The Bipolar Depression Bulletin

Transcription

1 The Bipolar Depression Bulletin Bipolar Depression in Pediatric Patients Sponsored by Sunovion Pharmaceuticals Inc. Please see Important Safety Information, including BOXED WARNING, on page 13 INDICATIONS AND USAGE LATUDA is indicated for monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) and adjunctive treatment with lithium or valproate in adult patients with bipolar depression. The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically re-evaluate the long-term usefulness of the drug for the individual patient. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established. IMPORTANT SAFETY INFORMATION Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. About 50% to 66% of adults with bipolar disorder report onset of the illness during childhood or adolescence. 1,2 Early onset of bipolar disorder during childhood or adolescence may lead to poorer outcomes compared to onset of bipolar disorder during adulthood. 1,3 Approximately 1.8% of children and adolescents are affected by bipolar spectrum disorders, and about 1.2% are affected by bipolar I disorder, specifically. 4 This interactive newsletter will focus on bipolar disorder in pediatric patients, as well as a new treatment option for depressive episodes associated with bipolar I disorder (bipolar depression) in pediatric patients (10 to 17 years), LATUDA (lurasidone HCl). The newsletter will follow two fictional psychiatrists, Dr. Rosenfeld and Dr. Kahn, as they discuss a hypothetical patient, Mason, who is suffering from depressive symptoms associated with bipolar I disorder. Hypothetical Patient Case Mason, 13 years old Mason is a 13-year-old student with general anxiety disorder. When Mason started middle school at age 11, his parents noticed he wasn t acting like himself. He was extremely talkative, irritable, and filled with unrestrained energy. During that time, Mason ended up breaking his leg after trying to jump his bike over a high fence. His teacher said: Mason was just constantly talking and very energetic. During recess, he tried to jump over the school fence and broke his leg. Four months ago, Mason began to lose interest in his favorite activities. He stopped playing video games and didn t ride his bike for weeks. Mason s academic performance also declined. He complained of being constantly tired, had a hard time getting out of bed in the morning, and was very irritable. Mason repeatedly belittled himself, saying he was the worst student in class and that his family would be better off without him. Mason s mom said: Mason looked so sad and had no energy. He wasn t interested in any of his favorite activities. Mason s parents took him to the psychiatrist. After performing a thorough clinical evaluation, the psychiatrist identified a past manic episode and a current depressive episode. Mason was diagnosed with bipolar I disorder with a current depressive episode. LAT Click here to see Important Safety Information, including BOXED WARNING

2 Newsletter 3 Page 2 Dr. Rosenfeld: Mason was diagnosed with bipolar I disorder at age 13. I recently noticed an increase in the number of pediatric patients, just like Mason, who meet the diagnostic criteria for bipolar disorder. Has the prevalence of bipolar disorder in pediatric Sponsored by Sunovion Pharmaceuticals Inc. patients increased in recent years? Dr. Kahn: The prevalence of bipolar disorder in pediatric patients appears to be relatively stable and has not increased over time. 4 It is estimated that 1.8% of children and adolescents are affected by bipolar spectrum disorders and about 1.2% are affected by bipolar I disorder. 4 However, some evidence suggests an increase in the rate of office visits for pediatric patients with the diagnosis of bipolar disorder. For example, one study found about 40-fold increase in the number of office visits for pediatric patients with the diagnosis of bipolar disorder between 1995 and In addition, the rate of hospital discharge of pediatric patients with a primary diagnosis of bipolar disorder increased between 1996 and 2004 as well. 6 Dr. Rosenfeld: That s interesting. Based on studies in adults with bipolar disorder, approximately 50% to 66% of adults report an early onset of the illness during childhood or adolescence. 1,2 Dr. Kahn, what is the current criteria for the diagnosis of bipolar disorder in pediatric patients? Dr. Kahn: The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) applies the same diagnostic criteria for bipolar disorder in Check Your Knowledge: Click the Right Answer In pediatric patients, irritability may be a symptom of 7 : A) Manic episode Click to Expand Your Knowledge What is the DSM-5 criteria for bipolar depression in pediatric patients? pediatric patients as it does for adults. 7 However, the presentation of certain symptoms of bipolar disorder in pediatric patients may differ from the presentation in adults. For example, depressed mood in children and adolescents may manifest as irritable mood. 7 Therefore, in pediatric patients, irritability may be a symptom of both a depressed mood and a manic episode, which may make diagnosis more challenging. 7 Furthermore, in children, failure to make expected weight gain should be considered as a symptom for depressed mood. 7 These factors, combined with the normal difficulties children and adolescents have in modulating their emotions, may contribute to the challenges in the diagnosis of bipolar I disorder in this population. 8 Dr. Rosenfeld: That s very true. Bipolar disorder may be misdiagnosed in children and adolescents. One study reassessed the diagnosis of 64 pediatric patients and identified that nearly 62% of patients with bipolar disorder were initially diagnosed with either attention-deficit/hyperactivity disorder (ADHD) or major depressive disorder (MDD). 9 In addition to misdiagnosis, bipolar disorder in children and adolescents is also associated with several concomitant disorders. 10 Can you share with me your approach for differential diagnosis of bipolar disorder in pediatric patients? Previous Diagnosis in Pediatric Patients With Bipolar Disorder *9 B) Major depressive episode C) Irritability is a normal behavior for children and adolescents D) Both A and B Bipolar Disorder 38.1% ADHD 28.6% MDD 33.3% *Previous diagnosis in 21 pediatric patients aged 7 to 18 with a current diagnosis of bipolar disorder. 9 Click here to see Important Safety Information, including BOXED WARNING

