Class: Immunosuppressive Agents
VA Class: IM600
CAS Number: Azathioprine: 446-86-6
Brands: Azasan, Imuran
Special Alerts:
[Posted 04/14/2011] ISSUE: FDA continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL, primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factors (TNF) blockers, as well as with azathioprine, and/or mercaptopurine. TNF blockers include infliximab (Remicade), etancercept (Enbrel), adalimumab (Humira), certolizumab pegol (Cimzia) and golimumab (Simponi).
BACKGROUND: HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.
Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.
Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.
Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.
Know that people with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or meracaptopurine.
Read the Drug Safety Communications for other specific recommendations for Healthcare Professionals and Patients and the Data Summary for additional information. For more information visit the FDA website at: and .
Long-term immunosuppression with azathioprine increases risk of neoplasia in humans.100 134
Only clinicians familiar with the risks, mutagenic potential, and possible hematologic toxicity should prescribe azathioprine.100 134
Introduction
Immunosuppressive antimetabolite.100 134
Uses for Azathioprine Sodium
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Renal Allotransplantation
Prevention of rejection of renal allografts.100 134
Rheumatoid Arthritis
Management of the signs and symptoms of rheumatoid arthritis.100 134
Crohn’s Disease
Has been used to induce and maintain remission in adults with moderate to severely or chronically active Crohn’s disease†.110 111 112 113 114 117 118 119 120 122
Has been used in the management of fistulizing Crohn’s disease†.111 115 116 131 132
Has been used in children with refractory or corticosteroid-dependent Crohn’s disease†.128 129 133
Azathioprine Sodium Dosage and Administration
General
Azathioprine is an antimetabolite and is handled according to guidelines for cytotoxic drugs.100 c Consult specialized references for procedures for proper handling and disposal of hazardous drugs.100 134
Administration
Administer orally or by slow IV injection or IV infusion.100 134
Low-dose corticosteroids and NSAIAs (including aspirin) may be continued in patients with rheumatoid arthritis.100 134 The manufacturers state that combined use of azathioprine and other disease modifying antirheumatic drugs (DMARDs) has not been studied and is not recommended.100 134
Oral Administration
Administer once or twice daily.100 134
IV Administration
When used for renal allotransplantation, the IV route may be used initially in patients unable to tolerate oral medication.100 Institute oral therapy as soon as possible (at the same dosage).100 c
Reconstitution and Dilution
For solution and drug compatibility information, see Compatibility under Stability.
Reconstitute vial containing 100 mg of azathioprine with 10 mL of sterile water for injection.100 Reconstituted solution may be further diluted prior to administration (final volume depends on infusion time).100
Rate of Administration
Usually infused over 30–60 minutes; may be administered over 5 minutes to 8 hours.100
Dosage
Available as azathioprine and azathioprine sodium; dosage expressed as azathioprine.100 134
Consider determining thiopurine methyl transferase (TPMT) phenotype or genotype prior to initiation of therapy and using results to select dosage.100 (See Hematologic Effects and TPMT Testing under Cautions.)
If rapid fall in leukocyte count, persistent leukopenia, or other evidence of bone marrow suppression develops, temporarily discontinue or reduce dosage.100 134 Consider TPMT testing in patients with abnormal CBC results that persist despite dosage reduction.100 (See Hematologic Effects and TPMT Testing under Cautions.)
If used with allopurinol, adjustment in the treatment regimen recommended.100 134 (See Specific Drugs under Interactions.)
