Clozapine is an active pharmaceutical ingredient in the Diazepines, Oxazepines, Thiazepines and Oxepines group (N05AH). The information below is compiled per regulator from the product labels on record, with direct links to the original documents.
CAOfficial regulatory label· revised August 7, 2025[1]
CLOZARIL® (clozapine) tablet is indicated in the management of symptoms of treatment- resistant schizophrenia. In controlled clinical trials, clozapine was found to improve both positive and negative symptoms. Due to the significant risk of neutropenia and seizure associated with its use, clozapine should be limited to treatment-resistant schizophrenic patients who are non-responsive to, or intolerant of, conventional antipsychotic drugs.
Non-responsiveness is defined as the lack of satisfactory clinical response, despite treatment with appropriate courses of at least two marketed chemically-unrelated antipsychotic drugs. Intolerance is defined as the inability to achieve adequate benefit with conventional antipsychotic drugs because of dose-limiting, intolerable adverse effects.
Because of the significant risk of neutropenia and seizure, events which both present a continuing risk over time, the extended treatment of patients failing to show an acceptable level of clinical response to clozapine should ordinarily be avoided.
GBUnited Kingdom· MHRA
20 products
Uses
GBOfficial regulatory label· revised July 18, 2025[2]
Treatment-resistant schizophrenia Clozapine is indicated in treatment-resistant schizophrenic patients and in schizophrenia patients who have severe, untreatable neurological adverse reactions to other antipsychotic agents, including atypical antipsychotics.
Treatment resistance is defined as a lack of satisfactory clinical improvement despite the use of adequate doses of at least two different antipsychotic agents, including an atypical antipsychotic agent, prescribed for adequate duration.
Psychosis during the course of Parkinson’s disease Clozapine is also indicated in psychotic disorders occurring during the course of Parkinson's disease, in cases where standard treatment has failed.
How to take
USUnited States· FDA
2 products
Uses
USOfficial regulatory label· revised March 13, 2026[3]
1 INDICATIONS AND USAGE Clozapine orally disintegrating tablets (Clozapine ODT) is an atypical antipsychotic indicated for: Treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.
1 Treatment-resistant Schizophrenia Clozapine Orally Disintegrating Tablets (Clozapine ODT) are indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment.
4) ]. 1) ]. 2 Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder Clozapine ODT is indicated for reducing the risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder who are judged to be at chronic risk for re-experiencing suicidal behavior, based on history and recent clinical state.
Suicidal behavior refers to actions by a patient that put him/herself at risk for death. 2) ] .
Drug interactions
Known interactions involving Clozapine. Select one for details. This list is informational and not a complete interaction checker.
Showing 240 of 600. Type above to find a specific drug.
Interaction data compiled from DDInter (academic, CC-BY). Severity classification only - this is not a complete interaction checker and not medical advice.
[1]Health Canada (DPD) · 00894737 · revised August 7, 2025
[2]MHRA (UK) · PL325530008 · revised July 18, 2025
[3]FDA DailyMed · 09231d80-6343-4a… · revised March 13, 2026 [PDF]
[4]OpenFDA adverse-event reports (US), 12 months ending June 4, 2026.
Information on this page is compiled from public regulatory records. Drugvu is not affiliated with any regulator or pharmaceutical manufacturer. This is not medical advice. Always consult a qualified healthcare professional.
Seizure risk is dose-related and is more likely to occur with rapid dose increases. Titrate gradually and use divided doses. Use with caution in patients with history of seizure or risk factors for seizure. Clozapine can be used only if regular hematological examinations can be guaranteed, as specified under 7 WARNINGS AND PRECAUTIONS, Hematologic and 4 DOSAGE AND ADMINISTRATION.
CLOZARIL® is available only through a distribution system the CLOZARIL® Support and Assistance Network® (“CSAN®”) that ensures weekly, every-two-week or every-four-week hematological testing prior to the dispensing of the next period's supply of CLOZARIL® (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
This requires: • all patients taking clozapine, the physician must have obtained consent from the patient; and registration of the patient, their current location, treating physician, testing laboratory and dispensing pharmacist in the CSAN® system.
• maintenance of a national HLS Therapeutics Inc. monitoring system of the hematological results of all patients on CLOZARIL® and provides timely feedback (within 24 hours of receipt of the blood test results) to the treating physician and dispensing pharmacist/or pharmacy • the ability to identify patients who have been assigned "Non-rechallengeable Status" (see 7 WARNINGS AND PRECAUTIONS).
This requires that HLS Therapeutics Inc. both provide to, and obtain from, all other approved suppliers† of clozapine, the Non- rechallengeable Status / Hematological Status of all patients (see 4 DOSAGE AND ADMINISTRATION). HLS Therapeutics Inc.
must be able to provide this information within 24 hours of receiving a written request. † “approved supplier” is a manufacturer who holds a valid Notice of Compliance (NOC) for clozapine CLOZARIL® (clozapine) Product Monograph Page 5 of 47 July 03, 2025 Physicians should not prescribe CLOZARIL® until the non-rechallengeable status and the hematological status of the patient has been verified.
For the distribution system to be effective, treating physicians must ensure that the hematological testing is performed at the required frequency (see 7 WARNINGS AND PRECAUTIONS, Hematologic) and that arrangements are made for the hematological results to be sent to CSAN®.
Physicians may obtain details on the CSAN® distribution system by calling a toll-free phone number 1 (800) 267-2726. Other Monitoring and Distribution Systems Between 1991 and 2003, clozapine was distributed by a single manufacturer, and patients were monitored by this manufacturer's specific registry and distribution system.
The introduction of clozapine from other manufacturers has now resulted in the establishment of manufacturer- specific registry and distribution systems. In order to ensure the safe use and continued monitoring of all patients taking clozapine, the physician must have obtained consent from the patient for the potential sharing of hematological and other safety data between clozapine registries.
Patients may not be switched from one brand of clozapine to another without the completion of a new registry-specific patient registration form signed by the prescribing physician. If a patient is switched from one brand of clozapine to another, the frequency of hematological monitoring may continue unaltered unless a change is clinically indicated.
1 Pediatrics Pediatrics (< 18 years of age): No pediatric studies have been performed. The safety and efficacy of CLOZARIL® in children and adolescents have not been established. No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
4 Geriatrics. 2 Recommended Dose and Dosage Adjustment, Dosing Considerations in Special Populations.
How to take
CAOfficial regulatory label· revised August 7, 2025[1]
CLOZARIL® is available only through a distribution system the CLOZARIL® Support and Assistance Network® (“CSAN®”) that ensures weekly, every-two-week or every-four-week hematological testing prior to the dispensing of the next period's supply of CLOZARIL® (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
This requires: • all patients taking clozapine, the physician must have obtained consent from the patient; and registration of the patient, their current location, treating physician, testing laboratory and dispensing pharmacist in the CSAN® system.
