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Drug Details

IMURAN

• Drug Class Description
  Cytotoxic immunosuppressants (DMARDs).
• Generic Name
  Azathioprine - rheumatoid arthritis
• Presentation
  Orange, round, biconvex, film-coated tablets, impressed `GX EL5' and containing 25 mg Azathioprine BP in each tablet
• Description
  Imuran tablets 25 mg
• 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.

• Adult Dosage
  

  Transplantation - adults and children

  Depending on the immunosuppressive regimen employed, a dosage of up to 5 mg/kg body weight/day may be given on the first day of therapy, either orally or intravenously.

  Maintenance dosage should range from 1 to 4 mg/kg body weight/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 body weight/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 body weight/day to 3 mg/kg body weight/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.

  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.

• Contra Indications
  

  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.

• Special 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 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.

  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.

  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 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.

• Interactions
  

  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 6mercaptopurine 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 indometacin may have myelosuppressive effects, which may be enhanced by concomitant administration of Imuran.

  Other interactions

  As there is in vitro evidence that aminosalicylate derivatives (eg. olsalazine, mesalazine or sulfasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent Imuran therapy.

  Furosemide 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 Drug Reactions
  

  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 < 1/1000; 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.

  Neoplasms benign and malignant (including cysts and polyps)

  Rare: Neoplasms including non-Hodkin'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.

  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:	Depression of bone marrow function; leucopenia.
  Common:	Thrombocytopenia.
  Uncommon:	Anaemia.
  Rare:	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:	Pancreatitis.
  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 re-challenge, 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 inflammtory 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:	Cholestasis and degeneration 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 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

  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.