Consumer medicine information

AZATHIOPRINE AN TABLETS

Azathioprine

BRAND INFORMATION

Brand name

Azathioprine AN Tablets

Active ingredient

Azathioprine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using AZATHIOPRINE AN TABLETS.

What is in this leaflet

This leaflet answers some of the common questions about Azathioprine AN.

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 taking Azathioprine AN against the benefits the medicine is expected to have for you.

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

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

What Azathioprine AN is used for

Azathioprine AN tablets contain azathioprine. This belongs to a group of medicines called immunosuppressants which work by reducing the body’s own natural immunity.

Azathioprine AN tablets are used to treat patients who have received an organ transplant to help prevent their body from rejecting the transplanted organs (eg. a heart or kidney). It works by suppressing the body’s immune defence system.

Azathioprine AN tablets are also used to suppress the body’s immunity to treat “autoimmune” conditions where your immune system is acting against your body. These may include:

  • severe rheumatoid arthritis systemic lupus erythematosus chronic active hepatitis
  • certain skin, muscle and blood diseases.

Azathioprine AN is usually taken in combination with other immunosuppressive drugs.

Azathioprine AN tablets may also be used to treat other conditions as determined by your doctor.

Ask your doctor if you have any questions about why Azathioprine AN has been prescribed for you.

Your doctor may have prescribed it for another purpose.

Azathioprine AN is a very powerful medicine. Never let anyone else take your medicine even if his or her condition seems similar to yours.

Have regular check ups with your doctor.

Azathioprine AN tablets are not addictive.

Before you take Azathioprine AN

When you must not take it

  • If you are female and you are pregnant or there is a chance that you may become pregnant; or if you are male and there is a chance that you may father a child.
    Azathioprine is not recommended during pregnancy. It may cause birth defects if either the male or female are using it at the time of conception.
    Your partner should take adequate contraceptive precautions while you are taking Azathioprine AN.
  • If you are breastfeeding or are planning to breastfeed.
    Azathioprine passes into breast milk and may cause serious side effects to your baby.
  • If you are taking any other medicines or drugs.
  • If you have ever had an allergy to Azathioprine AN or any of its ingredients (listed at the end of this leaflet), or to another immunosuppressant medicine (eg. 6-mercaptopurine).
    Symptoms of an allergic reaction may be mild or severe. Signs if you are suffering an allergic reaction usually include some of the following:
    wheezing, swelling of the face, lips / mouth and other parts of the body, difficulty in breathing, hayfever, lumpy rash (hives) itching or fainting.
  • If you have rheumatoid arthritis which has previously been treated with an alkylating agent (eg. chlorambucil, melphalan or cyclophosphamide).
  • If you take Azathioprine AN after the expiry date (EXP.) printed on the pack. If you take Azathioprine AN after the expiry date has passed, it may not work as well.
  • Do not take Azathioprine AN if the packaging is torn or shows signs of tampering.

Do not take this medicine to treat any other complaints unless your doctor has instructed you to do so.

If you're not sure whether you should be taking Azathioprine AN, talk to your doctor.

All of these factors need to be taken into consideration by your doctor when he/she considers the most appropriate dose for you.

Before you start to take it

Tell your doctor if you:

  • Are allergic to foods, dyes, preservatives or any other medicines.
  • Have any other medical conditions.
  • Have liver or kidney disease.
  • A condition where your body produces too little of a natural chemical called thiopurine methyltransferase (TPMT).
  • Lesh-Nyhan Syndrome
  • Have been or are considering being vaccinated.
  • Have been exposed to chickenpox or herpes zoster or have never had chickenpox or herpes zoster.
  • Hepatitis-B
  • Are currently having or are considering dental treatment.

Tell your doctor if you have recently been vaccinated or immunised or plan to do so.

Azathioprine may affect the way the vaccine works or your reaction to the vaccine.

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 AN.

Tell your doctor if you are breastfeeding or planning to breastfeed.

Azathioprine is not recommended while breast feeding as it may cause serious side effects to your baby.

Tell your dentist that you are taking Azathioprine AN.

Dental work, whenever possible, should be completed before you start taking Azathioprine or delayed until your blood cell counts are normal.

Taking other medicines

If you are taking other medicines you must tell your doctor. This includes medicines that you can buy without a prescription from a pharmacy, supermarket or a health food shop.

