Hepatic Impairment

In a study in subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. INVEGA® has not been studied in patients with severe hepatic impairment.

Elderly

No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and DOSAGE AND ADMINISTRATION].

Race

No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians.

Gender

No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women.

Smoking

No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Clinical Studies

The short-term efficacy of INVEGA® (3 mg to 15 mg once daily) was established in three placebo-controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without regard to meals.

Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in the domains of socially useful activities (e.g., work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors.

In all 3 studies (n = 1665), INVEGA® was superior to placebo on the PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. INVEGA® was also superior to placebo on the PSP in these trials.

An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age (there were few patients over 65), or geographic region. There were insufficient data to explore differential effects based on race.

In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically responded (defined as PANSS score ≤ 70 or ≤ 4 on pre-defined PANSS subscales, as well as having been on a stable fixed dose of INVEGA® for the last two weeks of an 8-week run- in phase) were entered into a 6-week open-label stabilization phase where they received INVEGA® (doses ranging from 3 mg to 15 mg once daily). After the stabilization phase, patients were randomized in a double-blind manner to either continue on INVEGA® at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly longer time to relapse in patients treated with INVEGA® compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated.

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