PALIPERIDONE- paliperidone_tablet, extended release

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 2A In vitro, paliperidone acts as an antagonist at the central dopamine Type 2 (D 2 2A 2 2A 1 2 1 1 2 in vitro. Following a single dose, the plasma concentrations of paliperidone gradually rise to reach peak plasma concentration (C max Steady-state concentrations of paliperidone are attained within 4-5 days of dosing with paliperidone in most subjects. The mean steady-state peak: trough ratio for a paliperidone dose of 9 mg was 1. 7 with a range of 1. Following administration of paliperidone extended-release tablets, the (+) and (-) enantiomers of paliperidone interconvert, reaching an AUC (+) to (-) ratio of approximately 1. 6 at steady state. Absorption and Distribution The absolute oral bioavailability of paliperidone following paliperidone extended-release tablet administration is 28%. Administration of a 12 mg paliperidone extended-release tablet to healthy ambulatory subjects with a standard high-fat/high-caloric meal gave mean C max [see Dosage and Administration (2. 3) Based on a population analysis, the apparent volume of distribution of paliperidone is 487 L. The plasma protein binding of racemic paliperidone is 74%. Metabolism and Elimination Although in vitro in vivo [see Drug Interactions (7) One week following administration of a single oral dose of 1 mg immediate-release 14 in vivo Population pharmacokinetic analyses found no difference in exposure or clearance of paliperidone between extensive metabolizers and poor metabolizers of CYP2D6 substrates. Special Populations Renal Impairment The dose of paliperidone should be reduced in patients with moderate or severe renal impairment [see Dosage and Administration (2. 5) Hepatic Impairment In a study in adult subjects with moderate hepatic impairment (Child-Pugh class B), the plasma concentrations of free paliperidone were similar to those of healthy subjects, although total paliperidone exposure decreased because of a decrease in protein binding. Consequently, no dose adjustment is required in patients with mild or moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment. Adolescents (12-17 years of age) Paliperidone systemic exposure in adolescents weighing >= 51 kg (>= 112 lbs) was similar to that in adults. In adolescents weighing < 51 kg (<112 lbs), a 23% higher exposure was observed; this is considered not to be clinically significant. Age did not influence the paliperidone exposure. Elderly No dosage adjustment is recommended based on age alone. However, dose adjustment may be required because of age-related decreases in creatinine clearance [see Renal Impairment above and Dosage and Administration ( 2. 5 Race No dosage adjustment is recommended based on race. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in Japanese and Caucasians. Gender No dosage adjustment is recommended based on gender. No differences in pharmacokinetics were observed in a pharmacokinetic study conducted in men and women. Smoking No dosage adjustment is recommended based on smoking status. Based on in vitro studies utilizing human liver enzymes, paliperidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of paliperidone.

Paliperidone is an atypical antipsychotic agent indicated for Treatment of schizophrenia ( 1. 1 Adults: Efficacy was established in three 6-week trials and one maintenance trial. 1 Adolescents (ages 12-17): Efficacy was established in one 6-week trial. 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 Paliperidone extended-release tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14. 1) The efficacy of paliperidone 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. 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 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 - 12 mg/day 12 mg/day Schizophrenia- Weight < 51kg 3 mg/day 3 - 6 mg/day 6 mg/day Weight >= 51kg 3 mg/day 3 - 12 mg/day 12 mg/day Schizoaffective disorder - adults (2. 2) 6 mg/day 3 - 12 mg/day 12 mg/day Tablet should be swallowed whole and should not be chewed, divided, or crushed. 3 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 has been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on paliperidone for 6 weeks [see Clinical Studies (14) Adolescents (12-17 years of age) The recommended starting dose of paliperidone extended-release tablets for the treatment of schizophrenia in adolescents 12-17 years of age is 3 mg administered once daily. 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. , 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. The recommended dose of paliperidone extended-release tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. 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. 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. Concomitant use of paliperidone 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. 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 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 is 3 mg every other day or 1. 5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As paliperidone 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) 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 is 3 mg once daily [see Renal Impairment above].