Some medicines may interfere with Azathioprine. These include:

  • penicillamine, used mainly in the treatment of rheumatoid arthritis
  • captopril, used mainly to treat high blood pressure and heart failure
  • cimetidine, used to treat stomach ulcers and indigestion
  • indomethacin, used as a painkiller and anti-inflammatory
  • co-trimoxazole, used to treat infections
  • allopurinol, oxipurinol or thiopurinol, used mainly to treat gout
  • tubocurarine, 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 mainly to treat ulcerative colitis
  • phenytoin, phenobarbital, rifampicin, ketoconazole, erythromycin
  • methotrexate, used in the treatment of cancer
  • ribavirin, used to treat a type of respiratory infection.

These medicines may be affected by Azathioprine or may affect how well it works. You may need to take different amounts of your medicine or you may need to take different medicines.

Some medicines are affected by others. Your doctor or pharmacist will be able to tell you what you should do when you have to take other medicines while you are on Azathioprine AN.

Use in children

Azathioprine AN tablets may be used in children. Your doctor will advise the dose to use for children.

How to take Azathioprine AN

How much to take

Use Azathioprine AN tablets only as directed by your doctor.

Your doctor has carefully determined your dose of Azathioprine AN. Your dose of Azathioprine AN is determined by the condition being treated, your body weight and any other medical conditions that you may have. Do not alter the amount you are taking or change your treatment regime unless directed to do so by your doctor.

From time to time, while you are taking Azathioprine, your doctor will want you to have a blood test. This is to check your blood cell count and to change your dose if necessary.

How to take it

Azathioprine AN tablets should only be taken orally.

Swallow Azathioprine AN tablets with a glass of water. Do not crush or chew the tablets.

When to take it

Take Azathioprine AN tablets at least 1 hour before or 3 hours after food or milk.

Take Azathioprine AN at the same time every day.

Keeping a regular time for taking Azathioprine AN will help to remind you to take them.

Azathioprine AN tablets may sometimes cause mild nausea and vomiting.

How long to take it

Do not stop taking Azathioprine AN tablets without first checking with your doctor.

Your doctor will discuss with you how long you need to take Azathioprine AN tablets. You could have to take Azathioprine AN for some weeks or months before you will be able to receive the full effects.

Patients that are taking Azathioprine AN tablets because they have had an organ transplant will need to take Azathioprine AN continuously to reduce the risk of the body rejecting the transplanted organ.

If you forget to take it

If it is almost time for 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 Azathioprine AN as you would normally.

Never take a double dose to make up for the dose that you missed.

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

Do not use Azathioprine AN tablets if the blister foil is broken or shows signs of tampering.

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (13 11 26) if you think that you or anyone else may have taken too many Azathioprine AN tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical treatment.

While you are taking Azathioprine AN

Things you must do

Take Azathioprine AN exactly as your doctor has prescribed.

You should always tell your doctor about any other medicines that you take, even if you have bought the medicines, vitamins or herbal products without a doctor’s prescription.

Some medicines can affect the way Azathioprine AN works.

It is especially important that you tell your doctor if you are taking any of the following:

  • Allopurinol (eg. ZYLOPRIM™) - may reduce the removal of azathioprine from your body
  • Corticosteroids (cortisone like medicines) these may be prescribed by your doctor to increase the effects of Azathioprine AN
  • Cytotoxic medicines (eg. mercaptopurine, chlorambucil, cyclosporin, cyclophosphamide)
  • Warfarin (eg. Coumadin and Marevan). Azathioprine inhibits the anticoagulant effect of warfarin.

Make regular visits to your doctor to ensure that Azathioprine AN tablets are working properly for you and that you are not suffering any unwanted side effects.

Your doctor may take regular blood tests to check how you are reacting to Azathioprine AN tablets.

If you have to have or are planning to have an operation, tell your surgeon and anaesthetist that you are taking Azathioprine AN tablets.

Tell any other doctor, dentist or pharmacist who is treating you that you are taking Azathioprine especially if you are about to be started on any new medicines.

Tell your doctor if you have recently been vaccinated or immunised or plan to do so.

Azathioprine AN may affect the way some vaccines work or your reaction to the vaccine.

Azathioprine AN tablets suppress your immune system, lowering your body’s immune defence system. This increases your risk of infection, skin cancer and other cancers while taking Azathioprine AN.

Always protect yourself from the sun, wear sunscreen, a hat and protective clothing.

Tell your doctor:

  • If you become pregnant or you are trying to become pregnant or you are planning to father a child.
  • If you plan to have any vaccinations or immunisations.
  • If you have come into contact with an infected person with chickenpox or herpes zoster.
  • If you notice any new moles or changes in existing moles.
  • If you notice any lumps on your body or if you feel unwell.

Avoid contact with anyone suffering from chickenpox or shingles.

Infection with chickenpox or shingles can become severe in patients taking drugs such as azathioprine.

