BOXED WARNING
1. AGRANULOCYTOSIS
BECAUSE OF A SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE -THREATENING ADVERSE EVENT, CLOZARIL ® (CLOZAPINE) SHOULD BE RESERVED FOR USE IN (1) THE TREATMENT OF SEVERELY ILL PATIENTS WITH SCHIZOPHRENIA WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD ANTIPSYCHOTIC DRUG TREATMENT, OR (2) FOR REDUCING THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR.
PATIENTS BEING TREATED WITH CLOZAPINE MUST HAVE A BASELINE WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) BEFORE INITIATION OF TREATMENT AS WELL AS REGULAR WBC COUNTS AND ANCs DURING TREATMENT AND FOR AT LEAST 4 WEEKS AFTER DISCONTINUATION OF TREATMENT (SEE WARNINGS).
CLOZAPINE IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WBC COUNT AND ANC ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION (SEE WARNINGS).
2. SEIZURES
SEIZURES HAVE BEEN ASSOCIATED WITH THE USE OF CLOZAPINE. DOSE APPEARS TO BE AN IMPORTANT PREDICTOR OF SEIZURE, WITH A GREATER LIKELIHOOD AT HIGHER CLOZAPINE DOSES. CAUTION SHOULD BE USED WHEN ADMINISTERING CLOZAPINE TO PATIENTS HAVING A HISTORY OF SEIZURES OR OTHER PREDISPOSING FACTORS. PATIENTS SHOULD BE ADVISED NOT TO ENGAGE IN ANY ACTIVITY WHERE SUDDEN LOSS OF CONSCIOUSNESS COULD CAUSE SERIOUS RISK TO THEMSELVES OR OTHERS. (SEE WARNINGS.)
3. MYOCARDITIS
ANALYSES OF POSTMARKETING SAFETY DATABASES SUGGEST THAT CLOZAPINE IS ASSOCIATED WITH AN INCREASED RISK OF FATAL MYOCARDITIS, ESPECIALLY DURING, BUT NOT LIMITED TO, THE FIRST MONTH OF THERAPY. IN PATIENTS IN WHOM MYOCARDITIS IS SUSPECTED, CLOZAPINE TREATMENT SHOULD BE PROMPTLY DISCONTINUED. (SEE WARNINGS.)
4. OTHER ADVERSE CARDIOVASCULAR AND RESPIRATORY EFFECTS
ORTHOSTATIC HYPOTENSION, WITH OR WITHOUT SYNCOPE, CAN OCCUR WITH CLOZAPINE TREATMENT. RARELY, COLLAPSE CAN BE PROFOUND AND BE ACCOMPANIED BY RESPIRATORY AND/OR CARDIAC ARREST. ORTHOSTATIC HYPOTENSION IS MORE LIKELY TO OCCUR DURING INITIAL TITRATION IN ASSOCIATION WITH RAPID DOSE ESCALATION. IN PATIENTS WHO HAVE HAD EVEN A BRIEF INTERVAL OFF CLOZAPINE, i.e., 2 OR MORE DAYS SINCE THE LAST DOSE, TREATMENT SHOULD BE STARTED WITH 12.5 mg ONCE OR TWICE DAILY. (SEE WARNINGS and DOSAGE AND ADMINISTRATION.)
SINCE COLLAPSE, RESPIRATORY ARREST AND CARDIAC ARREST DURING INITIAL TREATMENT HAS OCCURRED IN PATIENTS WHO WERE BEING ADMINISTERED BENZODIAZEPINES OR OTHER PSYCHOTROPIC DRUGS, CAUTION IS ADVISED WHEN CLOZAPINE IS INITIATED IN PATIENTS TAKING A BENZODIAZEPINE OR ANY OTHER PSYCHOTROPIC DRUG. (SEE WARNINGS.)
