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standards of non-Merck sources.
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.
Medication Safety Issues
Sound-alike/look-alike issues:
AzaTHIOprine may be confused with azaCITIDine, azatadine, azidothymidine, Azulfidine®
Imuran® may be confused with Elmiron®, Enduron®, Imdur®, Inderal®, Tenormin®
Azathioprine is metabolized to mercaptopurine; concurrent use of these commercially-available products has resulted in profound myelosuppression.
Pronunciation
(ay za THYE oh preen)
U.S. Brand Names
Index Terms
Generic Available
Yes
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Adjunctive therapy in prevention of rejection of kidney transplants; active rheumatoid arthritis
Use: Dental
Adjunct with prednisone for managing severe erosive lichen planus, major aphthous stomatitis, erythema multiforme, and benign mucous membrane pemphigoid
Use: Unlabeled/Investigational
Adjunct in prevention of rejection of solid organ (nonrenal) transplants; steroid-sparing agent for corticosteroid-dependent Crohn's disease (CD) and ulcerative colitis (UC); maintenance of remission in CD; fistulizing Crohn's disease
Pregnancy Risk Factor
D
Pregnancy Considerations
Azathioprine was found to be teratogenic in animal studies; temporary depression in spermatogenesis and reduction in sperm viability and sperm count were also reported in mice. Azathioprine crosses the placenta in humans; congenital anomalies, immunosuppression, and intrauterine growth retardation have been reported. There are no adequate and well-controlled studies in pregnant women. Azathioprine should not be used to treat arthritis during pregnancy. The potential benefit to the mother versus possible risk to the fetus should be considered when treating other disease states. The National Transplantation Pregnancy Registry (NTPR, Temple University) is a registry for pregnant women taking immunosuppressants following any solid organ transplant. The NTPR encourages reporting of all immunosuppressant exposures during pregnancy in transplant recipients at 877-955-6877.
Lactation
Enters breast milk/not recommended
Breast-Feeding Considerations
Due to risk of immunosuppression, breast-feeding is not recommended.
Contraindications
Hypersensitivity to azathioprine or any component of the formulation; pregnancy
Warnings/Precautions
Boxed warnings:
• Neoplasia: See “Concerns related to adverse effects” below.
Concerns related to adverse effects:
• Gastrointestinal toxicity: Within the first several weeks of therapy gastrointestinal toxicity (reversible) may occur; symptoms may include severe nausea, vomiting, diarrhea, rash, fever, malaise, myalgia, hypotension, and liver enzyme abnormalities.
• Hematologic toxicity: Dose-related hematologic toxicities (pancytopenia, thrombocytopenia) may occur, may be more severe with renal transplants undergoing rejection; monitor hematologic function closely.
• Infections: Chronic immunosuppression increases the risk of serious infections.
• Neoplasia: [U.S. Boxed Warning]: Chronic immunosuppression increases the risk of neoplasia; azathioprine has mutagenic potential to both men and women.
Disease-related concerns:
• Hepatic impairment: Use with caution in patients with hepatic impairment.
• Renal impairment: Use with caution in patients with renal impairment.
• Thiopurine methyltransferase (TPMT) deficiency: Patients with genetic deficiency of thiopurine methyltransferase (TPMT) may be sensitive to myelosuppressive effects.
Concurrent drug therapy issues:
• Mercaptopurine: Azathioprine is metabolized to mercaptopurine; concomitant use may result in profound myelosuppression and should be avoided.
• TPMT or xanthine oxidase inhibitors: Patients on concurrent therapy with drugs which may inhibit TPMT (eg, olsalazine) or xanthine oxidase (eg, allopurinol) may be sensitive to myelosuppressive effects.
Adverse Reactions
Frequency not defined; dependent upon dose, duration, and concomitant therapy.
Central nervous system: Chills, fever, malaise
Dermatologic: Alopecia, rash (erythematous or maculopapular)
Gastrointestinal: Diarrhea, nausea, pancreatitis, vomiting
Hematologic: Bleeding, leukopenia, macrocytic anemia, pancytopenia, thrombocytopenia
Hepatic: Hepatotoxicity, hepatic veno-occlusive disease, steatorrhea
Neuromuscular & skeletal: Arthralgia, myalgia
Respiratory: Interstitial pneumonitis
Miscellaneous: Hypersensitivity reactions (rare), infection secondary to immunosuppression, neoplasia
Drug Interactions
5-ASA Derivatives: May decrease the metabolism of Thiopurine Analogs. Risk C: Monitor therapy
ACE Inhibitors: May enhance the neutropenic effect of AzaTHIOprine. Risk C: Monitor therapy
Allopurinol: May decrease the metabolism of AzaTHIOprine. Risk D: Consider therapy modification
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Mercaptopurine: AzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine. Risk D: Consider therapy modification
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Vaccinal infections may develop. Immunosuppressants may also decrease therapeutic response to vaccines. Risk X: Avoid combination
Vitamin K Antagonists (eg, warfarin): AzaTHIOprine may diminish the anticoagulant effect of Vitamin K Antagonists. Risk C: Monitor therapy
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid cat's claw, echinacea (have immunostimulant properties).
