Consumer medicine information

Puri-Nethol

Mercaptopurine monohydrate

BRAND INFORMATION

Brand name

Puri-Nethol

Active ingredient

Mercaptopurine monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Puri-Nethol.

What is in this leaflet

This leaflet answers some common questions about PURI-NETHOL. It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you taking PURI-NETHOL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What PURI-NETHOL is used for

PURI-NETHOL contains mercaptopurine monohydrate as the active ingredient. It belongs to a group of medicines called cytotoxics.

PURI-NETHOL is used solely or in combination with other medicines to treat acute leukaemia, a cancer of certain blood cells.

It works by interfering with the growth of cancer cells.

Ask your doctor if you have any questions about why PURI-NETHOL has been prescribed for you. Your doctor may have prescribed it for another purpose.

This medicine is only available with a doctor's prescription.

There is no evidence that it is addictive.

Before you take it

When you must not take it

Do not take PURI-NETHOL if you have ever had an allergic reaction to:

  • Mercaptopurine monohydrate
  • Azathioprine
  • any of the tablet ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.

Do not take PURI-NETHOL if you are planning to become pregnant or father a child unless you and your doctor have discussed the risks and benefits involved. As with all cytotoxic drugs, PURI - NETHOL may harm eggs and sperm. Reliable contraceptive methods must be taken to avoid pregnancy whilst you or your partner is taking this medicine. Contraception is advised for at least 3 months after receiving the last dose of PURI-NETHOL.

Do not take PURI-NETHOL if you are pregnant unless you and your doctor have discussed the risks and benefits involved. It may affect your developing baby if you take it during pregnancy.

Do not take this medicine whilst breast feeding. It is not recommended for use while breast feeding as it is found in breast milk.

Do not take PURI-NETHOL after the expiry date printed on the pack. If you take it after the expiry (EXP) date has passed, it may not work as well.

Do not take it if the packaging is torn or shows signs of tampering.

Before you start to take it

Tell your doctor if you are allergic to any other medicines or any other foods, dyes or preservatives.

Tell your doctor if you have or have had any of the following conditions:

  • you have recently received or are receiving radiotherapy or chemotherapy
  • you have recently been vaccinated or are planning to be vaccinated
  • kidney or liver disease
  • a condition where your body produces too little of a natural chemical called thiopurine methyltransferase (TPMT).

If you have not told your doctor about any of the above, tell them before you start taking PURI-NETHOL.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from a pharmacy, supermarket or health food shop.

Some medicines may be affected by PURI-NETHOL or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines. These include:

  • allopurinol, oxipurinol and/or thiopurinol and other xanthine oxidase inhibitors such as febuxostat.
  • Methotrexate
  • Infliximab
  • anticoagulants e.g. warfarin
  • 6-thioguanine
  • aminosalicylate derivatives such as olsalazine, mesalazine or sulphasalazine
  • vaccinations with 'live' organism vaccines
  • myelosuppressive agents
  • ribavirin

Your doctor or pharmacist has more information on medicines to be careful with or avoid while taking this medicine.

How to take it

How much to take

Take PURI-NETHOL exactly as directed by your doctor.

Your doctor will decide what dose and for how long you will be taking PURI-NETHOL. This depends on factors such as:

  • your age and weight
  • any pre-existing conditions such as kidney or liver disease, (especially in the elderly)
  • your response to the treatment
  • other medicines taken in combination with PURI-NETHOL.

Your doctor may change the dose and frequency of your medicine as your condition changes.

Your doctor may order regular blood cell count, liver function and urinetests while you are taking PURI-NETHOL in order to monitor your condition and to change your dose if necessary.

How to take it

Do not crush or chew the tablets.

Like all cytotoxic drugs, PURI-NETHOL is irritant to the eyes and skin. To prevent irritation it is important to wash your hands immediately after handling or halving the tablets, to avoid contact with the eyes and be careful not to inhale any particle of the tablet.

How long to take it

Your doctor will tell you how long to take PURI-NETHOL for.

Do not stop taking it or change the dose without first checking with your doctor.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 131126) for advice, if you think you or anyone else may have taken too much PURI-NETHOL, even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

While you are taking it

Things you must do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed. Otherwise, your doctor may think that it was not working as it should and change your treatment unnecessarily.