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 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. 16) 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 Inventia Healthcare Limited at 1-800-270-7585 or FDA at 1-800-FDA-1088 or www. gov/medwatch The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with paliperidone 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 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-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 -treated subjects. [See Adverse Reactions (6) The safety of paliperidone was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received paliperidone 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 at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of paliperidone was evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received paliperidone in the dose range of 1. 5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. The safety of paliperidone Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of paliperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for paliperidone 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 Table 4. Adverse Reactions Reported by >= 2% of Paliperidone en dashTreated Adult Subjects with Schizophrenia in Three Short-Term, Fixed-Dose, Placebo-Controlled Clinical Trials * * [see Clinical Studies (14) Percentage of Patients Paliperidone extended-release Tablets Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily Body System or Organ Class (N=355) (N=127) (N=235) (N=246) (N=242) Total percentage of subjects with adverse reactions 37 48 47 53 59 Cardiac disorders Gastrointestinal disorders General disorders Nervous system disorders Vascular disorders Adolescent Patients with Schizophrenia Table 5 Table 5. Adverse Reactions Reported by >= 2% of Paliperidone-Treated Adolescent Subjects with Schizophrenia in a Fixed-Dose, Placebo-Controlled Clinical Trial * Percentage of Patients Paliperidone extended-release tablets Body System or Organ Class Placebo 1. 5 mg (N=54) 3 mg (N=16) 6 mg (N=45) 12 mg (N=35) Total percentage of subjects with adverse reactions 43 37 50 58 74 Cardiac disorders Eye disorders Gastrointestinal disorders General disorders Infections and infestations Investigations Nervous system disorders Psychiatric disorders Reproductive system and breast disorders Respiratory, thoracic and mediastinal disorders * Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials en dash Schizoaffective Disorder in Adults Table 6 Table 6. Adverse Drug Reactions Reported by >= 2% of Paliperidone-Treated Adult Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials * Body System or Organ Class Percentage of Patients Placebo Paliperidone once-daily fixed-dose Paliperidone once-daily fixed-dose Paliperidone once-daily flexible dose (N=202) (N=108) (N=98) (N=214) Total percentage of subjects with adverse reactions 32 48 50 43 Cardiac disorders Gastrointestinal disorders General disorders Infections and Infestations Investigations Metabolism and nutrition disorders Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders Respiratory, thoracic and mediastinal disorders * Table includes adverse reactions that were reported in 2% or more of subjects in any of the paliperidone 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 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 to 12 mg. Among the 420 subjects treated with paliperidone, 230 (55%) received paliperidone as monotherapy and 190 (45%) received paliperidone 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. 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 as monotherapy and 190 (45%) subjects received paliperidone 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 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-and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in paliperidone-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-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 - and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in paliperidone- 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, 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, 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. , a difference of at least 2%) in subjects who received higher doses of paliperidone 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), (Table 8). Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication en dash Schizophrenia Studies in Adults EPS Group Percentage of Patients Paliperidone extended-release tablets Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily (N=355) (N=127) (N=235) (N=246) (N=242) Parkinsonism 1 9 11 3 15 14 Akathisia 2 6 6 4 7 9 Use of Anticholinergic medications 3 10 10 9 22 22 1 For Parkinsonism, percent of patients with Simpson-Angus global score > 0. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term en dash Schizophrenia Studies in Adults Dyskinesia group includes: Dyskinesia, extrapyramidal disorder, muscle twitching, tardive dyskinesia EPS Group Percentage of Patients Paliperidone extended-release Tablets Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily (N=355) (N=127) (N=235) (N=246) (N=242) Overall percentage of 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 Table 9. