azathioprine 50 mg tablet generic imuran

Uses

Renal Allotransplantation

Azathioprine is used as an adjunct for prevention of the rejection of kidney allografts. The drug is usually used in conjunction with other immunosuppressive therapy including local radiation therapy, corticosteroids, and other cytotoxic agents.

The maximum effectiveness of azathioprine occurs when the drug is administered during the induction period of the antibody response, starting either at the time of antigenic stimulation or within 2 days following. Under certain conditions of pretreatment with mercaptopurine, followed by an interval of at least 5 days before administration of the antigen and no subsequent treatment, a paradoxical enhancement of antibody formation has been observed. The effects of azathioprine and its active metabolite, mercaptopurine, may not be observed until several days after initiation of therapy and may persist for several days after clearance of the compounds is completed.

Rheumatoid Arthritis

Azathioprine is used for the management of the signs and symptoms of rheumatoid arthritis in adults. Azathioprine is one of several disease modifying antirheumatic drugs (DMARDs) that can be used when DMARD therapy is appropriate. Nonsteroidal anti-inflammatory agents (NSAIAs), including aspirin, and/or corticosteroids may be continued when treatment with azathioprine is initiated. The manufacturers state that combined use of azathioprine and other DMARDS has not been studied and is not recommended.

Crohn's Disease

Azathioprine has been used in the management of moderately to severely or chronically active Crohn's disease, and to maintain clinical remission in corticosteroid-dependent patients, and to provide benefit in patients with fistulizing Crohn's disease.

Azathioprine (e.g., 2-3 mg/kg daily) has been used in conjunction with corticosteroids to induce remission in patients with mildly to severely active refractory Crohn's disease; however, onset of action of azathioprine is slow and several months usually are required to achieve clinical response. Therefore, the role, if any, of azathioprine in the management of acute disease activity is uncertain. Azathioprine is used in patients with chronically active corticosteroid-dependent Crohn's disease. Results of several placebo-controlled trials indicate that azathioprine may be effective in maintaining remission in patients with corticosteroid-induced clinical remissions and in allowing reduction of oral corticosteroid therapy in corticosteroid-dependent patients. In several studies, frequency of relapse associated with azathioprine has been substantially lower than that associated with placebo. Results of long-term follow-up studies indicate that treatment with azathioprine may be effective for up to 4 years. Limited data indicate that relapse rates after 4 years of immunosuppressive therapy may be similar whether therapy has been maintained or discontinued; however, further larger studies are needed to confirm such data.

Azathioprine also has been found effective in the management of fistulizing Crohn's disease. Current clinical practice concerning use of azathioprine is based on a point analysis of 5 controlled trials in which fistula closure was considered a secondary end point and on several uncontrolled case studies. Data from these studies indicate that long-term (several years) therapy with azathioprine may be effective in the management of fistulizing Crohn's disease. However, because there currently are no controlled studies employing fistula closure as a primary end point, additional study is needed to more clearly establish efficacy.

Azathioprine (1.5-2 mg/kg daily) has been used effectively in pediatric patients with refractory or corticosteroid-dependent Crohn's disease. In these patients, therapy with azathioprine may result in improvement of disease symptoms and reduction of corticosteroid dosage, and frequency of hospitalization.

Risks and benefits of azathioprine therapy should be carefully considered in patients with inflammatory bowel disease, especially in adolescents and young adults with the disease. Cases of hepatosplenic T-cell lymphoma have been reported in patients receiving azathioprine for the management of inflammatory bowel disease.(See Cautions: Malignancies and Lymphoproliferative Disorders.)

Dosage and Administration

Reconstitution and Administration

Azathioprine is usually administered orally. Following renal transplantation, azathioprine may initially be given IV to patients unable to tolerate oral medication. Oral therapy should replace parenteral therapy as soon as possible.

Since azathioprine is an antimetabolite, the manufacturer states that consideration should be given to handling and disposal according to guidelines issued for hazardous drugs , although there is no general agreement that all of the procedures recommended in such guidelines are necessary or appropriate.

Azathioprine sodium powder for injection is reconstituted by adding 10 mL of sterile water for injection to a vial labeled as containing 100 mg of the drug. The resultant solution contains 10 mg/mL, and may be given by direct IV injection or further diluted in 0.9% sodium chloride or 5% dextrose injection for IV infusion. IV infusions of the drug are usually administered over 30-60 minutes; however, infusions have been given over periods ranging from 5 minutes to 8 hours.

