FDA label 7ec07ddf-81e2-435e-8836-0fb4e238fe35

WARNINGS : INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS 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. Risperidone is not approved for use in patients with dementia-related psychosis. ( 5.1 ) 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. Risperidone is not approved for the treatment of patients with dementia-related psychosis [See Warnings and Precautions (5.1) ]

5. WARNINGS AND PRECAUTIONS Cerebrovascular events, including stroke, in elderly patients with dementia-related psychosis. Risperidone is not approved for use in patients with dementia-related psychosis ( 5.2 ) Neuroleptic Malignant Syndrome ( 5.3 ) Tardive dyskinesia ( 5.4 ) Hyperglycemia and diabetes mellitus ( 5.5 ) Hyperprolactinemia ( 5.6 ) Orthostatic hypotension ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics, including risperidone. Patients with a history of a clinically significant low white blood cell count (WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. ( 5.8 ) Potential for cognitive and motor impairment ( 5.9 ) Seizures ( 5.10 ) Dysphagia ( 5.11 ) Priapism ( 5.12 ) Thrombotic Thrombocytopenic Purpura (TTP) ( 5.13 ) Disruption of body temperature regulation ( 5.14 ) Antiemetic Effect ( 5.15 ) Suicide ( 5.16 ) Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies ( 5.17 ) Diseases or conditions that could affect metabolism or hemodynamic responses ( 5.17 ) 5.1 Increased Mortality in Elderly Patients with Dementia-Related Psychosis Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Risperidone is not approved for the treatment of dementia-related psychosis [see Boxed Warning ]. 5.2 Cerebrovascular Adverse Events, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73-97) in trials of risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse events in patients treated with risperidone compared to patients treated with placebo. Risperidone is not approved for the treatment of patients with dementia-related psychosis. [See also Boxed Warnings and Warnings and Precautions (5.1) ] 5.3 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. In arriving at a diagnosis, it is important to identify cases in which the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection, etc.) and untreated or inadequately treated extrapyramidal signs and symptoms (EPS). Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology. The management of NMS should include: (1) immediate discontinuation of antipsychotic drugs and other drugs not essential to concurrent therapy; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for uncomplicated NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. The patient should be carefully monitored, since recurrences of NMS have been reported. 5.4 Tardive Dyskinesia A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome. Whether antipsychotic drug products differ in their potential to cause tardive dyskinesia is unknown. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotic drugs administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Antipsychotic treatment, itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. Given these considerations, risperidone should be prescribed in a manner that is most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who suffer from a chronic illness that: (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment producing a satisfactory clinical response should be sought. The need for continued treatment should be reassessed periodically. If signs and symptoms of tardive dyskinesia appear in a patient treated with risperidone, drug discontinuation should be considered. However, some patients may require treatment with risperidone despite the presence of the syndrome. 5.5 Hyperglycemia and Diabetes Mellitus Hyperglycemia and diabetes mellitus, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics including risperidone. Assessment of the relationship between atypical antipsychotic use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics are not available. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics, including risperidone, should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) who are starting treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including risperidone, should be monitored for symptoms of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia during treatment with atypical antipsychotics, including risperidone, should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic, including risperidone, was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of risperidone. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, risperidone elevates prolactin levels and the elevation persists during chronic administration. Risperidone is associated with higher levels of prolactin elevation than other antipsychotic agents. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotropin secretion. This, in turn, may inhibit reproductive function by impairing gonadal steroidogenesis in both female and male patients. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Long-standing hyperprolactinemia when associated with hypogonadism may lead to decreased bone density in both female and male subjects. Tissue culture experiments indicate that approximately one-third of human breast cancers are prolactin dependent in vitro , a factor of potential importance if the prescription of these drugs is contemplated in a patient with previously detected breast cancer. An increase in pituitary gland, mammary gland, and pancreatic islet cell neoplasia (mammary adenocarcinomas, pituitary and pancreatic adenomas) was observed in the risperidone carcinogenicity studies conducted in mice and rats [see Non-Clinical Toxicology (13.1) ]. Neither clinical studies nor epidemiologic studies conducted to date have shown an association between chronic administration of this class of drugs and tumorigenesis in humans; the available evidence is considered too limited to be conclusive at this time. 5.7 Orthostatic Hypotension Risperidone may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, especially during the initial dose-titration period, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of risperidone-treated patients in Phase 2 and 3 studies in adults with schizophrenia. The risk of orthostatic hypotension and syncope may be minimized by limiting the initial dose to 2 mg total (either once daily or 1 mg twice daily) in normal adults and 0.5 mg twice daily in the elderly and patients with renal or hepatic impairment [see Dosage and Administration ( 2.1 , 2.4 )]. Monitoring of orthostatic vital signs should be considered in patients for whom this is of concern. A dose reduction should be considered if hypotension occurs. Risperidone should be used with particular caution in patients with known cardiovascular disease (history of myocardial infarction or ischemia, heart failure, or conduction abnormalities), cerebrovascular disease, and conditions which would predispose patients to hypotension, e.g., dehydration and hypovolemia. Clinically significant hypotension has been observed with concomitant use of risperidone and antihypertensive medication. 