Imuran Special Precautions



GlaxoSmithKline Indonesia
Full Prescribing Info
Special Precautions
Immunisation using a live organism vaccine has the potential to cause infection in immunocompromised hosts. Therefore, it is recommended that patients do not receive live organism vaccines until at least three months after the end of their treatment with azathioprine (see Interactions).
Co-administration of ribavirin and azathioprine is not advised. Ribavirin may reduce efficacy and increase toxicity of azathioprine (see Interactions).
There are potential hazards to the use of azathioprine. It should be prescribed only if the patient can be adequately monitored for toxic effects throughout the duration of therapy.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
It is suggested that during the first eight 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 three months.
At the first signs of an abnormal fall in blood counts, treatment should be interrupted immediately as leucocytes and platelets may continue to fall after treatment is stopped.
Azathioprine may be given long-term unless the patient cannot tolerate the preparation. Withdrawal of an effective dose in certain instances eg, SLE with nephritis, may result in a serious relapse of the condition.
In other instances such as rheumatoid arthritis and certain hematological conditions, treatment may be withdrawn after a suitable interval without any ill-effect. Withdrawal should always be a gradual process performed under close supervision.
In the presence of severe renal or hepatic impairment, careful monitoring is initially required, since the dosage of azathioprine may have to be reduced.
Patients receiving azathioprine should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression. Bone marrow suppression is reversible if azathioprine is withdrawn early enough.
Azathioprine is hepatotoxic and liver function tests should be routinely monitored during treatment. More frequent monitoring may be advisable in those with pre-existing liver disease or receiving other potentially hepatotoxic therapy. The patient should be instructed to discontinue azathioprine immediately if jaundice becomes apparent.
There are individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppresive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with azathioprine. This problem could be exacerbated by co-administration 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 Adverse Reactions). 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. When possible, concomitant administration of cytostatic drugs or drugs which may have a myelosuppression effect should be avoided.
Hypersensitivity: Patients suspected to have previously presented a hypersensitivity reaction to 6-mercaptopurine should not be recommended to use its pro-drug azathioprine, and vice-versa, unless the patient has been confirmed as hypersensitive to the culprit drug with allergological tests, and tested negative for the other.
Infection: Severe secondary infections, often with uncommon organisms are a hazard of immunosuppressive therapy. These are seen more frequently in transplant recipients than in patients being treated for other indications.
Mutagenicity: Chromosomal abnormalities have been demonstrated in both male and female patients treated with azathioprine. It is difficult to assess the role of azathioprine 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 azathioprine. Except in extremely rare cases, no overt physical evidence of abnormality has been observed in the offspring of patients treated with azathioprine.
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.
Teratogenicity: The potential teratogenicity of azathioprine should be borne in mind. Although it has been shown to be teratogenic in laboratory animals clinical evidence suggests that the risk is not appreciable in man. There is no doubt that azathioprine and its metabolites cross the placenta. A temporary impairment of immune function has been noted following exposure in utero to azathioprine combined with prednisone. The long-term consequences of these properties of azathioprine are unknown, but many children exposed in utero have now completed the first decade of life without reported problems.
Carcinogenicity: An increased number of malignant tumours, especially lymphoreticular and epithelial, has been observed in transplant recipients. The skin tumours that have occurred in transplant patients have been primarily on sun exposed skin. Patients should be cautioned against undue sun exposure and the skin should be examined at regular intervals. There is, however, as yet no conclusive evidence of an increased incidence of tumours in other azathioprine treated subjects. In such patients, the risk may be indistinguishable from that accompanying some of the diseases under treatment.
The few cases reported show a different pattern from that seen in transplantation; tumour occurrence is much less common, has an increased latency, is seen mainly after prolonged continuous therapy, is less exclusively lymphoreticular and tends to occur in those patients also treated with alkylating agents.
Patients receiving immunosuppressive therapy, including azathioprine are at an increased risk of developing lymphoproliferative disorders and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's) and uterine cervical cancer in situ. The increased risk appears to be related to the degree and duration of immunosuppression. It has been reported that discontinuation of immunosuppression may provide partial regression of the lymphoproliferative disorder.
A treatment regimen containing multiple immunosuppressants (including thiopurines) should therefore be used with caution as this could lead to lymphoproliferative disorders, some with reported fatalities. A combination of multiple immunosuppressants, given concomitantly increases the risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disorders.
Reports of hepatosplenic T-cell lymphoma have been received when azathioprine is used alone or in combination with anti-TNF agents or other immunosuppressants. Although most reported cases occurred in the IBD population, there have also been cases reported outside of this population.
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.
Macrophage Activation Syndrome: Macrophage Activation Syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with autoimmune conditions, in particular with Inflammatory Bowel Disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of azathioprine. If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.
Varicella Zoster Virus Infection (see Adverse Reactions): 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.
Progressive Multifocal Leukoencephalopathy (PML): PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first sign or symptoms suggestive of PML and appropriate evaluation undertaken to establish a diagnosis (see Adverse Reactions).
Hepatitis B (see Adverse Reactions): Hepatitis B carriers (defined as patients positive for hepatitis B surface antigen [HBsAg] for more than six months), or patients with documented past HBV infection, who receive immunosuppressive drugs are at risk of reactivation of HBV replication, with asymptomatic increases in serum HBV DNA and ALT levels. Local guidelines may be considered including prophylactic therapy with oral anti-HBV agents.
Xanthine Oxide Inhibitors: If allopurinol, oxipurinol and/or thipurinol are given concomitantly with azathioprine, the dosage of azathioprine must be reduced to a quarter of the original dose (see Interactions).
Neuromuscular Agents: Special care is necessary when azathioprine is given concomitantly with neuromuscular acting agents like tubucurarine or succinylcholine (see Interactions). It can also potentiate the neuromuscular block that is produced by depolarising agents such as succinylcholine (see Interactions). Patients should be advised to inform their anaesthesiologist of their treatment with azathioprine prior to surgery.
Effects on the 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.
Renal and/or Hepatic Impairment: Caution is advised during the administration of azathioprine in patients with renal impairment and/or hepatic impairment. Consideration should be given to reducing the dosage in these patients and haematological response should be carefully monitored (see Dosage & Administration and Pharmacokinetics under Actions).
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