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term en dash Schizoaffective Disorder Studies in Adults Dyskinesia group includes: Dyskinesia, muscle twitching EPS Group Percentage of Patients Paliperidone Placebo 3-6 mg once-daily fixed-dose range 9-12 mg once-daily fixed-dose range 3-12 mg once-daily flexible dose (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 en dash Schizophrenia Studies in Adolescent Subjects Hyperkinesia group includes: Akathisia Percentage of Patients Paliperidone extended-release tablets EPS Group Placebo (N=51) 1. 5 mg once daily (N=54) 3 mg once daily (N=16) 6 mg once daily (N=45) 12 mg once daily (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: 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 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 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 was associated with increases in serum prolactin [see Warnings and Precautions (5. 7) Other Adverse Reactions Observed During Premarketing Evaluation of Paliperidone The following additional adverse reactions occurred in < 2% of Paliperidone-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-treated subjects who participated in other clinical studies. Cardiac disorders: Eye disorders: Gastrointestinal disorders: General disorders: Immune system disorders: Infections and infestations: Investigations: Musculoskeletal and connective tissue disorders: Nervous system disorders: Psychiatric disorders: Reproductive system and breast disorders: Respiratory thoracic and mediastinal disorders: Skin and subcutaneous tissue disorders: Vascular disorders: The safety of paliperidone was also evaluated in a long-term trial designed to assess the maintenance of effect with paliperidone in adults with schizophrenia [see Clinical Studies (14) The following adverse reactions have been identified during post-approval use of paliperidone; 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. 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.

Paliperidone is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the Paliperidone 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. Known hypersensitivity to paliperidone, risperidone, or to any excipients in paliperidone.

Renal impairment: Dosing must be individualized according to renal function status. 5 Elderly: Same as for younger adults (adjust dose according to renal function status). 4 Pregnancy: May cause extrapyramidal and/or withdrawal symptoms in neonates with third trimester exposure. 1 Pediatric Use: Safety and effectiveness in the treatment of schizophrenia not established in patients less than 12 years of age. Safety and effectiveness in the treatment of schizoaffective disorder not established in patients less than 18 years of age. 4 Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to atypical antipsychotics, including paliperidone, during pregnancy. Healthcare providers are encouraged to register patients by contacting the National Pregnancy Registry for Atypical Antipsychotics at 1-866-961-2388 or online at. Risk Summary Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery (see Clinical Considerations) (see Data) (see Clinical Considerations) The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2en dash4% and 15en dash20%, respectively. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the maximum recommended human dose (MRHD) based on mg/m 2 (see Animal Data) Clinical Considerations Disease-associated maternal and/or embryo/fetal risk There is a risk to the mother from untreated schizophrenia, including increased risk of relapse, hospitalization, and suicide. Schizophrenia are associated with increased adverse perinatal outcomes, including preterm birth. It is not known if this is a direct result of the illness or other comorbid factors. Fetal/Neonatal Adverse Reactions Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder have been reported in neonates who were exposed to antipsychotic drugs, including paliperidone, during the third trimester of pregnancy. These symptoms have varied in severity. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Data Human Data Published data from observational studies, birth registries, and case reports on the use of atypical antipsychotics during pregnancy do not report a clear association with antipsychotics and major birth defects. A prospective observational study including 6 women treated with risperidone, the parent compound of paliperidone, demonstrated placental passage of risperidone and paliperidone. A retrospective cohort study from a Medicaid database of 9258 women exposed to antipsychotics during pregnancy did not indicate an overall increased risk for major birth defects. There was a small increase in the risk of major birth defects (RR= 1. 26, 95% CI 1. 56) and of cardiac malformations (RR=1. 26, 95% CI 0. 