The following are discussed in more detail in other sections of the labeling:

• Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and WARNINGS and PRECAUTIONS]
• Cerebrovascular adverse events, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS and PRECAUTIONS]
• Neuroleptic malignant syndrome [see WARNINGS and PRECAUTIONS]
• QT prolongation [see WARNINGS and PRECAUTIONS]
• Tardive dyskinesia [see WARNINGS and PRECAUTIONS]
• Hyperglycemia and diabetes mellitus [see WARNINGS and PRECAUTIONS]
• Hyperprolactinemia [seeWARNINGS and PRECAUTIONS]
• Potential for Gastrointestinal Obstruction [see WARNINGS and PRECAUTIONS]
• Orthostatic hypotension and syncope [seeWARNINGS and PRECAUTIONS]
• Potential for cognitive and motor impairment [see WARNINGS and PRECAUTIONS]
• Seizures [see WARNINGS and PRECAUTIONS]
• Dysphagia [see WARNINGS and PRECAUTIONS]
• Suicide [see WARNINGS and PRECAUTIONS]
• Priapism [see WARNINGS and PRECAUTIONS]
• Thrombotic thrombocytopenic purpura (TTP) [see WARNINGS and PRECAUTIONS]
• Disruption of body temperature regulation [see WARNINGS and PRECAUTIONS]
• Antiemetic effect [see WARNINGS and PRECAUTIONS]
• Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see WARNINGS and PRECAUTIONS]
• Diseases or conditions that could affect metabolism or hemodynamic responses [see WARNINGS and PRECAUTIONS]

The most common adverse reactions in clinical trials (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were akathisia and extrapyramidal disorder.

The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders [see ADVERSE REACTIONS].

The safety of INVEGA® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA® at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA® at daily doses within the range of 3 mg to 15 mg (n=104), is also included.

Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials

Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies, listing those that occurred in 2% or more of subjects treated with INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo.

Table 1. Adverse Reactions in Short-Term, Fixed-Dose, Placebo-Controlled Trials in Adult Subjects with Schizophrenia*

Less Commonly-Observed Adverse Reactions

The following list contains all serious and non-serious adverse reactions reported at any time by individuals taking INVEGA® during any phase of a trial within the premarketing database (n = 2720), except (1) those listed in Table 1 above or elsewhere in labeling, (2) those for which a causal relationship to INVEGA® use was considered remote, and (3) those occurring in only one subject treated with INVEGA® and that were not acutely life-threatening.

Cardiac disorders: bradycardia, palpitations

Gastrointestinal disorders: abdominal pain, swollen tongue

General disorders: edema

Immune system disorders: anaphylactic reaction

Vascular disorders: ischemia

Discontinuations Due to Adverse Reactions

The percentages of subjects who discontinued due to adverse reactions in the three placebo-controlled, 6-week, fixed-dose studies were 3% and 1% in INVEGA®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in INVEGA®- and placebo-treated subjects, respectively).

Dose-Related Adverse Reactions

Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with INVEGA®, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, Parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose.

Demographic Differences

An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies did not reveal any evidence of differences in safety on the basis of gender or race alone; there was also no difference on the basis of age [see Use in Specific Populations].

Extrapyramidal Symptoms (EPS)

Pooled data from the three placebo-controlled, 6-week, fixed-dose studies provided information regarding treatment-emergent EPS. Several methods were used to measure EPS: (1) the Simpson-Angus global score (mean change from baseline) which broadly evaluates Parkinsonism, (2) the Barnes Akathisia Rating Scale global clinical rating score (mean change from baseline) which evaluates akathisia, (3) use of anticholinergic medications to treat emergent EPS (Table 2), and (4) incidence of spontaneous reports of EPS (Table 3). For the Simpson-Angus Scale, spontaneous EPS reports and use of anticholinergic medications, there was a dose-related increase observed for the 9 mg and 12 mg doses. There was no difference observed between placebo and INVEGA® 3 mg and 6 mg doses for any of these EPS measures.

Table 2. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication

Table 3. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Laboratory Test Abnormalities

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, a between-group comparison revealed no medically important differences between INVEGA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® was associated with increases in serum prolactin [see WARNINGS and PRECAUTIONS].

Weight Gain

In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA® 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA® 9 mg and 12 mg (9% and 9%, respectively).

Other Findings Observed During Clinical Trials

The safety of INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® in adults with schizophrenia [see Clinical Studies]. In general, adverse reaction types, frequencies, and severities during the initial 14-week open-label phase of this study were comparable to those observed in the 6-week, placebo-controlled, fixed-dose studies. Adverse reactions reported during the long-term double-blind phase of this study were similar in type and severity to those observed in the initial 14-week open-label phase.

Adverse Reactions Reported With Risperidone

Paliperidone is the major active metabolite of risperidone. Adverse reactions reported with risperidone can be found in the ADVERSE REACTIONS section of the risperidone package insert.

Potential for INVEGA® to Affect Other Drugs

Given the primary CNS effects of paliperidone [see ADVERSE REACTIONS], INVEGA® should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists.

Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA® is administered with other therapeutic agents that have this potential [see WARNINGS and PRECAUTIONS].

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitro studies in human liver microsomes showed that paliperidone does not substantially inhibit the metabolism of drugs metabolized by cytochrome P450 isozymes, including CYP1A2, CYP2A6, CYP2C8/9/10, CYP2D6, CYP2E1, CYP3A4, and CYP3A5. Therefore, paliperidone is not expected to inhibit clearance of drugs that are metabolized by these metabolic pathways in a clinically relevant manner. Paliperidone is also not expected to have enzyme inducing properties.

At therapeutic concentrations, paliperidone did not inhibit P-glycoprotein. Paliperidone is therefore not expected to inhibit P-glycoprotein-mediated transport of other drugs in a clinically relevant manner.

Potential for Other Drugs to Affect INVEGA®

Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in vitro studies indicate that CYP2D6 and CYP3A4 may be minimally involved in paliperidone metabolism,in vivostudies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance.

Paliperidone is metabolized to a limited extent by CYP2D6 [see CLINICAL PHARMACOLOGY]. In an interaction study in healthy subjects in which a single 3 mg dose of INVEGA® was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown.

Drug Abuse And Dependence

Controlled Substance

INVEGA® (paliperidone) is not a controlled substance.

Abuse

Paliperidone has not been systematically studied in animals or humans for its potential for abuse. It is not possible to predict the extent to which a CNS-active drug will be misused, diverted, and/or abused once marketed. Consequently, patients should be evaluated carefully for a history of drug abuse, and such patients should be observed closely for signs of INVEGA® misuse or abuse (e.g., development of tolerance, increases in dose, drug-seeking behavior).

Dependence

Paliperidone has not been systematically studied in animals or humans for its potential for tolerance or physical dependence.

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