Imuran 25 mg, 50 mg

/ Perrigo

General: When the oral route is impractical azathioprine injection may be administered by the i.v. route only, however, this route should be discontinued as soon as oral therapy can be tolerated once more. Imuran tablets should be administered at least 1 hour before or 3 hours after food or milk.
Dosage in transplantation – adults: Depending on the immunosuppressive regimen employed, a dosage of up to 5mg/kg bodyweight/day may be given on the first day of therapy, either orally or intravenously. Maintenance dosage should range from 1-4mg/kg bodyweight/day and must be adjusted according to clinical requirements and haematological tolerance. Corticosteroid therapy is usually given concomitantly with Imuran. 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: In general, starting dosage is from 1- mg/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. In general, starting dosage rarely exceeds 3mg/kg bodyweight/day, and should be reduced, 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 l mg/kg bodyweight/day to 3 mg/kg bodyweight/day, depending on the clinical condition being treated and the individual patient response, including haematological tolerance.
Paediatric population
Transplants: See Dosage in transplantation – adults.
Overweight children: Children considered to be overweight may require doses at the higher end of the dose range and therefore close monitoring of response to treatment is recommended.
Use in the elderly: The rapid in vivo cleavage of the azathioprine molecule followed by tissue fixation makes it impossible to relate plasma drug levels to toxicity. There are no specific data as to the tolerance of Imuran in elderly patients. 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 advisable to monitor renal and hepatic function, and to consider dosage reduction if there is impairment.
The dosage is adjusted on the basis of the clinical state and the response of the individual patient. If no improvement has occurred after 3 months, consideration should be given to discontinuing the drug.
Renal and/or hepatic impairment: In patients with renal and/or hepatic insufficiency, consideration should be given to reducing the dosage.
Drug interactions: When xanthine oxidase inhibitors, such as allopurinol, and azathioprine are administered concomitantly it is essential that only 25% of the usual dose of azathioprine is given since allopurinol decreases the rate of catabolism of azathioprine.
TPMT-deficient patients: Patients with inherited little or no thiopurine S- ethyltransferase (TPMT) activity are at increased risk for severe azathioprine toxicity from conventional doses of azathioprine and generally require substantial dose reduction. The optimal starting dose for homozygous deficient patients has not been established.
Most patients with heterozygous TPMT deficiency can tolerate recommended azathioprine doses, but some may require dose reduction. Genotypic and phenotypic tests of TPMT are available.

Renal, cardiac and hepatic transplants, rheumatoid arthritis.

* Hypersensitivity to the active ingredient azathioprine or to any of the excipients.
* Hypersensitivity to 6-mercaptopurine should alert the prescriber to probable hypersensitivity to azathioprine.

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. Complete blood counts are repeated monthly, or at least at intervals of no longer than 3 months. Patients should be instructed to report immediately any evidence of infection, unexpected bruising or bleeding or other manifestations of bone marrow depression.
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. Cases of non-cirrhotic portal hypertension/portosinusoidal vascular disease have been reported. Early clinical signs include liver enzyme abnormalities, mild jaundice, thrombocytopenia, and splenomegaly.
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 azathioprine. This problem could be exacerbated by co-administration with medicinal products 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. 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. The dosage of azathioprine may need to be reduced when this agent is combined with other medicinal products whose primary or secondary toxicity is myelosuppression.
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 starting dosage in these patients and haematological response should be carefully monitored.
Lesch-Nyhan syndrome
Limited evidence suggests that therapy is not beneficial to patients with Lesch-Nyhan syndrome.
Neuromuscular blocking agents
Special care is necessary when azathioprine is given concomitantly with neuromuscular blocking agents such as atracurium, rocuronium, cisatracurium or suxamethonium (also known as succinylcholine).
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 off-spring 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.
See prescribing information for full details.

Very common: Viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants, Bone marrow depression, leukopenia.
Common: Thrombocytopenia, Nausea.
See prescribing information for full details.

