PALIPERIDONE

Paliperidone extended-release tablets contain paliperidone, an atypical antipsychotic belonging to the chemical class of benzisoxazole derivatives. Paliperidone extended-release tablets contains a racemic mixture of (+)- and (-)- paliperidone. The chemical name is (±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one. Its molecular formula is C 23 H 27 FN 4 O 3 and its molecular weight is 426.49. The structural formula is: Paliperidone is sparingly soluble in dichloromethane, slightly soluble in 0.1 N hydrochloric acid and insoluble in water. Paliperidone extended-release tablets are intended for oral administration and are available in 1.5 mg (brown), 3 mg (white), 6 mg (beige), and 9 mg (pink) strengths. Paliperidone extended-release tablets utilize osmotic drug release technology . Inactive ingredients are butylated hydroxy toluene, cellulose acetate, hydroxy propyl cellulose, hypromellose, iron oxide black, iron oxide red, iron oxide yellow, lactose monohydrate, polyethylene glycol, polyethylene oxide, povidone, propylene glycol, shellac, sodium chloride, stearic acid, and titanium dioxide. Delivery System Components and Performance Paliperidone extended-release tablets use osmotic pressure to deliver paliperidone at a controlled rate. The delivery system, which resembles a round-shaped tablet in appearance, consists of an osmotically active bilayer core surrounded by a subcoat and semipermeable membrane. The bilayer core is composed of drug layer 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. Image

Paliperidone extended-release tablets are an atypical antipsychotic agent indicated for Treatment of schizophrenia ( 1.1 ) Adults: Efficacy was established in three 6-week trials and one maintenance trial. ( 14.1 ) Adolescents (ages 12 to 17): Efficacy was established in one 6-week trial. ( 14.1 ) Treatment of schizoaffective disorder as monotherapy and as an adjunct to mood stabilizers and/or antidepressants. ( 1.2 ) Efficacy was established in two 6-week trials in adult patients. ( 14.2 ) 1.1 Schizophrenia Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [ see CLINICAL STUDIES ( 14.1 )]. The efficacy of paliperidone extended-release tablets 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 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 paliperidone extended-release tablets in schizoaffective disorder was established in two 6-week trials in adults.

Initial Dose Recommended Dose Maximum Dose Schizophrenia – adults ( 2.1 ) 6 mg/day 3 mg/day to 12 mg/day 12 mg/day Schizophrenia- adolescents ( 2.1 ) Weight < 51 kg 3 mg/day 3 mg/day to 6 mg/day 6 mg/day Weight ≥ 51 kg 3 mg/day 3 mg/day to 12 mg/day 12 mg/day Schizoaffective disorder - adults ( 2.2 ) 6 mg/day 3 mg/day to 12 mg/day 12 mg/day Tablet should be swallowed whole and should not be chewed, divided, or crushed. ( 2.3 ) 2.1 Schizophrenia Adults The recommended dose of paliperidone extended-release tablets for the treatment of schizophrenia in adults is 6 mg administered once daily. Initial dose titration is not required. Although it has not been systematically established that doses above 6 mg have additional benefit, there was a general trend for greater effects with higher doses. This must be weighed against the dose-related increase in adverse reactions. Thus, some patients may benefit from higher doses, up to 12 mg/day, and for some patients, a lower dose of 3 mg/day may be sufficient. Dose increases above 6 mg/day should be made only after clinical reassessment and generally should occur at intervals of more than 5 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day. In a longer-term study, paliperidone extended-release tablets have been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone extended-release tablets for 6 weeks [see CLINICAL STUDIES ( 14 )]. Paliperidone extended-release tablets should be prescribed at the lowest effective dose for maintaining clinical stability and the physician should periodically reevaluate the long-term usefulness of the drug in individual patients. Adolescents (12 years to 17 years of age) The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12 years to 17 years of age is 3 mg administered once daily. Initial dose titration is not required. Dose increases, if considered necessary, should be made only after clinical reassessment and should occur at increments of 3 mg/day at intervals of more than 5 days. Prescribers should be mindful that, in the adolescent schizophrenia study, there was no clear enhancement to efficacy at the higher doses, i.e., 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater, while adverse events were dose-related. 2.2 Schizoaffective Disorder The recommended dose of 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 mg 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 Paliperidone extended-release tablets can be taken with or without food. Paliperidone extended-release tablets 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 paliperidone extended-release tablets 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 paliperidone extended-release tablets. 