FDA label 2a09a7f2-caaa-5291-e063-6294a90ad5d7

WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISVAN is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 ) ] . WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS See full prescribing information for complete boxed warning. Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. RISVAN is not approved for use in patients with dementia-related psychosis. ( 5.1 )

5 WARNINGS AND PRECAUTIONS Cerebrovascular Adverse Reactions in Elderly Patients with Dementia-Related Psychosis: Increased risk of cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack. RISVAN is not approved for use in patients with dementia-related psychosis. ( 5.1 ) Neuroleptic Malignant Syndrome: Manage with immediate discontinuation of RISVAN and close monitoring. ( 5.3 ) Tardive Dyskinesia: Discontinue treatment if clinically appropriate. ( 5.4 ) Metabolic Changes: Monitor for hyperglycemia, dyslipidemia, and weight gain. ( 5.5 ) Hyperprolactinemia: Prolactin elevations occur and persist during chronic administration. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in females and males. ( 5.6 ) Orthostatic Hypotension and Syncope: Monitor heart rate and blood pressure and warn patients with known cardiovascular disease or cerebrovascular disease, and risk of dehydration or syncope. ( 5.7 ) Leukopenia, Neutropenia, and Agranulocytosis: Perform complete blood counts (CBC) in patients with a history of a clinically significant low white blood cell count (WBC) or history of leukopenia or neutropenia. Consider discontinuing RISVAN if a clinically significant decline in WBC occurs in absence of other causative factors. ( 5.9 ) Potential for Cognitive and Motor Impairment: Use caution when operating machinery. ( 5.10 ) Seizures: Use caution in patients with a history of seizures or with conditions that lower the seizure threshold. ( 5.11 ) Priapism: Priapism has been reported. Severe priapism may require surgical intervention. ( 5.13 ) 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. 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 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. In two of four placebo-controlled trials in elderly patients with dementia-related psychosis, a higher incidence of mortality was observed in patients treated with furosemide plus oral risperidone when compared to patients treated with oral risperidone alone or with placebo plus furosemide. No pathological mechanism has been identified to explain this finding, and no consistent pattern for cause of death was observed. RISVAN is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning and Warnings and Precautions ( 5.2 )] . 5.2 Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-Related Psychosis Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatalities, were reported in patients (mean age 85 years; range 73 to 97) in trials of oral risperidone in elderly patients with dementia-related psychosis. In placebo-controlled trials, there was a significantly higher incidence of cerebrovascular adverse reactions in patients treated with oral risperidone compared to patients given placebo. RISVAN is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1 )] . 5.3 Neuroleptic Malignant Syndrome (NMS) NMS, a potentially fatal symptom complex, has been reported in association with antipsychotic drugs. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status including delirium, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If NMS is suspected, immediately discontinue RISVAN and provide symptomatic treatment and monitoring. 5.4 Tardive Dyskinesia 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 predict which patients will 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 is believed to increase as the duration of treatment and the total cumulative dose. The syndrome can develop, after relatively brief treatment periods, even at low doses. It may also occur after discontinuation of treatment. Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. 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, RISVAN should be prescribed in a manner most likely to minimize the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: 1) who suffer from a chronic illness that 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, use the lowest dose and the shortest duration of treatment producing a satisfactory clinical response should. Periodically reassess the need for continued treatment. If signs and symptoms of tardive dyskinesia appear in a patient treated with RISVAN, drug discontinuation should be considered. However, some patients may require treatment with RISVAN despite the presence of the syndrome. 5.5 Metabolic Changes Atypical antipsychotic drugs have been associated with metabolic changes that may increase cardiovascular/cerebrovascular risk. These metabolic changes include hyperglycemia, dyslipidemia, and body weight gain. While all drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile. 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 hyperglycemia-related adverse reactions in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycemia-related 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 RISVAN, 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 RISVAN, should undergo fasting blood glucose testing at the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics, including RISVAN, 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 RISVAN, 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. Data from a 12-week double-blind, placebo-controlled study with RISVAN in adults with schizophrenia are presented in Table 1. Table 1. Changes in Fasting Glucose and Postbaseline Abnormal Values of Glucose > 126 mg/dL from Baseline to End of Treatment in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia RISVAN 75 mg N = 144 RISVAN 100 mg N = 146 Placebo N = 147 Serum Glucose, mg/dL, mean † Mean Change from Baseline to End of Treatment 6.0 (n= 129) 1.80 (n = 125) 0.3 (n = 119) Glucose, > 126 mg/dL Proportion of patients with Postbaseline Abnormal Values ‡ 22/142 (15.5%) 27/142 (19%) 8/109 (7.3%) †The “n”s in the Serum Glucose mean row are the number of patients with data at baseline and end of treatment visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator In longer-term, controlled and uncontrolled studies, oral risperidone was associated with a mean change in glucose of +2.8 mg/dL at Week 24 (n=151) and +4.1 mg/dL at Week 48 (n=50). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics, including risperidone. Before or soon after initiation of antipsychotic medications, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Weight Gain Weight gain has been observed with atypical antipsychotic use. Monitor weight at baseline and frequently thereafter. Data from a 12-week double-blind, placebo-controlled study with RISVAN in adults with schizophrenia are presented in Table 2. Table 2. Mean Change in Body Weight from Baseline to End of Study and ≥ 7% Increase from Baseline in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia RISVAN 75mg RISVAN 100mg Placebo Weight (kg) † Change from baseline n=129 2.2 n=126 2.0 n=121 0.2 Weight (kg) ‡ ≥ 7% increase from baseline 15/129 (11.6%) 20/126 (15.9%) 5/121 (4.1%) †The “n”s in the Weight Change mean row are the number of patients with data at baseline and end of treatment visits. ‡ Data shown as number of patients with at least one postbaseline value as denominator and number of patients satisfying the predefined criterion as numerator. Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. In an open-label, 12-month long-term safety study, mean weight increased by approximately 0.4 kg from baseline to Day 85 and 1.1 kg from baseline to Day 365 in patients receiving RISVAN. 5.6 Hyperprolactinemia As with other drugs that antagonize dopamine D2 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 gonadotropin releasing hormone, resulting in reduced pituitary gonadotropin secretion. This 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 Nonclinical 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 and Syncope RISVAN may induce orthostatic hypotension associated with dizziness, tachycardia, and in some patients, syncope, probably reflecting its alpha-adrenergic antagonistic properties. Syncope was reported in 0.2% (6/2607) of patients treated with oral risperidone in Phase 2 and 3 studies in adults with schizophrenia. RISVAN should be used with particular caution in ( 1 ) 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, and ( 2 ) in the elderly and patients with renal or hepatic impairment. Monitoring of orthostatic vital signs should be considered in all such patients, and a dose reduction should be considered if hypotension occurs. Clinically significant hypotension has been observed with concomitant use of oral risperidone and antihypertensive medication. 5.8 Falls Antipsychotics, including RISVAN, may cause somnolence, postural hypotension, motor and sensory instability which may lead to falls and, consequently, fractures or other fall-related injuries. Somnolence, postural hypotension, motor and sensory instability have been reported with the use of risperidone. For patients, particularly the elderly, with diseases, conditions, or medications that could exacerbate these effects, assess the risk of falls when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy. 5.9 Leukopenia, Neutropenia, and Agranulocytosis In clinical trial and/or postmarketing experience, events of leukopenia and 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. In patients with a history of a clinically significant low WBC/ANC or a drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of RISVAN at the first sign of a clinically significant decline in WBC in the absence of other causative factors. Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Discontinue RISVAN in patients with severe neutropenia (absolute neutrophil count <1000/mm3) and follow their WBC until recovery. 5.10 Potential for Cognitive and Motor Impairment Somnolence, sedation, and dizziness were reported as adverse reactions in patients treated with RISVAN [see Adverse Reactions (6.1)] . Antipsychotics, including RISVAN, have the potential to impair judgment, thinking, or motor skills. In a 12-week, double-blind, placebo-controlled study, sedation (including somnolence) was reported by 4%, 6%, and 3% of patients treated with 75 mg of RISVAN, 100 mg of RISVAN, and placebo, respectively. Dizziness was reported by 4%, 4%, and 3% of 75 mg of RISVAN, 100 mg of RISVAN, and placebo, respectively. Patients should be cautioned about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that RISVAN does not adversely affect them. 5.11 Seizures During premarketing studies of oral risperidone in adult patients with schizophrenia, seizures occurred in 0.3% of patients (9 out of 2,607 patients), two in association with hyponatremia. Use RISVAN cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold. 5.12 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. Antipsychotic drugs, including RISVAN, should be used cautiously in patients at risk for aspiration . 5.13 Priapism Priapism has been reported during postmarketing surveillance for other risperidone products. Severe priapism may require surgical intervention. 5.14 Body Temperature Regulation Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Both hyperthermia and hypothermia have been reported in association with oral risperidone use. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use RISVAN with caution in patients who may experience these conditions.

