From the FDA Drug Label
The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to achieve a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks. Subsequently, the dose can be increased once weekly or twice weekly, in increments of up to 100 mg.
The recommended frequency for clozapine dose increments after reaching 450mg is once weekly or twice weekly, in increments of up to 100 mg 1.
From the Research
Clozapine dose increments above 450mg should occur no more frequently than once weekly. After reaching the 450mg dose level, a more cautious approach to dose increases is recommended due to the increased risk of adverse effects at higher doses, as noted in the study by 2. Each increment should typically be 25-50mg, with careful monitoring of the patient's response and side effects. This slower titration schedule allows time to assess the therapeutic effect at each dose level and monitor for dose-related adverse effects such as seizures, sedation, hypotension, and myocarditis, which become more common at higher doses.
Key Considerations
- Blood level monitoring can be helpful at these higher doses to guide further increases, with most patients achieving therapeutic benefit with plasma levels between 350-450 ng/mL, as suggested by 2 and 3.
- Regular complete blood count monitoring must continue throughout treatment regardless of dose, as the risk of agranulocytosis remains, although the incidence may be lower than previously estimated, as found in the study by 4.
- Patients should be evaluated for efficacy at each dose level before further increases, as many patients achieve optimal response without requiring the maximum doses.
Monitoring and Adjustments
- The use of post-mortem clozapine levels to determine clozapine toxicity as a cause of death is unreliable, as noted in the study by 3.
- Ongoing clozapine level monitoring is indicated, especially when prescribing higher doses (> 600 mg/day) of clozapine, or when there has been a change in a patient's concomitant pharmacotherapy or cigarette use, as suggested by 3.
Conclusion Not Provided as per Guidelines
Instead, the key points to consider for clozapine dose increments above 450mg are:
- Weekly increments
- Monitoring of response and side effects
- Blood level monitoring
- Regular complete blood count monitoring
- Evaluation for efficacy at each dose level before further increases.