IMURAN 50MG TABLETS

Active substance: AZATHIOPRINE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Imuran Tablets 50mg

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Yellow, round, biconvex, scored, film-coated tablets, impressed ‘GX CH1’
and containing 50 mg Azathioprine BP in each tablet.

3

PHARMACEUTICAL FORM
Tablet.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Imuran tablets are used as an immunosuppressant antimetabolite either alone
or, more commonly, in combination with other agents (usually corticosteroids)
and procedures which influence the immune response. Therapeutic effect may
be evident only after weeks or months and can include a steroid-sparing effect,
thereby reducing the toxicity associated with high dosage and prolonged usage
of corticosteroids.
Imuran, in combination with corticosteroids and/or other immunosuppressive
agents and procedures, is indicated to enhance the survival of organ
transplants, such as renal transplants, cardiac transplants, and hepatic
transplants; and to reduce the corticosteroid requirements of renal transplant
recipients.
Imuran, either alone or more usually in combination with corticosteroids
and/or other drugs and 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 and polymyositis;
Auto-immune chronic active hepatitis;
Pemphigus vulgaris;
Polyarteritis nodosa;
Auto-immune haemolytic anaemia;
Chronic refractory idiopathic thrombocytopenic purpura.

4.2

Posology and method of administration
Route of administration: oral.
Transplantation - adults and children
Depending on the immunosuppressive regimen employed, a dosage of up to 5
mg/kg bodyweight/day may be given on the first day of therapy, either orally
or intravenously.
Maintenance dosage should range from 1 to 4 mg/kg bodyweight/day and
must be adjusted according to clinical requirements and haematological
tolerance.
Evidence indicates that Imuran therapy should be maintained indefinitely,
even if only low doses are necessary, because of the risk of graft rejection.
Dosage in other conditions - adults and children
In general, starting dosage is from 1 to 3 mg/kg bodyweight/day, and should
be adjusted, within these limits, depending on the clinical response (which
may not be evident for weeks or months) and haematological tolerance.
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
Imuran.
The maintenance dosage required may range from less than 1 mg/kg
bodyweight/day to 3 mg/kg bodyweight/day, depending on the clinical

condition being treated and the individual patient response, including
haematological tolerance.
In patients with renal and/or hepatic insufficiency, dosages should be given at
the lower end of the normal range (see Special Warnings and Precautions for
Use for further details).
Use in the elderly (see Renal and/or hepatic insufficiency)
There is limited experience of the administration of Imuran to elderly patients.
Although the available data do not provide evidence that the incidence of side
effects among elderly patients is higher than that among other patients treated
with Imuran, it is recommended that the dosages used should be at the lower
end of the range.
Particular care should be taken to monitor haematological response and to
reduce the maintenance dosage to the minimum required for clinical response.

4.3

Contraindications
Imuran is contra-indicated in patients known to be hypersensitive to
azathioprine. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the
prescriber to probable hypersensitivity to Imuran.
Imuran therapy should not be initiated in patients who may be pregnant, or
who are likely to become pregnant without careful assessment of risk versus
benefit (see Special Warnings and Precautions for Use & Pregnancy and
Lactation).

4.4

Special warnings and precautions for use
Monitoring
There are potential hazards in the use of Imuran. It should be prescribed only
if the patient can be adequately monitored for toxic effects throughout the
duration of therapy.
It is suggested that during the first 8 weeks of therapy, complete blood counts,
including platelets, should be performed weekly or more frequently if high
dosage is used or if severe renal and/or hepatic disorder is present. The blood
count frequency may be reduced later in therapy, but it is suggested that
complete blood counts are repeated monthly, or at least at intervals of not
longer than 3 months.

Patients receiving Imuran should be instructed to report immediately any
evidence of infection, unexpected bruising or bleeding 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 initiation of treatment with Imuran. This
problem could be exacerbated by co-administration with drugs that inhibit
TPMT, such as olsalazine, mesalazine or sulfasalazine. Also it has been
reported that decreased TPMT activity increases the risk of secondary
leukaemias and myelodysplasia in individuals receiving 6-mercaptopurine (the
active metabolite of azathioprine) in combination with other cytotoxics (see
section 4.8 Undesirable effects).
Renal and/or hepatic insufficiency
It has been suggested that the toxicity of Imuran may be enhanced in the
presence of renal insufficiency, but controlled studies have not supported this
suggestion. Nevertheless, it is recommended that the dosages used should be
at the lower end of the normal range and that haematological response should
be carefully monitored. Dosage should be further reduced if haematological
toxicity occurs.
Caution is necessary during the administration of Imuran to patients with
hepatic dysfunction, and regular complete blood counts and liver function tests
should be undertaken. In such patients the metabolism of Imuran may be
impaired, and the dosage of Imuran should therefore be reduced if hepatic or
haematological toxicity occurs.
Limited evidence suggests that Imuran 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 Imuran.
Mutagenicity
Chromosomal abnormalities have been demonstrated in both male and female
patients treated with Imuran. It is difficult to assess the role of Imuran in the
development of these abnormalities.
Effects on fertility
Relief of chronic renal insufficiency by renal transplantation involving the
administration of Imuran has been accompanied by increased fertility in both
male and female transplant recipients.
Carcinogenicity (see also section 4.8 Undesirable Effects)