• maintenance of a national HLS Therapeutics Inc. monitoring system of the hematological results of all patients on CLOZARIL® and provides timely feedback (within 24 hours of receipt of the blood test results) to the treating physician and dispensing pharmacist/or pharmacy • the ability to identify patients who have been assigned "Non-rechallengeable Status" (see 7 WARNINGS AND PRECAUTIONS).
This requires that HLS Therapeutics Inc. both provide to, and obtain from, all other approved suppliers† of clozapine, the Non- rechallengeable Status / Hematological Status of all patients (see 4 DOSAGE AND ADMINISTRATION). HLS Therapeutics Inc.
must be able to provide this information within 24 hours of receiving a written request. † “approved supplier” is a manufacturer who holds a valid Notice of Compliance (NOC) for clozapine CLOZARIL® (clozapine) Product Monograph Page 5 of 47 July 03, 2025 Physicians should not prescribe CLOZARIL® until the non-rechallengeable status and the hematological status of the patient has been verified.
For the distribution system to be effective, treating physicians must ensure that the hematological testing is performed at the required frequency (see 7 WARNINGS AND PRECAUTIONS, Hematologic) and that arrangements are made for the hematological results to be sent to CSAN®.
Physicians may obtain details on the CSAN® distribution system by calling a toll-free phone number 1 (800) 267-2726. Other Monitoring and Distribution Systems Between 1991 and 2003, clozapine was distributed by a single manufacturer, and patients were monitored by this manufacturer's specific registry and distribution system.
The introduction of clozapine from other manufacturers has now resulted in the establishment of manufacturer- specific registry and distribution systems. In order to ensure the safe use and continued monitoring of all patients taking clozapine, the physician must have obtained consent from the patient for the potential sharing of hematological and other safety data between clozapine registries.
Patients may not be switched from one brand of clozapine to another without the completion of a new registry-specific patient registration form signed by the prescribing physician. If a patient is switched from one brand of clozapine to another, the frequency of hematological monitoring may continue unaltered unless a change is clinically indicated.
1 Pediatrics Pediatrics (< 18 years of age): No pediatric studies have been performed. The safety and efficacy of CLOZARIL® in children and adolescents have not been established. No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
4 Geriatrics. 2 Recommended Dose and Dosage Adjustment, Dosing Considerations in Special Populations. 2 CONTRAINDICATIONS • CLOZARIL® (clozapine) is contraindicated in patients who are hypersensitive to clozapine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
For a complete listing, see
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
CAOfficial regulatory label· Adverse reactions· revised August 7, 2025[1]
1 Adverse Reaction Overview The most serious adverse reactions experienced with CLOZARIL® (clozapine) are neutropenia seizure, cardiovascular effects and fever (see 7 WARNINGS AND PRECAUTIONS, Hematologic). The most common side effects are drowsiness/sedation, dizziness, hypersalivation, tachycardia, and constipation.
Adverse Events Leading to Discontinuation Of 1080 patients who received clozapine in premarketing clinical trials, 16% 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:
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. 2 Clinical Trial Adverse 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. CLOZARIL® (clozapine) Product Monograph Page 26 of 47 July 03, 2025 Table 4 Treatment-Emergent Adverse Experience Incidence Among Patients Taking Clozapine in Clinical Trials Body System % Patients Adverse Eventa (N=842) 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 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 CLOZARIL® (clozapine) Product Monograph Page 27 of 47 July 03, 2025 Body System % Patients Adverse Eventa (N=842) 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 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 a Events reported by at least 1% of clozapine patients are included.
b Rate based on population of approximately 1700 exposed during premarket clinical evaluation of clozapine. 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 CLOZARIL® treatment group were: salivary hypersecretion, somnolence, weight increase, anxiety, depression, dizziness (excluding vertigo), psychotic disorder, suicidal ideation, constipation, and insomnia.
1 Clinical Trial Adverse Reactions (Pediatrics) No pediatric studies have been performed. 3 Less Common Clinical Trial Adverse Reactions 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 in alphabetical order by organ system. CLOZARIL® (clozapine) Product Monograph Page 28 of 47 July 03, 2025 Autonomic Nervous System: dry throat, hot flashes, mydriasis, numbness, polydipsia.
CAOfficial regulatory label· Warnings and precautions· revised August 7, 2025[1]
, Hematologic and 4 DOSAGE AND ADMINISTRATION. CLOZARIL® is available only through a distribution system the CLOZARIL® Support and Assistance Network® (“CSAN®”) that ensures weekly, every-two-week or every-four-week hematological testing prior to the dispensing of the next period's supply of CLOZARIL® (see 7 WARNINGS AND PRECAUTIONS, Hematologic).
This requires: • all patients taking clozapine, the physician must have obtained consent from the patient; and registration of the patient, their current location, treating physician, testing laboratory and dispensing pharmacist in the CSAN® system.
• maintenance of a national HLS Therapeutics Inc. monitoring system of the hematological results of all patients on CLOZARIL® and provides timely feedback (within 24 hours of receipt of the blood test results) to the treating physician and dispensing pharmacist/or pharmacy • the ability to identify patients who have been assigned "Non-rechallengeable Status" (see 7 WARNINGS AND PRECAUTIONS).
This requires that HLS Therapeutics Inc. both provide to, and obtain from, all other approved suppliers† of clozapine, the Non- rechallengeable Status / Hematological Status of all patients (see 4 DOSAGE AND ADMINISTRATION). HLS Therapeutics Inc.
must be able to provide this information within 24 hours of receiving a written request. † “approved supplier” is a manufacturer who holds a valid Notice of Compliance (NOC) for clozapine CLOZARIL® (clozapine) Product Monograph Page 5 of 47 July 03, 2025 Physicians should not prescribe CLOZARIL® until the non-rechallengeable status and the hematological status of the patient has been verified.
For the distribution system to be effective, treating physicians must ensure that the hematological testing is performed at the required frequency (see 7 WARNINGS AND PRECAUTIONS, Hematologic) and that arrangements are made for the hematological results to be sent to CSAN®.
Physicians may obtain details on the CSAN® distribution system by calling a toll-free phone number 1 (800) 267-2726. Other Monitoring and Distribution Systems Between 1991 and 2003, clozapine was distributed by a single manufacturer, and patients were monitored by this manufacturer's specific registry and distribution system.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
CAOfficial regulatory label· Contraindications· revised August 7, 2025[1]
• CLOZARIL® (clozapine) is contraindicated in patients who are hypersensitive to clozapine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
• Patients with myeloproliferative disorders, a history of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy). [Clozapine should not be used simultaneously with other agents known to suppress bone marrow function].
CLOZARIL® (clozapine) Product Monograph Page 6 of 47 July 03, 2025 • Patients with active liver disease associated with nausea, anorexia, or jaundice; progressive liver disease; hepatic failure. • Patients unable to undergo blood tests.
