What is the recommended dosing introduction for clozapine (Clozaril)?

Clozapine Dosing Introduction

Initiate clozapine at 12.5 mg once or twice daily, then titrate slowly with gradual dose increases to minimize the risk of orthostatic hypotension, bradycardia, syncope, and seizures, which are highest during the initial titration period. 1

Initial Dosing Strategy

• Start at 12.5 mg once or twice daily to minimize cardiovascular risks including orthostatic hypotension, bradycardia, syncope, and cardiac arrest 1
• The risk of serious cardiovascular reactions is highest during initial titration, particularly with rapid dose escalation, and can occur with the first dose or with doses as low as 12.5 mg per day 1
• Use divided dosing during titration to further reduce risk 1

Titration Approach

• Titrate gradually based on therapeutic response and tolerability 2
• Slow titration is essential to minimize seizure risk, which is dose-related 1
• The optimal dosage for treating acute psychosis is 300-450 mg/day given orally in divided doses 3
• Continue gradual dose increases until reaching a target trough plasma level of at least 350 ng/mL 4, 2

Target Therapeutic Levels

• Aim for a trough plasma level of at least 350 ng/mL for optimal therapeutic efficacy 4, 2
• Measure trough serum levels on at least two occasions separated by at least one week at a stable dose 4
• If obtaining blood levels is not possible, a minimum dose of 500 mg/day is recommended unless limited by tolerability 4
• If positive symptoms persist after achieving 350 ng/mL, the dose may be increased to produce plasma concentrations up to 550 ng/mL 2

Monitoring During Titration

• Baseline ANC must be at least 1500/μL for the general population before initiating treatment 1
• Regular ANC monitoring is required throughout treatment due to the risk of severe neutropenia 1
• Monitor for cardiovascular side effects closely during the initial titration period 1
• Many adverse effects including orthostatic hypotension, tachycardia, and sedation are transient during the titration phase 3

Special Precautions During Introduction

• Use caution in patients with cardiovascular or cerebrovascular disease, or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) 1
• Exercise particular caution in patients with a history of seizures or other predisposing risk factors (CNS pathology, medications that lower seizure threshold, alcohol abuse) 1
• Consider concomitant metformin when starting clozapine to attenuate potential weight gain 2
• The median dose in clinical practice is 300 mg/day, though patients who develop adverse drug reactions often receive lower doses (median 250 mg/day) 5

Common Pitfalls to Avoid

• Do not escalate doses rapidly as this significantly increases the risk of orthostatic hypotension, syncope, and seizures 1
• Do not restart clozapine at the previous dose after even a brief interruption in treatment; reinitiate at 12.5 mg and retitrate slowly 1
• Pre-existing damage to organ systems is the main risk factor for adverse drug reactions, so careful baseline assessment is critical 5
• Adverse drug reactions can occur even at low doses, with significant events documented at doses as low as 250 mg/day 5