Do not take a double dose to make up for the one you have missed.

Visit your doctor regularly so they can check your progress and make sure your medicine is working.

Tell any other specialist, doctor, dentist or pharmacist that you are on PURI-NETHOL, especially if you are about to be started on any new medicines, immunisations, vaccinations or radiotherapy.

Tell your doctor if you become pregnant, are trying to become pregnant or trying to father a child.

Use a sunscreen with a high SPF and protective clothing and limit exposure to sunlight and UV light.

Things you must not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use PURI-NETHOL to treat any other complaints unless your doctor says to.

Things to be careful of

Be careful driving or operating machinery until you know how PURI-NETHOL affects you.

Do not have any vaccinations without your doctor's approval.

PURI-NETHOL can lower the number of white blood cells and platelets in your blood. This means that you have an increased chance of getting an infection or bleeding.

Side effects

Tell your doctor as soon as possible if you do not feel well while you are taking PURI-NETHOL.

All medicines can cause some side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

The following side effects have been reported with PURI-NETHOL:

  • production of bone marrow cells may be reduced. You may notice an increase in infections. Your doctor will do regular blood tests, but you should tell them at once if you notice any signs of fever or infection or any unexpected bruising, bleeding or signs of blood in your urine
  • increased risk of liver disease
  • in men, sperm production may be reduced
  • as with all cytotoxic medicines, there is an increased risk of damage to the genes in some cells.

Tell your doctor if you notice any of the following:

  • nausea and vomiting
  • diarrhoea
  • frequent infections such as fever, severe chills, sore throat or mouth ulcers
  • bruising or bleeding more easily than normal
  • weight loss
  • jaundice, a yellowing of the whites of the eyes or the skin
  • painful, swollen joints
  • skin rash
  • hair loss.

Tell your doctor immediately if you notice any of the following allergic-type symptoms:

  • wheezing
  • swelling of the lips/mouth
  • difficulty in breathing
  • hayfever
  • lumpy rash (hives)
  • fainting.

Tell your doctor if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not referred to in this leaflet. Other side effects not listed above may also occur in some people.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking it

Storage

Keep your tablets in the bottle until it is time to take them. If you take the medicine out of the bottle it may not keep as well.

Keep it in a cool, dry place, protected from light, where the temperature stays below 25°C.

Do not leave it in a car, on window sills, near a sink or in the bathroom. Heat and dampness can affect some medicines.

Keep it where children cannot reach it. A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Product description

What it looks like

PURI-NETHOL tablets are pale yellow, round, biconvex tablets, marked PT above the line and 50 below the line on one side and plain on the other. Available in bottles of 25 tablets.

Ingredients

Active ingredient:

Each tablet contains 50 mg mercaptopurine monohydrate.

Inactive ingredients:

  • lactose monohydrate
  • magnesium stearate
  • starch-hydrolyzed maize
  • starch- maize
  • stearic acid.

Sponsor

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Phone: +61 2 8436 8300
Web: www.aspenpharma.com.au

Australian Registration Number:
AUST R 10993

This leaflet was revised in February 2021

Published by MIMS May 2021

BRAND INFORMATION

Brand name

Puri-Nethol

Active ingredient

Mercaptopurine monohydrate

Schedule

S4

 

1 Name of Medicine

Mercaptopurine monohydrate.

2 Qualitative and Quantitative Composition

Puri-Nethol tablets contain 50 mg mercaptopurine monohydrate.
Mercaptopurine monohydrate is odourless or practically odourless, yellow crystalline powder, with a solubility of 0.26 mg/mL in water at 37°C.
Contains lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets, uncoated.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of acute leukaemia. It is of value in remission induction and is particularly indicated for maintenance therapy in acute lymphoblastic leukaemia and acute myelogenous leukaemia.
Puri-Nethol is also used in the treatment of chronic granulocytic leukaemia.

4.2 Dose and Method of Administration

Adults and children.

For adults and children the usual dose is 2.5 mg/kg bodyweight/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.
When allopurinol and mercaptopurine monohydrate are administered concomitantly it is essential that only a quarter of the usual dose of mercaptopurine monohydrate is given since allopurinol decreases the rate of catabolism of mercaptopurine monohydrate.

