ADVERSE REACTIONS
The following adverse reactions are discussed in more detail in other sections of the labeling:
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•Agranulocytosis [see Warnings and Precautions ].
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•Orthostatic Hypotension, Bradycardia, and Syncope [see Warnings and Precautions].
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•Seizures [see Warnings and Precautions ].
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•Myocarditis and Cardiomyopathy [see Warnings and Precautions].
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•Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions ].
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•Eosinophilia [see Warnings and Precautions].
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•QT Interval Prolongation [see Warnings and Precautions ].
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•Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) [see Warnings and Precautions]
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•Neuroleptic Malignant Syndrome [see Warnings and Precautions ].
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•Fever [see Warnings and Precautions].
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•Pulmonary Embolism [see Warnings and Precautions ].
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•Anticholinergic Toxicity [see Warnings and Precautions].
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•Interference with Cognitive and Motor Performance [see Warnings and Precautions ].
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•Tardive Dyskinesia [see Warnings and Precautions].
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•Cerebrovascular Adverse Reactions [see Warnings and Precautions ].
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•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 chlorpromazine-treated 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
|
Chlorpromazine
|
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(N = 126)
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(N = 142)
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|
(%)
|
(%)
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Sedation
|
21
|
13
|
Tachycardia
|
17
|
11
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Constipation
|
16
|
12
|
Dizziness
|
14
|
16
|
Hypotension
|
13
|
38
|
Fever (hyperthermia)
|
13
|
4
|
Hypersalivation
|
13
|
1
|
Hypertension
|
12
|
5
|
Headache
|
10
|
10
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Nausea/vomiting
|
10
|
12
|
Dry mouth
|
5
|
20
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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
|
Clozapine
|
Adverse Reaction*
|
N = 842
|
|
Percentage of Patients
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Central Nervous System
|
|
Drowsiness/Sedation
|
39
|
Dizziness/Vertigo
|
19
|
Headache
|
7
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Tremor
|
6
|
Syncope
|
6
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Disturbed Sleep/Nightmares
|
4
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Restlessness
|
4
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Hypokinesia/Akinesia
|
4
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Agitation
|
4
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Seizures (convulsions)
|
3†
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Rigidity
|
3
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Akathisia
|
3
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Confusion
|
3
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Fatigue
|
2
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Insomnia
|
2
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Cardiovascular
|
|
Tachycardia
|
25†
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Hypotension
|
9
|
Hypertension
|
4
|
|
|
Gastrointestinal
|
|
Constipation
|
14
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Nausea
|
5
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Abdominal discomfort/Heartburn
|
4
|
Nausea/Vomiting
|
3
|
Vomiting
|
3
|
Diarrhea
|
2
|
|
|
Urogenital
|
|
Urinary abnormalities
|
2
|
|
|
Autonomic Nervous System
|
|
Salivation
|
31
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Sweating
|
6
|
Dry mouth
|
6
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Visual disturbances
|
5
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Skin
|
|
Rash
|
2
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Hemic/Lymphatic
|
|
Leukopenia/Decreased
WBC/Neutropenia
|
3
|
|
|
Miscellaneous
|
|
Fever
|
5
|
Weight Gain
|
4
|
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)
|
Clozapine
|
Olanzapine
|
|
N = 479
|
N = 477
|
Adverse Reactions
|
% Reporting
|
% Reporting
|
Salivary hypersecretion
|
48%
|
6%
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Somnolence
|
46%
|
25%
|
Weight increased
|
31%
|
56%
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Dizziness (excluding vertigo)
|
27%
|
12%
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Constipation
|
25%
|
10%
|
Insomnia
|
20%
|
33%
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Nausea
|
17%
|
10%
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Vomiting
|
17%
|
9%
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Dyspepsia
|
14%
|
8%
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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, ventricular tachycardia, QT interval prolongation, Torsades de Pointes, myocardial infarction, cardiac arrest, and periorbital edema.
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.
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REPORTS OF SUSPECTED CLOZAPINE SIDE EFFECTS / ADVERSE REACTIONS
Below is a sample of reports where side effects / adverse reactions may be related to Clozapine. The information is not vetted and should not be considered as verified clinical evidence.
Possible Clozapine side effects / adverse reactions in 65 year old female
Reported by a health professional (non-physician/pharmacist) from Netherlands on 2011-10-03
Patient: 65 year old female
Reactions: Humerus Fracture, Pulmonary Toxicity, Drug Interaction, Toxicity TO Various Agents, Bronchoalveolar Lavage Abnormal, Interstitial Lung Disease, Respiratory Failure, Antipsychotic Drug Level Above Therapeutic, Inflammation
Adverse event resulted in: death, hospitalization
Suspect drug(s):
Clozapine
Other drugs received by patient possibly interacting with the suspect drug: Clozapine
Dosage: 300 mg, qd
Amitriptyline HCL
Dosage: 50 mg,
Amitriptyline HCL
Dosage: 250 mg, qd
Other drugs received by patient: Acetaminophen; Promethazine
Possible Clozapine side effects / adverse reactions in 51 year old male
Reported by a consumer/non-health professional from Finland on 2011-10-03
Patient: 51 year old male
Reactions: Overdose, Loss of Consciousness
Adverse event resulted in: death
Suspect drug(s):
Clozapine
Possible Clozapine side effects / adverse reactions in 65 year old female
Reported by a physician from Netherlands on 2011-10-03
Patient: 65 year old female
Reactions: Pulmonary Toxicity, Humerus Fracture, Drug Interaction, Toxicity TO Various Agents, Bronchoalveolar Lavage Abnormal, Interstitial Lung Disease, Respiratory Failure, Antipsychotic Drug Level Above Therapeutic, Inflammation
Adverse event resulted in: death, hospitalization
Suspect drug(s):
Clozapine
Other drugs received by patient possibly interacting with the suspect drug: Amitriptyline HCL
Dosage: 250 mg, qd
Clozapine
Dosage: 300 mg, qd
Amitriptyline HCL
Dosage: 50 mg,
Other drugs received by patient: Acetaminophen; Promethazine
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