Data from FDA - Curated by EPG Health - Last updated 28 June 2018

Indication(s)

1 INDICATIONS AND USAGE INVEGA® 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. (14.1) Adolescents (ages 12–17): 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 INVEGA® (paliperidone) Extended-Release Tablets are indicated for the treatment of schizophrenia [see Clinical Studies (14.1)]. The efficacy of INVEGA® in schizophrenia was established in three 6-week trials in adults and one 6-week trial in adolescents, as well as one maintenance trial in adults. 1.2 Schizoaffective Disorder INVEGA® (paliperidone) Extended-Release Tablets are indicated for the treatment of schizoaffective disorder as monotherapy and an adjunct to mood stabilizers and/or antidepressant therapy [see Clinical Studies (14.2)]. The efficacy of INVEGA® in schizoaffective disorder was established in two 6-week trials in adults.

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Advisory information

contraindications
4 CONTRAINDICATIONS INVEGA® is contraindicated in patients with a known hypersensitivity to either paliperidone or risperidone, or to any of the excipients in the INVEGA® 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 INVEGA®. (4)
Adverse reactions
6 ADVERSE REACTIONS 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 Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Overall Adverse Reaction Profile 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)] Suicide [see Warnings and Precautions (5.15)] Priapism [see Warnings and Precautions (5.16)] Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.17)] Disruption of body temperature regulation [see Warnings and Precautions (5.18)] Antiemetic effect [see Warnings and Precautions (5.19)] Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.20)] Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.20)] The most common adverse reactions in clinical trials in adult subjects with schizophrenia (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate in any of the dose groups) were extrapyramidal symptoms, tachycardia, and akathisia. The most common adverse reactions in clinical trials in adult patients with schizoaffective disorder (reported in 5% or more of subjects treated with INVEGA® and at least twice the placebo rate) were extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizophrenia (causing discontinuation in 2% of INVEGA®-treated subjects) were nervous system disorders. The most common adverse reactions that were associated with discontinuation from clinical trials in adult subjects with schizoaffective disorder were gastrointestinal disorders, which resulted in discontinuation in 1% of INVEGA®-treated subjects. [See Adverse Reactions (6.4)]. The safety of INVEGA® was evaluated in 1205 adult subjects with schizophrenia who participated in three placebo-controlled, 6-week, double-blind trials, of whom 850 subjects received INVEGA® at fixed doses ranging from 3 mg to 12 mg once daily. The information presented in this section was derived from pooled data from these three trials. Additional safety information from the placebo-controlled phase of the long-term maintenance study, in which subjects received INVEGA® at daily doses within the range of 3 mg to 15 mg (n=104), is also included. The safety of INVEGA® was evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. The safety of INVEGA® was also evaluated in 622 adult subjects with schizoaffective disorder who participated in two placebo-controlled, 6-week, double-blind trials. In one of these trials, 206 subjects were assigned to one of two dose levels of INVEGA®: 6 mg with the option to reduce to 3 mg (n=108) or 12 mg with the option to reduce to 9 mg (n=98) once daily. In the other study, 214 subjects received flexible doses of INVEGA® (3–12 mg once daily). Both studies included subjects who received INVEGA® either as monotherapy or as an adjunct to mood stabilizers and/or antidepressants. Adverse events during exposure to study treatment were obtained by general inquiry and recorded by clinical investigators using their own terminology. Consequently, to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology. Throughout this section, adverse reactions are reported. Adverse reactions are adverse events that were considered to be reasonably associated with the use of INVEGA® (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for INVEGA® often cannot be reliably established in individual cases. Further, because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. 6.2 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 INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 4. Adverse Reactions Reported by ≥ 2% of INVEGA®-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 INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from three studies; one study included once-daily INVEGA® 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 INVEGA® incidence was equal to or less than placebo are not listed in the table, but included the following: vomiting. Percentage of Patients INVEGA® 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) Dictionary-Derived Term 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 12–17 years of age with schizophrenia, listing those that occurred in 2% or more of subjects treated with INVEGA® in any of the dose groups, and for which the incidence in