Azathioprine

Approved Indications:

• Organ Transplantation: Prevention of acute and chronic rejection following renal, hepatic, or cardiac transplantation.
• Rheumatoid Arthritis: Active, moderate-to-severe cases not responding adequately to conventional therapy (DMARDs).
• Systemic Lupus Erythematosus (SLE): Especially in lupus nephritis and systemic involvement.
• Inflammatory Bowel Disease:
• Crohn’s Disease: Maintenance of remission and steroid-sparing.
• Ulcerative Colitis: Maintenance therapy after achieving remission.
• Autoimmune Hepatitis: For induction and long-term maintenance therapy.
• Myasthenia Gravis: As an immunosuppressive agent when corticosteroids are not tolerated.
• Dermatological Autoimmune Disorders: Pemphigus vulgaris, bullous pemphigoid, chronic actinic dermatitis, and other steroid-refractory conditions.

Clinically Accepted Off-label Uses:

• Multiple Sclerosis (MS): Less commonly used as a disease-modifying agent.
• Autoimmune Uveitis: Particularly in posterior uveitis unresponsive to corticosteroids.
• Vasculitis syndromes: Including Behçet's disease, granulomatosis with polyangiitis.

Route: Oral (tablet), parenteral (IV – rarely used)

Adults:

• Transplant Rejection Prophylaxis:
• Initial: 3–5 mg/kg/day PO or IV.
• Maintenance: 1–3 mg/kg/day adjusted based on response and blood counts.
• Rheumatoid Arthritis:
• Initial: ~1 mg/kg/day (typically 50 mg/day).
• Titration: Increase by 0.5 mg/kg every 4 weeks as tolerated.
• Maintenance: 1–2.5 mg/kg/day.
• IBD (Crohn’s Disease / Ulcerative Colitis):
• Typical: 2–2.5 mg/kg/day PO.
• Monitor response over 3–6 months.
• Autoimmune Hepatitis:
• 1–2 mg/kg/day, often combined with prednisone.

Pediatrics:

• Usual Dose: 1–3 mg/kg/day PO.
• Dosing must be individualized with frequent monitoring of liver function and hematologic parameters.

Renal/Hepatic Impairment:

• Use cautiously.
• Start with lower doses and adjust based on therapeutic response and lab monitoring.

Administration Tips:

• Take after meals to minimize gastrointestinal upset.
• Do not crush or split tablets.
• IV administration reserved for patients who cannot tolerate oral dosing.

Azathioprine is a prodrug converted in vivo to 6-mercaptopurine (6-MP). This compound is further metabolized to thioguanine nucleotides (TGNs), which are incorporated into DNA and RNA, inhibiting purine synthesis. The end result is the suppression of T and B lymphocyte proliferation, reducing immune responses and autoimmune activity.

• Absorption: ~30–60% (oral); food may delay peak but not total absorption.
• Distribution: Broad tissue distribution; crosses placenta; minimal CSF penetration.
• Protein Binding: ~30%.
• Metabolism: Hepatic conversion to 6-MP, further metabolized by:
• TPMT (thiopurine methyltransferase),
• Xanthine oxidase,
• HGPRT (hypoxanthine-guanine phosphoribosyltransferase).
• Half-life: Azathioprine: 3–5 hours; active metabolites: longer.
• Excretion: Primarily renal (as inactive metabolites).

• Pregnancy:
• Category D (under old FDA system).
• Use only if potential benefit justifies risk.
• Associated with prematurity and low birth weight but not with consistent teratogenic effects.
• Used in transplant and autoimmune patients during pregnancy under specialist supervision.
• Lactation:
• Azathioprine and 6-MP are excreted in breast milk in low amounts.
• Considered compatible with breastfeeding by some authorities if the infant is monitored.
• Breastfeeding is best done at least 4 hours after dosing.

• Pharmacologic Class: Purine antimetabolite
• Therapeutic Class: Immunosuppressive Agent
• Chemical Class: Thiopurine derivative

• Hypersensitivity to azathioprine or 6-mercaptopurine.
• Severe myelosuppression.
• Known TPMT or NUDT15 deficiency.
• Concurrent treatment with allopurinol (unless azathioprine dose is drastically reduced).
• Pregnancy (relative, unless no safer alternative).
• Severe hepatic impairment.

• Myelosuppression: May cause leukopenia, thrombocytopenia, and anemia.
• Hepatotoxicity: Monitor liver enzymes regularly.
• Infection risk: Higher incidence of bacterial, viral, and fungal infections.
• Malignancy risk: Long-term use may increase risk of lymphoma, particularly hepatosplenic T-cell lymphoma in young males with IBD.
• TPMT/NUDT15 Testing: Strongly recommended prior to initiation to avoid severe toxicity.
• Photosensitivity: Risk of skin cancers; sun protection advised.
• Avoid live vaccines during therapy.

Common:

• Nausea, vomiting, anorexia
• Fatigue
• Rash
• Leukopenia, anemia
• Elevated liver enzymes

Serious:

• Severe bone marrow suppression
• Opportunistic infections
• Acute pancreatitis (especially in IBD patients)
• Hepatotoxicity
• Malignancy (lymphoma, skin cancers)

Rare:

• Pulmonary toxicity
• Hypersensitivity reactions (fever, arthralgia, hypotension)

• Allopurinol/Febuxostat: Inhibit xanthine oxidase → ↑ azathioprine toxicity. Reduce azathioprine dose to 25% if used together.
• ACE Inhibitors: May enhance risk of anemia or leukopenia.
• Aminosalicylates (e.g., mesalamine): Inhibit TPMT → ↑ risk of bone marrow toxicity.
• Warfarin: May decrease anticoagulant effect.
• Live vaccines: Contraindicated during treatment.

Enzymatic Pathways Involved:

• TPMT
• NUDT15
• Xanthine oxidase

• TPMT and NUDT15 testing is now widely recommended prior to therapy initiation to reduce severe myelotoxicity risks.
• British Society of Gastroenterology and ECCO guidelines highlight azathioprine as a key maintenance agent in IBD and autoimmune hepatitis.
• Azathioprine remains a cornerstone in combination therapy for transplant immunosuppression in resource-limited settings.

• Temperature: Store below 25°C (77°F).
• Humidity: Store in a dry location.
• Light: Protect from light.
• Container: Keep in original tightly closed container.
• Handling:
• Use gloves when handling broken tablets.
• Wash hands after handling.
• Follow safe cytotoxic handling protocols where applicable.