Consumer medicine information

Azapin

Azathioprine

BRAND INFORMATION

Brand name

Azapin

Active ingredient

Azathioprine

Schedule

SUMMARY CMI

AZAPIN

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 taking AZAPIN?

AZAPIN contains the active ingredient azathioprine. AZAPIN is used to help prevent the body from rejecting transplanted organs such as the heart or kidney.

For more information, see Section 1. Why am I taking AZAPIN? in the full CMI.

2. What should I know before I take AZAPIN?

Do not take it if you have ever had an allergic reaction to 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 or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I take AZAPIN? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with AZAPIN 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 take AZAPIN?

Take AZAPIN at about the same time each day. Taking at the same time each day will have the best effect. It will also help you remember when to take it.
Take AZAPIN at least one hour before or three hours after food or milk.

More instructions can be found in Section 4. How do I take AZAPIN? in the full CMI.

5. What should I know while taking AZAPIN?

Things you should do	Remind any doctor, dentist, or pharmacist you visit that you are taking AZAPIN. If you are about to be started on a new medicine, remind your doctor and pharmacist that you are taking this medicine.
Things you should not do	Do not stop taking AZAPIN or change the dosage without first checking with your doctor. Do not take AZAPIN to treat any other complaints unless your doctor tells you to.
Driving or using machines	Azathioprine may cause dizziness and tiredness in some people. If you have any of these symptoms, do not drive or operate machinery or do anything else that is dangerous.
Drinking alcohol	Tell your doctor if you drink alcohol.
Looking after your medicine	Keep your medicine in a cool dry place where the temperature stays below 25°C. Do not store your medicine or any other medicine in the bathroom or near a sink. Do not leave it on a windowsill or in the car.

For more information, see Section 5. What should I know while taking AZAPIN? in the full CMI.

6. Are there any side effects?

There are a number of side effects associated with AZAPIN. It is important to be aware of them so that you can identify any symptoms if they occur. 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

AZAPIN

Active ingredient: Azathioprine

Consumer Medicine Information (CMI)

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

Where to find information in this leaflet:

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

1. Why am I taking AZAPIN?

AZAPIN contains the active ingredient azathioprine. Azathioprine belongs to a group of medicines called immunosuppressants. It works by suppressing the body's immune defence system.

Azathioprine is usually taken in combination with other medicines such as corticosteroids or other immunosuppressants.

Azathioprine is used to help prevent the body from rejecting transplanted organs such as the heart or kidney.

It is also used to treat autoimmune diseases, where your immune system is reacting against your own body. These include:

Severe rheumatoid arthritis.
Systemic lupus erythematous.
Chronic active hepatitis.
Certain skin muscle, and blood disease.

2. What should I know before I take AZAPIN?

Warnings

Do not take AZAPIN if:

You are allergic to azathioprine, or any of the ingredients listed at the end of this leaflet.
Always check the ingredients to make sure you can use this medicine.
Do not take this medicine if you have an allergy to:
- Azathioprine.
- 6-mercaptopurine.
- Any of the ingredients listed at the end of this leaflet.
Some of the symptoms of an allergic reaction may include:
- Shortness of breath.
- Wheezing or difficulty breathing.
- Swelling of the face, lips, tongue, throat, or other parts of the body.
- Rash, itching or hives on the skin.

Check with your doctor if you:

Have any other medical conditions:
- Liver or kidney disease.
- A condition where your body produces too little of a natural chemical called thiopurine methyltransferase (TPMT).
- Lesch-Nyhan Syndrome.
- Chickenpox or shingles.
- Hepatitis B.
- Irritable bowel syndrome.
- A history of cytomegalovirus disease.
Take any medicines for any other condition.
Do not take this medicine if you have rheumatoid arthritis previously treated with alkylating agents (medicines such as chlorambucil, melphalan or cyclophosphamide).

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

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

AZAPIN may cause birth defects if either male or female is taking it at the time of conception. Both you and your partner should take adequate contraceptive precautions while taking AZAPIN to prevent pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

AZAPIN is not recommended for use during breastfeeding as it passes into breastmilk and may affect your baby.

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.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives, or dyes.
Tell your doctor if you have recently been vaccinated or immunised or plan to get a vaccination or immunisation. AZAPIN may affect the way the vaccine works or your reaction to the vaccine.
Tell your doctor if you are planning to have surgery or an anesthetic.
Tell your doctor if you are currently receiving or are planning to receive dental treatment. Tell your dentist that you are taking AZAPIN. Dental work, whenever possible, should be completed before you start taking AZAPIN or delayed until your blood cell counts are normal.

