Azathioprine Information
Azathioprine () Description
Azathioprine () , an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 50 mg Azathioprine () USP and the inactive ingredients anhydrous lactose, magnesium stearate, povidone, pregelatinized starch (corn starch), and stearic acid.
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. The sodium salt of Azathioprine () is sufficiently soluble to make a 10 mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). 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.
Azathioprine () is chemically 1-Purine, 6-[(1-methyl-4-nitro-1-imidazol-5-yl)thio]-. The structural formula of Azathioprine () is:
Azathioprine () Clinical Pharmacology
Azathioprine () is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 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 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 (
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 ). The cytotoxicity of Azathioprine () is due, in part, to the incorporation of 6-TGN into DNA.
6-MP undergoes two major inactivation routes (). 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. 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 () . TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing Azathioprine () toxicity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions (see , : , : and sections).
Azathioprine () 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.
Azathioprine () Contraindications
Azathioprine () Tablets USP should not be given to patients who have shown hypersensitivity to the drug. Azathioprine () Tablets USP 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 neoplasia if treated with Azathioprine () Tablets USP.
Azathioprine () Warnings
Azathioprine () is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s . 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. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia due to Azathioprine () . 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 () . Data on neoplasia in patients receiving Azathioprine () can be found under .
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 human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.
Azathioprine () Adverse Reactions
The principal and potentially serious toxic effects of Azathioprine () are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see ). The frequency and severity of adverse reactions depend on the dose and duration of Azathioprine () 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 () for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:
Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with Azathioprine () . 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. Macrocytic anemia and/or bleeding have been reported.
TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from Azathioprine () (see , and : ). Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving Azathioprine () .
Azathioprine () Overdosage
The oral LDs for single doses of Azathioprine () 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 Azathioprine () is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis. A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg Azathioprine () . 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.
Azathioprine () Dosage And Administration
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING Azathioprine () TABLETS
Azathioprine () 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. 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.
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.
Procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. Several guidelines on this subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
Azathioprine () How Supplied
NDC 0054-8084-25: Unit dose, 10 tablets per strip, 10 strips per shelf pack, 10 shelf packs per shipper.
NDC 0054-4084-25: Bottles of 100 tablets.
Azathioprine () References
Azathioprine () Package Label -
Each tablet contains 50 mg Azathioprine () .
