GN-AZATHIOPRINE azathioprine 50mg tablet blister pack

Main information

  • Trade name:
  • GN-AZATHIOPRINE azathioprine 50mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • GN-AZATHIOPRINE azathioprine 50mg tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 184934
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

184934

GN-AZATHIOPRINE azathioprine 50mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Eris Pharmaceuticals (Australia) Pty Ltd

Postal Address

5 / 148 Spit Road,Mosman, NSW, 2088

Australia

ARTG Start Date

5/06/2012

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. GN-AZATHIOPRINE azathioprine 50mg tablet blister pack

Product Type

Single Medicine Product

Effective date

17/11/2014

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific 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 effect may be evident only after weeks or months and can include a

steroid sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids. Azathioprine, in combination

with corticosteroids and/or other immunosuppressive agents and procedures, is indicated in the management of patients receiving organ transplants.

Azathioprine, either alone or more usually in combination with corticosteroids and/or other procedures, has been used with clinical benefit which may

include reduction of dosage or discontinuation of corticosteroids, in a proportion of patients suffering from the following: Severe rheumatoid arthritis,

systemic lupus erythematosus, dermatomyositis/polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa,

autoimmune haemolytic anaemia and chronic refractory idiopathic thrombocytopenic purpura.

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PVC/PVDC/Al

3 Years

Store below 30

degrees Celsius

Not recorded

Protect from Light

Protect from Moisture

Pack Size/Poison information

Pack Size

Poison Schedule

100 tablets

(S4) Prescription Only Medicine

Components

1.

Dosage Form

Tablet, film coated

Route of Administration

Oral

Visual Identification

A Light yellow, circular, biconvex tablet engraved "AZA" breakline "50" on

one side and plain on the other side.

Active Ingredients

Azathioprine

50 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 03:57:29 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

Page 1 of 11

PRODUCT INFORMATION

GN-AZATHIOPRINE

25 mg & 50 mg

Tablets

NAME OF THE MEDICINE

The active ingredient in GN-AZATHIOPRINE is azathioprine.

Chemical structure:

Chemical formula:C

CAS no.: 446-86-6

Chemical name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-7H-purine.

Molecular weight: 277.3.

DESCRIPTION

Azathioprine is a pale yellow powder. It is practically insoluble in water or ethanol (96%). It is

soluble in dilute solutions of alkali hydroxides and sparingly soluble in dilute mineral acids.

GN-AZATHIOPRINE tablets also contain the following ingredients: microcrystalline

cellulose, croscarmellose sodium, mannitol, povidone, sodium stearylfumarate, maize

starch and

25 mg only: Opadry Buff OY-3682, Opadry Buff OY-3690 and Opadry OY-1315G.

50 mg only: Opadry clear OY-7240.

PHARMACOLOGY

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). It is rapidly broken

down in-vivo into 6-MP and a methylnitro-imidazole 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

Page 2 of 11

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 thio-

analogues.

Because of these mechanisms, the therapeutic effect of azathioprine may be evident only

after several weeks or months of treatment.

Studies in mice with

S-azathioprine showed no unusually large concentration in any

particular tissue although concentrations of

S-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;

Page 3 of 11

dermatomyositis/polymyositis;

autoimmune chronic active hepatitis;

pemphigus vulgaris;

polyarteritis nodosa;

autoimmune haemolytic anaemia; and

chronic refractory idiopathic thrombocytopenic purpura.

CONTRAINDICATIONS

The use of azathioprine 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 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

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.

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 co-existent 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.

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. This problem could be exacerbated by

coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or

sulfasalazine. 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.

Page 4 of 11

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 to patients with hepatic

dysfunction, and regular complete blood counts and liver function tests should be

undertaken. In such patients the metabolism of azathioprine may be impaired, and the

dosage of azathioprine should therefore be reduced to the lower end of the

recommended range. Dosage should be further reduced if hepatic or haematological

toxicity occurs.

Limited evidence suggests that azathioprine is not beneficial to patients with hypoxanthine

– guanine – phosphoribosyltransferase deficiency (Lesch – Nyhan syndrome). Therefore,

given the abnormal metabolism in these patents, it is not prudent to recommend that these

patients should receive azathioprine.

