1.1 Schizophrenia

INVEGA ®(paliperidone) Extended-Release Tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)] .

The efficacy of INVEGA ®in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults.

1.2 Schizoaffective Disorder

INVEGA ®(paliperidone) Extended-Release Tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)] .

The efficacy of INVEGA ®in schizoaffective disorder was established in two 6-week trials in adults.

2.1 Schizophrenia

2.2 Schizoaffective Disorder

The recommended dose of INVEGA ®(paliperidone) Extended-Release Tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses. This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day.

2.3 Administration Instructions

INVEGA ®can be taken with or without food.

INVEGA ®must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet.

2.4 Use with Risperidone

Concomitant use of INVEGA ®with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with INVEGA ®.

2.5 Dosage in Special Populations

5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA ®(paliperidone) is not approved for the treatment of dementia-related psychosis [see Boxed Warning] .

5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis

In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks) including fatalities compared to placebo-treated subjects. INVEGA ®was not marketed at the time these studies were performed. INVEGA ®is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warningand Warnings and Precautions (5.1)] .

5.3 Neuroleptic Malignant Syndrome

Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with antipsychotic drugs, including paliperidone. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure.

If NMS is suspected, immediately discontinue INVEGA ®and provide symptomatic treatment and monitoring.

5.4 QT Prolongation

Paliperidone causes a modest increase in the corrected QT (QTc) interval. The use of paliperidone should be avoided in combination with other drugs that are known to prolong QTc including Class 1A (e.g., quinidine, procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic medications, antipsychotic medications (e.g., chlorpromazine, thioridazine), antibiotics (e.g., gatifloxacin, moxifloxacin), or any other class of medications known to prolong the QTc interval. Paliperidone should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.

The effects of paliperidone on the QT interval were evaluated in a double-blind, active-controlled (moxifloxacin 400 mg single dose), multicenter QT study in adults with schizophrenia and schizoaffective disorder, and in three placebo- and active-controlled 6-week, fixed-dose efficacy trials in adults with schizophrenia.

In the QT study (n=141), the 8 mg dose of immediate-release oral paliperidone (n=50) showed a mean placebo-subtracted increase from baseline in QTcLD of 12.3 msec (90% CI: 8.9; 15.6) on day 8 at 1.5 hours post-dose. The mean steady-state peak plasma concentration for this 8 mg dose of paliperidone immediate-release was more than twice the exposure observed with the maximum recommended 12 mg dose of INVEGA ®(C max ss= 113 ng/mL and 45 ng/mL, respectively, when administered with a standard breakfast). In this same study, a 4 mg dose of the immediate-release oral formulation of paliperidone, for which C max ss= 35 ng/mL, showed an increased placebo-subtracted QTcLD of 6.8 msec (90% CI: 3.6; 10.1) on day 2 at 1.5 hours post-dose. None of the subjects had a change exceeding 60 msec or a QTcLD exceeding 500 msec at any time during this study.

For the three fixed-dose efficacy studies in subjects with schizophrenia, electrocardiogram (ECG) measurements taken at various time points showed only one subject in the INVEGA ®12 mg group had a change exceeding 60 msec at one time-point on Day 6 (increase of 62 msec). No subject receiving INVEGA ®had a QTcLD exceeding 500 msec at any time in any of these three studies.

5.5 Tardive Dyskinesia

Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements, may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown.

The risk of developing tardive dyskinesia and the likelihood that it will become irreversible appear to increase with duration of treatment and the cumulative dose. The syndrome can develop after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment.

Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.

Given these considerations, INVEGA ®should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response. Periodically reassess the need for continued treatment.

If signs and symptoms of tardive dyskinesia appear in a patient on INVEGA ®, drug discontinuation should be considered. However, some patients may require treatment with INVEGA ®despite the presence of the syndrome.

5.6 Metabolic Changes

Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

5.7 Hyperprolactinemia

Like other drugs that antagonize dopamine D 2receptors, paliperidone elevates prolactin levels and the elevation persists during chronic administration. Paliperidone has a prolactin-elevating effect similar to that seen with risperidone, a drug that is associated with higher levels of prolactin than other antipsychotic drugs.

Hyperprolactinemia, regardless of etiology, may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects.

Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro, a factor of potential importance if the prescription of these drugs is considered in a patient with previously detected breast cancer. An increase in the incidence of pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Nonclinical Toxicology (13.1)] . Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans, but the available evidence is too limited to be conclusive.

