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Azathioprine

Class: Immunosuppressive Agents
- Disease-modifying Antirheumatic Drugs
- DMARDs
- Immunosuppressive Agents
VA Class: IM600
CAS Number: Azathioprine: 446-86-6
Brands: Azasan, Imuran

Medically reviewed by Drugs.com on Jan 11, 2021. Written by ASHP.

Warning

  • Long-term immunosuppression with azathioprine increases risk of malignancy in humans. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

  • Malignancies, including posttransplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease, reported. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

  • Only clinicians familiar with the risks, mutagenic potential, and possible hematologic toxicity should prescribe azathioprine.

  • Inform patients of risk of malignancy associated with azathioprine. (See Advice to Patients.)

Introduction

Immunosuppressive antimetabolite.

Uses for Azathioprine

Renal Allotransplantation

Prevention of rejection of renal allografts.

Rheumatoid Arthritis

Management of the signs and symptoms of rheumatoid arthritis.

Crohn’s Disease

Has been used to induce and maintain remission in adults with moderate to severely or chronically active Crohn’s disease.

Has been used in the management of fistulizing Crohn’s disease.

Has been used in children with refractory or corticosteroid-dependent Crohn’s disease.

Carefully consider risks and benefits in patients with inflammatory bowel disease, especially in adolescents and young adults. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Azathioprine Dosage and Administration

General

  • Azathioprine is an antimetabolite and is handled according to guidelines for cytotoxic drugs. Consult specialized references for procedures for proper handling and disposal of hazardous drugs.

Administration

Administer orally or by slow IV injection or IV infusion.

Low-dose corticosteroids and NSAIAs (including aspirin) may be continued in patients with rheumatoid arthritis. The manufacturers state that combined use of azathioprine and other disease modifying antirheumatic drugs (DMARDs) has not been studied and is not recommended.

Oral Administration

Administer once or twice daily.

IV Administration

When used for renal allotransplantation, the IV route may be used initially in patients unable to tolerate oral medication. Institute oral therapy as soon as possible (at the same dosage).

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. Reconstituted solution may be further diluted prior to administration (final volume depends on infusion time).

Rate of Administration

Usually infused over 30–60 minutes; may be administered over 5 minutes to 8 hours.

Dosage

Available as azathioprine and azathioprine sodium; dosage expressed as azathioprine.

Consider determining thiopurine methyl transferase (TPMT) phenotype or genotype prior to initiation of therapy and using results to select dosage. (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. Consider TPMT testing in patients with abnormal CBC results that persist despite dosage reduction. (See Hematologic Effects and TPMT Testing under Cautions.)

If used with allopurinol, adjustment in the treatment regimen recommended. (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.

Pediatric Patients

Crohn’s Disease†
Oral

1.5–2 mg/kg daily has been used.

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). Reduction to maintenance dosage of 1–3 mg/kg daily usually possible.

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).

Rheumatoid Arthritis
Oral

Initially, 1 mg/kg (50–100 mg) daily in 1 or 2 doses.

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. 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. Patients whose disease does not improve after 12 weeks of therapy are considered nonresponders.

When used for maintenance dosage, use lowest effective dosage to reduce toxicities. Dosage can be reduced in increments of 0.5 mg/kg (approximately 25 mg) daily every 4 weeks while other therapy is kept constant.

Optimum duration of therapy undetermined.

Crohn’s Disease†
Oral

2–4 mg/kg daily has been used.

Prescribing Limits

Adults

Rheumatoid Arthritis
Oral

Maximum 2.5 mg/kg daily.

Special Populations

Renal Impairment

Use low initial dosage in patients with renal impairment.

Renal Allotransplantation

Lower dosage may be necessary in relatively oliguric patients, especially in those with tubular necrosis in the immediate posttransplant period.

Cautions for Azathioprine

Contraindications

  • Known hypersensitivity to azathioprine or any ingredient in the formulation.

  • Management of rheumatoid arthritis in pregnant women.

  • Management of rheumatoid arthritis in patients previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan), because of prohibitive risk of neoplasia. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Warnings/Precautions

Warnings

Malignancies and Lymphoproliferative Disorders

Increased risk of lymphoma and other malignancies, particularly of the skin. Monitor for occurrence of malignancies.