If severe, continuous rejection occurs, it is probably preferable to allow the allograft to be rejected than to increase the dosage of azathioprine to very toxic levels.c
Pediatric Patients
Renal Allotransplantation
Oral
Initially, 3–5 mg/kg as a single daily dose has been used beginning on the day of transplantation (and in some cases 1–3 days before transplantation).100 134 c Reduction to maintenance dosage of 1–3 mg/kg daily usually possible.100 134 c
IV
3–5 mg/kg as a single daily dose has been used beginning on the day of transplantation (and in some cases 1–3 days before transplantation) until the patient is able to tolerate oral administration (usually 1–4 days).100 c
Crohn’s Disease†
Oral
1.5–2 mg/kg daily has been used.128 129 133
Adults
Renal Allotransplantation
Oral
Initially, 3–5 mg/kg as a single daily dose beginning on the day of transplantation (and in some cases 1–3 days before transplantation).100 134 c Reduction to maintenance dosage of 1–3 mg/kg daily usually possible.100 134
IV
3–5 mg/kg as a single daily dose beginning on the day of transplantation (and in some cases 1–3 days before transplantation) until the patient is able to tolerate oral administration (usually 1–4 days).100
Rheumatoid Arthritis
Oral
Initially, 1 mg/kg (50–100 mg) daily in 1 or 2 doses.100 134
If initial response unsatisfactory and there are no serious adverse effects after 6–8 weeks, the daily dosage may be increased by 0.5 mg/kg.100 134 Thereafter, daily dosage may be increased, if needed, by 0.5 mg/kg every 4 weeks up to a maximum dosage of 2.5 mg/kg daily.100 134 Patients whose disease does not improve after 12 weeks of therapy are considered nonresponders.100 134
When used for maintenance dosage, use lowest effective dosage to reduce toxicities.100 134 Dosage can be reduced in increments of 0.5 mg/kg (approximately 25 mg) daily every 4 weeks while other therapy is kept constant.100 134
Optimum duration of therapy undetermined.100 134
Crohn’s Disease†
Oral
2–4 mg/kg daily has been used.116 119 126 132
Prescribing Limits
Adults
Rheumatoid Arthritis
Oral
Maximum 2.5 mg/kg daily.100 134
Special Populations
Renal Impairment
Use low initial dosage in patients with renal impairment.c
Renal Allotransplantation
Lower dosage may be necessary in relatively oliguric patients, especially in those with tubular necrosis in the immediate posttransplant period.100 134
Cautions for Azathioprine Sodium
Contraindications
Known hypersensitivity to azathioprine or any ingredient in the formulation.100 134
Management of rheumatoid arthritis in pregnant women.100 134
Management of rheumatoid arthritis in patients previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan), because of prohibitive risk of neoplasia.100 134 c
Warnings/Precautions
Warnings
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Hematologic Effects
Severe leukopenia, thrombocytopenia, macrocytic anemia, pancytopenia reported.100 134 Delayed hematologic suppression may occur.100 134
When receiving usual dosages of azathioprine, patients with low or absent levels of S- methyl transferase (TPMT) activity (0.3% of the population) are at increased risk of life-threatening myelotoxicity; alternative therapy advised.100 135 Patients with intermediate TPMT activity (10–11% of the population) are at increased risk of hematologic toxicity; dosage reduction recommended.100 135
Hematologic toxicity is dose-related and may be more severe in patients undergoing graft rejection.100 134
Perform CBC, including platelet count, weekly during the first month of therapy, twice monthly during the second and third months, then monthly thereafter; monitor more frequently if therapy changes are needed.100 134
If rapid decrease in leukocyte count, persistent leukopenia, or other evidence of bone marrow suppression develops, promptly reduce dosage or temporarily discontinue the drug.100 134
Azathioprine-induced leukopenia does not correlate with therapeutic effect; do not increase dosage intentionally to decrease leukocyte count.100
Infectious Complications
Increased susceptibility to infection (i.e., opportunistic infections, sepsis, life-threatening/fatal infections).100 134 Reduce dosage or consider alternative therapy.100 134
Carcinogenicity
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Increased risk of neoplasia.100 134
Fetal/Neonatal Morbidity and Mortality
May cause fetal harm; teratogenicity demonstrated in animals.100 134
Avoid use in pregnant women unless benefits outweigh risks.100 134
Avoid pregnancy during therapy.100 134 If patient becomes pregnant, apprise of potential fetal hazard.100 134
Manufacturers state that azathioprine should not be used to treat rheumatoid arthritis in pregnant women;100 134 some clinicians state that use in pregnancy should be limited to women with severe or life-threatening rheumatoid arthritis.109
Serious neonatal leukopenia and thrombocytopenia may be prevented by reducing azathioprine dosage at 32 weeks’ gestation; monitor prenatal growth and follow offspring long-term.109
Sensitivity Reactions
GI Hypersensitivity
Severe nausea and vomiting, sometimes accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, hypotension, reported.100 134 Develops during the first several weeks of therapy; reversible upon discontinuation; can occur after rechallenge.100 134
General Precautions
TPMT Testing
Genetically determined differences in TPMT activity may lead to differences in patient response and/or toxicity.100 135 (See Hematologic Effects under Cautions.) The most common nonfunctional alleles associated with reduced TPMT activity are TPMT*2, TPMT*3A, and TPMT*3C.100 Patients with 2 nonfunctional alleles (homozygous) have low or absent TPMT activity; those with 1 nonfunctional allele (heterozygous) have intermediate activity.100
Consider determining the TPMT genotype or phenotype prior to initiating therapy and in patients with abnormal CBC results that persist despite dose reduction.100 (See Hematologic Effects under Cautions and see Dosage.)