Reconstituted solutions of azathioprine should be inspected visually prior to administration, whenever solution and container permit.

Dosage

Dosage of azathioprine must be carefully adjusted and individualized according to the patient's response and tolerance. Dosage may need to be reduced in patients with impaired renal function. (See Cautions: Precautions and Contraindications.) Dosage of azathioprine sodium is expressed in terms of azathioprine. Azathioprine may be given as a single daily dose or in divided doses.

The manufacturers and some clinicians recommend that thiopurine methyl transferase (TPMT) phenotype or genotype be determined prior to initiation of azathioprine therapy, since risk of hematologic toxicity may be increased in patients with intermediate, low, or absent activity of the enzyme and decreased dosage or alternative therapy should be considered in these individuals.(See Pharmacokinetics: Elimination and see Cautions: Precautions and Contraindications.)

Renal Allotransplantation

The usual oral dosage of azathioprine in adults undergoing renal transplantation is 3-5 mg/kg daily beginning on the day of (and in some cases 1-3 days before) transplantation. Following transplantation, the drug may be given IV in the same dosage until the patient can tolerate oral therapy (usually 1-4 days). Dosage reduction to maintenance levels of 1-3 mg/kg daily is usually possible. When severe hematologic or other toxicity occurs, discontinuance of azathioprine therapy may be required even if rejection of the allograft may be a consequence of drug withdrawal.

Rheumatoid Arthritis

For the treatment of severe, active rheumatoid arthritis, the usual initial oral adult dosage of azathioprine is 1 mg/kg (approximately 50-100 mg) daily. If the initial response is unsatisfactory and no serious adverse effects occur after 6-8 weeks of therapy, daily dosage may be increased by 0.5 mg/kg; daily dosage may then be increased as necessary at 4-week intervals by 0.5 mg/kg up to a maximum of 2.5 mg/kg. A therapeutic response usually occurs after 6-8 weeks of therapy; an adequate trial should be a minimum of 12 weeks. Patients who do not respond after 12 weeks can be considered unresponsive to the drug. Therapy may be continued in patients who respond, but patients must be closely monitored and gradual dosage reduction to the lowest possible effective level should be attempted. Daily maintenance dosage may be reduced to the lowest possible effective level in increments of 0.5 mg/kg (or approximately 25 mg) every 4 weeks, while keeping other therapy constant. The optimum duration of maintenance therapy has not been determined. Azathioprine may be administered in a single or twice-daily doses.

Crohn's Disease

For the management of Crohn's disease, adults have received an oral azathioprine dosage of 2-4 mg/kg daily, while pediatric patients have received 1.5-2 mg/kg daily.

Cautions

Malignancies and Lymphoproliferative Disorders

Chronic immunosuppression with azathioprine increases the risk of malignancy. Patients receiving immunosuppressive drugs, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Malignancies, including posttransplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease, have been reported.(See Cautions: Precautions and Contraindications.)

Renal transplant recipients have an increased risk of developing malignancy (e.g., skin cancer, reticulum cell sarcoma, lymphomas). The risk of posttransplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including azathioprine. Therefore, therapy with immunosuppressive drugs should be maintained at the lowest effective dosage.

The incidence of lymphoproliferative disease in patients with rheumatoid arthritis appears to be substantially higher than that in the general population. The precise risk of malignancy associated with azathioprine is unknown; however, evidence suggests that the risk may be elevated in patients with rheumatoid arthritis, although to a lesser extent than in renal transplant patients. Limited data are available on the incidence and risk of malignancy in patients with rheumatoid arthritis receiving azathioprine. In one study, the incidence of lymphoproliferative disease in patients with rheumatoid arthritis receiving higher-than-recommended doses of azathioprine 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 the drug. However, the proportion of risk attributable to the azathioprine dosage or to other therapies (e.g., alkylating agents) in these patients has not been determined. Acute myelogenous leukemia and solid tumors have been reported in patients with rheumatoid arthritis who received the drug. Patients with rheumatoid arthritis who have previously been treated with alkylating agents (e.g., cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of malignancy if treated with azathioprine.

Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal type of T-cell lymphoma, has been reported during postmarketing experience mainly in adolescent and young adult males with Crohn's disease or ulcerative colitis who received treatment with thiopurine analogs (azathioprine or mercaptopurine) and/or tumor necrosis factor (TNF) blocking agents. Although most of the reported cases occurred in patients who had received a combination of immunosuppressive agents, including TNF blocking agents and thiopurine analogs (azathioprine or mercaptopurine), cases have been reported in patients receiving azathioprine or mercaptopurine alone. As of December 31, 2010, the US Food and Drug Administration (FDA) had identified 12 cases of hepatosplenic T-cell lymphoma in patients with Crohn's disease or ulcerative colitis who had received azathioprine without concomitant or sequential immunosuppressive therapy. These 12 cases of hepatosplenic T-cell lymphoma occurred mostly in patients 15-45 years of age (median age: 21 years) following 4-17 years of azathioprine therapy; most of the patients were males, and 10 of the 12 cases were fatal. In addition, FDA identified 25 cases of hepatosplenic T-cell lymphoma in patients with Crohn's disease or ulcerative colitis who had received a TNF blocking agent (infliximab or both infliximab and adalimumab); in 22 of these cases, a thiopurine analog (azathioprine or mercaptopurine) was used concomitantly. In some cases, potential confounding factors could not be excluded because complete medical histories were not available. Since patients with certain conditions (e.g., Crohn's disease, rheumatoid arthritis) may be at increased risk for lymphoma, it may be difficult to measure the added risk of treatment with TNF blocking agents, azathioprine, and/or mercaptopurine.(See Cautions: Precautions and Contraindications.)

Hematologic Effects

The principal toxic effect of azathioprine is bone marrow depression manifested by leukopenia, anemias including macrocytic anemia, pancytopenia, and thrombocytopenia, which may result in prolongation of clotting time and eventual hemorrhage. Hematologic effects are dose related and may be more severe in renal transplant patients whose allograft is undergoing rejection. Delayed hematologic suppression may occur. Hematologic status must be carefully monitored. (See Cautions: Precautions and Contraindications.)

When receiving usual dosages of azathioprine, patients with intermediate levels of thiopurine methyl transferase (TPMT) activity (about 10-11% of the population) may be at increased risk of developing myelotoxicity, while those with low or absent levels of the enzyme (0.3% of the population) are at increased risk of life-threatening myelotoxicity. Reduced dosage is recommended in patients with intermediate TPMT activity, while alternative therapy may be considered in those with low or absent levels of TPMT.

GI Effects

Nausea, vomiting, anorexia, and diarrhea may occur in patients receiving large doses of azathioprine. Adverse GI effects may be minimized by giving the drug in divided doses and/or after meals. Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis.

A GI hypersensitivity reaction characterized by severe nausea and vomiting has been reported. This reaction also may be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and, occasionally, hypotension. Symptoms of GI toxicity most often develop within the first several weeks of azathioprine therapy and are reversible upon discontinuance of the drug. The reaction can occur within several hours after rechallange with a single dose of the drug.

Other adverse GI effects include ulceration of the mucous membranes of the mouth, esophagitis with possible ulceration, and steatorrhea.

Hepatic Effects

Hepatotoxicity manifested by increased serum alkaline phosphatase, bilirubin, and/or aminotransferase concentrations may occur in patients receiving azathioprine, principally in allograft recipients. Azathioprine-induced hepatotoxicity following transplantation occurs most frequently within 6 months of transplantation and is generally reversible following discontinuance of the drug. Rare, but life-threatening hepatic veno-occlusive disease has occurred during chronic azathioprine therapy in several renal allograft recipients and in a patient with panuveitis; serious complications, including progressive portal hypertension, progressive liver failure requiring a portacaval shunt, progressive chronic liver failure with portal hypertension and esophageal varices, and/or rapid deterioration resulting in death, occurred in most of these patients. Veno-occlusive disease was associated with cytomegalovirus infection in some of these patients and with use of azathioprine but not with dosage of the drug, type or duration of renal allograft, or type of underlying renal disease. Reports to date suggest that the onset of hepatic veno-occlusive disease generally occurs after 1-2 years of therapy and that the disease occurs principally in males. The clinical syndrome is usually manifested initially by jaundice, often followed by the development of ascites and other signs of portal hypertension. Serum alkaline phosphatase and bilirubin concentrations are usually elevated. Prognosis is poor. Because hepatic veno-occlusive disease may result in rapid clinical deterioration, prompt diagnosis and therapeutic intervention are necessary. Many clinicians suggest that liver biopsy to diagnose veno-occlusive disease should be performed in renal allograft recipients receiving azathioprine at the first sign of mild hepatic dysfunction. If veno-occlusive disease is evident, azathioprine therapy should be promptly and permanently discontinued; alternative immunosuppressive therapy should be considered and, if liver failure is progressive, anticoagulation, a portacaval shunt, or hepatic allotransplantation should be considered.