3 Newsletter 3 Page 3 Dr. Kahn: Absolutely. We should be vigilant with the diagnosis of bipolar disorder in pediatric patients. Just like in adults, the symptoms of a major depressive episode associated with bipolar I disorder or with MDD are identical. 7 Therefore, identifying a Sponsored by Sunovion Pharmaceuticals Inc. past manic episode is necessary for differentiating bipolar I disorder from MDD. 7 However, many symptoms of mania in pediatric patients, including rapid speech, racing thoughts, distractibility, and reduced need for sleep, overlap with the symptoms of other mental health disorders. 7 It is therefore important to clarify that these types of symptoms represent a distinct manic episode for the diagnosis of bipolar I disorder. 7 Family history is another important clue in the diagnosis of bipolar disorder. Several studies demonstrated an increased risk for pediatric onset of bipolar disorder in the offspring of parents with bipolar disorder. 11,12 For example, one study found a 14-fold increase in the rate of bipolar spectrum disorders in pediatric patients in offspring of parents with bipolar disorder, compared to offspring of parents who do not have bipolar disorder (10.6% versus 0.8%, respectively). 11 Dr. Rosenfeld: Those are very good points. I typically interview both the parents and their child or adolescent to identify past manic episodes and Offspring With Pediatric-Onset Bipolar Spectrum Disorder The Risk for Pediatric-Onset Bipolar Disorder Among Offspring of Parents With Bipolar Disorder *11 12% 10% 8% 6% 4% 2% 0% 10.6% Offspring of Parents With Bipolar Disorder (N=388) 14-fold increase 0.8% Offspring of Control Parents (N=251) *Offspring aged 6 to 18 years. 11 Amongst these 10.6% offspring (n=41), 75.6% had childhood onset (<12 years), and 24.4% had adolescentonset (12 to 18 years). 11 Check Your Knowledge: Click the Right Answer Which of the following statements is true about the MDQ-A? 13 A) It is a diagnostic tool for depressive symptoms in adolescents B) It is a screening tool for mania symptoms in adults C) It contains questions for the parent about their adolescent D) Both A and C learn about their family history. In adult patients, the Mood Disorder Questionnaire (MDQ) is a useful screening tool designed to identify previous mania symptoms, although it is not designed as a diagnostic tool. 14 Would you use the MDQ as a screening tool in pediatric patients as well? Dr. Kahn: I like to use the Mood Disorder Questionnaire Adolescent version (MDQ-A) as a screening tool for identifying previous manic episodes in adolescents. 13 The MDQ-A is filled out by the parents and contains questions about their adolescent (12 to 17 years). 13 Similar to the MDQ, the MDQ-A is also comprised of questions about 13 symptoms or behaviors that may indicate manic symptoms. 13,14 However, the questions are adapted for behaviors and activities common to adolescents. In addition, the MDQ-A asks if these symptoms caused problems at school, with family and friends, or legal trouble. 13 Unlike the MDQ, which is a patient self-report, the MDQ-A was found to have higher sensitivity when completed by a parent. 13,14 Dr. Rosenfeld: It s good to know there is an adolescent-specific questionnaire for identifying past manic symptoms. You mentioned earlier that offspring of parents with bipolar disorder have an increased risk for pediatric-onset (<18 years) bipolar disorder. 11 Are there any other risk factors for bipolar disorder in pediatric patients? Click here to see Important Safety Information, including BOXED WARNING