Specific Populations
Pregnancy
Category D.100 134 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Lactation
Distributed into human milk.100 134 Discontinue nursing or the drug because of potential tumorigenicity.100 134
Pediatric Use
Safety and efficacy not established.100 134
Renal Impairment
Dosage adjustment may be needed.100 134
Common Adverse Effects
Hematologic, GI (nausea, vomiting).100 134
Interactions for Azathioprine Sodium
Specific Drugs
Drug | Interaction | Comments |
---|---|---|
ACE inhibitors | Potential for increased toxicity (anemia, severe leukopenia)100 134 | |
Allopurinol | Possible pharmacokinetic interaction; increased risk of azathioprine toxicity100 134 | Reduce azathioprine dosage to 25–33% of usual dosage; consider further dosage reduction or alternative therapy in patients with low or absent TPMT activity100 134 |
Aminosalicylates (mesalamine, olsalazine, sulfasalazine) | Possible pharmacokinetic interaction; increased risk of azathioprine toxicity100 134 | Use concomitantly with caution100 134 |
Drugs affecting myelopoiesis (e.g., co-trimoxazole) | Possible increased toxicity (leukopenia) especially in renal transplant recipients100 134 | |
Warfarin | Possible reduced anticoagulant effect100 134 |
Azathioprine Sodium Pharmacokinetics
Absorption
Bioavailability
Well absorbed following oral administration, with peak serum concentration attained within 1–2 hours.100 134
Onset
Following oral administration in patients with rheumatoid arthritis, therapeutic response usually occurs after 6–8 weeks.100 134
Distribution
Extent
Not fully characterized.c
Plasma Protein Binding
30%.100 134
Elimination
Metabolism
Metabolized to 6-mercaptopurine.100 134 6-Mercaptopurine is metabolized by 2 competing metabolic pathways or is incorporated as cytotoxic nucleotides into DNA.100 6-Mercaptopurine undergoes thiol methylation (catalyzed by TPMT) to an inactive metabolite.100 6-Mercaptopurine also undergoes oxidation (catalyzed by xanthine oxidase).100
Elimination Route
Excreted in urine, principally as metabolites.c
Half-life
Radiolabeled metabolites: 5 hours.100 134
Stability
Storage
Oral
Tablets
Controlled room temperature; protect from light.100 134
Parenteral
Powder for Injection
15–25°C; protect from light.100 Following reconstitution, use within 24 hours.100
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Parenteral
Solution CompatibilityHID
Compatible |
---|
Dextrose 5% |
Sodium Chloride 0.45% or 0.9% |
ActionsActions
Imidazolyl derivative of 6-mercaptopurine; a purine antimetabolite.100 134
Exact mechanism(s) of immunosuppression not fully elucidated; cytotoxicity due, in part, to incorporation of cytotoxic (6-thioguanine) nucleotides into DNA.100 134
Inhibits graft rejection; little effect on established graft rejections or secondary responses.100 134
Suppresses disease manifestations and underlying pathology in animal models of autoimmune disease.100 134
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.
