Consumer medicine information

APO-Azathioprine

Azathioprine

BRAND INFORMATION

Brand name

APO-Azathioprine

Active ingredient

Azathioprine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Azathioprine.

What is in this leaflet

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

All medicines have risks and benefits. Your doctor has weighed the risks of you using this medicine against the benefits they expect it will have for you.

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

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

What this medicine is used for

Azathioprine is used to help prevent the body from rejecting transplanted organs, such as a 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 erythematosus
  • chronic active hepatitis
  • certain skin, muscle, and blood diseases.

Azathioprine belongs to a group of medicines called immunosuppressants. It works by supressing the body's immune defence system. Azathioprine is usually taken in combination with other medicines such as corticosteroids or other immunosuppressants.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed this medicine for another reason.

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

This medicine is not addictive.

Before you take this medicine

When you must not take it

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

Do not take this medicine if you have rheumatoid arthritis previously treated with alkylating agents (medicines such as chlorambucil, melphalan or cyclophosphamide).

Do not take this medicine if you are pregnant, plan to become pregnant or intending to father a child. Azathioprine 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 azathioprine to prevent pregnancy.

Do not take this medicine if you are breastfeeding, or plan to breastfeed. Azathioprine is not recommended for use during breastfeeding as it passes into breastmilk and may affect your baby.

Do not take this medicine after the expiry date printed on the pack or the packaging is torn or shows signs of tampering. If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

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 or have had any of the following 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 disease
  • a history of cytomegalovirus disease.

Tell your doctor if you are pregnant, may be pregnant, plan to become pregnant or intending to father a child. You or your partner should take adequate contraceptive precautions while you are taking azathioprine to prevent pregnancy.

Tell your doctor if you have recently been vaccinated or immunised or plan to get a vaccination or immunisation. Azathioprine 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 anaesthetic.

Tell your doctor if you are currently receiving or are planning to receive dental treatment. Tell your dentist that you are taking azathioprine. Dental work, whenever possible, should be completed before you start taking azathioprine or delayed until your blood cell counts are normal.

Taking other medicines

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

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

  • penicillamine, 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 anaesthesia
  • frusemide, 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 amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist 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.

How to take this medicine

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.

How much to take

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 medicines.

How to take it

Swallow the tablets whole with a glass of water.

Do not break, chew or crush the tablets.

When to take it

Take this medicine 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.

How long to take it for

Continue taking your medicine for as long as your doctor tells you.

Patients with a transplant will need to take azathioprine continuously to reduce the risk of organ rejection.

For other conditions, your doctor will discuss with you how long you need to take this medicine. It could take some weeks or months for it to take full effect.

Make sure you have enough to last over weekends and holidays.

If you forget to take it

If it is 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 (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice or go to Accident and Emergency at your nearest hospital, if you think that you or anyone else may have taken too much of this medicine.

Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

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

While you are taking this medicine

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking this medicine.

Tell any other doctors, dentists and pharmacists who are treating you that you take 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 anaesthetic or are going into hospital.

Keep all your doctor's 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 azathioprine.

Before you start azathioprine, 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 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 azathioprine. 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. Azathioprine 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 female, tell your doctor if you notice unusual vaginal discharge or bleeding, and make sure to have regular Pap smears.

Things you must 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 taking it suddenly, your condition may worsen.

Things to be careful of

Be careful when driving or operating machinery until you know how this medicine affects you. 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.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking azathioprine.

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

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor as soon as possible if you notice any of the following:

  • any infection or fever
  • unexpected bruising or bleeding, black 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
  • sores in the mouth and on the lips
  • feeling of ants creeping in or under the skin
  • change in sense of smell or taste.

If any of the happen, stop taking your medicine and contact your doctor immediately or go to the Accident and Emergency department at your nearest hospital:

  • muscle weakness, pain or stiffness
  • severe joint pain
  • kidney problems
  • feeling faint especially when standing up
  • severe abdominal pain
  • diarrhoea
  • jaundice, a yellow discoloration 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, acing 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

Side-effects reported particularly in organ transplant 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.