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 nonKaposi’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. It has been reported that reduction or discontinuation of
immunosuppression may be associated with partial or complete regression of
non-Hodgkin’s lymphomas and Kaposi’s sarcomas.
Patients receiving multiple immunosuppressive agents may be at risk of overimmunosuppression, therefore such therapy should be maintained at the lowest
effective level.
Exposure to sunlight and UV light should be limited and patients should wear
protective clothing and use a sunscreen with a high protection factor to
minimize the risk of skin cancer and photosensitivity (see also section 4.8
Undesirable Effects).
Varicella Zoster Virus Infection (see also section 4.8 Undesirable 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.

4.5

Interaction with other medicinal products and other forms of interaction
Allopurinol/oxipurinol/thiopurinol
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and
thiopurinol which results in reduced conversion of biologically active 6thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol,
oxipurinol 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:

Imuran can potentiate the neuromuscular blockade produced by depolarising
agents such as succinylcholine and can reduce the blockade produced by nondepolarising agents such as tubocurarine. There is considerable variation in
the potency of this interaction.
Warfarin
Inhibition of the anticoagulant effect of warfarin, when administered with
azathioprine, has been reported.
Cytostatic/myelosuppressive 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 Imuran and co-trimoxazole.
There has been a case report suggesting that haematological abnormalities
may develop due to the concomitant administration of Imuran and captopril.
It has been suggested that cimetidine and indomethacin may have
myelosuppressive effects, which may be enhanced by concomitant
administration of Imuran.
Other interactions
As there is in vitro evidence that aminosalicyclate derivatives(eg. olsalazine,
mesalazine or sulphasalazine) inhibit the TPMT enzyme, they should be
administered with caution to patients receiving concurrent Imuran therapy (see
4.4 Special Warning and Special Precautions for Use).
Frusemide has been shown to impair the metabolism of azathioprine by human
hepatic tissue in vitro. The clinical significance is unknown.
Vaccines
The immunosuppressive activity of Imuran could result in an atypical and
potentially deleterious response to live vaccines and so the administration of
live vaccines to patients receiving Imuran 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.
A small clinical study has indicated that standard therapeutic doses of Imuran
do not deleteriously affect the response to polyvalent pneumococcal vaccine,
as assessed on the basis of mean anti-capsular specific antibody concentration.

4.6

Fertility, Pregnancy and lactation
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 fetal abnormalities. Teratogenicity was evident in rabbits
at 10 mg/kg bodyweight/day.
Evidence of the teratogenicity of Imuran in man is equivocal. As with all
cytotoxic chemotherapy, adequate contraceptive precautions should be advised
when either partner is receiving Imuran.
Mutagenicity
Chromosomal abnormalities, which disappear with time, have been
demonstrated in lymphocytes from the offspring of patients treated with
Imuran. Except in extremely rare cases, no overt physical evidence of
abnormality has been observed in the offspring of patients treated with
Imuran. 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.
Use in Pregnancy and Lactation
Imuran should not be given to patients who are pregnant or likely to become
pregnant without careful assessment of risk versus benefit.
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 maternal administration of azathioprine.
Leucopenia and/or thrombocytopenia have been reported in a proportion of
neonates whose mothers took azathioprine throughout their pregnancies.
Extra care in haematological monitoring is advised during pregnancy.
Lactation
6-Mercaptopurine has been identified in the colostrum and breast-milk of
women receiving azathioprine treatment.

4.7

Effects on ability to drive and use machines

None known.