5.8 Potential for Gastrointestinal Obstruction

Because the INVEGA ®tablet is non-deformable and does not appreciably change in shape in the gastrointestinal tract, INVEGA ®should ordinarily not be administered to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic, for example: esophageal motility disorders, small bowel inflammatory disease, "short gut" syndrome due to adhesions or decreased transit time, past history of peritonitis, cystic fibrosis, chronic intestinal pseudo-obstruction, or Meckel's diverticulum). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of drugs in non-deformable controlled-release formulations. Because of the controlled-release design of the tablet, INVEGA ®should only be used in patients who are able to swallow the tablet whole [see Dosage and Administration (2.3)and Patient Counseling Information (17)] .

A decrease in transit time, e.g., as seen with diarrhea, would be expected to decrease bioavailability and an increase in transit time, e.g., as seen with gastrointestinal neuropathy, diabetic gastroparesis, or other causes, would be expected to increase bioavailability. These changes in bioavailability are more likely when the changes in transit time occur in the upper GI tract.

5.9 Orthostatic Hypotension and Syncope

Paliperidone can induce orthostatic hypotension and syncope in some patients because of its alpha-blocking activity. In pooled results of the three placebo-controlled, 6-week, fixed-dose trials in subjects with schizophrenia, syncope was reported in 0.8% (7/850) of subjects treated with INVEGA ®(3 mg, 6 mg, 9 mg, 12 mg) compared to 0.3% (1/355) of subjects treated with placebo.

INVEGA ®should be used with caution in patients with known cardiovascular disease (e.g., heart failure, history of myocardial infarction or ischemia, conduction abnormalities), cerebrovascular disease, or conditions that predispose the patient to hypotension (e.g., dehydration, hypovolemia, and treatment with antihypertensive medications). Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.

5.10 Falls

Somnolence, postural hypotension, motor and sensory instability have been reported with the use of antipsychotics, including INVEGA ®, which may lead to falls and, consequently, fractures or other fall-related injuries. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including INVEGA ®. Agranulocytosis has also been reported.

Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of INVEGA ®at the first sign of a clinically significant decline in WBC in the absence of other causative factors.

Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue INVEGA ®in patients with severe neutropenia (absolute neutrophil count < 1000/mm 3) and follow their WBC until recovery.

5.12 Potential for Cognitive and Motor Impairment

Somnolence, sedation, and dizziness were reported as adverse reactions in subjects treated with INVEGA ®[see Adverse Reactions (6.2)] . Antipsychotics, including INVEGA ®, have the potential to impair judgment, thinking, or motor skills. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that paliperidone therapy does not adversely affect them.

5.13 Seizures

During premarketing clinical trials in subjects with schizophrenia (the three placebo-controlled, 6-week, fixed-dose studies and a study conducted in elderly schizophrenic subjects), seizures occurred in 0.22% of subjects treated with INVEGA ®(3 mg, 6 mg, 9 mg, 12 mg) and 0.25% of subjects treated with placebo. Like other antipsychotic drugs, INVEGA ®should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

5.14 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer's dementia. INVEGA ®and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.15 Priapism

Drugs with alpha-adrenergic blocking effects have been reported to induce priapism. Priapism has been reported with INVEGA ®during postmarketing surveillance. Severe priapism may require surgical intervention.

5.16 Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing INVEGA ®to patients who will be experiencing conditions which may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

6.1 Clinical Trials Experience

The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA ®and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA ®and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis.

The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA ®-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA ®-treated subjects. [See Adverse Reactions (6)] .

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.

The safety of INVEGA ®was evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA ®in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

The safety of INVEGA ®was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA ®: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of INVEGA ®(3–12 mg once daily). Both studies included subjects who received INVEGA ®either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. 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.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of INVEGA ®; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, catatonia, ileus, priapism, somnambulism, swollen tongue, tardive dyskinesia, thrombotic thrombocytopenic purpura, urinary incontinence, urinary retention.

6.3 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.

7.1 Potential for INVEGA ®to Affect Other Drugs

Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)] , 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 (5.9)] .

Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In vitrostudies 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.

Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivodata are available and the clinical relevance is unknown.

Pharmacokinetic interaction between lithium and INVEGA ®is unlikely.

In a drug interaction study, co-administration of INVEGA ®(12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC 24hand C max,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when INVEGA ®3–15 mg/day was added to their existing valproate treatment.