Hepatotoxicity occurs in less than 1% of patients with rheumatoid arthritis who receive azathioprine.

Other Adverse Effects

Azathioprine may also cause rash, infection, drug fever, serum sickness, alopecia, arthralgia, retinopathy, Raynaud's disease, reversible interstitial pneumonitis, and pulmonary edema. Some of these adverse effects can occur as manifestations of rare hypersensitivity reactions. Azathioprine-induced hypersensitivity reactions are often characterized by a combination of symptoms, including fever, rigors, musculoskeletal symptoms (arthralgias, myalgias), and/or cutaneous effects (generalized erythematous or maculopapular rash with nonspecific inflammatory changes demonstrated on biopsy); pulmonary manifestations (e.g., cough and/or dyspnea) and hypotension (which may be severe and, in the presence of fever, mimic septic shock) may also occur. Sweet's syndrome (acute febrile neutrophilic dermatosis) also has been reported.

Precautions and Contraindications

Azathioprine is a toxic drug and must be used only under close medical supervision. Clinicians using azathioprine should be thoroughly familiar with the risks for development of malignancy, the mutagenic potential of the drug in female and male patients, and the possible hematologic toxicities associated with the immunosuppressant. Other immunosuppressive therapy given concomitantly with azathioprine therapy may increase the toxic potential of the drug.

Patients who have received azathioprine therapy should be monitored for the occurrence of malignancies since these patients are at increased risk for developing lymphoma and other malignancies, particularly of the skin. Because therapy with thiopurine analogs (azathioprine or mercaptopurine) and/or TNF blocking agents may increase the risk of malignancies, including hepatosplenic T-cell lymphoma, the risks and benefits of these agents should be carefully considered, especially in adolescents and young adults with Crohn's disease or ulcerative colitis. Patients and caregivers should be informed of the increased risk of malignancy associated with azathioprine, including the potential increased risk of hepatosplenic T-cell lymphoma, especially in adolescents and young adults with inflammatory bowel disease who receive treatment with thiopurine analogs (azathioprine or mercaptopurine) and/or TNF blocking agents, and should be advised of the relative risks and benefits of these and other immunosuppressive agents. Patients and caregivers should be informed of the signs and symptoms of malignancies such as hepatosplenic T-cell lymphoma (e.g., splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) and advised to contact a clinician if such signs or symptoms occur. Patients should be advised not to discontinue therapy without consulting a clinician. Because therapy with azathioprine increases the risk for skin cancer, patients receiving the drug should be advised to limit exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor.(See Cautions: Malignancies and Lymphoproliferative Disorders.)

Because patients with intermediate levels of thiopurine methyl transferase (TPMT; an enzyme involved in the methylation of 6-mercaptopurine, a metabolite of azathioprine) may be at increased risk of developing hematologic toxicity and those with low or absent levels of the enzyme are at increased risk of life-threatening hematologic toxicity, the manufacturers and some clinicians recommend that TPMT phenotype or genotype be determined prior to initiation of azathioprine therapy.(See Pharmacokinetics: Elimination.) TPMT testing should be considered in patients with abnormal complete blood cell count (CBC) results that persist despite dosage reduction of azathioprine.

Hematologic status must be carefully monitored in patients receiving azathioprine. When azathioprine therapy is initiated, patients should be informed of the need for periodic blood counts while receiving the drug and encouraged to report any unusual bleeding or bruising to their clinician. Complete blood counts, including platelet counts, should be monitored weekly during the first month of therapy, twice monthly for the second and third months of therapy, and monthly thereafter (or more frequently if dosage alterations or other therapy changes are necessary). Since the drug effect may continue for several days after the last dose of azathioprine, to avoid irreversible depression of the bone marrow, dosage of azathioprine should be reduced or therapy interrupted from the first sign of abnormal depression of the bone marrow until the count stabilizes. Since azathioprine-induced leukopenia does not correlate with therapeutic effect, dosage of the drug should not be increased intentionally to decrease the leukocyte count.

Hepatic function must be carefully monitored in patients receiving azathioprine. Serum alkaline phosphatase, bilirubin, and aminotransferase concentrations should be determined periodically for early detection of possible hepatotoxicity. Consideration should be given to discontinuing the drug if jaundice occurs. If hepatic veno-occlusive disease is clinically suspected, azathioprine therapy should be promptly and permanently discontinued; appropriate diagnostic and therapeutic measures should be initiated.(See Cautions: Hepatic Effects.) In patients with preexisting liver dysfunction, azathioprine should be administered with caution.