5. 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. ANALYSES OF SEVENTEEN PLACEBO -CONTROLLED TRIALS (MODAL DURATION OF 10 WEEKS) , LARGELY IN PATIENTS TAKING ATYPICAL ANTIPSYCHOTIC DRUGS, REVEALED A RISK OF DEATH IN THE DRUG -TREATED PATIENTS OF BETWEEN 1.6 TO 1.7 TIMES THE RISK OF DEATH IN PLACEBO -TREATED PATIENTS. OVER THE COURSE OF A TYPICAL 10 -WEEK CONTROLLED TRIAL, THE RATE OF DEATH IN DRUG -TREATED PATIENTS WAS ABOUT 4.5%, COMPARED TO A RATE OF ABOUT 2.6% IN THE PLACEBO GROUP. ALTHOUGH THE CAUSES OF DEATH WERE VARIED, MOST OF THE DEATHS APPEARED TO BE EITHER CARDIOVASCULAR (e.g., HEART FAILURE, SUDDEN DEATH) OR INFECTIOUS (e.g., PNEUMONIA) IN NATURE. OBSERVATIONAL STUDIES SUGGEST THAT, SIMILAR TO ATYPICAL ANTIPSYCHOTIC DRUGS, TREATMENT WITH CONVENTIONAL ANTIPSYCHOTIC DRUGS MAY INCREASE MORTALITY. 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. CLOZARIL ® (CLOZAPINE) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA -RELATED PSYCHOSIS.
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CLOZARIL SUMMARY
BOXED WARNING
CLOZARIL® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, 8-chloro-11-(4-methyl-1-piperazinyl)-5
H
-dibenzo [
b,e
] [1,4] diazepine.
CLOZARIL® (clozapine) is indicated for the following:
TREATMENT-RESISTANT SCHIZOPHRENIA
CLOZARIL® (clozapine) is indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia. Because of the significant risk of agranulocytosis and seizure associated with its use, CLOZARIL should be used only in patients who have failed to respond adequately to treatment with appropriate courses of standard drug treatments for schizophrenia, either because of insufficient effectiveness or the inability to achieve an effective dose due to intolerable adverse effects from those drugs. (See WARNINGS.)
The effectiveness of CLOZARIL in a treatment resistant schizophrenic population was demonstrated in a 6-week study comparing CLOZARIL and chlorpromazine. Patients meeting DSM-III criteria for schizophrenia and having a mean BPRS total score of 61 were demonstrated to be treatment resistant by history and by open, prospective treatment with haloperidol before entering into the double-blind phase of the study. The superiority of CLOZARIL to chlorpromazine was documented in statistical analyses employing both categorical and continuous measures of treatment effect.
Because of the significant risk of agranulocytosis 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 should ordinarily be avoided. In addition, the need for continuing treatment in patients exhibiting beneficial clinical responses should be periodically re-evaluated.
REDUCTION IN THE RISK OF RECURRENT SUICIDAL BEHAVIOR IN SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDERS
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 puts him/herself at risk for death.
The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was demonstrated over a 2-year treatment period in the InterSePT Trial (see Clinical Trial Data under CLINICAL PHARMACOLOGY). Therefore, CLOZARIL treatment to reduce the risk of suicidal behavior should be continued for at least 2 years (see DOSAGE AND ADMINISTRATION).
The prescriber should be aware that a majority of patients in both treatment groups in InterSePT received other treatments as well to reduce suicide risk, such as antidepressants and other medications, hospitalization, and/or psychotherapy. The contributions of these additional measures are unknown.
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NEWS HIGHLIGHTSMedia Articles Related to Clozaril (Clozapine)
Minimal Relationship Between Cannabis And Schizophrenia Or Psychosis Suggested By New UK Study
Source: Schizophrenia News From Medical News Today [2009.10.24]
Last year the UK government reclassified cannabis from a class C to a class B drug, partly out of concerns that cannabis, especially the more potent varieties, may increase the risk of schizophrenia in young people. But the evidence for the relationship between cannabis and schizophrenia or psychosis remains controversial. A new study has determined that it may be necessary to stop thousands of cannabis users in order to prevent a single case of schizophrenia.
Unlocking Mysteries Of The Brain With PET
Source: MRI / PET / Ultrasound News From Medical News Today [2009.11.04]
Inflammatory response of brain cells-as indicated by a molecular imaging technique-could tell researchers more about why certain neurologic disorders, such as migraine headaches and psychosis in schizophrenic patients, occur and provide insight into how to best treat them, according to two studies published in the November issue of The Journal of Nuclear Medicine.
Molecular Imaging Pinpoints Inflammation In The Brains Of Schizophrenics And Migraine Sufferers
Source: Headache / Migraine News From Medical News Today [2009.11.02]
Inflammatory response of brain cells - as indicated by a molecular imaging technique - could tell researchers more about why certain neurologic disorders, such as migraine headaches and psychosis in schizophrenic patients, occur and provide insight into how to best treat them, according to two studies published in the November issue of The Journal of Nuclear Medicine.
