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CLOZAPINE is a brand name for Clozapine, supplied as a tablet. The medicine, its uses, side effects and dosage are the same regardless of brand.
Used for: AND CLINICAL USE ............................................................................... 3 CONTRAINDICATIONS .................................................................................................. 5 WARNINGS AND PRECAUTIONS…
Verbatim from this product's HC label. Tap a section to expand.
Adverse Drug Reaction Overview The most serious adverse reactions experienced with clozapine are agranulocytosis, seizure, cardiovascular effects and fever (see WARNINGS AND PRECAUTIONS). The most common side effects are drowsiness/sedation, dizziness, hypersalivation, tachycardia, and constipation.
Adverse Events Leading to Discontinuation Sixteen percent of 1080 patients who received clozapine in premarketing clinical trials discontinued treatment due to an adverse event, including both those that could be reasonably attributed to (clozapine) treatment and those that might more appropriately be considered intercurrent illness.
The more common events considered to be causes of discontinuation included:
CNS (psychotic disorder), primarily drowsiness/sedation, somnolence, seizures, dizziness (excluding vertigo)/syncope; cardiovascular, primarily tachycardia, hypotension and ECG changes; gastrointestinal, primarily nausea/vomiting; hematologic, primarily leukopenia/ granulocytopenia/ agranulocytosis; and fever.
7% of all discontinuations attributed to adverse clinical event. Most Frequent Adverse Events Adverse events observed in association with the use of clozapine 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. Clinical Trials Adverse Drug Reactions The following table enumerates adverse events that occurred at a frequency of 1% or greater among clozapine patients who participated in clinical trials.
These rates are not adjusted for duration of exposure. Product Monograph August 2018 Page 22 of 57 Treatment-Emergent Adverse Experience Incidence Among Patients Taking clozapine in Clinical Trials (N = 842) (Percentage of Patients Reporting) Body System Adverse Eventa Percent Nervous System disorders Drowsiness/Sedation 39 Dizziness/Vertigo 19 Headache 7 Tremor 6 Disturbed sleep/Nightmares 4 Hypokinesia/Akinesia 4 Seizures (convulsions) 3b Rigidity 3 Akathisia 3 Confusion 3 Insomnia 2 Hyperkinesia 1 Weakness 1 Lethargy 1 Ataxia 1 Slurred speech 1 Depression 1 Epileptiform movements/Myoclonic jerks 1 Anxiety 1 Psychiatric disorders Agitation 4 Restlessness 4 Cardiac disorders Tachycardia 25b Chest pain/Angina 1 ECG changes/Cardiac abnormality 1 Product Monograph August 2018 Page 23 of 57 Vascular disorders Syncope 6 Hypotension 9 Hypertension 4 Gastrointestinal disorders Constipation 14 Nausea 5 Abdominal discomfort/Heartburn 4 Nausea/Vomiting 3 Vomiting 3 Dry mouth 6 Diarrhea 2 Anorexia 1 Hepatobiliary disorders Liver test abnormality 1 Renal and urinary disorders Urinary abnormalities 2 Urinary incontinence 1 Urinary urgency/frequency 1 Urinary retention 1 Reproductive system disorders Abnormal ejaculation 1 Autonomic Nervous System Salivation 31 Sweating 6 Visual disturbances 5 Skin and subcutaneous tissue disorders Rash 2 Musculoskeletal Muscle weakness 1 Pain (back, neck, legs) 1 Product Monograph August 2018 Page 24 of 57 Muscle spasm 1 Muscle pain, ache 1 Respiratory disorders Throat discomfort 1 Dyspnea, shortness of breath 1 Nasal congestion 1 Blood and lymphatic disorders Leukopenia/Decreased WBC/Neutropenia 3 Agranulocytosis 1b Eosinophilia 1 Metabolism and nutrition disorders Weight gain 4 Miscellaneous Fever 5 Fatigue 2 Tongue numb/sore 1 aEvents reported by at least 1% of clozapine patients are included.
). If the diagnosis of neuroleptic malignant syndrome is confirmed, clozapine should be discontinued immediately and appropriate medical measures should be administered. Fever that is otherwise unexplained can accompany myocarditis (see WARNINGS AND PRECAUTIONS - Cardiovascular).
Interference with Cognitive and Motor Performance:
Because of the potential for initial sedation, clozapine may impair mental and/or physical abilities especially during the first few days of therapy. ) (see DOSAGE AND ADMINISTRATION).
Anticholinergic Activity:
Clozapine has potent anticholinergic effects, which may produce undesirable effects throughout the body. Great care should be exercised in using the drug in the presence of prostatic enlargement, narrow-angle glaucoma or paralytic ileus.
Probably on account of its anticholinergic properties, clozapine has been associated with varying degrees of impairment of intestinal peristalsis, ranging from constipation to intestinal obstruction, faecal impaction and paralytic ileus.
On rare occasions, these cases have been fatal. Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation.
It is vital that constipation is recognized and actively treated. g. because of leukopenia), the patient should be carefully observed for the recurrence of psychotic symptoms and symptoms related to cholinergic rebound such as profuse sweating, headache, nausea, vomiting and diarrhea.