5.8 Leukopenia, Neutropenia, and Agranulocytosis Class Effect: In clinical trial and/or postmarketing experience, events of leukopenia/neutropenia have been reported temporally related to antipsychotic agents, including risperidone. Agranulocytosis has also been reported. Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients with a history of a clinically significant low WBC or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and discontinuation of risperidone should be considered at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Patients with clinically significant neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count <1000/mm 3 ) should discontinue risperidone and have their WBC followed until recovery. 5.9 Potential for Cognitive and Motor Impairment Somnolence was a commonly reported adverse event associated with risperidone treatment, especially when ascertained by direct questioning of patients. This adverse event is dose-related, and in a study utilizing a checklist to detect adverse events, 41% of the high-dose patients (risperidone 16 mg/day) reported somnolence compared to 16% of placebo patients. Direct questioning is more sensitive for detecting adverse events than spontaneous reporting, by which 8% of risperidone 16 mg/day patients and 1% of placebo patients reported somnolence as an adverse event. Since risperidone has the potential to impair judgment, thinking, or motor skills, patients should be cautioned about operating hazardous machinery, including automobiles, until they are reasonably certain that risperidone therapy does not affect them adversely. 5.10 Seizures During premarketing testing in adult patients with schizophrenia, seizures occurred in 0.3% (9/2607) of risperidone-treated patients, two in association with hyponatremia. Risperidone should be used cautiously in patients with a history of seizures. 5.11 Dysphagia Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in patients with advanced Alzheimer’s dementia. Risperidone and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia. [See also Boxed Warning and Warnings and Precautions (5.1) ] 5.12 Priapism Priapism has been reported during postmarketing surveillance [see Adverse Reactions (6.9) ]. Severe priapism may require surgical intervention. 5.13 Thrombotic Thrombocytopenic Purpura (TTP) A single case of TTP was reported in a 28 year-old female patient receiving oral risperidone in a large, open premarketing experience (approximately 1300 patients). She experienced jaundice, fever, and bruising, but eventually recovered after receiving plasmapheresis. The relationship to risperidone therapy is unknown. 5.14 Body Temperature Regulation Disruption of body temperature regulation has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Caution is advised when prescribing for patients who will be exposed to temperature extremes. 5.15 Antiemetic Effect Risperidone has an antiemetic effect in animals; this effect may also occur in humans, and may mask signs and symptoms of overdosage with certain drugs or of conditions such as intestinal obstruction, Reye’s syndrome, and brain tumor. 5.16 Suicide The possibility of a suicide attempt is inherent in patients with schizophrenia and bipolar mania, including children and adolescent patients, and close supervision of high-risk patients should accompany drug therapy. Prescriptions for risperidone should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose. 5.17 Use in Patients with Concomitant Illness Clinical experience with risperidone in patients with certain concomitant systemic illnesses is limited. Patients with Parkinson’s Disease or Dementia with Lewy Bodies, who receive antipsychotics, including risperidone, are reported to have an increased sensitivity to antipsychotic medications. Manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome. Caution is advisable in using risperidone in patients with diseases or conditions that could affect metabolism or hemodynamic responses. Risperidone has not been evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from clinical studies during the product's premarket testing. Increased plasma concentrations of risperidone and 9-hydroxyrisperidone occur in patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m 2 ), and an increase in the free fraction of risperidone is seen in patients with severe hepatic impairment. A lower starting dose should be used in such patients [see Dosage and Administration (2.4) ]. 5.18 Monitoring: Laboratory Tests No specific laboratory tests are recommended.

6. ADVERSE REACTIONS The most common adverse reactions in clinical trials (≥10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash. ( 6 ) The most common adverse reactions that were associated with discontinuation from clinical trials were nausea, somnolence, sedation, vomiting, dizziness, and akathisia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Torrent pharma Inc. at 1-269-544-2299 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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) ] Tardive dyskinesia [see Warnings and Precautions (5.4) ] Hyperglycemia and diabetes mellitus [see Warnings and Precautions (5.5) ] Hyperprolactinemia [see Warnings and Precautions (5.6) ] Orthostatic hypotension [see Warnings and Precautions (5.7) ] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions (5.8) ] Potential for cognitive and motor impairment [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Dysphagia [see Warnings and Precautions (5.11) ] Priapism [see Warnings and Precautions (5.12) ] Thrombotic Thrombocytopenic Purpura (TTP) [see Warnings and Precautions (5.13) ] Disruption of body temperature regulation [see Warnings and Precautions (5.14) ] Antiemetic effect [see Warnings and Precautions (5.15) ] Suicide [see Warnings and Precautions (5.16) ] Increased sensitivity in patients with Parkinson’s disease or those with dementia with Lewy bodies [see Warnings and Precautions (5.17) ] Diseases or conditions that could affect metabolism or hemodynamic responses [see Warnings and Precautions (5.17) ] . The most common adverse reactions in clinical trials (≥ 10%) were somnolence, increased appetite, fatigue, insomnia, sedation, parkinsonism, akathisia, vomiting, cough, constipation, nasopharyngitis, drooling, rhinorrhea, dry mouth, abdominal pain upper, dizziness, nausea, anxiety, headache, nasal congestion, rhinitis, tremor, and rash. The most common adverse reactions that were associated with discontinuation from clinical trials (causing discontinuation in >1% of adults and/or >2% of pediatrics) were nausea, somnolence, sedation, vomiting, dizziness, and akathisia [see Adverse Reactions (6.5) ]. The data described in this section are derived from a clinical trial database consisting of 9712 adult and pediatric patients exposed to one or more doses of risperidone for the treatment of schizophrenia, bipolar mania, autistic disorder, and other psychiatric disorders in pediatrics and elderly patients with dementia. Of these 9712 patients, 2626 were patients who received risperidone while participating in double-blind, placebo-controlled trials. The conditions and duration of treatment with risperidone varied greatly and included (in overlapping categories) double-blind, fixed- and flexible-dose, placebo- or active-controlled studies and open-label phases of studies, inpatients and outpatients, and short-term (up to 12 weeks) and longer-term (up to 3 years) exposures. Safety was assessed by collecting adverse events and performing physical examinations, vital signs, body weights, laboratory analyses, and ECGs. 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 risperidone (adverse drug reactions) based on the comprehensive assessment of the available adverse event information. A causal association for risperidone 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 majority of all adverse reactions were mild to moderate in severity. 6.1 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Schizophrenia Adult Patients with Schizophrenia Table 1 lists the adverse reactions reported in 1% or more of risperidone-treated adult patients with schizophrenia in three 4- to 8-week, double-blind, placebo-controlled trials. Table 1. Adverse Reactions in ≥ 1% of Risperidone-Treated Adult Patients with Schizophrenia in Double-Blind, Placebo-Controlled Trials. Percentage of Patients Reporting Event Risperidone System/Organ Class 2-8 mg per day >8-16 mg per day Placebo Adverse Reaction (N=366) (N=198) (N=225) Blood and Lymphatic System Disorders Anemia <1 1 0 Cardiac Disorders Tachycardia 1 3 0 Ear and Labyrinth Disorders Ear pain <1 1 0 Eye Disorders Vision blurred 3 1 1 Gastrointestinal Disorders Nausea 9 4 4 Constipation 8 9 6 Dyspepsia 8 6 5 Vomiting 7 5 7 Dry mouth 4 0 1 Abdominal discomfort 3 1 1 Salivary hypersecretion 2 1 <1 Diarrhea 2 1 1 Abdominal pain 1 1 0 Abdominal pain upper 1 1 0 Stomach discomfort 1 1 1 General Disorders Fatigue 3 1 0 Chest pain 2 2 1 Asthenia 2 1 <1 Immune System Disorders Hypersensitivity <1 1 0 Infections and Infestations Nasopharyngitis 3 4 3 Upper respiratory tract infection 2 3 1 Sinusitis 1 2 1 Urinary tract infection 1 3 0 Investigations Weight increased 1 1 0 Blood creatine phosphokinase increased 1 2 <1 Heart rate increased <1 2 0 Metabolism and Nutrition Disorders Decreased appetite 1 0 <1 Musculoskeletal and Connective Tissue Disorders Back pain 4 1 1 Arthralgia 2 3 <1 Pain in extremity 2 1 1 Joint stiffness 1 1 0 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tumor. Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis. 14 17 8 Akathisia 10 10 3 Dizziness 7 4 2 Somnolence 7 2 1 Dystonia 3 4 2 Sedation 3 3 1 Tremor 2 3 1 Dizziness postural 2 0 0 Dyskinesia 1 2 2 Syncope 1 1 0 Psychiatric Disorders Insomnia 32 25 27 Anxiety 16 11 11 Nervousness 1 1 <1 Renal and Urinary Disorders Urinary incontinence 1 1 0 Reproductive System and Breast Disorders Ejaculation failure <1 1 0 Respiratory , Thoracic and Mediastinal Disorders Nasal congestion 4 6 2 Dyspnea 1 2 0 Epistaxis <1 2 0 Skin and Subcutaneous Tissue Disorders Rash 1 4 1 Dry skin 1 3 0 Dandruff 1 1 0 Seborrheic dermatitis <1 1 0 Hyperkeratosis 0 1 1 Vascular Disorders Orthostatic hypotension 2 1 0 Hypotension 1 1 0 Pediatric Patients with Schizophrenia Table 2 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with schizophrenia in a 6-week double-blind, placebo-controlled trial. Table 2. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients with Schizophrenia in a Double-Blind Trial Percentage of Patients Reporting Event Risperidone System/Organ Class 1-3 mg per day 4-6 mg per day Placebo Adverse Reaction (N=55) (N=51) (N=54) Gastrointestinal Disorders Salivary hypersecretion 0 10 2 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration. 16 28 11 Sedation 13 8 2 Somnolence 11 4 2 Tremor 11 10 6 Akathisia 9 10 4 Dizziness 7 14 2 Dystonia 2 6 0 Psychiatric Disorders Anxiety 7 6 0 6.2 Commonly-Observed Adverse Reactions in Double-Blind, Placebo-Controlled Clinical Trials – Bipolar Mania Adult Patients with Bipolar Mania Table 3 lists the adverse reactions reported in 1% or more of risperidone-treated adult patients with bipolar mania in four 3-week, double-blind, placebo-controlled monotherapy trials. Table 3. Adverse Reactions in ≥1% Risperidone-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Monotherapy Trials Percentage of Patients Reporting Event Risperidone Placebo System/Organ Class 1-6 mg per day (N=424) Adverse Reaction (N=448) Cardiac Disorders Tachycardia 1 <1 Eye Disorders Vision blurred 2 1 Gastrointestinal Disorders Nausea 5 2 Diarrhea 3 2 Salivary hypersecretion 3 1 Dyspepsia 2 2 Stomach discomfort 2 <1 General Disorders Fatigue 2 1 Asthenia 1 1 Pyrexia 1 1 Infections and Infestations Nasopharyngitis 1 1 Investigations Aspartate aminotransferase increased 1 <1 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. Dyskinesia includes muscle twitching and dyskinesia. 25 9 Akathisia 9 3 Tremor* 6 3 Dizziness 6 5 Sedation 6 2 Somnolence 5 2 Dystonia* 5 1 Lethargy 2 1 Dyskinesia 1 <1 Reproductive System and Breast Disorders Galactorrhea 1 0 Skin and Subcutaneous Tissue Disorders Acne 1 0 Table 4 lists the adverse reactions reported in 2% or more of risperidone-treated adult patients with bipolar mania in two 3-week, double-blind, placebo-controlled adjuvant therapy trials. Table 4. Adverse Reactions in ≥2% of Risperidone-Treated Adult Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Adjuvant Therapy Trials. Percentage of Patients Reporting Event Risperidone + Placebo + System/Organ Class Mood Stabilizer Mood Stabilizer Adverse Reaction (N=127) (N=126) Cardiac Disorders Palpitations 2 0 Gastrointestinal Disorders Dyspepsia 9 8 Nausea 6 4 Diarrhea 6 4 Dry mouth 4 4 Vomiting 4 6 Constipation 3 3 Salivary hypersecretion 2 0 General Disorders Chest pain 2 1 Fatigue 2 2 Infections and Infestations Nasopharyngitis 2 3 Urinary tract infection 2 1 Investigations Weight increased 2 2 Nervous System Disorders Parkinsonism Parkinsonism includes extrapyramidal disorder, hypokinesia and bradykinesia. Akathisia includes hyperkinesia and akathisia. 