Vaccines
The immunosuppressive activity of azathioprine could result in an atypical and potentially deleterious response to live vaccines. It is therefore recommended that patients do not receive live vaccines until at least 3 months after the end of their treatment with azathioprine.
Effect of concomitant medicinal products on azathioprine
Ribavirin
Ribavirin inhibits the enzyme inosine monophosphate dehydrogenase (IMPDH), leading to a lower production of the active 6-thioguanine nucleotides. Severe myelosuppression has been reported following concomitant administration of azathioprine and ribavirin; therefore co-administration is not advised.
Cytostatic/myelosuppressive agents
Where possible, concomitant administration of cytostatic agents, or medicinal products 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 azathioprine and trimethoprim/sulfamethoxazole.
* There have been case reports suggesting that haematological abnormalities may develop due to the concomitant administration of azathioprine and ACE Inhibitors.
Allopurinol/oxipurinol/thiopurinol and other xanthine oxidase inhibitors
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 25 % of the original dose. Fatal cases have been reported in patients treated concomitantly with azathioprine and allopurinol.
Methotrexate
Methotrexate (20 mg/m2 orally) increased 6-mercaptopurine AUC by approximately 31% and methotrexate (2 or 5 g/m2 intravenously) increased 6-mercaptopurine AUC by 69 and 93%, respectively.
Infliximab
An interaction has been observed between azathioprine and infliximab. Patients receiving ongoing azathioprine experienced transient increases in 6-TGN (6-thioguanine nucleotide, an active metabolite of azathioprine) levels and a decrease in the mean leukocyte count in the initial weeks following infliximab infusion, which returned to previous levels after 3 months.
Neuromuscular agents
There is clinical evidence that azathioprine antagonises the effect of non-depolarising muscle relaxants such as curare, d-tubocurarine and pancuronium. Experimental data confirm that azathioprine reverses the neuromuscular blockade produced by d-tubocurarine, and show that azathioprine potentiates the neuromuscular blockade produced by succinylcholine. There is considerable variation in the potency of this interaction.
Effect of azathioprine on other medicinal products
Anticoagulants
Inhibition of the anticoagulant effect of warfarin and acenocoumarol has been reported when co-administered with azathioprine; therefore higher doses of the anticoagulant may be needed. It is recommended that coagulation tests are closely monitored when anticoagulants are concurrently administered with azathioprine.

Pregnancy:
Azathioprine should only be used during pregnancy (or when planning a pregnancy) after a careful risk-benefit assessment.
Contraception: Evidence of birth defects in humans is inconclusive. However, because it is a cytotoxic drug, adequate contraception is advised if either partner is taking it.
Pregnancy Cholestasis: This liver condition is rare but possible. If confirmed, stopping the drug early can minimize fetal risk, balancing maternal benefit against fetal impact.
Chromosomal Changes: Temporary chromosome abnormalities have been found in infants’ white blood cells, but they fade over time. Visible physical defects are extremely rare.
Birth Complications: Amniotic exposure especially when combined with corticosteroids is linked to risks of premature birth, low birth weight, and intrauterine growth restriction. Spontaneous abortions have been reported following both maternal and paternal exposure.
Blood Counts: Infants exposed throughout pregnancy run a risk of leukopenia (low white blood cells) or thrombocytopenia (low platelets). Extra hematological monitoring is recommended during pregnancy.
Lactation: 6-mercaptopurine has been identified in the colostrum and breast-milk of women receiving azathioprine treatment. Available data has shown that the excreted levels in breast-milk are low. From the limited available data, the risk to newborns/infants is considered to be unlikely but cannot be excluded.
Because 6-mercaptopurine is a strong immunosuppressant, the breastfed infant should be closely monitored for signs of immunosuppression, leukopenia, thrombocytopenia, hepatotoxicity, pancreatitis or other symptoms of 6-mercaptopurine exposure.