From the FDA Drug Label
2.2 Dosing Information The starting dose is 12. 5 mg once daily or twice daily. 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 maximum dose is 900 mg per day
The recommended dose adjustment for Clozapine (Clozaril) after reaching a daily dose of 500 milligrams is to increase the dose in increments of up to 100 mg once weekly or twice weekly, as tolerated, with a maximum dose of 900 mg per day 1.
- Key considerations:
- Dose increases should be based on patient tolerance.
- The dose should be administered in divided doses.
- Patients should be monitored for signs of orthostatic hypotension, bradycardia, and syncope.
From the Research
Clozapine doses above 500mg should be increased cautiously with close monitoring, with increments of 25-50mg at weekly intervals, not exceeding 900mg daily, guided by clinical response and blood levels between 350-600 ng/mL, as evidenced by the most recent study 2. When adjusting the dose of Clozapine, it is crucial to consider the risk of agranulocytosis, which, although rare, can be life-threatening. The risk of agranulocytosis is concentrated in the first 18 weeks of treatment, as suggested by a recent study 3.
Key Considerations for Dose Adjustment
- Before any increase, check recent clozapine blood levels, complete blood counts, and assess for side effects like sedation, hypotension, seizures, and metabolic changes.
- Dose increases should be guided by clinical response and blood levels, with therapeutic ranges generally between 350-600 ng/mL, as supported by a systematic review and meta-analysis 2.
- Consider dividing the total daily dose to minimize side effects, with larger portions given at bedtime to manage sedation.
- Patients may need more frequent monitoring of vital signs, blood work, and ECGs with higher doses due to increased risk of adverse effects.
Monitoring and Risk Assessment
- The decision to exceed 500mg should be based on inadequate response at lower doses and careful consideration of risks versus benefits, as higher doses increase the likelihood of serious side effects without always providing additional therapeutic benefit.
- Regular monitoring of white blood cell count is essential, especially during the first 18 weeks of treatment, as recommended by recent research 3.
- The risk of agranulocytosis can be minimized by regular white blood cell count monitoring, and the treatment should only be used in schizophrenic patients who are resistant to, or intolerant of, conventional antipsychotic medications, as initially suggested by an early study 4.