Clozapine Missed Doses: Maximum Duration Before Retitration Required
If you miss clozapine for more than 2 days, you cannot restart at your previous dose and must contact your physician for retitration instructions. 1
Critical Timeframe
- ≤2 days missed: Can generally resume at the previous dose 1
- >2 days missed: Requires dose retitration due to increased risk of severe hypotension, bradycardia, syncope, and seizures upon restarting at full dose 1
The FDA label explicitly states that patients who miss clozapine for more than 2 days should not restart their medication at the same dosage but must contact their physician for dosing instructions 1. This is a mandatory safety requirement, not a suggestion.
Why Retitration Is Required After >2 Days
The risk of severe cardiovascular adverse effects increases dramatically when restarting clozapine after interruption. The body loses tolerance to clozapine's cardiovascular effects (particularly orthostatic hypotension and tachycardia) within just a few days of discontinuation 1. Restarting at full dose after this brief interruption can cause:
- Severe orthostatic hypotension
- Bradycardia
- Syncope
- Seizures
- Respiratory or cardiac arrest 1
Retitration Protocol After >2 Days Interruption
When restarting clozapine after missing >2 days, follow a gradual titration schedule similar to initial dosing 1:
- Start at 12.5 mg once or twice daily
- Increase gradually by 25-50 mg/day increments
- Monitor closely for orthostatic hypotension, tachycardia, and sedation during retitration
- Target the previous therapeutic dose over 1-2 weeks depending on tolerance 1
A reasonable retitration approach after ciprofloxacin interaction (which provides a useful model) suggests: 150 mg twice daily for 3 days, then 200 mg twice daily for 3 days, then 250 mg twice daily for 3 days, then return to original dose 2. However, the specific retitration schedule must be individualized based on the duration of interruption and previous dose.
Monitoring During Retitration
Monitor for signs of clozapine toxicity during retitration, including 2:
- Sedation
- Hypotension
- Tachycardia
- Seizures
- Myoclonus
- Delirium
Obtain trough clozapine levels 2-3 days after reaching the target dose to confirm therapeutic levels between 350-550 ng/mL 2, 3.
Common Pitfall to Avoid
The most dangerous error is allowing patients to restart clozapine at their previous full dose after missing >2 days. This can result in life-threatening cardiovascular collapse 1. Always err on the side of caution—if there is any uncertainty about whether the patient missed exactly 2 days versus 3 days, treat it as >2 days and require retitration.