81) in a subgroup of 1566 women exposed to the parent compound of paliperidone, risperidone, during the first trimester of pregnancy; however, there is no mechanism of action to explain the difference in malformation rates. Animal Data In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated with paliperidone during the period of organogenesis with up to 8 times the MRHD of 12 mg based on mg/m 2 Additional reproduction toxicity studies were conducted with orally administered risperidone, which is extensively converted to paliperidone. Cleft palate was observed in the offspring of pregnant mice treated with risperidone at 3 to 4 times the MRHD of 16 mg based on mg/m 2 2 2 In rat reproduction studies with risperidone, pup deaths occurred at oral doses which are less than the MRHD of risperidone based on mg/m 2 registered Risk Summary Limited data from published literature report the presence of paliperidone in human breast milk. There is no information on the effects on the breastfed infant, or the effects on milk production; however, there are reports of sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements) in breastfed infants exposed to paliperidone's parent compound, risperidone (see Clinical Considerations) Clinical Considerations Infants exposed to paliperidone through breastmilk should be monitored for excess sedation, failure to thrive, jitteriness, and extrapyramidal symptoms (tremors and abnormal muscle movements). Infertility Females Based on the pharmacologic action of paliperidone (D 2 [see Warnings and Precautions (5. 7) Safety and effectiveness of paliperidone in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12-17 years of age with schizophrenia who received paliperidone 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 paliperidone for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of paliperidone for the treatment of schizoaffective disorder in patients< 18 years of age have not been studied. Juvenile Animal Studies In a study in which juvenile rats were treated with oral paliperidone from days 24 to 73 of age, a reversible impairment of performance in a test of learning and memory was seen, in females only, with a no-effect dose of 0. 63 mg/kg/day, which produced plasma levels (AUC) of paliperidone similar to those in adolescents at MRHD of 12 mg/day. No other consistent effects on neurobehavioral or reproductive development were seen up to the highest dose tested (2. 5 mg/kg/day), which produced plasma levels of paliperidone 2-3 times those in adolescents. Juvenile dogs were treated for 40 weeks with oral risperidone, which is extensively metabolized to paliperidone in animals and humans, at doses of 0. 25, or 5 mg/kg/day. Decreased bone length and density were seen with a no-effect dose of 0. 31 mg/kg/day, which produced plasma levels (AUC) of risperidone plus paliperidone which were similar to those in children and adolescents receiving the MRHD of risperidone. In addition, a delay in sexual maturation was seen at all doses in both males and females. The above effects showed little or no reversibility in females after a 12-week drug-free recovery period. The long-term effects of paliperidone on growth and sexual maturation have not been fully evaluated in children and adolescents. The safety, tolerability, and efficacy of paliperidone 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 paliperidone (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 paliperidone (3 mg to 15 mg once daily) [see Clinical Studies (14) Overall, of the total number of subjects in schizophrenia clinical studies of paliperidone (n = 1796), including those who received paliperidone 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) [see Dosage and Administration (2. 5) Dosing must be individualized according to the patient’s renal function status [see Dosage and Administration (2. 5) No dosage adjustment is required in patients with mild to moderate hepatic impairment. Paliperidone has not been studied in patients with severe hepatic impairment. Patients with Parkinson’s Disease or Dementia with Lewy Bodies can experience increased sensitivity to paliperidone. Manifestations can include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with neuroleptic malignant syndrome.

Centrally-acting drugs: Due to CNS effects, use caution in combination. Avoid alcohol. 1 Drugs that may cause orthostatic hypotension: An additive effect may be observed when co-administered with paliperidone. 1 Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of paliperidone when a strong inducer of both CYP3A4 and P-gp (e. , carbamazepine) is co-administered. Conversely, on discontinuation of the strong inducer, it may be necessary to decrease the dose of paliperidone. 2 Co-administration of divalproex sodium increased C max 7. 2 Given the primary CNS effects of paliperidone [see Adverse Reactions 6. 2 Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when paliperidone 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 vitro Paliperidone is a weak inhibitor of P-glycoprotein (P-gp) at high concentrations. No in vivo Pharmacokinetic interaction between lithium and paliperidone is unlikely. In a drug interaction study, co-administration of paliperidone (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2,000 mg once daily) did not affect the steady-state pharmacokinetics (AUC 24h max ss 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 in vivo In vitro Co-administration of paliperidone 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 Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12. 3) Co-administration of a single dose of paliperidone 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 Pharmacokinetic interaction between lithium and paliperidone is unlikely.

