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Clozaril (CLOZAPINE)

Clozapine's efficacy in schizophrenia may be due to its antagonism of D2 and 5-HT2A receptors.

Clozaril (CLOZAPINE) is a small molecule atypical antipsychotic medication originally developed by Novartis and currently owned by Jazz. It targets the histamine H1 receptor and has been FDA-approved since 1989 for the treatment of suicidal behavior in schizoaffective disorder and schizophrenia, as well as treatment-resistant schizophrenia. Clozaril is available as a generic medication due to its off-patent status. Key safety considerations include its potential for agranulocytosis, a rare but serious blood disorder. As an off-patent medication, Clozaril is widely available from generic manufacturers.

At a glance

Mechanism of action

It is thought that clozapine helps treat schizophrenia by blocking certain receptors in the brain, specifically the dopamine D2 and serotonin 5-HT2A receptors. Additionally, it affects other receptors like adrenergic, cholinergic, and histaminergic ones.

Approved indications

• Suicidal Behavior in Schizoaffective Disorder
• Suicidal Behavior in Schizophrenia
• Treatment-Resistant Schizophrenia

Boxed warnings

• WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Severe Neutropenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) have caused severe neutropenia which is associated with an increased risk of serious and fatal infections. Prior to initiating Clozapine ODT treatment, obtain baseline ANC(s). Clozapine ODT 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)). See recommendations for dosage modifications based on ANC levels during Clozapine ODT treatment [see Dosage and Administration (2.4 , 2.5) ] . Consider a hematology consultation before initiating Clozapine ODT or during Clozapine ODT treatment [see Warnings and Precautions (5.1) ] . Orthostatic Hypotension, Bradycardia, Syncope Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day, or when restarting patients who have had even a brief interruption in treatment with Clozapine ODT. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages to minimize risk. Use Clozapine ODT cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications) [see Dosage and Administration (2.3 and 2.6) , Warnings and Precautions (5.2) ] . Seizures Seizures have occurred with clozapine treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering Clozapine ODT to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others [see Dosage and Administration (2.3) , Warnings and Precautions (5.4) ] . Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with clozapine treatment. Discontinue Clozapine ODT and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with clozapine-related myocarditis or cardiomyopathy should not be rechallenged with Clozapine ODT. Consider the possibility of myocarditis, pericarditis, or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur [see Warnings and Precautions (5.5) ] . Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Clozapine ODT is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.6) ] . WARNING: SEVERE NEUTROPENIA; ORTHOSTATIC HYPOTENSION, BRADYCARDIA, AND SYNCOPE; SEIZURE; MYOCARDITIS, PERICARDITIS, AND CARDIOMYOPATHY; INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Severe Neutropenia: Clozapine has caused severe neutropenia, which is associated with an increased risk of serious and fatal infections. Prior to initiating Clozapine Orally Disintegrating Tablets (Clozapine ODT) treatment, obtain baseline ANC(s). Clozapine ODT 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)). See recommendations for dosage modifications based on ANC levels during Clozapine ODT treatment. ( 2.1 , 2.3 , 2.4 , 5.1 ) Orthostatic Hypotension, Bradycardia, and Syncope: Risk is dose-related. Starting dose is 12.5 mg. Titrate gradually and use divided dosages. ( 2.2 , 5.2 ) Seizure: Risk is dose-related. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. ( 5.4 ) Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence: Can be fatal. Discontinue and obtain cardiac evaluation if findings suggest these cardiac reactions. ( 5.5 ) Increased Mortality in Elderly Patients with Dementia-Related Psychosis: Clozapine ODT is not approved for this condition. ( 5.6 )

Common side effects

• Sedation
• Tachycardia
• Constipation
• Dizziness
• Hypotension
• Fever (hyperthermia)
• Hypersalivation
• Hypertension
• Headache
• Nausea/vomiting
• Dry mouth

Drug interactions

• High Risk QT Prolonging Agents
• altretamine
• aminoglutethimide
• amphotericin B
• anastrozole
• aprepitant
• arsenic trioxide
• axitinib
• azacitidine
• azathioprine
• bendamustine
• bexarotene

Key clinical trials

• An Exploratory Analysis of Immune and Inflammatory Response Associated With Clozapine (PHASE4)
• The Combination of Pharmacotherapy and Cognitive Behavioral Psychotherapy Under the Recovery Perspective. (PHASE1)
• CLOZAPINE Response in Biotype-1 (PHASE4)
• Τhe Combination of Pharmacotherapy With RECOVERYTRSGR and RECOVERYTRSBDGR. (PHASE4)
• Maintenance ElectroConvulsive Therapy in Clozapine RESISTant Schizophrenia - the MECT-RESIST Trial (NA)
• Clozapine for the Prevention of Violence in Schizophrenia: a Randomized Clinical Trial (PHASE4)
• A Study of the Safety and Tolerability of GA in the Treatment of Patients With Refractory Neuropathic Pain (EARLY_PHASE1)
• Intensified Pharmacological Treatment for Schizophrenia, Major Depressive Disorder and Bipolar Depression After a First-time Treatment Failure (PHASE3)

Patents

Primary sources

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Competitive intelligence

For the full competitive landscape — auto-detected comparators, recent regulatory actions across the set, upcoming PDUFA, patent timeline, sponsor landscape:

• Clozaril CI brief — competitive landscape report
• Clozaril updates RSS · CI watch RSS
• Jazz Pharmaceuticals portfolio CI