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Clozapine (Clozapine) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

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 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

(N = 126)

(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

Clozapine

Adverse Reaction*

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 1

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

1 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)

Clozapine

Olanzapine

N = 479

N = 477

Adverse Reactions

% Reporting

% 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, 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.



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



See index of all Clozapine side effect reports >>

Drug label data at the top of this Page last updated: 2014-06-12

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