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adverse reactions
6 ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Increased mortality in elderly patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions (5.1) ] Cerebrovascular adverse events, 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) ] Hyperglycemia and diabetes mellitus [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) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.10) ] Potential for cognitive and motor impairment [ see Warnings and Precautions (5.11) ] Seizures [see Warnings and Precautions (5.12) ] Dysphagia [see Warnings and Precautions (5.13) ] Suicide [see Warnings and Precautions (5.14) ] Priapism [see Warnings and Precautions (5.15) ] Thrombotic thrombocytopenic purpura (TTP) [see Warnings and Precautions (5.16) ] Disruption of body temperature regulation [see Warnings and Precautions (5.17) ] Antiemetic effect [see Warnings and Precautions (5.18) ] Increased sensitivity in patients with Parkinson's disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.19) ] Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.19) ] The most common adverse reactions in clinical trials in 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 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 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 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 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. The most common adverse reactions (incidence ≥ 5% and at least twice that for placebo) were extrapyramidal symptoms, tachycardia, and akathisia in the schizophrenia trials, and extrapyramidal symptoms, somnolence, dyspepsia, constipation, weight increased, and nasopharyngitis in the schizoaffective disorder trials. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Janssen, Division of Ortho-McNeil-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 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials - Schizophrenia Table 1 enumerates the pooled incidences of adverse reactions reported in the three placebo-controlled, 6-week, fixed-dose studies, listing those that occurred in 2% or more of subjects treated with INVEGA ® in any of the dose groups, and for which the incidence in INVEGA ® -treated subjects in any of the dose groups was greater than the incidence in subjects treated with placebo. Table 1. Adverse Reactions Reported by ≥ 2% of INVEGA ® -Treated 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. Percent of Patients Reporting Event INVEGA ® Placebo 3 mg once daily 6 mg once daily 9 mg once daily 12 mg once daily Body System or Organ Class Dictionary-Derived Term (N=355) (N=127) (N=235) (N=246) (N=242) Total percentage of subjects with adverse reactions 37 48 47 53 59 Cardiac disorders Atrioventricular block first degree 1 2 0 2 1 Bundle branch block 2 3 1 3 <1 Sinus arrhythmia 0 2 1 1 <1 Tachycardia 7 14 12 12 14 Gastrointestinal disorders Abdominal pain upper 1 1 3 2 2 Dry mouth 1 2 3 1 3 Salivary hypersecretion <1 0 <1 1 4 General disorders Asthenia 1 2 <1 2 2 Fatigue 1 2 1 2 2 Nervous system disorders Akathisia 4 4 3 8 10 Dizziness 4 6 5 4 5 Extrapyramidal symptoms 8 10 7 20 18 Headache 12 11 12 14 14 Somnolence 7 6 9 10 11 Vascular disorders Orthostatic hypotension 1 2 1 2 4 6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizoaffective Disorder Table 2 enumerates the pooled incidences of adverse reactions reported in the two placebo-controlled 6-week studies, 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 2. Adverse Drug Reactions Reported by ≥ 2% of INVEGA ® -Treated Subjects with Schizoaffective Disorder in Two Double-Blind, Placebo-Controlled Clinical Trials Placebo INVEGA ® 3–6 mg once-daily fixed-dose range INVEGA ® 9–12 mg once-daily fixed-dose range INVEGA ® 3–12 mg once-daily flexible-dose Body System or Organ Class (N=202) (N=108) (N=98) (N=214) Dictionary-Derived Term * 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. 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 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. 6.3 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, bundle branch block left, palpitations Endocrine disorders: hyperprolactinemia Eye disorders: vision blurred Gastrointestinal disorders: abdominal pain, flatulence, small intestinal obstruction, swollen tongue General disorders: edema, edema peripheral Immune system disorders: anaphylactic reaction Infections and infestations: urinary tract infection Investigations: electrocardiogram abnormal Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity Nervous system disorders: cerebrovascular accident, convulsion, dizziness postural, grand mal convulsion, lethargy, syncope, transient ischemic attack, additional extrapyramidal symptoms (cogwheel rigidity, muscle spasms, musculoskeletal pain, torticollis, trismus) Psychiatric disorders: agitation, nightmare Reproductive system and breast disorders: amenorrhea, breast discharge, breast engorgement, breast tenderness, breast pain, erectile dysfunction, galactorrhea, gynecomastia, menstruation irregular, retrograde ejaculation Respiratory, thoracic and mediastinal disorders: nasal congestion, pneumonia aspiration Skin and subcutaneous tissue disorders: pruritus, rash, rash papular Vascular disorders: hypotension, ischemia 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 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). Schizoaffective Disorder Trials The percentages of subjects who discontinued due to adverse reactions in the two schizoaffective disorder placebo‑controlled 6-week studies 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 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. Schizoaffective Disorder Trials In a placebo-controlled, 6-week, high- and low-dose study in 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 subjects with schizophrenia and in the two placebo-controlled, 6-week studies in 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 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 3 ), and (4) incidence of spontaneous reports of EPS ( Table 4 ). 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 3. Treatment-Emergent Extrapyramidal Symptoms (EPS) Assessed by Incidence of Ratings Scales and Use of Anticholinergic Medication – Schizophrenia Studies Percentage of Patients INVEGA ® Placebo 3 mg 6 mg 9 mg 12 mg once daily once daily once daily once daily EPS Group (N=355) (N=127) (N=235) (N=246) (N=242) Parkinsonism For Parkinsonism, percent of patients with Simpson-Angus global score > 0.3 (Global score defined as total sum of items score divided by the number of items) 9 11 3 15 14 Akathisia For Akathisia, percent of patients with Barnes Akathisia Rating Scale global score ≥ 2 6 6 4 7 9 Use of anticholinergic medications Percent of patients who received anticholinergic medications to treat emergent EPS 10 10 9 22 22 Table 4. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizophrenia Studies Percentage of Patients INVEGA ® Placebo 3 mg 6 mg 9 mg 12 mg once daily once daily once daily 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 schizophrenia, pooled data from the two placebo-controlled 6-week studies in 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 5 shows the EPS data from the pooled schizoaffective disorder trials. Table 5. Treatment-Emergent Extrapyramidal Symptoms (EPS)-Related Adverse Events by MedDRA Preferred Term – Schizoaffective Disorder Studies 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 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 subjects with schizophrenia and from the two placebo-controlled, 6-week studies in 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 Weight Gain Schizophrenia Trials In the pooled data from the three placebo-controlled, 6-week, fixed-dose studies in subjects with schizophrenia, the proportions of subjects meeting a weight gain criterion of ≥ 7% of body weight were compared, revealing a similar incidence of weight gain for INVEGA ® 3 mg and 6 mg (7% and 6%, respectively) compared with placebo (5%), and a higher incidence of weight gain for INVEGA ® 9 mg and 12 mg (9% and 9%, respectively). Schizoaffective Disorder Trials In the pooled data from the two placebo-controlled, 6-week studies in subjects with schizoaffective disorder, a higher percentage of INVEGA ® -treated subjects (5%) had an increase in body weight of ≥ 7% compared with placebo-treated subjects (1%). In the study that examined high- and low-dose groups, the increase in body weight of ≥ 7% was 3% in the low-dose group, 7% in the high-dose group, and 1% in the placebo group. 6.10 Other Findings Observed During Clinical Trials The safety of INVEGA ® was also evaluated in a long-term trial designed to assess the maintenance of effect with INVEGA ® in adults with schizophrenia [see Clinical Studies (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. 6.11 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, priapism, swollen tongue, tardive dyskinesia, urinary incontinence, urinary retention. 6.12 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.