Consumer medicine information

Azapin

Azathioprine

BRAND INFORMATION

Brand name

Azapin

Active ingredient

Azathioprine

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Azapin.

What is in this leaflet

This leaflet answers some of the common questions about AZAPIN. 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 AZAPIN 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 AZAPIN is used for

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

AZAPIN tablets are used to treat patients who have received an organ transplant to help prevent their body from rejecting the transplanted organs (e.g. a heart or kidney).

This medicine is also used to suppress the body’s immunity to treat “autoimmune” conditions like rheumatoid arthritis, and SLE (systemic lupus erythematosus).

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

AZAPIN 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.

Before you take it

When you must not take it

Do not take AZAPIN if you have ever had an allergic reaction to:

  • azathioprine
  • 6-mercaptopurine (Puri-Nethol), a medicine which is similar to AZAPIN
  • any of the ingredients listed at the end of this leaflet.

Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.

Do not take AZAPIN if you are pregnant, may be pregnant, plan to become pregnant or intending to father a child. This medicine may cause birth defects if either the male or female is taking it at the time of conception.

Do not take AZAPIN if you are breastfeeding unless you and your doctor have discussed the risks and benefits involved. It is not recommended for use while breastfeeding as it may cause serious side effects to your baby.

Do not take AZAPIN if you have rheumatoid arthritis that has previously been treated with some other medicines, such as chlorambucil, melphalan or cyclophosphamide.

Do not take AZAPIN after the expiry date printed on the pack. If you take this medicine after the expiry date has passed, it may not work as well

Do not take AZAPIN 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.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Before you start to take it

Tell your doctor if you:

Are allergic to foods, dyes, and preservatives.

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

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

Tell your doctor if you are breastfeeding or planning to breastfeed. AZAPIN is not recommended for use while breastfeeding as it may cause serious side effects to your baby.

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

Taking other medicines

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

Some medicines may interfere with AZAPIN. 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 AZAPIN 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.

Your doctor or pharmacist has a more complete list of medicines to avoid while taking AZAPIN

How to take it

How much to take

Use AZAPIN tablets only as directed by your doctor.

Your dose 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.

How to take it

AZAPIN tablets should only be taken orally.

Swallow your tablets whole with a glass of water. Do not crush or chew the tablets

When to take it

AZAPIN tablets may sometimes cause mild nausea and vomiting. Take your medicine after food or at bedtime to minimise stomach upset.

How long to take it for

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

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

Patients that are taking AZAPIN because they have had an organ transplant will need to take it 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 AZAPIN 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 AZAPIN tablets if the blister foil is broken or show 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 AZAPIN tablets. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical treatment.

While you are using it

Things you must do

Take AZAPIN exactly as your doctor has prescribed.

Your doctor may order regular blood tests while you are taking this medicine to check how it affects you. The frequency of your blood tests will usually decrease the longer you continue to take AZAPIN.

Tell any other doctor, dentist or pharmacist who is treating you that you are taking AZAPIN, 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. AZAPIN may affect the way some vaccines work or your reaction to the vaccine.

Tell your doctor if you become pregnant, are trying to become pregnant or planning to father a child.

If you have to have an operation, tell your surgeon and anaesthetist that you are taking AZAPIN.

Tell your doctor immediately if you notice new moles, changes in existing moles, any lumps on your body or you feel unwell.

Immunosuppressant drugs, like AZAPIN, lower the body's immune defence system. There may be an increased risk of developing infections or tumours, including skin cancer, whilst taking this medicine.

Protect yourself from the sun while you are taking AZAPIN. If you go out in the sun, wear a hat, protective clothing and use sunscreen.

Avoid contact with anyone suffering from chickenpox or shingles. Infection with chickenpox or shingles can become severe in patients taking drugs such as AZAPIN

Things you must not do

Do not:

  • Stop taking AZAPIN 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 doctors approval. Avoid contact with any person in your household who has an oral polio vaccine recently. Try to avoid contact with people who have infectious diseases (such as the ‘flu).
  • 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 AZAPIN affects you. This medicine generally does not cause any problems with your ability to drive a car or operate machinery. However, as with many other medicines, AZAPIN tablets may cause headache or dizziness in some people.

Side Effects

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

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

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

Tell your 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
  • nausea and vomiting
  • tiredness, dizziness or generally unwell
  • irregular heart beat
  • you come into contact with anyone who is suffering from chickenpox or shingles
  • sores in the mouth and on the lips
  • feeling of ants creeping in or under the skin
  • change in sense of smell or taste.

AZAPIN could cause your hepatitis B to become active again.

Tell your doctor immediately, or go to Accident and Emergency at your nearest hospital if you notice any of the following symptoms:

  • allergic type reactions e.g. 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.

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.

Tell your doctor 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 referred to in this leaflet. Other side effects not listed above may also occur in some people.

Do not be alarmed by this list of possible side-effects. You may not experience any of them.

After using it

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 AZAPIN tablets in a cool dry place where the temperature stays below 30°C.

Do not leave or store AZAPIN tablets in the bathroom, near a sink or stove, on a windowsill or in a car. Heat and dampness can destroy some medicines.

Keep AZAPIN 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 AZAPIN tablets look like

AZAPIN 50 mg – yellow film coated tablet, embossed AZA, break line 50 on one face, the other face plain.

