Clozapine

CLOZARIL is an atypical antipsychotic indicated for: • Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment. • 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.

The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D 2 ) and the serotonin type 2A (5-HT 2A ) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.

• Recommended starting oral dosage is 12.5 mg once daily or twice daily. • If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks. • Subsequently may increase the dosage in increments up to 100 mg once or twice weekly. • Maximum daily dosage is 450 mg twice daily. • Administer with or without food. • See the dosage modifications based on ANC results and recommended frequency of ANC testing in the full prescribing information. • See recommendations for discontinuing CLOZARIL treatment, restarting CLOZARIL after interrupting dosing, dosage modifications for drug interactions, dosage recommendations in patients with renal or hepatic impairment and CYP2D6 poor metabolizers in the full prescribing information.

CLOZARIL is contraindicated in patients with a history of hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson syndrome) or any other component of CLOZARIL. Known hypersensitivity to clozapine or any other component of CLOZARIL.

Boxed warning: Severe Neutropenia CLOZARIL has caused severe neutropenia which is associated with an increased risk of serious and potentially fatal infections. Prior to initiating CLOZARIL treatment, obtain baseline ANC(s). CLOZARIL initiation is not recommended in patients with a baseline ANC less than 1500/μL (less than 1000/μL for those with Benign Ethnic Neutropenia (also known as Duffy-null associated neutrophil count)). • Severe neutropenia: See Boxed Warnings. • Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of CLOZARIL. If constipation is identified, close monitoring and prompt treatment is advised. • Eosinophilia: Assess for organ involvement (e.g., myocarditis, pancreatitis, hepatitis, colitis, nephritis). Discontinue if these occur. • QT Interval Prolongation: Can be fatal.

The following adverse reactions are discussed in more detail in other sections of the labeling: • Severe Neutropenia • Orthostatic Hypotension, Bradycardia, and Syncope • Falls • Seizures • Myocarditis, Pericarditis, Cardiomyopathy, and Mitral Valve Incompetence • Increased Mortality in Elderly Patients with Dementia-Related Psychosis • Gastrointestinal Hypomotility with Severe Complications • Eosinophilia • QT Interval Prolongation • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) • Neuroleptic Malignant Syndrome • Hepatotoxicity • Fever • Pulmonary Embolism • Anticholinergic Toxicity • Interference with Cognitive and Motor Performance • Tardive Dyskinesia • Cerebrovascular Adverse Reactions • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation Most common adverse reactions (≥5%) were: CNS reactions (sedation…

• Concomitant use of Strong CYP1A2 Inhibitors: Reduce CLOZARIL dose to one-third when coadministered with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, enoxacin). • Concomitant use of Strong CYP3A4 Inducers is not recommended. • Discontinuation of CYP1A2 or CYP3A4 Inducers: Consider reducing CLOZARIL dose when CYP1A2 inducers (e.g., tobacco smoke) or CYP3A4 inducers (e.g., carbamazepine) are discontinued. • Anticholinergic drugs: Concomitant use may increase the risk for anticholinergic toxicity.

Store CLOZARIL at room temperature between 20°C to 25°C (68°F to 77°F), excursion permitted between 15°C to 30°C (59°F to 86°F).