL
45-47, rte d'Arlon
L – 1140 Luxembourg
8. Marketing Authorisation Number(S)
PL 36637/0006
9. Date Of First Authorisation/Renewal Of The Authorisation
29 August 2006
10. Date Of Revision Of The Text
September 2010
11. LEGAL STATUS
POM
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