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Azathioprine was originally FDA approved in 1968 as an adjunct immunosuppressant for use in renal transplant patients. Prior to the advent of cyclosporine, the combination of azathioprine and corticosteroids (prednisone or prednisolone) was the mainstay of immunosuppressive therapy for solid organ transplantation. However, in recent years the use of azathioprine in transplantation has declined markedly as it has largely been supplanted by mycophenolate, a more specific inhibitor of lymphocyte purine metabolism.
Azathioprine is a pro-drug which is converted in the body via a non-enzymatic reaction to 6-mercaptopurine (6-MP), a purine analog that acts as an antimetabolite chemotherapeutic agent interfering with the synthesis of nucleotides, thereby inhibiting T-cell proliferation. Azathioprine is a non-specific immunosuppressant whose primary targets are the bone marrow stem cells. As an immunosuppressant, azathioprine is also indicated for the treatment of rheumatoid arthritis, and may be useful for lupus nephritis, Crohn's disease, psoriatic arthritis, and other autoimmune diseases.
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Pharmacokinetics |
Oral azathioprine is well absorbed, and both azathioprine and 6-mercaptopurine (6-MP) distribute throughout the body and are able to cross the placenta. Azathioprine is converted by hepatic xanthine oxidase to 6-mercaptopurine, which is further metabolized to several compounds including 6-thiourate. These metabolites are excreted in the urine. The plasma half-life of azathioprine is <15 minutes, whereas the half-life of its active derivative (6-MP) is 1 - 3 hrs. Azathioprine is only slightly dialyzable (10%) through conventional hemodialysis membranes.
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Contraindications and Warnings |
- Azathioprine is pregnancy-risk-category D, based on human data indicating risk to the fetus. Therefore, the use of azathioprine is contraindicated in pregnant patients. It is also contraindicated in breast-feeding mothers.
- Myelosuppression occurs in >50% of patients. Complete blood counts should be performed regularly and if necessary, the azathioprine dose should be reduced or discontinued promptly.
- Azathioprine can be hepatotoxic and should be used with caution in patients with preexisting liver disease. Veno-occlusive disease of the liver has been reported to occur due to chronic azathioprine therapy. Liver function should be monitored regularly in all patients.
- Azathioprine should be used with caution in presence of sever renal impairment due to the potential for the accumulation of drug metabolites.
- Immunosuppressants should be used cautiously in patients with infections.
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Available As |
- Tablets (50 mg)
- Injectable solution (100 mg / 20 mL vials).
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Dose and Administration |
- Azathioprine is available in both oral and injectable forms [50-mg scored tablets and 100-mg vials for IV use). The intravenous and oral doses are equivalent. The intramuscular route should not be used.
- The recommended initial dose is 3 - 5 mg/kg once a day. After a variable period ranging from days to weeks, the dose is usually reduced to a maintenance regimen of l - 2 mg/kg once daily. Myelosuppression (mainly leukopenia and thrombocytopenia) is a frequent, dose-dependent and dose-limiting complication that prompts dose reduction and can lead to discontinuation of azathioprine therapy.
- Dose reduction due to severely impaired renal function (CLcr<25 mL/min) may be necessary since the metabolites of azathioprine and 6-mercaptopurine are cleared via the kidney.
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Main Side Effects |
- Bone marrow depression, resulting in leukopenia, pancytopenia, thrombocytopenia, and/or macrocytic anemia, occurs to varying degree in >50% of patients. This adverse reaction is usually dose-dependent and can lead to further complications including infections and bleeding. For these reasons the patient's hematologic status should be closely monitored, and the patient should promptly report unusual symptoms such as bleeding or bruising.
- Hepatotoxicity occurs in 2-10% of transplant patients receiving azathioprine. A life-threatening condition known as veno-occlusive disease of the liver occurs in <1% of the patients following chronic azathioprine therapy. Regular monitoring of liver function tests is essential.
- Gastrointestinal Symptoms: Nausea and vomiting occur in 10 - 15% of patients particularly during the first few weeks or months. Less frequently, these symptoms would be accompanied by diarrhea. More rarely, vomiting with abdominal pain may occur due to hypersensitivity pancreatitis.
- Other Side effects occurring in <1% of patients include rash, fever, serum sickness, interstitial nephritis, alopecia, and retinopathy. A rare hypersensitivity reaction characterized by Raynaud's disease and pulmonary edema can also occur.
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Drug Interactions |
- Exacerbation of hematologic toxicity: ganciclovir, ACE-inhibitors, carbamazepine, clozapine, co-trimoxazole, etc.
- Allopurinol, an analog of hypoxanthine, is a powerful inhibitor of xanthine oxidase, the enzyme responsible for the inactivation of 6-mercaptopurine [see note below]. The combination of allopurinol and azathioprine leads to accumulation of 6-MP and increased exposure of the patient to the immunosuppressive and myelosuppressive effects of the drug. If allopurinol is absolutely necessary, azathioprine dose should be reduced by 50 - 75%.
- Note: xanthine oxidase catalyzes the conversion of 6-MP to 6-thiouric acid plus other inactive metabolites. As a result of the inhibition of xanthine oxidase, allopurinol blocks also the production of uric acid from hypoxanthine and xanthine.
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References |
- Mele TS, Halloran PF. The use of mycophenolate mofetil in transplant recipients. Immunopharmacology. 2000;47(2-3):215-45.
- Sterneck M et al. Azathioprine hepatotoxicity after liver transplantation. Hepatology. 1991;14(5):806-10.
- Chan GL et al. The therapeutic use of azathioprine in renal transplantation. Pharmacotherapy. 1987;7(5):165-77.
- Imuran PI
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