Taking other medicines

Some medicines and azathioprine may interfere with each other. These include:

Pencillamine, used in the treatment of rheumatoid arthritis.
Captopril, used in high blood pressure and heart failure.
Cimetidine, used in stomach ulcers and indigestion.
Indomethacin, used as a painkiller and anti-inflammatory.
Co-trimoxazole, ketoconazole, erythromycin and rifampicin used to treat infections.
Allopurinol, oxipurinol, thiopurinol or febuxostat, used mainly to treat gout.
Tubocurarine and succinylcholine used during anesthesia.
Furosemide may be used to reduce swelling caused by excess fluid.
Warfarin, used to prevent blood clots.
Mesalazine, olsalazine or sulphasalazine, used in the treatment of ulcerative colitis.
Phenytoin, phenobarbital, rifampicin, ketoconazole or erythromycin.
Methotrexate, used in the treatment of cancer.
Ribavirin, used to treat a type of respiratory infection.
Infliximab, used to treat autoimmune diseases.

These medicines may be affected by azathioprine or may affect how well it works. You may need different amount of medicine, or you may need to take different medicines.

Your doctor and pharmacists have more information on medicines to be careful with or avoid while taking this medicine.

Other medicines not listed above may also interact with azathioprine.

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

4. How do I take AZAPIN?

How much to take

Follow all directions given to you by your doctor or pharmacist carefully.
They may differ to the information contained in this leaflet.
If you do not understand the instructions on the label, ask your doctor or pharmacist for help.
Your doctor will tell you how much of this medicine you should take. This will depend on your condition and whether you are taking any other medicine.

When to take AZAPIN

AZAPIN should be taken at about the same time each day.
Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
Take this medicine at least one hour before or three hours after food or milk.
Food can interfere with the absorption of this medicine.

If you forget to take AZAPIN

AZAPIN should be taken regularly at the same time each day.

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

Otherwise, take it as soon as you remember, and then go back to taking your medicine as you would normally.

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

This may increase the chance of you experiencing side effects.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints to help you remember.

If you take too much AZAPIN

If you think that you have taken too much AZAPIN, 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.

If you take too much AZAPIN you may get an unexpected infection, ulcers in the throat, bruising and bleeding.

5. What should I know while taking AZAPIN?

Things you should do

Call your doctor straight away if you:

If you are about to be started on any new medicine, remind your doctor or pharmacist that you are taking this medicine.
If you become pregnant, father a child, or start to breastfeed while taking this medicine, tell your doctor immediately.
Tell your doctor if you plan to have any vaccinations or immunisations.
This medicine may affect the way some vaccines work, or your reaction to the vaccine.
Tell your doctor if you are about to have any blood tests.
Tell your doctor if you are going to have surgery or an anesthetic or going into hospital.
Keep all your doctors' appointments so that your progress can be checked.
Your doctor will perform blood tests every week for the first eight weeks, then at least once a month after that, while you are taking AZAPIN.
Before you start AZAPIN, your doctor should also test for thiopurine methyltransferase (TPMT) enzyme deficiency.
Try to avoid contact with people who have infectious diseases, such as the flu, chickenpox, or shingles.
Tell your doctor immediately if you do come into contact with someone who has chickenpox or shingles.
Avoid contact with sports or other situations where bruising or injury may occur. Be careful to avoid cutting yourself with sharp objects (e.g., razors).
Protect yourself from the sun while you are taking AZAPIN.
If you go out in the sun, wear a hat, protective clothing, and use sunscreen.
Tell your doctor immediately if you notice new moles, changes in existing moles, lumps on your body or you feel unwell.
AZAPIN suppresses your immune system. Lowering your body's immune defence system increases your risk of skin cancer, cervical cancer, lymphoma, and other cancers.
If you are a female, tell your doctor if you notice unusual vaginal discharge or bleeding, and make sure to have regular Pap smears.

Remind any doctor, dentist, or pharmacist you visit that you are taking AZAPIN.

Things you should not do

Do not give this medicine to anyone else even if they have the same condition as you.
Do not take your medicine to treat any other complaints unless your doctor tells you to.
Do not stop taking your medicine or change the dosage without first checking with your doctor.
If you stop it suddenly, your condition may worsen

Things to be careful of

Driving or using machines

Be careful before you drive or use any machines or tools until you know how AZAPIN affects you.

