azathioprine 50 MG Oral Tablet

INDICATIONS AND USAGE 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.

DOSAGE AND ADMINISTRATION Renal Homotransplantation The dose of azathioprine 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 is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Azathioprine is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the postoperative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of azathioprine 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 is usually given on a daily basis. The initial dose should be approximately 1 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/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 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 azathioprine has not been determined. Azathioprine 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 azathioprine or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. Parenteral Administration Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 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.

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.

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.

CLINICAL PHARMACOLOGY Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 35 S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35 S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low (<1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable (see OVERDOSAGE ). Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites (see Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA. 6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism. 1,2,3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at increased risk of myelotoxicity if receiving conventional doses of azathioprine. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of azathioprine. 4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing azathioprine toxicity. 2,3,7,8,9 Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions (see WARNINGS , PRECAUTIONS: Drug Interactions , PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections). Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA. GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU: Thiouric acid; XO: Xanthine oxidase. (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.) Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (see PRECAUTIONS: Drug Interactions ). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. Homograft Survival The use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses. Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. Immunoinflammatory Response Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine. The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued. figure 1