CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4- methyl-1-piperazinyl)-5H-dibenzo [b,e] [1,4] diazepine.
CLOZARIL is available in pale yellow tablets of 25 mg, 50 mg, 100 mg and 200 mg for oral administration.
Active Ingredient: clozapine.
Inactive Ingredients are colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.
Treatment-Resistant Schizophrenia: CLOZARIL is indicated for the treatment of severely ill patients with schizophrenia who fail to respond adequately to standard antipsychotic treatment. Because of the risks of severe neutropenia and of seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to standard antipsychotic treatment.
Reduction in the Risk of Recurrent Suicidal Behavior in Schizophrenia or Schizoaffective Disorder: CLOZARIL 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.
Mechanism of Action
The mechanism of action of clozapine is unknown. However, it has been proposed that the therapeutic efficacy of clozapine in schizophrenia is mediated through antagonism of the dopamine type 2 (D2) and the serotonin type 2A (5- HT2A) receptors. CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and other dopaminergic and serotonergic receptors.
Clozapine demonstrated binding affinity to the following receptors: histamine H1 (Ki 1.1 nM), adrenergic α1A (Ki 1.6 nM), serotonin 5-HT6 (Ki 4 nM), serotonin 5-HT2A (Ki 5.4 nM), muscarinic M1 (Ki 6.2 nM), serotonin 5-HT7 (Ki 6.3 nM), serotonin 5-HT2C (Ki 9.4 nM), dopamine D4 (Ki 24 nM), adrenergic α2A (Ki 90 nM), serotonin 5-HT3 (Ki 95 nM), serotonin 5-HT1A (Ki 120 nM), dopamine D2 (Ki 160 nM), dopamine D1 (Ki 270 nM), dopamine D5 (Ki 454 nM), and dopamine D3 (Ki 555 nM).
Clozapine causes little or no prolactin elevation.
Clinical electroencephalogram (EEG) studies demonstrated that clozapine increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs. Sharp wave activity and spike and wave complexes may also develop. Patients have reported an intensification of dream activity during clozapine therapy. REM sleep was found to be increased to 85% of the total sleep time. In these patients, the onset of REM sleep occurred almost immediately after falling asleep.
Absorption: In humans, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a CLOZARIL solution. Following oral administration of CLOZARIL 100 mg twice daily, the average steady-state peak plasma concentration was 319 ng/mL (range: 102 to 771 ng/mL), occurring at the average of 2.5 hours (range: 1 to 6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41 to 343 ng/mL), after 100 mg twice daily dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food.
Distribution: Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine and other highly proteinbound drugs has not been fully evaluated but may be important.
Metabolism and Excretion: Clozapine is almost completely metabolized prior to excretion, and only trace amounts of unchanged drug are detected in the urine and feces. Clozapine is a substrate for many cytochrome P450 isozymes, in particular CYP1A2, CYP2D6, and CYP3A4. Approximately 50% of the administered dose is excreted in the urine and 30% in the feces. The demethylated, hydroxylated, and N-oxide derivatives are components in both urine and feces.
Pharmacological testing has shown the desmethyl metabolite (norclozapine) to have only limited activity, while the hydroxylated and N-oxide derivatives were inactive. The mean elimination half-life of clozapine after a single 75 mg dose was 8 hours (range: 4 to 12 hours), compared to a mean elimination half-life of 12 hours (range: 4 to 66 hours), after achieving steady state with 100 mg twice daily dosing.
A comparison of single-dose and multiple-dose administration of clozapine demonstrated that the elimination half-life increased significantly after multiple dosing relative to that after single-dose administration, suggesting the possibility of concentration-dependent pharmacokinetics. However, at steady state, approximately dose-proportional changes with respect to AUC (area under the curve), peak, and minimum clozapine plasma concentrations were observed after administration of 37.5, 75, and 150 mg twice daily.
CLOZARIL (clozapine) is available as 25 mg, 50 mg and 100 mg round, pale-yellow, uncoated tablets with a facilitated score on one side. Clozaril (clozapine) 200 mg tablets are capsule-shaped, pale yellow, uncoated tablets with a facilitated score on one side.
The starting dose is 12.5 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 achieve 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 once weekly or twice weekly, in increments of up to 100 mg. The maximum dose is 900 mg per day. To minimize the risk of orthostatic hypotension, bradycardia, and syncope, it is necessary to use this low starting dose, gradual titration schedule, and divided dosages.
