Data Sheet
IMURAN ™
Azathioprine 50mg tablets
Presentation
Each tablet contains 50mg azathioprine BP.
Pharmaceutical form
Film coated tablet
Uses
Therapeutic Indications
IMURAN is 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 is indicated for the treatment of moderate to severe Crohn's disease in patients in whom corticosteroid therapy is required, in patients who cannot tolerate corticosteroid therapy, or in patients whose disease is refractory to other standard first line therapy.
IMURAN, either alone or more usually in combination with corticosteroids and/or other medicines 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;
- ulcerative colitis;
Dosage and Administration
When the oral route is impractical, IMURAN injection may be administered by
the intravenous route only, however, this route should be discontinued as
soon as oral therapy can be tolerated once more.
Specialist medical literature should be consulted for guidance as to clinical
experience in particular conditions.
Use in Adults
Adult dose in transplants
Depending on the immunosuppressive regimen employed, a dosage of up to 5mg/kg bodyweight/day may be given orally on the first day of therapy.
Maintenance dosage should range from 1-4mg/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.
Adult dose for other indications
In general, starting dosage is from 1-3mg/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. However, for patients with Crohn's disease, a treatment duration of at least 12 months should be considered and a response to treatment may not be clinically apparent until after 3-4 months of treatment.
The maintenance dosage required may range from less than 1mg/kg bodyweight/day to 3mg/kg bodyweight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.
Use in the elderly: (see Use in patients with 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 (see Dosage in other conditions, above).
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
Use in children
Dose in transplants
See adult dose in transplants.
Dose for other indications
See adult dose for other indications.
Use in patients with renal and/or hepatic insufficiency
In patients with renal and/or hepatic insufficiency, dosages should be given at
the lower end of the normal range (see Special Warnings and Special
Precautions for Use for further details).
Contraindications
IMURAN is contraindicated in patients known to be hypersensitive to azathioprine or any other component of the preparation. Hypersensitivity to 6-mercaptopurine (6-MP) should alert the prescriber to probable hypersensitivity to IMURAN.
Warnings and Precautions
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 coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. 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 Undesirable Effects). Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.
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 to the lower end of the recommended range. Dosage should be further 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.
Chromosomal abnormalities, which disappear with time, have been demonstrated in lymphocytes from the off-spring 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.
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 (see section Use During Pregnancy and Lactation).
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. 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. 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.
Varicella Zoster Virus Infection (see also 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.
Use in Pregnancy
Pregnancy Category D
IMURAN should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefit.
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.
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.
Use in Lactation
6-Mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment.
Effects on Ability to Drive and Use Machines
There are no data on the effect of azathioprine on driving performance or the ability to operate machinery. A detrimental effect on these activities cannot be predicted from the pharmacology of the drug.
Interactions
Allopurinol/oxipurinol/thiopurinol:-
Xanthine oxidase activity is inhibited by allopurinol, oxipurinol and thiopurinol which results in reduced conversion of biologically active 6- thioinosinic 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 non-depolarising 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.
Aminosalicylates:- As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent IMURAN therapy (see Special Warnings and Special Precautions for Use).
Other interactions:- 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.
Adverse Effects
For this product there is no modern clinical documentation which 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, <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000.
Infections and infestations
Very common: viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants
Uncommon: viral, fungal and bacterial infections in other patient populations.
Patients receiving IMURAN 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 also Special Warnings and Special 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 myeloid leukaemia and myelodysplasia. (see 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 chromosomal abnormalities).
Blood and lymphatic system disorders
Very common: depression of bone marrow function; leucopenia
Common: thrombocytopenia
Uncommon: anaemia
Rare: agranulocytosis, pancytopenia, aplastic anemia, megaloblastic anaemia, erythroid 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 are rare.
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, rechallenge 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.
Respiratory, thoracic and mediastinal disorders
Very rare: reversible pneumonitis
Gastrointestinal disorders
Common: nausea
Uncommon: pancreatitis
Very rare: 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 drug-related 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 rechallenge has confirmed an association with IMURAN on occasions.
Hepato-biliary disorders
Uncommon: cholestasis and deterioration of liver function tests
Rare: 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 Immune system disorders).
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
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.
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 9-14 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 7.5g 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.
Pharmacological Properties
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.
Mode of action:-
While the precise modes of action remain 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 the immune response.
- damage to deoxyribonucleic acid (DNA) through incorporation of purine thio-analogues.
Because of these mechanisms, the therapeutic effect of IMURAN may be evident only after several weeks or months of treatment.
Pharmacokinetic Properties
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.
Preclinical Safety Data
Teratogenicity
Studies in pregnant rats, mice and rabbits using azathioprine in dosages from 5-15 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.
Pharmaceutical Precautions
Incompatibilities
None reported.
Shelf Life
5 years
Special Precautions for Storage
Store below 30°C.
Instructions for Use/Handling
Safe handling:- Health professionals who handle IMURAN uncoated tablets should follow guidelines for the handling of cytotoxic drugs according to prevailing local recommendations and/or regulations.
Provided that the film-coating is intact, there is no risk in handling film-coated IMURAN tablets. Film-coated IMURAN tablets should not be divided and, provided the coating is intact, no additional precautions are required when handling them.
Disposal:- IMURAN tablets should be disposed of in a manner appropriate to the prevailing local regulatory requirements for the destruction of dangerous substances.
Package Quantities
50mg tablets Blister pack of 100
Medicines classification
Prescription Only Medicine
Name and address
Pharmacy Retailing (NZ) Limited
Trading as Healthcare Logistics
58 Richard Pearse Drive
Airport Oaks
Auckland
New Zealand
Date of preparation
9 April 2009