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.

SUMMARY CMI

Puri-Nethol®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using PURI-NETHOL?

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

For more information, see Section 1. Why am I using PURI-NETHOL? in the full CMI.

2. What should I know before I use PURI-NETHOL?

Do not use if you have ever had an allergic reaction to mercaptopurine monohydrate, azathioprine, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant, plan to become pregnant or father a child, or are breastfeeding.

For more information, see Section 2. What should I know before I use PURI-NETHOL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with PURI-NETHOL and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use PURI-NETHOL?

  • The dose may vary from person to person. Your doctor will tell you how much to take, and when to take it.
  • Do not crush or chew.

More instructions can be found in Section 4. How do I use PURI-NETHOL? in the full CMI.

5. What should I know while using PURI-NETHOL?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using PURI-NETHOL.
  • Tell your doctor if you are planning to become pregnant or father a child, and tell them immediately if you become pregnant while trying to take PURINETHOL.
  • Use high SPF sunscreen and protective clothing and limit exposure to sunlight and UV light.
Things you should not do
  • Do not stop taking PURI-NETHOL or change the dose without first checking with your doctor.
  • Do not have any vaccinations without your doctor's approval
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how PURI-NETHOL affects you.
Looking after your medicine
  • Keep your tablets in the bottle until it is time to take them.
  • Keep it in a cool dry place, away from moisture, heat, or light where the temperature stays below 25°C

For more information, see Section 5. What should I know while using PURI-NETHOL? in the full CMI.

6. Are there any side effects?

Tell your doctor as soon as possible if you do not feel well while you are taking PURI-NETHOL, as any side effects may potentially be serious. Common side effects include unusual tiredness, being short of breath and looking pale; bruising or bleeding more easily than normal (e.g. more frequent nose bleeds); frequent infections such as fever, sore throat or mouth ulcers; nausea and vomiting; and increased risk of liver disease. More serious side effects include signs of an allergic reaction, such as wheezing; swelling of the lips and mouth; difficulty in breathing; severe rash; and fainting.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

Puri-Nethol®

Active ingredient(s): Mercaptopurine monohydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using PURI-NETHOL. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using PURI-NETHOL.

Where to find information in this leaflet:

1. Why am I using PURI-NETHOL?
2. What should I know before I use PURI-NETHOL?
3. What if I am taking other medicines?
4. How do I use PURI-NETHOL?
5. What should I know while using PURI-NETHOL?
6. Are there any side effects?
7. Product details

1. Why am I using PURI-NETHOL?

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 PURINETHOL 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.

2. What should I know before I use PURI-NETHOL?

Warnings

Do not use PURI-NETHOL if:

  • You are allergic to mercaptopurine monohydrate, azathioprine, or any of the ingredients listed at the end of this leaflet.
    - Some 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.
    - Always check the ingredients to make sure you can use this medicine. Check with your doctor or pharmacist if you are unsure.
  • The expiry date printed on the pack has passed.
  • The packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • Have or have had any other medical conditions, especially the following:
    - 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)
    - inherited mutated NUDT15 gene
  • Take any medicines for any other condition.
  • Have had any allergy to any other medicines, or any other substances, such as foods, preservatives, or dyes.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy, breastfeeding, and fathering a child

Do not take PURI-NETHOL if you are pregnant or breast feeding 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 PURI-NETHOL if you are planning to become pregnant or intending to father a child. As with all cytotoxic drugs, PURI-NETHOL may harm eggs and sperm. You or your partner should take adequate contraceptive precautions while you are taking this medicine.

3. What if I am taking other medicines?

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

Some medicines may interfere with PURI-NETHOL and affect how it works. 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

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect PURI-NETHOL.

4. How do I use PURI-NETHOL?

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 PURINETHOL.

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 urine tests while you are taking PURINETHOL 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, PURINETHOL 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 it for.

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

If you forget to take it

Tell your doctor if you forget to take it.

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

If you take too much

If you think that you have used too much PURI-NETHOL, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

5. What should I know while using PURI-NETHOL?

Things you should 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 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.

Call your doctor straight away if you:

  • Become pregnant while taking this medicine

Things you should not do

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.

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

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.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how PURI-NETHOL affects you.

Looking after your medicine

  • Keep your tablets in the bottle until it is time to take them. If you take the tablets out of the bottle, they may not keep well.
  • Keep PURI-NETHOL in a cool dry place, away from moisture, heat, or light where the temperature stays below 25°C. For example, do not store it:
    - In the bathroom or near a sink, or
    - In the car or on window sills
    Heat and dampness can destroy some medicines.

Follow the instructions in the carton on how to take care of your medicine properly.

Keep it where young children cannot reach it.

A locked cupboard at least one and a half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

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

Serious side effects

Serious side effectsWhat to do
Associated with the drop in production of bone marrow cells:
  • frequent infections such as fever, sore throat or mouth ulcers
  • bruising or bleeding more easily than normal, nose bleeds
  • unusual tiredness, being short of breath, looking pale.
Other:
  • nausea and vomiting
  • diarrhoea
  • jaundice, a yellowing of the whites of the eyes or skin
  • rash
  • tender, red bumps, usually found symmetrically on the shins
  • painful, swollen joints
  • weight loss
  • hair loss
  • persistent cough or breathlessness
  • in men, sperm production may be reduced.
  • increased risk of liver disease
  • increased risk of damage to genes in some cells
  • Bacterial and viral infections, infections associated with neutropenia
    - Tell your doctor immediately if you experience diarrhea, localized pigmented rash (dermatitis), and decline in your memory, reasoning or other thinking skills as these symptoms may suggest vitamin B3 deficiency (nicotinic acid deficiency/pellagra). Your doctor will likely prescribe vitamin supplements (niacin/nicotinamide) to help you improving the condition.
Speak to your doctor immediately if you notice any of these side effects.

