The dosage of clozapine is titrated up gradually, to minimize side effects. Some side effects, such as sedation, orthostatic hypotension, and seizures are related to rate of titration and dose. Side effects often diminish over time at a stable dosage. Titration starts with 12.5 mg once daily or twice daily. The total daily dosage is increased by increments of 25 or 50 mg per day, every 2 or 3 days, using divided dosing, as tolerated. A typical total daily dose is 100 mg per day at the end of week 1, and 200 mg per day at the end of week 2. During the second or third week, the full dose is often moved to bedtime, if tolerated, to reduce daytime sedation. A sample outpatient titration schedule is listed below. Titration then continues at a similar rate to between 300 and 450 mg per day, when substantial efficacy often becomes apparent. A blood level of clozapine and norclozapine can be helpful when there are more side effects or less efficacy than expected. See the SMI Adviser tip on interpretation of blood levels. The maximum dosage in the clozapine FDA label is 900 mg per day. Patients rarely tolerate this large a daily dosage due to side effects. The titration schedule should be slower for older adults or patients sensitive to side effects. A sample slower outpatient titration is listed below. Sudden, very large increases in clozapine dosage have led to cardiovascular collapse and death, particularly in patients taking respiratory depressant medication. This is a particular issue when a patient has been non-compliant or medication has been discontinued. If it has been more than two days since the patient last took clozapine, their dosage should be substantially reduced. The clinician should consider the duration of not taking clozapine and potential risks and benefits, with consideration of restarting at 12.5 mg once or twice a day. Then, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment. If discontinuing clozapine for a non-urgent reason, reduce the dose gradually over a period of 1 to 2 weeks or more. Monitor closely, since there is a high risk for severe psychotic relapse with lowering of clozapine dosage. Note that changing between different generic forms of clozapine can cause the clozapine blood level to change by 5 to 10%.
(clozapine 25 mg #18)
(clozapine 25 mg #6 and clozapine 100 mg #11)
This titration will be used with people who may be more susceptible than usual to side effects.
Slow First Week
(clozapine 25 mg #9)
Slow Second Week
(clozapine 25 mg #24)