Azathioprine

TPMT or NUDT15 Deficiency
1. Avoid in Homozygous patients (or significantly decrease Azathioprine dose)
2. Homozygous patients are at risk of severe myelosuppression
  1. Thiopurine methyltransferase Deficiency (TPMT Deficiency)
  2. Nucleotide Diphosphatase Deficiency (NUDT15 Deficiency)

Azathioprine is a Purine Analog with cytotoxic and Immunosuppressant activity
1. Purine Analogs, resembling adenine or guanine, and incorporate into DNA
2. Result in DNA cross-linking and inhibition of synthesis and repair of DNA
Azathioprine is a imidazolyl derivative of Mercaptopurine
1. Metabolized to the Mercaptopurine (6-MP) by hepatic xanthine oxidase
2. Mercaptopurine is further metabolized to metabolites that inhibit Nucleotide interconversion
3. Inhibits Purine, DNA, RNA synthesis (as well as the related Protein synthesis), especially in Lymphocytes and Leukocytes

See other references for specific dosing
Prescribers are typically specialists knowledgeable about the risks and monitoring
Rheumatoid Arthritis (severe, refractory)
1. Start 1 mg/kg (up to 50 to 100 mg) orally daily or divided twice daily
2. May increase to 1.5 mg/kg/day at 6 to 8 weeks if tolerated without toxicity
3. May increase to 2.0 mg/kg/day after an additional 1 month
4. Maximum: 2.5 mg/kg/day
5. Maintain the lowest effective dose
Kidney Transplant (renal homograft maintenance, dosing is also used off-label in children)
1. Start: 3-5 mg/kg IV or oral daily
2. Maintenance: 1 to 3 mg/kg/day
Autoimmune Conditions (e.g. Myasthenia Gravis, Multiple Sclerosis, Lupus Nephritis, Inflammatory Bowel Disease)
1. Typical dosing: 2 to 2.5 mg/kg/day (or 50 to 100 mg) orally daily
2. Dosing Range: 1.5 to 3 mg/kg/day

Bone Marrow suppression
1. Mild to severe Leukopenia
2. Anemia
3. Thrombocytopenia
Skin rash
Drug Fever
Secondary malignancy (black box warning)
1. Post-transplant Lymphoma
2. Hepatosplenic T-Cell Lymphoma (HSTCL)
3. Skin Cancer
Gastrointestinal
1. Nausea and Vomiting
2. Diarrhea
3. Hepatic dysfunction (cholestasis, hepatitis)
4. Drug-Induced Pancreatitis

Considered safe in Lactation
May be used in pregnancy if benefit outweighs risk
1. Skeletal and visceral malformations have been found in animal studies
2. Cytopenias have been observed in infants born to mothers taking Azathioprine
Monitoring
1. Complete Blood Count (CBC)
  1. Obtain baseline, weekly for 1 month, every 2 weeks for months 2-3, then monthly
2. Liver Function Tests

See Cytochrome P-450 3A4
See Purine Synthesis Inhibitor
Allopurinol
1. Allopurinol inhibits xanthine oxidase conversion of Azathioprine to Mercaptopurine (6-MP)
2. May increase serum Azathioprine to toxic levels
3. Decrease Azathioprine dose by 66 to 75% if concurrently taking Allopurinol
Other drugs that increase Azathioprine toxicity
Azathioprine decreases other drug levels