GBOfficial regulatory label· revised July 18, 2025[2]
Posology The dosage must be adjusted individually. For each patient the lowest effective dose should be used. For doses not realisable/practicable with this strength, other strengths of this medicinal product are available. Cautious titration and a divided dosage schedule are necessary to minimise the risks of hypotension, seizure and sedation.
0x109/l) within standardised normal limits. 5). Switching from a previous antipsychotic therapy to clozapine It is generally recommended that clozapine should not be used in combination with other antipsychotics. When clozapine therapy is to be initiated in a patient undergoing oral antipsychotic therapy, it is recommended that the other antipsychotic should first be discontinued by tapering the dosage downwards.
5 mg once or twice on the first day, followed by 25 mg once or twice on the second day. If well tolerated, the daily dose may then be increased slowly in increments of 25 to 50 mg in order to achieve a dose level of up to 300 mg/day within 2 to 3 weeks.
Thereafter, if required, the daily dose may be further increased in increments of 50 to 100 mg at half-weekly or, preferably, weekly intervals. Therapeutic dose range In most patients, antipsychotic efficacy can be expected with 200 to 450 mg/day given in divided doses.
The total daily dose may be divided unevenly, with the larger portion at bedtime. Maximum dose To obtain full therapeutic benefit, a few patients may require larger doses, in which case judicious increments (not exceeding 100 mg) are permissible up to 900 mg/day.
However, the possibility of increased adverse reactions (in particular seizures) occurring at doses over 450 mg/day must be borne in mind. Maintenance dose After achieving maximum therapeutic benefit, many patients can be maintained effectively on lower doses.
Careful downward titration is therefore recommended. Treatment should be maintained for at least 6 months. If the daily dose does not exceed 200 mg, once daily administration in the evening may be appropriate. Ending therapy In the event of planned termination of clozapine therapy, a gradual reduction in dose over a 1 to 2-week period is recommended.
4). 5 mg given once or twice on the first day. If this dose is well tolerated, it may be feasible to titrate the dose to the therapeutic level more quickly than is recommended for initial treatment. 4) but was then able to be successfully titrated to a therapeutic dose, re- titration should be carried out with extreme caution.
5 mg/day, taken in the evening. 5 mg increments, with a maximum of two increments a week up to a maximum of 50 mg, a dose that cannot be reached until the end of the second week. The total daily amount should preferably be given as a single dose in the evening.
5 mg/day. 5 mg/week. Maximum dose The dose of 50 mg/day should only be exceeded in exceptional cases, and the maximum dose of 100 mg/day must never be exceeded. Dose increases should be limited or deferred if orthostatic hypotension, excessive sedation or confusion occurs.
Blood pressure should be monitored during the first weeks of treatment. Maintenance dose When there has been complete remission of psychotic symptoms for at least 2 weeks, an increase in anti-parkinsonian medication is possible if indicated on the basis of motor status.
5 mg/week up to a maximum of 100 mg/day, taken in one or two divided doses (see above). 5 mg over a period of at least one week (preferably two) is recommended. 4). In this situation, careful psychiatric monitoring of the patient is essential since symptoms may recur quickly.
4). Paediatric population No paediatric studies have been performed. The safety and efficacy of clozapine in children and adolescents under the age of 16 years have not yet been established. It should not be used in this group until further data become available.
5 mg given once on the first day), with subsequent dose increments restricted to 25 mg/day. Method of administration Zaponex is administered orally. Immediately upon opening the blister or bottle, using dry hands, remove the tablet and […]
This is not medical advice. Consult a qualified healthcare professional.
Side effects & warnings
GBOfficial regulatory label· Adverse reactions· revised July 18, 2025[2]
Summary of the safety profile For the most part, the adverse event profile of clozapine is predictable from its pharmacological properties. 4). Because of this risk, its use is restricted to treatment-resistant schizophrenia and psychosis occurring during the course of Parkinson’s disease in cases where standard treatment has failed.
While blood monitoring is an essential part of the care of patients receiving clozapine, the physician should be aware of other rare but serious adverse reactions, which may be diagnosed in the early stages only by careful observation and questioning of the patient in order to prevent morbidity and mortality.
4). The most common side effects are drowsiness/sedation, dizziness, tachycardia, constipation, and hypersalivation. 6%) were discontinued due to an adverse event, including only those that could be reasonably attributed to clozapine.
The more common events considered to be causes of discontinuation were leukopenia, somnolence, dizziness (excluding vertigo) and psychotic disorder. Blood and lymphatic system Development of granulocytopenia and agranulocytosis is a risk inherent to clozapine treatment.
Although generally reversible on withdrawal of treatment, agranulocytosis may result in sepsis and can prove fatal. 4). Table 3 below summarises the estimated incidence of agranulocytosis for each clozapine treatment period. 8 1 From the UK Clozaril Patient Monitoring Service lifetime registry experience between 1989 and 2001.
2 Person-time is the sum of individual units of time that the patients in the registry were exposed to clozapine before experiencing agranulocytosis. For example, 100,000 person-weeks could be observed in 1,000 patients who were in the registry for 100 weeks (100*1000=100,000), or in 200 patients who were in the registry for 500 weeks (200*500=100,000) before experiencing agranulocytosis.
78%. The majority of cases (approximately 70%) occur within the first 18 weeks of treatment. Metabolic and nutritional disorders Impaired glucose tolerance and/or development or exacerbation of diabetes mellitus has been reported rarely during treatment with clozapine.
On very rare occasions, severe hyperglycaemia, sometimes leading to ketoacidosis/hyperosmolar coma, has been reported in patients on clozapine treatment with no prior history of hyperglycaemia. Glucose levels normalised in most patients after discontinuation of clozapine and in a few cases hyperglycaemia recurred when treatment was reinitiated.
4). Nervous system disorders The very common adverse reactions observed include drowsiness/sedation, and dizziness. Clozapine can cause EEG changes, including the occurrence of spike and wave complexes. It lowers the seizure threshold in a dose-dependent manner and may induce myoclonic jerks or generalised seizures.
These symptoms are more likely to occur with rapid dose increases and in patients with pre-existing epilepsy. In such cases the dose should be reduced and, if necessary, anticonvulsant treatment initiated. Carbamazepine should be avoided because of its potential to depress bone marrow function, and with other anticonvulsant the possibility of a pharmacokinetic interaction should be considered.
In rare cases, patients treated with clozapine may experience delirium. Very rarely, tardive dyskinesia has been reported in patients on clozapine who had been treated with other antipsychotic agents. Patients in whom tardive dyskinesia developed with other antipsychotics have improved on clozapine.
Cardiac disorders Tachycardia and postural hypotension with or without syncope may occur, especially in the initial weeks of treatment. The prevalence and severity of hypotension is influenced by the rate and magnitude of dose titration.
Circulatory collapse as a result of profound hypotension, in particular related to aggressive titration, with the possible serious consequences of cardiac or pulmonary arrest, has been reported with clozapine. A minority of clozapine-treated patients experience ECG changes similar to those seen with other antipsychotics, including S-T segment depression and flattening or inversion of T waves, which normalise after discontinuation of clozapine.
