Purine Antimetabolite

Imuran

Approved 20 Mar 1968OralTablet

The FDA lists this product in 2 strengths and forms.

Indications

IMURAN is 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. Renal Homotransplantation: IMURAN is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables.

The effect of IMURAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: IMURAN is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with IMURAN. The combined use of IMURAN with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects.

The use of IMURAN with these agents cannot be recommended.

Contraindications

IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN 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 malignancy if treated with IMURAN.

Warnings and precautions

Malignancy Patients receiving immunosuppressants, including IMURAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with IMURAN. As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant 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, including IMURAN. Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Rheumatoid Arthritis Information is available on the risk of malignancy with the use of IMURAN in rheumatoid arthritis (see ADVERSE REACTIONS ).

Indications

The use of IMURAN with these agents cannot be recommended.

Contraindications

Warnings and precautions

Interactions

Drug Interactions: Use with xanthine oxidase (XO) inhibitors: One of the pathways for inactivation of azathioprine is inhibited by XO inhibitors (allopurinol or febuxostat). Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, to approximately 1/ 3 to 1/ 4 the usual dose. Concomitant use of IMURAN and febuxostat is not recommended. Inhibition of XO may cause increased plasma concentrations of azathioprine or its metabolite, 6-MP, leading to toxicity.

It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving IMURAN and xanthine oxidase inhibitors 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 IMURAN 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: IMURAN may inhibit the anticoagulant effect of warfarin. Use with ribavirin: The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioionosine monophosphate (6-MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia).

Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary.

Adverse reactions

The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see WARNINGS ). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN 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 IMURAN for rheumatoid arthritis.

The relative incidences in clinical studies are summarized below: * Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine.

However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined. Toxicity Renal Homograft Rheumatoid Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm 3 16% 5.3% Infections 20% <1% Neoplasia * Lymphoma 0.5% Others 2.8% Hematologic: Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN.

Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia, and/or bleeding have been reported. Patients with low or absent TPMT or NUDT15 activity are at increased risk for severe, life-threatening myelosuppression from IMURAN (see CLINICAL PHARMACOLOGY, WARNINGS: Cytopenias and PRECAUTIONS: Laboratory Tests, DOSAGE AND ADMINISTRATION).

Gastrointestinal: Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS ).

Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN.

A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis. 11, 12, 13 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn.

Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma (see Warnings – Malignancy ), and Sweet's Syndrome (acute febrile neutrophilic dermatosis). Postmarketing Experience The following adverse reactions have been identified during postapproval use of IMURAN.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a casual relationship to drug exposure. intrahepatic cholestasis of pregnancy (see WARNINGS, Pregnancy).

Imuran

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Imuran

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

Adverse reactions

Composition

Strengths and forms

Official product information

At a glance