INVEGA®-treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 5. Adverse Reactions Reported by ≥ 2% of INVEGA®-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 INVEGA® 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 INVEGA® Placebo 1.5 mg once daily 3 mg once daily 6 mg once daily 12 mg once daily Body System or Organ Class (N=51) (N=54) (N=16) (N=45) (N=35) Dictionary-Derived Term 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 6.3 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 INVEGA® and for which the incidence in INVEGA®-treated subjects was greater than the incidence in subjects treated with placebo. Table 6. Adverse Drug Reactions Reported by ≥ 2% of INVEGA®-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 INVEGA® dose groups and which occurred at greater incidence than in the placebo group. Data are pooled from two studies. One study included once-daily INVEGA® 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 INVEGA®, 230 (55%) received INVEGA® as monotherapy and 190 (45%) received INVEGA® 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 INVEGA® INVEGA® INVEGA® Placebo 3–6 mg once-daily fixed-dose range 9–12 mg once-daily fixed-dose range 3–12 mg once-daily flexible dose Body System or Organ Class (N=202) (N=108) (N=98) (N=214) Dictionary-Derived Term 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 INVEGA® as monotherapy and 190 (45%) subjects received INVEGA® 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 INVEGA® as monotherapy. 6.4 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 INVEGA®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were nervous system disorders (2% and 0% in INVEGA®- and placebo-treated subjects, respectively). Among the adverse reactions in the 6-week, fixed-dose, placebo-controlled study in adolescents with schizophrenia, only dystonia led to discontinuation (<1% of INVEGA®-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 INVEGA®- and placebo-treated subjects, respectively. The most common reasons for discontinuation were gastrointestinal disorders (1% and 0% in INVEGA®- and placebo-treated subjects, respectively). 6.5 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 INVEGA®, the incidences of the following adverse reactions increased with dose: somnolence, orthostatic hypotension, akathisia, dystonia, extrapyramidal disorder, hypertonia, parkinsonism, and salivary hypersecretion. For most of these, the increased incidence was seen primarily at the 12 mg dose, and, in some cases, the 9 mg dose. 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 INVEGA®, 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 INVEGA® compared with subjects who received lower doses. 6.6 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)]. 6.7 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 INVEGA® 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 INVEGA® 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 AkathisiaFor Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 6 6 4 7 9 Use of anticholinergic medicationsPercent 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 Percentage of Patients INVEGA® 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) 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 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 Percentage of Patients INVEGA® Placebo 3–6 mg once-daily fixed-dose range 9–12 mg once-daily fixed-dose range 3–12 mg once-daily flexible dose EPS Group (N=202) (N=108) (N=98) (N=214) 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 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 Percentage of Patients INVEGA® 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) 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 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. 6.8 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 INVEGA® and placebo in the proportions of subjects experiencing potentially clinically significant changes in routine serum chemistry, hematology, or urinalysis parameters. Similarly, there were no differences between INVEGA® and placebo in the incidence of discontinuations due to changes in hematology, urinalysis, or serum chemistry, including mean changes from baseline in fasting glucose, insulin, c-peptide, triglyceride, HDL, LDL, and total cholesterol measurements. However, INVEGA® was associated with increases in serum prolactin [see Warnings and Precautions (5.7)]. 6.9 Other Adverse Reactions Observed During Premarketing Evaluation of INVEGA® The following additional adverse reactions occurred in < 2% of INVEGA®-treated subjects in the above schizophrenia and schizoaffective disorder clinical trial datasets. The following also includes additional adverse reactions reported at any frequency by INVEGA®-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: opisthotonus 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 INVEGA® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA® in adults with schizophrenia [see Clinical Studies (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. 6.10 Postmarketing Experience The following adverse reactions have been identified during postapproval use of INVEGA®; because these reactions were reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: angioedema, ileus, priapism, somnambulism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention. 6.11 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.