Ingredients

Active ingredient
Azathioprine.

Other ingredients (excipients)
Cellulose microcrystalline, mannitol, povidone, maize starch, croscarmellose sodium, sodium stearylfumarate and Opadry clear OY-7240 (macrogol 400 and hypromellose).

AZAPIN tablets do not contain sucrose or gluten.

SPONSOR

Arrotex Pharmaceuticals Pty Ltd
15 – 17 Chapel street
Cremorne VIC 3121

AZAPIN 50 mg tablets AUST R 92801

Date of preparation: December 2022

Published by MIMS February 2023

BRAND INFORMATION

Brand name

Azapin

Active ingredient

Azathioprine

Schedule

S4

 

1 Name of Medicine

Azathioprine.

2 Qualitative and Quantitative Composition

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

3 Pharmaceutical Form

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

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Azapin tablets are intended for oral administration only.

Transplantation - adults and children.

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

Other conditions - adults and children.

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

Use in the elderly.

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

Renal/hepatic impairment.

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

4.3 Contraindications

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

4.4 Special Warnings and Precautions for Use

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

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

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

Monitoring.

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

TPMT testing.

There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initial treatment with Azapin. There have been fatal cases of myelosuppression in patients with low or absent TPMT activity treated with thiopurines. This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulfasalazine. Also, a possible association between decreased TPMT activity and secondary leukaemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics (see Section 4.8 Adverse Effects (Undesirable Effects)).
Patients should be tested for TPMT activity before starting Imuran. TPMT testing cannot substitute for complete blood count monitoring in patients receiving Imuran. TPMT genotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity (homozygous for non-functional alleles) are at an increased risk of developing severe, life-threatening myelotoxicity from Imuran if conventional doses are given. Alternative therapies may be considered for patients who have low or absent TPMT activity. Imuran should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. The dosage of azathioprine may need to be reduced when this agent is combined with other drugs whose primary or secondary toxicity is myelosuppression.
TPMT testing is widely available through pathology laboratories and genetic testing services.

NUDT15 testing.

Patients with inherited mutated NUDT15 gene are at increased risk for severe thiopurine toxicity, such as early leukopenia and alopecia, from conventional doses of thiopurine therapy and generally require substantial dose reduction. The precise mechanism of NUDT15-associated thiopurine related toxicity is not understood. Patients of Asian ethnicity are particularly at risk, due to the increased frequency of the mutation in this population. The optimal starting dose for heterozygous or homozygous deficient patients has not been established. Close monitoring of blood count is necessary.
Genotypic and phenotypic testing of NUDT15 variants should be considered before initiating thiopurine therapy in all patients (including paediatric patients) to reduce the risk of thiopurine related severe leukocytopenia and alopecia, especially in Asian populations.

Lesch-Nyhan syndrome.

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

Use in hepatic or renal impairment.

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

Carcinogenicity.

Patients receiving immunosuppressive therapy, including azathioprine, are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder. A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV) associated lymphoproliferative disorders.

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

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

Progressive multifocal leukoencephalopathy (PML).

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

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

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

Macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a known life threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD) and there could potentially be an increased susceptibility for developing the condition with the use of azathioprine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

Metabolism and nutrition disorders.

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

Other precautions.

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

Hypersensitivity.

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

Use in the elderly.

See Section 4.2 Dose and Method of Administration.

Paediatric use.

See Section 4.2 Dose and Method of Administration.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Allopurinol/oxypurinol/thiopurinol and other xanthine oxidase inhibitors.

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

Neuromuscular blocking agents.

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

Cytostatic/myelosuppressive agents.

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

Anticoagulants.

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

Aminosalicylates.

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

Vaccines.

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

Methotrexate.

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

Ribavirin.

Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore co-administration is not advised.

Infliximab.

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

Other.

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

4.6 Fertility, Pregnancy and Lactation

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

Teratogenicity.

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

Effects on fertility.

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

4.7 Effects on Ability to Drive and Use Machines

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

4.8 Adverse Effects (Undesirable Effects)

Hypersensitivity reactions.

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

Neoplasms benign and malignant (including cysts and polyps).

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

Haematopoiesis.

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

Alopecia.

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

Susceptibility to infection.

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

Gastrointestinal reactions.

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

Pulmonary reactions.

Reversible pneumonitis has been described very rarely.

Hepatotoxicity.

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

Immune system disorders.

Erythema nodosum.

Other adverse effects.

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

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

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

Symptoms.

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

Treatment.

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

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

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

Distribution.

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

Metabolism.

No data available.

Excretion.

No data available.

5.3 Preclinical Safety Data

Genotoxicity.

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

Carcinogenicity.

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

6 Pharmaceutical Particulars

6.1 List of Excipients

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

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 30°C. Protect from light and moisture.

Safe handling of azathioprine tablets.

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

6.5 Nature and Contents of Container

Azapin tablets are available in blister packs of 100 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). Its chemical name is 6-[(1-methyl-4-nitro-1H-imidazol-5-yl) sulfanyl]-7H-purine.
Structurally it is represented as:
Molecular Weight: 277.3.
Molecular Formula: C9H7N7O2S.

CAS number.

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

7 Medicine Schedule (Poisons Standard)

Prescription Medicine (S4).

Summary Table of Changes