AzathioprineRx

Trade Names: Imuran

Drug Class: Immunosuppressive, purine antagonist

Preparations: Tablets: 50 mg, scored

Dose: Adult, 1.0–2.5 mg/kg/day (given once or twice daily)

Indications: SLE; dermatomyositis/polymyositis; vasculitis; used as a steroid-sparing agent in a wide range of autoimmune disorders when the disease requires prolonged high doses of corticosteroids; RA (very seldom)

Mechanism of Action: Azathioprine is an inactive prodrug that is metabolized to 6-mercaptopurine then to 6-thioguanine nucleotides (6-TGN)  which act as a purine analogue that interferes with purine synthesis and thus with DNA synthesis.

Contraindications: Hypersensitivity, concomitant xanthine oxidase inhibitor (allopurinol, febuxostat), lactation, or pregnancy

Precautions: Consider genetic testing for thiopurine methyltransferase deficiency (see Comments). Use caution in hepatic or renal impairment. Reduce dose for renal impairment. Azathioprine is carcinogenic in animals and increases the risk of malignancy, primarily lymphoma, leukemia, and skin cancer in humans.

Monitoring: CBC and platelet count weekly  for first month and every 2 weeks for months 2-3 or after a dose increase, then monthly on stable dose. Do LFTs every 1–3 months. Consider skin cancer screening.

Pregnancy Risk: D

Adverse Effects
Common: Fever, chills, GI symptoms (vomiting, diarrhea, nausea), dose-related effects on bone marrow (thrombocytopenia, leukopenia)
Less common: Herpes zoster, infections, hepatotoxicity, pancreatitis, pneumonitis, hypersensitivity, stomatitis, rash, increased risk of lymphoma/leukemia, skin cancer,  hepatic venoocclusive disease

Drug Interactions
Xanthine oxidase inhibitor (allopurinol, febuxostat): Accumulation of 6-mercaptopurine and thus toxicity. Avoid concurrent treatment if at all possible; if necessary, for allopurinol reduce azathioprine dose markedly (to 25% or less of usual dose) and monitor frequently; for febuxostat there are no data.
Sulfasalazine: Increased leukopenia.
Cotrimoxazole and ACE-inhibitors: Increased leukopenia.
Warfarin: May increase anticoagulant effect.
Immunosuppressants: Concurrent use with other immunosuppressants increases the risk of infection and long-term risk of malignancy.
Live vaccines: Replication of the attenuated virus may occur because of immunosuppression.

Patient Instructions: Use contraception to avoid pregnancy. Do not exceed prescribed dose. Regular monitoring of blood count is essential. Report to physician if persistent sore throat, unusual bleeding, bruises, or fatigue develops. Reduce risk of skin cancer by avoiding the sun.

Comments: Often used for SLE and seldom for RA. Rather than starting with a high maintenance dose, it is advisable to start at a low dose, usually 50 mg/day and increase by 25 mg increments at 1- to 2-week intervals. Onset of action is delayed, so reduce dose at first sign of a large or persistent (<3,000/mm3) decrease in WBCs or platelets (<100,000/mm3). Consider genetic testing before starting treatment. A complete genetic deficiency of the enzyme thiopurine methyltransferase (TPMT) occurs in one in 300 persons and partial deficiency in 10%. Complete TPMT deficiency is associated with severe, life-threatening myelosuppression because of impaired metabolism; thus, AZA should be avoided if possible. Partial deficiency is associated with increased side effects and lower doses are indicated. Genetic testing for TPMT deficiency is available, and it is prudent to check before starting therapy. GI tolerability may improve with split (twice daily) dosing. Response in RA may not occur for several months. AZA is not more effective than other DMARDs, but adverse effects are more common. Combination studies in RA show that MTX + AZA is more effective than AZA alone, but the MTX + AZA combination is not more effective than MTX alone and may have added toxicity. AZA combination therapy should not be undertaken routinely; avoid with tofacitinib and leflunomide.

Clinical Pharmacology: AZA is well absorbed orally and largely biotransformed to 6-mercaptopurine and 6-thioinosinic acid; it is further metabolized by xanthine oxidase and renally excreted as metabolites. Half-life is 5 hours (drug and active metabolites), but immunosuppressive action is prolonged for weeks because of the intracellular accumulation of active thioguanine nucleotides.

Cost: $$$

BIBLIOGRAPHY

Willkens RF, Urowitz MB, Stablein DM, et al. Comparison of azathioprine, methotrexate, and the combination of both in the treatment of rheumatoid arthritis. Arthritis Rheum 1992;35:849–856. PMID:8849352

Relling MV, Gardner EE, Sandborn WJ, et al. Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing: 2013 update. Clin Pharmacol Ther 2013;93:324-5. PMID: 23422873