Storage
Tablet: Store at room temperature of 15°C to 25?C (59?F to 77?F); protect from light.
Powder for injection: Store at room temperature of 15°C to 25?C (59?F to 77?F) and protect from light. Parenteral admixture is stable at room temperature (25°C ) for 24 hours, and stable under refrigeration (4°C) for 16 days.
Compatibility
Stable in D5W, 1/2NS, NS. Stable in neutral or acid solutions, but is hydrolyzed to mercaptopurine in alkaline solutions.
Mechanism of Action
Azathioprine is an imidazolyl derivative of mercaptopurine; antagonizes purine metabolism and may inhibit synthesis of DNA, RNA, and proteins; may also interfere with cellular metabolism and inhibit mitosis. The 6-thioguanine nucleotides appear to mediate the majority of azathioprine's immunosuppressive and toxic effects.
Pharmacodynamics/Kinetics
Distribution: Crosses placenta
Protein binding: ?30%
Metabolism: Hepatic, to 6-mercaptopurine (6-MP), possibly by glutathione S-transferase (GST). Further metabolism of 6-MP (in the liver and GI tract), via three major pathways: Hypoxanthine guanine phosphoribosyltransferase (to 6-thioguanine-nucleotides, or 6-TGN), xanthine oxidase (to 6-thiouric acid), and thiopurine methyltransferase (TPMT), which forms 6-methylmercapotpurine (6-MMP).
Half-life elimination: Parent drug: 12 minutes; mercaptopurine: 0.7-3 hours; End-stage renal disease: Slightly prolonged
Time to peak, plasma: 1-2 hours (including metabolites)
Excretion: Urine (primarily as metabolites)
Dosage
I.V. dose is equivalent to oral dose (dosing should be based on ideal body weight):
Children (unlabeled) and Adults:
Renal transplantation: Oral, I.V.: Initial: 3-5 mg/kg/day usually given as a single daily dose, then 1-3 mg/kg/day maintenance
Rheumatoid arthritis: Oral:
Initial: 1 mg/kg/day given once daily or divided twice daily for 6-8 weeks; increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 mg/kg/day; an adequate trial should be a minimum of 12 weeks
Maintenance dose: Reduce dose by 0.5 mg/kg every 4 weeks until lowest effective dose is reached; optimum duration of therapy not specified; may be discontinued abruptly
Adults: Oral:
Adjunctive management of severe recurrent aphthous stomatitis (unlabeled use): 50 mg once daily in conjunction with prednisone
Reduction of steroid use in CD or UC, maintenance of remission in CD or fistulizing disease (unlabeled uses): Initial: 50 mg daily; may increase by 25 mg/day every 1-2 weeks as tolerated to target dose of 2-3 mg/kg/day
Dosing adjustment in renal impairment:
Clcr 10-50 mL/minute: Administer 75% of normal dose daily
Clcr <10 mL/minute: Administer 50% of normal dose daily
Hemodialysis: Dialyzable (?45% removed in 8 hours)
Administer dose posthemodialysis: CAPD effects: Unknown; CAVH effects: Unknown
Dental Usual Dosing
Adjunctive management of severe recurrent aphthous stomatitis (unlabeled use): Adults: Oral: 50 mg once daily in conjunction with prednisone
Administration: Oral
Administering tablets after meals or in divided doses may decrease adverse GI events.
Administration: I.V.
Can be administered IVP over 5 minutes at a concentration not to exceed 10 mg/mL or azathioprine can be further diluted with normal saline or D5W and administered by intermittent infusion usually over 30-60 minutes; may be extended up to 8 hours.
Administration: I.V. Detail
pH: 9.6
Monitoring Parameters
CBC, platelet counts, total bilirubin, liver function tests, TPMT genotyping or phenotyping
For use as immunomodulatory therapy in CD or UC, monitor CBC with differential weekly for 1 month, then biweekly for 1 month, followed by monitoring every 1-2 months throughout the course of therapy. LFT's should be assessed every 3 months.
Dietary Considerations
May be taken with food.
Patient Education
Take as prescribed (may take in divided doses or with food if GI upset occurs). You will be susceptible to infection (avoid crowds and exposure to infection and do not have any vaccinations unless approved by prescriber). You may experience nausea, vomiting, loss of appetite (small frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help). Report abdominal pain and unresolved GI upset (eg, persistent vomiting or diarrhea); unusual fever or chills; bleeding or bruising; sore throat, unhealed sores, or signs of infection; yellowing of skin or eyes; or change in color of urine or stool.
Rheumatoid arthritis: Response may not occur for up to 3 months; do not discontinue medication without consulting prescriber.
Organ transplant: Azathioprine will usually be prescribed with other antirejection medications.