AZAPIN may cause dizziness and tiredness in some people. If you have any of these symptoms, do not drive or operate machinery or do anything else that is dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may have some effects while taken with AZAPIN.

Looking after your medicine

Keep your medicine in the pack until it is time to take it.
If you take the medicine out of the pack It may not keep well.
Keep your medicine in a cool and dry place where the temperature stays below 25°C.

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

Store it in a cool dry place away from moisture, heat, or sunlight; for example, do not store it:

in the bathroom or near a sink, or
in the car or on windowsills.

Keep it where young children cannot reach it.

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

When to discard your medicine

If your doctor tells you to stop taking this medicine or the expiry date has passed, ask your doctor what to do with any medicine that is left over.

Getting rid of any unwanted medicine

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

Do not take 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 effects

What to do

Any infection or fever.
Unexpected bruising or bleeding, black tarry stools or blood in the urine or stools.
You come into contact with anyone who is suffering from chickenpox or shingles.
New marks on skin or any change to marks that may have been there previously.
Headache, stiff neck and extreme sensitivity to bright light.
Nausea and vomiting.
Tiredness, dizziness or generally unwell.
Irregular heart beat.
Sore in the mouth and on the lips.
Feeling of ants creeping in or under the skin.
Change in sense of smell or taste.

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Muscle weakness, pain or stiffness.
Severe joint pain.
Kidney problems.
Feeling faint especially when standing up.
Severe abdominal pain.
Diarrhoea.
Jaundice, a yellow discolouration of the skin/eyes.
Serious skin reactions such as blistering or peeling.
Muscle weakness, with or without a skin rash.
A rash that appears as tender red or purple lumps or patches on the skin that may ulcerate, tiredness lack of energy and feeling unwell, fever, aching joints and muscles, mouth ulcers and sore red eyes-symptoms of Sweet's syndrome.
Symptoms of an allergic reaction including cough, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue, throat or other parts of the body, rash, itching or hives on the skin.

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.

Very Serious side effects

Very Serious side effects	What to do
Side-effects reported particularly in organ transplanted patients are: Viral, fungal and bacterial infections. Hair loss (particularly following a kidney transplant). Diarrhoea, usually with blood and mucus. Stomach pain with fever and vomiting.	Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these very serious side effects. You may need urgent hospitalisation.

Other side effects not listed above may occur in some patients.

Some of these side effects can only be found when your doctor does tests from time to time to check your progress (e.g., low blood cell count).

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 AZAPIN contains

Active ingredient (Main ingredient)	Azathioprine
Other ingredients (Inactive ingredients)	Croscarmellose sodium Mannitol Microcrystalline cellulose Maize starch Povidone Sodium stearylfumarate Opadry clear OY-7240 (macrogol 400 and hypromellose)
Potential allergens	N/A

This medicine does not contain gluten and sucrose.

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

What AZAPIN looks like

50 mg tablets

AZAPIN is a light yellow, circular, biconvex tablet engraved “AZA” breakline “50” on one side and plain on the other side. AUST R 92801.

Available in pack size of 100 tablets.

Who distributes AZAPIN

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia
Web: www.arrotex.com.au

This leaflet was prepared in July 2024.

Published by MIMS September 2024

BRAND INFORMATION

Brand name

Azapin

Active ingredient

Azathioprine

Schedule

1 Name of Medicine

Azathioprine.

2 Qualitative and Quantitative Composition

Azapin tablets contain 50 mg azathioprine.
Azathioprine is a pale yellow powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Azapin 50 mg tablets are pale yellow, round, film coated, biconvex, tablets engraved with "AZA", breakline and "50" on one face. The other face is plain.

4 Clinical Particulars

4.1 Therapeutic Indications

Azathioprine is used as an immunosuppressant/antimetabolite either alone or, more commonly, in combination with the other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effects may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.
Azathioprine, in combination with corticosteroids and/or other immunosuppressive agents and procedures, is indicated in the management of patients receiving organ transplants.
Azathioprine, either alone or more, usually in combination with corticosteroids and/or other procedures, has been used with clinical benefit which may include reduction of dosage or discontinuation of corticosteroids, in a proportion of patients suffering from the following: severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis/polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune haemolytic anaemia and chronic refractory idiopathic thrombocytopenic purpura.

4.2 Dose and Method of Administration

Azapin tablets are intended for oral administration only.

Transplantation - adults and children.

Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg bodyweight/day may be given orally on the first day of therapy.
The maintenance dosage should range from 1 to 4 mg/kg/day orally and must be adjusted according to clinical requirements and haematological tolerance.
Evidence indicates that azathioprine therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.

Other conditions - adults and children.

In general, the starting dose is from 1 mg/kg/day, gradually increasing in increments of 0.5 mg/kg/day over several weeks, if necessary, up to a maximum of 2.5 mg/kg/day.
When therapeutic response is evident, consideration should be given to reducing the maintenance dosage to the lowest level compatible with the maintenance of that response. If no improvement occurs in the patient's condition within 3 months, consideration should be given to withdrawing azathioprine.
The maintenance dosage required may range from less than 1 mg/kg/day to 3 mg/kg/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Use in the elderly.

(See Section 4.8 Adverse Effects (Undesirable Effects), Haematopoiesis).
The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate plasma levels to drug toxicity. There are no specific data as to the tolerance of elderly patients to azathioprine. It is recommended that the dosages used be at the lower end of the range given for adults and children.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.

Renal/hepatic impairment.

See Section 4.4 Special Warnings and Precautions for Use, Use in hepatic or renal impairment.

4.3 Contraindications

The use of Azapin is contraindicated in patients with a previous history of hypersensitivity to azathioprine, any other component of the preparation, or any of the excipients in this product (listed previously). Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to azathioprine.
Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive risk of neoplasia if treated with azathioprine.
Therapy with Azapin should not be initiated in patients who may be pregnant, who are likely to become pregnant in the near future, or who are known to be pregnant. (See Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine.

Cytomegalovirus (CMV) disease (see Section 4.8 Adverse Effects (Undesirable Effects)).

Cytomegalovirus (CMV) viraemia resulting in severe pneumonitis and associated haemophagocytic syndrome manifesting in patients with inflammatory bowel disease has been reported in the literature.
Caution should be exercised and specialist literature consulted when determining the risks of CMV reactivation and IBD deterioration.

Monitoring.

There are potential hazards associated with the use of azathioprine. Azathioprine should be prescribed only if the patient can be adequately monitored for toxic effects throughout the entire duration of treatment.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
During the first eight weeks of therapy, complete blood counts, including platelets, must be performed weekly or more frequently if high dosage is used or if a coexistent severe renal and/or hepatic disorder is present. The blood count frequency may be reduced later in therapy, but it is recommended that complete blood counts be repeated at intervals of not longer than one month or more frequently if dosage alterations or other changes to therapy are made. Delayed haematological suppression may occur.
A prompt reduction in dosage or the temporary withdrawal of the drug may be necessary if there is a rapid fall in, or a persistently low, leucocyte count or other evidence of bone marrow suppression.
Patients receiving azathioprine should be instructed to report immediately if there is any evidence of infection, unexpected bruising or bleeding, black tarry stools and blood in the urine or stools, or other manifestations of bone marrow depression. Bone marrow suppression is reversible if azathioprine is withdrawn early enough.

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 azathioprine and prone to developing rapid bone marrow depression following the initial treatment with Azapin. There have been fatal cases of myelosuppression in patients with low or absent TPMT activity treated with thiopurines. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also, a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be tested for TPMT activity before starting Imuran. TPMT testing cannot substitute for complete blood count monitoring in patients receiving Imuran. 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 Imuran if conventional doses are given. Alternative therapies may be considered for patients who have low or absent TPMT activity. Imuran 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. The dosage of azathioprine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
TPMT testing is widely available through pathology laboratories and genetic testing services.

NUDT15 testing.

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. The precise mechanism of NUDT15-associated thiopurine related toxicity is not understood. 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. Close monitoring of blood count is necessary.
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.

Lesch-Nyhan syndrome.

Limited evidence suggests that Azapin is not beneficial to patients with hypoxanthine-guanine-phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the abnormal metabolism in these patients, it is not prudent to recommend that these patients should receive Azapin.

Use in hepatic or renal impairment.

It is impossible to relate plasma levels of azathioprine or 6-mercaptopurine to therapeutic efficacy or toxicity. The conversion of 6-thioinosinic acid to 6-thiouric acid by xanthine oxidase is not dependent on intact hepatic and/or renal function. Nevertheless, it is recommended that the dosages used are at the lower end of the normal range and that haematological response is carefully monitored. Dosage should be further reduced if haematological toxicity occurs.
Caution is necessary during the administration of Azapin to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of Azapin may be impaired, and the dosage of Azapin should, therefore, be reduced to the lower end of the recommended range. Dosage should be further reduced if hepatic or haematological toxicity occurs.