<table border="0" width="100%"><caption>Table 1. Changes in Fasting Glucose and Postbaseline Abnormal Values of Glucose &gt; 126 mg/dL from Baseline to End of Treatment in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia</caption><tbody><tr><td/><td><content styleCode="bold">RISVAN 75 mg N = 144 </content></td><td><content styleCode="bold">RISVAN 100 mg N = 146 </content></td><td><content styleCode="bold">Placebo N = 147 </content></td></tr><tr><td><content styleCode="bold">Serum Glucose, mg/dL, mean</content>&#x2020; Mean Change from Baseline to End of Treatment </td><td>6.0 (n= 129)</td><td>1.80 (n = 125)</td><td>0.3 (n = 119)</td></tr><tr><td><content styleCode="bold">Glucose, &gt; 126 mg/dL</content> Proportion of patients with Postbaseline Abnormal Values ^&#x2021;</td><td><paragraph>22/142 (15.5%)</paragraph></td><td>27/142 (19%)</td><td>8/109 (7.3%)</td></tr></tbody></table>

<table border="0" width="100%"><caption>Table 2. Mean Change in Body Weight from Baseline to End of Study and &#x2265; 7% Increase from Baseline in a 12-Week Double Blind, Placebo-Controlled Study in Adults with Schizophrenia</caption><tbody><tr><td/><td><content styleCode="bold">RISVAN 75mg</content></td><td><content styleCode="bold">RISVAN 100mg</content></td><td><content styleCode="bold">Placebo</content></td></tr><tr><td><paragraph><content styleCode="bold">Weight (kg)</content> &#x2020; </paragraph> Change from baseline </td><td><paragraph><content styleCode="bold">n=129</content></paragraph> 2.2 </td><td><paragraph><content styleCode="bold">n=126</content></paragraph> 2.0 </td><td><paragraph><content styleCode="bold">n=121</content></paragraph> 0.2 </td></tr><tr><td><paragraph><content styleCode="bold">Weight (kg)</content> &#x2021; </paragraph> &#x2265; 7% increase from baseline </td><td>15/129 (11.6%)</td><td>20/126 (15.9%)</td><td>5/121 (4.1%)</td></tr></tbody></table>

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 reactions, including stroke, in elderly patients with dementia-related psychosis [see Warnings and Precautions ( 5.2 )] Neuroleptic malignant syndrome (NMS) [see Warnings and Precautions ( 5.3 )] Tardive dyskinesia [see Warnings and Precautions ( 5.4 )] Metabolic changes [see Warnings and Precautions ( 5.5 )] Hyperprolactinemia [see Warnings and Precautions ( 5.6 )] Orthostatic hypotension and syncope [see Warnings and Precautions ( 5.7 )] Falls [see Warnings and Precautions ( 5.8 )] Leukopenia, neutropenia, and agranulocytosis [see Warnings and Precautions ( 5.9 )] Potential for cognitive and motor impairment [see Warnings and Precautions ( 5.10 )] Seizures [see Warnings and Precautions ( 5.11 )] Dysphagia [see Warnings and Precautions ( 5.12 )] Priapism [see Warnings and Precautions ( 5.13 )] Body temperature regulation [see Warnings and Precautions ( 5.14 )] The most frequently reported adverse reactions in clinical trials (≥ 5% and twice placebo): hyperprolactinaemia, blood prolactin increased, akathisia, headache, sedation (including somnolence), weight increased, injection site pain, and alanine aminotransferase increased. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Laboratorios Farmacéuticos Rovi at 1-888-703-0896 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience 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 practice. The safety of RISVAN for the treatment of schizophrenia in adults is based on adequate and well controlled studies of oral risperidone in studies of patients with schizophrenia and other indications as well as in one 12-week placebo-controlled trial of RISVAN in adult patients with schizophrenia [see Clinical Studies ( 14 )] . The safety of RISVAN was evaluated in a total of 562 adult patients with schizophrenia who received at least 1 dose of RISVAN during the clinical development program. Of the 386 patients with schizophrenia who received one dose of Risvan during the 12-week, placebo-controlled trial, 168 patients received at least 13 doses of RISVAN during the double-blind and open label extension (OLE) phases. During double-blind period, RISVAN 75 mg was administered