More serious side effects

More serious side effectsWhat to do
Signs of allergy
  • wheezing
  • swelling of the lips/mouth
  • difficulty in breathing
  • hayfever
  • lumpy rash (hives)
  • fainting.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

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

What PURI-NETHOL contains

Active ingredient
(main ingredient)		Mercaptopurine monohydrate 50mg
Other ingredients
(inactive ingredients)		Lactose monohydrate
Magnesium stearate
Starch-hydrolyzed maize
Starch-maize
Stearic acid
Potential allergensLactose

Do not take this medicine if you are allergic to any of these ingredients.

What PURI-NETHOL 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.

(AUST R 10993)

Who distributes PURI-NETHOL

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos St
St Leonards NSW 2065
Australia

This leaflet was revised in March 2025

Published by MIMS May 2025

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

Puri-Nethol treatment should be supervised by a physician or other healthcare professional experienced in the administration of such agents.
Puri-Nethol may be taken with food or on an empty stomach, but patients should standardise the timing of mercaptopurine administration in relation to food. The dose should not be taken with milk or dairy products (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Puri-Nethol should be taken at least 1 hour before or 2 hours after milk or dairy products.

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.
The dosage of Puri-Nethol 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).
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.

Tumour lysis syndrome.

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 Puri-Nethol 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).

NUDT15 mutation.

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leucopenia 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 5.2 Pharmacokinetic Properties).

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 Puri-Nethol nor its pro-drug azathioprine are effective in patients with the rare inherited condition complete hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). The use of Puri-Nethol or azathioprine is not recommended in these patients.
Patients with rare hereditary problems of galactose intolerance, complete lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Metabolism and nutrition disorders.

Administration of purine analogues (azathioprine and mercaptopurine) may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency/pellagra. Few cases have been reported with the use of azathioprine, especially in patients with IBD (Crohn's disease, colitis ulcerative). Diagnosis of pellagra should be considered in a patient presenting with localised pigmented rash (dermatitis); gastroenteritis (diarrhoea); and widespread neurologic deficits, including cognitive decline (dementia). Appropriate medical care with niacin/nicotinamide supplementation must be initiated, and dose reduction or discontinuation of azathioprine must be considered.

Use in the elderly.

Please see Section 4.2 Dose and Method of Administration.

Paediatric use.

Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving Puri-Nethol [see Section 4.8 Adverse Effects (Undesirable Effects)]. The majority of reported cases were in children under the age of six or with a low body mass index.

Cholestasis of pregnancy.

Cholestasis of pregnancy has occasionally been reported in association with mercaptopurine therapy (see Section 4.6 Fertility, Pregnancy and Lactation). Monitoring of 6-methyl mercaptopurine (6-MMP) should be considered in the presence of pruritus with elevated maternal total serum bile acid levels in second trimester of pregnancy to establish early diagnosis and minimise impact on the foetus. If cholestasis of pregnancy occurs, case by case assessment is necessary considering the risk-benefit profile of the product (potential withdrawal/dose reduction).

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

The administration of Puri-Nethol with food may decrease systemic exposure slightly. Puri-Nethol may be taken with food or on an empty stomach. Patients should standardise the timing of Puri-Nethol administration in relation to food to avoid large variability in exposure. The dose should not be taken with milk or dairy products since they contain xanthine oxidase, an enzyme which metabolises 6-mercaptopurine and might therefore lead to reduced plasma concentrations of mercaptopurine.
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 (20 mg/m2 orally) increased mercaptopurine monohydrate AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased mercaptopurine monohydrate AUC by 69 and 93%, respectively. Therefore, when mercaptopurine monohydrate is administered concomitantly with high dose methotrexate, the dose should be adjusted and white blood cell counts should be very closely monitored.

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. Therefore, close monitoring of haematological parameters is necessary if Puri-Nethol is administered with concomitant infliximab therapy.

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.
Cholestasis of pregnancy has occasionally been reported in association with mercaptopurine therapy. Early diagnosis and discontinuation of mercaptopurine may minimise impact on the foetus. However, a careful assessment of benefit to the mother and impact on the foetus should be performed, if cholestasis of pregnancy is confirmed (see Section 4.4 Special Warnings and Precautions for Use).

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.

Paternal exposure.

Congenital abnormalities and spontaneous abortions have been reported after paternal exposure to Puri-Nethol.
 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 breastfeed.

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 frequency categories assigned to the adverse drug 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 agents.
The main side effect of treatment with mercaptopurine monohydrate is bone marrow suppression leading to leucopenia and thrombocytopenia.
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.
Common: 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.
Not known: hypoglycaemia*.
* In the paediatric population.

Gastrointestinal disorders.

Common: nausea; vomiting; pancreatitis in the IBD population (an unlicensed indication).
Rare: oral ulceration; intestinal ulceration; pancreatitis (in the licensed indication).
Not known: stomatitis.

Hepatobiliary disorders.

Common: biliary stasis; hepatotoxicity.
Rare: hepatic necrosis.
Not known: cholestasis of pregnancy.
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.

Infections and infestations.

Uncommon: bacterial and viral infections, infections associated with neutropenia.

Paediatric population.

Hypoglycaemia has been reported in the paediatric population.

General disorders and administration site conditions.

Not known: photosensitivity.
Not known: mucosal inflammation.

Description of selected adverse reactions.

Hepatobiliary disorders.

Puri-Nethol is hepatotoxic in animals and man. 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 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. Hepatotoxicity is usually reversible if Puri-Nethol therapy is stopped soon enough but fatal liver damage has occurred.

Paediatric population.

Hypoglycaemia has been reported in the paediatric population.

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.

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

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

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