Azathioprine

Pronunciation

(ay za THYE oh preen)

U.S. Brand Names

Azasan®; Imuran®

Synonyms

Azathioprine Sodium

Generic Available

Yes

Canadian Brand Names

Alti-Azathioprine; Apo-Azathioprine®; Gen-Azathioprine; Imuran®

Use

Adjunct with other agents in prevention of rejection of kidney transplants; also used in severe active rheumatoid arthritis unresponsive to other agents; other autoimmune diseases (ITP, SLE, MS, Crohn's disease)

Use - Unlabeled/Investigational

Adjunct in prevention of rejection of solid organ (nonrenal) transplants

Pregnancy Risk Factor

Lactation

Excretion in breast milk unknown/not recommended

Contraindications

Hypersensitivity to azathioprine or any component of the formulation; pregnancy

Warnings/Precautions

Chronic immunosuppression increases the risk of neoplasia; has mutagenic potential to both men and women and with possible hematologic toxicities; use with caution in patients with liver disease, renal impairment; monitor hematologic function closely. Patients with genetic deficiency of thiopurine methyltransferase (TPMT) or concurrent therapy with drugs which may inhibit TPMT may be sensitive to myelosuppressive effects.

Adverse Reactions

Frequency not defined.

Central nervous system: Fever, chills

Dermatologic: Alopecia, erythematous or maculopapular rash

Gastrointestinal: Nausea, vomiting, anorexia, diarrhea, aphthous stomatitis, pancreatitis

Hematologic: Leukopenia, thrombocytopenia, anemia, pancytopenia (bone marrow suppression may be determined, in part, by genetic factors, ie, patients with TPMT deficiency are at higher risk)

Hepatic: Hepatotoxicity, jaundice, hepatic veno-occlusive disease

Neuromuscular & skeletal: Arthralgias

Ocular: Retinopathy

Miscellaneous: Rare hypersensitivity reactions which include myalgia, rigors, dyspnea, hypotension, serum sickness, rash; secondary infection may occur secondary to immunosuppression

Overdosage/Toxicology

Symptoms of overdose include nausea, vomiting, diarrhea, and hematologic toxicity. Following initiation of essential overdose management, symptomatic and supportive treatment should be instituted. Dialysis has been reported to remove significant amounts of the drug and its metabolites, and should be considered as a treatment option in those patients who deteriorate despite established forms of therapy.

Drug Interactions

ACE inhibitors: Concomitant therapy may induce leukopenia.

Allopurinol: May increase serum levels of azathioprine's active metabolite (mercaptopurine). Decrease azathioprine dose to ¹ /3 to ¹ /4 of normal dose.

Aminosalicylates (olsalazine, mesalamine, sulfasalazine): May inhibit TPMT, increasing toxicity/myelosuppression of azathioprine. Use caution.

Warfarin: Effect may be decreased by azathioprine.

Ethanol/Nutrition/Herb Interactions

Herb/Nutraceutical: Avoid cat's claw, echinacea (have immunostimulant properties).

Stability

Stability of parenteral admixture at room temperature (25°C ): 24 hours

Stability of parenteral admixture at refrigeration temperature (4°C): 16 days

Stable in neutral or acid solutions, but is hydrolyzed to mercaptopurine in alkaline solutions

Compatibility

Stable in D5W, ¹ /2NS, NS

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

Pharmacodynamics/Kinetics

Distribution: Crosses placenta

Protein binding: ~30%

Metabolism: Extensively hepatic via xanthine oxidase to mercaptopurine (active); mercaptopurine requires detoxification by thiopurine methyltransferase (TPMT)

Half-life elimination: Parent drug: 12 minutes; mercaptopurine: 0.7-3 hours; End-stage renal disease: Slightly prolonged

Excretion: Urine (primarily as metabolites)

Dosage

I.V. dose is equivalent to oral dose (dosing should be based on ideal body weight):

Children and Adults: Renal transplantation: Oral, I.V.: 2-5 mg/kg/day to start, then 1-3 mg/kg/day maintenance

Adults: Rheumatoid arthritis: Oral: 1 mg/kg/day for 6-8 weeks; increase by 0.5 mg/kg every 4 weeks until response or up to 2.5 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: Slightly dialyzable (5% to 20%)

Administer dose posthemodialysis: CAPD effects: Unknown; CAVH effects: Unknown

Administration

Azathioprine 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 over 15-60 minutes

Monitoring Parameters

CBC, platelet counts, total bilirubin, alkaline phosphatase

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 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.

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Aphthous stomatitis.

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

Dosage Forms

Injection, powder for reconstitution, as sodium: 100 mg

Tablet [scored]: 50 mg

Azasan®: 25 mg, 50 mg, 75 mg, 100 mg

Imuran®: 50 mg

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.

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.

International Brand Names

Alti-Azathioprine (CA); Apo-Azathioprine® (CA); Azafalk® (DE); Azahexal® (AU); Azamedac® (DE); Azamun® (AU, CZ, FI, NZ, RO); Azamune® (GB); Azanin® (JP); Azapress® (ZA); Aza-Q® (DE); Azarek® (CH, DE); azathiodura® (DE); Azathioprin 1A Pharma® (DE); Azathioprin AL® (DE); Azathioprin beta® (DE); Azathioprine® (GB, PL, RO, TR); Azathioprine PCH® (SG, TR); Azathioprine Pharmachemie® (TH); Azathioprin Hexal® (DE); Azathioprin-Puren® (DE); Azathioprin-ratiopharm® (DE); Azathioprin Stada® (DE); Azatioprina Asofarma® (AR); Azatioprina® (CL); Azatioprina Filaxis® (AR); Azatioprina Wellcome® (IT); Azatioprin NM Pharma® (SE); Azatrilem® (MX); Azopi® (IL); Azopine® (IE); Azoran® (IN); Colinsan® (DE); Gen-Azathioprine (CA); Immunoprin® (GB); Imuger® (IE); Imunen® (BR); Imuprin® (CY, FI, RO); Imuran® (AR, AU, BD, BE, BG, BR, CA, CL, CZ, EC, GB, HR, HU, ID, IE, IL, IN, KW, LU, MX, NL, NZ, PL, RO, RU, SG, SI, TH, TR, YU); Imuran® [inj.] (RO, TR); Imuran Paranova® (DK); Imurek® (AT, CH, DE); Imurek® [inj.] (AT, CH, DE); Imurel® (DK, ES, FI, FR, NO, SE); Oprisine® (GB); Thioprine® (AU, NZ); Transimune® (IN); Zaprine 50® (ZA); Zytrim® (DE)

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