For IMURAN, 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 <1/100 ; very rare <1/10,000.
Infections and infestations:
Very common: viral, fungal and bacterial infections in transplant patients receiving IMURAN 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. Reactivation of varicella zoster virus, hepatitis B and other infectious agents are also uncommon. (See Precautions).
Very rare: cases of JC virus associated PML have been reported following the use of azathioprine in combination with other immunosuppressants (see Precautions).
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), uterine cervical cancer in situ
, acute myeloid leukaemia and myelodysplasia (see Precautions).
The risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and nonmelanoma), 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).
Very rare: Hepatosplenic T-cell lymphoma (see Precautions).
Blood and lymphatic system disorders:
Very common: depression of bone marrow function; leucopenia. Common: thrombocytopenia. Uncommon: anaemia. Rare: agranulocytosis, pancytopenia, aplastic anaemia, 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 as follows).
In many cases, rechallenge has confirmed an association with IMURAN.
Immediate withdrawal of IMURAN and institution 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.
Common: nausea (with IMURAN tablets only). Uncommon: pancreatitis. Very rare: colitis, diverticulitis and bowel perforation reported in transplant population, severe diarrhoea in inflammatory bowel disease population (un-licensed indication).
A minority of patients experience nausea when first given oral 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 (un-licensed indication). 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 (un-licensed indication). There are difficulties in relating the pancreatitis to the administration of one particular drug, although rechallenge has confirmed an association with IMURAN on occasions.
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 under Adverse Reactions).
Rare, but life-threatening hepatic damage associated with chronic administration of IMURAN 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 IMURAN has resulted in either a temporary or permanent improvement in liver histology and symptoms.
Skin and subcutaneous tissue disorders:
Hair loss has been described on a number of occasions in patients receiving IMURAN and other immunosuppressive agents. In many instances the condition resolved spontaneously despite continuing therapy. The relationship between alopecia and IMURAN treatment is uncertain.