Things you must not do

Do not:

  • Stop taking Azathioprine AN tablets or change the dose without first checking with your doctor.
  • Give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Have any immunisations without your doctor’s approval. Avoid contact with any person in your household who has had an oral polio vaccine recently. Try to avoid contact with people who have infectious diseases (such as the flu, chickenpox or herpes zoster)
  • Participate in contact sports or other situations where bruising or injury may occur. Be careful to avoid cutting yourself with sharp objects (eg. razors).

Things to be careful of

Be careful driving or operating machinery until you know how Azathioprine AN affects you.

Azathioprine AN generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, Azathioprine AN tablets may cause headache or dizziness in some people.

Side Effects

Check with your doctor if you experience any problems while taking Azathioprine AN even if you do not think that the problems you are having have anything to do with you taking Azathioprine AN tablets.

Your doctor will have assessed the risk of possible side effects against the importance of you taking this medication.

Some side effects may have signs or symptoms that you can see or feel. Your doctor will watch for other side effects by performing certain tests.

Ensure that you have regular check ups with your doctor.

Side effects commonly found in patients who have received an organ transplant are:

  • viral, fungal and bacterial infections that include the skin
  • hair loss (common in kidney transplant patients)
  • stomach pain with vomiting and fever
  • diarrhoea, usually with blood and mucus
  • sores in the mouth and on the lips
  • feeling of pins and needles
  • change in sense of smell or taste
  • skin rash, skin peeling and sores on the mucous membranes
  • tiredness and generally feeling unwell.

Tell the doctor immediately if you notice any of the following:

  • any infection, or fever
  • unexpected bruising or bleeding, black tarry stools or blood in the urine or stools
  • new marks on skin or any change to marks that may have been there previously
  • headache, stiff neck and extreme sensitivity to bright light
  • muscle pain or stiffness
  • severe joint pain
  • coughing, difficulty in breathing and wheezing
  • muscle weakness, with or without skin rash
  • irregular heart beat
  • yellow discolouration of the skin and eyes
  • severe abdominal pain
  • nausea, vomiting, diarrhoea
  • dizziness or feeling faint
  • sores in the mouth and on the lips
  • feeling of pins and needles
  • change in sense of smell or taste
  • you come into contact with anyone who is suffering from chickenpox or shingles.

Azathioprine AN could cause your hepatitis B to become active again.

Immediately contact your doctor or go to the casualty department at your nearest hospital if you observe any of the following symptoms:

  • allergic type reactions eg. skin rash, itching and difficulty breathing, wheezing or coughing
  • muscle weakness, with or without a skin rash
  • muscle 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

This is not a complete list of possible side effects. You may react in a different way.

Contact your Doctor or Pharmacist if you notice anything else that is making you feel unwell, even if you think the problems are not connected with this medicine and are not on this list.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

After taking Azathioprine AN

Storage

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

If you take the tablets out of the blister strip they may not keep as well.

Keep Azathioprine AN tablets in a cool dry place where the temperature stays below 30°C.

Do not leave or store Azathioprine AN tablets in the bathroom, near a sink or stove, on a windowsill or in a car.

Heat and dampness can destroy some medicines.

Keep Azathioprine AN tablets where children cannot reach them.

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

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.

Disposal

Tell your doctor if you stop taking the tablets or the tablets have passed their expiry date. Ask your pharmacist what to do with any tablets which are left over.

Product description

What Azathioprine AN looks like

Azathioprine AN 25 mg - peach coloured film coated tablet, embossed AZA, break line 25 on one face, the other face plain (AUST R 184935).
Azathioprine AN 50 mg - yellow film coated tablet, embossed AZA, break line 50 on one face, the other face plain (AUST R 184936).

Ingredients

Active ingredient:
Azathioprine

Other ingredients (excipients):

  • Cellulose microcrystalline,
  • mannitol,
  • povidone,
  • maize starch,
  • croscarmellose sodium,
  • sodium stearylfumarate in the tablet core.

The 50 mg tablet coating contains Opadry clear OY- 7240 (macrogol 400 and hypromellose).

Azathioprine AN tablets do not contain sucrose or gluten.

Name and Address of the Sponsor

Scentia Pharmaceuticals Pty Ltd
8 - 12 Ordish Road,
Dandenong South,
VIC - 3175, Australia

Date of Preparation

29 November 2013

Doc ID: 41.AN.M.1.0

BRAND INFORMATION

Brand name

Azathioprine AN Tablets

Active ingredient

Azathioprine

Schedule

S4

 

Name of the medicine

Azathioprine.

Excipients.