The clinical significance of these changes is unclear. However, such abnormalities have been observed in patients with myocarditis, which should therefore be considered. Isolated cases of cardiac arrhythmias, pericarditis/pericardial effusion and myocarditis have been reported, some of which have been fatal.
The majority of the cases of myocarditis occurred within the first 2 months of initiation of therapy with clozapine. Cardiomyopathy generally occurred later in the treatment. Eosinophilia has been co-reported with some cases of myocarditis (approximately 14%) and pericarditis/pericardial effusion; it is not known, however, whether eosinophilia is a reliable predictor of carditis.
Signs and symptoms of myocarditis or cardiomyopathy include […]
GBOfficial regulatory label· Warnings and precautions· revised July 18, 2025[2]
Agranulocytosis Clozapine can cause agranulocytosis. The incidence of agranulocytosis and the fatality rate in those developing agranulocytosis have decreased markedly since the institution of white blood cell (WBC) counts and absolute neutrophil count (ANC) monitoring.
The following precautionary measures are therefore mandatory and should be carried out in accordance with official recommendations. 0x109/l), and - in whom regular WBC counts and ANC can be performed weekly for the first 18 weeks and at least 4- week intervals thereafter.
Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of clozapine. Before initiating clozapine therapy patients should have a blood test (see “agranulocytosis”) and a history and physical examination.
3). The treating physician should consider performing a pre-treatment ECG. Prescribing physicians must comply fully with the required safety measures. Prior to treatment initiation, physicians must ensure, to the best of their knowledge, that the patient has not previously experienced an adverse haematological reaction to clozapine that necessitated its discontinuation.
Prescriptions should not be issued for periods longer than the interval between two blood counts. 5x109/l) at any time during clozapine treatment. Patients in whom clozapine has been discontinued as a result of either WBC or ANC deficiencies must not be re-exposed to clozapine.
At each consultation, a patient receiving clozapine must be reminded to contact the treating physician immediately if any kind of infection begins to develop. Particular attention should be paid to flu-like complaints such as fever or sore throat and to other evidence of infection, which may be indicative of neutropenia.
Patients and their caregivers must be informed that, in the event of any of these symptoms, they must have a blood cell count performed immediately. Prescribers are encouraged to keep a record of all patients’ blood results and to take any steps necessary to prevent these patients from accidentally being rechallenged in the future.
Patients with a history of primary bone marrow disorders may be treated only if the benefit outweighs the risk. They should be carefully reviewed by a haematologist prior to starting clozapine. Patients who have low WBC counts because of benign ethnic neutropenia should be given special consideration and may only be started on clozapine with the agreement of a haematologist.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
GBOfficial regulatory label· Contraindications· revised July 18, 2025[2]
1. - Patients unable to undergo regular blood tests. - History of toxic or idiosyncratic granulocytopenia/agranulocytosis (with the exception of granulocytopenia/agranulocytosis from previous chemotherapy). - History of clozapine-induced agranulocytosis.
- Clozapine treatment must not be started concurrently with substances known to have a substantial potential for causing agranulocytosis; concomitant use of depot antipsychotics is to be discouraged. - Impaired bone marrow function.
- Uncontrolled epilepsy. - Alcoholic and other toxic psychoses, drug intoxication, comatose conditions. - Circulatory collapse and/or CNS depression of any cause. g. myocarditis). - Active liver disease associated with nausea, anorexia or jaundice; progressive liver disease, hepatic failure.
- Paralytic ileus.
This is not medical advice. Consult a qualified healthcare professional.
How to take
USOfficial regulatory label· revised March 13, 2026[3]
5 mg once daily or twice daily. 2 ) If well-tolerated, increase the total daily dosage in increments of 25 mg to 50 mg per day at target dosage of 150 mg to 225 mg twice per day by the end of two weeks. 2 ) Subsequently may increase the doage in increments up to 100 mg, once or twice weekly.
2 ) Maximum daily dosage is 450 mg twice daily. 2 ) Administer with or without food. Clozapine ODT may be allowed to disintegrate or chewed, and may be taken with or without water. See additional administration instructions in the full prescribing information.
2 ) See dosage modification based on ANC results. 8 ) in the full prescribing information. Tablets rapidly disintegrate after placement in the mouth and may be chewed if desired. No water is needed. 1 Absolute Neutrophil Count Testing Prior to Clozapine ODT Initiation Prior to initiating Clozapine ODT treatment, obtain a baseline absolute neutrophil count (ANC).
1) ] . For patients with documented Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count)), obtain at least two baseline ANC levels. 1) ] . 4) . 2) ] . 5 mg once or twice daily. If well-tolerated, increase the total daily dose in increments of 25 mg to 50 mg per day to achieve a target dosage of 150 mg to 225 mg twice per day by the end of two weeks.
Subsequently, may increase the dosage in increments of up to 100 mg once weekly or twice weekly. The maximum recommended Clozapine ODT oral dosage is 450 mg twice daily. 3) ] . After removing Clozapine ODT from the bottle, immediately place in the mouth.
1) ] . 4) ] . , patient had neutropenia which required dosage interruption and now has a normal ANC level) for: < 30 days, continue the previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients who initiate treatment Mild Neutropenia (ANC between 1000 to 1499/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours No dosage modification; continue treatment Three times weekly Once ANC ≥ 1500/µL, recommend returning to the patient’s last Normal Range ANC testing frequency Moderate Neutropenia (ANC between 500 to 999/µL) Interrupt treatment and recommend hematology consultation Resume treatment once ANC ≥ 1000/µL Daily Once ANC ≥ 1000/µL, three times weekly Once ANC ≥ 1500/µL, test weekly for 4 weeks.
1) ] . 3) ] .
Table 2:
Clozapine ODT Dosage Modifications Based on ANC Results and Frequency of ANC Testing in Patients with Benign Ethnic Neutropenia Benign Ethnic Neutropenia (BEN) is also known as Duffy-null associated neutrophil count. , patient had neutropenia which required dosage interruption and now their ANC (≥ 1000/µL and ≥ the patient’s ANC baseline prior to treatment) for: < 30 days, continue previous ANC testing frequency ≥ 30 days, obtain ANC tests according to the frequency for patients with BEN who initiate treatment Neutropenia in Patients with BEN (ANC level between 500 to 999/µL) Confirm all initial reports of ANC less than 1500/µL with a repeat ANC measurement within 24 hours Recommend hematology consultation No dosage modification; continue treatment Three times weekly Once ANC ≥ 1000/µL and ≥ the patient’s ANC baseline, obtain ANC tests weekly for 4 weeks If ANC ≥ 1000/µL and ≥ the patient’s baseline after monitoring for 4 weeks, return to the patient’s last Normal ANC Range testing frequency for patients with BEN.
