Section 07 · Monograph

Azathioprine

Reviewed Nov 2026FDA label

ImuranPurine antagonist

Black Box Warning

Chronic immunosuppression with azathioprine increases the risk of malignancy in humans, including post-transplant lymphomas and, in patients treated for inflammatory bowel disease, hepatosplenic T-cell lymphoma
Reported malignancies also include skin cancers and other solid tumors; risk appears to correlate with dose and duration of immunosuppression
Patients should be counseled about increased malignancy risk and monitored accordingly (periodic skin examinations, minimizing cumulative immunosuppression when possible)

Prevention of rejection in renal (kidney) transplantation, usually as an adjunct to other immunosuppressive agentsFDA-labeled
Management of active rheumatoid arthritis (RA) in patients who have failed an adequate trial of at least one other agentFDA-labeled

Steroid-sparing immunosuppressant in myasthenia gravis, typically combined with corticosteroids to allow lower long-term steroid doses; onset of clinical benefit is slow (often 6-12 months or longer)Off-label
Other autoimmune conditions: inflammatory bowel disease, autoimmune hepatitis, and other autoimmune neurologic and rheumatologic disordersOff-label

Prodrug, nonenzymatically converted in vivo to 6-mercaptopurine (6-MP), which is further metabolized to active 6-thioguanine nucleotides (6-TGNs)
6-TGNs are incorporated into DNA and RNA, causing chain termination, inhibition of purine synthesis, and cytotoxicity preferentially in rapidly proliferating cells, including activated lymphocytes
Net effect is suppression of both cell-mediated (T-cell) and humoral (B-cell/antibody) immune responses
In MG, this translates to reduced production of pathogenic anti-AChR (or anti-MuSK) autoantibodies over the course of months, underlying its slow onset of clinical benefit
Metabolism regulated by TPMT and NUDT15, which inactivate thiopurine metabolites; genetic deficiency in either enzyme markedly increases myelosuppression risk

Rheumatoid arthritis: initial dose approximately 1 mg/kg/day; may increase by 0.5 mg/kg/day increments at 6-8 week intervals up to a maximum of 2.5 mg/kg/day
Myasthenia gravis (off-label): commonly started at 50 mg/day and titrated by 25-50 mg increments over several weeks to a target maintenance dose of approximately 2-3 mg/kg/day, used as an adjunct to allow corticosteroid tapering
TPMT and NUDT15 genotype/phenotype should be assessed prior to initiating therapy to guide starting dose and monitoring intensity
Patients with homozygous TPMT or NUDT15 deficiency generally require markedly reduced doses or an alternative agent
Concomitant allopurinol/febuxostat requires azathioprine dose reduction to approximately 1/3 to 1/4 of usual dose

Renal transplantation: initial dose 3-5 mg/kg/day (oral or IV); maintenance dose 1-3 mg/kg/day, individualized to clinical response and hematologic tolerance
Dose reduction required in renal impairment/oliguria

Known hypersensitivity to azathioprine or its components
Pregnant women being treated for rheumatoid arthritis
Prior treatment with alkylating agents (e.g., cyclophosphamide, chlorambucil, melphalan) in rheumatoid arthritis patients, due to substantially increased malignancy risk with the combination

Xanthine oxidase inhibitors (allopurinol, febuxostat) block a major inactivation pathway of 6-MP, causing significant increases in active metabolites and myelosuppression risk — requires dose reduction (allopurinol) or avoidance (febuxostat)
Aminosalicylates (mesalamine, sulfasalazine) inhibit TPMT activity and can increase thiopurine toxicity
ACE inhibitors co-administered with azathioprine have been associated with anemia and severe leukopenia
Warfarin: azathioprine may inhibit the anticoagulant effect, requiring closer INR monitoring
Co-trimoxazole and other myelosuppressive antibiotics may exaggerate hematologic toxicity
Ribavirin increases risk of severe myelotoxicity when combined with azathioprine
Live/live-attenuated vaccines should be avoided during immunosuppressive therapy

Dose-related bone marrow suppression: leukopenia (common, dose-limiting), thrombocytopenia, macrocytic anemia; more frequent in TPMT/NUDT15-deficient patients
Hepatotoxicity: elevated transaminases and bilirubin, cholestasis, rarely hepatic veno-occlusive disease
GI: nausea, vomiting, diarrhea; a distinct idiosyncratic hypersensitivity-like reaction (fever, malaise, myalgia, rash, hypotension) can occur early and requires immediate discontinuation
Increased risk of serious infections due to immunosuppression
Increased risk of malignancy, particularly lymphoma and non-melanoma skin cancer, with long-term use
Pancreatitis (idiosyncratic)
Alopecia, rash, arthralgias, rarely interstitial pneumonitis

Baseline TPMT and/or NUDT15 genotype or phenotype testing prior to starting therapy
CBC with platelets: weekly during the first month, twice monthly for months 2-3, then at least monthly thereafter
Liver function tests periodically, especially early in treatment and after dose increases
Renal function monitoring, particularly in transplant recipients
Ongoing surveillance for infection and periodic skin examinations given long-term malignancy risk
Clinical assessment of MG response over months given delayed onset of benefit
Watch for the early idiosyncratic hypersensitivity reaction in the first weeks of therapy

Crosses the placenta and is teratogenic in animal studies at clinically relevant doses
Human data have not shown a strong teratogenic signal but are associated with increased rates of prematurity and low birth weight; specifically contraindicated for the RA indication in pregnant patients
Postmarketing cases of intrahepatic cholestasis of pregnancy have been reported; discontinue if this develops
Use in nursing mothers not recommended by the manufacturer due to detection of thiopurine metabolites in breast milk, though some guidelines consider it compatible with breastfeeding under specialist guidance
Decisions regarding use in MG patients who are pregnant or breastfeeding should be individualized with neurology and maternal-fetal medicine specialists