2.5 Dosage in Special Populations Renal Impairment Dosing must be individualized according to the patient's renal function status. For patients with mild renal impairment (creatinine clearance ≥ 50 mL/min to < 80 mL/min), the recommended initial dose of paliperidone extended-release tablets is 3 mg once daily. The dose may then be increased to a maximum of 6 mg once daily based on clinical response and tolerability. For patients with moderate to severe renal impairment (creatinine clearance ≥ 10 mL/min to < 50 mL/min), the recommended initial dose of paliperidone extended-release tablets is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone extended-release tablet has not been studied in patients with creatinine clearance below 10 mL/min, use is not recommended in such patients. [see CLINICAL PHARMACOLOGY ( 12.3 )] Hepatic Impairment For patients with mild to moderate hepatic impairment, (Child-Pugh Classification A and B), no dose adjustment is recommended [see CLINICAL PHARMACOLOGY ( 12.3 )] . Paliperidone extended-release tablet has not been studied in patients with severe hepatic impairment. Elderly Because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status. In general, recommended dosing for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. For patients with moderate to severe renal impairment (creatinine clearance 10 mL/min to < 50 mL/min), the maximum recommended dose of paliperidone extended-release tablets is 3 mg once daily [see Renal Impairment above] .

Known hypersensitivity to paliperidone, risperidone, or to any excipients in paliperidone extended-release tablets. ( 4 ) Paliperidone extended-release tablets are contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the paliperidone extended-release tablets formulation. Hypersensitivity reactions, including anaphylactic reactions and angioedema, have been reported in patients treated with risperidone and in patients treated with paliperidone. Paliperidone is a metabolite of risperidone.

The following adverse reactions 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 ( 5.1 )] Cerebrovascular adverse reactions, including stroke, in elderly patients with dementia-related psychosis [see WARNINGS AND PRECAUTIONS ( 5.2 )] Neuroleptic malignant syndrome [see WARNINGS AND PRECAUTIONS ( 5.3 )] QT prolongation [see WARNINGS AND PRECAUTIONS ( 5.4 )] Tardive dyskinesia [see WARNINGS AND PRECAUTIONS ( 5.5 )] Metabolic changes [see WARNINGS AND PRECAUTIONS ( 5.6 )] Hyperprolactinemia [see WARNINGS AND PRECAUTIONS ( 5.7 )] Potential for gastrointestinal obstruction [see WARNINGS AND PRECAUTIONS ( 5.8 )] Orthostatic hypotension and syncope [see WARNINGS AND PRECAUTIONS ( 5.9 )] Falls [see WARNINGS AND PRECAUTIONS ( 5.10 )] Leukopenia, neutropenia, and agranulocytosis [see WARNINGS AND PRECAUTIONS ( 5.11 )] Potential for cognitive and motor impairment [see WARNINGS AND PRECAUTIONS ( 5.12 )] Seizures [see WARNINGS AND PRECAUTIONS ( 5.13 )] Dysphagia [see WARNINGS AND PRECAUTIONS ( 5.14 )] Priapism [see WARNINGS AND PRECAUTIONS ( 5.15 )] Disruption of body temperature regulation [see WARNINGS AND PRECAUTIONS ( 5.17 )] Commonly observed adverse reactions (incidence ≥ 5% and at least twice that for placebo) were ( 6 ) Adults with schizophrenia: extrapyramidal symptoms, tachycardia, and akathisia. Adolescents with schizophrenia: somnolence, akathisia, tremor, dystonia, cogwheel rigidity, anxiety, weight increased, and tachycardia. Adults with schizoaffective disorder: extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 paliperidone extended-release tablets 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 paliperidone extended-release tablets 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 paliperidone extended-release tablets-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 paliperidone extended-release tablets-treated subjects. [see ADVERSE REACTIONS ( 6.4 )] . The safety of paliperidone extended-release tablets were evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone extended-release tablets 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 paliperidone extended-release tablets at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of paliperidone extended-release tablets were evaluated in 150 adolescent subjects 12 years to 17 years of age with schizophrenia who received paliperidone extended-release tablets in the dose range of 1.5 mg/day to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. The safety of paliperidone extended-release tablets were 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 paliperidone extended-release tablets: 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 paliperidone extended-release tablets (3 mg to 12 mg once daily). Both studies included subjects who received paliperidone extended-release tablets 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 paliperidone extended-release tablets (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone extended-release tablets 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 – Schizophrenia in Adults and Adolescents Adult Patients with Schizophrenia Table 4 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies in adults, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups, and for which the incidence in paliperidone extended-release tablets-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 4. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablet -Treated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials * * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablet dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily paliperidone extended-release tablet doses of 3 mg and 9 mg, the second study included 6 mg, 9 mg, and 12 mg, and the third study included 6 mg and 12 mg [see CLINICAL STUDIES (14)] . Extrapyramidal symptoms includes the terms dyskinesia, dystonia, extrapyramidal disorder, hypertonia, muscle rigidity, oculogyration, parkinsonism, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Adverse reactions for which the paliperidone extended-release tablets incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting. Percentage of Patients Paliperidone Extended-Release Tablets Body System or Organ Class Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily Dictionary-Derived Term (N = 355) (N = 127) (N = 235) (N = 246) (N = 242) Total percentage of subjects with adverse reactions 37 48 47 53 59 Cardiac disorders Atrioventricular block first degree 1 2 0 2 1 Bundle branch block 2 3 1 3 < 1 Sinus arrhythmia 0 2 1 1 < 1 Tachycardia 7 14 12 12 14 Gastrointestinal disorders Abdominal pain upper 1 1 3 2 2 Dry mouth 1 2 3 1 3 Salivary hypersecretion < 1 0 < 1 1 4 General disorders Asthenia 1 2 < 1 2 2 Fatigue 1 2 1 2 2 Nervous system disorders Akathisia 4 4 3 8 10 Dizziness 4 6 5 4 5 Extrapyramidal symptoms 8 10 7 20 18 Headache 12 11 12 14 14 Somnolence 7 6 9 10 11 Vascular disorders Orthostatic hypotension 1 2 1 2 4 Adolescent Patients with Schizophrenia Table 5 lists the adverse reactions reported in a fixed-dose, placebo-controlled study in adolescent subjects 12 years to 17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets in any of the dose groups, and for which the incidence in paliperidone extended-release tablet-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 5. Adverse Reactions Reported by ≥ 2% of Paliperidone Extended-Release Tablet-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial * * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Extrapyramidal symptoms includes the terms oculogyric crisis, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, torticollis, trismus, bradykinesia, cogwheel rigidity, dyskinesia, dystonia, extrapyramidal disorder, hypertonia, hypokinesia, muscle contractions involuntary, parkinsonian gait, parkinsonism, tremor, and restlessness. Somnolence includes the terms somnolence, sedation, and hypersomnia. Insomnia includes the terms insomnia and initial insomnia. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Hypertension includes the terms hypertension and blood pressure increased. Gynecomastia includes the terms gynecomastia and breast swelling. Percentage of Patients Paliperidone Extended-Release Tablets Body System or Organ Class Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily Dictionary-Derived Term (N = 51) (N = 54) (N = 16) (N = 45) (N = 35) Total percentage of subjects with adverse reactions 43 37 50 58 74 Cardiac disorders Tachycardia 0 0 6 9 6 Eye disorders Vision blurred 0 0 0 0 3 Gastrointestinal disorders Dry mouth 2 0 0 0 3 Salivary hypersecretion 0 2 6 2 0 Swollen tongue 0 0 0 0 3 Vomiting 10 0 6 11 3 General disorders Asthenia 0 0 0 2 3 Fatigue 0 4 0 2 3 Infections and infestations Nasopharyngitis 2 4 0 4 0 Investigations Weight increased 0 7 6 2 3 Nervous system disorders Akathisia 0 4 6 11 17 Dizziness 0 2 6 2 3 Extrapyramidal symptoms 0 4 19 18 23 Headache 4 9 6 4 14 Lethargy 0 0 0 0 3 Somnolence 4 9 13 20 26 Tongue paralysis 0 0 0 0 3 Psychiatric disorders Anxiety 4 0 0 2 9 Reproductive system and breast disorders Amenorrhea 0 0 6 0 0 Galactorrhea 0 0 0 4 0 Gynecomastia 0 0 0 0 3 Respiratory, thoracic and mediastinal disorders Epistaxis 0 0 0 2 0 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder in Adults Table 6 enumerates the pooled incidences of adverse reactions reported in the two placebo- controlled 6-week studies in adult subjects, listing those that occurred in 2% or more of subjects treated with paliperidone extended-release tablets and for which the incidence in paliperidone