4) ] . Normal or mild neutropenia, reduce the dosage gradually over a period of 1 to 2 weeks, and continue monitoring ANC levels until their ANC is ≥ 1500/µL. 5) ] . ANC within their normal range of ANC reduce the dosage gradually over a period of 1 to 2 weeks.
, profuse sweating, headache, nausea, vomiting, diarrhea). 2) ] . If one day’s dosage is missed, resume Clozapine ODT treatment at 40% to 50% of the previous dosage. If two days of dosing is missed, resume Clozapine ODT treatment at approximately 25% of the previous dosage.
5 mg once or twice daily. If this dosage is well-tolerated, may increase the dosage to the previous dosage more quickly than recommended than for initial Clozapine ODT treatment. 7 Dosage Modifications for Drug Interactions See Table 3 for recommended dosage modifications to reduce the risk of Clozapine ODT-associated adverse reactions or reduce the risk of lower effectiveness [see Drug Interactions (7) ] .
Table 3:
Clozapine ODT Dosage Modifications for Drug Interactions Strong CYP1A2 Inhibitors Administer one third of the Clozapine ODT dosage. Moderate or Weak CYP1A2 Inhibitors Consider reducing the Clozapine ODT dosage if necessary. CYP2D6 or CYP3A4 Inhibitors Strong CYP3A4 Inducers Concomitant use is not recommended.
However, if concomitant use is necessary, it may be necessary to increase the Clozapine ODT dosage. Monitor for decreased effectiveness. Moderate or weak CYP1A2 or CYP3A4 Inducers Consider increasing the Clozapine ODT dosage if necessary.
7) ] .
This is not medical advice. Consult a qualified healthcare professional.
Most-reported reactions to the US regulator (12 mo to June 4, 2026): 5,804 reports total. [4]
Death 976
Hospitalisation 499
Neutropenia 428
Off Label Use 389
Treatment Noncompliance 318
Malaise 227
Drug Interaction 226
Myocarditis 225
Schizophrenia 221
Drug Ineffective 192
White Blood Cell Count Decreased 192
Leukocytosis 188
Side effects & warnings
USOfficial regulatory label· Adverse reactions· revised March 13, 2026[3]
20) ] Most common adverse reactions (≥ 5%) were: CNS reactions (sedation, dizziness/vertigo, headache, and tremor); cardiovascular reactions (tachycardia, hypotension, and syncope); autonomic nervous system reactions (hypersalivation, sweating, dry mouth, and visual disturbances); gastrointestinal reactions (constipation and nausea); and fever.
gov/medwatch. 1 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 9 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 9:
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 10 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 10:
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 11 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 11:
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. 2 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, pericarditis, and periorbital edema.
Endocrine System Pseudopheochromocytoma. Gastrointestinal System Acute pancreatitis, dysphagia, salivary gland swelling, megacolon, fecal incontinence, and intestinal ischemia, infarction, perforation, ulceration or necrosis. Hepatobiliary System Cholestasis, hepatitis, jaundice, hepatotoxicity, hepatic steatosis, hepatic necrosis, hepatic fibrosis, hepatic cirrhosis, liver injury (hepatic, cholestatic, and mixed), and liver failure.
Immune System Disorders Angioedema, leukocytoclastic vasculitis. Urogenital System Acute interstitial nephritis, nocturnal enuresis, priapism, and renal failure. Skin and Subcutaneous Tissue Disorders Hypersensitivity reactions: photosensitivity, vasculitis, erythema multiforme, skin pigmentation disorder, and Stevens-Johnson Syndrome.
Musculoskeletal System and Connective Tissue Disorders Myasthenic syndrome, rhabdomyolysis, and systemic lupus erythematosus. Respiratory System Aspiration, pleural effusion, pneumonia, lower respiratory tract infection. Hemic and Lymphatic System Mild, moderate, or severe leukopenia, agranulocytosis, granulocytopenia, WBC decreased, deep vein thrombosis, elevated hemoglobin/hematocrit, erythrocyte sedimentation rate (ESR) increased, sepsis, thrombocytosis, and thrombocytopenia.
USOfficial regulatory label· Warnings and precautions· revised March 13, 2026[3]
1 ) Gastrointestinal Hypomotility with Severe Complications: Severe gastrointestinal adverse reactions have occurred with the use of clozapine. If constipation is identified, close monitoring and prompt treatment is advised. , myocarditis, pancreatitis, hepatitis, colitis, nephritis).
Discontinue if these occur. 8 ) QT Interval Prolongation: Can be fatal. Consider additional risk factors for prolonged QT interval (disorders and drugs). 9 ) Metabolic Changes: Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk.
10 ): Hyperglycemia and Diabetes Mellitus: Monitor for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Monitor glucose regularly in patients with diabetes or at risk for diabetes.
Dyslipidemia:
Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics.
Weight Gain:
Significant weight gain has occurred. Monitor weight gain.
Neuroleptic Malignant Syndrome (NMS):
Immediately discontinue and monitor closely. Assess for co-morbid conditions. 11 ) Hepatotoxicity: Can be fatal. Monitor for hepatotoxicity. Discontinue treatment if hepatitis or transaminase elevations combined with other symptoms occur.
12 ) Fever: Evaluate for infection and for neutropenia, NMS. 13 ) Pulmonary Embolism (PE): Consider PE if respiratory distress, chest pain, or deep vein thrombosis occurs. 14 ) Anticholinergic Toxicity: When possible, avoid use with other anticholinergic drugs and use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.
1 ) Interference with Cognitive and Motor Performance: Advise caution when operating machinery, including automobiles. 2) ] and is associated with an increased risk of serious and potentially fatal infections. Severe neutropenia occurred in a small percentage of clozapine-treated patients.
This is not medical advice. Consult a qualified healthcare professional.
Who should not take it
USOfficial regulatory label· Contraindications· revised March 13, 2026[3]
2) ] . Known hypersensitivity to clozapine or any other component of Clozapine ODT ( 4 )
This is not medical advice. Consult a qualified healthcare professional.
The introduction of clozapine from other manufacturers has now resulted in the establishment of manufacturer- specific registry and distribution systems. In order to ensure the safe use and continued monitoring of all patients taking clozapine, the physician must have obtained consent from the patient for the potential sharing of hematological and other safety data between clozapine registries.
Patients may not be switched from one brand of clozapine to another without the completion of a new registry-specific patient registration form signed by the prescribing physician. If a patient is switched from one brand of clozapine to another, the frequency of hematological monitoring may continue unaltered unless a change is clinically indicated.
1 Pediatrics Pediatrics (< 18 years of age): No pediatric studies have been performed. The safety and efficacy of CLOZARIL® in children and adolescents have not been established. No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
4 Geriatrics. 2 Recommended Dose and Dosage Adjustment, Dosing Considerations in Special Populations. 2 CONTRAINDICATIONS • CLOZARIL® (clozapine) is contraindicated in patients who are hypersensitive to clozapine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.