14 4 Headache 14 15 Akathisia 8 0 Dizziness 7 2 Sedation 6 3 Tremor 6 2 Somnolence 3 1 Lethargy 2 1 Psychiatric Disorders Insomnia 4 8 Anxiety 3 2 Respiratory , Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 5 2 Cough 2 0 Pediatric Patients with Bipolar Mania Table 5 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients with bipolar mania in a 3-week double-blind, placebo-controlled trial. Table 5. Adverse Reactions in ≥ 5% of Risperidone-Treated Pediatric Patients with Bipolar Mania in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Event Risperidone System/Organ Class 0.5-2.5 mg per day 3-6 mg per day Placebo Adverse Reaction (N=50) (N=61) (N=58) Eye Disorders Vision blurred 4 7 0 Gastrointestinal Disorders Abdominal pain upper 16 13 5 Nausea 16 13 7 Vomiting 10 10 5 Diarrhea 8 7 2 Dyspepsia 10 3 2 Stomach discomfort 6 0 2 General Disorders Fatigue 18 30 3 Metabolism and Nutrition Disorders Increased appetite 4 7 2 Nervous System Disorders Somnolence 22 30 12 Sedation 20 23 7 Dizziness 16 13 5 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, bradykinesia, and nuchal rigidity. Dystonia includes dystonia, laryngospasm, and muscle spasms. Akathisia includes restlessness and akathisia. 6 12 3 Dystonia 6 5 0 Akathisia 0 8 2 Psychiatric Disorders Anxiety 0 8 3 Respiratory , Thoracic and Mediastinal Disorders Pharyngolaryngeal pain 10 3 5 Skin and Subcutaneous Tissue Disorders Rash 0 7 2 6.3 Commonly-Observed Adverse Reactions in Double-Blind, Placebo - Controlled Clinical Trials – Autistic Disorder Table 6 lists the adverse reactions reported in 5% or more of risperidone-treated pediatric patients treated for irritability associated with autistic disorder in two 8-week, double-blind, placebo-controlled trials. Table 6. Adverse Reactions in ≥5% of Risperidone-Treated Pediatric Patients Treated for Irritability Associated with Autistic Disorder in Double-Blind, Placebo-Controlled Trials Percentage of Patients Reporting Event System/Organ Class Risperidone Placebo Adverse Reaction 0.5-4.0 mg per day (N=80) (N=76) Cardiac Disorders Tachycardia 5 0 Gastrointestinal Disorders Vomiting 25 21 Constipation 21 8 Dry mouth 15 6 Salivary hypersecretion 9 0 Nausea 8 6 General Disorders Fatigue 42 13 Feeling abnormal 5 0 Infections and Infestations Nasopharyngitis 21 10 Rhinitis 13 10 Upper respiratory tract infection 8 3 Investigations Weight increased 5 0 Metabolism and Nutrition Disorders Increased appetite 47 19 Nervous System Disorders Somnolence 49 18 Sedation 29 3 Drooling 16 5 Tremor 12 1 Parkinsonism Parkinsonism includes musculoskeletal stiffness, extrapyramidal disorder, muscle rigidity, cogwheel rigidity, and muscle tightness. 11 1 Dizziness 9 3 Dyskinesia 7 3 Lethargy 5 3 Respiratory , Thoracic and Mediastinal Disorders Cough 24 18 Rhinorrhea 16 13 Nasal congestion 13 5 Skin and Subcutaneous Tissue Disorders Rash 11 8 In another study with patients treated for irritability associated with autistic disorder, headache (6%), epistaxis (6%) and pyrexia (6%) were also observed in risperidone-treated pediatric subjects. 6.4 Other Adverse Reactions Observed During the Clinical Trial Evaluation of Risperidone The following adverse reactions occurred in < 1% of the adult patients and in < 5% of the pediatric patients treated with risperidone in the above double-blind, placebo-controlled clinical trial data sets. In addition, the following also includes adverse reactions reported in risperidone-treated patients who participated in other studies, including double-blind, active-controlled and open-label studies in schizophrenia and bipolar mania studies in pediatric patients with psychiatric disorders other than schizophrenia, bipolar mania, or autistic disorder, and studies in elderly patients with dementia. Blood and Lymphatic System Disorders: granulocytopenia, neutropenia Cardiac Disorders: sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders: tinnitus Endocrine Disorders: hyperprolactinemia Eye Disorders: ocular hyperemia, eye discharge, conjunctivitis, eye rolling, eyelid edema, eye swelling, eyelid margin crusting, dry eye, lacrimation increased, photophobia, glaucoma, visual acuity reduced Gastrointestinal Disorders: dysphagia, fecaloma, fecal incontinence, gastritis, lip swelling, cheilitis, aptyalism General Disorders: edema peripheral, thirst, gait disturbance, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, chest discomfort, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness Immune System Disorders: drug hypersensitivity Infections and Infestations: pneumonia, influenza, ear infection, viral infection, pharyngitis, tonsillitis, bronchitis, eye infection, localized infection, cystitis, cellulitis, otitis media, onychomycosis, acarodermatitis, bronchopneumonia, respiratory tract infection, tracheobronchitis, otitis media chronic Investigations: body temperature increased, blood prolactin increased, alanine aminotransferase increased, electrocardiogram abnormal, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders: polydipsia, anorexia Musculoskeletal and Connective Tissue Disorders: joint swelling, musculoskeletal chest pain, posture abormal, myalgia, neck pain, muscular weakness, rhabdomyolysis Nervous System Disorders: balance disorder, disturbance in attention, dysarthria, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypersomnia, transient ischemic attack, coordination abnormal, cerebrovascular accident, speech disorder, loss of consciousness, hypoesthesia, tardive dyskinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders: agitation, blunted affect, confusional state, middle insomnia, sleep disorder, listlessness, libido decreased, anorgasmia Renal and Urinary Disorders: enuresis, dysuria, pollakiuria Reproductive System and Breast Disorders: menstruation irregular, amenorrhea, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders: wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders: erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, rash generalized, rash maculopapular Vascular Disorders: flushing 6.5 Discontinuations Due to Adverse Reactions Schizophrenia - Adults Approximately 7% (39/564) of risperidone-treated patients in