Published Studies Related to Clozaril (Clozapine)
Treatment of clozapine-induced hypersalivation with ipratropium bromide: a randomized, double-blind, placebo-controlled crossover study. [2009.08]
CONCLUSIONS: Despite the reports of some preliminary studies that ipratropium is an efficacious treatment for CIH, ipratropium failed to demonstrate significant clinical effect in comparison to placebo. Further research should explore the efficacy of other locally acting anticholinergic agents or other classes of medications. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00381589. 2009 Physicians Postgraduate Press, Inc.
Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study. [2009.08]
This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or= 80, and CGI-S score >or= 4...
Extended release metformin for metabolic control assistance during prolonged clozapine administration: a 14 week, double-blind, parallel group, placebo-controlled study. [2009.08]
BACKGROUND: Clozapine is the most effective agent in treatment-resistant schizophrenia. However, it is frequently associated with excessive body weight (BW) gain, type 2 diabetes mellitus and hyperlipidemia. The antidiabetic metformin (MET) has proved effective to assist in BW control during olanzapine administration. Therefore, we aimed to test whether MET may improve the metabolic profile in patients under prolonged clozapine administration... CONCLUSIONS: MET improves metabolic control during prolonged clozapine administration.
The efficacies of clozapine and haloperidol in refractory schizophrenia are related to DTNBP1 variation. [2009.06]
OBJECTIVE: The prototypical atypical antipsychotic agent, clozapine, is more efficacious for refractory schizophrenia than the 'typical' antipsychotics, but the mechanism underlying this enhanced efficacy is still under investigation. Since 2002, at least 22 association studies have shown that the DTNBP1 can be associated with the risk for schizophrenia. We hypothesized that DTNBP1 might also influence the response to antipsychotic treatments. This study aimed to investigate the relationship between the DTNBP1 and the effects of clozapine and haloperidol on refractory schizophrenia... CONCLUSION: This study shows that the DTNBP1 gene modulates the effects of both the atypical antipsychotic clozapine and the typical antipsychotic haloperidol. Participants with different DTNBP1 diplotypes, haplotypes, genotypes, or alleles might have different responses to these antipsychotics.
A double-blind, placebo-controlled trial of rosiglitazone for clozapine-induced glucose metabolism impairment in patients with schizophrenia. [2009.06]
CONCLUSION: Rosiglitazone may have a role in addressing insulin resistance and lipid abnormalities associated with clozapine.
Clinical Trials Related to Clozaril (Clozapine)
FazaClo Outcomes in the Control of Schizophrenia (FOCUS) Study Survey [Completed]
AZUR Pharma has received several reports from practicing psychiatrists prescribing FazaClo
showing that FazaClo patients start losing body weight instead of keep gaining it, after
being switched from other clozapine products or other atypical antipsychotics treatments.
Another important clinical observation reported by doctors is a considerable reduction in
hypersalivation when FazaClo administration is compared to other antipsychotic treatments.
Based on the findings described above, and on the real need for effective and safer
treatments for schizophrenia, AZUR Pharma has decided to design and conduct an observational
study in a large number of patients taking FazaClo to prove the received clinical reports
from physicians. Better understanding and evaluation of these beneficial findings are
necessary to provide physicians information for improved treatment decision.
A Study to Evaluate the Safety and Efficacy of Clozapine in Patients With Treatment-Resistant Schizophrenia [Active, not recruiting]
Clozapine is an antipsychotic. This 24-week study will evaluate the safety and efficacy of
clozapine in patients with treatment-resistant schizophrenia.
This study is not recruiting in the United States.
A Long Term Study of Clozapine in Patients With Treatment-Resistant Schizophrenia [Active, not recruiting]
Clozapine is an antipsychotic. This open study will evaluate the safety and efficacy of long
term treatment of clozapine in patients with treatment-resistant schizophrenia.
Equivalence of Generic Clozapine to Orally Dissolving Clozapine in Schizophrenia or Schizoaffective Disorder [Recruiting]
Alcoholism and Schizophrenia: Effects of Clozapine [Terminated]
The purpose of this study is to examine the short – term effects of clozapine on alcohol use
in persons with schizophrenia and an alcohol use disorder. The hypothesis is that clozapine
will have greater efficacy in reducing alcohol use than other antipsychotic medications.
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Page last updated: 2009-11-04
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