For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING. • Patients with myeloproliferative disorders, a history of toxic or idiosyncratic agranulocytosis or severe granulocytopenia (with the exception of granulocytopenia/ agranulocytosis from previous chemotherapy).
[Clozapine should not be used simultaneously with other agents known to suppress bone marrow function]. CLOZARIL® (clozapine) Product Monograph Page 6 of 47 July 03, 2025 • Patients with active liver disease associated with nausea, anorexia, or jaundice; progressive liver disease; hepatic failure.
• Patients unable to undergo blood tests. , myocarditis), paralytic ileus, uncontrolled epilepsy. 5 x 109/L. Severe neutropenia can lead to serious infection and death. 0 x 109/L for patients with documented Benign Ethnic Neutropenia (BEN).
Regular hematologic monitoring is required prior to dispensing, because of the significant risk of this potentially life-threatening adverse event (see 7 WARNINGS AND PRECAUTIONS, Hematologic). Advise patients to immediately report the appearance of lethargy, weakness, fever, sore throat, flu-like complaints or any other signs of infection.
Because of the risk of severe neutropenia, CLOZARIL® is available only through a distribution system (“CSAN®”) that ensures weekly, every-two-week or every-four-week hematological testing prior to the dispensing of the next period's supply of CLOZARIL® (see 7 WARNINGS AND PRECAUTIONS).
Myocarditis, Pericarditis, and Cardiomyopathy and Mitral Valve Incompetence Fatal myocarditis and cardiomyopathy have occurred with the use of CLOZARIL®. Discontinue CLOZARIL® and obtain a cardiac evaluation upon suspicion of myocarditis or cardiomyopathy.
Consider the […]
0x109/l)) will receive clozapine. After the start of clozapine treatment regular WBC count and ANC must be performed and monitored weekly for the first 18 weeks, and at least at four-week intervals thereafter. Monitoring must continue throughout treatment and for 4 weeks after complete discontinuation of clozapine or until haematological recovery has occurred (see “Low WBC count/ANC” below).
At each consultation, the patient must be reminded to contact the treating physician immediately if any kind of infection, fever, sore throat or other flu-like symptoms develop. WBC and differential blood counts must be performed immediately if any symptoms or signs of an infection occur.
0x109/l), respectively, or higher. 5x109/l) during clozapine treatment. WBC counts and differential blood counts should then be performed daily and patients should be carefully monitored for flu-like symptoms or other symptoms suggestive of infection.
Confirmation of the haematological values is recommended by performing two blood counts on two consecutive days; however, clozapine should be discontinued after the first blood count. Following discontinuation of clozapine, haematological evaluation is required until haematological recovery has occurred.
5x109) Immediately stop clozapine treatment, sample blood daily until haematological abnormality is resolved, monitor for infection. Do not re-expose the patient. 0x109/l), the management of this condition must be guided by an experienced haematologist.
[…]
The risk of severe neutropenia appears greatest during the first 18 weeks of Clozapine ODT treatment. The mechanism by which Clozapine ODT causes neutropenia is unknown. Neutropenia is not dose-dependent. Consider a hematology consultation before initiating Clozapine ODT treatment or during treatment.
ANC Monitoring and Dosage Modifications Prior to initiating Clozapine ODT treatment, obtain a baseline ANC. Clozapine ODT initiation is not recommended in patients with a baseline ANC less than 1500/µL. Throughout Clozapine ODT treatment, regularly monitor ANC.
4) ] . ANC Monitoring and Dosage Modification in Patients with Benign Ethnic Neutropenia Patients with Benign Ethnic Neutropenia (BEN) (also known as Duffy-null associated neutrophil count) generally have lower baseline neutrophil counts but they are not at higher risk for developing infections, and they are not at increased risk for developing Clozapine ODT-induced neutropenia.
For patients with documented BEN, obtain at least two baseline ANC levels prior to Clozapine ODT initiation. Clozapine ODT initiation is not recommended in patients with BEN with an ANC less than 1000/µL. There are different ANC dosage modification recommendations in Clozapine ODT-treated patients with BEN due to their lower baseline ANC levels.
4) ] . 5 °C) or greater and obtain an ANC level. If the ANC is less than 1000/µL in patients without BEN, initiate appropriate workup and treatment for infection. 3) ] . 13) for fever. Restarting Clozapine ODT in Patients Who Recovered from Severe Neutropenia Generally, do not rechallenge patients with Clozapine ODT in those who experienced severe neutropenia.
, patients who have no treatment options other than Clozapine ODT). Concomitant Use of Clozapine ODT with Other Drugs Known to Cause Neutropenia If Clozapine ODT is used concomitantly with another drug known to cause neutropenia, consider more frequently ANC monitoring than the recommendations provided in Tables 1 and 2.
2 Orthostatic Hypotension, Bradycardia, and Syncope Hypotension, bradycardia, syncope, and cardiac arrest have occurred with clozapine treatment. The risk is highest during the initial titration period, particularly with rapid dose-escalation.
5 mg. These reactions can be fatal. The syndrome is consistent with neurally mediated reflex bradycardia (NMRB). 5 mg once daily or twice daily. The total daily dose can be increased in increments of 25 mg to 50 mg per day, if well-tolerated, to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of 2 weeks.
Subsequently, the dose can be increased weekly or twice weekly, in increments of up to 100 mg. The maximum Clozapine ODT dosage is 900 mg per day. 2) ] . Consider reducing the dose if hypotension occurs. When restarting Clozapine ODT in patients who have had even a brief interruption in treatment with Clozapine ODT, the dosage must be reduced.
6) ] . , concomitant use of antihypertensives, dehydration and hypovolemia). 3 Falls Clozapine ODT may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries.
For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic treatment. 5%).
The risk of seizure is dose-related. 5 mg), titrate slowly, and use divided dosing. , head trauma or other CNS pathology, use of medications that lower the seizure threshold, or alcohol abuse). , driving an automobile, operating complex machinery, swimming, climbing).
5 Myocarditis, Pericarditis, Cardiomyopathy and Mitral Valve Incompetence Myocarditis, pericarditis, and cardiomyopathy have occurred with the use of clozapine. These reactions can be fatal. Discontinue Clozapine ODT and obtain a cardiac evaluation upon suspicion of myocarditis, pericarditis, or cardiomyopathy.
Generally, patients with a history of clozapine-associated myocarditis, pericarditis or cardiomyopathy should not be rechallenged with Clozapine ODT. However, if the benefit of Clozapine ODT treatment is judged to outweigh the potential risks of recurrence, the clinician may consider rechallenge with Clozapine ODT in consultation with a cardiologist.
Consider the possibility of myocarditis or cardiomyopathy in patients receiving Clozapine ODT who present with chest pain, dyspnea, persistent tachycardia at rest, palpitations, fever, flu-like symptoms, hypotension, other signs or symptoms of heart failure, or electrocardiographic findings (low voltages, ST-T abnormalities, arrhythmias, right axis deviation, and poor R wave progression).