double-blind, placebo-controlled trials discontinued treatment due to an adverse event, compared with 4% (10/225) who were receiving placebo. The adverse reactions associated with discontinuation in 2 or more risperidone-treated patients were: Table 7. Adverse Reactions Associated With Discontinuation in 2 or More Risperidone-Treated Adult Patients in Schizophrenia Trials Risperidone 2-8 mg/day >8-16 mg/day Placebo Adverse Reaction (N=366) (N=198) (N=225) Dizziness 1.4% 1.0% 0% Nausea 1.4% 0% 0% Vomiting 0.8% 0% 0% Parkinsonism 0.8% 0% 0% Somnolence 0.8% 0% 0% Dystonia 0.5% 0% 0% Agitation 0.5% 0% 0% Abdominal pain 0.5% 0% 0% Orthostatic hypotension 0.3% 0.5% 0% Akathisia 0.3% 2.0% 0% Discontinuation for extrapyramidal symptoms (including Parkinsonism, akathisia, dystonia, and tardive dyskinesia) was 1% in placebo-treated patients, and 3.4 % in active control-treated patients in a double-blind, placebo- and active-controlled trial. Schizophrenia - Pediatrics Approximately 7% (7/106), of risperidone-treated patients discontinued treatment due to an adverse event in a double-blind, placebo-controlled trial, compared with 4% (2/54) placebo-treated patients. The adverse reactions associated with discontinuation for at least one risperidone-treated patient were dizziness (2%), somnolence (1%), sedation (1%), lethargy (1%), anxiety (1%), balance disorder (1%), hypotension (1%), and palpitation (1%). Bipolar Mania - Adults In double-blind, placebo-controlled trials with risperidone as monotherapy, approximately 6% (25/448) of risperidone-treated patients discontinued treatment due to an adverse event, compared with approximately 5% (19/424) of placebo-treated patients. The adverse reactions associated with discontinuation in risperidone-treated patients were: Table 8. Adverse Reactions Associated with Discontinuation in 2 or More Risperidone-Treated Adult Patients in Bipolar Mania Clinical Trials Risperidone 1 - 6 mg / day Placebo Adverse Reaction ( N = 448 ) ( N = 424 ) Parkinsonism 0.4% 0% Lethargy 0.2% 0% Dizziness 0.2% 0% Alanine aminotransferase increased 0.2% 0.2% Aspartate aminotransferase increased 0.2% 0.2% Bipolar mania – Pediatrics In a double-blind, placebo-controlled trial 12% (13/111) of risperidone-treated patients discontinued due to an adverse event, compared with 7% (4/58) of placebo-treated patients. The adverse reactions associated with discontinuation in more than one risperidone-treated pediatric patient were nausea (3%), somnolence (2%), sedation (2%), and vomiting (2%). Autistic Disorder - Pediatrics In the two 8-week, placebo-controlled trials in pediatric patients treated for irritability associated with autistic disorder (n = 156), one risperidone-treated patient discontinued due to an adverse reaction (Parkinsonism), and one placebo-treated patient discontinued due to an adverse event. 6.6 Dose Dependency of Adverse Reactions in Clinical Trials Extrapyramidal Symptoms Data from two fixed-dose trials in adults with schizophrenia provided evidence of dose-relatedness for extrapyramidal symptoms associated with risperidone treatment. Two methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 4 fixed doses of risperidone (2, 6, 10, and 16 mg/day), including (1) a Parkinsonism score (mean change from baseline) from the Extrapyramidal Symptom Rating Scale, and (2) incidence of spontaneous complaints of EPS: Dose Groups Placebo Risperidone 2 mg Risperidone 6 mg Risperidone 10 mg Risperidone 16 mg Parkinsonism EPS Incidence 1.2 13% 0.9 17% 1.8 21% 2.4 21% 2.6 35% Similar methods were used to measure extrapyramidal symptoms (EPS) in an 8-week trial comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day): Dose Groups Risperidone Risperidone Risperidone Risperidone Risperidone 1 mg 4 mg 8 mg 12 mg 16 mg Parkinsonism 0.6 1.7 2.4 2.9 4.1 EPS 7% 12% 17% 18% 20% Incidence 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. Other Adverse Reactions Adverse event data elicited by a checklist for side effects from a large study comparing 5 fixed doses of risperidone (1, 4, 8, 12, and 16 mg/day) were explored for dose-relatedness of adverse events. A Cochran-Armitage Test for trend in these data revealed a positive trend (p<0.05) for the following adverse reactions: somnolence, vision abnormal, dizziness, palpitations, weight increase, erectile dysfunction, ejaculation disorder, sexual function abnormal, fatigue, and skin discoloration. 6.7 Changes in Body Weight The proportions of risperidone and placebo-treated adult patients with schizophrenia meeting a weight gain criterion of ≥ 7% of body weight were compared in a pool of 6- to 8-week, placebo-controlled trials, revealing a statistically significantly greater incidence of weight gain for risperidone (18%) compared to placebo (9%). In a pool of placebo-controlled 3-week studies in adult patients with acute mania, the incidence of weight increase of ≥ 7% at endpoint was comparable in the risperidone (2.5%) and placebo (2.4%) groups, and was slightly higher in the active-control group (3.5%). Changes in body weight were also evaluated in pediatric patients [see Use in Specific Populations (8.4) ] 6.8 Changes in ECG Between-group comparisons for pooled placebo-controlled trials in adults revealed no statistically significant differences between risperidone and placebo in mean changes from baseline in ECG parameters, including QT, QTc, and PR intervals, and heart rate. When all risperidone doses were pooled from randomized controlled trials in several indications, there was a mean increase in heart rate of 1 beat per minute compared to no change for placebo patients. In short-term schizophrenia trials, higher doses of risperidone (8-16 mg/day) were associated with a higher mean increase in heart rate compared to placebo (4-6 beats per minute). In pooled placebo-controlled acute mania trials in adults, there were small decreases is mean heart rate, similar among all treatment groups. In the two placebo-controlled trials in children and adolescents with autistic disorder (aged 5 - 16 years) mean changes in heart rate were an increase of 8.4 beats per minute in the risperidone groups and 6.5 beats per minute in the placebo group. There were no other notable ECG changes. In a placebo-controlled acute mania trial in children and adolescents (aged 10 - 17 years), there were no significant changes in ECG parameters, other than the effect of risperidone to transiently increase pulse rate (< 6 beats per minute). In two controlled schizophrenia trials in adolescents (aged 13 - 17 years), there were no clinically meaningful changes in ECG parameters including corrected QT intervals between treatment groups or within treatment groups over time. 6.9 Postmarketing Experience The following adverse reactions have been identified during postapproval use of risperidone; because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency: agranulocytosis, alopecia, anaphylactic reaction, angioedema, atrial fibrillation, blood cholesterol increased, blood triglycerides increased, diabetes mellitus, diabetic ketoacidosis in patients with impaired glucose metabolism, drug withdrawal syndrome neonatal, dysgeusia, hypoglycemia, hypothermia, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, priapism, QT prolongation, sleep apnea syndrome, thrombocytopenia, urinary retention, and water intoxication. Other adverse events reported since market introduction, which were temporally related to risperidone but not necessarily causally related, include the following: pituitary adenoma, pulmonary embolism, precocious puberty, cardiopulmonary arrest, and sudden death.