Microcrystalline cellulose, mannitol, maize starch, povidone, croscarmellose sodium, and sodium stearylfumarate in the tablet core. The 25 mg tablet coating contains Opadry pink OY-1315G, Opadry buff OY-3682, and Opadry buff OY-3690. The 50 mg tablet coating contains Opadry clear OY-7240.

Description

Chemical name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. Molecular formula: C9H7N7O2S. MW: 277.3. CAS: 446-86-6. It is a pale yellow powder, which 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.

Pharmacology

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 concentrations of 35S-azathioprine are very low in the brain.

Pharmacokinetics.

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.

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.

Contraindications

The use of Azathioprine AN 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 Azathioprine AN 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 Precautions).

Precautions

Coadministration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine (see Interactions with Other Medicines).

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.
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 Azathioprine-PS. 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 Adverse Effects). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore, close monitoring of blood counts is still necessary.
The dosage of azathioprine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.

Renal and/or hepatic insufficiency.

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 Azathioprine AN to patients with hepatic dysfunction, and regular complete blood counts and liver function tests should be undertaken. In such patients the metabolism of Azathioprine AN may be impaired, and the dosage of Azathioprine AN should therefore be reduced to the lower end of the recommended range. Dosage should be further reduced if hepatic or haematological toxicity occurs.

Lesch-Nyhan syndrome.

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

Carcinogenesis, mutagenesis, impairment of fertility.

Mutagenesis.

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.

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 Azathioprine AN.

Carcinogenicity.

Patients receiving immunosuppressive therapy are at an increased risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and nonmelanoma), 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 overimmunosuppression, 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.

Varicella zoster virus infection (see Adverse 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 Adverse Effects).

Hepatitis B.

(See Adverse Effects.) Hepatitis B carriers (defined a 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.

Use in pregancy

The decision to maintain or discontinue azathioprine treatment during pregnancy, or to terminate the pregnancy, depends on the condition being treated, in which maternal wellbeing 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.
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 after the maternal administration of azathioprine.
The rare possibility of neonatal leucopenia and/or thromobocytopenia 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.

Use in lactation.

6-mercaptopurine has been identified in the colostrums and breastmilk 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.
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.

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.

Interactions

Allopurinol/ oxypurinol/ thiopurinol.

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.

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 Azathioprine AN 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 AN.

Warfarin.

Inhibition of the anticoagulant effect of warfarin, when 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 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 Precautions).

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 AN could result in an atypical and potentially deleterious response to live vaccines and so the administration of live vaccines in patients receiving Azathioprine AN 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.

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, erythomycin) hepatic microsomal enzymes may alter the hepatic clearance of azathioprine.
The coadministration of azathioprine and captopril may result in increased susceptibility to leucopenia.

Adverse 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, rigors, 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 nonmelanoma), 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.

Azathioprine AN 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 AN 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 with varicella, herpes zoster and other infectious agents (see Precautions) and reactivation with VZV, hepatitis B 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 Precautions).

Gastrointestinal.

Nausea, vomiting and gastrointestinal discomfort may occur during the first few months of therapy with azathioprine. This side effect was reported to occur in 12% of patients taking azathioprine for rheumatoid arthritis. These effects may be minimised by dosage adjustment, by administering the tablets in divided doses and/or after food. 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. Cholestasis and deterioration of liver function have occasionally been reported in association with Azathioprine AN therapy and are usually reversible on withdrawal of therapy. This may be associated with symptoms of a hypersensitivity reaction (see Hypersensitivity reactions).

Respiratory.

Reversible pneumonitis has been described very rarely.

Hepatotoxicity.

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. Azathioprine AN should be permanently withdrawn in patients with hepatic veno-occlusive disease.

Other.

Other adverse reactions include sores in the mouth and on the lips, meningitis, formication, exacerbation of myasthenia gravis and dermatomyositis and alterations in the senses of smell and taste.

Dosage and Administration

Azathioprine AN tablets are intended for oral administration only.
Azathioprine tablets should be administered at least 1 hour before or 3 hours after food or milk.

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 per 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 per day, to 3 mg/kg per day depending on the clinical condition being treated and the individual patient response, including haematological tolerance.

Use in the elderly.

(See Precautions, Renal and/or hepatic insufficiency.) 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.

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.

Overdosage

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.
Contact the Poisons Information Centre on 131 126 for advice on the management of overdosage.

Presentation

Tablet (round, film coated, plain on one side), 25 mg* (peach, marked AZA 25, AUST R 184935, PVC/PE/PVDC/ aluminium), 50 mg (pale yellow, biconvex, scored, marked AZA/50, AUST R 184936, PVC/PVDC/ aluminium): 100's (blister pack).
*Not currently marketed in Australia.

Storage

Store below 30°C, protect from light and moisture.

Poison Schedule

S4.