FDA-Approved Indications for Clozapine
Clozapine is FDA-approved for two specific indications: treatment-resistant schizophrenia and reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder. 1
Treatment-Resistant Schizophrenia
Clozapine is indicated for patients with schizophrenia who have failed to respond adequately to standard antipsychotic treatment. The FDA approval for this indication is based on its demonstrated effectiveness in a 6-week, randomized, double-blind, active-controlled study comparing clozapine and chlorpromazine in patients who had failed other antipsychotics. 1
The criteria for treatment resistance typically include:
- Failure to respond to at least two different antipsychotic medications given at adequate doses for adequate duration (typically 6 weeks each) 2
- For proper diagnosis of treatment resistance, medication adherence must be confirmed (≥80% of prescribed doses) 2
Reducing Risk of Recurrent Suicidal Behavior
Clozapine is also FDA-approved for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state. 1
- This indication is supported by data from the InterSePT™ trial, which demonstrated effectiveness over a two-year treatment period 1
- It's important to note that this indication is specifically for patients with schizophrenia or schizoaffective disorder, not for patients with mood disorders, which constitute the largest portion of patients who commit suicide 2
Important Considerations for Clozapine Use
Despite its proven efficacy, clozapine is typically not considered a first-line agent due to its significant potential adverse effects:
- Clozapine is generally used only after therapeutic trials of at least two other antipsychotic medications (one or both of which should be an atypical agent) 2
- The medication is available only through a restricted program under a Risk Evaluation Mitigation Strategy (REMS) called the Clozapine REMS Program due to the risk of severe neutropenia 1
Key Monitoring Requirements
When prescribing clozapine, several monitoring protocols are essential:
- Baseline absolute neutrophil count (ANC) must be at least 1500/μL for the general population and at least 1000/μL for patients with documented Benign Ethnic Neutropenia (BEN) 1
- Regular ANC monitoring throughout treatment 1
- Monitoring for other serious adverse effects including:
- Orthostatic hypotension, bradycardia, and syncope
- Seizures
- Myocarditis and cardiomyopathy
- Gastrointestinal hypomotility
- Metabolic changes
Dosing Considerations
- Starting dose is 12.5 mg once or twice daily
- Gradual titration with divided dosing is recommended to minimize risks
- Target dose is typically 300-450 mg/day in divided doses by the end of 2 weeks
- Maximum FDA-approved dose is 900 mg/day 1
Off-Label Uses
While not FDA-approved for these indications, clozapine has been used off-label in the treatment of:
- Bipolar disorder
- Major depressive disorder
- Parkinson's disease 3
However, these uses are not supported by FDA approval and should be considered only in specific clinical scenarios where approved treatments have failed.