Brand names: Azasan, Imuran
Drug class: Antimetabolites, Immunosuppressive Therapy, Miscellaneous

Medically reviewed by Drugs.com on Jun 10, 2024. Written by ASHP.

Introduction

Immunosuppressive antimetabolite.^{100 134 136}

Uses for Azathioprine

Renal Allotransplantation

Prevention of rejection of renal allografts.^{100 134 136}

Rheumatoid Arthritis

Management of the signs and symptoms of rheumatoid arthritis.^{100 134 136}

Crohn’s Disease

Has been used to induce and maintain remission in adults with moderate to severely or chronically active Crohn’s disease^{† [off-label]}.^{110 111 112 113 114 117 118 119 120 122}

Has been used in the management of fistulizing Crohn’s disease^{† [off-label]}.^{111 115 116 131 132}

Has been used in children with refractory or corticosteroid-dependent Crohn’s disease^{† [off-label]}.^{128 129 133}

Carefully consider risks and benefits in patients with inflammatory bowel disease^{† [off-label]}, especially in adolescents and young adults.^{100 136 137} (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.^{100 136 c} Consult specialized references for procedures for proper handling and disposal of hazardous drugs.^{100 134 136}

Administration

Administer orally or by slow IV injection or IV infusion.^{100 134 136}

Low-dose corticosteroids and NSAIAs (including aspirin) may be continued in patients with rheumatoid arthritis.^{100 134 136} The manufacturers state that combined use of azathioprine and other disease modifying antirheumatic drugs (DMARDs) has not been studied and is not recommended.^{100 134 136}

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.¹³⁶ Institute oral therapy as soon as possible (at the same dosage).^{136 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.¹³⁶ Reconstituted solution may be further diluted prior to administration (final volume depends on infusion time).¹³⁶

Rate of Administration

Usually infused over 30–60 minutes; may be administered over 5 minutes to 8 hours.¹³⁶

Dosage

Available as azathioprine and azathioprine sodium; dosage expressed as azathioprine.^{100 134 136}

Consider determining thiopurine methyl transferase (TPMT) phenotype or genotype prior to initiation of therapy and using results to select dosage.^{100 136} (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.^{100 134 136} Consider TPMT testing in patients with abnormal CBC results that persist despite dosage reduction.^{100 136} (See Hematologic Effects and TPMT Testing under Cautions.)

If used with allopurinol, adjustment in the treatment regimen recommended.^{100 134 136} (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

Crohn’s Disease† [off-label]

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).^{136 c}

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.^{100 134 136}

Cautions for Azathioprine

Contraindications

• Known hypersensitivity to azathioprine or any ingredient in the formulation.^{100 134 136}

• Management of rheumatoid arthritis in pregnant women.^{100 134 136}

• Management of rheumatoid arthritis in patients previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan), because of prohibitive risk of neoplasia.^{100 134 136} (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.^{100 134 136 137} Monitor for occurrence of malignancies.¹³⁷

Risk of posttransplant lymphomas may be increased in patients receiving aggressive immunosuppressive therapy; maintain therapy at lowest effective dosage.^{100 136}

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.^{100 136} Acute myelogenous leukemia and solid tumors reported in azathioprine-treated patients with rheumatoid arthritis.^{100 136} 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.^{100 136}

Hepatosplenic T-cell lymphoma, a rare, aggressive, usually fatal malignancy, reported in azathioprine-treated patients with inflammatory bowel disease.^{100 136 137}

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.^{100 136 137} Carefully consider risks and benefits of these agents, especially in adolescents and young adults with Crohn’s disease or ulcerative colitis.¹³⁷

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.¹³⁷

Hematologic Effects

Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia reported.^{100 134 136} Delayed hematologic suppression may occur.^{100 134 136}

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.^{100 135 136} Patients with intermediate TPMT activity (10–11% of the population) are at increased risk of hematologic toxicity; dosage reduction recommended.^{100 135 136}

Hematologic toxicity is dose related and may be more severe in patients undergoing graft rejection.^{100 134 136}

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.^{100 134 136}

If rapid decrease in leukocyte count, persistent leukopenia, or other evidence of bone marrow suppression develops, promptly reduce dosage or temporarily discontinue the drug.^{100 134 136}

Azathioprine-induced leukopenia does not correlate with therapeutic effect; do not increase dosage intentionally to decrease leukocyte count.^{100 136}

Infectious Complications

Increased susceptibility to infection (i.e., opportunistic infections, sepsis, life-threatening/fatal infections).^{100 134 136} Treat infection promptly and reduce azathioprine dosage or consider alternative therapy.^{100 134 136}

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm; teratogenicity demonstrated in animals.^{100 134 136}

