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Clozaril (Clozapine) - Summary

 
 



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.

 

CLOZARIL SUMMARY

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.


See all Clozaril indications & dosage >>

NEWS HIGHLIGHTS

Media Articles Related to Clozaril (Clozapine)

New Drug Shows Early Promise in Treating Parkinson's Psychosis
Source: MedicineNet clozapine Specialty [2013.11.01]
Title: New Drug Shows Early Promise in Treating Parkinson's Psychosis
Category: Health News
Created: 10/31/2013 7:36:00 PM
Last Editorial Review: 11/1/2013 12:00:00 AM

more news >>

Published Studies Related to Clozaril (Clozapine)

Choice of randomization to clozapine versus other second generation antipsychotics in the CATIE schizophrenia trial. [2012]
There is evidence to suggest that clozapine is underutilized in treatment-refractory schizophrenia. Data from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE), a multi-phase, randomized comparative effectiveness trial for schizophrenia, were used to identify factors associated with choosing randomization to clozapine...

Effects of sertindole on cognition in clozapine-treated schizophrenia patients. [2012]
CONCLUSION: The clozapine-treated patients displayed marked cognitive deficits at

Augmentation of clozapine with a second antipsychotic - a meta-analysis. [2012]
CONCLUSION: Augmentation with a second antipsychotic is modestly beneficial in

Pharmacological augmentation strategies for schizophrenia patients with insufficient response to clozapine: a quantitative literature review. [2012]
treatment in schizophrenia spectrum disorder... CONCLUSIONS: Evidence for efficacy of clozapine augmentation is currently scarce.

Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial. [2011.11]
Antidepressant drugs have often been used as an augmentation strategy for those patients who have demonstrated a suboptimal response to clozapine. The present 16-week double-blind, randomized, placebo-controlled trial study aimed to explore the efficacy and tolerability of duloxetine add-on pharmacotherapy on clinical symptomatology and executive cognitive functioning in a sample of patients with treatment-resistant schizophrenia receiving clozapine.

more studies >>

Clinical Trials Related to Clozaril (Clozapine)

Treat Clozapine-Resistant Schizophrenia Comparing Between Clozapine + Haloperidol Versus Clozapine + Electroconvulsive Therapy (ECT) [Recruiting]
Clozapine treatment resistant schizophrenia is still prevalent. The effectiveness of augmenting clozapine : one augmenting with haloperidol and the other with electroconvulsive therapy should be determined. This study is a randomized control trial.

Clozapine Versus Amisulpride in Treatment-resistant Schizophrenia Patients [Recruiting]
Background: schizophrenia is a debilitating mental disorder affecting about 1% of the general population. About 30% of patients will not react to current drug treatment and defined as treatment-resistant schizophrenia patients (TRSP). The best studied therapeutic option for this population is clozapine therapy. Clozapine was shown to be effective than any other antipsychotic drug in TRSP. Moreover, augmentation of clozapine was not demonstrated to be more effective than clozapine monotherapy. Albeit Clozapine superiority in TRSP, its use may be involved with many adverse effects, some of them are life-threatening, and need for routine blood tests. Amisulpride is an atypical antipsychotic drug with a different mechanism of action than clozapine, with less adverse effects. No study compared directly amisulpride and clozapine in TRSP.

Study objective: to compare, for the first time, the broad clinical effectiveness of clozapine and amisulpride and their combination in TRSP.

Study Design: a clinical, prospective, naturalistic, randomized, comparative study simulating a real-world approach of clinical decision making.

Methods: a total of 140 TRSP will be recruited from a large regional mental health center. Participants will be randomized into two treatment groups (70 in each group): clozapine monotherapy and amisulpride monotherapy. Assessment will be done following 10 and 20 weeks of treatment. In case of treatment failure (insufficient clinical response or severe adverse effect) participants will be offered either to switch to clozapine treatment (for failed amisulpride treatment) or to augment clozapine with amisulpride (for failed clozapine monotherapy patients). Thereafter, participants will be followed-up for a year. Assessment will be made using clinician rated scales and self-completed questionnaires, rating the broad phenomenology of schizophrenia (psychosis, mood, anxiety, obsessive-compulsive, cognitive and quality of life) and drug-related adverse effects (objective and subjective).

Analysis: comparison of the effectiveness of the three treatment groups: amisulpride, clozapine and their combination, in the various dimensions of TRSP.

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.

Clozapine for Cannabis Use in Schizophrenia [Not yet recruiting]
Many individuals with schizophrenia also suffer from marijuana addiction that worsens their problems related to schizophrenia. Most of the medications prescribed for schizophrenia have no effect on reducing marijuana use. Preliminary data suggests that clozapine, an atypical antipsychotic, may limit marijuana use in people diagnosed with schizophrenia, but it is not commonly used due to its side effects and is reserved for people who do not respond to other antipsychotic medications.

In the proposed study, 132 individuals who are diagnosed with both schizophrenia and a cannabis use disorder will be randomized to a 12-week treatment course with either clozapine or risperidone (another commonly prescribed antipsychotic medication) to test the hypothesis that patient treated with clozapine will have decreased cannabis use as compared to patients treated with risperidone.

Should this study indicate that clozapine will lessen marijuana use in persons diagnosed with schizophrenia more than risperidone, it will provide evidence needed to begin to shift clinical practice toward its use in this population.

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.

more trials >>

Reports of Suspected Clozaril (Clozapine) Side Effects

White Blood Cell Count Increased (651)White Blood Cell Count Decreased (523)Neutrophil Count Increased (513)Death (423)Neutrophil Count Decreased (407)Platelet Count Decreased (398)Malaise (352)Neutropenia (345)Haemoglobin Decreased (310)Pyrexia (235)more >>


Page last updated: 2013-11-01

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