Carcinogenicity.

Patients receiving immunosuppressive therapy, including azathioprine, 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.

Varicella zoster virus infection (see Section 4.8 Adverse Effects (Undesirable Effects)).

Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, immunisations with live organism vaccines are not recommended.
Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised especially with respect to the following.
Before starting the administration of immunosuppressants, the prescriber should check to see if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure. Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. If the patient is exposed to VZV, special care must be taken to avoid patients developing chickenpox or herpes zoster and passive immunisation with varicella zoster immunoglobulin (VZIG) may be considered.
If the patient is infected with VZV, appropriate measures should be taken, which may include antiviral therapy and supportive care.

Progressive multifocal leukoencephalopathy (PML).

PML, an opportunistic infection caused by the JC virus (a type of human polyomavirus) has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hepatitis B (see Section 4.8 Adverse Effects (Undesirable Effects)).

Hepatitis B carriers (defined as patients positive for hepatitis B surface antigen [HBsAg] for more than six months), or patients with documented past HBV infection, who receive immunosuppressive drugs are at risk of reactivation of HBV replication, with asymptomatic increases in serum HBV DNA and ALT levels. Specialist medical literature should be consulted for guidance including prophylactic therapy with oral anti-HBV agents.

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 azathioprine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

Metabolism and nutrition disorders.

Administration of purine analogues (azathioprine, mercaptopurine and thioguanine) may interfere with the niacin pathway, potentially leading to nicotinic acid deficiency/pellagra. A few cases have been reported with the use of azathioprine, especially in patients with IBD (Crohn's disease, colitis ulcerative); therefore, health care professionals should be aware of this condition and provide appropriate medical care if pellagra occurs (such as niacin/nicotinamide supplementation).

Other precautions.

Azathioprine should be used with caution in hypersplenism.
The withdrawal of azathioprine should be gradual and performed under close supervision.
Dental work, whenever possible, should be completed prior to initiation of azathioprine therapy or deferred until blood counts are normal.

Hypersensitivity.

Patients suspected to have previously presented a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, and vice-versa, unless the patient has been confirmed as hypersensitive to the culprit drug with allergological tests, and tested negative for the other.

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Allopurinol/oxypurinol/thiopurinol and other xanthine oxidase inhibitors.

The activity of the enzyme xanthine oxidase is inhibited by allopurinol, oxipurinol and thiopurinol. This results in the reduced conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxypurinol and/or thiopurinol are given concomitantly with 6-mercaptopurine or azathioprine, the dose of 6-mercaptopurine and azathioprine should be reduced to one-quarter of the original dose. For example, an azathioprine dose of 100 mg should be reduced to 25 mg when used concomitantly with allopurinol.
Other xanthine oxidase inhibitors, such as febuxostat my decrease the metabolism of azathioprine. Concomitant administration is not recommended as data are insufficient to determine an adequate dose reduction.

Neuromuscular blocking agents.

Azathioprine can potentiate the neuromuscular blockade produced by depolarising agents such as succinylcholine, and can reduce the blockade produced by nondepolarising agents such as tubocurarine.

Cytostatic/myelosuppressive agents.

Azathioprine should be used with caution in patients receiving, or who have recently received, other bone marrow suppressive agents.
Where possible, concomitant administration of cytostatic drugs or drugs which may have a myelosuppressive effect, such as penicillamine, should be avoided. There are conflicting clinical reports of interactions, resulting in serious haematological abnormalities, between Azapin and co-trimoxazole.
There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and ACE inhibitors.
It has been suggested that cimetidine and indomethacin may have myelosuppressive effects which may be enhanced by concomitant administration of Azapin.

Anticoagulants.

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

Aminosalicylates.

As there is in vitro and in vivo evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent azathioprine therapy (see Section 4.4 Special Warnings and Precautions for Use).

Vaccines.

The immunosuppressive activity of Azapin could result in an atypical and potentially deleterious response to live vaccines and so the administration of live vaccines in patients receiving Azapin therapy is contraindicated on theoretical grounds.
A diminished response to killed vaccines is likely and such a response to hepatitis B vaccine has been observed among patients treated with a combination of azathioprine and corticosteroids.
A small clinical study has indicated that standard therapeutic doses of azathioprine do not deleteriously affect the response to polyvalent pneumococcal vaccine, as assessed on the basis of mean anti-capsular specific antibody concentration.