Avoid use in pregnant women unless benefits outweigh risks.^{100 134 136}

Avoid pregnancy during therapy.^{100 134 136} If patient becomes pregnant, apprise of potential fetal hazard.^{100 134 136}

Manufacturers state that azathioprine should not be used to treat rheumatoid arthritis in pregnant women;^{100 134 136} 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.^{100 134 136} Develops during the first several weeks of therapy; reversible upon discontinuation; can occur after rechallenge.^{100 134 136}

General Precautions

TPMT Testing

Genetically determined differences in TPMT activity may lead to differences in patient response and/or toxicity.^{100 135 136} (See Hematologic Effects under Cautions.) The most common nonfunctional alleles associated with reduced TPMT activity are TPMT*2, TPMT*3A, and TPMT*3C.^{100 136} Patients with 2 nonfunctional alleles (homozygous) have low or absent TPMT activity; those with 1 nonfunctional allele (heterozygous) have intermediate activity.^{100 136}

Consider determining the TPMT genotype or phenotype prior to initiating therapy and in patients with abnormal CBC results that persist despite dose reduction.^{100 136} (See Hematologic Effects under Cautions and see Dosage.)

Specific Populations

Pregnancy

Category D.^{100 134 136} (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Lactation

Distributed into human milk.^{100 134 136} Discontinue nursing or the drug because of potential tumorigenicity.^{100 134 136}

Pediatric Use

Safety and efficacy not established.^{100 134 136}

Hepatosplenic T-cell lymphoma reported in adolescents receiving azathioprine for the management of inflammatory bowel disease.^{100 136 137} (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Renal Impairment

Dosage adjustment may be needed.^{100 134 136}

Common Adverse Effects

Hematologic, GI (nausea, vomiting).^{100 134 136}

Drug Interactions

Drugs Affecting Myelopoiesis

Risk of severe leukopenia, especially in renal transplant recipients.^{100 134 136}

Specific Drugs

Azathioprine Pharmacokinetics

Absorption

Bioavailability

Well absorbed following oral administration, with peak serum concentration attained within 1–2 hours.^{100 134 136}

Onset

Following oral administration in patients with rheumatoid arthritis, therapeutic response usually occurs after 6–8 weeks.^{100 134 136}

Distribution

Extent

Not fully characterized.^c

Plasma Protein Binding

30%.^{100 134 136}

Elimination

Metabolism

Metabolized to 6-mercaptopurine.^{100 134 136} 6-Mercaptopurine is metabolized by 2 competing metabolic pathways or is incorporated as cytotoxic nucleotides into DNA.^{100 136} 6-Mercaptopurine undergoes thiol methylation (catalyzed by TPMT) to an inactive metabolite.^{100 136} 6-Mercaptopurine also undergoes oxidation (catalyzed by xanthine oxidase).^{100 136}

Elimination Route

Excreted in urine, principally as metabolites.^c

Half-life

Radiolabeled metabolites: 5 hours.^{100 134 136}

Stability

Storage

Oral

Tablets

Controlled room temperature; protect from light.^{100 134}

Parenteral

Powder for Injection

15–25°C; protect from light and store in carton until time of use.¹³⁶ Following reconstitution, use within 24 hours.¹³⁶

Compatibility

Parenteral

Solution CompatibilityHID

Actions

• Imidazolyl derivative of 6-mercaptopurine; a purine antimetabolite.^{100 134 136}

• Exact mechanism(s) of immunosuppression not fully elucidated; cytotoxicity due, in part, to incorporation of cytotoxic (6-thioguanine) nucleotides into DNA.^{100 134 136}

• Inhibits graft rejection; little effect on established graft rejections or secondary responses.^{100 134 136}

• Suppresses disease manifestations and underlying pathology in animal models of autoimmune disease.^{100 134 136}

Advice to Patients

• Increased risk of malignancy.^{100 136} 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.^{100 134 136 137} Importance of patients not discontinuing therapy without consulting clinician.¹³⁷

• 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.¹³⁷

• Importance of limiting exposure to sunlight and UV light by wearing protective clothing and using sunscreen with high protection factor.^{100 136}

• Necessity of routine laboratory testing (e.g., CBC).^{100 134 136}

• Importance of informing clinician of any evidence of infection, unusual bleeding, bruising, or other manifestation of bone marrow suppression.^{100 134 136}

• Importance of taking azathioprine as directed.^{100 134 136}

• 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.^{100 134 136}

• Importance of informing clinicians of existing or contemplated therapy, including prescription (e.g., allopurinol) or OTC drugs, as well as concomitant illnesses.^{100 134 136}

• Importance of informing patients of other important precautionary information.^{100 134 136} (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

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