The above list includes very serious side effects and you may need urgent medical attention or hospitalisation.

Tell your doctor or pharmacist if you notice anything that is making you feel unwell.

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).

Storage and disposal

Storage

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

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 window sill or in the car. Heat and dampness can destroy some medicines.

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

Disposal

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

Product description

What it looks like

25 mg tablets
Orange coloured, round, biconvex film coated tablet with "AZA 25" embossed on one side and break line on other side. AUST R 205759.

50 mg tablets
Pale yellow coloured, round, biconvex film coated tablet with "AZA 50" embossed on one side and break line on other side. AUST R 205762

Available in packs of 100 tablets.

* Not all strengths, pack types and/or pack sizes may be available.

Ingredients

Each tablet contains 25 or 50 mg of azathioprine as the active ingredient.

It also contains the following:

  • lactose monohydrate
  • microcrystalline cellulose
  • maize starch
  • magnesium stearate
  • purified water
  • Opadry complete film coating system 03B52231 yellow (25 mg tablet only)
  • Opadry clear YS-1R-7006 (50 mg tablet only).

This medicine does not contain gluten, sucrose, tartrazine and other azo dyes.

Sponsor

Apotex Pty Ltd
16 Giffnock Avenue
Macquarie Park NSW 2113
Australia
Tel: (02) 8877 8333
Web: www1.apotex.com/au

APO and APOTEX are registered trademarks of Apotex Inc.

This leaflet was prepared in December 2019.

Published by MIMS March 2020

BRAND INFORMATION

Brand name

APO-Azathioprine

Active ingredient

Azathioprine

Schedule

S4

 

1 Name of Medicine

Azathioprine.

6.7 Physicochemical Properties

Azathioprine is a pale yellow powder, practically insoluble in water and in alcohol. It is soluble in dilute solutions of alkali hydroxides and sparingly soluble in dilute mineral acids.
Chemical Name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)sulfanyl]-7-H-purine. Molecular Formula: C9H7N7O2S. Molecular Weight: 277.3.

Chemical structure.


CAS number.

446-86-6.

2 Qualitative and Quantitative Composition

Each tablet contains 25 mg or 50 mg azathioprine as the active ingredient.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

APO-Azathioprine 25 mg tablets.

Orange coloured, round, biconvex film coated tablet with "AZA 25" embossed on one side and break line on other side.

APO-Azathioprine 50 mg tablets.

Pale yellow coloured, round, biconvex film coated tablet with "AZA 50" embossed on one side and break line on other side.
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.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). Azathioprine is used for the suppression of the immune system.

Mechanism of action.

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.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Azathioprine tablets appear to be well absorbed from the upper gastrointestinal tract. Azathioprine is rapidly broken down in vivo into 6-MP and a methylnitroimidazole moiety.

Distribution.

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 traverse cell membranes and therefore do not circulate in body fluids. The determination of plasma concentrations of azathioprine or 6-MP have no prognostic value regarding effectiveness or toxicity of these compounds.
Studies in mice with 35S-azathioprine showed no unusually large concentration in any particular tissue, but there as very little 35S-azathioprine found in the brain.

Metabolism.

Oxidation is brought about by xanthine oxidase, an enzyme which 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.

Excretion.

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.

5.3 Preclinical Safety Data

Genotoxicity.

Chromosomal abnormalities, which can 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 4.8 Adverse Effects (Undesirable Effects)).

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 there 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. Patients receiving multiple immunosuppressive agents may be at risk of over immunosuppression, 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 by wearing protective clothing and using a sunscreen with a high protection factor.
Renal transplant recipients in some geographical areas are at great 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.

Teratogenicity.

Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 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 man 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 azathioprine.