7.2 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 vitrostudies 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. In vitrostudies have shown that paliperidone is a P-gp substrate.

Co-administration of INVEGA ®6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state C maxand AUC of paliperidone. This decrease is caused, to a substantial degree, by a 35% increase in renal clearance of paliperidone. A minor decrease in the amount of drug excreted unchanged in the urine suggests that there was little effect on the CYP metabolism or bioavailability of paliperidone during carbamazepine co-administration. On initiation of carbamazepine, the dose of INVEGA ®should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA ®should be re-evaluated and decreased if necessary.

Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)] . 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.

Co-administration of a single dose of INVEGA ®12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C maxand AUC of paliperidone. Dosage reduction for INVEGA ®should be considered when INVEGA ®is co-administered with valproate after clinical assessment.

Pharmacokinetic interaction between lithium and INVEGA ®is unlikely.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

Safety and effectiveness of INVEGA ®in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA ®in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial.

Safety and effectiveness of INVEGA ®for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of INVEGA ®for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied.

8.5 Geriatric Use

The safety, tolerability, and efficacy of INVEGA ®were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of INVEGA ®(3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of INVEGA ®(3 mg to 15 mg once daily) [see Clinical Studies (14)] . There were no subjects ≥ 65 years of age in the schizoaffective disorder studies.

Overall, of the total number of subjects in schizophrenia clinical studies of INVEGA ®(n=1796), including those who received INVEGA ®or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)] , who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)] .

8.6 Renal Impairment

Dosing must be individualized according to the patient's renal function status [see Dosage and Administration (2.5)] .

8.7 Hepatic Impairment

No dosage adjustment is required in patients with mild to moderate hepatic impairment. INVEGA ®has not been studied in patients with severe hepatic impairment.

8.8 Patients with Parkinson's Disease or Lewy Body Dementia

Patients with Parkinson's Disease or Dementia with Lewy Bodies can experience increased sensitivity to INVEGA ®. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

9.1 Controlled Substance

INVEGA ®(paliperidone) is not a controlled substance.

9.2 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).

9.3 Dependence

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

10.1 Human Experience

While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of INVEGA ®was 405 mg. Observed signs and symptoms included extrapyramidal symptoms and gait unsteadiness. Other potential signs and symptoms include those resulting from an exaggeration of paliperidone's known pharmacological effects, i.e., drowsiness and somnolence, tachycardia and hypotension, and QT prolongation. Torsade de pointes and ventricular fibrillation have been reported in a patient in the setting of overdose.

Paliperidone is the major active metabolite of risperidone. Overdose experience reported with risperidone can be found in the OVERDOSAGE section of the risperidone package insert.

10.2 Management of Overdosage

There is no specific antidote to paliperidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Consideration should be given to the extended-release nature of the product when assessing treatment needs and recovery. Multiple drug involvement should also be considered.

In case of acute overdose, establish and maintain an airway and ensure adequate oxygenation and ventilation. Administration of activated charcoal together with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of additive QT-prolonging effects when administered in patients with an acute overdose of paliperidone. Similarly, the alpha-blocking properties of bretylium might be additive to those of paliperidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures, such as intravenous fluids and/or sympathomimetic agents (epinephrine and dopamine should not be used, since beta stimulation may worsen hypotension in the setting of paliperidone-induced alpha blockade). In cases of severe extrapyramidal symptoms, anticholinergic medication should be administered.

Delivery System Components and Performance

INVEGA ®uses osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a capsule-shaped tablet in appearance, consists of an osmotically active trilayer core surrounded by a subcoat and semipermeable membrane. The trilayer core is composed of two drug layers containing the drug and excipients, and a push layer containing osmotically active components. There are two precision laser-drilled orifices on the drug-layer dome of the tablet. Each tablet strength has a different colored water-dispersible overcoat and print markings. In an aqueous environment, such as the gastrointestinal tract, the water-dispersible color overcoat erodes quickly. Water then enters the tablet through the semipermeable membrane that controls the rate at which water enters the tablet core, which, in turn, determines the rate of drug delivery. The hydrophilic polymers of the core hydrate and swell, creating a gel containing paliperidone that is then pushed out through the tablet orifices. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool as a tablet shell, along with insoluble core components.

