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Pharmacodynamics

FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) 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 FazaClo® (clozapine, USP) is preferentially more active at limbic than at striatal dopamine receptors, may explain the relative freedom of FazaClo® (clozapine, USP) from extrapyramidal side effects.

FazaClo® (clozapine, USP) also acts as an antagonist at adrenergic, cholinergic, histaminergic, and serotonergic receptors.

Absorption, Distribution, Metabolism, and Excretion

In man, clozapine tablets (25 and 100 mg) are equally bioavailable relative to a clozapine solution. FazaClo® (clozapine, USP) orally disintegrating tablets are bioequivalent to Clozaril® (clozapine) tablets, a registered trademark of Novartis Pharmaceuticals Corporation. Following a dosage of 100 mg b.i.d., the average steady-state peak plasma concentration was 413 ng/mL (range: 132-854 ng/mL), occurring at the average of 2.3 hours (range: 1-6 hours) after dosing. The average minimum concentration at steady state was 168 ng/mL (range: 45-574 ng/mL), after 100 mg b.i.d. dosing.

A comparative bioequivalence/bioavailability study was conducted in 32 patients (with schizophrenia or schizoaffective disorder) comparing FazaClo® 200 mg tablets to 2 × FazaClo® 100 mg tablets (the approved reference product) under fasted conditions. The study also evaluated the effect of food and chewing on the pharmacokinetics of the 200 mg tablet. Under fasted conditions, the mean AUCss and Cmin,ss of clozapine for the 200 mg tablets were equivalent to those of the 2 x 100 mg tablets. The mean Cmax,ss of clozapine for FazaClo® 200 mg tablets was 85% that for 2 x 100 mg FazaClo® tablets. This decrease in Cmax,ss for FazaClo® 200 mg tablets is not clinically significant.

For FazaClo® 200 mg tablets, food significantly increased the Cmin,ss of clozapine by 21%. However, this increase is not clinically significant. The mean AUCss and Cmax,ss of clozapine under fed conditions were equivalent to those under fasted conditions. Food delayed clozapine absorption by 1.5 hours, from a median Tmax of 2.5 hours under fasted conditions to 4 hours under fed conditions.

The mean Cmax,ss of clozapine under chewed conditions for FazaClo® 200 mg tablets was about 86% that for 2 x 100 mg FazaClo® tablets under non-chewed conditions, while the AUCss and Cmin,ss values were similar between the chewed and non-chewed conditions.

In a food-effect study, a single dose of FazaClo® (clozapine, USP) orally disintegrating tablets 12.5 mg was administered to healthy volunteers under fasting conditions and after a high-fat meal. When FazaClo® was administered after a high-fat meal, the Cmax of both clozapine and its active metabolite, desmethylclozapine, were decreased by approximately 20%, compared to administration under fasting conditions, while the AUC values were unchanged. This decrease in Cmax is not clinically significant. Therefore, FazaClo® (clozapine, USP) orally disintegrating tablets can be taken without regard to meals.

Clozapine is approximately 97% bound to serum proteins. The interaction between clozapine 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 (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: 4-12 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, 75, and 150 mg b.i.d.

Human Pharmacology

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

As is true of more typical antipsychotic drugs, clinical electroencephalogram (EEG) studies have shown 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, on rare occasions, may report 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.

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 clozapine in reducing the risk of recurrent suicidal behavior was assessed in the International Suicide Prevention Trial (InterSePT™, a trademark of Novartis Pharmaceuticals Corporation), which was a prospective, randomized, international, parallel-group comparison of clozapine (Clozaril®) versus olanzapine (Zyprexa®, a registered trademark of Eli Lilly and Company) 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 three years prior to their baseline evaluation.
• They had been hospitalized to prevent a suicide attempt within the three years prior to their baseline evaluation.
• They demonstrated moderate-to-severe suicidal ideation with a depressive component within one week prior to their baseline evaluation.
• They demonstrated moderate-to-severe suicidal ideation accompanied by command hallucinations to do self-harm within one 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 clozapine and 5–20 mg/day for olanzapine. For the 956 patients who received clozapine or olanzapine 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 olanzapine 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 of age (range 18–69). Most patients were Caucasian (71%), 15% were Black, 1% were Asian, and 13% were classified as being of “other” races.

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

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 clozapine patients than for olanzapine patients at Week 104: clozapine 24% versus olanzapine 32%; 95% CI (Confidence Interval) 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

Last reviewed on RxList: 1/24/2012
This monograph has been modified to include the generic and brand name in many instances.