4 Clinical Particulars

4.1 Therapeutic Indications

Azathioprine is used as an immunosuppressant anti-metabolite either alone or, more commonly, in combination with other agents (usually corticosteroids) and procedures which influence the immune response. Therapeutic effect 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; chronic refractory idiopathic thrombocytopenic purpura.

4.3 Contraindications

Azathioprine is contraindicated in patients known to be hypersensitive to azathioprine or any other component of the preparation. 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.
Azathioprine therapy 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

Coadministration 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 (IBD) has been reported in the literature.
Caution should be exercised and specialist literature consulted when determining the risks of CMV reactivation and lBD deterioration.

Monitoring.

There are potential hazards to the use of azathioprine. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy.
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 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 are repeated at intervals of no longer than one month or more frequently if dosage alterations or other changes to therapy are made. Delayed haematological suppression may occur.
Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low, leucocyte count or other evidence of bone marrow depression.
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 initiation of treatment with azathioprine. 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 Azathioprine. TPMT testing cannot substitute for complete blood count monitoring in patients receiving Azathioprine. 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 azathioprine if conventional doses are given. Alternative therapies may be considered for patients who have low or absent TPMT activity. Azathioprine 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.

Lesch-Nyhan syndrome.

Limited evidence suggests that azathioprine 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 azathioprine.

Genotoxicity.

Chromosomal abnormalities, which can 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.

Teratogenicity.

Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 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 man 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 azathioprine.

Carcinogenicity (see Section 4.8 Adverse Effects (Undesirable Effects)).

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.

Other precautions.

Azathioprine should be used with caution in hypersplenism.
Withdrawal of azathioprine should be gradual and performed under close supervision.

Dental work.

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 hepatic impairment.

It is impossible to relate plasma levels of azathioprine or 6-mercaptopurine to therapeutic efficacy or toxicity. 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 azathioprine to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of azathioprine may be impaired, and the dosage of azathioprine further reduced if hepatic or haematological toxicity occurs.

Use in renal impairment.

See Use in hepatic impairment.

Use in the elderly (see Use in hepatic impairment).

The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate drug plasma levels to toxicity. There are no specific data as to the tolerance of azathioprine in elderly patient. It is recommended that the dosages used be at the lower end of the range given for adults and children.

Paediatric use.

No data available.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

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 are given concomitantly with 6-mercaptopurine (6-MP) or azathioprine, the dose of 6-MP and azathioprine should be reduced to one quarter of the original dose.
Other xanthine oxidase inhibitors, such as febuxostat may 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 reduce the blockade produced by nondepolarising agents such as tubocurarine.

Anticoagulants.

Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when coadministered with azathioprine. 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.

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 azathioprine and cotrimoxazole.
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 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).

Methotrexate.

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

Vaccines.

The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines and so the administration of live vaccines to patients receiving azathioprine 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 anticapsular specific antibody concentration.

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 coadministration 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.

Miscellaneous.

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

4.6 Fertility, Pregnancy and Lactation

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.
(Category D)
The decision to maintain or discontinue azathioprine during pregnancy, or to terminate the pregnancy, depends on the condition under treatment in which the maternal wellbeing has to be weighed against possible risks to the foetus. As a general rule, azathioprine therapy should not be initiated in patients known to be pregnant.
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 birthweight 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.
The rare possibility of neonatal leucopaenia and/or thrombocytopenia which may not be clinically evident appears to be preventable by reducing maternal dosage of azathioprine if, at 32 weeks' gestation, the maternal leucocyte count is at or below 8.6 x 109 per litre. The possibility of neonatal immunosuppression is a serious and potentially fatal complication.
Extra care in haematological monitoring is advised during pregnancy.

6-Mercaptopurine has been identified in the colostrum and breast milk of 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.

4.8 Adverse Effects (Undesirable Effects)

Hypersensitivity reactions.