Risk of posttransplant lymphomas may be increased in patients receiving aggressive immunosuppressive therapy; maintain therapy at lowest effective dosage.

Risk of malignancy may be increased in patients with rheumatoid arthritis, although to a lesser extent than in renal transplant patients; precise risk of malignancy associated with azathioprine unknown. Acute myelogenous leukemia and solid tumors reported in azathioprine-treated patients with rheumatoid arthritis. Patients with rheumatoid arthritis previously treated with alkylating agents (e.g., cyclophosphamide, chlorambucil, melphalan) may have a prohibitive risk of malignancy if treated with azathioprine.

Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal malignancy, reported in azathioprine-treated patients with inflammatory bowel disease.

Hepatosplenic T-cell lymphoma mostly reported in adolescents and young adult males with Crohn’s disease or ulcerative colitis receiving a combination of immunosuppressive agents, including tumor necrosis factor (TNF) blocking agents and/or thiopurine analogs (azathioprine or mercaptopurine); however, cases also reported in patients receiving azathioprine or mercaptopurine alone. Carefully consider risks and benefits of these agents, especially in adolescents and young adults with Crohn’s disease or ulcerative colitis.

Patients with certain conditions (e.g., Crohn’s disease, rheumatoid arthritis) may be at increased risk for lymphoma; may be difficult to measure added risk of TNF-blocking agents, azathioprine, and/or mercaptopurine.

Hematologic Effects

Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia reported. Delayed hematologic suppression may occur.

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. Patients with intermediate TPMT activity (10–11% of the population) are at increased risk of hematologic toxicity; dosage reduction recommended.

Hematologic toxicity is dose related and may be more severe in patients undergoing graft rejection.

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.

If rapid decrease in leukocyte count, persistent leukopenia, or other evidence of bone marrow suppression develops, promptly reduce dosage or temporarily discontinue the drug.

Azathioprine-induced leukopenia does not correlate with therapeutic effect; do not increase dosage intentionally to decrease leukocyte count.

Infectious Complications

Increased susceptibility to infection (i.e., opportunistic infections, sepsis, life-threatening/fatal infections). Treat infection promptly and reduce azathioprine dosage or consider alternative therapy.

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.

Avoid use in pregnant women unless benefits outweigh risks.

Avoid pregnancy during therapy. If patient becomes pregnant, apprise of potential fetal hazard.

Manufacturers state that azathioprine should not be used to treat rheumatoid arthritis in pregnant women; some clinicians state that use in pregnancy should be limited to women with severe or life-threatening rheumatoid arthritis.

Serious neonatal leukopenia and thrombocytopenia may be prevented by reducing azathioprine dosage at 32 weeks’ gestation; monitor prenatal growth and follow offspring long-term.

Sensitivity Reactions

GI Hypersensitivity

Severe nausea and vomiting, sometimes accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, hypotension, reported. Develops during the first several weeks of therapy; reversible upon discontinuation; can occur after rechallenge.

General Precautions

TPMT Testing

Genetically determined differences in TPMT activity may lead to differences in patient response and/or toxicity. (See Hematologic Effects under Cautions.) The most common nonfunctional alleles associated with reduced TPMT activity are TPMT*2, TPMT*3A, and TPMT*3C. Patients with 2 nonfunctional alleles (homozygous) have low or absent TPMT activity; those with 1 nonfunctional allele (heterozygous) have intermediate activity.

Consider determining the TPMT genotype or phenotype prior to initiating therapy and in patients with abnormal CBC results that persist despite dose reduction. (See Hematologic Effects under Cautions and see Dosage.)

Specific Populations

Pregnancy

Category D. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into human milk. Discontinue nursing or the drug because of potential tumorigenicity.

Pediatric Use

Safety and efficacy not established.

Hepatosplenic T-cell lymphoma reported in adolescents receiving azathioprine for the management of inflammatory bowel disease. (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Renal Impairment

Dosage adjustment may be needed.

Common Adverse Effects

Hematologic, GI (nausea, vomiting).