to 144 patients and RISVAN 100 mg to 146 patients. During the OLE period, RISVAN 75 mg was administered to 116 patients and RISVAN 100 mg to 99 patients. Adverse Reactions in the 12-Week Placebo-Controlled Trial in Adults with Schizophrenia The safety data presented below are derived from the 12-week double-blind placebo-controlled study of RISVAN in adult patients with schizophrenia. Adverse reactions that led to discontinuation in RISVAN-treated patients in the 12-week placebo-controlled trial in adults with schizophrenia include abscess limb (0.3%), skin infection (0.3%), fall (0.3%), humerus fracture (0.3%), liver function test increased (0.3%), neutrophil count decreased (0.3%), mental impairment (0.3%), erectile dysfunction (0.3%), galactorrhea (0.3%), lactation disorder (0.3%), and pruritis (0.3%). The most frequently reported adverse reactions (≥5% and twice placebo) are blood prolactin increase, hyperprolactinemia, akathisia, headache, sedation (including somnolence), weight increased, injection site pain, and alanine aminotransferase increased. Table 3 shows the incidence of adverse reactions that occurred in ≥2% of patients treated with RISVAN and at a greater frequency than placebo. Table 3. Adverse Reactions Occurring in ≥ 2% of RISVAN-Treated Adult Patients and at a Greater Frequency than Placebo in a 12-Week Placebo-Controlled Study in Schizophrenia System Organ Class Preferred Term RISVAN 75 mg (n = 146) % RISVAN 100 mg (n = 144) % Placebo (n = 147) % Cardiac disorders Tachycardia 1 3 0 Endocrine disorders Hyperprolactinemia 6 9 1 Gastrointestinal disorders Constipation 3 1 1 General disorders and administration site conditions Injection site pain 6 3 3 Infections and infestations Nasopharyngitis 4 3 0 Investigations Blood prolactin increased 9 14 0 Weight increased 7 6 2 Alanine aminotransferase increased 3 5 2 Aspartate aminotransferase increased 1 3 2 Blood triglycerides increased 3 2 1 Blood creatine phosphokinase increased 2 1 1 Blood cholesterol increased 0 2 0 Musculoskeletal and connective tissue disorders Myalgia 2 1 0 Muscle tightness 2 0 0 Nervous system disorders Headache 10 8 3 Akathisia 4 8 2 Sedation 1 4 6 3 Dizziness 4 4 3 Dystonia 2 4 4 1 1 Sedation includes sedation and somnolence 2 Dystonia includes dystonia and oromandibular dystonia Other Adverse Drug Reactions Observed During the Clinical Trial Evaluation of RISVAN Other adverse reactions of <2% incidence but greater than placebo are shown below. The following list does not include reactions: 1) already listed in previous tables or elsewhere in labeling, 2) which are part of the disease state, 3) for which a drug cause was remote, 4) which were so general as to be uninformative, or 5) which were not considered to have significant clinical implications. General Disorders and Administration Site Conditions: asthenia, fatigue, injection site reaction (including injection site erythema, swelling and discomfort) Metabolism and Nutrition Disorders: diabetes mellitus, increased appetite Nervous System Disorders: dysarthria, dyskinesia, drooling, mental impairment, restless legs syndrome Psychiatric Disorders: anorgasmia, enuresis, restlessness, tension Renal and Urinary disorders: glycosuria, micturition urgency Reproductive System and Breast Disorders: amenorrhea, dysmenorrhea, erectile dysfunction, galactorrhea Vascular Disorders: hypotension, orthostatic hypotension Additional Adverse Reactions Reported at an Incidence of 2% or more in Oral Risperidone-treated Adult Patients and Greater than Placebo The following is a list of adverse reactions that are not reported in Table 3 above for RISVAN and occurred at an incidence of 2% or more in oral risperidone-treated adult patients and greater than placebo during the clinical trial evaluation of oral risperidone: Eye Disorders: blurred vision Gastrointestinal Disorders: nausea, dyspepsia, dry mouth, abdominal discomfort, salivary hypersecretion, diarrhea General Disorders: fatigue, chest pain, asthenia Infections and Infestations: upper respiratory tract infection, sinusitis, urinary tract infection