Azathioprine

Azathioprine is a purine antimetabolite prodrug of mercaptopurine used as a steroid-sparing agent and maintenance immunosuppressant in lupus, vasculitis, inflammatory bowel disease, autoimmune hepatitis, myasthenia gravis and solid organ transplantation. It is a preferred maintenance option in pregnancy.

Class. Purine analogue, antimetabolite immunosuppressant.

Mechanism. Converted to mercaptopurine and then to thioguanine nucleotides, which are incorporated into DNA and RNA and block de novo purine synthesis, reducing proliferation of T and B lymphocytes.

Pharmacokinetics. Well absorbed orally (about 60 percent). Mercaptopurine is metabolised by thiopurine methyltransferase, xanthine oxidase and NUDT15. Low or absent enzyme activity causes toxic accumulation of active nucleotides and severe myelosuppression. Onset takes 6 to 12 weeks.

Rheumatological and vasculitis maintenance (lupus, ANCA vasculitis).

• Start 25 to 50 mg daily orally (about 0.5 to 1 mg/kg/day) and increase over 4 to 6 weeks.

• Maintenance: 1 to 2.5 mg/kg/day in one or two doses. Usual lupus dose is 1 to 2 mg/kg/day.

• Maximum dose: 3 mg/kg/day.

• Loading dose: none.

• Duration: long term; usually continued for 2 years or more after vasculitis remission, then reviewed.

Inflammatory bowel disease (maintenance of remission). 2 to 2.5 mg/kg/day after confirming normal enzyme activity.

Autoimmune hepatitis. Start 50 mg daily, titrate to 1 to 2 mg/kg/day, combined with a glucocorticoid taper.

Solid organ transplantation (adjunct to calcineurin inhibitor). Usual maintenance 1 to 3 mg/kg/day; the older loading regimen of 3 to 5 mg/kg on the day of surgery is rarely used now.

Dose modification.

• Thiopurine methyltransferase or NUDT15 intermediate activity: start at about half of the usual dose (0.5 to 1 mg/kg/day) with close monitoring.

• Absent activity: avoid azathioprine.

• Concurrent allopurinol: reduce azathioprine to one quarter of the usual dose, or avoid; concurrent febuxostat: avoid.

Contraindications. Hypersensitivity (including to mercaptopurine), absent thiopurine methyltransferase activity, severe infection, and pre-existing marrow failure. Avoid live vaccines.

Boxed-warning-level risks. Malignancy: non-melanoma skin cancer, lymphoma, and hepatosplenic T cell lymphoma, mainly in young males with inflammatory bowel disease on combination therapy.

Adverse effects. Common: nausea, vomiting, malaise. Serious: leucopenia and pancytopenia, hypersensitivity reaction within the first weeks (fever, rash, hypotension), pancreatitis, hepatotoxicity including sinusoidal obstruction and nodular regenerative hyperplasia, opportunistic infection, skin cancer.

Major interactions. Allopurinol and febuxostat (life-threatening myelosuppression), warfarin (reduced effect), ACE inhibitors (anaemia and leucopenia), co-trimoxazole and trimethoprim (myelosuppression), mesalazine and sulfasalazine (raised thioguanine levels), ribavirin, methotrexate, and live vaccines.

Common prescribing errors. Skipping enzyme testing; failing to reduce the dose with allopurinol; stopping blood monitoring after the first months.

Special groups.

• Pregnancy: acceptable at 2 mg/kg/day or less; continue in disease control.

• Breastfeeding: acceptable; infant exposure is low.

• Children: 1 to 2.5 mg/kg/day, specialist use.

• Older adults: start at the lower end and monitor closely.

• Kidney impairment: eGFR under 30 mL/min, start at the lower end and watch for cytopenia.

• Liver impairment: use cautiously and monitor liver enzymes; avoid in severe disease.

• Region: skin cancer risk is lower in dark skin but not absent; advise sun protection. HIV, hepatitis B and tuberculosis screening applies.

Formulations. 25 mg and 50 mg tablets, taken with food to reduce nausea; intravenous form for those unable to take oral treatment (same dose).

Baseline. Thiopurine methyltransferase and NUDT15 status where available (enzyme activity or genotype), full blood count, liver enzymes, creatinine, and hepatitis and HIV serology.

Monitoring. Full blood count and liver enzymes every 1 to 2 weeks for the first 4 weeks and after each dose change, monthly for 3 months, then every 3 months. Annual skin examination.

Stop thresholds. White cell count under 3.5 x 10^9/L, neutrophils under 1.6 x 10^9/L, platelets under 140 x 10^9/L, ALT over twice the upper limit of normal, or pancreatitis. Hold and repeat; restart at a lower dose if counts recover and the cause is explained.

Overdose. No specific antidote. Supportive care, activated charcoal if early, and monitoring of blood counts for several weeks.

Referral and escalation. Refer for unexplained cytopenia, hypersensitivity reaction, or rising liver enzymes on a stable dose.