Methotrexate.

When azathioprine is administered concomitantly with high dose methotrexate, the dose should be adjusted to maintain a suitable white blood cell count.

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 azathioprine and ribavirin; therefore co-administration is not advised.

Infliximab.

An interaction has been observed between azathioprine and infliximab. Patients receiving ongoing azathioprine experienced increase in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and a decrease in the mean leukocyte count following infliximab infusion.

Other.

Frusemide has been shown to impair the metabolism of azathioprine by human hepatic tissue in vitro. The clinical significance is unknown.
Drugs known to either induce (phenytoin, phenobarbital, rifampicin) or inhibit (ketoconazole, erythromycin) hepatic microsomal enzymes may alter the hepatic clearance of azathioprine.
The coadministration of azathioprine and captopril may result in increased susceptibility to leucopenia.

4.6 Fertility, Pregnancy and Lactation

(Category D)
The decision to maintain or discontinue azathioprine treatment during pregnancy, or to terminate the pregnancy, depends on the condition being treated, in which maternal well being has to be weighed against the possible risks to the foetus. As a general rule therapy with azathioprine should not be initiated in patients known to be pregnant.
Cholestasis of pregnancy has occasionally been reported in association with azathioprine therapy. If cholestasis of pregnancy occurs, case by case assessment is necessary considering the risk-benefit profile of the drug.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving azathioprine.
There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure.
Azathioprine and/or its metabolites have been found in low concentrations in foetal blood and amniotic fluid after the maternal administration of azathioprine.
The rare possibility of neonatal leucopenia and/or thrombocytopenia that may not be clinically evident appears to be preventable by the reduction in maternal dose of azathioprine if, at 32 weeks gestation, the maternal leucocyte count is at or below 8.6 x 10⁹/L. The possibility of neonatal immunosuppression is a serious and potentially fatal complication. Extra care in haematological monitoring is advised during pregnancy.

Teratogenicity.

Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5 to 15 mg/kg bodyweight/day over the period of organogenesis, have shown varying degrees of foetal abnormalities. Teratogenicity was evident in rabbits at 10 mg/kg bodyweight/day.
Epidemiological evidence in humans indicates that the frequency of occurrence of congenital abnormalities in the offspring of maternal transplant recipients is similar to that in the general population.
As with all cytotoxic chemotherapy, adequate contraceptive precautions should be advised when either partner is receiving Azapin.
6-Mercaptopurine has been identified in the colostrum and breast milk of the women receiving azathioprine treatment. Nursing mothers should be advised to consult their physician, since use by nursing mothers is not recommended because of possible adverse effects on the infant.

Effects on fertility.

Relief of chronic progressive renal failure by renal transplantation involving the use of azathioprine has been accompanied by increased fertility in both male and female transplant recipients.

4.7 Effects on Ability to Drive and Use Machines

No specific studies have been conducted to assess the direct effect of azathioprine on the ability to drive and use machines. However, adverse effects of azathioprine include dizziness which could affect the ability to drive or use machines. See Section 4.8 Adverse Effects (Undesirable Effects).

4.8 Adverse Effects (Undesirable Effects)

Hypersensitivity reactions.

There have been occasional reports of several different clinical syndromes that appear to be of an idiosyncratic hypersensitivity nature. These include general malaise, headache, dizziness, nausea, vomiting, diarrhoea, fever, rigours, exanthema, rash, vasculitis, myalgia, muscular pain, arthralgia, hypotension, disturbed hepatic function, cholestatic jaundice, pancreatitis, cardiac dysrhythmia and renal dysfunction. In many cases, rechallenge has confirmed an association with azathioprine.
Additional adverse reactions have been reported at a low frequency. These include skin rashes (approximately 2%), steatorrhoea, negative nitrogen balance, Stevens-Johnson syndrome and toxic epidermal necrolysis (all less than 1%).
It has been suggested that the imidazole side chain gives rise to hypersensitivity, whereas the 6-mercaptopurine (6-MP) molecule gives rise to cholestasis.
The immediate withdrawal of azathioprine and initiation of supportive circulatory measures have led to recovery in the majority of cases. Other marked underlying pathology has contributed to the very rare deaths reported.
Azathioprine use should be permanently withdrawn after any such clinical hypersensitivity syndrome.

Neoplasms benign and malignant (including cysts and polyps).

The risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ, is increased in patients who receive immunosuppressive drugs, particularly in transplant recipients receiving aggressive treatment, and such therapy should be maintained at the lowest effective levels. The increased risk of developing non-Hodgkin's lymphomas in immunosuppressed rheumatoid arthritis patients compared with the general population appears to be related at least in part to the disease itself.
There have been rare reports of acute myeloid leukaemia and myelodysplasia (some in association with chromosomal abnormalities).

Haematopoiesis.

Azapin may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia. These occur particularly in patients predisposed to myelotoxicity such as those with TPMT deficiency and renal or hepatic insufficiency, and in patients failing to reduce the dose of Azapin when receiving concurrent allopurinol therapy.
The therapeutic use of azathioprine has also been associated with reversible, dose related reduction in numbers of circulating total white cells, granulocytes and lymphocytes together with increases in mean corpuscular volume and red cell haemoglobin content. Megaloblastic bone marrow changes have been observed, but severe megaloblastic anaemia and erythroid hypoplasia are rare.
Azathioprine may produce thrombocytopenia that is dose related and may be delayed.

Alopecia.

Hair loss has been described in 50% of renal transplant recipients receiving azathioprine and corticosteroids, but does not appear to be a major problem when azathioprine is used for other indications. It is reversible in over 80% of cases despite continuing immunosuppression.

Susceptibility to infection.

Patients receiving azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection and reactivation with VZV, hepatitis B, herpes zoster, cytomegalovirus (CMV) and other infectious agents (see Section 4.4 Special Warnings and Precautions for Use). Viral, fungal and bacterial infections are very common in transplant patients receiving azathioprine in combination with other immunosuppressants.
Very rare cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants (see Section 4.4 Special Warnings and Precautions for Use).

Gastrointestinal reactions.

Nausea, vomiting and gastrointestinal discomfort may occur during the first few months of therapy with azathioprine. These effects are usually reduced by dosage adjustment and by administering the tablets in divided doses and/or after meals.
Serious complications, including colitis, diverticulitis and bowel perforation, have been described in transplant recipients receiving immunosuppressive therapy. However, the aetiology is not clearly established and high-dose corticosteroids may be implicated. Severe diarrhoea, recurring on rechallenge, has been reported in patients treated with azathioprine for inflammatory bowel disease. The possibility that exacerbation of symptoms might be medicine-related should be borne in mind when treating such patients.
Pancreatitis has been reported in a small percentage of patients on azathioprine therapy, particularly in renal transplant patients and those diagnosed as having inflammatory bowel disease. There are difficulties in relating the pancreatitis to the administration of one particular medicine, although rechallenge has confirmed an association with azathioprine on occasions.

Pulmonary reactions.

Reversible pneumonitis has been described very rarely.

Hepatotoxicity.

Cholestasis and deterioration of liver function have occasionally been reported in association with azathioprine therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Hypersensitivity reactions).
Hepatotoxicity may manifest by the elevation of serum alkaline phosphatase, bilirubin and/or serum transaminases and is generally reversible after interruption of azathioprine. The periodic measurement of serum transaminases, alkaline phosphatase and bilirubin is indicated for the early detection of hepatotoxicity. Hepatotoxicity has been uncommon (less than 1%) in patients with rheumatoid arthritis.
Rare, but life threatening, hepatic damage associated with chronic administration of azathioprine has been described, primarily in transplant patients. Histological findings include sinusoidal dilation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms. Azapin should be permanently withdrawn in patients with hepatic veno-occlusive disease.

Immune system disorders.

Erythema nodosum.

Other adverse effects.

Other adverse reactions include sores in the mouth and on the lips, meningitis, formication, acute febrile neutrophilic dermatosis (Sweet' Syndrome), exacerbation of myasthenia gravis and dermatomyositis and alterations in the senses of smell and taste.

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

The oral LD₅₀ for single doses of azathioprine in mice and rats is 2500 mg/kg and 400 mg/kg, respectively.

Symptoms.

Unexplained infection, ulceration of the throat, bruising and bleeding are the main signs of overdosage with azathioprine and result from bone marrow depression which may be maximal after 9 to 14 days. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose. Occasional reports describe ingestion of azathioprine from 0.5 to 7.5 g on a single occasion with apparent uneventful recovery.

Treatment.