4 Newsletter 3 Page 4 Dr. Kahn: There is some evidence suggesting a correlation between childhood trauma or abuse and pediatric onset of bipolar disorder. One study of 634 adult outpatients with bipolar disorder identified a correlation Sponsored by Sunovion between Pharmaceuticals childhood Inc. abuse and the age of onset of bipolar disorder. 15 In this study, adult patients that were exposed to verbal, physical or sexual abuse during childhood experienced a pediatric onset (<18 years) of bipolar disorder. 15 Exposure to more than one type of abuse was correlated with an earlier age of onset. 15 In contrast, patients with bipolar disorder who were not exposed to abuse experienced a later onset at a mean age of 20.6 years. 15 Another study of 446 pediatric patients (7 to 17 years and 11 months) identified a higher rate of negative life events in children and adolescents with bipolar spectrum disorders compared to healthy controls. 16 It is important to note that not all patients with bipolar disorder experience childhood trauma or abuse. Childhood Abuse Is Associated With Pediatric-Onset of Bipolar Disorder 15 Verbal, Sexual, and Physical Abuse (n=87) Verbal and Physical Abuse (n=90) Verbal and Sexual Abuse (n=46) Sexual Abuse Only (n=30) Verbal Abuse Only (n=151) No Abuse (n=223) Pediatric-Onset (<18 Years) Mean Age of Onset (Years) Dr. Rosenfeld: Let s discuss the outcomes of bipolar disorder in pediatric patients. Our hypothetical patient, Mason, was not exposed to any specific negative life event but was diagnosed with bipolar I disorder at age 13. Does the age of onset of bipolar disorder affect the course of the illness? Dr. Kahn: Yes, onset of bipolar disorder during childhood or adolescence may lead to poorer outcomes compared to onset of bipolar disorder during adulthood. 1,17 There is also some correlation between age of onset and prognosis. For example, the rate of substance abuse is nearly twice as high in people with bipolar disorder onset during childhood (<13 years) or adolescence (13 to 18 years) compared to people with adult-onset (>18 years). 3 Furthermore, there is a higher rate of lifetime suicidal behavior in people with pediatric-onset (<18 years) bipolar disorder compared to adult-onset (>18 years) bipolar disorder. 3 Dr. Rosenfeld: Psychiatric comorbidities are very common. About 75% of people with bipolar disorder suffer from comorbid anxiety disorders, and over 50% suffer from comorbid ADHD, conduct disorder, or substance use disorder. 7 What are the common psychiatric comorbidities in pediatric patients? Dr. Kahn: According to one report, the most common psychiatric comorbidities in pediatric patients with bipolar disorder are ADHD, anxiety disorders, conduct disorders, oppositional defiant disorder, substance abuse, and learning disabilities. 10 Check Your Knowledge: Click the Right Answer Which psychiatric comorbidity is less common in pediatric patients with bipolar disorder? 10 A) Eating disorder B) Substance use disorder C) Conduct disorders D) Anxiety disorders Click here to see Important Safety Information, including BOXED WARNING

5 Newsletter 3 Page 5 Dr. Rosenfeld: Let s get back to our hypothetical patient, Mason. He was recently diagnosed with bipolar I disorder with a current depressive episode. What options are available for someone like Mason? Sponsored by Sunovion Pharmaceuticals Inc. Dr. Kahn: The FDA recently approved LATUDA (lurasidone HCl) for the treatment of depressive episode associated with bipolar I disorder (bipolar depression) in pediatric patients (10 to 17 years) as monotherapy. 18 LATUDA is also indicated for the treatment of depressive episode associated with bipolar I disorder (bipolar depression) in adults as monotherapy and as an adjunctive therapy with lithium or valproate. 18 It is important to read the full Prescribing Information, including BOXED WARNING, and Important Safety Information for LATUDA. Commonly observed adverse reactions ( 5% incidence and at least twice the rate of placebo) for LATUDA in pediatric patients (10 to 17 years) with bipolar depression were: nausea, weight increase, and insomnia. 18 Click to Expand Your Knowledge Click to view the efficacy data for the LATUDA study in pediatric patients (10 to 17 years) with bipolar depression Click to view the safety and tolerability data for the LATUDA study in pediatric patients (10 to 17 years) with bipolar depression Click to learn about dosing and administration of LATUDA in pediatric patients (10 to 17 years) with bipolar depression Click here to see Important Safety Information, including BOXED WARNING