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 reduce the Puri-Nethol dosage.

Renal or hepatic impairment.

Consideration should be given to reducing the dosage in patients with impaired hepatic or renal function.

4.3 Contraindications

Hypersensitivity to any component of the preparation.
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 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 in patients with leukaemia. In all cases, patients in remission should not receive live organism vaccines until at least 3 months after their chemotherapy treatment has been completed.
Coadministration of ribavirin and Puri-Nethol is not advised. Ribavirin may reduce efficacy and increase toxicity of mercaptopurine monohydrate (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
The handling of Puri-Nethol tablets should follow standard guidelines for the handling and disposal of cytotoxic drugs.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised if either partner is receiving Puri-Nethol tablets.

Monitoring.

Since Puri-Nethol is strongly myelosuppressive, full blood counts must be monitored daily during remission induction. Patients must be carefully monitored during therapy.
Treatment with mercaptopurine monohydrate causes bone marrow suppression leading to leucopenia and thrombocytopenia, and less frequently anaemia. Full blood counts must be taken daily during remission induction. During maintenance therapy, complete blood counts, including platelets, should be performed weekly or more frequently if high dosage is used or if severe renal and or hepatic disorder is present.
Haematological monitoring of the patient is advised when switching formulations.
The leucocyte and platelet counts continue to fall after treatment is stopped, so at the first sign of 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.

TPMT testing.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of mercaptopurine monohydrate and prone to developing rapid bone marrow depression following the initiation of treatment with Puri-Nethol. There have been fatal cases of myelosuppression in patients with low or absent TPMT activity treated with thiopurines. This problem could be exacerbated by coadministration 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 cytotoxics (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be tested for TPMT activity before starting Puri-Nethol. TPMT testing cannot substitute for complete blood count monitoring in patients receiving Puri-Nethol. TPMT genotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity (homozygous for non-functional alleles) are at an increased risk of developing severe, life-threatening myelotoxicity from Puri-Nethol if conventional doses are given. Alternative therapies may be considered for patients who have low or absent TPMT activity. Puri-Nethol should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity.
TPMT testing is widely available through pathology laboratories and genetic testing services.
Cross resistance usually exists between mercaptopurine monohydrate and 6-thioguanine (Lanvis).
The dosage of mercaptopurine monohydrate may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Myelosuppressive agents).

Hypersensitivity.

Patients suspected to have previously presented with a hypersensitivity reaction to mercaptopurine monohydrates should not be advised to use its pro-drug azathioprine, unless the patient has been confirmed as hypersensitive to mercaptopurine monohydrate with allergological test, and has tested negative for azathioprine. As azathioprine is a prodrug of mercaptopurine monohydrate, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to mercaptopurine monohydrate prior to initiating treatment.

Renal and/or hepatic impairment.

Caution is advised during the administration of Puri-Nethol 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 Dose and Method of Administration).

Carcinogenesis and mutagenesis.

Puri-Nethol in common with other anti-metabolites is potentially mutagenic and chromosome damage has been reported in rats and humans.
Increases in chromosomal aberrations were observed in the peripheral lymphocytes of leukaemic patients and in a hyper nephroma patient who received an unstated dose of mercaptopurine monohydrate 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), mercaptopurine monohydrate is potentially carcinogenic and consideration should be given to the theoretical risk of carcinogenesis with this treatment. Three cases have been documented of the occurrence of acute nonlymphatic leukaemia in patients who received mercaptopurine monohydrate for non-neoplastic disorders. A single case has been reported where a patient was treated for pyoderma gangrenosum with mercaptopurine monohydrate and later developed acute nonlymphatic leukaemia.
A patient with Hodgkin's disease treated with mercaptopurine monohydrate and multiple additional cytotoxic agents developed acute myelogenous leukaemia.
Twelve and a half years after mercaptopurine monohydrate treatment for myasthenia gravis, a female patient developed chronic myeloid leukaemia.
Reports of hepatosplenic T-cell lymphoma in the inflammatory bowel disease population have been received when mercaptopurine monohydrate is used in combination with anti-TNF agents (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Infections.

Patients treated with mercaptopurine monohydrate 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.
Serologic testing prior to starting treatment should be considered with respect to varicella zoster virus and 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 measure should be taken, which may include antiviral therapy and supportive care.