4.8

Undesirable effects
For this product there is no modern clinical documentation that can be used as
support for determining the frequency of undesirable effects. Undesirable
effects may vary in their incidence depending on the indication. The
following convention has been utilised for the classification of frequency:
Very common, ≥ 1/10; common, ≥ 1/100 and < 1/10; uncommon, ≥ 1/1000
and < 1/100; rare, ≥ 1/10000 and < 1/1000; very rare, < 1/10000.
Infection and infestations
Transplant patients receiving Imuran in combination with other
immunosuppressants.
Very common:

Viral, fungal and bacterial infections.

Other indications.
Uncommon:

Viral, fungal and bacterial infections.

Patients receiving Imuran alone, or in combination with other
immunosupressants, 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
also section 4.4 Special Warnings and Precautions for Use).
Neoplasms benign and malignant (including cysts and polyps)
Rare: Neoplasms including non-Hodgkin’s lymphomas, skin cancers
melanoma and non-melanoma), sarcomas (Kaposi’s and non-Kaposi’s) and
uterine cervical cancer in situ, acute myloid leukaemia and myelodysplasia
(see also section 4.4 Special Warnings and Special Precautions for Use)
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 chromasomal abnormalities)

Blood and lymphatic system disorders
Very common:
Common:
Uncommon:
Rare:

Depression of bone marrow function; leucopenia.
Thrombocytopenia.
Anaemia.
Agranulocytosis, pancytopenia, aplastic anaemia,
megaloblastic anaemia, erythriod hypoplasia.

Imuran 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 Imuran
when receiving concurrent allopurinol therapy.
Reversible, dose-related increases in mean corpuscular volume and red cell
haemoglobin content have occurred in association with Imuran therapy.
Megaloblastic bone marrow changes have also been observed but severe
megaloblastic anaemia and erythroid hypoplasia is rare.
Respiratory, thorasic and mediastinal disorders
Very rare:

Reversible pneumonitis.

Reversible pneumonitis has been described very rarely.
Gastrointestinal disorders
Uncommon:
Rare:

Pancreatitis.
Colitis, diverticulitis and bowel perforation reported
in transplant population, severe diarrhoea in
inflammatory bowel disease population.

A minority of patients experience nausea when first given Imuran. This
appears to be relieved by administering the tablets 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 Imuran for inflammatory
bowel disease. The possibility that exacerbation of symptoms might be drugrelated should be borne in mind when treating such patients.
Pancreatitis has been reported in a small percentage of patients on Imuran
therapy, particularly in renal transplant patients and those diagnosed as having
inflammatory bowel disease. There are difficulties in relating the pancreatitis
to the administration of one particular drug, although re-challenge has
confirmed an association with Imuran on occasions.

Hepato-biliary disorders
Uncommon:
Rare:

Cholestasis and degeneration of liver function tests.
Life-threatening hepatic damage.

Cholestasis and deterioration of liver function have occasionally been reported
in association with Imuran therapy and are usually reversible on withdrawal of
therapy. This may be associated with symptoms of a hypersensitivity reaction
(see Hypersensitivity reactions).
Rare, but life-threatening hepatic damage associated with chronic
administration of azathioprine has been described primarily in transplant
patients. Histological findings include sinusoidal dilatation, 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.
Skin and subcutaneous tissue disorders
Rare:

Alopecia, photosensitivity.

Hair loss has been described on a number of occasions in patients receiving
azathioprine and other immunosuppressive agents. In many instances the
condition resolved spontaneously despite continuing therapy. The relationship
between alopecia and azathioprine treatment is uncertain.

Immune system disorders
Uncommon:

Hypersensitivity reactions

Very rare:

Stevens-Johnson syndrome and toxic epidermal
necrolysis.

Several different clinical syndromes, which appear to be idiosyncratic
manifestations of hypersensitivity, have been described occasionally following
administration of Imuran. Clinical features include general malaise, dizziness,
nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, vasculitis,
myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction and
cholestasis (see Hepato-biliary disorders).
In many cases, re-challenge has confirmed an association with Imuran.
Immediate withdrawal of azathioprine and institution of circulatory support
where appropriate have led to recovery in the majority of cases.
Other marked underlying pathology has contributed to the very rare deaths
reported.

Following a hypersensitivity reaction to Imuran, the necessity for continued
administration of Imuran should be carefully considered on an individual
basis.