Myocarditis and pericarditis most frequently present within the first two months of clozapine treatment. Symptoms of cardiomyopathy generally occur later than clozapine-associated myocarditis and usually after 8 weeks of treatment. However, myocarditis, pericarditis, and cardiomyopathy can occur at any period during treatment with Clozapine ODT.
In patients who are diagnosed with cardiomyopathy while taking clozapine, mitral valve incompetence has been reported. 6 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.
7 times the risk of death in placebo-treated patients. 6% in the placebo group. , pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality in this population.
The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. Clozapine ODT is not approved for the treatment of patients with dementia-related psychosis [see] .
7 Gastrointestinal Hypomotility with Severe Complications Severe gastrointestinal adverse reactions have occurred with the use of clozapine, primarily due to its potent anticholinergic effects and resulting gastrointestinal hypomotility.
In post marketing experience, reported effects range from constipation to paralytic ileus. 2) ] . These reactions have resulted in hospitalization, surgery, and death. 1) ] . Prior to initiating Clozapine ODT, screen for constipation and treat as necessary.
Subjective symptoms of constipation may not accurately reflect the degree of gastrointestinal hypomotility in Clozapine ODT-treated patients. , nausea, vomiting, abdominal distension, abdominal pain). If constipation or gastrointestinal hypomotility are identified, monitor closely and treat promptly with appropriate laxatives, as necessary, to prevent severe complications.
Consider prophylactic laxatives in high risk patients. 8 Eosinophilia Eosinophilia, defined as a blood eosinophil count of greater than 700/μL, has occurred with clozapine treatment. In clinical trials, approximately 1% of patients developed eosinophilia.
Clozapine-related eosinophilia usually occurs during the first month of treatment. In some patients, it has been associated with myocarditis, pancreatitis, hepatitis, colitis, and nephritis. Such organ involvement could be consistent with a drug reaction with eosinophilia and systemic symptoms syndrome (DRESS), also known as drug induced hypersensitivity syndrome (DIHS).
If eosinophilia develops during Clozapine ODT treatment, evaluate promptly for signs and symptoms of systemic reactions, such as rash or other allergic symptoms, myocarditis, or other organ-specific disease associated with eosinophilia.
If clozapine-related systemic disease is suspected, discontinue Clozapine ODT immediately. , asthma, allergies, collagen vascular disease, parasitic infections, and specific neoplasms), treat the underlying cause and continue Clozapine ODT.
Clozapine-related eosinophilia has also occurred in the absence of organ involvement and can resolve without intervention. There are reports of successful rechallenge after discontinuation of Clozapine ODT, without recurrence of eosinophilia.
In the absence of organ involvement, continue Clozapine ODT under careful monitoring. If the total eosinophil count continues to increase over several weeks in the absence of systemic disease, the decision to interrupt Clozapine ODT therapy and rechallenge after the eosinophil count decreases should be based on the overall clinical assessment, in consultation with an internist or hematologist.
9 QT Interval Prolongation QT prolongation, Torsades de Pointes and other life-threatening ventricular arrhythmias, cardiac arrest, and sudden death have occurred with clozapine treatment. When prescribing Clozapine ODT, consider the presence of additional risk factors for QT prolongation and serious cardiovascular reactions.
Conditions that increase these risks include the following: history of QT prolongation, long QT syndrome, family history of long QT syndrome or sudden cardiac death, significant cardiac arrhythmia, recent myocardial infarction, uncompensated heart failure, treatment with other medications that cause QT prolongation, treatment with medications that inhibit the metabolism of clozapine, and electrolyte abnormalities.
Prior to initiating treatment with Clozapine ODT, perform a careful physical examination, medical history, and concomitant medication history. Consider obtaining a baseline ECG and serum chemistry panel. Correct electrolyte abnormalities.
Discontinue Clozapine ODT if the QTc interval exceeds 500 msec. , syncope, presyncope, dizziness, or palpitations), obtain a cardiac evaluation and discontinue Clozapine ODT. Use caution when administering concomitant medications that prolong the QT interval or inhibit the metabolism of clozapine.
, pentamidine, levomethadyl acetate, methadone, halofantrine, mefloquine, dolasetron mesylate, probucol or tacrolimus). Clozapine is primarily metabolized by CYP isoenzymes 1A2, 2D6, and 3A4. 3) ] . Hypokalemia and hypomagnesemia increase the risk of QT prolongation.
Hypokalemia can result from diuretic therapy, diarrhea, and other causes. Use caution when treating patients at risk for significant electrolyte disturbance, particularly hypokalemia. Obtain baseline measurements of serum potassium and magnesium levels, and periodically monitor electrolytes.
Correct electrolyte abnormalities before initiating treatment with Clozapine ODT. 10 Metabolic Changes Atypical antipsychotic drugs, including clozapine, have been associated with metabolic changes that can increase cardiovascular and cerebrovascular risk.
These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While atypical antipsychotic drugs may produce some metabolic changes, each drug in the class has its own specific risk profile. Hyperglycemia and Diabetes Mellitus Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics including clozapine.
Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population.
Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse reactions is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent, hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics.
Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on Clozapine ODT should be monitored regularly for worsening of glucose control.
, obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness.
Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
In a pooled data analysis of 8 studies in adult subjects with schizophrenia, the mean changes in fasting glucose concentration in the clozapine and chlorpromazine groups were +11 mg/dL and +4 mg/dL, respectively. A higher proportion of the clozapine group demonstrated categorical increases from baseline in fasting glucose concentrations, compared to the chlorpromazine group (Table 4).
The clozapine doses were 100 to 900 mg per day (mean modal dose: 512 mg per day). The maximum chlorpromazine dose was 1800 mg per day (mean modal dose: 1029 mg per day). The median duration of exposure was 42 days for clozapine and chlorpromazine.
Table 4:
Categorical Changes in Fasting Glucose Level in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from Baseline Treatment Arm N n (%) Fasting Glucose Normal (< 100 mg/dL) to High (≥ 126 mg/dL) Clozapine 198 53 (27) Chlorpromazine 135 14 (10) Borderline (100 to 125 mg/dL) to High (≥ 126 mg/dL) Clozapine 57 24 (42) Chlorpromazine 43 12 (28) Dyslipidemia Undesirable alterations in lipids have occurred in patients treated with atypical antipsychotics, including clozapine.
Clinical monitoring, including baseline and periodic follow-up lipid evaluations in patients using Clozapine ODT, is recommended. In a pooled data analysis of 10 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in serum total cholesterol.
No data were collected on LDL and HDL cholesterol. The mean increase in total cholesterol was 13 mg/dL in the clozapine group and 15 mg/dL in the chlorpromazine group. In a pooled data analysis of 2 studies in adult subjects with schizophrenia, clozapine treatment was associated with increases in fasting serum triglyceride.
