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Clozaril (Clozapine) - Side Effects and Adverse Reactions

 
 



ADVERSE REACTIONS

Associated with Discontinuation of Treatment

Sixteen percent of 1,080 patients who received CLOZARIL® (clozapine) in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to CLOZARIL treatment and those that might more appropriately be considered intercurrent illness. The more common events considered to be causes of discontinuation included: CNS, primarily drowsiness/sedation, seizures, dizziness/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/ granulocytopenia/ agranulocytosis; and fever. None of the events enumerated accounts for more than 1.7% of all discontinuations attributed to adverse clinical events.

Extrapyramidal Symptoms

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. Clozapine, an atypical antipsychotic, is associated with a low incidence of dystonia (see WARNINGS, Tardive Dyskinesia).

Commonly Observed

Adverse events observed in association with the use of CLOZARIL in clinical trials at an incidence of greater than 5% were: central nervous system complaints, including drowsiness/sedation, dizziness/vertigo, headache and tremor; autonomic nervous system complaints, including salivation, sweating, dry mouth and visual disturbances; cardiovascular findings, including tachycardia, hypotension and syncope; and gastrointestinal complaints, including constipation and nausea; and fever. Complaints of drowsiness/sedation tend to subside with continued therapy or dose reduction. Salivation may be profuse, especially during sleep, but may be diminished with dose reduction.

Incidence in Clinical Trials

The following table enumerates adverse events that occurred at a frequency of 1% or greater among CLOZARIL patients who participated in clinical trials. These rates are not adjusted for duration of exposure.

Treatment -Emergent Adverse Experience Incidence
Among Patients Taking CLOZARIL
® (clozapine) in Clinical Trials
(excluding the InterSePT™ Study)

(N = 842)

(Percentage of Patients Reporting)

Body System
      Adverse Event a
Percent
Central Nervous System
      Drowsiness/Sedation39
      Dizziness/Vertigo19
      Headache7
      Tremor6
      Syncope6
      Disturbed Sleep/Nightmares4
      Restlessness4
      Hypokinesia/Akinesia4
      Agitation4
      Seizures (convulsions)3b
      Rigidity3
      Akathisia3
      Confusion3
      Fatigue2
      Insomnia2
      Hyperkinesia1
      Weakness1
      Lethargy1
      Ataxia1
      Slurred Speech1
      Depression1
      Epileptiform Movements/Myoclonic Jerks1
      Anxiety1
Cardiovascular
      Tachycardia25b
      Hypotension9
      Hypertension4
      Chest Pain/Angina1
      ECG Change/Cardiac Abnormality1
Gastrointestinal
      Constipation14
      Nausea5
      Abdominal Discomfort/Heartburn4
      Nausea/Vomiting3
      Vomiting3
      Diarrhea2
      Liver test Abnormality1
      Anorexia1
Urogenital
      Urinary Abnormalities2
      Incontinence1
      Abnormal Ejaculation1
      Urinary Urgency/Frequency1
      Urinary Retention1
Autonomic Nervous System
      Salivation31
      Sweating6
      Dry Mouth6
      Visual Disturbances5
Integumentary (Skin)
      Rash2
Musculoskeletal
      Muscle Weakness1
      Pain (Back, Neck, Legs)1
      Muscle Spasm1
      Muscle Pain, Ache1
Respiratory
      Throat Discomfort1
      Dyspnea, Shortness of Breath1
      Nasal Congestion1
Hemic/Lymphatic
      Leukopenia/Decreased WBC/Neutropenia3
      Agranulocytosis1b
      Eosinophilia1
Miscellaneous
      Fever5
      Weight Gain4
      Tongue Numb/Sore1
a      Events reported by at least 1% of CLOZARIL patients are included.
b      Rate based on population of approximately 1,700 exposed during premarket clinical evaluation of CLOZARIL.

The following table enumerates adverse events that occurred at a frequency of 10% for either treatment group in patients who took at least 1 dose of study medication during their participation in InterSePT, which was an adequate and well-controlled 2-year study evaluating the efficacy of CLOZARIL relative to Zyprexa in reducing the risk of emergent suicidal behavior in patients with schizophrenia or schizoaffective disorder. These rates are not adjusted for duration of exposure.

Treatment -Emergent Adverse Experience Incidence 1  
Among Patients Taking CLOZARIL
® (clozapine) or Zyprexa ® (olanzapine)
in the InterSePT™ Study

(Percentage of Patients Reporting)

Clozaril ®  
N=479 %

Reporting
Zyprexa ®  
N=477 %
Reporting
Adverse Events
Salivary hypersecretion48%6%
Somnolence46%25%
Weight increased31%56%
Dizziness (excluding vertigo)27%12%
Constipation25%10%
Insomnia NEC20%33%
Nausea17%10%
Vomiting NOS17%9%
Dyspepsia14%8%
1AEs are listed by frequency in CLOZARIL group, and included in the table are those for which the risk ratio of CLOZARIL over Zyprexa or of Zyprexa over CLOZARIL was greater than 1.5.
NEC - not elsewhere classified
NOS - not otherwise specified

Other Events Observed During the Premarketing Evaluation of CLOZARIL ® (clozapine)

This section reports additional, less frequent adverse events which occurred among the patients taking CLOZARIL in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to CLOZARIL treatment cannot be determined in the absence of appropriate controls in some of the studies. The table above enumerates adverse events that occurred at a frequency of at least 1% of patients treated with CLOZARIL. The list below includes all additional adverse experiences reported as being temporally associated with the use of the drug which occurred at a frequency less than 1%, enumerated by organ system.

