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. Food does not appear to affect the systemic bioavailability of clozapine. Thus, FazaClo® (clozapine, USP) may be administered with or without food.

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.

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