What is the typical dosage and use of Imuran (azathioprine)?

Azathioprine (Imuran): Dosage and Clinical Use

FDA-Approved Indications and Standard Dosing

Azathioprine is FDA-approved for renal transplantation (3-5 mg/kg/day initially, then 1-3 mg/kg/day maintenance) and rheumatoid arthritis (starting at 1.0 mg/kg/day, maximum 2.5 mg/kg/day), but is widely used off-label for autoimmune conditions including immune thrombocytopenia, atopic dermatitis, psoriasis, autoimmune hepatitis, and lupus nephritis. 1

Renal Transplantation

• Initial dose: 3-5 mg/kg daily as a single dose beginning at time of transplant 1
• Maintenance: Reduce to 1-3 mg/kg daily after initial period 1
• Do not increase to toxic levels even if rejection is threatened 1

Rheumatoid Arthritis

• Initial dose: 1.0 mg/kg/day (50-100 mg) as single or twice-daily dosing 1
• Increase by 0.5 mg/kg every 4 weeks starting at 6-8 weeks if no toxicity and inadequate response 1
• Maximum dose: 2.5 mg/kg/day 1
• Therapeutic response typically occurs after 6-8 weeks; minimum trial should be 12 weeks 1

Off-Label Uses with Evidence-Based Dosing

Autoimmune Hepatitis

• Start predniso(lo)ne first, then add azathioprine after 2 weeks once bilirubin is below 6 mg/dL (100 μmol/L) 2
• Initial dose: 50 mg/day, increase based on tolerance and response up to maintenance of 1-2 mg/kg/day 2
• Target maintenance: 2 mg/kg/day achieves 87% remission rates with 94% showing inactive/minimal histological disease 3
• Continue indefinitely as maintenance therapy; long-term treatment is advisable after relapse 2, 3

Lupus Nephritis (Maintenance Therapy)

• Standard maintenance dose: 2 mg/kg/day combined with low-dose prednisone (2.5-5 mg/day) 4
• Continue for at least 3-5 years following initial induction therapy 4
• Used after induction with mycophenolic acid, cyclophosphamide, or multitarget therapy 4

Atopic Dermatitis

• Dose range: 1-3 mg/kg/day, with most studies using this range 2
• Graduated dosing preferred to maximize benefit while limiting side effects 2
• Delayed effect common; may need 12 weeks or more for full clinical benefit 2
• Once clearance achieved, taper or discontinue with maintenance via emollients and topical agents 2

Immune Thrombocytopenia (ITP)

• Oral dose: 50-200 mg/day in adults 2
• Takes several months for full effect 2
• Durable response rates: 51-64%, though approximately half require ongoing therapy to maintain response 2
• One of few ITP medications deemed safe in pregnancy 2

Psoriasis

• Dose range: 100-300 mg/day in adults 2
• Limited evidence base; no randomized trials available 2

Critical Pre-Treatment Requirements

TPMT Testing (Mandatory)

Testing for thiopurine methyltransferase (TPMT) activity is mandatory before initiating azathioprine to prevent life-threatening pancytopenia. 2, 4

• Homozygous deficiency (absent TPMT): Azathioprine is contraindicated 2, 1
• Heterozygous deficiency (intermediate TPMT): Reduce dose to 1-1.5 mg/kg/day 3, 1
• Normal TPMT activity: Proceed with standard dosing 3
• Up to 0.25% of population lacks TPMT enzyme, risking serious cytopenias 2

NUDT15 Testing

• Consider testing for NUDT15 deficiency in patients with severe bone marrow toxicity 1
• Homozygous NUDT15 deficiency: Consider alternative therapies 1
• Heterozygous NUDT15 deficiency: Dosage reduction recommended 1
• Patients heterozygous for both TPMT and NUDT15 may require more substantial dose reductions 1

Baseline Laboratory Tests

• Complete blood count (CBC) with differential 2
• Liver function tests including transaminases 2
• Renal function tests 2
• Hepatitis B surface antigen (HBsAg) and anti-HBV core antibodies (anti-HBc) 2
• Consider hepatitis C screening 2

Practical Dosing Strategy to Minimize Side Effects

Start azathioprine at 50 mg daily (approximately 1 mg/kg/day for most adults) to minimize early gastrointestinal side effects, which are the most common reason for discontinuation. 3

• Take with or shortly after food to reduce nausea 3
• Consider splitting daily dose if gastrointestinal symptoms occur 3
• Maintain initial dose for at least 4 weeks before considering increases 3
• Graduated dosing approach reduces the 15-27% withdrawal rate due to nausea and vomiting 2, 5

Monitoring Requirements

Initial Phase (First 4 Weeks)

• Weekly CBC and liver function tests until maintenance dose achieved 2, 3
• More frequent monitoring if hepatic/renal impairment, elderly, or high doses used 2