OVERDOSAGE
While experience with paliperidone overdose is limited, among the few cases of overdose reported in pre-marketing trials, the highest estimated ingestion of paliperidone 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. , 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. 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.
NONCLINICAL TOXICOLOGY
Carcinogenesis Carcinogenicity studies with paliperidone administered orally have not been performed. Carcinogenicity studies with risperidone, which is extensively converted to paliperidone in rats, mice, and humans, were conducted in Swiss albino mice and Wistar rats. Risperidone was administered in the diet at daily doses of 0.63, 2.5, and 10 mg/kg for 18 months to mice and for 25 months to rats. A maximum tolerated dose was not achieved in male mice. There were statistically significant increases in pituitary gland adenomas, endocrine pancreas adenomas, and mammary gland adenocarcinomas. The no-effect dose for these tumors was less than or equal to the MRHD of risperidone based on mg/m 2 2 [see Warnings and Precautions (5.7) Mutagenesis No evidence of genotoxic potential for paliperidone was found in the Ames reverse mutation test, the mouse lymphoma assay, or the in vivo Impairment of Fertility In a study of fertility, the percentage of treated female rats that became pregnant was not affected at oral doses of paliperidone of up to 2.5 mg/kg/day which is 2 times the MRHD based on mg/m 2 2 The fertility of male rats was not affected at oral doses of paliperidone of up to 2 times the MRHD of 12 mg/day based on mg/m 2 2
CLINICAL STUDIES
Adults The acute efficacy of paliperidone (3 mg to 15 mg once daily) was established in three placebo-controlled and active-controlled (olanzapine), 6-week, fixed-dose trials in non-elderly adult subjects (mean age of 37) who met DSM-IV criteria for schizophrenia. Studies were carried out in North America, Eastern Europe, Western Europe, and Asia. The doses studied among these three trials included 3 mg/day, 6 mg/day, 9 mg/day, 12 mg/day, and 15 mg/day. Dosing was in the morning without regard to meals. Efficacy was evaluated using the Positive and Negative Syndrome Scale (PANSS), a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. Efficacy was also evaluated using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in the domains of socially useful activities (e. , work and study), personal and social relationships, self-care, and disturbing and aggressive behaviors. In all 3 studies (n = 1665), paliperidone was superior to placebo on the PANSS at all doses. Mean effects at all doses were fairly similar, although the higher doses in all studies were numerically superior. Paliperidone was also superior to placebo on the PSP in these trials. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age (there were few patients over 65), or geographic region. There were insufficient data to explore differential effects based on race. In a longer-term trial, adult outpatients meeting DSM-IV criteria for schizophrenia who had clinically responded (defined as PANSS score <= 70 or <= 4 on pre-defined PANSS subscales, as well as having been on a stable fixed dose of paliperidone for the last two weeks of an 8-week run-in phase) were entered into a 6-week open-label stabilization phase where they received paliperidone (doses ranging from 3 mg to 15 mg once daily). After the stabilization phase, patients were randomized in a double-blind manner to either continue on paliperidone at their achieved stable dose, or to placebo, until they experienced a relapse of schizophrenia symptoms. Relapse was pre-defined as significant increase in PANSS (or pre-defined PANSS subscales), hospitalization, clinically significant suicidal or homicidal ideation, or deliberate injury to self or others. An interim analysis of the data showed a significantly longer time to relapse in patients treated with paliperidone compared to placebo, and the trial was stopped early because maintenance of efficacy was demonstrated. Adolescents The efficacy of paliperidone in adolescent subjects with schizophrenia was established in a randomized, double-blind, parallel-group, placebo-controlled, 6-week study using a fixed-dose weight-based treatment group design over the dose range of 1. 