Pregnancy/breast-feeding precautions: Do not get pregnant while taking this medication; use appropriate contraceptive measures. Breast-feeding is not recommended.
Geriatric Considerations
Toxicity to immunosuppressives is increased in elderly. Start with lowest recommended adult doses. Signs of infection, such as fever and WBC rise, may not occur. Lethargy and confusion may be more prominent signs of infection. In the elderly, adjust dose to creatinine clearance.
Dental Health: Effects on Dental Treatment
No significant effects or complications reported
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
None reported
Mental Health: Effects on Psychiatric Treatment
May produce pancytopenia; use caution with clozapine and carbamazepine
Nursing: Physical Assessment/Monitoring
Assess effectiveness and interactions of other medications patient may be taking. Assess results of laboratory tests, therapeutic effectiveness (according to purpose for use) and adverse reactions at beginning of therapy and periodically throughout therapy, especially opportunistic infection. Assess knowledge/teach patient appropriate use, interventions to reduce side effects, and adverse symptoms to report.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 100 mg
Tablet [scored]: 50 mg
Azasan®: 75 mg, 100 mg
Imuran®: 50 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Azasan)
75 mg (30): $87.27
100 mg (30): $106.45
Tablets (Azathioprine)
50 mg (30): $27.99
Tablets (Imuran)
50 mg (30): $101.49
Extemporaneously Prepared
A 50 mg/mL oral suspension can be prepared by crushing one hundred twenty (120) 50 mg tablets in a mortar (reducing to a fine powder), and then mixing in a small amount of vehicle (a 1:1 combination of Ora-Sweet® or Ora-Sweet® SF and Ora-Plus®) to create a uniform paste. Continue to add vehicle in geometric amounts (while mixing) until near-final volume is achieved. Transfer to a graduate and add sufficient quantity to make 120 mL. Label “shake well” and “refrigerate.” Refrigerated stability is 60 days.
Allen LV Jr and Erickson MA III, “Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids,” Am J Health Syst Pharm, 1996, 53(16):1944-9.
Nahata MC, Morosco RS, and Hipple TF, 4th ed, Pediatric Drug Formulations, Cincinnati, OH: Harvey Whitney Books Co, 2000.
References
American College of Rheumatology Ad Hoc Committee on Clinical Guidelines, “Guidelines for Monitoring Drug Therapy in Rheumatoid Arthritis,” Arthritis Rheum, 1996, 39(5):723-31.
Baum D, Bernstein D, Starnes VA, et al, “Pediatric Heart Transplantation at Stanford: Results of a 15-Year Experience,” Pediatrics, 1991, 88(2):203-14.
Brookes MJ and Green JR, “Maintenance of Remission in Crohn's Disease: Current and Emerging Therapeutic Options,” Drugs, 2004, 64(10):1069-89.
Hodgins C, Mosley M, and Pola-Strowd M, “Recommendations for the Diagnosis and Management of Recurrent Aphthous Stomatitis,” University of Texas at Austin, School of Nursing, Family Nurse Practitioner Program, Austin; May 2003.
Hutchins LF and Lipschitz DA, “Cancer, Clinical Pharmacology, and Aging,” Clin Geriatr Med, 1987, 3(3):483-503.
Kaplan HG, “Use of Cancer Chemotherapy in the Elderly,” Drug Treatment in the Elderly, Vestal RE, ed, Boston, MA: ADIS Health Science Press, 1984, 338-49.
Leichter HE, Sheth KJ, Gerlach MJ, et al, “Outcome of Renal Transplantation in Children Aged 1-5 and 6-18 Years,” Child Nephrol Urol, 1992, 12(1):1-5.
Lichtenstein GR, Abreu MT, Cohen R, et al, “American Gastroenterological Association Institute Medical Position Statement on Corticosteroids, Immunomodulators, and Infliximab in Inflammatory Bowel Disease,” Gastroenterology, 2006, 130(3):935-9.
Matalon ST, Ornoy A, and Lishner M, et al, “Review of the \Potential Effects of Three Commonly Used Antineoplastic and Immunosuppressive Drugs (Cyclophosphamide, Azathioprine, Doxorubicin on the Embryo and Placenta),” Reprod Toxicol, 2004, 18(2):219-30.
Petri M, “Immunosuppressive Drug Use in Pregnancy,” Autoimmunity, 2003, 36(1):51-6.
Sandborn WJ, “A Review of Immune Modifier Therapy for Inflammatory Bowel Disease: Azathioprine, 6-mercaptopurine, Cyclosporine, and Methotrexate,” Am J Gastroenterol, 1996, 91(3):423-33.
Simon L, Lipman AG, Jacox A, et al, “Guideline for the Management of Osteoarthritis, Rheumatoid Arthritis and Juvenile Chronic Arthritis Pain,” 2nd ed, Glenview IL, American Pain Society, 2002.
International Brand Names
Lexi-Comp.com
Last full review/revision August 2008
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