Consumer medicine information

Mercaptopurine-Link

Mercaptopurine monohydrate

BRAND INFORMATION

Brand name

Mercaptopurine-Link

Active ingredient

Mercaptopurine monohydrate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Mercaptopurine-Link.

SUMMARY CMI

MERCAPTOPURINE-LINK®

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 MERCAPTOPURINE-LINK?

MERCAPTOPURINE-LINK contains the active ingredient mercaptopurine monohydrate. MERCAPTOPURINE-LINK is used to treat acute leukaemia, a cancer of certain blood cells.

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

2. What should I know before I use MERCAPTOPURINE-LINK?

Do not use if you have ever had an allergic reaction to MERCAPTOPURINE-LINK, the active ingredient mercaptopurine, or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions or take any other medicines. Do not take MERCAPTOPURINE-LINK if you are planning to become pregnant or father a child, or if you are already pregnant or breastfeeding until you have discussed the risk and benefits with your doctor.

Tell your doctor if you are allergic to azathioprine, a medicine used to suppress the immune system.

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

3. What if I am taking other medicines?

Some medicines may interfere with MERCAPTOPURINE-LINK 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 MERCAPTOPURINE-LINK?

  • Take MERCAPTOPURINE-LINK exactly as directed by your doctor.

Your doctor will decide what dose and for how long you will be taking MERCAPTOPURINE -LINK depending on factors such as your age and weight, medical condition, whether you are taking any other medications, and your response to treatment.

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

5. What should I know while using MERCAPTOPURINE-LINK?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using MERCAPTOPURINE-LINK.
  • Tell your doctor if for any reason you have not taken your medicine exactly as directed.
  • Visit your doctor regularly so they may monitor your condition and the effectiveness of medicine.
  • Tell your doctor if you become pregnant, are trying to become pregnant or trying to father a child.
Things you should not do
  • Do not stop using this medicine or change the dose without consulting your doctor.
  • Do not take a double dose to make up for the one you have missed.
Driving or using machines
  • Be careful driving or operating machinery until you know how MERCAPTOPURINE-LINK affects you.
Looking after your medicine
  • Store below 25°C, keep dry and protect from light.
  • Keep out of reach of children.

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

6. Are there any side effects?

Side effects of this medicine include: A reduced number of red cells, white cells or platelets in the blood, which can be measured by a blood test; nausea; vomiting; liver problems. Side effects that require urgent medical attention include: Signs of an allergic reaction, such as chest tightness, difficulty breathing, swelling of face lips and tongue, rash; 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, vitamin B3 deficiency associated with a localised pigmented skin rash, diarrhoea or decrease in memory, reasoning or other thinking skills.

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

MERCAPTOPURINE-LINK®

Active ingredient(s): mercaptopurine monohydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using MERCAPTOPURINE-LINK. 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 MERCAPTOPURINE-LINK.

Where to find information in this leaflet:

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

1. Why am I using MERCAPTOPURINE-LINK?

MERCAPTOPURINE-LINK contains the active ingredient mercaptopurine monohydrate. MERCAPTOPURINE-LINK belongs to a group of medicines called antineoplastics, which are used in the treatment of cancer.

MERCAPTOPURINE-LINK is used to treat acute leukaemia and chronic granulocytic leukaemia, which are cancers of certain blood cells.

It works by interfering with the growth of cancer cells.

2. What should I know before I use MERCAPTOPURINE-LINK?

Warnings

Do not use MERCAPTOPURINE-LINK if:

  • you are allergic to mercaptopurine monohydrate, or any of the ingredients listed at the end of this leaflet.
  • Always check the ingredients to make sure you can use this medicine.

Check with your doctor if you:

  • are allergic to azathioprine, a medicine used to suppress the immune system
  • have recently received or are receiving radiotherapy or chemotherapy
  • have recently been vaccinated, or are planning to be vaccinated
  • have a condition where your body produces too little of a natural chemical called thiopurine methyltransferase (TPMT)
  • have inflammatory bowel disease
  • have a condition called Lesch-Nyhan Syndrome
  • have an inherited mutation in the NUDT15 gene (a gene which is involved in the breakdown of MERCAPTOPURINE-LINK in the body) - you may have a higher risk of infections and hair loss and your doctor may give you a lower dose.
  • Vitamin B3 deficiency (pellagra) - Tell your doctor immediately if you have diarrhoea, localized pigmented rash (dermatitis) or deterioration of your memory, reasoning and thinking skills (dementia), as these symptoms may indicate a vitamin B3 deficiency.
  • take any medicines for any other condition

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 and breastfeeding

Do not take MERCAPTOPURINE-LINK 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 other antineoplastic drugs, MERCAPTOPURINE-LINK may harm eggs and sperm. Reliable contraceptive methods must be used to avoid pregnancy whilst you or your partner is taking this medicine, and for at least 3 months after receiving the last dose of MERCAPTOPURINE-LINK.

Do not take MERCAPTOPURINE-LINK 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.

