Purine Antimetabolite

Azathioprine

Approved 15 Mar 2007OralTablet

The FDA lists this product in 12 strengths and forms.

Indications

Azathioprine tablets, USP 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. Renal Homotransplantation Azathioprine tablets, USP are 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 azathioprine tablets on these variables has not been tested in controlled trials. Rheumatoid Arthritis Azathioprine tablets, USP are 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 azathioprine tablets. The combined use of azathioprine tablets with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects.

The use of azathioprine tablets with these agents cannot be recommended.

Contraindications

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 malignancy if treated with azathioprine tablets.

Warnings and precautions

Malignancy Patients receiving immunosuppressants, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with azathioprine. 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 azathioprine. 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 azathioprine in rheumatoid arthritis (see ADVERSE REACTIONS ).

At a glance

Brand name: Azathioprine
Pharmacologic class: Purine Antimetabolite
Route: Oral
Dosage form: Tablet
Applicant: Zydus Pharms USA
Status: Prescription
FDA approval: 15 Mar 2007
Application: ANDA077621-002

Indications

The use of azathioprine tablets 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 azathioprine and allopurinol concomitantly should have a dose reduction of azathioprine, to approximately 1/ 3 to 1/ 4 the usual dose. Concomitant use of azathioprine with 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 azathioprine 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 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. 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 (6MTITP), 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. Carcinogenesis, Mutagenesis, Impairment of Fertility See WARNINGS section .

Pregnancy and breastfeeding

Pregnancy Azathioprine tablets can cause fetal harm when administered to a pregnant woman. Azathioprine tablets should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of azathioprine tablets in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 3 Azathioprine tablets are teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily).

Abnormalities included skeletal malformations and visceral anomalies. 2 Postmarketing cases of intrahepatic cholestasis of pregnancy (ICP) have been reported in women treated with azathioprine during pregnancy. ICP symptoms and evaluated bile acid levels improved following azathioprine discontinuation. Discontinue azathioprine tablets if ICP develops in a pregnant woman. Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine tablets.

In a detailed case report, 4 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 5 There have been two published reports of abnormal physical findings.

Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 6 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 7 Benefit versus risk must be weighed carefully before use of azathioprine tablets in patients of reproductive potential.

There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.

Adverse reactions

The principal and potentially serious toxic effects of azathioprine tablets 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 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: Toxicity Renal Homograft Rheumatoid Arthritis * 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. Leukopenia (any degree) >50% 28% <2,500 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 azathioprine tablets.

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 azathioprine (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 azathioprine tablets, 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 azathioprine tablets.

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 azathioprine tablets 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, azathioprine tablets 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 azathioprine tablets.

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 ).

Azathioprine

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Azathioprine

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

Adverse reactions

Composition

Strengths and forms

Official product information