Despite the use of immunosuppressive therapy, the successful outcome of renal transplantation is largely dependent on careful donor selection. Although acute rejection of kidney transplants may be prevented or treated by the use of immunosuppressive therapy, signs of chronic rejection of the organ may occur; these changes may not be apparent until several months or years after transplantation.

Infection, which may be fatal, is a common hazard during therapy with immunosuppressive agents. Fungal, protozoal, viral, and uncommon bacterial infections may occur. Patients receiving azathioprine should be advised of the danger of infection during therapy with the drug and encouraged to report signs and symptoms of infection to their clinician. When infection occurs, dosage of azathioprine and/or other drugs used to prevent rejection should be reduced, and appropriate therapy for the infection instituted.

Patients receiving azathioprine, particularly those with impaired renal function or those receiving allopurinol concomitantly, should be given careful dosage instructions.(See Drug Interactions: Allopurinol.) Only small initial doses of azathioprine should be administered to patients with renal impairment, since the drug and its metabolites may be excreted more slowly in these patients and result in a greater cumulative effect. Because cadaveric kidneys often develop tubular necrosis and delayed onset of adequate function, clearance of azathioprine and mercaptopurine may be impaired; dosage should be appropriately reduced in these patients.

Persistent negative nitrogen balance and/or muscle wasting have been reported in some patients receiving prolonged therapy with azathioprine and corticosteroids; dosage should be reduced if this occurs.

Azathioprine is contraindicated in patients who are hypersensitive to the drug. If severe, continuous rejection occurs, it is probably preferable to allow the allograft to be rejected than to increase the dosage of azathioprine to very toxic levels.

Pediatric Precautions

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

Cases of hepatosplenic T-cell lymphoma have been reported in adolescents receiving azathioprine for the management of inflammatory bowel disease.(See Cautions: Malignancies and Lymphoproliferative Disorders.)

Mutagenicity and Carcinogenicity

Chronic immunosuppression with azathioprine increases the risk of malignancy in humans; malignancies, including posttransplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease, have been reported.(See Cautions: Malignancies and Lymphoproliferative Disorders.)

Azathioprine is mutagenic in humans. Chromosomal abnormalities have been documented in humans receiving azathioprine, but the abnormalities were reversed following discontinuance of the drug.

Pregnancy, Fertility, and Lactation

Pregnancy

Azathioprine is teratogenic in rabbits and mice when given in dosages equivalent to the human dosage (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies.

Azathioprine can cause fetal harm when administered to a pregnant woman. Limited immunologic and other abnormalities have occurred in some infants born to renal transplant recipients who received azathioprine. Lymphopenia, decreased IgG and IgM concentrations, cytomegalovirus infection, and a decreased thymic shadow were observed in one infant whose mother had received 150 mg of azathioprine and 30 mg of prednisone daily throughout pregnancy; most of these findings had apparently normalized by 10 weeks of age. Pancytopenia and severe immunodeficiency were reported in a premature infant whose mother received 125 mg of azathioprine and 12.5 mg of prednisone throughout pregnancy. Preaxial polydactyly was observed in one infant whose mother received 200 mg of azathioprine daily and 20 mg of prednisone every other day during pregnancy, while a large myelomeningocele in the upper lumbar region and bilateral lower limb deformities were reported in another infant whose father was receiving long-term azathioprine therapy. Azathioprine should not be used during pregnancy unless the potential benefits outweigh the possible risks; whenever possible, use of the drug during pregnancy should be avoided. If azathioprine is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be informed about the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant. The manufacturer states that azathioprine should not be used for the treatment of rheumatoid arthritis in pregnant women. Some clinicians state that, because of the potential for carcinogenesis and unknown long-term effects on fetal immunosuppression, use of azathioprine in pregnancy should be limited to women with severe or life-threatening rheumatoid arthritis. If azathioprine is administered during pregnancy, serious neonatal leukopenia and thrombocytopenia may be prevented by reducing the azathioprine dosage at 32 weeks' gestation; close prenatal monitoring for growth and long-term follow-up of offspring are essential.

Fertility

Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the usual human dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.

Lactation

Azathioprine or its metabolites are distributed into milk. Because of the potential for tumorigenicity associated with the drug, a decision should be made whether to discontinue nursing or the drug taking into account the importance of the drug to the woman.