extended-release tablet-treated subjects was greater than the incidence in subjects treated with placebo. Table 6. Adverse Drug Reactions Reported by ≥2% of Paliperidone Extended-Release Tablet-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo- Controlled Clinical Trials * * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone extended-release tablets dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily paliperidone extended-release tablet doses of 6 mg (with the option to reduce to 3 mg) and 12 mg (with the option to reduce to 9 mg). The second study included flexible once-daily doses of 3 mg to 12 mg. Among the 420 subjects treated with paliperidone extended-release tablets, 230 (55%) received paliperidone extended-release tablets as monotherapy and 190 (45%) received paliperidone extended-release tablets as an adjunct to mood stabilizers and/or antidepressants. Extrapyramidal symptoms includes the terms bradykinesia, drooling, dyskinesia, dystonia, hypertonia, muscle rigidity, muscle twitching, oculogyration, parkinsonian gait, parkinsonism, restlessness, and tremor. Somnolence includes the terms sedation and somnolence. Tachycardia includes the terms tachycardia, sinus tachycardia, and heart rate increased. Percentage of Patients Paliperidone Extended-Release Tablets Paliperidone Extended-Release Tablets Paliperidone Extended-Release Tablets Body System or Organ Class Placebo 3 mg to 6 mg once-daily fixed-dose range 9 mg to 12 mg once-daily fixed-dose range 3 mg to 12 mg once-daily flexible dose Dictionary-Derived Term (N = 202) (N = 108) (N = 98) (N = 214) Total percentage of subjects with adverse reactions 32 48 50 43 Cardiac disorders Tachycardia 2 3 1 2 Gastrointestinal disorders Abdominal discomfort/ Abdominal pain upper 1 1 0 3 Constipation 2 4 5 4 Dyspepsia 2 5 6 6 Nausea 6 8 8 5 Stomach discomfort 1 0 1 2 General disorders Asthenia 1 3 4 < 1 Infections and Infestations Nasopharyngitis 1 2 5 3 Rhinitis 0 1 3 1 Upper respiratory tract infection 1 2 2 2 Investigations Weight increased 1 5 4 4 Metabolism and nutrition disorders Decreased appetite < 1 1 0 2 Increased appetite < 1 3 2 2 Musculoskeletal and connective tissue disorders Back pain 1 1 1 3 Myalgia < 1 2 4 1 Nervous system disorders Akathisia 4 4 6 6 Dysarthria 0 1 4 2 Extrapyramidal symptoms 8 20 17 12 Somnolence 5 12 12 8 Psychiatric disorders Sleep disorder <1 2 3 0 Respiratory, thoracic and mediastinal disorders Cough 1 1 3 1 Pharyngolaryngeal pain <1 0 2 1 Monotherapy versus Adjunctive Therapy The designs of the two placebo-controlled, 6-week, double-blind trials in adult subjects with schizoaffective disorder included the option for subjects to receive antidepressants (except monoamine oxidase inhibitors) and/or mood stabilizers (lithium, valproate, or lamotrigine). In the subject population evaluated for safety, 230 (55%) subjects received paliperidone extended-release tablets as monotherapy and 190 (45%) subjects received paliperidone extended-release tablets as an adjunct to mood stabilizers and/or antidepressants. When comparing these 2 subpopulations, only nausea occurred at a greater frequency (≥ 3% difference) in subjects receiving paliperidone extended-release tablets as monotherapy. Discontinuations Due to Adverse Reactions Schizophrenia Trials The percentages of subjects who discontinued due to adverse reactions in the three schizophrenia placebo-controlled, 6-week, fixed-dose studies in adults were 3% and 1% in paliperidone extended-release tablets- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone extended-release tablets- and placebo-treated subjects, respectively). Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (< 1% of paliperidone extended-release tablets-treated subjects). Schizoaffective Disorder Trials The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo-controlled 6-week studies in adults were 1% and < 1% in paliperidone extended-release tablets- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone extended-release tablets- and placebo-treated subjects, respectively). Dose-Related Adverse Reactions Schizophrenia Trials Based on the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia, among the adverse reactions that occurred with a greater than 2% incidence in the subjects treated with paliperidone extended-release tablets, 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. In the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, among the adverse reactions that occurred with > 2% incidence in the subjects treated with paliperidone extended-release tablets, the incidences of the following adverse reactions increased with dose: tachycardia, akathisia, extrapyramidal symptoms, somnolence, and headache. Schizoaffective Disorder Trials In a placebo-controlled, 6-week, high- and low-dose study in adult subjects with schizoaffective disorder, akathisia, dystonia, dysarthria, myalgia, nasopharyngitis, rhinitis, cough, and