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) 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.

Lesch-Nyhan syndrome.

Limited evidence suggests that neither mercaptopurine monohydrate nor its pro-drug azathioprine are effective in patients with hypoxanthine guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of mercaptopurine monohydrate or azathioprine is not recommended in these patients.

UV exposure.

Patients treated with mercaptopurine monohydrate are more sensitive to the sun. Exposure to sunlight and UV light should be limited, and patients should be advised to wear protective clothing and to use a sunscreen with a high protection factor.

Paternal exposure.

Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to mercaptopurine monohydrate.
A leukaemia patient treated with mercaptopurine monohydrate 100 mg/day (plus splenic irradiation) throughout pregnancy gave birth to a normal, premature baby. A second baby, born to the same mother who was treated as before, together with busulfan 4 mg/day, had multiple severe abnormalities, including corneal opacities, microphthalmia, cleft palate and hypoplasia of the thyroid and ovaries. 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.
Transient profound oligospermia was observed in a young man who received mercaptopurine monohydrate 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 fathered a normal child.

Use in the elderly.

Please see Section 4.2 Dose and Method of Administration.

Paediatric use.

No data available.

Effects on laboratory tests.

Please see Section 4.4 Special Warnings and Precautions for Use, Monitoring; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions, Anticoagulants; Section 4.8 Adverse Effects (Undesirable Effects), Hepatobiliary disorders.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Vaccinations with live organism vaccines are not recommended in immunocompromised individuals (see Section 4.4 Special Warnings and Precautions for Use).

Effect of concomitant drugs on Puri-Nethol.

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 mercaptopurine monohydrate and ribavirin; therefore concomitant administration of ribavirin and Puri-Nethol is not advised (see Section 4.4 Special Warnings and Precautions for Use).

Myelosuppressive agents.

When Puri-Nethol 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 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 mercaptopurine monohydrate are administered concomitantly it is essential that only a 25% of the usual dose of mercaptopurine monohydrate is given (see Section 4.2 Dose and Method of Administration) since allopurinol decreases the rate of catabolism of mercaptopurine monohydrate.
Other xanthine oxidase inhibitors, such as febuxostat, may decrease the metabolism of mercaptopurine monohydrate. Concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction.

Aminosalicylates.

Inhibition of the anticoagulant effect of warfarin when given with mercaptopurine monohydrate, has been reported.
There is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme. Therefore, lower doses of Puri-Nethol may need to be considered when administered concomitantly with aminosalicylate derivatives (see Section 4.4 Special Warnings and Precautions for Use).
Following unregulated consumption of salicylates, sulphonamides or undefined tranquillisers by patients receiving mercaptopurine monohydrate therapy, a slower onset of pancytopenia has been documented.

Methotrexate.

Methotrexate may increase mercaptopurine monohydrate AUC. Therefore when mercaptopurine monohydrate is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.

Infliximab.

Interactions have been observed between azathioprine, a pro-drug of mercaptopurine monohydrate, and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and decreases in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months.

Effect of Puri-Nethol on other drugs.

Anticoagulants.

Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with Puri-Nethol; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with Puri-Nethol.

4.6 Fertility, Pregnancy and Lactation

Fertility.

The effect of mercaptopurine monohydrate therapy on human fertility is unknown. There are reports of successful father/ motherhood after receiving treatment during childhood or adolescence.
Transient oligospermia has been reported following exposure to mercaptopurine monohydrate.
(Category D)
Cytotoxic agents can produce spontaneous abortion, fetal loss and birth defects.
Substantial transplacental and transamniotic transmission of mercaptopurine monohydrate and its metabolites from the mother to the foetus have been shown to occur.
The use of mercaptopurine monohydrate 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 during treatment and for at least three months after receiving the last dose.
Puri-Nethol has been shown to be embryotoxic in rats at doses that are not toxic to the mother. It has also been proven to be embryolethal when administered at higher doses in the first half of the gestation period. The potential risk for humans is largely unknown.
Mercaptopurine monohydrate 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.

Maternal exposure.