Symptomatic; it has included gastric lavage. If overdosage occurs the blood picture and hepatic function in particular should be monitored. Azathioprine is dialysable but the procedure is of doubtful value since azathioprine is rapidly metabolised with entry of metabolites into tissue cells.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken down in vivo into 6-MP and a methylnitroimidazole moiety. The 6-MP readily crosses cell membranes and is converted intracellularly into a number of purine thioanalogues, which include the main active nucleotide, thioinosinic acid. The rate of conversion varies from one person to another. Nucleotides do not transverse cell membranes and, therefore, do not circulate in body fluids.
Irrespective of whether it is given directly or is derived in vivo from azathioprine, 6-MP is eliminated mainly as the inactive oxidised metabolite thiouric acid. This oxidation is brought about by xanthine oxidase, an enzyme that is inhibited by allopurinol. The activity of the methylnitroimidazole moiety has not been defined clearly. However, in several systems it appears to modify the activity of azathioprine as compared with that of 6-MP.
The determination of azathioprine or 6-MP plasma concentrations has no prognostic value as regards effectiveness or toxicity of these compounds.
While the precise mode of action remains to be elucidated, some suggested mechanisms include:
The release of 6-MP which acts as a purine antimetabolite;
The possible blockade of -SH groups by alkylation;
The inhibition of many pathways in nucleic acid biosynthesis, hence preventing proliferation of cells involved in determination and amplification of immune response;
Damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues.
Because of these mechanisms, the therapeutic effect of azathioprine may be evident only after several weeks or months of treatment.
Studies in mice with ³⁵S-azathioprine showed no unusually large concentration in any particular tissue although, but there was very little ³⁵S-azathioprine found in the brain.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Azathioprine is well absorbed from the gastrointestinal tract after oral administration. Peak plasma levels occur in 1 to 2 hours with a biological half-life of 5 hours following single doses.

Distribution.

After oral administration it disappears rapidly from the circulation and is extensively metabolised to mercaptopurine. Both azathioprine and mercaptopurine are about 30% bound to plasma proteins. About 10% of the dose of azathioprine is split between the sulphur and the purine ring to give 1-methyl-4-nitro-5-thioimidazole. Small amounts of unchanged azathioprine and mercaptopurine are eliminated in the urine.

Metabolism.

No data available.

Excretion.

No data available.

5.3 Preclinical Safety Data

Genotoxicity.

Chromosomal abnormalities, which may occur independently of the influence of azathioprine, have been demonstrated in both male and female transplant recipients.
Chromosomal abnormalities, which disappear in time, have been demonstrated in offspring of transplant recipients. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in these offspring.
Azathioprine and long-wave ultraviolet light have been shown to have a synergistic clastogenic effect in patients treated with azathioprine for a range of disorders.

Carcinogenicity.

See Section 4.4 Special Warnings and Precautions for Use.
Patients receiving immunosuppressive therapy are at an increased risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent.
Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppressive, therefore such therapy should be maintained at the lowest effective level.
As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited, and patients should wear protective clothing and use a sunscreen with a high protection factor.
Renal transplant recipients in some geographical areas are at greater risk of skin cancers than those in other areas.
Other neoplasms reportedly associated with azathioprine include carcinoma of the urinary bladder and adenocarcinoma of the lung (see Section 4.4 Special Warnings and Precautions for Use; Section 4.8 Adverse Effects (Undesirable Effects)).

6 Pharmaceutical Particulars

6.1 List of Excipients

Other ingredients of Azapin tablets are: cellulose microcrystalline, mannitol, maize starch, povidone, croscarmellose sodium, and sodium stearylfumarate and Opadry clear OY-7240 (macrogol 400 and hypromellose).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

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 30°C. Protect from light and moisture.

Safe handling of azathioprine tablets.

Azathioprine tablets should not be divided, crushed or broken.
Provided that the film coating is intact, there is no risk in handling film coated tablets.

6.5 Nature and Contents of Container

Azapin tablets are available in blister packs of 100 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

Chemical structure.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). Its chemical name is 6-[(1-methyl-4-nitro-1H-imidazol-5-yl) sulfanyl]-7H-purine.
Structurally it is represented as:

Molecular Weight: 277.3.
Molecular Formula: C₉H₇N₇O₂S.

CAS number.

446-86-6.
Azathioprine is stable under ordinary conditions. It is practically insoluble in water, in ethanol (96%), and in chloroform and is sparingly soluble in dilute mineral acids. It dissolves in dilute solutions of alkali hydroxides.

7 Medicine Schedule (Poisons Standard)

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Azapin 50 mg