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Special Alerts
Tumor Necrosis Factor (TNF) Blockers, Azathioprine, and/or Mercaptopurine: Reports of Hepatosplenic T-Cell Lymphoma (HSTCL)
April 2011
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals and the public of continued reports of a rare malignancy, Hepatosplenic T-Cell Lymphoma (HSTCL), occurring in patients receiving TNF blockers (eg, adalimumab, certolizumab pegol, etanercept, golimumab), azathioprine, and/or mercaptopurine. HSTCL is an aggressive form of a rare white blood cell cancer that is usually fatal. These reports have occurred predominately in adolescents and young adults being treated with these agents for Crohn's disease or ulcerative colitis; however, some case reports occurred in patients treated for psoriasis (one report) or rheumatoid arthritis (two reports). In addition, most of the reported cases of HSTCL have occurred in patients treated with a combination of immunosuppressant agents (including TNF blockers, azathioprine, mercaptopurine), although there have been reports of HSTCL in patients receiving azathioprine or mercaptopurine monotherapy.
The FDA is recommending prescribers discuss with patients the increased risk of HSTCL development, particularly in adolescents and young adults, when prescribing these and other immunosuppressant therapies. Healthcare professionals should monitor for the emergence of malignancies during therapy with TNF blockers, azathioprine, and/or mercaptopurine. Patients should be educated on the signs/symptoms of malignancy (eg, splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss) during use. The FDA is also reminding healthcare professionals that patients with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, and plaque psoriasis may be more likely to develop lymphoma compared to the general U.S. population, which can make assessing the additional risk of immunosuppressant use difficult to determine.
For additional information, please refer to http://www.fda.gov/Drugs/DrugSafety/ucm250913.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Pronunciation
(ay za THYE oh preen)
Generic Available (U.S.)
Yes
Index Terms
U.S. Brand Names
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Adjunctive therapy in prevention of rejection of kidney transplants; management of active rheumatoid arthritis (RA)
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 CD; dermatomyositis/polymyositis
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, hematologic toxicities (lymphopenia, pancytopenia), 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 and serious adverse effects in the nursing infant, breast-feeding is not recommended.
Contraindications
Hypersensitivity to azathioprine or any component of the formulation; pregnancy (in patients with rheumatoid arthritis); patients with rheumatoid arthritis and a history of treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of neoplasia with azathioprine treatment
Warnings/Precautions
Boxed warnings:
• Experienced physician: See “Other warnings/precautions” below.
• Neoplasia: See “Concerns related to adverse effects” below.
Special handling:
• Hazardous agent: Use appropriate precautions for handling and disposal.
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, delayed hematologic toxicities (leukopenia, thrombocytopenia, macrocytic anemia, pancytopenia) may occur; may be more severe with renal transplants undergoing rejection and patients with thiopurine methyltransferase (TPMT) deficiency; monitor hematologic function closely. May require dosage modification.
• Hepatotoxicity: Hepatotoxicity (transaminase, bilirubin, and alkaline phosphatase elevations) may occur, usually in renal transplant patients. Usually occurs within 6 months of transplant and is normally reversible with discontinuation. Monitor liver function periodically. Rarely, hepatic veno-occlusive disease (VOD) has been reported; discontinue if hepatic VOD is suspected.
• 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; dosage reductions may be necessary.
• TPMT deficiency: Patients with genetic deficiency of TPMT may be sensitive to myelosuppressive effects. Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity are at risk for developing severe and life-threatening hematologic toxicity. TPMT genotyping or phenotyping may assist in identifying patients at risk for developing toxicity. TPMT testing does not substitute for CBC monitoring.
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. Dose adjustment of azathioprine may be recommended when used concurrently with allopurinol; patients with low or absent TPMT activity may require further dose reductions or discontinuation.
• Vaccines: Immune response to vaccines may be diminished.
Other warnings/precautions:
• Experienced physician: [U.S. Boxed Warning]: Should be prescribed by physicians familiar with the risks, including hematologic toxicities and mutagenic potential.
Adverse Reactions
Frequency not always defined; dependent upon dose, duration, indication, and concomitant therapy.
