norclozapine and Disorders-of-Excessive-Somnolence

This study compared the bioequivalence of FazaClo (clozapine orally disintegrating tablets) 100 mg to Clozaril (clozapine standard oral tablets) 100 mg after multiple doses in patients with schizophrenia.. This was a randomized, open-label, multiple-dose study in which patients with schizophrenia received FazaClo or Clozaril 100 mg twice daily for 5 days before crossing over to the alternate therapy. Blood samples were obtained at regular intervals during and after the completion of treatment, and standard pharmacokinetic parameters were calculated. Safety and patient satisfaction with FazaClo were also assessed.. Thirty-six patients were enrolled, of whom 33 completed the study and 30 were included in the steady-state analyses. All pharmacokinetic parameters for clozapine and desmethylclozapine (the major metabolite of clozapine) were similar between FazaClo and Clozaril in both the completer and steady-state populations. Geometric mean values for steady-state maximum and minimum concentrations and area under the plasma concentration-time curve for FazaClo were all within 95-105% of those for Clozarilwell within the range considered by the US FDA as acceptable for bioequivalence (80-125%). Patients also expressed a high level of satisfaction with the FazaClo orally disintegrating tablet formulation.. FazaClo produced pharmacokinetic profiles almost identical to those of Clozaril. This should provide clinicians with reassurance that patients who receive FazaClo will achieve plasma drug concentrations similar to those produced by the same daily dose of Clozaril, and that no cross-titration is necessary when switching from one of these clozapine formulations to the other.

Topics: Administration, Oral; Adolescent; Adult; Antipsychotic Agents; Area Under Curve; Clozapine; Cross-Over Studies; Disorders of Excessive Somnolence; Dose-Response Relationship, Drug; Drug Administration Schedule; Drugs, Generic; Female; Half-Life; Humans; Intestinal Obstruction; Intestine, Small; Male; Metabolic Clearance Rate; Middle Aged; Patient Dropouts; Patient Satisfaction; Schizophrenia; Sweating; Tablets; Therapeutic Equivalency

Clozapine is associated with non-neurological side effects that can be subjectively unpleasant and/or clinically serious. We sought to: (i) assess the nature and prevalence of side effects experienced by patients receiving maintenance treatment with clozapine and (ii) explore the relationship between clozapine plasma concentration and side effect burden. Patients were receiving clozapine maintenance treatment. Open questioning followed by systematic enquiry using the Antipsychotic Non-neurological Side Effects Rating Scale were used to assess side effects. Trough plasma clozapine and norclozapine concentrations were measured. One hundred and three patients participated. On open questioning, 61 patients reported a total of 117 side effects, whereas systematic enquiry identified an additional 649 side effects, with each patient reporting at least one. Clozapine plasma concentrations were significantly but weakly correlated with total Antipsychotic Non-neurological Side Effects Rating Scale score (Pearson correlation=0.29, P<0.004). Patients with a plasma clozapine concentration >0.25 mg/l were significantly more likely to have moderate/severe side effects than patients with lower plasma concentrations (63/76 vs. 12/23, chi=9.07, d.f.=1, P<0.01). The side-effect burden associated with maintenance clozapine treatment is high and the true extent can only be ascertained by systematic inquiry. The use of target plasma concentrations below those used for acute treatment should be explored as a strategy for minimizing side effects.

Topics: Adolescent; Adult; Aged; Antipsychotic Agents; Clozapine; Disorders of Excessive Somnolence; Female; Humans; Male; Middle Aged; Prevalence; Psychotic Disorders; Schizophrenia; Sexual Dysfunction, Physiological; Sialorrhea