Investigations: heart rate increased Musculoskeletal and Connective Tissue Disorders: back pain, arthralgia, pain in extremity Nervous System Disorders: parkinsonism (includes extrapyramidal disorder, musculoskeletal stiffness, parkinsonism, cogwheel rigidity, akinesia, bradykinesia, hypokinesia, masked facies, muscle rigidity, and Parkinson’s disease), tremor (includes tremor and parkinsonian rest tremor), dizziness postural Psychiatric Disorders: insomnia, anxiety Respiratory, Thoracic and Mediastinal Disorders: nasal congestion, dyspnea, epistaxis Skin and Subcutaneous Tissue Disorders: rash, dry skin Other Adverse Reactions Reported in Clinical Trials with Oral Risperidone The following is a list of additional adverse reactions that have been reported during the clinical trial evaluation of oral risperidone, regardless of frequency of occurrence: Blood and Lymphatic System Disorders : anemia, granulocytopenia, neutropenia Cardiac Disorders : tachycardia, sinus bradycardia, sinus tachycardia, atrioventricular block first degree, bundle branch block left, bundle branch block right, atrioventricular block Ear and Labyrinth Disorders : ear pain, tinnitus Eye Disorders : vision blurred, oculogyration, 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, chest pain, influenza-like illness, pitting edema, edema, chills, sluggishness, malaise, face edema, discomfort, generalized edema, drug withdrawal syndrome, peripheral coldness, feeling abnormal Immune System Disorders : drug hypersensitivity Infections and Infestations : nasopharyngitis, upper respiratory tract infection, sinusitis, urinary tract infection, 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, alanine aminotransferase increased, electrocardiogram abnormal, heart rate increased, eosinophil count increased, white blood cell count decreased, blood glucose increased, hemoglobin decreased, blood creatine phosphokinase increased, hematocrit decreased, body temperature decreased, blood pressure decreased, transaminases increased Metabolism and Nutrition Disorders : decreased appetite, polydipsia, anorexia Musculoskeletal, Connective Tissue, and Bone Disorders : joint stiffness, joint swelling, musculoskeletal chest pain, posture abnormal, myalgia, neck pain, muscular weakness, muscle rigidity, muscle contracture, rhabdomyolysis Nervous System Disorders : balance disorder, dizziness postural, disturbance in attention, unresponsive to stimuli, depressed level of consciousness, movement disorder, hypokinesia, bradykinesia, transient ischemic attack, coordination abnormal, cerebrovascular accident, masked facies, speech disorder, syncope, loss of consciousness, hypoesthesia, tardive dyskinesia, muscle contractions involuntary, Parkinson’s disease, tongue paralysis, akinesia, cerebral ischemia, cerebrovascular disorder, neuroleptic malignant syndrome, diabetic coma, head titubation Psychiatric Disorders : agitation, blunted affect, confusional state, middle insomnia, nervousness, sleep disorder, listlessness, libido decreased, anorgasmia Renal and Urinary Disorders : enuresis, dysuria, pollakiuria, urinary incontinence Reproductive System and Breast Disorders : menstrual irregular, gynecomastia, vaginal discharge, menstrual disorder, erectile dysfunction, retrograde ejaculation, ejaculation disorder, sexual dysfunction, breast enlargement Respiratory, Thoracic, and Mediastinal Disorders : nasal congestion, dyspnea, epistaxis, wheezing, pneumonia aspiration, sinus congestion, dysphonia, productive cough, pulmonary congestion, respiratory tract congestion, rales, respiratory disorder, hyperventilation, nasal edema Skin and Subcutaneous Tissue Disorders : rash, dry skin, erythema, skin discoloration, skin lesion, pruritus, skin disorder, rash erythematous, rash papular, acne, hyperkeratosis, seborrheic dermatitis, rash generalized, rash maculopapular Vascular Disorders : flushing Dose Dependent Adverse Reactions in Clinical Trials Increased Prolactin In the 12-week double-blind, placebo-controlled study, there was an increase in mean prolactin levels in fasting blood samples from