<table ID="ID86" width="100%"> <col width="61%"/> <col width="13%"/> <col width="13%"/> <col width="13%"/> <thead> <tr> <td align="left" valign="bottom" colspan="1"/> <td align="center" valign="bottom" colspan="3"> <paragraph> <content styleCode="bold">Percentage of Patients Reporting Event </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"/> <td align="center" valign="bottom" colspan="3"> <paragraph> <content styleCode="bold">Risperidone </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">System/Organ Class</content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">2-8 mg per day </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">&gt;8-16 mg per day </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">Placebo </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1">Adverse Reaction </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=366) </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=198) </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=225) </content> </paragraph> </td> </tr> </thead> <tbody> <tr> <td align="left" valign="bottom" styleCode=" Toprule"> <content styleCode="bold">Blood </content> <content styleCode="bold">and </content> <content styleCode="bold">Lymphatic </content> <content styleCode="bold">System </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom" styleCode=" Toprule"> </td> <td align="center" valign="bottom" styleCode=" Toprule"> </td> <td align="center" valign="bottom" styleCode=" Toprule"> </td> </tr> <tr> <td align="left" valign="bottom">Anemia </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Cardiac </content> <content styleCode="bold">Disorders</content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Tachycardia </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Ear </content> <content styleCode="bold">and </content> <content styleCode="bold">Labyrinth </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Ear pain </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Eye </content> <content styleCode="bold">Disorders</content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Vision blurred </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Gastrointestinal </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Nausea </td> <td align="center" valign="bottom">9 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">4 </td> </tr> <tr> <td align="left" valign="bottom">Constipation </td> <td align="center" valign="bottom">8 </td> <td align="center" valign="bottom">9 </td> <td align="center" valign="bottom">6 </td> </tr> <tr> <td align="left" valign="bottom">Dyspepsia </td> <td align="center" valign="bottom">8 </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">5 </td> </tr> <tr> <td align="left" valign="bottom">Vomiting </td> <td align="center" valign="bottom">7 </td> <td align="center" valign="bottom">5 </td> <td align="center" valign="bottom">7 </td> </tr> <tr> <td align="left" valign="bottom">Dry mouth </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">0 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Abdominal discomfort </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Salivary hypersecretion </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom">Diarrhea </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Abdominal pain </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Abdominal pain upper </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Stomach discomfort </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">General </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Fatigue </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Chest pain </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Asthenia </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Immune </content> <content styleCode="bold">System </content> <content styleCode="bold">Disorders</content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Hypersensitivity </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Infections </content> <content styleCode="bold">and </content> <content styleCode="bold">Infestations</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Nasopharyngitis </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">3 </td> </tr> <tr> <td align="left" valign="bottom">Upper respiratory tract infection </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Sinusitis </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Urinary tract infection<content styleCode="bold"> </content> </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Investigations</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Weight increased </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Blood creatine phosphokinase increased </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom">Heart rate increased </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Metabolism </content> <content styleCode="bold">and </content> <content styleCode="bold">Nutrition </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Decreased appetite </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Musculoskeletal </content> <content styleCode="bold">and </content> <content styleCode="bold">Connective </content> <content styleCode="bold">Tissue </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Back pain </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Arthralgia </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom">Pain in extremity </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Joint stiffness </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Nervous </content> <content styleCode="bold">System </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Parkinsonism<footnote ID="ID18_1">Parkinsonism includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson&#x2019;s disease. Akathisia includes akathisia and restlessness. Dystonia includes dystonia, muscle spasms, muscle contractions involuntary, muscle contracture, oculogyration, tongue paralysis. Tremor includes tremor and parkinsonian rest tumor. Dyskinesia includes dyskinesia, muscle twitching, chorea, and choreoathetosis.