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The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Agranulocytosis [see WARNINGS AND PRECAUTIONS].
  • Orthostatic Hypotension, Bradycardia, and Syncope [see WARNINGS AND PRECAUTIONS].
  • Seizures [see WARNINGS AND PRECAUTIONS].
  • Myocarditis and Cardiomyopathy [see WARNINGS AND PRECAUTIONS].
  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see WARNINGS AND PRECAUTIONS].
  • Eosinophilia [see WARNINGS AND PRECAUTIONS].
  • QT Interval Prolongation [see WARNINGS AND PRECAUTIONS].
  • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see WARNINGS AND PRECAUTIONS].
  • Neuroleptic Malignant Syndrome [see WARNINGS AND PRECAUTIONS].
  • Fever [see WARNINGS AND PRECAUTIONS].
  • Pulmonary Embolism [see WARNINGS AND PRECAUTIONS].
  • Anticholinergic Toxicity [see WARNINGS AND PRECAUTIONS].
  • Interference with Cognitive and Motor Performance [see WARNINGS AND PRECAUTIONS].
  • Tardive Dyskinesia [see WARNINGS AND PRECAUTIONS].
  • Cerebrovascular Adverse Reactions [see WARNINGS AND PRECAUTIONS].
  • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The most commonly reported adverse reactions ( ≥ 5%) across clozapine clinical trials were: CNS reactions, including sedation, dizziness/vertigo, headache, and tremor; cardiovascular reactions, including tachycardia, hypotension, and syncope; autonomic nervous system reactions, including hypersalivation, sweating, dry mouth, and visual disturbances; gastrointestinal reactions, including constipation and nausea; and fever. Table 8 summarizes the most commonly reported adverse reactions ( ≥ 5%) in clozapine-treated patients (compared to chlorpromazinetreated patients) in the pivotal, 6-week, controlled trial in treatment-resistant schizophrenia.

Table 8: Common Adverse Reactions ( ≥ 5%) in the 6-Week, Randomized, Chlorpromazine-controlled Trial in Treatment-Resistant Schizophrenia

Adverse Reaction Clozapine
(N = 126)
(%)
Chlorpromazine
(N = 142)
(%)
Sedation 21 13
Tachycardia 17 11
Constipation 16 12
Dizziness 14 16
Hypotension 13 38
Fever (hyperthermia) 13 4
Hypersalivation 13 1
Hypertension 12 5
Headache 10 10
Nausea/vomiting 10 12
Dry mouth 5 20

Table 9 summarizes the adverse reactions reported in clozapine-treated patients at a frequency of 2% or greater across all clozapine studies (excluding the 2-year InterSePT™ Study). These rates are not adjusted for duration of exposure.

Table 9: Adverse Reactions ( ≥ 2%) Reported in Clozapine-treated Patients (N=842) across all Clozapine Studies (excluding the 2-year InterSePT™ Study)

Body System Adverse Reaction Clozapine
N = 842
Percentage of Patients
Central Nervous System
  Drowsiness/Sedation 39
  Dizziness/Vertigo 19
  Headache 7
  Tremor 6
  Syncope 6
  Disturbed Sleep/Nightmares 4
  Restlessness 4
  Hypokinesia/Akinesia 4
  Agitation 4
  Seizures (convulsions) 3†
  Rigidity 3
  Akathisia 3
  Confusion 3
  Fatigue 2
  Insomnia 2
Cardiovascular
  Tachycardia 25†
  Hypotension 9
  Hypertension 4
Gastrointestinal
  Constipation 14
  Nausea 5
  Abdominal Discomfort/Heartburn 4
  Nausea/Vomiting 3
  Vomiting 3
  Diarrhea 2
Urogenital
  Urinary Abnormalities 2
Autonomic Nervous System
  Salivation 31
  Sweating 6
  Dry Mouth 6
  Visual Disturbances 5
Skin
  Rash 2
Hemic/Lymphatic
  Leukopenia/Decreased WBC/Neutropenia 3
Miscellaneous
  Fever 5
  Weight Gain 4
† Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine.

Table 10 summarizes the most commonly reported adverse reactions ( > 10% of the clozapine or olanzapine group) in the InterSePT™ Study. This was an adequate and well-controlled, two-year study evaluating the efficacy of clozapine relative to olanzapine in reducing the risk of suicidal behavior in patients with schizophrenia or schizoaffective disorder. The rates are not adjusted for duration of exposure.

Table 10: Incidence of Adverse Reactions in Patients Treated with Clozapine or Olanzapine in the InterSePT™ Study ( ≥ 10% in the clozapine or olanzapine group)

Adverse Reactions Clozapine
N = 479
% Reporting
Olanzapine
N = 477
% Reporting
Salivary hypersecretion 48% 6%
Somnolence 46% 25%
Weight increased 31% 56%
Dizziness (excluding vertigo) 27% 12%
Constipation 25% 10%
Insomnia 20% 33%
Nausea 17% 10%
Vomiting 17% 9%
Dyspepsia 14% 8%

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clozapine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Central Nervous System

Delirium, EEG abnormal, myoclonus, paresthesia, possible cataplexy, status epilepticus, obsessive compulsive symptoms, and post-discontinuation cholinergic rebound adverse reactions.

Cardiovascular System

Atrial or ventricular fibrillation, periorbital edema, and myocardial infarction, Ventricular tachycardia, cardiac arrest, QT prolongation, and Torsades de Pointes.

Gastrointestinal System

Acute pancreatitis, dysphagia, salivary gland swelling.

Hepatobiliary System

Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.

Urogenital System

Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure.

Skin

Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.

Musculoskeletal System

Myasthenic syndrome and rhabdomyolysis.

Respiratory System

Aspiration, pleural effusion, pneumonia, lower respiratory tract infection.

Hemic and Lymphatic System

Deep-vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.

Vision Disorders

Narrow-angle glaucoma.

Miscellaneous

Creatine phosphokinase elevation, hyperuricemia, hyponatremia, and weight loss.