Central nervous system: Fever, malaise
Gastrointestinal: Nausea/vomiting (RA: 12%), diarrhea
Hematologic: Leukopenia (renal transplant: >50%; RA: 28%), thrombocytopenia
Hepatic: Alkaline phosphatase increased, bilirubin increased, hepatotoxicity, transaminases increased
Neuromuscular & skeletal: Myalgia
Miscellaneous: Infection (renal transplant: 20%; RA: <1%; includes bacterial, fungal, protozoal, viral), neoplasia (other than lymphoma: 3%)
<1%, postmarketing, and/or case reports: Abdominal pain, alopecia, arthralgia, bleeding, bone marrow suppression, fever, hepatic veno-occlusive disease, hepatosplenic T-cell lymphoma, hypersensitivity, hypotension, interstitial pneumonitis, lymphoma, macrocytic anemia, negative nitrogen balance, pancreatitis, pancytopenia, rash, steatorrhea
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
BCG: Immunosuppressants may diminish the therapeutic effect of BCG. Risk X: Avoid combination
Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Risk C: Monitor therapy
Echinacea: May diminish the therapeutic effect of Immunosuppressants. Risk D: Consider therapy modification
Febuxostat: May increase the serum concentration of AzaTHIOprine. Risk X: Avoid combination
Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Risk D: Consider therapy modification
Mercaptopurine: AzaTHIOprine may enhance the myelosuppressive effect of Mercaptopurine. Risk X: Avoid combination
Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Risk X: Avoid combination
Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Ribavirin: May increase serum concentrations of the active metabolite(s) of AzaTHIOprine. Specifically, concentrations of potentially myelotoxic methylated metabolites may be increased, while concentrations of active 6-thioguanine nucleotides may be decreased. Management: Consider using alternative agent(s) when possible. When these drugs are used in combination, monitor patients extra closely for signs/symptoms of myelosuppression. Risk D: Consider therapy modification
Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Risk X: Avoid combination
Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Risk C: Monitor therapy
Sulfamethoxazole: May enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Risk X: Avoid combination
Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Risk C: Monitor therapy
Trimethoprim: May enhance the myelosuppressive effect of AzaTHIOprine. Risk C: Monitor therapy
Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Risk C: Monitor therapy
Vaccines (Live): AzaTHIOprine may enhance the adverse/toxic effect of Vaccines (Live). Risk D: Consider therapy modification
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 intact vials at room temperature of 15°C to 25°C (59°F to 77°F). Protect from light. Reconstituted solution is stable for up to 2 weeks at room temperature or up to 4 days refrigerated; solutions diluted in D5W, 1/2NS, or NS for infusion are stable at room temperature or refrigerated for up to 16 days; however, the manufacturer recommends use within 24 hours of reconstitution.
Reconstitution
Powder for injection: Reconstitute each vial with 10 mL sterile water for injection; may further dilute for infusion (in D5W, 1/2NS, or NS). Use appropriate precautions for handling and disposal.
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
Absorption: Oral: Well absorbed
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
Note: Patients with intermediate TPMT activity may be at risk for increased myelosuppression; those with low or absent TPMT activity receiving conventional azathioprine doses are at risk for developing severe, life-threatening myelotoxicity. Dosage reductions are recommended for patients with reduced TPMT activity.
I.V. dose is equivalent to oral dose (dosing should be transitioned from I.V. to oral as soon as tolerated):
Children (unlabeled) and Adults:
Renal transplantation (treatment usually started the day of transplant, however, has been initiated [rarely] 1-3 days prior to transplant): 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
Adjunctive management of dermatomyositis/polymyositis (unlabeled use): 50 mg/day in conjunction with prednisone; increase by 50 mg/week to total dose of 2-3 mg/kg/day (Briemberg, 2003); Note: Onset of beneficial effects may take 3-6 months; however, may be preferred over methotrexate in patients with pulmonary or hepatic toxicity.