</footnote> </td> <td align="center" valign="bottom">14 </td> <td align="center" valign="bottom">17 </td> <td align="center" valign="bottom">8 </td> </tr> <tr> <td align="left" valign="bottom">Akathisia<footnoteRef IDREF="ID18_1"/> </td> <td align="center" valign="bottom">10 </td> <td align="center" valign="bottom">10 </td> <td align="center" valign="bottom">3 </td> </tr> <tr> <td align="left" valign="bottom">Dizziness </td> <td align="center" valign="bottom">7 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Somnolence </td> <td align="center" valign="bottom">7 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Dystonia<footnoteRef IDREF="ID18_1"/> </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Sedation </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Tremor<footnoteRef IDREF="ID18_1"/> </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Dizziness postural </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">0 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Dyskinesia<footnoteRef IDREF="ID18_1"/> </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Syncope </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Psychiatric </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Insomnia </td> <td align="center" valign="bottom">32 </td> <td align="center" valign="bottom">25 </td> <td align="center" valign="bottom">27 </td> </tr> <tr> <td align="left" valign="bottom">Anxiety </td> <td align="center" valign="bottom">16 </td> <td align="center" valign="bottom">11 </td> <td align="center" valign="bottom">11 </td> </tr> <tr> <td align="left" valign="bottom">Nervousness </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Renal </content> <content styleCode="bold">and </content> <content styleCode="bold">Urinary </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Urinary incontinence </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Reproductive </content> <content styleCode="bold">System </content> <content styleCode="bold">and </content> <content styleCode="bold">Breast </content> <content styleCode="bold">Disorders </content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Ejaculation failure </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Respiratory</content> <content styleCode="bold">, </content> <content styleCode="bold">Thoracic </content> <content styleCode="bold">and </content> <content styleCode="bold">Mediastinal </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Nasal congestion </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Dyspnea </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Epistaxis </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Skin </content> <content styleCode="bold">and </content> <content styleCode="bold">Subcutaneous </content> <content styleCode="bold">Tissue </content> <content styleCode="bold">Disorders</content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Rash </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Dry skin </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Dandruff </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Seborrheic dermatitis </td> <td align="center" valign="bottom">&lt;1 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom">Hyperkeratosis </td> <td align="center" valign="bottom">0 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Vascular </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Orthostatic hypotension </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom" styleCode=" Botrule">Hypotension </td> <td align="center" valign="bottom" styleCode=" Botrule">1 </td> <td align="center" valign="bottom" styleCode=" Botrule">1 </td> <td align="center" valign="bottom" styleCode=" Botrule">0 </td> </tr> </tbody> </table>

<table ID="ID88" width="100%"> <col width="35%"/> <col width="24%"/> <col width="24%"/> <col width="17%"/> <thead> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold"/> </paragraph> </td> <td align="center" valign="bottom" colspan="3"> <paragraph> <content styleCode="bold">Percentage of Patients Reporting Event </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold"/> </paragraph> </td> <td align="center" valign="bottom" colspan="3"> <paragraph> <content styleCode="bold">Risperidone </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">System/Organ Class</content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">1-3 mg per day </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">4-6 mg per day </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">Placebo </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1">Adverse Reaction </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=55) </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=51) </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=54) </content> </paragraph> </td> </tr> </thead> <tbody> <tr> <td align="left" valign="bottom" styleCode=" Toprule"> <content styleCode="bold">Gastrointestinal </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="left" valign="bottom" styleCode=" Toprule"> </td> <td align="left" valign="bottom" styleCode=" Toprule"> </td> <td align="left" valign="bottom" styleCode=" Toprule"> </td> </tr> <tr> <td align="left" valign="bottom">Salivary hypersecretion<content styleCode="bold"> </content> </td> <td align="center" valign="bottom">0 </td> <td align="center" valign="bottom">10 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Nervous </content> <content styleCode="bold">System </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Parkinsonism<footnote ID="ID19_1">Parkinsonism includes extrapyramidal disorder, muscle rigidity, musculoskeletal stiffness, and hypokinesia. Akathisia includes akathisia and restlessness. Dystonia includes dystonia and oculogyration.