Can a patient stable on clozapine 50 mg in the morning and 125 mg at night resume the same dosing after missing a single 24‑hour dose?

Resuming Clozapine After Missing One Day

No, do not resume the full dose of 50 mg morning and 125 mg evening after missing one full day—restart at approximately 40-50% of the established dose (roughly 25 mg morning and 60 mg evening) to minimize the risk of severe hypotension, bradycardia, and syncope. 1

Retitration Protocol After One Missed Day

The FDA-approved clozapine prescribing information provides explicit guidance for dose resumption based on duration of interruption 1:

• If one day's dosing has been missed: Resume treatment at 40-50% of the established dose 1
• If two days' dosing have been missed: Resume at approximately 25% of the established dose 1
• For longer interruptions: Re-initiate at 12.5 mg once or twice daily 1

Specific Dosing for This Patient

For your patient on 175 mg total daily dose (50 mg AM + 125 mg PM):

• Day 1 after missed dose: Start with 70-87.5 mg total daily (approximately 25 mg morning and 50-60 mg evening) 1
• If well-tolerated: The dose may be increased back to the previous dosage more quickly than recommended for initial treatment 1
• Typical timeline: Most patients can return to their established dose within 3-5 days if tolerating the retitration well 1

Critical Safety Rationale

The risk of severe cardiovascular collapse is substantial even after brief interruptions. The FDA mandates this conservative approach because 1:

• Clozapine causes significant orthostatic hypotension, bradycardia, and syncope, particularly during dose initiation and escalation 1
• These cardiovascular effects can be life-threatening, especially in clozapine-naïve or recently interrupted patients 2
• Even a single "therapeutic" dose can be fatal in patients who have lost tolerance 2

Research confirms that clozapine toxicity is highly variable and unpredictable—a 34-year-old patient died after taking 350 mg as a single dose when not regularly taking clozapine, with post-mortem blood levels of only 0.48 mg/L 2. This underscores that even modest doses can be dangerous after interruption.

Monitoring During Retitration

Monitor closely for the following during dose resumption 1:

• Orthostatic vital signs: Check blood pressure and heart rate supine and standing, particularly in the first 3-4 hours after each dose
• Cardiovascular symptoms: Dizziness, lightheadedness, syncope, or palpitations
• Sedation level: Excessive somnolence may indicate overshooting the appropriate dose
• Temperature: Any fever ≥38.5°C (101.3°F) requires immediate ANC monitoring 1

Common Pitfall to Avoid

Do not assume that missing "only one day" is insignificant. The FDA specifically addresses even single-day interruptions because clozapine's cardiovascular tolerance is lost rapidly 1. Healthcare providers often underestimate this risk, leading to preventable adverse events including syncope-related falls and cardiac events 2.

The interpatient variability in clozapine metabolism is substantial—up to 12-fold variation in plasma concentrations at the same dose 3—making it impossible to predict which patients will experience severe reactions without conservative retitration.

Alternative Consideration

If the patient has been stable on this regimen for an extended period and has no cardiovascular risk factors, some clinicians might consider a slightly more aggressive retitration (starting at 50% rather than 40%), but this deviates from FDA guidance and increases risk 1. The safest approach remains the 40-50% restart as specified in the drug label.