Reduction of steroid use in CD or UC, maintenance of remission in CD or fistulizing disease (unlabeled uses): Initial: 50 mg once daily; may increase by 25 mg/day every 1-2 weeks as tolerated to target dose of 2-3 mg/kg/day
Dosage adjustment for concomitant use with allopurinol: Reduce azathioprine dose to one-third or one-fourth the usual dose when used concurrently with allopurinol. Patients with low or absent TPMT activity may require further dose reductions or discontinuation.
Dosage adjustment for toxicity:
Rapid WBC count decrease, persistently low WBC count, or serious infection: Reduce dose or temporarily withhold treatment
Severe toxicity in renal transplantation: May require discontinuation
Hepatic veno-occlusive disease: Permanently discontinue
Dosing adjustment in renal impairment: Although dosage reductions are recommended, specific guidelines are not available in the FDA-approved labeling; the following guidelines have been used by some clinicians (Aronoff, 2007):
Clcr >50 mL/minute: No adjustment recommended
Clcr 10-50 mL/minute: Administer 75% of normal dose
Clcr <10 mL/minute: Administer 50% of normal dose
Hemodialysis (dialyzable; ~45% removed in 8 hours): Children: Administer 50% of normal dose; Adults: Supplement: 0.25 mg/kg
CAPD: Children: Administer 50% of normal dose; Adults: Unknown
CRRT: Children and Adults: Administer 75% of normal dose
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 with differential and platelets (weekly during first month, twice monthly for months 2 and 3, then monthly; monitor more frequently with dosage modifications), 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. LFTs should be assessed every 3 months.
Test Interactions
TPMT phenotyping results will not be accurate following recent blood transfusions.
Dietary Considerations
May be taken with food.
Patient Education
May take in divided doses or with food if GI upset occurs. You will be susceptible to infection. You may experience nausea, vomiting, loss of appetite. 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. For rheumatoid arthritis, response may not occur for up to 3 months. For organ transplant, azathioprine will usually be prescribed with other antirejection medications.
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
Monitor for opportunistic infection.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Injection, powder for reconstitution: 100 mg
Tablet, oral: 50 mg
Azasan®: 75 mg, 100 mg [scored]
Imuran®: 50 mg [scored]
Pricing: U.S. (www.drugstore.com)
Tablets (Azasan)
75 mg (30): $129.99
100 mg (30): $161.89
Tablets (AzaTHIOprine)
50 mg (30): $27.99
Tablets (Imuran)
50 mg (30): $159.99
Extemporaneously Prepared
A 50 mg/mL oral suspension may be made with tablets. Crush one-hundred-twenty 50 mg tablets in a mortar and reduce to a fine powder. Add 40 mL of either cherry syrup (diluted 1:4 with Simple Syrup, USP); a 1:1 mixture of Ora-Sweet® and Ora-Plus®; or a 1:1 mixture of Ora-Sweet® SF and Ora-Plus®, and mix to a uniform paste. Mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable for 60 days.
Allen LV Jr and Erickson MA 3rd, "Stability of Acetazolamide, Allopurinol, Azathioprine, Clonazepam, and Flucytosine in Extemporaneously Compounded Oral Liquids," Am J Health Syst Pharm, 1996, 53(16):1944-9.
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.
Aronoff GR, Bennett WM, Berns JS, et al, Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children, 5th ed. Philadelphia, PA: American College of Physicians; 2007, p 97, 177.
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.
Briemberg HR and Amato AA, “Dermatomyositis and Polymyositis,” Curr Treat Options Neurol, 2003, 5(5):349-56.
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.
Johnson CA and Porter WA, “Compatibility of Azathioprine Sodium With Intravenous Fluids,” Am J Hosp Pharm, 1981, 38(6):871-5.
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.
Kornbluth A and Sachar DB, “Ulcerative Colitis Practice Guidelines in Adults: American College of Gastroenterology, Practice Parameters Committee,” Am J Gastroenterol, 2010, 105(3):501-23.
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.
Lichtenstein GR, Hanauer SB, and Sandborn WJ, “Management of Crohn's Disease in Adults,” Am J Gastroenterol, 2009, 104(2):465-83.
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 May 2011
Content last modified May 2011
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