</footnote> </td> <td align="center" valign="bottom">16 </td> <td align="center" valign="bottom">28 </td> <td align="center" valign="bottom">11 </td> </tr> <tr> <td align="left" valign="bottom">Sedation </td> <td align="center" valign="bottom">13 </td> <td align="center" valign="bottom">8 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Somnolence </td> <td align="center" valign="bottom">11 </td> <td align="center" valign="bottom">4 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Tremor </td> <td align="center" valign="bottom">11 </td> <td align="center" valign="bottom">10 </td> <td align="center" valign="bottom">6 </td> </tr> <tr> <td align="left" valign="bottom">Akathisia<footnoteRef IDREF="ID19_1"/> </td> <td align="center" valign="bottom">9 </td> <td align="center" valign="bottom">10 </td> <td align="center" valign="bottom">4 </td> </tr> <tr> <td align="left" valign="bottom">Dizziness </td> <td align="center" valign="bottom">7 </td> <td align="center" valign="bottom">14 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Dystonia<footnoteRef IDREF="ID19_1"/> </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Psychiatric </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> <td align="center" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom" styleCode=" Botrule">Anxiety </td> <td align="center" valign="bottom" styleCode=" Botrule">7 </td> <td align="center" valign="bottom" styleCode=" Botrule">6 </td> <td align="center" valign="bottom" styleCode=" Botrule">0 </td> </tr> </tbody> </table>

<table ID="ID91" width="100%"> <col width="53%"/> <col width="29%"/> <col width="18%"/> <thead> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold"/> </paragraph> </td> <td align="center" valign="bottom" colspan="2"> <paragraph> <content styleCode="bold">Percentage of Patients Reporting Event </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold"/> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">Risperidone </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">Placebo </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">System/Organ Class </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">1-6 mg per day </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=424) </content> </paragraph> </td> </tr> <tr> <td align="left" valign="bottom" colspan="1">Adverse Reaction </td> <td align="center" valign="bottom" colspan="1"> <paragraph> <content styleCode="bold">(N=448) </content> </paragraph> </td> <td align="center" valign="bottom" colspan="1"/> </tr> </thead> <tbody> <tr> <td align="left" valign="bottom" styleCode=" Toprule"> <content styleCode="bold">Cardiac </content> <content styleCode="bold">Disorders</content> <content styleCode="bold"> </content> </td> <td align="left" valign="bottom" styleCode=" Toprule"> </td> <td align="left" valign="bottom" styleCode=" Toprule"> </td> </tr> <tr> <td align="left" valign="bottom">Tachycardia </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Eye </content> <content styleCode="bold">Disorders</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Vision blurred </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Gastrointestinal </content> <content styleCode="bold">Disorders</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Nausea </td> <td align="center" valign="bottom">5 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Diarrhea </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Salivary hypersecretion </td> <td align="center" valign="bottom">3 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Dyspepsia </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Stomach discomfort </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">General </content> <content styleCode="bold">Disorders</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Fatigue </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Asthenia </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Pyrexia </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Infections </content> <content styleCode="bold">and </content> <content styleCode="bold">Infestations</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Nasopharyngitis </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Investigations</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Aspartate aminotransferase increased </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Nervous </content> <content styleCode="bold">System </content> <content styleCode="bold">Disorders</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Parkinsonism<footnote ID="ID20_1">Parkinsonism includes extrapyramidal disorder, parkinsonism, musculoskeletal stiffness, hypokinesia, muscle rigidity, muscle tightness, bradykinesia, cogwheel rigidity. Akathisia includes akathisia and restlessness. Tremor includes tremor and parkinsonian rest tremor. Dystonia includes dystonia, muscle spasms, oculogyration, torticollis. Dyskinesia includes muscle twitching and dyskinesia.</footnote> </td> <td align="center" valign="bottom">25 </td> <td align="center" valign="bottom">9 </td> </tr> <tr> <td align="left" valign="bottom">Akathisia<footnoteRef IDREF="ID20_1"/> </td> <td align="center" valign="bottom">9 </td> <td align="center" valign="bottom">3 </td> </tr> <tr> <td align="left" valign="bottom">Tremor* </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">3 </td> </tr> <tr> <td align="left" valign="bottom">Dizziness </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">5 </td> </tr> <tr> <td align="left" valign="bottom">Sedation </td> <td align="center" valign="bottom">6 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Somnolence </td> <td align="center" valign="bottom">5 </td> <td align="center" valign="bottom">2 </td> </tr> <tr> <td align="left" valign="bottom">Dystonia* </td> <td align="center" valign="bottom">5 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Lethargy </td> <td align="center" valign="bottom">2 </td> <td align="center" valign="bottom">1 </td> </tr> <tr> <td align="left" valign="bottom">Dyskinesia<footnoteRef IDREF="ID20_1"/> </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">&lt;1 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Reproductive </content> <content styleCode="bold">System </content> <content styleCode="bold">and </content> <content styleCode="bold">Breast </content> <content styleCode="bold">Disorders </content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom">Galactorrhea </td> <td align="center" valign="bottom">1 </td> <td align="center" valign="bottom">0 </td> </tr> <tr> <td align="left" valign="bottom"> <content styleCode="bold">Skin </content> <content styleCode="bold">and </content> <content styleCode="bold">Subcutaneous </content> <content styleCode="bold">Tissue </content> <content styleCode="bold">Disorders</content> </td> <td align="left" valign="bottom"> </td> <td align="left" valign="bottom"> </td> </tr> <tr> <td align="left" valign="bottom" styleCode=" Botrule">Acne </td> <td align="center" valign="bottom" styleCode=" Botrule">1 </td> <td align="center" valign="bottom" styleCode=" Botrule">0 </td> </tr> </tbody> </table>