Drug Interactions

Allopurinol

Allopurinol inhibits one of the metabolic pathways of azathioprine (i.e., the oxidative metabolism of mercaptopurine by xanthine oxidase), thus increasing the possibility of toxic effects of azathioprine, particularly bone marrow depression. When azathioprine and allopurinol are administered concomitantly, dosage of azathioprine should be reduced to 25-33% of the usual dosage, and subsequent dosage adjusted according to the patient response and toxic effects.

Angiotensin-converting Enzyme Inhibitors

Anemia and severe leukopenia may occur when angiotensin-converting enzyme (ACE) inhibitors are administered concomitantly with azathioprine.

Aminosalicylates

In vitro, aminosalicylates (mesalamine, olsalazine, sulfasalazine) have been shown to inhibit the enzyme thiopurine methyl transferase (TPMT), an enzyme involved in the methylation of 6-mercaptopurine (a metabolite of azathioprine). Caution should be used during concomitant administration of azathioprine with aminosalicylates.

Drugs affecting Myelopoiesis

Concomitant use of drugs affecting myelopoiesis (e.g., co-trimoxazole) with azathioprine may result in severe leukopenia, especially in patients who have undergone renal transplantation.

Ribavirin

Use of ribavirin for the treatment of hepatitis C virus (HCV) infection in patients receiving azathioprine has been reported to result in severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Ribavirin inhibits inosine monophosphate dehydrogenase, an enzyme required for one of the metabolic pathways of azathioprine; this leads to accumulation of an azathioprine metabolite, 6-methylthiopurine ribonucleoside-5'-phosphate (6-methylthioinosine monophosphate), that is associated with myelotoxicity (e.g., neutropenia, thrombocytopenia, anemia). Patients receiving azathioprine concomitantly with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month of therapy, twice monthly for the second and third months of therapy, and monthly thereafter (or more frequently if dosage or other therapy changes are necessary).

Warfarin

Azathioprine may inhibit the anticoagulant effect of warfarin.

Pharmacokinetics

Absorption

Azathioprine is readily absorbed from the GI tract. Following oral administration of usual doses of azathioprine, blood concentrations of the drug are usually less than 1 mcg/mL; however, because purine antagonists rapidly enter into anabolic and catabolic pathways of purines, blood measurements actually represent several compounds and the importance of blood concentrations is questionable.

Distribution

Distribution of azathioprine has not been fully characterized, but the drug is rapidly cleared from blood. Both mercaptopurine and azathioprine are approximately 30% bound to serum proteins, but both appear to be dialyzable. Azathioprine and its metabolites have been shown to cross the placenta.

Elimination

Azathioprine is metabolized in vivo to 6-mercaptopurine, apparently by sulfhydryl compounds such as glutathione. The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact. 6-Mercaptopurine is metabolized by 2 major competing metabolic pathways in erythrocytes and liver or, alternatively, 6-mercaptopurine is incorporated as cytotoxic 6-thioguanine nucleotides into DNA. The proportion of metabolites varies among individuals. 6-Mercaptopurine is oxidized to 6-thiouric acid by the enzyme xanthine oxidase. In addition, the sulfhydryl group of 6-mercaptopurine undergoes methylation, catalyzed by thiopurine methyl transferase (TPMT) to form the inactive metabolite methyl-6-mercaptopurine. The degree of activity of TPMT is under genetic control and is subject to individual variation. The most common nonfunctional alleles associated with reduced TPMT activity are TPMT*2, TPMT*3A, and TPMT*3C. Approximately 10% of Caucasians and African Americans inherit 1 nonfunctional allele (heterozygous) and have intermediate TPMT activity while about 0.3% of such populations inherit 2 nonfunctional alleles (homozygous) and have low or absent TPMT activity. Nonfunctional alleles are less common in the Asian population. There is an inverse relationship between TPMT activity and 6-thioguanine nucleotide concentrations in erythrocytes and, possibly, other hematopoietic tissues, because these cells have negligible amounts of xanthine oxidase (the enzyme involved in the other [oxidative] metabolism of 6-mercaptopurine), leaving TPMT methylation as the only inactivation pathway in these cells. Patients who have low TPMT activity have increased concentrations of the immunosuppressive 6-thiogunanine nucleotides in erythrocytes and, therefore, they may develop myelotoxicity. (See Cautions: Hematologic Effects and see Cautions: Precautions and Contraindications.) The fate of the nitromethylimidazole portion of azathioprine has not been completely elucidated. Small amounts of azathioprine are also split to give 1-methyl-4-nitro-5-thioimidazole. azathioprine is only partially dialyzable.