Necessity of routine laboratory testing (e.g., CBC).100 134
Importance of informing clinician of any evidence of infection, unusual bleeding, bruising, or other manifestation of bone marrow suppression.100 134
Importance of taking azathioprine as directed.100 134
Increased risk of neoplasia.100 134
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed; importance of advising women to avoid pregnancy while receiving azathioprine.100 134
Importance of informing clinicians of existing or contemplated therapy, including prescription (e.g., allopurinol) or OTC drugs, as well as concomitant illnesses.100 134
Importance of informing patients of other important precautionary information.100 134 (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Oral | Tablets | 50 mg* | Azathioprine Tablets (with povidone; scored) | Roxane, Sandoz |
Imuran (with povidone; scored) | Prometheus | |||
75 mg | Azasan (with povidone; scored) | Salix | ||
100 mg | Azasan (with povidone; scored) | Salix |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
---|---|---|---|---|
Parenteral | For injection, for IV use | 100 mg (of azathioprine)* | Azathioprine Sodium for injection | Bedford |
Imuran | Prometheus |
Comparative Pricing
This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 05/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.
Azasan 100MG Tablets (SALIX PHARMACEUTICALS INC.): 30/$161.89 or 90/$474.07
Azasan 75MG Tablets (SALIX PHARMACEUTICALS INC.): 30/$129.99 or 90/$365.97
AzaTHIOprine 50MG Tablets (ROXANE): 30/$27.99 or 90/$70.97
Imuran 50MG Tablets (PROMETHEUS): 30/$159.99 or 60/$299.97
Disclaimer
This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.
The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.
AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions April 14, 2011. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
References
Only references cited for selected revisions after 1984 are available electronically.
100. Prometheus Laboratories. Imuran (azathioprine) tablets and IV injection prescribing information. San Diego, CA; 2005 Oct.
101. Marubbio AT, Danielson B. Hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine. Gastroenterology. 1975; 69:739-43. [PubMed 1098955]
102. Weitz H, Grokel JM, Loeschke K et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch Pathol Anat. 1982; 395:245-56. [PubMed 7051531]
103. Katzka DA, Saul SH, Jorkasky D et al. Azathioprine and hepatic venoocclusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-54. [IDIS 210427] [PubMed 3510146]
104. Read AE, Wiesner RH, LaBrecque DR et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine. Ann Intern Med. 1986; 104:651-5. [IDIS 215747] [PubMed 3008617]
105. Eisenhauer T, Hartmann H, Rumpf KW et al. Favourable outcome of hepatic veno-occlusive disease in a renal transplant patient receiving azathioprine, treated by portacaval shunt: report of a case and review of the literature. Digestion. 1984; 30:185-90. [PubMed 6389237]
106. Saway PA, Heck LW, Bonner JR et al. Azathioprine hypersensitivity: case report and review of the literature. Am J Med. 1988; 84:960-4. [IDIS 241206] [PubMed 3284343]
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110. Sandborn WJ. Azathioprine: state of the art in inflammatory bowel disease. Scand J Gastroenterol. 1998; 33(Suppl 225):92-9.
111. Hanauer SB, Sandborn W, and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults: Practice Guidelines. Am J Gastroenterol. 2001; 96:635-43. [IDIS 461432] [PubMed 11280528]
112. Feagan BG. Maintenance therapy for inflammatory bowel disease. Am J Gastroenterol. 2003 Dec; 98(12 Suppl): S6-S17.
113. Podolsky DK. Inflammatory Bowel Disease. N Engl J Med. 2002; 347:417-29. [IDIS 484721] [PubMed 12167685]
114. Scribano M, Pantera C. Review article: medical treatment of moderate to severe Crohn’s disease. Aliment Pharmacol Ther. 2003; 17(Suppl. 2):23-30. [PubMed 12786609]
115. Biancone L, Tosti V, Fina D et al. Review article: maintenance treatment of Crohn’s disease. Aliment Pharmacol Ther. 2003; 17(Suppl. 2):31-37. [PubMed 12786610]
116. American Gastroenterological Association position statement on perianal Crohn’s disease. Gastroenterology. 2003; 125:1503-1507.
117. Pearson DC, May GR, Fick G et al. Azathioprine for maintenance of remission in Crohn’s disease Cochrane review). Cochrane Database Sys Rev. . 2000; 2:CD 000067.
