Azathioprine Dose Escalation Protocol After Reintroduction
After reintroduction of azathioprine, the dose should be increased to 2 mg/kg daily as the dose of prednisone is gradually withdrawn, and then continued indefinitely as maintenance therapy. 1
Initial Reintroduction Protocol
- Start azathioprine at 50 mg daily (approximately 1 mg/kg/day for most adults) to minimize early gastrointestinal side effects 2
- Take medication with or shortly after food to reduce nausea 2
- Consider splitting the daily dose if gastrointestinal symptoms occur 2
- Maintain this initial dose for at least 4 weeks before considering dose increases 2
Dose Escalation Strategy
- After 4 weeks at the initial dose, begin increasing azathioprine by 0.5 mg/kg (approximately 25 mg) increments at 4-week intervals 3
- Continue dose escalation until reaching the target maintenance dose of 2 mg/kg/day 1
- As azathioprine dose increases, gradually taper prednisone dose by 2.5 mg each month 1
- The goal is to completely withdraw prednisone while maintaining disease control on azathioprine monotherapy 1
Monitoring During Dose Escalation
- Monitor complete blood count weekly for the first 4 weeks of therapy 2
- Continue weekly monitoring until maintenance dose is achieved 2
- Check liver function tests monthly for the first 3 months 4
- After stable maintenance dose is established, reduce monitoring frequency to once every 3 months 2
- Monitor for clinical efficacy and disease activity markers specific to the underlying condition 4
Special Considerations
- Consider TPMT testing prior to initiating therapy to identify patients at risk for severe myelosuppression 3
- For patients with intermediate (heterozygous) TPMT activity, reduce target dose to 1-1.5 mg/kg/day 3
- For patients with absent (homozygous deficient) TPMT activity, azathioprine is contraindicated 3
- Dose escalation beyond 2.5 mg/kg/day is associated with diminishing efficacy and substantially increased risk of adverse reactions 5
Management of Side Effects During Dose Escalation
- For mild cytopenia, reduce azathioprine dose 4
- For severe cytopenia, discontinue medication and consult hematology 4
- Gastrointestinal symptoms can be managed by taking medication with food, splitting the daily dose, or temporarily reducing the dose 4
- Transient elevations in liver enzymes are common (41% of patients) but rarely clinically significant 6
Long-Term Maintenance
- The target maintenance dose of 2 mg/kg/day has shown 87% remission rates over a median follow-up of 67 months 1, 7
- Follow-up liver biopsy assessments show inactive or minimal histological disease in 94% of patients 1, 7
- Corticosteroid-related side effects improve or disappear in most patients on azathioprine maintenance therapy 1
- Long-term, probably permanent, maintenance treatment is advisable in patients after a relapse 1
Cautions and Pitfalls
- Avoid concomitant use with allopurinol, which inhibits xanthine oxidase and prolongs azathioprine action, potentially increasing toxicity 2
- Live vaccines are contraindicated during azathioprine therapy 2
- Approximately 30% of patients may not achieve adequate active metabolite (6-TGN) levels despite appropriate dosing, which may explain lack of response in some cases 8
- Injury may first arise after a dose escalation, with a median latency of 44 days after dose increase 9
- Common side effects include withdrawal arthralgia (63%), lymphopenia (57%), and myelosuppression (7%) 1