Clozaril, Page 1

Clozaril® (clozapine), an atypical antipsychotic drug, is a tricyclic dibenzodiazepine derivative, indicated for the management of severely ill schizophrenic patients who fail to respond adequately to standard drug treatment for schizophrenia.

CLOZARIL- clozapine tablet
Cardinal Health

CLOZARIL ®

( clozapine ) Tablets

Rx only

Prescribing Information

Before prescribing CLOZARIL® (clozapine), the physician should be thoroughly familiar with the details of this prescribing information.

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 (see WARNINGS ).

DESCRIPTION

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.

The structural formula is

CLOZARIL (clozapine) structural formula

CLOZARIL is available in pale yellow tablets of 25 mg and 100 mg for oral administration.

25 mg and 100 mg Tablets

Active Ingredient: clozapine is a yellow, crystalline powder, very slightly soluble in water.

Inactive Ingredients: colloidal silicon dioxide, lactose, magnesium stearate, povidone, starch (corn), and talc.

CLINICAL PHARMACOLOGY

Pharmacodynamics

CLOZARIL® (clozapine) is classified as an ‘atypical’ antipsychotic drug because its profile of binding to dopamine receptors and its effects on various dopamine-mediated behaviors differ from those exhibited by more typical antipsychotic drug products. In particular, although CLOZARIL does interfere with the binding of dopamine at D1, D2, D3 and D5 receptors, and has a high affinity for the D4 receptor, it does not induce catalepsy nor inhibit apomorphine-induced stereotypy. This evidence, consistent with the view that CLOZARIL is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of CLOZARIL from extrapyramidal side effects.

CLOZARIL also acts as an antagonist at adrenergic, cholinergic, histaminergic and serotonergic receptors.

Absorption, Distribution, Metabolism and Excretion

In man, CLOZARIL tablets (25 mg and 100 mg) are equally bioavailable relative to a clozapine solution. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 319 ng/mL (range: 102-771 ng/mL), occurring at the average of 2.5 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 122 ng/mL (range: 41-343 ng/mL), after 100 mg b.i.d. dosing. Food does not appear to affect the systemic bioavailability of CLOZARIL. Thus, CLOZARIL may be administered with or without food.

Clozapine is approximately 97% bound to serum proteins. The interaction between CLOZARIL and other highly protein-bound drugs has not been fully evaluated but may be important. (See PRECAUTIONS.)

Clozapine is almost completely metabolized prior to excretion and only trace amounts of unchanged drug are detected in the urine and feces. 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 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: 4-12 hours), compared to a mean elimination half-life, after achieving steady state with 100 mg b.i.d. dosing, of 12 hours (range: 4-66 hours). A comparison of single-dose and multiple-dose administration of clozapine showed 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, linearly dose-proportional changes with respect to AUC (area under the curve), peak and minimum clozapine plasma concentrations were observed after administration of 37.5 mg, 75 mg, and 150 mg b.i.d.

Human Pharmacology

In contrast to more typical antipsychotic drugs, CLOZARIL therapy produces little or no prolactin elevation.

As is true of more typical antipsychotic drugs, clinical EEG studies have shown that CLOZARIL increases delta and theta activity and slows dominant alpha frequencies. Enhanced synchronization occurs, and sharp wave activity and spike and wave complexes may also develop. Patients, on rare occasions, may report an intensification of dream activity during CLOZARIL 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.

Clinical Trial Data (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)

The effectiveness of CLOZARIL in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™), which was a prospective, randomized, international, parallel-group comparison of CLOZARIL vs. Zyprexa®* (olanzapine) in patients with schizophrenia or schizoaffective disorder (DSM-IV) who were judged to be at risk for reexperiencing suicidal behavior. Only about one-fourth of these patients (27%) were considered resistant to standard antipsychotic drug treatment, and the remainder were not. Patients met one of the following criteria:

  • They had attempted suicide within the 3 years prior to their baseline evaluation.
  • They had been hospitalized to prevent a suicide attempt within the 3 years prior to their baseline evaluation.
  • They demonstrated moderate-to-severe suicidal ideation with a depressive component within 1 week prior to their baseline evaluation.
  • They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within 1 week prior to their baseline evaluation.

Dosing regimens for each treatment group were determined by individual investigators and were individualized by patient. Dosing was flexible, with a dose range of 200-900 mg/day for CLOZARIL and 5-20 mg/day for Zyprexa. For the 956 patients who received CLOZARIL or Zyprexa in this study, there was extensive use of concomitant psychotropics: 84% with antipsychotics; 65% with anxiolytics; 53% with antidepressants, and 28% with mood stabilizers. There was significantly greater use of concomitant psychotropic medications among the patients in the Zyprexa group.

The primary efficacy measure was time to (1) a significant suicide attempt, including a completed suicide, (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized), or (3) worsening of suicidality severity as demonstrated by “much worsening” or “very much worsening” from baseline in the Clinical Global Impression of Severity of Suicidality as assessed by the Blinded Psychiatrist (CGI-SS-BP) scale. A determination of whether or not a reported event met criterion 1 or 2 above was made by the Suicide Monitoring Board (SMB, a group of experts blinded to patient data).

A total of 980 patients were randomized to the study and 956 received study medication. Sixty-two percent of the patients were diagnosed with schizophrenia, and the remainder (38%) were diagnosed with schizoaffective disorder. Only about one-fourth of the total patient population (27%) was identified as “treatment resistant” at baseline. There were more males than females in the study (61% of all patients were male). The mean age of patients entering the study was 37 years (range 18-69). Most patients were Caucasian (71%), 15% were Black, 1% were Oriental, and 13% were classified as being of “other” races.