5 to 12 mg/day. The study was carried out in the US, India, Romania, Russia, and Ukraine, and involved subjects 12-17 years of age meeting DSM-IV criteria for schizophrenia, with diagnosis confirmation using the Kiddie Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version (K-SADSPL). Eligible subjects were randomly assigned to 1 of 4 treatment groups: a placebo group or paliperidone Low, Medium, or High dose groups. Doses were administered based on body weight to minimize the risk of exposing lower-weight adolescents to high doses of paliperidone. Subjects weighing between 29 kg and less than 51 kg at the baseline visit were randomly assigned to receive placebo or 1. 5 mg (Low dose), 3 mg (Medium dose), or 6 mg (High dose) of paliperidone daily, and subjects weighing at least 51 kg at the baseline visit were randomly assigned to receive placebo or 1. 5 mg (Low dose), 6 mg (Medium dose), or 12 mg (High dose) of paliperidone daily. Efficacy was evaluated using PANSS. Overall, this study demonstrated the efficacy of paliperidone in adolescents with schizophrenia in the dose range of 3 to 12 mg/day. Doses within this broad range were shown to be effective, however, there was no clear enhancement to efficacy at the higher doses, i. , 6 mg for subjects weighing less than 51 kg and 12 mg for subjects weighing 51 kg or greater. Although paliperidone was adequately tolerated within the dose range of 3 to 12 mg/day, adverse events were dose related. Adults The acute efficacy of paliperidone (3 mg to 12 mg once daily) in the treatment of schizoaffective disorder was established in two placebo-controlled, 6-week trials in non-elderly adult subjects. Enrolled subjects 1) met DSM-IV criteria for schizoaffective disorder, as confirmed by the Structured Clinical Interview for DSM-IV Disorders, 2) had a Positive and Negative Syndrome Scale (PANSS) total score of at least 60, and 3) had prominent mood symptoms as confirmed by a score of at least 16 on the Young Mania Rating Scale and/or Hamilton Rating Scale for Depression. The population included subjects with schizoaffective bipolar and depressive types. In one of these trials, efficacy was assessed in 211 subjects who received flexible doses of paliperidone (3-12 mg once daily). In the other study, efficacy was assessed in 203 subjects who were assigned to one of two dose levels of paliperidone: 6 mg with the option to reduce to 3 mg (n = 105) or 12 mg with the option to reduce to 9 mg (n = 98) once daily. Both studies included subjects who received paliperidone either as monotherapy [no mood stabilizers and/or antidepressants (55%)] or as an adjunct to mood stabilizers and/or antidepressants (45%). The most commonly used mood stabilizers were valproate and lithium. The most commonly used antidepressants were SSRIs and SNRIs. Paliperidone was dosed in the morning without regard to meals. Studies were carried out in the United States, Eastern Europe, Russia, and Asia. Efficacy was evaluated using the PANSS, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. As secondary outcomes, mood symptoms were evaluated using the Hamilton Depression Rating Scale (HAM-D-21) and the Young Mania Rating Scale (YMRS). The paliperidone group in the flexible-dose study (dosed between 3 and 12 mg/day, mean modal dose of 8. 6 mg/day) and the higher dose group of paliperidone in the 2 dose-level study (12 mg/day with option to reduce to 9 mg/day) were each superior to placebo in the PANSS. Numerical improvements in mood symptoms were also observed, as measured by the HAM-D21 and YMRS. In the lower dose group of the 2 dose-level study (6 mg/day with option to reduce to 3 mg/day), paliperidone was not significantly different from placebo as measured by the PANSS. Taking the results of both studies together, paliperidone improved the symptoms of schizoaffective disorder at endpoint relative to placebo when administered either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. An examination of population subgroups did not reveal any evidence of differential responsiveness on the basis of gender, age, or geographic region.

ANI Pharmaceuticals, Inc.

PALIPERIDONE- paliperidone_tablet, extended release Product manual source documgent