Several different clinical syndromes, which appear to be of an idiosyncratic hypersensitivity nature, have been described occasionally. They include general malaise, headache, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, vasculitis, myalgia, muscular pains, arthralgia, hypotension, disturbed liver function, cholestatic jaundice, pancreatitis, cardiac dysrhythmia, and renal dysfunction. In many cases, rechallenge has confirmed an association with azathioprine.
Additional adverse reactions of low frequency have been reported. 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. Immediate withdrawal of azathioprine and supportive circulatory measures has led to recovery in the majority of cases. Other marked underlying pathology has contributed to the very rare deaths reported.
Azathioprine should be permanently withdrawn after any such clinical syndrome.

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

The risk of developing lymphomas and other malignancies, notably skin cancers 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 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).
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).

Haematopoiesis.

Azathioprine 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 azathioprine when receiving concurrent allopurinol therapy.
Therapeutic use of azathioprine is associated with a 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 which 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, cytomegalovirus (CMV) and other infectious agents. 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 azathioprine therapy. 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 and appear to relate to high dosage of corticosteroids rather than to azathioprine per se.
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 drug 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 drug, 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 Section 4.8 Adverse Effects (Undesirable Effects), Hypersensitivity reactions).
Hepatotoxicity may manifest by elevation of serum alkaline phosphatase, bilirubin and/or serum transaminases and is generally reversible after interruption of azathioprine. Periodic measurement of serum transaminases, alkaline phosphatase and bilirubin is indicated for early detection of hepatotoxicity. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients.
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. Azathioprine should be permanently withdrawn in patients with hepatic veno-occlusive disease.

Other adverse effects.

Other adverse reactions include sores in the mouth and on the lips, meningitis, formication, acute febrile neutrophilic dermatosis (Sweet's syndrome), exacerbation of myasthenia gravis and dermatomyositis and alterations in the senses of smell or 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 and contact Apotex Medical Information enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.2 Dose and Method of Administration

Azathioprine tablets are intended for oral administration.
Azathioprine tablets should be administered at least 1 hour before or 3 hours after food or milk.
Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.

Dosage in transplantation.

Adults and children.

Depending on the immunosuppressive regimen adopted, a loading dose of up to 5 mg/kg bodyweight/day may be given orally on the first day of therapy.
Maintenance dosage may range from 1 to 4 mg/kg bodyweight/day orally (or intravenously only if oral therapy is not tolerated) 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 risk of graft rejection.

Dosage in other conditions.

Adults and children.

In general, initial dose should be approximately 1.0 mg/kg/day (50 mg to 100 mg), gradually increasing in increments of 0.5 mg/kg/day over several weeks, if necessary up to a maximum dose 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 three months, consideration should be given to withdrawing azathioprine.
The maintenance dosage required may range from less than 1 mg/kg bodyweight/day, to 3 mg/kg bodyweight/day depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Use in the elderly (see Section 4.4 Special Warnings and Precautions for Use, Use in hepatic impairment).

The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate plasma drug levels to toxicity. There are no specific data as to the tolerance of azathioprine in elderly patient. It is recommended that the dosages used are 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 impairment.

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.

4.9 Overdose

Signs.

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 9-14 days. These signs are more likely to be manifest following chronic overdosage, rather than after a single acute overdose. Occasional reports describe ingestion of from 0.5-7.5 g azathioprine on a single occasion with apparent uneventful recovery.

Treatment.

Treatment is symptomatic and 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, microcrystalline cellulose, maize starch, magnesium stearate, purified water.
In addition, the 25 mg tablet also contains Opadry complete film coating system 03b52231 yellow, and the 50 mg tablet contains Opadry clear YS-1R-7006.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

APO-Azathioprine 25 mg tablets.

Blister pack (PVC/PVDC/Al) containing 100's (AUST R 205759).

APO-Azathioprine 50 mg tablets.

Blister pack (PVC/PVDC/Al) containing 100's (AUST R 205762).

6.6 Special Precautions for Disposal

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

Summary Table of Changes