Imuran Information
Imuran ()
Imuran ()
Imuran () Description:
Imuran () (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid.
Azathioprine is chemically 6-[(1-methyl-4-nitro-1-imidazol-5-yl)thio]-1-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.
Imuran () 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 Imuran () . Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of Imuran () . TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing Imuran () toxicity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See , , and sections.
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 2002; 3:89-98; and 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 ). 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.
Imuran () Indications And Usage:
Imuran () 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:
Rheumatoid Arthritis:
Imuran () Contraindications:
Imuran () should not be given to patients who have shown hypersensitivity to the drug. Imuran () 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 Imuran () .
Imuran () Warnings:
Patients receiving immunosuppressants, including Imuran () , are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with Imuran () . 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.
Imuran () Precautions:
General:
Information for Patients:
Drug Interactions
DOSAGE AND ADMINISTRATION
Laboratory Tests:
Complete Blood Count (CBC) Monitoring:
TPMT Testing:
TPMT*2, TPMT*3A and TPMT*3C
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING Imuran () .
CLINICAL PHARMACOLOGY
WARNINGS
ADVERSE REACTIONS
DOSAGE AND ADMINISTRATION
Use with Aminosalicylates:
Use with Other Agents Affecting Myelopoesis:
Use with Angiotensin-Converting Enzyme Inhibitors:
Use with Warfarin:
Use with ribavirin:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
WARNINGS
Pregnancy:
Teratogenic Effects:
WARNINGS
Nursing Mothers:
17, 18, 19
Pediatric Use:
Imuran () Adverse Reactions:
The principal and potentially serious toxic effects of Imuran () are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see ). The frequency and severity of adverse reactions depend on the dose and duration of Imuran () 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 Imuran () for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:
Hematologic:
TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from Imuran () . See , and . Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.
Gastrointestinal:
PRECAUTIONS
21, 22, 23
Others:
Warnings – Malignancy
Imuran () Overdosage:
The oral LDs for single doses of Imuran () 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 Imuran () 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 Imuran () . 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.
Imuran () Dosage And Administration:
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING Imuran () .
Renal Homotransplantation:
Rheumatoid Arthritis:
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 Imuran () has not been determined. Imuran () can be discontinued abruptly, but delayed effects are possible.
Use in Renal Dysfunction:
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.
Imuran () How Supplied:
50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “Imuran () ” and “50” on each tablet; bottle of 100 (NDC 65483-590-10).
Imuran () References:
Imuran () and ZYLOPRIM are registered trademarks of Prometheus Laboratories Inc.
© 2011 Prometheus Laboratories Inc.
May 2011IM005I
Imuran ()