Maintenance Phase

• Minimum frequency: Once every 3 months for duration of therapy 2, 3
• Some guidelines recommend monthly or every 2 months 2
• After dose increases: Return to weekly monitoring for 4 weeks 2

Therapeutic Drug Monitoring

• Target 6-thioguanine nucleotide (6-TGN) levels: 100-300 pmol/8×10⁸ RBCs 4, 6
• Low 6-TGN (<100 pmol/8×10⁸ RBCs) are subtherapeutic in most patients with normal kidney function 6
• High 6-TGN concentrations associated with increased leucopenia frequency and severity 6
• Monitored high-dose therapy (keeping 6-TGN 100-200 pmol/8×10⁸ RBCs) reduces rejection episodes by 21% in transplant recipients 7

Special Populations and Dose Adjustments

Renal Dysfunction

• Oliguric patients, especially with tubular necrosis post-transplant, may have delayed clearance 1
• Use lower doses in these patients 1
• However, controlled studies show no enhanced toxicity with renal insufficiency 2
• Dosage at lower end of normal range recommended with careful CBC monitoring 2
• No dose adjustment needed for hemodialysis 2

Hepatic Disease

• Cautious administration with regular CBC and liver function monitoring 2
• Drug metabolism may be impaired 2
• Reduce dosage if hepatic or haematological toxicity occurs 2

Pregnancy and Lactation

• Azathioprine is one of few immunosuppressants considered safe in pregnancy with no increased fetal malformation rate 2, 4
• Safe during lactation per some sources 2
• Contraindicated during breastfeeding per other sources as it appears in breast milk 4

Elderly Patients

• More frequent monitoring advised 2
• Higher risk of infection-related mortality when combined with corticosteroids, particularly in bullous pemphigoid 2, 8

Critical Drug Interactions

Allopurinol (Most Important)

Avoid concurrent allopurinol, which inhibits xanthine oxidase and prolongs azathioprine action, potentially causing severe myelosuppression. 3, 4

• If combination unavoidable, reduce azathioprine dose to 25% of standard dose 4

Other Interactions

• Concomitant phototherapy not advised due to increased DNA damage risk and photocarcinogenicity, especially with UVA 2
• May potentiate glucose-lowering effect of glibenclamide 2
• May interfere with contraceptive effect of microdosed progestin minipill 2
• Combination with methotrexate requires caution due to dual hepatotoxicity risk 2

Vaccination Considerations

• Live vaccines are contraindicated during azathioprine therapy 2, 3
• Diminished response to killed vaccines may occur, particularly with concomitant corticosteroids 2
• Vaccinate against hepatitis B if seronegative before starting therapy 2

Infection Management

Varicella Zoster Exposure

• Patients without prior chickenpox should seek immediate attention if exposed 2, 3
• Consider temporary withdrawal with prompt antiviral therapy 8

Active Sepsis/Bacteremia

Immediately discontinue azathioprine upon recognition of sepsis and initiate appropriate sepsis management including blood cultures, broad-spectrum antimicrobials, and fluid resuscitation. 8

• Hold until infection completely resolved and patient clinically stable 8
• When restarting post-infection, monitor weekly CBC and liver function tests for at least 4 weeks 8
• Combination with corticosteroids amplifies infection risk and mortality 8

Common Adverse Effects and Management

Gastrointestinal (Most Common)

• Nausea, vomiting, bloating, anorexia, cramping 2
• Manage by taking with food, splitting doses, or starting at lower doses 3

Hematologic

• Leucopenia (14% develop; clinically significant <2500/mm³ in subset) 5
• Lymphopenia (57% in some series) 3
• Myelosuppression (7-9.9%) 2, 3
• Anemia and neutropenia 2

Hepatic

• Elevated liver enzymes 2
• Monitor regularly throughout therapy 2

Other

• Infection risk (9.9%) 2
• Headache 2
• Hypersensitivity reactions 2
• Pancreatitis (rare but well-recognized) 2
• Withdrawal arthralgia (63%) 3

Serious Long-Term Risks

• Secondary malignancies (increased risk in transplant recipients on multiple immunosuppressants) 2
• Non-melanoma skin cancer (variable data, often confounded by polypharmacy) 2
• Lymphoma risk (primarily in transplant populations) 2
• Infertility 2

When to Discontinue or Adjust

• Discontinue if no therapeutic response within 3 months 2
• Discontinue for severe hematologic or other toxicity, even if rejection may result 1
• Reduce dose if mild cytopenia develops; discontinue if severe 4
• Consider early discontinuation in patients with abnormal CBC not responding to dose reduction 1
• Patients displaying cytopenias should be tested for TPMT deficiency 2
• Measure serum amylase if acute abdominal pain or severe vomiting occurs (rule out pancreatitis) 2