AZATHIOPRINE SODIUM
Clinical safety rating: avoid
Allopurinol inhibits xanthine oxidase increasing levels of active metabolites leading to severe myelosuppression Myelosuppression is dose-related and requires frequent CBC monitoring.
Azathioprine is a prodrug of 6-mercaptopurine. It inhibits purine synthesis by interfering with the synthesis of DNA, RNA, and cellular proteins, thereby suppressing immune responses.
| Metabolism | Primarily metabolized by xanthine oxidase (XO) and thiopurine methyltransferase (TPMT) to active and inactive metabolites. Also metabolized by aldehyde oxidase and glutathione S-transferase. Concomitant use with allopurinol (XO inhibitor) requires dose reduction. |
| Excretion | Primarily renal: approximately 50% as unchanged drug and metabolites (6-mercaptopurine, thiouric acid) within 24 hours. Biliary/fecal excretion accounts for minor fraction (<5%). |
| Half-life | Terminal elimination half-life of azathioprine is approximately 3-5 hours; its active metabolite 6-mercaptopurine has a half-life of 0.5-1.5 hours. However, the pharmacodynamic effect (immunosuppression) persists longer due to intracellular accumulation of thioguanine nucleotides. |
| Protein binding | Approximately 30% bound to serum proteins, primarily albumin. |
| Volume of Distribution | Apparent volume of distribution is 0.6-1.0 L/kg, indicating distribution into total body water and tissues. |
| Bioavailability | Oral bioavailability of azathioprine is approximately 60-70% (range 27-82%) due to first-pass metabolism. Intravenous administration yields 100% bioavailability. |
| Onset of Action | Oral: 4-6 weeks for therapeutic effect in autoimmune conditions; IV: 3-5 days for acute rejection prophylaxis. |
| Duration of Action | The immunosuppressive effect persists for several weeks after discontinuation due to long-lived intracellular active metabolites. Clinical duration is dose-dependent and sustained with continued therapy. |
| Molecular Weight | 277.27 |
1-2 mg/kg/day IV or oral, initially; maintenance 0.5-1 mg/kg/day IV or oral. For severe organ rejection: 3-5 mg/kg/day IV.
| Dosage form | INJECTABLE |
| Renal impairment | GFR 50-80 mL/min: no adjustment. GFR 30-50 mL/min: reduce dose by 25% to 50%. GFR 10-30 mL/min: reduce dose by 50% to 75%. GFR <10 mL/min: avoid or use with extreme caution. |
| Liver impairment | Child-Pugh class A: no adjustment. Child-Pugh class B: reduce dose by 50%. Child-Pugh class C: avoid use. |
| Pediatric use | 2-5 mg/kg/day IV or oral, divided every 12-24 hours; dose based on body weight (mg/kg). |
| Geriatric use | Start at lower end of dosing range; monitor renal function and adjust accordingly. Consider reduced initial dose (e.g., 1 mg/kg/day) due to age-related decreased renal function. |
| 1st trimester | Associated with congenital malformations; use only if clearly needed. |
| 2nd trimester | Risk of fetal immunosuppression and growth restriction; use only if benefit outweighs risk. |
| 3rd trimester | Risk of neonatal immunosuppression, leukopenia, and thrombocytopenia; avoid near term. |
Clinical note
Allopurinol inhibits xanthine oxidase increasing levels of active metabolites leading to severe myelosuppression Myelosuppression is dose-related and requires frequent CBC monitoring.
| FDA category | Positive |
| Placental transfer | Azathioprine and its metabolite 6-mercaptopurine cross the placenta; fetal levels approximately 50-80% of maternal levels. |
| Breastfeeding |
■ FDA Black Box Warning
MALIGNANCY: Immunosuppression increases risk of lymphoma and other malignancies, particularly skin cancers. Monitor for neoplasia, especially in renal transplant patients.
| Common Effects | immunosuppression in transplants |
| Serious Effects |
Hypersensitivity to azathioprine or 6-mercaptopurineSevere immunosuppressionPregnancy (unless clearly needed)
| Precautions | Hematotoxicity (leukopenia, thrombocytopenia, anemia) - monitor CBC. Hepatotoxicity - monitor liver function tests. Increased infection risk. Pancreatitis. Hypersensitivity reactions. Increased risk of malignancy (skin cancer, lymphoma). Use with caution in renal/hepatic impairment. Test for TPMT deficiency before use. |
| Food/Dietary | Avoid raw or undercooked meats and fish to reduce infection risk; no specific dietary restrictions; grapefruit juice has no known interaction. |
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| Excreted into breast milk in low concentrations; potential for immunosuppression in infant. Breastfeeding generally not recommended during azathioprine therapy. |
| Lactation Rating | L4 |
| Teratogenic Risk | FDA Category D. Hematologic toxicity and immunosuppression in the neonate. Increased risk of congenital malformations (cleft palate, skeletal anomalies) and fetal growth restriction. First trimester exposure associated with highest risk; second and third trimester risks include intrauterine growth restriction and preterm birth. |
| Fetal Monitoring | Maternal: CBC with differential weekly for first 8 weeks, monthly thereafter; liver and renal function tests; monitoring for signs of infection. Fetal: Serial ultrasound for fetal growth and anatomy; neonatal assessment for lymphopenia, neutropenia, or thrombocytopenia. |
| Fertility Effects | May cause oligospermia or azoospermia in males; anovulation in females. Effects are usually reversible upon discontinuation. |
| Clinical Pearls | Monitor CBC and LFTs weekly for first month, then biweekly for next 2 months, then monthly; dose reduction required with allopurinol coadministration (reduce to 25% of usual dose); screen for TPMT and NUDT15 deficiency before initiating therapy; avoid live vaccines; increased risk of lymphoproliferative disorders; use sun protection due to photosensitivity; pregnancy category D. |
| Patient Advice | Take exactly as prescribed, do not stop without consulting your doctor. · Report any signs of infection (fever, sore throat, easy bruising or bleeding) immediately. · Use effective contraception during treatment and for at least 3 months after stopping. · Avoid live vaccines (e.g., MMR, varicella, nasal flu) while on this medication. · Limit sun exposure and use broad-spectrum sunscreen and protective clothing. · Do not take allopurinol without your doctor's knowledge. · Attend all scheduled blood tests to monitor for side effects. · May cause nausea; take with food if upset stomach occurs. |