Azathioprine

What it is used for

Azathioprine tablets are indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.

How to take it

TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING AZATHIOPRINE TABLETS. TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity from azathioprine tablets if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). Azathioprine tablets should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.

Side effects, and when to stop

The principal and potentially serious toxic effects of azathioprine tablets are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS ). The frequency and severity of adverse reactions depend on the dose and duration of azathioprine tablets as well as on the patient’s underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing azathioprine tablets for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Who should not take it

Azathioprine tablets should not be given to patients who have shown hypersensitivity to the drug. Azathioprine tablets should not be used for treating rheumatoid arthritis in pregnant women. Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with azathioprine tablets.

Warnings

Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine tablets. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of azathioprine tablets. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of azathioprine tablets. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing azathioprine tablets toxicity 2-9 (see PRECAUTIONS: Laboratory Tests ). Hematologic toxicities are dose-related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on azathioprine tablets have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.

Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered.

Azathioprine tablets are mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s risk of neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to azathioprine tablets. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving azathioprine tablets can be found under ADVERSE REACTIONS.

Azathioprine tablets have been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; 10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11

Other medicines and interactions

Use with Allopurinol

One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving azathioprine tablets and allopurinol concomitantly should have a dose reduction of azathioprine tablets, to approximately ⅓ to ¼ the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving azathioprine tablets and allopurinol because both TPMT and XO inactivation pathways are affected (see CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections).

Use with Aminosalicylates

There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with azathioprine tablets should be done with caution.

Use with Other Agents Affecting Myelopoesis

Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

Use with Angiotensin-Converting Enzyme Inhibitors

The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.

Use with Warfarin

Azathioprine tablets may inhibit the anticoagulant effect of warfarin.

Carcinogenesis, Mutagenesis, Impairment of Fertility

See WARNINGS section.