Taking MERCAPTOPURINE-LINK during pregnancy may cause severe, excessive itching without a rash. You may also experience nausea and loss of appetite at the same time, which may indicate a condition called cholestasis of pregnancy (a disease of the liver during pregnancy). Talk with your doctor immediately, as this condition can cause harm to your unborn child.

Do not take MERCAPTOPURINE-LINK whilst breastfeeding, as it has been found to pass into breast milk.

Low blood sugar has sometimes been seen in children, mainly in children under the age of six or with a low body mass index. Common symptoms of low blood sugar include, but are not limited to, fast heart rate, shaking, sweating, hunger, confusion and loss of consciousness. Talk to your child's doctor if this happens.

Monitoring and follow up

To check you are receiving the correct dose, and to detect any severe side effects, your doctor may carry out checkups and laboratory tests from time to time. These tests may include

  • Blood counts
  • Liver function tests
  • Kidney function tests

UV Exposure

Whilst using MERCAPTOPURINE-LINK, you may be more sensitive to sunlight. It is advised to limit exposure to the sun, wear protective clothing and use a sunscreen with a high protection.

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 MERCAPTOPURINE-LINK and affect how it works. These include:

  • Ribavirin, a medicine used to treat viral infections such as hepatitis C
  • Myelosuppressive agents, which may be used after transplants, as part of cancer treatment, or for inflammatory diseases such as ulcerative colitis, Crohn's disease, psoriasis, ankylosing spondylitis, and rheumatoid arthritis
  • Allopurinol, oxipurinol and/or thiopurinol and other xanthine oxidase inhibitors such as febuxostat, which are used for the treatment of gout
  • Aminosalicylate derivatives such as olsalazine, mesalazine or sulfasalazine, which are used for inflammatory conditions such as ulcerative colitis, Crohn's disease, and rheumatoid arthritis
  • Methotrexate
  • Infliximab

MERCAPTOPURINE-LINK affects medicines used to treat or prevent blood clots e.g. warfarin

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

4. How do I use MERCAPTOPURINE-LINK?

How much to take

MERCAPTOPURINE-LINK should be taken exactly as directed by your doctor.

Your doctor will decide what dose and for how long to take MERCAPTOPURINE-LINK depending on factors such as:

  • Age
  • Weight
  • Pre-existing medical conditions such as kidney or liver disease
  • Response to treatment
  • Other medications

Your doctor may change the dose and frequency of your medicine over the course of treatment.

When to take MERCAPTOPURINE-LINK

  • MERCAPTOPURINE-LINK should be used exactly as directed by your doctor.

How to take MERCAPTOPURINE-LINK

Do not crush or chew the tablets.

  • MERCAPTOPURINE-LINK is an irritant to the eyes and skin. It is important to wash your hands immediately after handling the tablets. Avoid contact with eyes and be careful not to inhale any particle of the tablet.

If you forget to use MERCAPTOPURINE-LINK

MERCAPTOPURINE-LINK should be used exactly as directed by your doctor. If you miss your dose at the usual time, let your doctor or pharmacist know.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

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

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.

Otherwise, your doctor may think your treatment was not working as it should and make unnecessary adjustments to your therapy.

If you use too much MERCAPTOPURINE-LINK

If you think that you have used too much MERCAPTOPURINE-LINK, 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 MERCAPTOPURINE-LINK?

Things you should do

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

Inform any health care professionals you are seeing that you are on MERCAPTOPURINE-LINK, especially if you are about to be started on any new medicines, immunisations, vaccinations or radiotherapy.

Call your doctor straight away if you:

  • notice any signs of fever or infection or any unexpected bruising, bleeding or signs of blood in your urine.

Things you should not do

  • Do not stop taking this medicine or change the dose without first checking with your doctor.
  • Do not use MERCAPTOPURINE-LINK to treat any other complaints unless your doctor says to
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Driving or using machines

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

Drinking alcohol

Tell your doctor if you drink alcohol.

Looking after your medicine

Keep your tablets in the bottle until it is time to take them.

Store it 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.

Keep it where young children cannot reach it.

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.

Less serious side effects

Less serious side effectsWhat to do
Gastrointestinal disorders:
  • Nausea, vomiting, diarrhoea
  • Abdominal pain
  • burning or tingling sensation in the mouth or lips (inflammation of the mucosa, stomatitis).
Blood and lymphatic system disorders:
  • production of bone marrow cells may be reduced. You may notice an increase in infections. Your doctor will do regular blood tests.
Metabolism and nutrition disorders:
  • Weight loss
Immune System disorders:
  • Painful, swollen joints
  • Skin rash
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Signs of an allergic reaction such as:
  • Swelling of the face, lips or tongue
  • Rash
  • Redness
  • Hives
  • Itching
  • Shortness of breath, wheezing or difficulty breathing
Signs of liver problems:
  • Jaundice - yellowing of the whites of the eyes or the skin
  • Fever or chills
  • Light brown urine
Gut and digestion:
  • Vitamin B3 deficiency (pellagra) associated with a localised pigmented skin rash, diarrhoea or decrease in memory, reasoning or other thinking skills.
In Children:
  • Low blood sugar (hypoglycaemia) - the frequency is unknown.
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 MERCAPTOPURINE-LINK contains

Active ingredient
(main ingredient)		Mercaptopurine monohydrate
Other ingredients
(inactive ingredients)		Lactose
Maize starch
Pregelatinized maize starch
Magnesium stearate
Stearic acid

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

What MERCAPTOPURINE-LINK looks like

MERCAPTOPURINE-LINK tablets are round, pale yellow coloured, and scored on one side (Aust R 306940).