Data from this study indicate that CLOZARIL had a statistically significant longer delay in the time to recurrent suicidal behavior in comparison with Zyprexa. This result should be interpreted only as evidence of the effectiveness of CLOZARIL in delaying time to recurrent suicidal behavior, and not a demonstration of the superior efficacy of CLOZARIL over Zyprexa.

The probability of experiencing (1) a significant suicide attempt, including a completed suicide, or (2) hospitalization due to imminent suicide risk (including increased level of surveillance for suicidality for patients already hospitalized) was lower for CLOZARIL patients than for Zyprexa patients at Week 104: CLOZARIL 24% vs. Zyprexa 32%; 95% C.I. of the difference: 2%, 14% (Figure 1).

Figure 1. Kaplan Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide.
(click image for full-size original)

Figure 1: Kaplan-Meier Estimates of Cumulative Probability of a Significant Suicide Attempt or Hospitalization to Prevent Suicide.

INDICATIONS AND USAGE

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 reevaluated.

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 reexperiencing 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.

CONTRAINDICATIONS

CLOZARIL® (clozapine) is contraindicated in patients with a previous hypersensitivity to clozapine or any other component of this drug, in patients with myeloproliferative disorders, uncontrolled epilepsy, paralytic ileus, or a history of CLOZARIL-induced agranulocytosis or severe granulocytopenia. As with more typical antipsychotic drugs, CLOZARIL is contraindicated in severe central nervous system depression or comatose states from any cause.

CLOZARIL should not be used simultaneously with other agents having a well-known potential to cause agranulocytosis or otherwise suppress bone marrow function. The mechanism of CLOZARIL-induced agranulocytosis is unknown; nonetheless, it is possible that causative factors may interact synergistically to increase the risk and/or severity of bone marrow suppression.

WARNINGS

General

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® (clozapine) IS NOT APPROVED FOR THE TREATMENT OF PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS (SEE BOXED WARNING).

AGRANULOCYTOSIS

BECAUSE OF THE SIGNIFICANT RISK OF AGRANULOCYTOSIS, A POTENTIALLY LIFE-THREATENING ADVERSE EVENT (SEE FOLLOWING), CLOZARIL® (clozapine) SHOULD BE RESERVED FOR USE IN THE FOLLOWING INDICATIONS: 1) FOR TREATMENT OF SEVERELY ILL SCHIZOPHRENIC PATIENTS WHO FAIL TO SHOW AN ACCEPTABLE RESPONSE TO ADEQUATE COURSES OF STANDARD DRUG TREATMENT FOR SCHIZOPHRENIA, EITHER BECAUSE OF INSUFFICIENT EFFECTIVENESS OR THE INABILITY TO ACHIEVE AN EFFECTIVE DOSE DUE TO INTOLERABLE ADVERSE EFFECTS FROM THOSE DRUGS. CONSEQUENTLY, BEFORE INITIATING TREATMENT WITH CLOZARIL® (clozapine); IT IS STRONGLY RECOMMENDED THAT A PATIENT BE GIVEN AT LEAST 2 TRIALS, EACH WITH A DIFFERENT STANDARD DRUG PRODUCT FOR SCHIZOPHRENIA, AT AN ADEQUATE DOSE, AND FOR AN ADEQUATE DURATION. 2) FOR REDUCING THE RISK FOR RECURRENT SUICIDAL BEHAVIOR IN PATIENTS WITH SCHIZOPHRENIA OR SCHIZOAFFECTIVE DISORDER WHO ARE JUDGED TO BE AT RISK OF REEXPERIENCING SUICIDAL BEHAVIOR.

CLOZARIL® (clozapine) IS AVAILABLE ONLY THROUGH A DISTRIBUTION SYSTEM THAT ENSURES MONITORING OF WHITE BLOOD CELL (WBC) COUNT AND ABSOLUTE NEUTROPHIL COUNT (ANC) ACCORDING TO THE SCHEDULE DESCRIBED BELOW PRIOR TO DELIVERY OF THE NEXT SUPPLY OF MEDICATION.

AS DESCRIBED IN TABLE 1, PATIENTS WHO ARE BEING TREATED WITH CLOZARIL® (clozapine) MUST HAVE A BASELINE WBC COUNT AND ANC BEFORE INITIATION OF TREATMENT, AND A WBC COUNT AND ANC EVERY WEEK FOR THE FIRST 6 MONTHS. THEREAFTER, IF ACCEPTABLE WBC COUNTS AND ANC (WBC ≥3500/mm3 and ANC ≥2000/mm3) HAVE BEEN MAINTAINED DURING THE FIRST 6 MONTHS OF CONTINUOUS THERAPY, WBC COUNTS AND ANC CAN BE MONITORED EVERY 2 WEEKS FOR THE NEXT 6 MONTHS. THEREAFTER, IF ACCEPTABLE WBC COUNTS AND ANC (WBC ≥3500/mm3 and ANC ≥2000/mm3) HAVE BEEN MAINTAINED DURING THE SECOND 6 MONTHS OF CONTINUOUS THERAPY, WBC COUNT AND ANC CAN BE MONITORED EVERY 4 WEEKS.

WHEN TREATMENT WITH CLOZARIL® (clozapine) IS DISCONTINUED (REGARDLESS OF THE REASON), WBC COUNT AND ANC MUST BE MONITORED WEEKLY FOR AT LEAST 4 WEEKS FROM THE DAY OF DISCONTINUATION OR UNTIL WBC ≥3500/mm3 AND ANC ≥2000/mm3.

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