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.

Carcinogenicity

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.

Page 5 of 11

Patients receiving multiple immunosuppressive agents may be at risk of over-

immunosuppression, therefore such therapy should be maintained at the lowest effective

level.

As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV

light should be limited, 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):

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.

Use in Pregnancy and Lactation (Pregnancy 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

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 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 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

/L. The possibility of neonatal immunosuppression is a serious and potentially fatal

complication. Extra care in haematological monitoring is advised during pregnancy.

6-Mercaptopurine has been identified in the colostrums and breast-milk of the women

receiving azathioprine treatment. Nursing mothers should be advised to consult their

Page 6 of 11

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 WITH OTHER MEDICINES

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 in-active 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 non-depolarising 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 and co-trimoxazole.

It has been suggested that cimetidine and indomethacin may have myelosuppressive

effects which may be enhanced by concomitant administration of azathioprine.

Warfarin:

Inhibition of the anticoagulant effect of warfarin, when administered with azathioprine, has

been reported.

Aminosalicylates:

As there is in-vitro evidence that aminosalicylate derivatives (e.g. olsalaxine, meslazine or

sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to

patients receiving concurrent azathioprine therapy (see PRECAUTIONS)

Page 7 of 11

Vaccines:

The immunosuppressive activity of azathioprine could result in an atypical and potentially

deleterious response to live vaccines and so the administration of live vaccines in patients

receiving azathioprine therapy is contra-indicated 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.

Other:

Frusemide has been shown to impair the metabolism of azathioprine by human hepatic

tissue in-vitro. The clinical significance is unknown

Medicines known to either induce (phenytoin, phenobarbital, rifampicin) or inhibit

(ketoconazole, erythomycin) hepatic microsomal enzymes may alter the hepatic clearance

of azathioprine.

The co-administration 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 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.

Page 8 of 11

There have been rare reports of acute myeloid leukaemia and myelodysplasia (some in

association with chromosomal abnormalities).

Haematopoiesis:

Azathioprine may be associated with a dose-related, generally reversible, depression of

bone marrow function, most frequently expressed as leucopenia, but also sometimes as

anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic

anaemia. These occur particularly in patients predisposed to myelotoxicity, such as those

with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the

dose of azathioprine when receiving concurrent allopurinol therapy.

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). Viral, fungal and bacterial infections are very

common in transplant patients receiving azathioprine in combination with other

immunosuppressants.

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.

Page 9 of 11

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)

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

than1%) 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 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 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 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.

Page 10 of 11

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.

OVERDOSAGE

The oral LD

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 (in Australia) 13 11 26 for advice on the

management of overdosage.

PRESENTATION AND STORAGE CONDITIONS

GN-AZATHIOPRINE (azathioprine) 25 mg tablets* are a peach coloured, film-coated,

circular, biconvex tablet engraved “AZA 25” on one side and plain on the other side. GN-

AZATHIOPRINE 25 mg tablets are available in blister (PVC/PVDC/Al) packs of 100

tablets (AUST R 184933).

GN-AZATHIOPRINE (azathioprine) 50 mg tablets* are a light yellow, circular, film-coated,

biconvex tablet engraved “AZA”, breakline & “50” on one side and plain on the other side.

GN-AZATHIOPRINE 50 mg tablets are available in blister (PVC/PVDC/Al) packs of 100

tablets (AUST R 184934).

*Some strengths and pack sizes may not be marketed.

Storage conditions:

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

Page 11 of 11

NAME AND ADDRESS OF THE SPONSOR

Eris Pharmaceuticals (Australia) Pty Ltd

6 Eastern Rd

South Melbourne

Victoria 3205, Australia

POISONS SCHEDULE OF THE MEDICINE

S4 (Prescription Only Medicine)

DATE OF FIRST INCLUSION ON THE AUSTRALIAN REGISTER OF THERAPEUTIC

GOODS (The ARTG)

of June 2012

DATE OF MOST RECENT AMENDMENT

of April 2014

Version 2