Since August 2009, the U.S. FDA has required warnings to be placed on packaging with respect to increased risks of certain cancers.The risks involved seem to be related both to the duration and the dosage used. People who have previously been treated with an alkylating agent may have an excessive risk of cancers if treated with azathioprine. Epidemiological studies by International Agency for Research on Cancer have provided "sufficient" evidence of azathioprine carcinogenicity in humans (group 1), although the methodology of past studies and the possible underlying mechanisms are questioned.The various diseases requiring transplantation may in themselves increase the risks of non-Hodgkin lymphoma, squamous cell carcinomas of the skin, hepatobiliary carcinomas, and mesenchymal tumours to which azathioprine may add additional risks. Those receiving azathioprine for rheumatoid arthritis may have a lower risk than those undergoing transplantation.Cases of hepatosplenic T-cell lymphoma – a rare type of lymphoma – have been reported in patients treated with azathioprine. The majority occurred in patients with inflammatory bowel disease. Adolescents and young adult males were the majority of cases. They presented with a very aggressive disease course, and with one exception, died of the lymphoma. The FDA has required changes to the labeling to inform users and clinicians of the issue. Skin cancers
In transplant patients, skin cancer is 50 to 250 times more common than in the general population, and between 60 and 90% of patients are affected 20 years after transplantation.
The use of immunosuppressive medication including azathioprine in organ transplantation has been linked to increased rates of developing skin cancer. Azathioprine causes the accumulation of 6-thioguanine (6-TG) in patients DNA, which might trigger cancer when the patient is later exposed to ultraviolet light. Patients taking azathioprine were found to be abnormally sensitive to UVA light. Overdose
Large single doses are generally well tolerated; a patient who took 7.5 g azathioprine (150 tablets) at once showed no relevant symptoms apart from vomiting, slightly decreased white blood cell count, and marginal changes in liver function parameters. Main symptoms of long-term overdosing are infections of unclear origin, mouth ulcers, and spontaneous bleeding, all of which are consequences of its bone-marrow suppression. Interactions
Other purine analogues, such as allopurinol, inhibit xanthine oxidase, the enzyme that breaks down azathioprine, thus increasing the toxicity of azathioprine. Low doses of allopurinol, though, have been shown to safely enhance the efficacy of azathioprine, especially in inflammatory bowel disease nonresponders. This may still lead to lower lymphocyte counts and higher rates of infection, therefore the combination requires careful monitoring.Azathioprine decreases the effects of the anticoagulant warfarin and of nondepolarizing muscle relaxants, but increases the effect of depolarizing muscle relaxants. It can also interfere with niacin (vitamin B3), resulting in at least one case to pellagra and fatal medullary aplasia. Pregnancy and breastfeeding
Azathioprine can cause birth defects. A 2003 population-based study in Denmark showed that the use of azathioprine and related mercaptopurine resulted in a seven-fold incidence of fetal abnormalities, as well as a 20-fold increase in miscarriage.