AZATHIOPRINE
Clinical safety rating: avoid
Positive evidence of fetus risks but benefits may outweigh risks in some cases
Azathioprine is a purine analog that inhibits purine nucleotide synthesis, thereby suppressing DNA replication and cell proliferation. It is converted to 6-mercaptopurine, which acts as a purine antagonist, inhibiting de novo purine synthesis and interfering with RNA and DNA synthesis, particularly in rapidly dividing cells such as T-lymphocytes.
| Metabolism | Azathioprine is metabolized by xanthine oxidase (XO) and thiopurine methyltransferase (TPMT) to active (6-mercaptopurine) and inactive metabolites. 6-Mercaptopurine is further metabolized by XO to 6-thiouric acid and by TPMT to 6-methylmercaptopurine. Genetic deficiency of TPMT increases risk of toxicity. |
| Excretion | Renal (approximately 2% as unchanged drug, 30% as 6-thiouric acid and other metabolites); biliary/fecal (minor, <10% as metabolites). |
| Half-life | Terminal elimination half-life of azathioprine is approximately 2–5 hours; its active metabolite 6-mercaptopurine has a half-life of 1–2 hours, but 6-thioguanine nucleotides accumulate in red blood cells with a half-life of several days, correlating with myelosuppression. |
| Protein binding | Approximately 30% bound, primarily to albumin. |
| Volume of Distribution | 0.8–1.0 L/kg, indicating distribution into total body water; extensive distribution into tissues including liver and erythrocytes. |
| Bioavailability | Oral bioavailability of azathioprine is 60–80% (mean 70%) with interindividual variability; absorption may be reduced by food. |
| Onset of Action | IV: immunosuppressive effects observed within 1–2 weeks; oral: 2–4 weeks for clinical response in autoimmune disease or transplant rejection. |
| Duration of Action | Duration of immunosuppression persists for weeks after discontinuation due to active metabolite accumulation; myelosuppression may peak 2–4 weeks after dose adjustment. |
| Action Class | Immunosuppressant- Purine analogs |
| Brand Substitutes | Transimune 50mg Tablet, Azap 50 Tablet, Zesoris-AZ 50mg Tablet, Autorin 50mg Tablet, Azawan Tablet |
1.5 to 2.5 mg/kg orally once daily; typical adult dose 50-150 mg/day orally. Intravenous dose is 3-5 mg/kg/day as a slow infusion over 30-60 minutes.
| Dosage form | TABLET |
| Renal impairment | GFR >50 mL/min: no adjustment. GFR 10-50 mL/min: administer 75% of normal dose. GFR <10 mL/min: administer 50% of normal dose. Hemodialysis: administer 50% of normal dose after dialysis. |
| Liver impairment | Child-Pugh Class A: no adjustment. Child-Pugh Class B: reduce dose by 25-50%. Child-Pugh Class C: contraindicated or use with extreme caution; reduce dose by at least 50%. |
| Pediatric use | 1.5 to 2.5 mg/kg orally once daily; maximum 150 mg/day. For inflammatory bowel disease: 2-3 mg/kg/day. Intravenous: 3-5 mg/kg/day as a slow infusion. |
| Geriatric use | Initiate at lower end of dosing range (1.5 mg/kg/day) due to potential for decreased renal and hepatic function; monitor renal function and hematologic parameters closely. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Allopurinol inhibits xanthine oxidase increasing levels of active metabolites leading to severe myelosuppression Myelosuppression is dose-related and requires frequent CBC monitoring.
| Breastfeeding | Azathioprine is excreted into breast milk in low concentrations. M/P ratio is approximately 0.7. Nursing infants of mothers on azathioprine have not shown adverse effects; however, theoretical risk of immunosuppression exists. Caution is advised; monitor infant for increased infections. |
| Teratogenic Risk | Azathioprine is pregnancy category D. First trimester: increased risk of congenital anomalies including ventricular septal defects, limb defects, and esophageal atresia. Second and third trimesters: risk of intrauterine growth restriction, preterm birth, and neonatal immunosuppression (leukopenia, thrombocytopenia). Use only if benefit outweighs risk. |
■ FDA Black Box Warning
Malignancy: Patients receiving immunosuppressive therapy including azathioprine have an increased risk of developing lymphoma and other malignancies, particularly skin cancers. The risk is related to the duration and intensity of immunosuppression. Hematologic toxicity: Severe leukopenia, thrombocytopenia, and anemia, which may be dose-related, can occur. Regular monitoring of blood counts is required. Hepatotoxicity: Hepatotoxicity, including fatal liver injury, has been reported, particularly at high doses.
| Serious Effects |
Hypersensitivity to azathioprine or 6-mercaptopurine; Pregnancy (unless benefit outweighs risk) - Category D; Lactation; Patients with TPMT deficiency (increased risk of severe myelotoxicity); Severely depressed bone marrow function; Active infections; Concurrent use of live vaccines; Pre-existing malignancy (except in organ transplantation context).
| Precautions | Hematologic monitoring: regular CBCs; Increased risk of infection; Hepatotoxicity; Pancreatitis; Carcinogenicity (lymphoma, skin cancer); TPMT deficiency increases myelotoxicity; Vaccination (live vaccines contraindicated); Renal and hepatic impairment; Drug interactions: allopurinol (reduce dose by 75%), ACE inhibitors (anemia), warfarin (anticoagulant effect decreased). |
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| Fetal Monitoring | Monitor maternal complete blood count and liver function tests every 1-3 months. During pregnancy: serial fetal ultrasounds for growth and anatomy; routine prenatal care. Breastfeeding infant: monitor complete blood count and for signs of infection. |
| Fertility Effects | Azathioprine does not appear to impair fertility in men or women. In women, it may restore fertility in those with inflammatory bowel disease or autoimmune hepatitis by controlling disease activity. No known adverse effect on spermatogenesis. |
| Food/Dietary | No known significant food interactions. Avoid grapefruit juice? (No interaction reported). Maintain consistent diet; no specific restrictions. Limit alcohol due to hepatotoxicity risk. |
| Clinical Pearls | Monitor CBC and LFTs weekly for first month, then biweekly for 2 months, then monthly. TPMT genotype testing before initiation. Avoid concurrent allopurinol unless dose reduced to 25% of original. Use with caution in renal impairment. May cause hepatotoxicity, pancreatitis, or lymphoproliferative disorders. |
| Patient Advice | Take exactly as prescribed; do not double dose if missed. · Avoid live vaccines during treatment and for 3 months after stopping. · Report any signs of infection, unexplained bruising/bleeding, or jaundice immediately. · Limit sun exposure and use sunscreen due to increased skin cancer risk. · Do not take allopurinol or other new medications without consulting doctor. · Maintain adequate hydration to reduce risk of hepatotoxicity. · Regular blood tests are required to monitor for side effects. |