Normal offspring have been born after mercaptopurine monohydrate therapy administered as a single chemotherapy agent during human pregnancy, particularly when given prior to conception or after the first trimester.
Abortions and prematurity have been reported after maternal exposure. Multiple congenital abnormalities have been reported following maternal mercaptopurine monohydrate treatment in combination with other chemotherapy agents.
 Mercaptopurine monohydrate has been detected in the breast milk of renal transplant patients receiving immunosuppressive therapy with azathioprine, a pro-drug of mercaptopurine monohydrate, and thus, mothers receiving Puri-Nethol should not breast feed.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

The following convention has been utilised for the classification of undesirable effects: very common (≥ 1/10), common (≥ 1/100 and < 1/10), uncommon (≥ 1/1000 and < 1/100), rare (≥ 1/10,000 and < 1/1000), very rare (< 1/10,000), not known (frequency cannot be estimated from the available data).

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

Very rare: secondary leukaemia and myelodysplasia; hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease (an unlicensed indication) when used in combination with anti-TNF agents has been reported very rarely (see Section 4.4 Special Warnings and Precautions for Use).
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 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 mercaptopurine monohydrate 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; intestinal ulceration; pancreatitis (in the licensed indication).

Hepatobiliary disorders.

Common: biliary stasis; hepatotoxicity.
Rare: hepatic necrosis.
Frequency Unknown: Portal hypertension*, nodular regenerative hyperplasia*, sinusoidal obstruction syndrome*.
* In patients with inflammatory bowel disease, an unlicensed indication.
Mercaptopurine monohydrate is hepatotoxic in animals and humans. The histological findings in humans 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 is exceeded.
Monitoring of liver function tests may allow early detection of liver toxicity. This is usually reversible if mercaptopurine monohydrate therapy is stopped soon enough. However, irreversible liver damage leading to a fatal outcome has occurred.

Skin and subcutaneous tissue disorders.

Rare: alopecia.
Unknown: erythema nodosum.

Reproductive system and breast disorders.

Very rare: transient oligospermia.

General disorders and administration site conditions.

Not known: photosensitivity.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

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 and haematological toxicity is likely to be more profound with chronic overdosage than with a single ingestion of Puri-Nethol.
The risk of overdosage is also increased when allopurinol is being given concomitantly with Puri-Nethol. Liver dysfunction and gastroenteritis may also occur.

Treatment.

As there is no known antidote blood counts 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 mercaptopurine monohydrate overdose unless the procedure can be undertaken within 60 minutes of ingestion.
Further management should be as clinically indicated. For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Mercaptopurine monohydrate is an analogue of adenine, one of the bases required for nucleic acid biosynthesis, and of the purine base hypoxanthine. Hence Puri-Nethol acts as an antimetabolite and interferes with the synthesis of nucleic acids in proliferating cells. Its metabolites are also pharmacologically active.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption of an oral dose of Puri-Nethol is incomplete and variable averaging about 50% of the administered dose. The half-life of mercaptopurine monohydrate in the circulation is of the order of 90 minutes. It is extensively metabolised and excreted via the kidneys and the active metabolites have a longer half-life than the parent drug. Mercaptopurine monohydrate has pKa's of 7.7 and 11.

5.3 Preclinical Safety Data

Genotoxicity.

See Section 4.4 Special Warnings and Precautions for Use, Carcinogenesis and mutagenesis.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use, Carcinogenesis and mutagenesis.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Puri-Nethol tablet also contains: lactose monohydrate; maize starch; hydrolysed maize starch; magnesium stearate; stearic acid.

6.2 Incompatibilities

No data available.

6.3 Shelf Life

30 months.

6.4 Special Precautions for Storage

Store below 25°C, keep dry and protect from light.

6.5 Nature and Contents of Container

Presentation: Puri-Nethol tablets are pale yellow, round, biconvex tablets, marked PT above the line and 50 below the line on one side and plain on the other. Each tablet contains 50 mg mercaptopurine monohydrate and is supplied in amber glass bottles with a child-resistant polyethylene/polypropylene cap.
Each bottle contains 25 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

The chemical name (CAS) of mercaptopurine monohydrate is 6H-purine-6-thione, 1,7-dihydro-, monohydrate, it has a relative molecular mass of 170.2, its molecular formula is C5H4N4S.H2O (monohydrate).

Chemical structure.

The chemical structure is:

CAS number.

6112-76-1.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription only medicine).

Summary Table of Changes