WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS 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. REXULTI is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions (5.1 )] . Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors. The safety and efficacy of REXULTI have not been established in pediatric patients [see Warnings and Precautions (5.2) , Use in Specific Populations (8.4 )] . WARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS; and SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at increased risk of death. REXULTI is not approved for the treatment of patients with dementia-related psychosis ( 5.1 ). • Antidepressants increase the risk of suicidal thoughts and behaviors in patients aged 24 years and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behaviors ( 5.2 ). • Safety and effectiveness of REXULTI have not been established in pediatric patients ( 8.4 ).
6 ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the labeling: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning , Warnings and Precautions (5.1) ] Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Boxed Warning , Warnings and Precautions (5.2) ] Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions (5.3) ] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4) ] Tardive Dyskinesia [see Warnings and Precautions (5.5) ] Metabolic Changes [see Warnings and Precautions (5.6) ] Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7) ] Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8) ] Falls [see Warnings and Precautions (5.9) ] Seizures [see Warnings and Precautions (5.10) ] Body Temperature Dysregulation [see Warnings and Precautions (5.11) ] Dysphagia [see Warnings and Precautions (5.12) ] Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.13) ] Most common adverse reactions were ( 6.1 ): MDD: Weight increased and akathisia (≥5% and at least twice the rate for placebo) Schizophrenia: Weight increased (≥4% and at least twice the rate for placebo) To report SUSPECTED ADVERSE REACTIONS, contact Otsuka America Pharmaceutical, Inc. at 1-800-438-9927 or FDA at 1-800-FDA-1088 (www.fda.gov/medwatch). 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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. Major Depressive Disorder The safety of REXULTI was evaluated 1,054 patients (18 to 65 years of age) diagnosed with MDD who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in patients with major depressive disorder in which REXULTI was administered at doses of 1 mg to 3 mg daily as adjunctive treatment to continued antidepressant therapy; patients in the placebo group continued to receive antidepressant therapy [see Clinical Studies (14.1) ] . Adverse Reactions Reported as Reasons for Discontinuation of Treatment A total of 3% (17/643) of REXULTI-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions. Common Adverse Reactions Adverse reactions associated with the adjunctive use of REXULTI (incidence of 2% or greater and adjunctive REXULTI incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 8. Table 8: Adverse Reactions in Pooled 6-Week, Placebo-Controlled, Fixed-Dose MDD Trials (Studies 1 and 2)* Placebo (N=411) REXULTI 1 mg/day (N=226) 2 mg/day (N=188) 3 mg/day (N=229) All REXULTI (N=643) Gastrointestinal Disorders Constipation 1% 3% 2% 1% 2% General Disorders and Administration Site Conditions Fatigue 2% 3% 2% 5% 3% Infections and Infestations Nasopharyngitis 2% 7% 1% 3% 4% Investigations Weight Increased 2% 7% 8% 6% 7% Blood Cortisol Decreased 1% 4% 0% 3% 2% Metabolism and Nutrition Increased Appetite 2% 3% 3% 2% 3% Nervous System Disorders Akathisia 2% 4% 7% 14% 9% Headache 6% 9% 4% 6% 7% Somnolence 0.5% 4% 4% 6% 5% Tremor 2% 4% 2% 5% 4% Dizziness 1% 1% 5% 2% 3% Psychiatric Disorders Anxiety 1% 2% 4% 4% 3% Restlessness 0% 2% 3% 4% 3% * Adverse reactions that occurred in ≥2% of REXULTI-treated patients and greater incidence than in placebo-treated patients Dose-Related Adverse Reactions in the MDD trials In Studies 1 and 2, among the adverse reactions that occurred at ≥2% incidence in the patients treated with REXULTI +ADT, the incidences of akathisia and restlessness increased with increases in dose. Schizophrenia The safety of REXULTI was evaluated in 852 patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in which REXULTI was administered at daily doses of 1 mg, 2 mg and 4 mg [see Clinical Studies (14.2) ]. Common Adverse Reactions Adverse reactions associated with REXULTI (incidence of 2% or greater and REXULTI incidence greater than placebo) during short-term (up to 6-weeks) trials in patients with schizophrenia are shown in Table 9. Table 9: Adverse Reactions in Pooled 6-Week, Placebo-Controlled, Fixed-Dose Schizophrenia Trials (Studies 3 and 4)* Placebo (N=368) REXULTI 1 mg/day (N=120) 2 mg/day (N=368) 4 mg/day (N=364) ALL REXULTI (N=852) Gastrointestinal Disorders Dyspepsia 2% 6% 2% 3% 3% Diarrhea 2% 1% 3% 3% 3% Investigations Weight Increased 2% 3% 4% 4% 4% Blood Creatine Phosphokinase Increased 1% 4% 2% 2% 2% Nervous System Disorders Akathisia 5% 4% 5% 7% 6% Tremor 1% 2% 2% 3% 3% Sedation 1% 2% 2% 3% 2% * Adverse reactions that occurred in ≥2% of REXULTI-treated patients and greater incidence than in placebo-treated patients Extrapyramidal Symptoms Major Depressive Disorder The incidence of reported EPS-related adverse reactions, excluding akathisia, was 6% for REXULTI+ADT-treated patients versus 3% for placebo+ADT-treated patients. The incidence of akathisia events for REXULTI+ADT-treated patients was 9% versus 2% for placebo+ADT-treated patients. In the 6-week, placebo-controlled MDD studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Score (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI+ADT-treated patients for the SAS, BARS and AIMS was comparable to placebo treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI+ADT-treated patients versus placebo+ADT for the BARS (4% versus 0.6%) and the SAS (4% versus 3%). Schizophrenia The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for REXULTI-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 6% versus 5% for placebo-treated patients. In the 6-week, placebo-controlled, fixed-dose schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for REXULTI-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in REXULTI-treated patients versus placebo for the BARS (2% versus 1%) and the SAS (7% versus 5%). Dystonia Symptoms of dystonia 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 Observed During the Premarketing Evaluation of REXULTI Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in patients with MDD and schizophrenia are shown below. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo. Eye Disorders: Vision Blurred Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence Infections and Infestations: Urinary Tract Infection Investigations: Blood Prolactin Increased Musculoskeletal and Connective Tissue Disorders: Myalgia Psychiatric Disorders: Abnormal Dreams, Insomnia Skin and Subcutaneous Tissue Disorders: Hyperhidrosis