baseline to end of the study in both the RISVAN 75 mg and 100 mg groups, while mean prolactin for the placebo group decreased during the study. Changes in mean prolactin were dose-dependent. See Table 3 for the percentage of RISVAN-treated patients with hyperprolactinemia with an incidence of greater than or equal to 2% and greater than placebo. Extrapyramidal Symptoms (EPS) Several methods were used to measure EPS, including: (1) the Barnes Akathisia Rating Scale (BARS) global clinical rating score which evaluates akathisia, (2) the Abnormal Involuntary Movement Scale (AIMS) scores which evaluates dyskinesia, (3) the Simpson-Angus Scale (SAS) global score which broadly evaluates parkinsonism, and (4) the incidence of spontaneous reports of EPS-related adverse reactions. In the 12-week double-blind, placebo-controlled study, the mean changes from baseline in BARS, AIMS, and SAS total scores were comparable between RISVAN- and placebo-treated patients. At all postbaseline assessments, mean changes from baseline were between 0.0 and 0.1 (inclusive) for the BARS, between 0.1 and -0.1(inclusive) for the AIMS, and between 0.1 and 0.2 (inclusive) for the SAS. In the 12-week double-blind, placebo-controlled study, there was a higher incidence of akathisia in RISVAN 100 mg (8%) compared with the RISVAN 75 mg (4%) and the placebo group (2%); reports of extrapyramidal disorders were higher in the RISVAN 100 mg group (12%) compared with the RISVAN 75 mg (8%) and the placebo group (3%). Dystonia 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. Injection Site Reactions with RISVAN Local injection site pain was assessed using a subject-reported VAS scale (0 = no pain to 10 = unbearably painful) administered approximately 1 hour after each injection. In the 12-week, double-blind placebo-controlled study, the mean subject-reported injection site pain VAS scores were similar for all treatment groups after each of the three injections. Median VAS scores were 1 for all treatment groups after each of the three injections. In the 12-month, long-term safety study, the injection site pain VAS scores were highest on day 1 (mean of 1.8) and tended to lessen over time (mean of 1.5 at day 337). The most commonly reported injection site related adverse reaction was pain. Throughout the double-blind placebo-controlled study and the long-term safety study, 14 out of 386 patients (4%) reported 18 cases of injection site pain after 2,827 injections (1%) of RISVAN. Of the 18 cases of injection site pain, 15 were rated as mild, and 3 were rated as moderate. Less common injection site adverse reactions were swelling (n=3, 1%), erythema (n=1, 0%), and discomfort (n=1, 0%), with all cases rated as mild in severity. The local injection site was assessed by site investigators. Throughout the double-blind placebo-controlled study (n=290 receiving RISVAN), 7% of patients had redness, 2% had swelling, and 1% had induration. Throughout the long-term safety study (n=215 receiving RISVAN), 3% of patients had redness, 0.5% had swelling, and no patients had induration. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of oral risperidone. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These adverse reactions include: alopecia, anaphylactic reaction, angioedema, atrial fibrillation, cardiopulmonary arrest, catatonia, diabetic ketoacidosis in patients with impaired glucose metabolism, dysgeusia, hypoglycemia, hypothermia, ileus, inappropriate antidiuretic hormone secretion, intestinal obstruction, jaundice, mania, pancreatitis, pituitary adenoma, precocious puberty, pulmonary embolism, QT prolongation, sleep apnea syndrome, somnambulism, Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), sudden death, thrombocytopenia, thrombotic thrombocytopenic purpura, urinary retention, and water intoxication. Postmarketing cases of extrapyramidal symptoms (dystonia and dyskinesia) have been reported in patients concomitantly taking methylphenidate and risperidone when there was an increase or decrease in dosage, initiation, or discontinuation of either or both medications.