Interactions for Azathioprine

Drugs Affecting Myelopoiesis

Risk of severe leukopenia, especially in renal transplant recipients.

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Potential for increased toxicity (anemia, severe leukopenia)

Allopurinol

Allopurinol inhibits metabolic pathway catalyzed by xanthine oxidase; may increase risk of azathioprine toxicity

Reduce azathioprine dosage to 25–33% of usual dosage; consider further dosage reduction or alternative therapy in patients with low or absent TPMT activity

Aminosalicylates (mesalamine, olsalazine, sulfasalazine)

Aminosalicylates inhibit metabolic pathway catalyzed by TPMT; may increase risk of azathioprine toxicity

Use concomitantly with caution

Co-trimoxazole

Possible increased leukopenia, especially in renal transplant recipients

Ribavirin

Ribavirin inhibits metabolic pathway catalyzed by inosine monophosphate dehydrogenase, resulting in accumulation of myelotoxic metabolite of azathioprine; severe pancytopenia reported

Monitor CBC, including platelet counts, weekly for first month, twice monthly during second and third months, then monthly thereafter (or more frequently if dosage or other therapy changes needed)

Warfarin

Possible reduced anticoagulant effect

Azathioprine Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak serum concentration attained within 1–2 hours.

Onset

Following oral administration in patients with rheumatoid arthritis, therapeutic response usually occurs after 6–8 weeks.

Distribution

Extent

Not fully characterized.

Plasma Protein Binding

30%.

Elimination

Metabolism

Metabolized to 6-mercaptopurine. 6-Mercaptopurine is metabolized by 2 competing metabolic pathways or is incorporated as cytotoxic nucleotides into DNA. 6-Mercaptopurine undergoes thiol methylation (catalyzed by TPMT) to an inactive metabolite. 6-Mercaptopurine also undergoes oxidation (catalyzed by xanthine oxidase).

Elimination Route

Excreted in urine, principally as metabolites.

Half-life

Radiolabeled metabolites: 5 hours.

Stability

Storage

Oral

Tablets

Controlled room temperature; protect from light.

Parenteral

Powder for Injection

15–25°C; protect from light and store in carton until time of use. Following reconstitution, use within 24 hours.

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%

Actions

  • Imidazolyl derivative of 6-mercaptopurine; a purine antimetabolite.

  • Exact mechanism(s) of immunosuppression not fully elucidated; cytotoxicity due, in part, to incorporation of cytotoxic (6-thioguanine) nucleotides into DNA.

  • Inhibits graft rejection; little effect on established graft rejections or secondary responses.

  • Suppresses disease manifestations and underlying pathology in animal models of autoimmune disease.

Advice to Patients

  • Increased risk of malignancy. Potential increased risk of hepatosplenic T-cell lymphoma, especially in adolescents and young adults with inflammatory bowel disease receiving thiopurines (azathioprine or mercaptopurine) and/or TNF blocking agents; importance of advising patients and caregivers of relative risks and benefits of these and other immunosuppressive agents. Importance of patients not discontinuing therapy without consulting clinician.

  • Importance of informing patients and caregivers of the signs and symptoms of malignancies such as hepatosplenic T-cell lymphoma (e.g., splenomegaly hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss), and importance of patients informing clinicians if such signs or symptoms occur.

  • Importance of limiting exposure to sunlight and UV light by wearing protective clothing and using sunscreen with high protection factor.

  • Necessity of routine laboratory testing (e.g., CBC).

  • Importance of informing clinician of any evidence of infection, unusual bleeding, bruising, or other manifestation of bone marrow suppression.

  • Importance of taking azathioprine as directed.

  • 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.

  • Importance of informing clinicians of existing or contemplated therapy, including prescription (e.g., allopurinol) or OTC drugs, as well as concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

azaTHIOprine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

50 mg*

Azathioprine Tablets (scored)

Imuran (scored)

Prometheus

75 mg

Azasan (scored)

Salix

100 mg

Azasan (scored)

Salix

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

azaTHIOprine Sodium

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection, for IV use

100 mg (of azathioprine)*

Azathioprine Sodium for injection

AHFS DI Essentials™. © Copyright 2022, Selected Revisions January 20, 2012. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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