4.9

Overdose
Symptoms and signs
Unexplained infection, ulceration of the throat, bruising and bleeding are the
main signs of overdosage with Imuran 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. There has been a report of a patient who ingested a single
overdose of 7.5 g of azathioprine. The immediate toxic effects of this
overdose were nausea, vomiting and diarrhoea, followed by mild leucopenia
and mild abnormalities in liver function. Recovery was uneventful.
Treatment
There is no specific antidote. Gastric lavage has been used. Subsequent
monitoring, including haematological monitoring is necessary to allow prompt
treatment of any adverse effects, which may develop. The value of dialysis in
patients who have taken an overdose of Imuran is not known, though
azathioprine is partially dialysable.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
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 traverse 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 which is inhibited by allopurinol. The activity of the
methylnitroimidazole moiety has not been defined clearly. However, in
several systems it appears to modify the activity of azathioprine as compared
with that of 6-MP. Determinations of plasma concentrations of azathioprine
or 6-MP have no prognostic value as regards effectiveness or toxicity of these
compounds.

While the precise modes of action remain to be elucidated, some suggested
mechanisms include:
1.

the release of 6-MP which acts as a purine antimetabolite.

2.

the possible blockade of-SH groups by alkylation.

3.

the inhibition of many pathways in nucleic acid biosynthesis, hence preventing
proliferation of cells involved in determination and amplification of the immune
response.

4.

damage to deoxyribonucleic acid (DNA) through incorporation of purine thioanalogues.

Because of these mechanisms, the therapeutic effect of Imuran may be evident
only after several weeks or months of treatment.
Imuran appears to be well absorbed from the upper gastro-intestinal tract.
Studies in mice with 35S-azathioprine showed no unusually large concentration
in any particular tissue, but there was very little 35S found in brain.
Plasma levels of azathioprine and 6-mercaptopurine do not correlate well with
the therapeutic efficacy or toxicity of Imuran.

5.2

Pharmacokinetic properties
Azathioprine is well absorbed following oral administration. After oral
administration of 35S-azathioprine, the maximum plasma radioactivity occurs
at 1-2 hours and decays with a half-life of 4-6 hours. This is not an estimate of
the half-life of azathioprine itself, but reflects the elimination from plasma of
azathioprine and the 35S-containing metabolites of the drug. As a consequence
of the rapid and extensive metabolism of azathioprine, only a fraction of the
radioactivity measured in plasma is comprised of unmetabolised drug. Studies
in which the plasma concentration of azathioprine and 6-mercaptopurine have
been determined following intravenous administration of azathioprine have
estimated the mean plasma T½ for azathioprine to be in the range of 6-28
minutes and the mean plasma T½ for 6-MP to be in the range 38-114 minutes
after IV administration of the drug.
Azathioprine is principally excreted as 6-thiouric uric acid in the urine. 1methyl-4-nitro-5-thioimidazole has also been detected in urine as a minor
excretory product. This would indicate that, rather than azathioprine being
exclusive cleaved by nucleophilic attack at the 5-position of the nitroimidazole
ring to generate 6-MP and 1-methyl-4-nitro-5-(S-glutathionyl)imidazole. A
small proportion of the drug may be cleaved between the S atom and the

purine ring. Only a small amount of the dose of azathioprine administered is
excreted unmetabolised in the urine.

5.3

Preclinical safety data
No additional data of clinical relevance to the prescriber.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Lactose, pregelatinised starch, maize starch, stearic acid, magnesium sterate,
purified water, methylhydroxylpropyl cellulose, polyethylene glycol 400.

6.2

Incompatibilities
None known.

6.3

Shelf life
5 years.

6.4

Special precautions for storage
Store below 25°C. Protect from light.

6.5

Nature and contents of container
Blister strips in a pack.
Pack size: 28, 30, 56, 60, 100 and 1000 tablets.

6.6

Special precautions for disposal
Health professionals who handle Imuran Injection should follow guidelines for
the handling of cytotoxic drugs (for example, the Royal Pharmaceutical
Society of Great Britain Working Party Report on the Handling of Cytotoxic
Drugs, 1983).
Provided that the film-coating is intact, there is no risk in handling film-coated
Imuran Tablets. Imuran Tablets should not be divided and, provided the
coating is intact, no additional precautions are required when handling them.

7

MARKETING AUTHORISATION HOLDER
Aspen Pharma Trading Limited
12/13 Exchange Place
I.F.S.C
Dublin 1, Ireland

8

MARKETING AUTHORISATION NUMBER(S)
PL 39699/0005

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
20th March, 1992.

10

DATE OF REVISION OF THE TEXT
05/01/2012

11

DOSIMETRY (IF APPLICABLE)

12

INSTRUCTIONS FOR PREPARATION OF
RADIOPHARMACEUTICALS (IF APPLICABLE)

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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