<table border="0" width="100%"><caption>Table 3. Adverse Reactions Occurring in &#x2265; 2% of RISVAN-Treated Adult Patients and at a Greater Frequency than Placebo in a 12-Week Placebo-Controlled Study in Schizophrenia</caption><tbody><tr><td><paragraph><content styleCode="bold">System Organ Class</content></paragraph><paragraph><content styleCode="bold">Preferred Term</content></paragraph></td><td><paragraph><content styleCode="bold">RISVAN</content></paragraph><paragraph><content styleCode="bold">75 mg</content></paragraph><paragraph><content styleCode="bold">(n = 146)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td><paragraph><content styleCode="bold">RISVAN</content></paragraph><paragraph><content styleCode="bold">100 mg</content></paragraph><paragraph><content styleCode="bold">(n = 144)</content></paragraph><content styleCode="bold">%</content></td><td><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(n = 147)</content></paragraph><content styleCode="bold">%</content></td></tr><tr><td>Cardiac disorders</td><td/><td/><td/></tr><tr><td>Tachycardia</td><td>1</td><td>3</td><td>0</td></tr><tr><td>Endocrine disorders</td><td/><td/><td/></tr><tr><td>Hyperprolactinemia</td><td>6</td><td>9</td><td>1</td></tr><tr><td>Gastrointestinal disorders</td><td/><td/><td/></tr><tr><td>Constipation</td><td>3</td><td>1</td><td>1</td></tr><tr><td><paragraph>General disorders and administration site conditions</paragraph></td><td/><td/><td/></tr><tr><td>Injection site pain</td><td>6</td><td>3</td><td>3</td></tr><tr><td>Infections and infestations</td><td/><td/><td/></tr><tr><td>Nasopharyngitis</td><td>4</td><td>3</td><td>0</td></tr><tr><td>Investigations</td><td/><td/><td/></tr><tr><td>Blood prolactin increased</td><td>9</td><td>14</td><td>0</td></tr><tr><td>Weight increased</td><td>7</td><td>6</td><td>2</td></tr><tr><td>Alanine aminotransferase increased</td><td>3</td><td>5</td><td>2</td></tr><tr><td>Aspartate aminotransferase increased</td><td>1</td><td>3</td><td>2</td></tr><tr><td>Blood triglycerides increased</td><td>3</td><td>2</td><td>1</td></tr><tr><td>Blood creatine phosphokinase increased</td><td>2</td><td>1</td><td>1</td></tr><tr><td>Blood cholesterol increased</td><td>0</td><td>2</td><td>0</td></tr><tr><td>Musculoskeletal and connective tissue disorders</td><td/><td/><td/></tr><tr><td>Myalgia</td><td>2</td><td>1</td><td>0</td></tr><tr><td>Muscle tightness</td><td>2</td><td>0</td><td>0</td></tr><tr><td>Nervous system disorders</td><td/><td/><td/></tr><tr><td>Headache</td><td>10</td><td>8</td><td>3</td></tr><tr><td>Akathisia</td><td>4</td><td>8</td><td>2</td></tr><tr><td>Sedation ¹</td><td>4</td><td>6</td><td>3</td></tr><tr><td>Dizziness</td><td>4</td><td>4</td><td>3</td></tr><tr><td>Dystonia ²</td><td>4</td><td>4</td><td>1</td></tr><tr><td/><td/><td/><td/></tr></tbody></table>