Usage information

Dosing and administration
2 DOSAGE AND ADMINISTRATION Initial Dose Recommended Dose Maximum Dose Schizophrenia - adults (2.1) 6 mg/day 3 – 12 mg/day 12 mg/day Schizophrenia-adolescents (2.1) 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. (2.3) 2.1 Schizophrenia Adults The recommended dose of INVEGA® (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, INVEGA® has been shown to be effective in delaying time to relapse in patients with schizophrenia who were stabilized on INVEGA® for 6 weeks [see Clinical Studies (14)]. INVEGA® 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 (12–17 years of age) The recommended starting dose of INVEGA® (paliperidone) Extended-Release Tablets for the treatment of schizophrenia in adolescents 12–17 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 INVEGA® (paliperidone) Extended-Release Tablets for the treatment of schizoaffective disorder in adults is 6 mg administered once daily. Initial dose titration is not required. Some patients may benefit from lower or higher doses within the recommended dose range of 3 to 12 mg once daily. A general trend for greater effects was seen with higher doses. This trend must be weighed against dose-related increase in adverse reactions. Dosage adjustment, if indicated, should occur only after clinical reassessment. Dose increases, if indicated, generally should occur at intervals of more than 4 days. When dose increases are indicated, increments of 3 mg/day are recommended. The maximum recommended dose is 12 mg/day. 2.3 Administration Instructions INVEGA® can be taken with or without food. INVEGA® must be swallowed whole with the aid of liquids. Tablets should not be chewed, divided, or crushed. The medication is contained within a nonabsorbable shell designed to release the drug at a controlled rate. The tablet shell, along with insoluble core components, is eliminated from the body; patients should not be concerned if they occasionally notice in their stool something that looks like a tablet. 2.4 Use with Risperidone Concomitant use of INVEGA® with risperidone has not been studied. Since paliperidone is the major active metabolite of risperidone, consideration should be given to the additive paliperidone exposure if risperidone is coadministered with INVEGA®. 2.5 Dosage in Special Populations 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 INVEGA® 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 INVEGA® is 1.5 mg once daily, which may be increased to a maximum of 3 mg once daily after clinical reassessment. As INVEGA® 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)]. INVEGA® 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 INVEGA® is 3 mg once daily [see Renal Impairment above].
Use in special populations
8 USE IN SPECIFIC POPULATIONS Renal impairment: Dosing must be individualized according to renal function status. (2.5) Elderly: Same as for younger adults (adjust dose according to renal function status). (2.4) Nursing Mothers: The benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. (8.3) 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. (8.4) 8.1 Pregnancy Pregnancy Category C. There are no adequate and well controlled studies of INVEGA® in pregnant women. Use of first generation antipsychotic drugs during the last trimester of pregnancy has been associated with extrapyramidal symptoms in the neonate. These symptoms are usually self-limited. It is not known whether paliperidone, when taken near the end of pregnancy, will lead to similar neonatal signs and symptoms. In animal reproduction studies, there were no increases in fetal abnormalities when pregnant rats and rabbits were treated during the period of organogenesis with up to 8 times the maximum recommended human dose of paliperidone (on a mg/m2 basis). In rat reproduction studies with risperidone, which is extensively converted to paliperidone in rats and humans, there were increases in pup deaths seen at oral doses which are less than the maximum recommended human dose of risperidone on a mg/m2 basis (see risperidone package insert). Non-teratogenic Effects Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been self-limited, in other cases neonates have required intensive care unit support and prolonged hospitalization. INVEGA® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 8.3 Nursing Mothers Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone. 8.4 Pediatric Use Safety and effectiveness of INVEGA® in the treatment of schizophrenia were evaluated in 150 adolescent subjects 12–17 years of age with schizophrenia who received INVEGA® in the dose range of 1.5 mg to 12 mg/day in a 6-week, double-blind, placebo-controlled trial. Safety and effectiveness of INVEGA® for the treatment of schizophrenia in patients < 12 years of age have not been established. Safety and effectiveness of INVEGA® for the treatment of schizoaffective disorder in patients < 18 years of age have not been studied. 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. 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 0.31, 1.25, 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 maximum recommended human dose 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 INVEGA® on growth and sexual maturation have not been fully evaluated in children and adolescents. 8.5 Geriatric Use The safety, tolerability, and efficacy of INVEGA® were evaluated in a 6-week placebo-controlled study of 114 elderly subjects with schizophrenia (65 years of age and older, of whom 21 were 75 years of age and older). In this study, subjects received flexible doses of INVEGA® (3 mg to 12 mg once daily). In addition, a small number of subjects 65 years of age and older were included in the 6-week placebo-controlled studies in which adult schizophrenic subjects received fixed doses of INVEGA® (3 mg to 15 mg once daily) [see Clinical Studies (14)]. There were no subjects ≥ 65 years of age in the schizoaffective disorder studies. Overall, of the total number of subjects in schizophrenia clinical studies of INVEGA® (n=1796), including those who received INVEGA® or placebo, 125 (7.0%) were 65 years of age and older and 22 (1.2%) were 75 years of age and older. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. This drug is known to be substantially excreted by the kidney and clearance is decreased in patients with moderate to severe renal impairment [see Clinical Pharmacology (12.3)], who should be given reduced doses. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Dosage and Administration (2.5)]. 8.6 Renal Impairment Dosing must be individualized according to the patient's renal function status [see Dosage and Administration (2.5)]. 8.7 Hepatic Impairment No dosage adjustment is required in patients with mild to moderate hepatic impairment. INVEGA® has not been studied in patients with severe hepatic impairment.
Pregnancy and lactation
8.3 Nursing Mothers Paliperidone is excreted in human breast milk. The known benefits of breastfeeding should be weighed against the unknown risks of infant exposure to paliperidone.

