What are the guidelines for restarting clozapine (Clozaril) after missed doses?

Restarting Clozapine After Missed Doses

If clozapine is missed for more than 2 days, do not restart at the previous dose—retitration is required starting at 12.5-25 mg daily with gradual increases to minimize risk of serious adverse effects including hypotension, seizures, and delirium. 1

Critical Threshold for Retitration

• The 48-hour rule is absolute: Missing more than 2 days of clozapine mandates retitration rather than resuming the previous maintenance dose 1
• Even brief interruptions (as short as 2-10 days) can precipitate delirium if the previous full dose is resumed without retitration 2
• The FDA explicitly instructs patients who miss clozapine for more than 2 days to contact their physician for dosing instructions rather than self-resuming 1

Standard Retitration Protocol

For interruptions >48 hours, restart with the standard initiation protocol:

• Begin at 12.5 mg once or twice daily on day 1
• Increase by 25-50 mg daily as tolerated
• Target dose increments should be conservative, typically reaching 300-450 mg/day by end of week 2 3
• The goal is to achieve therapeutic plasma levels ≥350 ng/mL 4, 5

Accelerated Retitration Option

For patients previously stable on higher doses who require faster return to therapeutic levels:

• Consider a more aggressive schedule: 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 6
• This accelerated approach should only be used with close monitoring and when clozapine levels can be checked 6
• Obtain trough clozapine level on day 2-3 after reaching target dose to confirm therapeutic range (350-550 ng/mL) 6, 4

Critical Monitoring During Retitration

Monitor intensively for signs of toxicity throughout the retitration period:

• Cardiovascular: Hypotension, tachycardia (particularly dangerous during retitration) 6, 1
• Neurological: Seizures (risk increases with rapid dose escalation), myoclonus, delirium 6, 1
• Sedation: Excessive sedation is common and dose-limiting 1
• Hematologic: Continue standard absolute neutrophil count monitoring per clozapine REMS protocol 6

Special Circumstances

For interruptions ≤48 hours:

• The previous maintenance dose may generally be resumed without retitration 1
• However, clinical judgment should guide this decision based on individual patient factors

If neutropenia caused the interruption:

• Rechallenge requires careful risk-benefit analysis and is only appropriate when non-clozapine causes of neutropenia are identified and eliminated 7
• Lithium co-therapy may be necessary to induce leukocytosis during rechallenge, though it does not protect against clozapine-induced agranulocytosis 7
• If clozapine clearly caused agranulocytosis (not just neutropenia), rechallenge should not be attempted except in exceptional circumstances with granulocyte colony-stimulating factor support 7

Common Pitfalls to Avoid

• Never resume the full previous dose after >2 days interruption—this is the most dangerous error and can precipitate life-threatening complications including delirium, severe hypotension, and seizures 1, 2
• Do not rush retitration even in severely ill patients—the risks of rapid escalation (seizures, cardiovascular collapse) outweigh the benefits of faster symptom control 2
• Do not assume brief interruptions are safe—even 2-10 day breaks require full retitration 2

Target Therapeutic Levels

• Aim for trough plasma levels of 350-550 ng/mL for optimal efficacy 6, 4, 5
• Measure trough levels on at least two occasions separated by one week once at stable dosing 4
• If levels cannot be obtained, ensure minimum dose of 500 mg/day (unless limited by tolerability) as doses >400 mg/day show superior efficacy 4