Azathioprine Tablet

INDICATIONS AND USAGE:
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.

Renal Homotransplantation: Azathioprine Tablets 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 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.

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:

*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.

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 Tablets (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.

1. •intrahepatic cholestasis of pregnancy (see WARNINGS, Pregnancy).

To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

WARNINGS:

Malignancy
Patients receiving immunosuppressants, including Azathioprine Tablets, 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 Tablets. 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 Tablets. 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 Tablets in rheumatoid arthritis (see ADVERSE REACTIONS). It has not been possible to define the precise risk of malignancy 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 Tablets.

Inflammatory Bowel Disease
Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with Azathioprine Tablets. These cases have had a very aggressive disease course and have been fatal. The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males. Some of the patients were treated with Azathioprine Tablets as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of Azathioprine Tablets for the treatment of Crohn's disease and ulcerative colitis have not been established.

Cytopenias: Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia and/or pancytopenia may occur in patients being treated with Azathioprine Tablets. Severe bone marrow suppression may also occur. 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.

TPMT or NUDT15 Deficiency

Patients with thiopurine S-methyl transferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency may be at an increased risk of severe and life-threatening myelotoxicity if receiving conventional doses of Azathioprine Tablets (see CLINICAL PHARMACOLOGY). Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine. In patients with severe myelosuppression, consider evaluation for TPMT and NUDT15 deficiency (see PRECAUTIONS: Laboratory Tests). Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency (see DOSAGE AND ADMINISTRATION).

Serious Infections
Patients receiving immunosuppressants, including Azathioprine Tablets, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes.

Progressive Multifocal Leukoencephalopathy
Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including Azathioprine Tablets. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft.

Effect on Sperm in Animals
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; ¹ a reduced percentage of fertile matings occurred when animals received 5 mg/kg. ²

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.

PRECAUTIONS:

General: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with Azathioprine Tablets and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of Azathioprine Tablets.

Information for Patients: Patients being started on Azathioprine Tablets should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving Azathioprine Tablets and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when Azathioprine Tablets are being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of Azathioprine Tablets during pregnancy and during the nursing period. The increased risk of malignancy following therapy with Azathioprine Tablets should be explained to the patient.

Laboratory Tests: Complete Blood Count (CBC) Monitoring: Patients on Azathioprine Tablets should 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.

TPMT and NUDT15 Testing: Consider genotyping or phenotyping patients for TPMT deficiency and genotyping for NUDT15 deficiency in patients with severe myelosuppression. TPMT and NUDT15 testing cannot substitute for complete blood count (CBC) monitoring in patients receiving Azathioprine Tablets. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions (see CLINICAL PHARMACOLOGY, WARNINGS: Cytopenias, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections).

DOSAGE AND ADMINISTRATION:
Renal Homotransplantation: The dose of Azathioprine Tablets required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine Tablets are usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of Azathioprine Tablets should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.

Rheumatoid Arthritis: Azathioprine Tablets are usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice-daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg per day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprine Tablets may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.

Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance for Azathioprine Tablets has not been determined. Azathioprine Tablets can be discontinued abruptly, but delayed effects are possible.

Patients with TPMT and/or NUDT15 Deficiency
Consider testing for TPMT and NUDT15 deficiency in patients who experience severe bone marrow toxicities. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction (see CLINICAL PHARMACOLOGY, WARNINGS: Cytopenias, and PRECAUTIONS: Laboratory Tests).
Homozygous deficiency in either TPMT or NUDT15
Because of the risk of increased toxicity, consider alternative therapies for patients who are known to have TPMT or NUDT15 deficiency (see CLINICAL PHARMACOLOGY, WARNINGS: Cytopenias, and PRECAUTIONS: Laboratory Tests).
Heterozygous deficiency in TPMT and/or NUDT15
Because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of TPMT or NUDT15. Patients who are heterozygous for both TPMT and NUDT15 deficiency may require more substantial dosage reductions (see CLINICAL PHARMACOLOGY, WARNINGS: Cytopenias, and PRECAUTIONS: Laboratory Tests).

Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate post-cadaveric transplant period, may have delayed clearance of Azathioprine Tablets or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published. ^15-21 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

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 Tablets and allopurinol concomitantly should have a dose reduction of Azathioprine Tablets, to approximately 1/3 to 1/4 the usual dose. Concomitant use of Azathioprine Tablets 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 Tablets 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 (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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section.

Pregnancy: Teratogenic Effects : See WARNINGS section.

Nursing Mothers: The use of Azathioprine Tablets in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. ^8,9,10 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use: Safety and efficacy of azathioprine in pediatric patients have not been established.