pharyngolaryngeal pain occurred more frequently (i.e., a difference of at least 2%) in subjects who received higher doses of paliperidone extended-release tablets compared with subjects who received lower doses. Demographic Differences An examination of population subgroups in the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia and in the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder did not reveal any evidence of clinically relevant 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 (8.5)]. Extrapyramidal Symptoms (EPS) Pooled data from the three placebo-controlled, 6-week, fixed-dose studies in adult subjects with schizophrenia 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 7), and (4) incidence of spontaneous reports of EPS (Table 8). 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 paliperidone extended-release tablets 3 mg and 6 mg doses for any of these EPS measures. Table 7. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies in Adults Percentage of Patients Paliperidone Extended - Release Tablets Placebo 3 mg once - daily 6 mg once - daily 9 mg once - daily 12 mg once - daily EPS Group ( N = 355 ) ( N = 127 ) ( N = 235 ) ( N = 246 ) ( N = 242 ) Parkinsonism For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items) 9 11 3 15 14 Akathisia For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 6 6 4 7 9 Use of anticholinergic medications Percent of patients who received anticholinergic medications to treat emergent EPS 10 10 9 22 22 Table 8. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term –Schizophrenia Studies in Adults Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia Dystonia group includes: Dystonia, muscle spasms, oculogyration, trismus Hyperkinesia group includes: Akathisia, hyperkinesia Parkinsonism group includes: Bradykinesia, cogwheel rigidity, drooling, hypertonia, hypokinesia, muscle rigidity, musculoskeletal stiffness, parkinsonism Tremor group includes: Tremor Percentage of Patients Paliperidone Extended - Release Tablets Placebo 3 mg once - daily 6 mg once - daily 9 mg once - daily 12 mg once - daily EPS Group ( N = 355 ) ( N = 127 ) ( N = 235 ) ( N = 246 ) ( N = 242 ) Overall percentage of patients with EPS- related AE 11 13 10 25 26 Dyskinesia 3 5 3 8 9 Dystonia 1 1 1 5 5 Hyperkinesia 4 4 3 8 10 Parkinsonism 2 3 3 7 6 Tremor 3 3 3 4 3 Compared to data from the studies in adults subjects with schizophrenia, pooled data from the two placebo-controlled 6-week studies in adult subjects with schizoaffective disorder showed similar types and frequencies of EPS as measured by rating scales, anticholinergic medication use, and spontaneous reports of EPS-related adverse events. For subjects with schizoaffective disorder, there was no dose-related increase in EPS observed for parkinsonism with the Simpson- Angus scale or akathisia with the Barnes Akathisia Rating Scale. There was a dose-related increase observed with spontaneous EPS reports of hyperkinesia and dystonia and in the use of anticholinergic medications. Table 9 shows the EPS data from the pooled schizoaffective disorder trials. Table 9. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies in Adults Dyskinesia group includes: Dyskinesia, muscle twitching Dystonia group includes: Dystonia, muscle spasms, oculogyration Hyperkinesia group includes: Akathisia, hyperkinesia, restlessness Parkinsonism group includes: Bradykinesia, drooling, hypertonia, muscle rigidity, muscle tightness, musculoskeletal stiffness, parkinsonian gait, parkinsonism Tremor group includes: Tremor Percentage of Patients Paliperidone Extended-Release Tablets Placebo 3 mg to 6 mg once-daily fixed-dose range 9 mg to 12 mg once-daily fixed-dose range 3 mg to 12 mg once-daily flexible dose EPS Group (N = 202) (N = 108) (N = 98) (N = 214) Overall percentage of patients with EPS-related AE 11 23 22 17 Dyskinesia 1 3 1 1 Dystonia 1 2 3 2 Hyperkinesia 5 5 8 7 Parkinsonism 3 14 7 7 Tremor 3 12 11 5 The incidences of EPS-related adverse events in the adolescent schizophrenia studies showed a similar dose-related pattern to those in the adult studies. There were notably higher incidences of dystonia, hyperkinesia, tremor, and parkinsonism in the adolescent population as compared to the adult studies (Table 10). Table 10. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies in Adolescent Subjects Hyperkinesia group includes: Akathisia Dystonia group includes: Dystonia, muscle contracture, oculogyric crisis, tongue paralysis, torticollis Tremor group includes: Tremor Parkinsonism group includes: Cogwheel rigidity, extrapyramidal disorder, muscle rigidity Dyskinesia group includes: Dyskinesia, muscle contractions involuntary Percentage of Patients Paliperidone Extended-Release Tablets Placebo 1.5 mg once-daily 3 mg once-daily 6 mg once-daily 12 mg once-daily EPS Group (N = 51) (N = 54) (N = 16) (N = 45) (N = 35) Overall percentage of patients with EPS- related AE 0 6 25 22 40 Hyperkinesia 0 4 6 11 17 Dystonia 0 2 0 11 14 Tremor 0 2 6 7 11 Parkinsonism 0 0 6 2 14 Dyskinesia 0 2 6 2 6 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 in adult subjects with schizophrenia and from the two placebo-controlled, 6-week studies in adult subjects with schizoaffective disorder, between-group comparisons revealed no medically important differences between paliperidone extended-release tablets 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 paliperidone extended-release tablets 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, paliperidone extended-release tablets were associated with increases in serum prolactin [see WARNINGS AND PRECAUTIONS ( 5.7 )]. Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone Extended-Release Tablets The following additional adverse reactions occurred in < 2% of paliperidone extended-release tablets-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by paliperidone extended-release tablets-treated subjects who participated in other clinical studies. Cardiac disorders Bradycardia, palpitations Eye disorders Eye movement disorder Gastrointestinal disorders Flatulence General disorders Edema Immune system disorders Anaphylactic reaction Infections and infestations Urinary tract infection Investigations Alanine aminotransferase increased, aspartate aminotransferase increased Musculoskeletal and connective tissue disorders Arthralgia, pain in extremity Nervous system disorders Opisthotonos Psychiatric disorders Agitation, insomnia, nightmare Reproductive system and breast disorders Breast discomfort, menstruation irregular, retrograde ejaculation Respiratory, thoracic and mediastinal disorders Nasal congestion Skin and subcutaneous tissue disorders Pruritus, rash Vascular disorders Hypertension The safety of paliperidone extended-release tablets were also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone in adults with schizophrenia [see CLINICAL STUDIES ( 14 )]. 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of paliperidone extended-release tablets; 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.

Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. ( 7.1 ) Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with paliperidone extended-release tablets. ( 7.1 ) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of paliperidone extended-release tablets when a strong inducer of both CYP3A4 and P-gp (e.g., carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone extended-release tablets. ( 7.2 ) Co-administration of divalproex sodium increased C max and AUC of paliperidone by approximately 50%. Adjust dose of paliperidone extended-release tablets if necessary based on clinical assessment. ( 7.2 ) 7.1 Potential for Paliperidone Extended-release Tablets to Affect Other Drugs Given the primary CNS effects of paliperidone [see ADVERSE REACTIONS ( 6.1 , 6.2 )], paliperidone extended-release tablets 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 paliperidone extended-release tablets are 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 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. Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo data are available and the clinical relevance is unknown. Pharmacokinetic interaction between lithium and paliperidone extended-release tablets are unlikely. In a drug interaction study, co-administration of paliperidone extended-release tablets (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 24h and 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 paliperidone extended-release tablets 3 mg/day to 15 mg/day was added to their existing valproate treatment. 7.2 Potential for Other Drugs to Affect Paliperidone Extended-release Tablets 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 vivo studies do not show decreased elimination by these isozymes and they contribute to only a small fraction of total body clearance. In vitro studies have shown that paliperidone is a P-gp substrate. Co-administration of paliperidone extended-release tablets 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 max and 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 paliperidone extended-release tablets should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of paliperidone extended-release tablets 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 paliperidone extended-release tablets were 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 paliperidone extended-release tablets 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the C max and AUC of paliperidone. Dosage reduction for paliperidone extended-release tablets should be considered when paliperidone extended-release tablets are co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and paliperidone extended-release tablets are unlikely.