Azasan

INDICATIONS AND USAGE: AZASAN 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: AZASAN 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 AZASAN on these variables has not been tested in controlled trials. Rheumatoid Arthritis: AZASAN 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 AZASAN. The combined use of AZASAN with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of AZASAN with these agents cannot be recommended.

DOSAGE AND ADMINISTRATION: Renal Homotransplantation: The dose of AZASAN 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. AZASAN is 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 AZASAN 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: AZASAN is 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. AZASAN 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 AZASAN has not been determined. AZASAN 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 postcadaveric transplant period, may have delayed clearance of AZASAN 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.

CONTRAINDICATIONS: AZASAN should not be given to patients who have shown hypersensitivity to the drug. AZASAN 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 AZASAN.

ADVERSE REACTIONS: The principal and potentially serious toxic effects of AZASAN 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 AZASAN 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 AZASAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: 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% *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 AZASAN. 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 AZASAN (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 AZASAN, 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 AZASAN. 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 AZASAN 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, AZASAN 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 fe …

DESCRIPTION: AZASAN ® (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 75 mg or 100 mg azathioprine and the inactive ingredients lactose monohydrate, pregelatinized starch, povidone, corn starch, magnesium stearate, and stearic acid. Azathioprine is chemically 6-[(1-methyl-4-nitro-1 H-imidazol-5-yl)thio]-1 H-purine. The structural formula of azathioprine is: It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound. Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide. chem structure

OVERDOSAGE: The oral LD 50 s for single doses of AZASAN in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of AZASAN is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis. 14 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg AZASAN. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.

HOW SUPPLIED: AZASAN Tablets, USP are available in: 75 mg, triangle-shaped, yellow, scored tablets, debossed with “75 mg” on one side, and “N” on the other side. 100 count bottles (NDC 65649-231-41) 100 mg, diamond-shaped, yellow, scored tablets, debossed with “100 mg” on one side, and “N” on the other side. 100 count bottles (NDC 65649-241-41) Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Store in a dry place and protect from light. Dispense in a tight, light-resistant container as defined in the USP.