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25 mg & 50 mg
NAME OF THE MEDICINE
The active ingredient in GN-AZATHIOPRINE is azathioprine.
CAS no.: 446-86-6
Chemical name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-7H-purine.
Molecular weight: 277.3.
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
25 mg only: Opadry Buff OY-3682, Opadry Buff OY-3690 and Opadry OY-1315G.
50 mg only: Opadry clear OY-7240.
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
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several systems it appears to modify the activity of azathioprine as compared with that of
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
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-
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.
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
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.
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
severe rheumatoid arthritis;
systemic lupus erythematosus;
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autoimmune chronic active hepatitis;
autoimmune haemolytic anaemia; and
chronic refractory idiopathic thrombocytopenic purpura.
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
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
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.
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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
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:
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.
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.
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.
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Patients receiving multiple immunosuppressive agents may be at risk of over-
immunosuppression, therefore such therapy should be maintained at the lowest effective
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
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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
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.
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.
Inhibition of the anticoagulant effect of warfarin, when administered with azathioprine, has
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)
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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
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
The co-administration of azathioprine and captopril may result in increased susceptibility to
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
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.
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There have been rare reports of acute myeloid leukaemia and myelodysplasia (some in
association with chromosomal abnormalities).
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.
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
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
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
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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
Reversible pneumonitis has been described very rarely.
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 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.
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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.
The oral LD
for single doses of azathioprine in mice and rats is 2500 mg/kg and 400
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
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.
Store below 30°C, protect from light and moisture.
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NAME AND ADDRESS OF THE SPONSOR
Eris Pharmaceuticals (Australia) Pty Ltd
6 Eastern Rd
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