12.1 Mechanism of Action

Paliperidone is the major active metabolite of risperidone. The mechanism of action of paliperidone in schizophrenia is unclear. However, the drug's therapeutic effect in schizophrenia could be mediated through a combination of central dopamine Type 2 (D 2) and serotonin Type 2 (5HT 2A) receptor antagonism.

12.2 Pharmacodynamics

In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D 2) and serotonin Type 2 (5HT 2A) receptors, with binding affinities (Ki values) of 1.6–2.8 nM for D 2and 0.8–1.2 nM for 5HT 2Areceptors. Paliperidone is also active as an antagonist at the α 1and α 2adrenergic receptors and H 1histaminergic receptors, which may explain some of the other effects of the drug. Paliperidone has no affinity for cholinergic muscarinic or β 1- and β 2-adrenergic receptors. The pharmacological activity of the (+)- and (-)- paliperidone enantiomers is qualitatively and quantitatively similar in vitro.

12.3 Pharmacokinetics

Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max) approximately 24 hours after dosing. The pharmacokinetics of paliperidone following INVEGA ®administration are dose-proportional within the available dose range. The terminal elimination half-life of paliperidone is approximately 23 hours.

Steady-state concentrations of paliperidone are attained within 4–5 days of dosing with INVEGA ®in most subjects. The mean steady-state peak:trough ratio for an INVEGA ®dose of 9 mg was 1.7 with a range of 1.2–3.1.

Following administration of INVEGA ®, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1.6 at steady state.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Schizophrenia

14.2 Schizoaffective Disorder

Storage and Handling

Store up to 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Keep out of reach of children.

Neuroleptic Malignant Syndrome (NMS)

Counsel patients about a potentially fatal adverse reaction, Neuroleptic Malignant Syndrome (NMS), that has been reported in association with administration of antipsychotic drugs. Advise patients, family members, or caregivers to contact their healthcare provider or report to the emergency room if they experience signs and symptoms of NMS, including hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia) [see Warnings and Precautions (5.3)].

Tardive Dyskinesia

Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their healthcare provider if these abnormal movements occur [see Warnings and Precautions (5.5)].

Metabolic Changes

Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Warnings and Precautions (5.6)].

Orthostatic Hypotension

Educate patients about the risk of orthostatic hypotension and syncope, particularly at the time of initiating treatment, re-initiating treatment, or increasing the dose [see Warnings and Precautions (5.9)] .

Leukopenia/Neutropenia

Advise patients with a pre-existing low WBC or a history of drug-induced leukopenia/neutropenia they should have their CBC monitored while taking INVEGA ®[see Warnings and Precautions (5.11)] .

Hyperprolactinemia

Counsel patients on signs and symptoms of hyperprolactinemia that may be associated with chronic use of INVEGA ®. Advise them to seek medical attention if they experience any of the following: amenorrhea or galactorrhea in females, erectile dysfunction or gynecomastia in males [see Warnings and Precautions (5.7)] .

Interference with Cognitive and Motor Performance

Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery, or operating a motor vehicle, until they are reasonably certain that INVEGA ®therapy does not affect them adversely [see Warnings and Precautions (5.12)] .

Priapism

Advise patients of the possibility of painful or prolonged penile erections (priapism). Instruct the patient to seek immediate medical attention in the event of priapism [see Warnings and Precautions (5.15)] .

Heat Exposure and Dehydration

Counsel patients on the importance of avoiding overheating and dehydration [see Warnings and Precautions (5.16)] .

Concomitant Medication

Advise patients to inform their healthcare providers if they are taking, or plan to take, any prescription or over-the-counter drugs, as there is a potential for interactions [see Drug Interactions (7)] .

Alcohol

Advise patients to avoid alcohol while taking INVEGA ®[see Drug Interactions (7.1)] .

Administration

Patients should be informed that INVEGA ®should be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice something that looks like a tablet in their stool [see Dosage and Administration (2.3)] .

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during treatment with INVEGA ®. Advise patients that INVEGA ®may cause extrapyramidal and/or withdrawal symptoms in a neonate. Advise patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to INVEGA ®during pregnancy [see Use in Specific Populations (8.1)] .

Lactation

Advise breastfeeding women using INVEGA ®to monitor infants for somnolence, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) and to seek medical care if they notice these signs [see Use in Specific Populations (8.2)] .

Infertility

Advise females of reproductive potential that INVEGA ®may impair fertility due to an increase in serum prolactin levels. The effects on fertility are reversible [see Use in Specific Populations (8.3)].