6 Newsletter 3 Page 6 Sponsored by Sunovion Pharmaceuticals Inc. EXPAND YOUR KNOWLEDGE Click here to see Important Safety Information, including BOXED WARNING

7 Newsletter 3 Page 7 The DSM-5 Diagnostic Criteria for Bipolar Depression in Pediatric Patients The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) diagnostic criteria of major depressive episode associated with bipolar I disorder (bipolar depression) in pediatric patients is identical to the diagnostic criteria in adults. 7 However, some of the symptoms of a major depressive episode may present differently in pediatric patients compared to adults. 7 The DSM-5 indicates that a diagnosis of bipolar I disorder requires a past manic episode. The criteria for a depressive episode is as follows: Criterion A. Five or more of the following symptoms have been present during the same 2-week period and represent change from previous functioning; at least one of the symptoms is either depressed mood, or loss of interest or pleasure. 7 Symptoms that are attributable to other medical conditions should not be included. 7 Depressed mood most of the day. In children and adolescents, depressed mood can manifest as irritable mood Markedly diminished interest or pleasure Significant weight loss or weight gain, or decrease or increase in appetite. In children, consider failure to make expected weight gain Insomnia or hypersomnia Psychomotor agitation or retardation Fatigue or loss of energy Feelings of worthlessness, or excessive or inappropriate guilt Diminished ability to think or concentrate, or indecisiveness Suicidal thoughts or suicidal ideation Criterion B. The symptoms cause clinically significant distress or impairment in social, occupational, or other important functioning. 7 Check Your Knowledge: Click the Right Answer In pediatric patients, irritability may be a symptom of 7 : A) Manic episode B) Major depressive episode C) Irritability is a normal behavior for children and adolescents Criterion C. The episode is not attributable to the physiological effects of a substance or other medical condition. 7 Identifying Previous Manic Symptoms in Adolescents For the diagnosis of bipolar I disorder, it is necessary to identify a manic episode. The manic episode may have been preceded by or may be followed by a major depressive episode 7 The MDQ-A is a screening tool designed to help identify previous manic symptoms in adolescents 13 The MDQ-A can point a clinician in the direction of a bipolar I disorder diagnosis, but should not be used as a diagnostic tool 13 Click to Expand Your Knowledge What is the MDQ-A? Back Click here to see Important Safety Information, including BOXED WARNING Next

8 Newsletter 3 Page 8 The Mood Disorder Questionnaire Adolescent Version The MDQ-A is a screening tool designed to identify previous manic symptoms in adolescents. 13 Similar to the MDQ, the MDQ-A also includes three questions: the first question is comprised of 13 yes/no items derived from both DSM-IV criteria and clinical experience 13 ; the second question asks if any of the symptoms marked in the first question occurred during the same time period 13 ; the third question assesses how problematic the symptoms were. 13 In the MDQ-A, the 13 yes/no questions were simplified and adapted for behaviors and activities common to adolescents. 13 For example, the MDQ question you felt much more self-confident than usual? was revised to felt he/she could do anything? in the MDQ-A; and the MDQ question you were much more social or outgoing than usual, for example, you telephoned friends in the middle of the night? was revised to had many boyfriends or girlfriends at the same time? in the MDQ-A. 13,14 Similarly, the third question assessing how problematic the symptoms were was revised for activities common to adolescents. 13 In the MDQ-A, examples for problematic behavior include: school problems, failing grades, problems with family and friends, and legal troubles. 13 A positive screen is considered as answering yes to five or more symptoms in question one, a yes to question two, and a moderate to serious problematic effect of these symptoms in question three. 13 The MDQ-A may point a clinician in the Check Your Knowledge: Click the Right Answer Which of the following statements is true about the MDQ-A? 13 A) It is a diagnostic tool for depressive symptoms in adolescents B) It is a screening tool for mania symptoms in adults D) Both A and C direction of a bipolar disorder diagnosis, but should not be used as a diagnostic tool. 13 The sensitivity of the MDQ-A for detecting past mania episodes was validated in a study of 104 adolescents (aged 12 to 17 years) and their parents. 13 In this study, both the adolescents and their parents were asked to answer the MDQ-A questionnaire. 13 The results from the parent-reported questionnaire, in which the parents completed the MDQ-A about their adolescent's symptoms, were superior to the results from the self-reported questionnaire, in which the adolescents completed the MDQ-A about themselves. 13 The sensitivity of the parent-reported MDQ-A (72%) was similar to the reported sensitivity of the MDQ (73%) in the screening of past manic episodes. 13,14 Positive MDQ-A Screen Checklist 1. Five or more symptoms were marked yes 2. Several of the symptoms happened at the same period of time 3. The symptoms caused the adolescent a moderate or serious problem Back Click here to see Important Safety Information, including BOXED WARNING Next

