What is the recommended protocol for restarting clozapine after a one‑week interruption, including absolute neutrophil count (ANC) thresholds, initial dose, titration schedule, and monitoring?

Restarting Clozapine After One-Week Interruption

After a one-week interruption of clozapine, you must verify that the absolute neutrophil count (ANC) is ≥1,500/μL (or ≥1,000/μL for patients with benign ethnic neutropenia), then restart at 12.5 mg once or twice daily and titrate gradually—more cautiously than the standard new-patient protocol—because even brief interruptions reset hematologic risk and require close monitoring. 1

Pre-Restart Requirements

Mandatory Laboratory Verification

• Obtain a complete blood count with ANC before restarting clozapine to confirm the patient meets the threshold for safe re-initiation: ANC ≥1,500/μL for general population patients or ANC ≥1,000/μL for patients with documented benign ethnic neutropenia. 1
• If the interruption was ≥30 days, treat the patient as a new clozapine initiation with weekly ANC monitoring for the first 6 months; however, for interruptions <30 days (including your one-week scenario), continue the previous monitoring schedule but verify baseline ANC first. 1

Clinical Context Assessment

• Determine the reason for the one-week gap: if the interruption was due to neutropenia (ANC 1,000–1,499/μL), the patient must have recovered to ANC ≥1,500/μL and remained infection-free before restarting. 1
• If the interruption was for non-hematologic reasons (e.g., patient non-adherence, hospitalization, supply issue), and the last ANC was in normal range, you may proceed with restart after confirming current ANC. 1

Dosing and Titration Protocol

Initial Dose

• Start at 12.5 mg once daily or 12.5 mg twice daily (total 25 mg/day), which is the standard new-patient starting dose, because even a one-week interruption resets some pharmacokinetic and hematologic parameters. 1
• Published case reports of successful rechallenges after neutropenia show that 6 out of 8 cases used more cautious titration than standard guidelines, suggesting slower escalation reduces risk when restarting after any interruption. 2

Titration Schedule

• Increase the dose by 25–50 mg/day every 1–2 days as tolerated, targeting the patient's previous therapeutic dose over 1–2 weeks, rather than the faster 2-week titration used for treatment-naïve patients. 1, 2
• Avoid large initial doses and rapid titration, as these increase the risk of orthostatic hypotension, seizures, and other adverse events without accelerating therapeutic response. 3
• Monitor for orthostatic hypotension, sedation, and seizure risk during dose escalation, particularly in the first 72 hours after each dose increase. 3

Hematologic Monitoring After Restart

Monitoring Frequency

• If the interruption was <30 days, resume the patient's prior monitoring schedule (weekly, biweekly, or monthly depending on treatment duration), but obtain an ANC at restart and again within 1 week to confirm stability. 1
• If the interruption was due to mild neutropenia (ANC 1,000–1,499/μL) that has now resolved, perform weekly ANC monitoring until ANC remains ≥1,500/μL for 4 consecutive weeks, then return to the patient's previous monitoring interval. 1
• The highest risk for agranulocytosis is during the first 18 weeks of treatment, so any restart within this window requires heightened vigilance even if the interruption was brief. 1, 4

Critical Action Thresholds

• If ANC drops to 1,000–1,499/μL after restart, interrupt clozapine immediately and perform ANC monitoring three times weekly until ANC ≥1,500/μL; once recovered, check ANC weekly for 4 weeks before resuming the prior monitoring schedule. 1
• If ANC falls below 1,000/μL, stop clozapine immediately, obtain daily ANC measurements, initiate infection surveillance, and consider hematology consultation; do not rechallenge unless the prescriber determines benefits outweigh risks. 1
• If fever (≥38.5°C or 101.3°F) develops at any time, interrupt clozapine as a precautionary measure and obtain an immediate ANC, as fever is often the first sign of neutropenic infection. 1

Special Considerations and Pitfalls

Benign Ethnic Neutropenia

• Patients with benign ethnic neutropenia (common in individuals of African descent, some Middle Eastern groups, and other non-Caucasian populations) have lower baseline ANC values (≥1,000/μL) but are not at increased risk for clozapine-induced neutropenia; use the BEN-specific algorithm with a restart threshold of ANC ≥1,000/μL. 1

Drug Interactions

• Never restart clozapine in patients concurrently taking myelosuppressive agents such as carbamazepine or azathioprine, as these combinations markedly increase agranulocytosis risk. 3

Rechallenge After Severe Neutropenia

• If the one-week interruption was due to severe neutropenia (ANC <500/μL), rechallenge is generally contraindicated unless the prescriber and patient determine that the risk of severe psychiatric illness from discontinuing clozapine outweighs the risk of recurrent agranulocytosis; hematology consultation is essential in such cases. 1, 5
• Rechallenge after agranulocytosis carries a very high likelihood of recurrence and should only be attempted in exceptional circumstances with granulocyte colony-stimulating factor co-therapy and very frequent monitoring. 5

Common Pitfalls to Avoid

• Do not assume that a one-week gap is "short enough" to skip ANC verification—always confirm ANC ≥1,500/μL (or ≥1,000/μL for BEN) before restarting. 1
• Do not restart at the patient's previous maintenance dose; always titrate from 12.5–25 mg/day to minimize orthostatic hypotension and seizure risk. 3, 2
• Do not delay obtaining an ANC if fever develops—fever in a clozapine patient is a hematologic emergency until proven otherwise. 1
• Do not rely solely on white blood cell count; always calculate or obtain the absolute neutrophil count, as it is the definitive parameter for clozapine safety monitoring. 1