Central Nervous System: loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, stuttering, dysarthria, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.

Cardiovascular System: edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nosebleed.

Gastrointestinal System: abdominal distention, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation.

Urogenital System: dysmenorrhea, impotence, breast pain/discomfort, and vaginal itch/infection.

Autonomic Nervous System: numbness, polydipsia, hot flashes, dry throat, and mydriasis.

Integumentary (Skin): pruritus, pallor, eczema, erythema, bruise, dermatitis, petechiae, and urticaria.

Musculoskeletal System: twitching and joint pain.

Respiratory System: coughing, pneumonia/pneumonia-like symptoms, rhinorrhea, hyperventilation, wheezing, bronchitis, laryngitis, and sneezing.

Hemic and Lymphatic System: anemia and leukocytosis.

Miscellaneous: chills/chills with fever, malaise, appetite increase, ear disorder, hypothermia, eyelid disorder, bloodshot eyes, and nystagmus.

Postmarketing Clinical Experience

Postmarketing experience has shown an adverse experience profile similar to that presented above. Voluntary reports of adverse events temporally associated with CLOZARIL not mentioned above that have been received since market introduction and that may have no causal relationship with the drug include the following:

Central Nervous System: delirium; EEG abnormal; exacerbation of psychosis; myoclonus; overdose; paresthesia; possible mild cataplexy; and status epilepticus.

Cardiovascular System: atrial or ventricular fibrillation and periorbital edema.

Gastrointestinal System: acute pancreatitis; dysphagia; fecal impaction; intestinal obstruction/paralytic ileus; and salivary gland swelling.

Hepatobiliary System: cholestasis; hepatitis; jaundice.

Hepatic System: cholestasis.

Urogenital System: acute interstitial nephritis and priapism.

Integumentary (Skin): hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, and Stevens-Johnson Syndrome.

Metabolic and Nutritional Disorders: hypercholesterolemia; and hypertriglyceridemia.

Musculoskeletal System: myasthenic syndrome and rhabdomyolysis.

Respiratory System: aspiration and pleural effusion.

Hemic and Lymphatic System: deep vein thrombosis; elevated hemoglobin/hematocrit; ESR increased; pulmonary embolism; sepsis; thrombocytosis; and thrombocytopenia.

Vision Disorders: narrow angle glaucoma.

Miscellaneous: CPK elevation; hyperglycemia; hyperuricemia; hyponatremia; and weight loss.



REPORTS OF SUSPECTED CLOZARIL SIDE EFFECTS / ADVERSE REACTIONS

Below is a sample of reports where side effects / adverse reactions may be related to Clozaril. The information is not vetted and should not be considered as verified clinical evidence.

Possible Clozaril side effects / adverse reactions in 30 year old male

Reported by a physician from Denmark on 2011-10-03

Patient: 30 year old male

Reactions: White Blood Cell Count Decreased, Neutrophil Count Decreased, Constipation

Suspect drug(s):
Levetiracetam
    Dosage: 1000 mg;qd
    Indication: Epilepsy

Valproic Acid
    Dosage: 2000 mg;qd

Clozaril
    Dosage: 400 mg;qd
    Indication: Schizophrenia
    Start date: 2004-04-28

Other drugs received by patient: Lactulose; Lansoprazole



Possible Clozaril side effects / adverse reactions in 36 year old female

Reported by a individual with unspecified qualification from United Kingdom on 2011-10-03

Patient: 36 year old female

Reactions: Electrocardiogram QT Prolonged, Ventricular Extrasystoles, Dyspnoea, Tachycardia, Condition Aggravated, Mental Disorder, Treatment Noncompliance

Adverse event resulted in: hospitalization

Suspect drug(s):
Clozaril
    Dosage: 50 mg, 1 in 1 d, oral
    Administration route: Oral
    Indication: Schizophrenia
    End date: 2003-12-15

Risperidone
    Indication: Product Used FOR Unknown Indication

Amisulpride (Amisulpride)
    Indication: Product Used FOR Unknown Indication



Possible Clozaril side effects / adverse reactions in 59 year old female

Reported by a physician from Denmark on 2011-10-04

Patient: 59 year old female

Reactions: Neutrophil Count Increased, Agranulocytosis, Pyrexia, Oropharyngeal Pain, White Blood Cell Count Increased

Adverse event resulted in: hospitalization

Suspect drug(s):
Clozaril
    Dosage: 300 mg
    Start date: 2011-02-03
    End date: 2011-04-06

Mirtazapine

Mirtazapine



See index of all Clozaril side effect reports >>

Drug label data at the top of this Page last updated: 2008-11-19

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