Azathioprine

# Azathioprine ## Overview - **Classification**: Immunosuppressant, purine antimetabolite - **Mechanism**: Metabolized to 6-mercaptopurine, which inhibits purine synthesis, leading to impaired DNA/RNA synthesis and reduced lymphocyte proliferation. ## Primary Indications 1. **Renal Transplant**: Prevention of rejection in combination with other agents. 2. **Rheumatoid Arthritis**: Management of severe, active, and erosive RA. 3. **Inflammatory Bowel Disease (IBD)**: Induction and maintenance of remission in Crohn's disease and ulcerative colitis. ## Adult Dosing ### Standard Dosing **Renal Transplant (Adjunct)** - **Initial Dose**: **3-5 mg/kg/day** - **Frequency**: Once daily - **Route**: Oral (PO) or Intravenous (IV) - **Maintenance Dose**: **1-3 mg/kg/day** (based on clinical response/hematologic tolerance) **Rheumatoid Arthritis** - **Initial Dose**: **1 mg/kg/day** (or **50 mg/day**) - **Frequency**: Once daily - **Route**: Oral (PO) - **Titration**: Increase by **0.5 mg/kg/day** (or **25 mg/day**) at 6-8 week intervals. - **Maximum Dose**: **2.5 mg/kg/day** (or **100-150 mg/day**) **Inflammatory Bowel Disease (Crohn's, Ulcerative Colitis)** - **Dose**: **2-3 mg/kg/day** - **Frequency**: Once daily - **Route**: Oral (PO) - **Duration**: Consider treatment for 4 months for clinical response. ### Dose Adjustments - **Renal Impairment**: - **CrCl 10-50 mL/min**: Reduce dose by **25%** of usual. - **CrCl <10 mL/min**: Reduce dose by **50%** of usual. - Monitor closely for hematologic toxicity. - **Hepatic Impairment**: Reduce dose by **25-50%** of usual. - Monitor liver function tests (LFTs) and blood counts closely. - **Elderly Patients**: - Start at lower end of adult dosing range. - Monitor closely for myelosuppression and other adverse effects. ## Pediatric Dosing ### Neonates (0-28 days) - **Special Notes**: Data is extremely limited. Use only if benefits outweigh risks in highly specialized settings. - Dosing should be individualized, often off-label, and very cautious. ### Infants (1-12 months) - **Indication**: Typically for organ transplant (e.g., renal, liver). - **Initial Dose**: **1-3 mg/kg/day** - **Frequency**: Once daily - **Route**: Oral (PO) or Intravenous (IV) - **Maintenance Dose**: **0.5-1 mg/kg/day** (adjust based on tolerance) - **Special Notes**: Monitor closely for myelosuppression and infections. ### Children (1-12 years) - **Indication**: Organ transplant, severe autoimmune conditions (e.g., IBD, JIA). - **Initial Dose**: **1-5 mg/kg/day** - **Frequency**: Once daily - **Route**: Oral (PO) or Intravenous (IV) - **Maintenance Dose**: **1-2.5 mg/kg/day** (titrate to response/toxicity) - **Maximum Dose**: Generally **150 mg/day** (or **2.5 mg/kg/day**). - **Special Notes**: Tablets can be crushed and mixed with liquid for easier administration; ensure consistent dosing. ### Adolescents (13-18 years) - **Dose**: Follow adult dosing guidelines. - **Frequency**: Once daily - **Route**: Oral (PO) or Intravenous (IV) - **Maximum Dose**: **150 mg/day** for most indications. ## Safety Information ### Contraindications - **Absolute**: Hypersensitivity to azathioprine or any component. - **Absolute**: Concurrent severe myelosuppression. - **Absolute**: Women of childbearing potential not using contraception. - **Relative**: Pregnancy (category D), breastfeeding. ### Common Adverse Effects - **Very Common (>10%)**: Leukopenia, nausea, vomiting, anorexia. - **Common (1-10%)**: Thrombocytopenia, anemia, increased LFTs, pancreatitis, alopecia. - **Serious but Rare**: Severe myelosuppression (aplastic anemia), hepatotoxicity (cholestatic, hepatocellular), increased risk of infections (opportunistic), increased risk of malignancy (lymphomas, skin cancers). ### Key Drug Interactions - **Allopurinol/Febuxostat**: Significantly increases azathioprine levels. - **Clinical Significance**: Life-threatening myelosuppression. - **Dose Adjustment**: Azathioprine dose must be reduced to **1/4 to 1/3** of original dose. - **Aminosalicylates (e.g., Mesalamine, Olsalazine)**: May inhibit TPMT enzyme. - **Clinical Significance**: Increased risk of myelosuppression. - **Monitoring Requirement**: Close monitoring of CBC. - **ACE Inhibitors/Co-trimoxazole**: May increase myelosuppression risk. - **Monitoring Requirement**: Frequent CBC monitoring. - **Warfarin**: May alter anticoagulant effect. - **Monitoring Requirement**: Monitor INR closely. ## Monitoring & Follow-up - **Before Treatment**: - **TPMT enzyme activity**: Essential to identify patients at high risk of severe myelosuppression. - **Complete Blood Count (CBC)** with differential. - **Liver Function Tests (LFTs)**: AST, ALT, alkaline phosphatase, bilirubin. - **Renal Function Tests**: BUN, creatinine. - **During Treatment**: - **CBC with differential**: Weekly for first month, then monthly or more frequently based on clinical need. - **LFTs**: Monthly for 3 months, then every 3-6 months. - **Renal Function**: Periodically. - **Clinical Signs**: Monitor for signs of infection, bruising, bleeding, jaundice, abdominal pain. ## Clinical Pearls - 💡 **TPMT Testing**: Pre-treatment TPMT genotyping/phenotyping is crucial to guide initial dosing and prevent severe toxicity. - 💡 **Onset of Action**: Therapeutic effects often take 6-12 weeks, sometimes up to 4 months for full benefit. - 💡 **GI Upset**: Administer with food to reduce nausea and vomiting. - 💡 **Sun Protection**: Advise patients to use sun protection due to increased skin cancer risk. - 💡 **Immunizations**: Avoid live vaccines during azathioprine therapy. > **⚠️ Important**: This information is for educational purposes only. Always consult current prescribing information, local guidelines, and clinical judgment before prescribing.