Interactions

7 DRUG INTERACTIONS 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 INVEGA®. (7.1) Strong CYP3A4/P-glycoprotein (P-gp) inducers: It may be necessary to increase the dose of INVEGA® 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 INVEGA®. (7.2) Co-administration of divalproex sodium increased Cmax and AUC of paliperidone by approximately 50%. Adjust dose of INVEGA® if necessary based on clinical assessment. (7.2) 7.1 Potential for INVEGA® to Affect Other Drugs Given the primary CNS effects of paliperidone [see Adverse Reactions (6.1, 6.2)], INVEGA® should be used with caution in combination with other centrally acting drugs and alcohol. Paliperidone may antagonize the effect of levodopa and other dopamine agonists. Because of its potential for inducing orthostatic hypotension, an additive effect may be observed when INVEGA® is administered with other therapeutic agents that have this potential [see Warnings and Precautions (5.9)]. Paliperidone is not expected to cause clinically important pharmacokinetic interactions with drugs that are metabolized by cytochrome P450 isozymes. In 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 INVEGA® is unlikely. In a drug interaction study, co-administration of INVEGA® (12 mg once daily for 5 days) with divalproex sodium extended-release tablets (500 mg to 2000 mg once daily) did not affect the steady-state pharmacokinetics (AUC24h and Cmax,ss) of valproate in 13 patients stabilized on valproate. In a clinical study, subjects on stable doses of valproate had comparable valproate average plasma concentrations when INVEGA® 3–15 mg/day was added to their existing valproate treatment. 7.2 Potential for Other Drugs to Affect INVEGA® Paliperidone is not a substrate of CYP1A2, CYP2A6, CYP2C9, and CYP2C19, so that an interaction with inhibitors or inducers of these isozymes is unlikely. While in 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 INVEGA® 6 mg once daily with carbamazepine, a strong inducer of both CYP3A4 and P-glycoprotein (P-gp), at 200 mg twice daily caused a decrease of approximately 37% in the mean steady-state Cmax 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 INVEGA® should be re-evaluated and increased if necessary. Conversely, on discontinuation of carbamazepine, the dose of INVEGA® should be re-evaluated and decreased if necessary. Paliperidone is metabolized to a limited extent by CYP2D6 [see Clinical Pharmacology (12.3)]. In an interaction study in healthy subjects in which a single 3 mg dose of INVEGA® was administered concomitantly with 20 mg per day of paroxetine (a potent CYP2D6 inhibitor), paliperidone exposures were on average 16% (90% CI: 4, 30) higher in CYP2D6 extensive metabolizers. Higher doses of paroxetine have not been studied. The clinical relevance is unknown. Co-administration of a single dose of INVEGA® 12 mg with divalproex sodium extended-release tablets (two 500 mg tablets once daily) resulted in an increase of approximately 50% in the Cmax and AUC of paliperidone. Dosage reduction for INVEGA® should be considered when INVEGA® is co-administered with valproate after clinical assessment. Pharmacokinetic interaction between lithium and INVEGA® is unlikely.

More information

Category Value
Authorisation number NDA021999
Agency product number 838F01T721
Orphan designation No
Product NDC 50458-552,50458-550,50458-551,50458-554
Date Last Revised 13-03-2018
Type HUMAN PRESCRIPTION DRUG
RXCUI 672567
Storage and handling Storage and Handling Store up to 25°C (77°F); excursions permitted to 15 – 30°C (59 – 86°F) [see USP Controlled Room Temperature]. Protect from moisture. Keep out of reach of children.
Marketing authorisation holder Janssen Pharmaceuticals, Inc.
Warnings WARNING-INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotic drugs, treatment with conventional antipsychotic drugs may increase mortality. The extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients is not clear. INVEGA® (paliperidone) Extended-Release Tablets is not approved for the treatment of patients with dementia-related psychosis. [see Warnings and Precautions (5.1)] WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. INVEGA® is not approved for use in patients with dementia-related psychosis. (5.1)