Product Monograph August 2018 Page 10 of 57 Cardiovascular CARDIOTOXICITY IMPORTANT SAFETY INFORMATION REGARDING A CONSTELLATION OF CARDIOVASCULAR EVENTS REPORTED IN PATIENTS TREATED WITH CLOZAPINE: CARDIOVASCULAR TOXICITY: Analysis of safety databases suggests that the use of clozapine is associated with an increased risk of myocarditis especially during, but not limited to, the first month of therapy.
Not medical advice. Always read the patient information leaflet and follow your prescriber or pharmacist.
Other brands of Clozapine in Canada.
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bRate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. Product Monograph August 2018 Page 25 of 57 Adverse Events Observed During the InterSePT Study Adverse events reported during the InterSePT study were consistent with the known safety profiles for clozapine and olanzapine.
The ten most frequently reported adverse events in the clozapine treatment group were: salivary hypersecretion, somnolence, weight increase, anxiety, depression, dizziness (excluding vertigo), psychotic disorder, suicidal ideation, constipation, and insomnia.
Other Adverse Events Observed during Clinical Trials This section reports additional, less frequent adverse events which occurred among the patients taking clozapine in clinical trials. Various adverse events were reported as part of the total experience in these clinical studies; a causal relationship to clozapine 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 clozapine. 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.
Nervous System disorders: loss of speech, amentia, tics, poor coordination, delusions/hallucinations, involuntary movement, amnesia/memory loss, histrionic movements, libido increase or decrease, paranoia, shakiness, Parkinsonism, and irritability.
Psychiatric disorders: dysarthria, dysphemia (stuttering). Eye disorders: eyelid disorder, bloodshot eyes, and nystagmus. Cardiac disorders: edema, palpitations, phlebitis/thrombophlebitis, cyanosis, premature ventricular contraction, bradycardia, and nose bleed; ischemic changes, arrhythmias, myocardial infarction, and sudden death.
Gastrointestinal disorders: abdominal distension, gastroenteritis, rectal bleeding, nervous stomach, abnormal stools, hematemesis, gastric ulcer, bitter taste, and eructation. Reproductive system […]
Myocarditis has been reported in patients 19 years of age and older, at dosages within the approved dosage range and during titration of clozapine. In Canada, there have been 9 reported cases of myocarditis. Of these, three have been fatal.
02% for myocarditis fatalities (or 1/5200). Pericarditis, pericardial effusion and cardiomyopathy have also been reported in association with clozapine use, as have heart failure, myocardial infarction and mitral insufficiency; these reports include fatalities.
g. chest pain, tachypnea (shortness of breath), or arrhythmias), the possibility of myocarditis, cardiomyopathy and/or other cardiovascular dysfunction must be considered. Other symptoms which may be present in addition to the above include fatigue, flu-like symptoms, fever that is otherwise unexplained, hypotension and/or raised jugular venous pressure.
The occurrence of such signs and symptoms necessitates an urgent diagnostic evaluation for myocarditis, cardiomyopathy and/or other cardiovascular dysfunction by a cardiologist. Patients with a family history of heart failure should have a cardiac evaluation prior to commencing treatment; clozapine is contraindicated in patients with severe cardiac disease.
In patients in whom myocarditis is suspected, clozapine treatment should be promptly discontinued. Patients with clozapine-induced myocarditis should not be re-exposed to clozapine. If cardiomyopathy and/or other cardiovascular dysfunction is diagnosed, discontinuation of clozapine, based on clinical grounds, should be considered.
Product Monograph August 2018 Page 11 of 57 BACKGROUND INFORMATION FOR CARDIOTOXICITY BOXED WARNING (as of early 2002): A Myocarditis, pericarditis and pericardial effusion Canadian Reports In Canada, a total of 16 post-marketing surveillance spontaneous reports of myocarditis/pericarditis/pericardial effusion have been received by Health Canada since marketing in 1991 (see also boxed warning regarding myocarditis cases).
Information additional to the Boxed Warning: the age range was 19-37 years; the shortest known clozapine treatment duration was 2 weeks. International Reports Reporting incidences for myocarditis can be reliably calculated from the four countries with clozapine national registries (USA, United Kingdom, Canada, Australia).
S. (1/20,000 person years) and the highest in Australia (1/800 person years). Of these 81 cases, 37% were fatal, with 80% of fatal cases showing evidence of myocarditis at autopsy. When all international reports of myocarditis are included (n = 213 cases), the myocarditis rate is 1/14,000 patient years; 23% of cases had a fatal outcome and 85% occurred within the first two months of initiation of clozapine therapy.
Recurrences of myocarditis upon rechallenge with clozapine have been documented. Another analysis of clozapine and myocarditis revealed that 70% of patients were under 50 years of age; thus, clozapine-associated myocarditis can occur in younger patients.
Dosages were mostly in accordance with current labelled dosage recommendations, with a third of patients taking less than therapeutic doses; this likely reflects the occurrence of myocarditis during dose titration. There are also reports of pericarditis/pericardial effusion, […]