Who distributes MERCAPTOPURINE-LINK

LINK MEDICAL PRODUCTS PTY LTD
5 Apollo Street
Warriewood, NSW 2102

This leaflet was updated in July 2024

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Mercaptopurine-Link

Active ingredient

Mercaptopurine monohydrate

Schedule

S4

 

1 Name of Medicine

Mercaptopurine monohydrate.

2 Qualitative and Quantitative Composition

Mercaptopurine-Link 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 anhydrous lactose.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Tablets, uncoated and scored on one side. The score line is not intended for breaking the tablet.

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 (ALL) and acute myelogenous leukaemia.
Mercaptopurine-Link 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 Mercaptopurine-Link.
The dosage should be carefully adjusted to suit the individual patient.
Mercaptopurine-Link 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 Mercaptopurine-Link dosage.

Renal or hepatic impairment.

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

TPMT.

Mercaptopurine is metabolised by the polymorphic thiopurine methyl transferase (TPMT) enzyme. Patients with little or no inherited TPMT activity are at increased risk for severe toxicity from conventional doses of mercaptopurine and generally require substantial dose reduction. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. TPMT testing cannot substitute for haematological monitoring in patients receiving mercaptopurine. The optimal starting dose for homozygous deficient patients has not been established (see Section 4.4 Special Warnings and Precautions for Use).

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

Mercaptopurine-Link is an active cytotoxic agent for use only under the direction of physicians experienced in the administration of such agents.
Co-administration of ribavirin and Mercaptopurine-Link 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 Mercaptopurine-Link 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 Mercaptopurine-Link tablets.

Immunisation.

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.

Cytotoxic and haematological monitoring.

Since Mercaptopurine-Link 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 Mercaptopurine-Link 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 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).

Hepatotoxicity.

Mercaptopurine-Link 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 Mercaptopurine-Link immediately if jaundice becomes apparent.

Renal toxicity.

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

Renal and/or hepatic impairment.

Caution is advised during the administration of Mercaptopurine-Link 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).

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 Mercaptopurine-Link. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. Also a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving mercaptopurine monohydrate in combination with other cytotoxics (see Section 4.8 Adverse Effects (Undesirable Effects)). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.
Cross resistance usually exists between mercaptopurine monohydrate and 6-thioguanine (Lanvis).

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 pro-drug of mercaptopurine monohydrate, patients with a previous history of hypersensitivity to azathioprine must be assessed for hypersensitivity to mercaptopurine monohydrate prior to initiating treatment.

Carcinogenesis and mutagenesis.

Mercaptopurine-Link 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.

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). Dose reduction or discontinuation of mercaptopurine treatment may not be required if appropriate medical care with niacin/nicotinamide supplementation is initiated. However, careful benefit-risk assessment is required on a case-by-case basis.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

Cases of symptomatic hypoglycaemia have been reported in children with ALL receiving 6-mercaptopurine (see Section 4.8). 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.

See Section 4.4 Special Warnings and Precautions for Use, Cytotoxic and haematological 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 Mercaptopurine-Link.

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 Mercaptopurine-Link is not advised (see Section 4.4 Special Warnings and Precautions for Use).

Myelosuppressive agents.

When Mercaptopurine-Link 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 Mercaptopurine-Link 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 Mercaptopurine-Link on other drugs.

Anticoagulants.

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

4.6 Fertility, Pregnancy and Lactation

Effects on 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 Mercaptopurine-Link tablets, during treatment and for at least three months after receiving the last dose.
Mercaptopurine monohydrate 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 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 Mercaptopurine-Link 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.
 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 Mercaptopurine-Link 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 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.
Frequency not known: hypoglycaemia+, pellagra (see Section 4.4).
+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 (IBD), 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, mucosal inflammation.

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 Mercaptopurine-Link.
The risk of overdosage is also increased when allopurinol is being given concomitantly with Mercaptopurine-Link. 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 Poisons Information Centre on 13 11 26 (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 Mercaptopurine-Link 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 Mercaptopurine-Link 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, Carcinogenicity.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Mercaptopurine-Link tablet also contains: anhydrous lactose, maize starch, pregelatinized maize starch, magnesium stearate, stearic acid.

6.2 Incompatibilities

No data available.

6.3 Shelf Life

24 months.

6.4 Special Precautions for Storage

Storage.

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

6.5 Nature and Contents of Container

Presentation.

Mercaptopurine-Link tablets are round yellowish tablets, scored on one side. They each contain 50 mg mercaptopurine monohydrate and are supplied in amber glass bottles with a child-resistant 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 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) and the chemical structure is:

Chemical structure.


CAS number.

6112-76-1.

7 Medicine Schedule (Poisons Standard)

S4 (Prescription only medicine).

Summary Table of Changes