The mean increase in fasting triglyceride was 71 mg/dL (54%) in the clozapine group and 39 mg/dL (35%) in the chlorpromazine group (Table 5). In addition, clozapine treatment was associated with categorical increases in serum total cholesterol and triglyceride, as illustrated in Table 6.
The proportion of patients with categorical increases in total cholesterol or fasting triglyceride increased with the duration of exposure. The median duration of clozapine and chlorpromazine exposure was 45 days and 38 days, respectively.
The clozapine dose range was 100 mg to 900 mg daily; the maximum chlorpromazine dose was 1800 mg daily.
Table 5:
Mean Changes in Total Cholesterol and Triglyceride Concentration in Studies in Adult Subjects with Schizophrenia Treatment Arm Baseline Total Cholesterol Concentration (mg/dL) Change from Baseline mg/dL (%) Clozapine (N = 334) 184 +13 (7) Chlorpromazine (N = 185) 182 +15 (8) Baseline Triglyceride Concentration (mg/dL) Change from Baseline mg/dL (%) Clozapine (N = 6) 130 +71 (54) Chlorpromazine (N = 7) 110 +39 (35) Table 6: Categorical Changes in Lipid Concentrations in Studies in Adult Subjects with Schizophrenia Laboratory Parameter Category Change (at least once) from Baseline Treatment Arm N n (%) Total Cholesterol (random or fasting) Increase by ≥ 40 mg/dL Clozapine 334 111 (33) Chlorpromazine 185 46 (25) Normal (< 200 mg/dL) to High (≥ 240 mg/dL) Clozapine 222 18 (8) Chlorpromazine 132 3 (2) Borderline (200 to 239 mg/dL) to High (≥ 240 mg/dL) Clozapine 79 30 (38) Chlorpromazine 34 14 (41) Triglycerides (fasting) Increase by ≥ 50 mg/dL Clozapine 6 3 (50) Chlorpromazine 7 3 (43) Normal (< 150 mg/dL) to High (≥ 200 mg/dL) Clozapine 4 0 (0) Chlorpromazine 6 2 (33) Borderline (≥ 150 mg/dL and < 200 mg/dL) to High (≥ 200 mg/dL) Clozapine 1 1 (100) Chlorpromazine 1 0 (0) Weight Gain Weight gain has occurred with the use of antipsychotics, including clozapine.
Monitor weight during treatment with Clozapine ODT. Table 7 summarizes the data on weight gain by the duration of exposure pooled from 11 studies with clozapine and active comparators. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
7 0 0 Table 8 summarizes pooled data from 11 studies in adult subjects with schizophrenia demonstrating weight gain ≥ 7% of body weight relative to baseline. The median duration of exposure was 609, 728, and 42 days, in the clozapine, olanzapine, and chlorpromazine group, respectively.
11 Neuroleptic Malignant Syndrome Antipsychotic drugs including Clozapine ODT can cause a potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmias).
Associated findings can include elevated creatine phosphokinase (CPK), myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. , severe neutropenia, infection, heat stroke, primary CNS pathology, central anticholinergic toxicity, extrapyramidal symptoms, and drug fever).
The management of NMS should include (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy, (2) intensive symptomatic treatment and medical monitoring, and (3) treatment of co-morbid medical conditions.
There is no general agreement about specific pharmacological treatments for NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
NMS can recur. Monitor closely if restarting treatment with antipsychotics. NMS has occurred with clozapine monotherapy and with concomitant CNS-active medications, including lithium. 2) ] . Monitor for the appearance of signs and symptoms of hepatotoxicity such as fatigue, malaise, anorexia, nausea, jaundice, bilirubinemia, coagulopathy, and hepatic encephalopathy.
Perform serum tests for liver injury and consider permanently discontinuing treatment if hepatitis or transaminase elevations combined with other systemic symptoms are due to Clozapine ODT. 13 Fever During clozapine therapy, patients have experienced transient, clozapine-related fever.
The peak incidence is within the first 3 weeks of treatment. While this fever is generally benign and self-limited, it may necessitate discontinuing treatment. The fever can be associated with an increase or decrease in WBC count. 1) ] .
11) ] . 14 Pulmonary Embolism Pulmonary embolism and deep vein thrombosis have occurred in patients treated with clozapine. Consider the possibility of pulmonary embolism in patients who present with deep vein thrombosis, acute dyspnea, chest pain, or with other respiratory signs and symptoms.
Whether pulmonary embolus and deep vein thrombosis can be attributed to clozapine or some characteristic(s) of patients is not clear. 15 Anticholinergic Toxicity Clozapine ODT has potent anticholinergic effects. Treatment with Clozapine ODT can result in CNS and peripheral anticholinergic toxicity, especially at higher dosages, or in overdose situations [see Overdosage (10) ] .
Use with caution in patients with a current diagnosis or prior history of constipation, urinary retention, clinically significant prostatic hypertrophy, or other conditions in which anticholinergic effects can lead to significant adverse reactions.
1) ] . 16 Interference with Cognitive and Motor Performance Clozapine ODT can cause sedation and impairment of cognitive and motor performance. Caution patients about operating hazardous machinery, including automobiles, until they are reasonably certain that Clozapine ODT does not affect them adversely.
These reactions may be dose-related. Consider reducing the dose if they occur. 17 Tardive Dyskinesia Tardive dyskinesia (TD) has occurred in patients treated with antipsychotic drugs, including clozapine. The syndrome consists of potentially irreversible, involuntary, dyskinetic movements.
The risk of TD and the likelihood that it will become irreversible are believed to increase with greater durations of treatment and higher total cumulative doses. However, the syndrome can develop after relatively brief treatment periods at low doses.
Prescribe Clozapine ODT in a manner that is most likely to minimize the risk of developing TD. Use the lowest effective dose and the shortest duration necessary to control symptoms. Periodically assess the need for continued treatment.
Consider discontinuing treatment if TD occurs. However, some patients may require treatment with Clozapine ODT despite the presence of the syndrome. TD may remit partially or completely if treatment is discontinued. Antipsychotic treatment, itself, may suppress (or partially suppress) the signs and symptoms, and it has the potential to mask the underlying process.
The effect of symptom suppression on the long-term course of TD is unknown. 18 Patients with Phenylketonuria Phenylketonuric patients should be informed that Clozapine ODT contain phenylalanine (a component of aspartame). 90 mg phenylalanine.
59 mg phenylalanine. 38 mg phenylalanine. 18 mg phenylalanine. , stroke, transient ischemic attack), including fatalities. The mechanism for this increased risk is not known. An increased risk cannot be excluded for Clozapine ODT or other antipsychotics or other patient populations.
Clozapine ODT should be used with caution in patients with risk factors for cerebrovascular adverse reactions. 1) ] , monitor carefully for the recurrence of psychotic symptoms and adverse reactions related to cholinergic rebound, such as profuse sweating, headache, nausea, vomiting, and diarrhea.