118. Hanauer SB, Present DH. The state of the art in the management of inflammatory bowel disease. Rev Gastroenterol Disord. 2003; 3:81-92. Selby WS. Current issues in Crohn’s disease. Rev Gastroenetrol Disord. 2003; 3:81-92.
119. Summers RW, Switz DM, Sessions JT Jr et al. National Cooperative Crohn’s Disease Study: results of drug treatment. Gastroenterology. 1979; 77:847-69. [IDIS 109536] [PubMed 38176]
120. Hanauer SB. Inflammatory bowel disease. N Engl J Med. 1996; 334:841-8. [IDIS 361805] [PubMed 8596552]
121. Markowitz J, Grancher K, Mandel F et al for the Subcommittee on Immunosuppressive Use of the Pediatric IBD Collaborative Research Forum. Immunosuppressive therapy in pediatric inflammatory bowel disease: results of a survey of the North American Society for Pediatric Gastroenterology and Nutrition. Am J Gastroenterol. 1993; 88:44-8. [IDIS 308848] [PubMed 8420272]
122. Candy S, Wright J, Gerber M et al. A controlled double blind study of azathioprine in the management of Crohn’s disease. Gut. 1995; 37:674-8. [IDIS 357251] [PubMed 8549944]
123. O’Donoghue DP, Dawson AM, Powell-Tuck J et al. Double-blind withdrawal trial of azathioprine as maintenance treatment for Crohn’s disease. Lancet. 1978; 2:955-7. [PubMed 81986]
124. Rosenberg JL, Levin B, Wall AJ et al. A controlled trial of azathioprine in Crohn’s disease. Am J Dig Dis. 1975; 20:721-6. [PubMed 1098449]
125. Willoughby JM, Beckett J, Kumar PJ et al. Controlled trial of azathiorpine in Crohn’s disease. Lancet. 1971; 2:944-7. [IDIS 25690] [PubMed 4107900]
126. Bouhnik Y, LĂ©mann M, Mary JY et al. Long-term follow-up of patients with Crohn’s disease treated with azathioprine or 6-mercaptopurine. Lancet. 1996; 347:215-9. [IDIS 359686] [PubMed 8551879]
127. Pearson DC, May GR, Gordon H et al. Azathioprine and 6-mercaptopurine in Crohn’s disease: a meta-analysis. Ann Intern Med. 1995; 123:132-42. [IDIS 349544] [PubMed 7778826]
128. Kirschner BS. Differences in the management of inflammatory bowel disease in children and adolescents compared to adults. Neth J Med. 1998; 53:S13-8. [PubMed 9883009]
129. Kirschner BS. Safety of azathioprine and 6-mercaptopurine in pediatric patients with inflammatory bowel disease. Gastroenterology. 1998; 115:813-21. [IDIS 415209] [PubMed 9753482]
130. Sandborn W, Sutherland L, Pearson D et al. Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev. 2000; 2:CD 000545.
131. Rutgeerts P. Treatment of perianal fistulizing Crohn’s disease. Aliment Pharmacol Ther. 2004; 20(Suppl 4):106-10. [PubMed 15352905]
132. Dejaco C, Harrer M, Waldhoer T et al. Antibiotics and azathioprine for the treatment of perianal fistulas in Crohn’s disease. Aliment Pharmacol Ther. 2003; 18:1113-20. [PubMed 14653831]
133. Verhave M, Winter HS, Grand RJ. Azathioprine in the treatment of children with inflammatory bowel disease. J Pediatr. 1990; 117:809-14. [IDIS 274975] [PubMed 2231216]
134. Salix Pharmaceuticals. Azasan (azathioprine) tablets prescribing information. Morrisville, NC; 2005 Oct.
135. Lichtenstein. Use of laboratory testing to guide 6-mercaptopurine/asathioprine therapy. Gastroenterol. 2004; 127:1558-64.
c. AHFS Drug Information 2005. McEvopy GK, ed. Azathioprine/Azathioprine Sodium. Bethesda, MDS: American Society of Health-System Pharmacists; 2005: 3654-6.
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