Generally, patients responding to CLOZARIL should continue maintenance treatment on their effective dose beyond the acute episode.
When restarting CLOZARIL in patients who have discontinued CLOZARIL (i.e., 2 days or more since the last dose), reinitiate with 12.5 mg once daily or twice daily. This is necessary to minimize the risk of hypotension, bradycardia, and syncope. If that dose is well-tolerated, the dose may be increased to the previously therapeutic dose more quickly than recommended for initial treatment.
CLOZARIL is contraindicated in patients with a history of serious hypersensitivity to clozapine (e.g., photosensitivity, vasculitis, erythema multiforme, or Stevens-Johnson Syndrome) or any other component of CLOZARIL.
Warnings and precautions
CLOZARIL treatment has caused severe neutropenia, defined as an absolute neutrophil count (ANC) less than 500/µL. Severe neutropenia can lead to serious infection and death. Prior to initiating treatment with CLOZARIL a baseline ANC must be at least 1500/µL for the general population; and must be at least 1000/µL for patients with documented Benign Ethnic Neutropenia (BEN). During treatment, patients must have regular ANC monitoring. Advise patients to immediately report symptoms consistent with severe neutropenia or infection (e.g., fever, weakness, lethargy, or sore throat)
Orthostatic Hypotension, Bradycardia, Syncope
Orthostatic hypotension, bradycardia, syncope, and cardiac arrest have occurred with CLOZARIL treatment. The risk is highest during the initial titration period, particularly with rapid dose escalation. These reactions can occur with the first dose, with doses as low as 12.5 mg per day. Initiate treatment at 12.5 mg once or twice daily; titrate slowly; and use divided dosages. Use CLOZARIL cautiously in patients with cardiovascular or cerebrovascular disease or conditions predisposing to hypotension (e.g., dehydration, use of antihypertensive medications)
Seizures have occurred with CLOZARIL treatment. The risk is dose-related. Initiate treatment at 12.5 mg, titrate gradually, and use divided dosing. Use caution when administering CLOZARIL to patients with a history of seizures or other predisposing risk factors for seizure (CNS pathology, medications that lower the seizure threshold, alcohol abuse). Caution patients about engaging in any activity where sudden loss of consciousness could cause serious risk to themselves or others
Myocarditis, Cardiomyopathy and Mitral Valve Incompetence
Fatal myocarditis and cardiomyopathy have occurred with CLOZARIL treatment. Discontinue CLOZARIL and obtain a cardiac evaluation upon suspicion of these reactions. Generally, patients with CLOZARIL-related myocarditis or cardiomyopathy should not be rechallenged with CLOZARIL. Consider the possibility of myocarditis or cardiomyopathy if chest pain, tachycardia, palpitations, dyspnea, fever, flu-like symptoms, hypotension, or ECG changes occur
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. CLOZARIL is not approved for use in patients with dementia-related psychosis.
- Severe Neutropenia
- Orthostatic Hypotension, Bradycardia, and Syncope
- Myocarditis, Cardiomyopathy, and Mitral Valve Incompetence
- Increased Mortality in Elderly Patients with Dementia-Related Psychosis
- Gastrointestinal Hypomotility with Severe Complications
- QT Interval Prolongation
- Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain)
- Neuroleptic Malignant Syndrome
- Pulmonary Embolism
- Anticholinergic Toxicity
- Interference with Cognitive and Motor Performance
- Tardive Dyskinesia
- Cerebrovascular Adverse Reactions
- Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation
Pregnancy: Pregnancy Category B. There are no adequate or well-controlled studies of clozapine in pregnant women.
Nursing Mothers: CLOZARIL is present in human milk. Because of the potential for serious adverse reactions in nursing infants from CLOZARIL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric Use: Safety and effectiveness in pediatric patients have not been established.
The most commonly reported signs and symptoms associated with clozapine overdose are: sedation, delirium, coma, tachycardia, hypotension, respiratory depression or failure; and hypersalivation. There are reports of aspiration pneumonia, cardiac arrhythmias, and seizure. Fatal overdoses have been reported with clozapine, generally at doses above 2500 mg. There have also been reports of patients recovering from overdoses well in excess of 4 g.
There is no available specific antidote to an overdose of CLOZARIL. Establish and maintain an airway; ensure adequate oxygenation and ventilation. Monitor cardiac status and vital signs. Use general symptomatic and supportive measures. Consider the possibility of multiple-drug involvement. Contact a Certified Poison Control Center for the most up to date information on the management of overdosage (1-800- 222-1222).