9 Newsletter 3 Page 9 Psychiatric Comorbidities in Pediatric Patients With Bipolar Disorder According to one report, the most common psychiatric comorbidities in pediatric patients (prepubertal and adolescents) with bipolar disorder are ADHD, anxiety disorders, conduct disorders, oppositional defiant disorder, substance abuse, and learning disabilities. 10 Amongst adolescent patients with bipolar disorder, ADHD and conduct disorders are the most common comorbidities with an estimated prevalence rate of 30%-60%. 10 In prepubertal patients with bipolar disorder, the estimated prevalence rate of comorbid ADHD is 70%-90%. 10 The estimated prevalence of substance abuse is higher in adolescent patients (range 40%-50%) compared to prepubertal patients (10%). 10 Check Your Knowledge: Click the Right Answer Which psychiatric comorbidity is less common in pediatric patients with bipolar disorder? 10 B) Substance use disorder C) Conduct disorders D) Anxiety disorders Estimated Rates of Select Frequent Comorbid Disorders in Pediatric Patients With Bipolar Disorder 10 Prepubertal 0% 20% 40% 60% 80% 100% ADHD 70%-90% Adolescent 0% 20% 40% 60% 80% 100% ADHD 30%-60% Anxiety Disorders 20%-30% Anxiety Disorders 30%-40% Conduct Disorders 30%-40% Conduct Disorders 30%-60% Oppositional Defiant Disorder* 60%-90% Oppositional Defiant Disorder 20%-30% Substance Abuse 10% Substance Abuse 40%-50% Learning Disabilities 30%-40% Learning Disabilities 30%-40% *Oppositional defiant disorder may not be considered a true comorbidity to bipolar disorder because, per DSM-5 criteria for oppositional defiant disorder, the behaviors do not occur exclusively during the course of a psychotic, substance use, depressive, or bipolar disorder. 7 Back Click here to see Important Safety Information, including BOXED WARNING Next

10 Newsletter 3 Page 10 Study Design for LATUDA in Pediatric Patients (10 to 17 Years) *18,19 Screen BL Double-Blind Open-Label Extension * Screening Baseline Lurasidone 20 mg/d N=176 Placebo N=17 Flexibly dosed lurasidone 20, 40, 60, or 80 mg/d Flexibly dosed lurasidone 20, 40, 60, or 80 mg/d 1-21 Days Day 1 1 Week 5 Weeks 24 Months BL, baseline. * Subjects who have completed all visits in the core efficacy study were eligible to enter the extension study. All eligible subjects who enrolled in the open-label extension study were dosed with 40 mg, and flexible dosing was permitted thereafter. Efficacy of LATUDA (lurasidone HCl) in Pediatric Patients (10 to 17 Years) With Bipolar Depression In the efficacy and safety study in pediatric patients (10 to 17 years) with bipolar depression, LATUDA was associated with statistically significant improvement in CDRS-R total scores at Week 6 compared to placebo 18,19 LATUDA was also associated with statistically significant improvement in the key secondary measure of CGI-BP-S on Week 6 compared to placebo 18,19 CDRS-R=Children s Depression Rating Scale-Revised; CGI-BP-S=Clinical Global Impressions-Bipolar Severity scale for use in bipolar illness Click to Expand Your Knowledge Click to view the safety and tolerability data for the LATUDA study in pediatric patients (10 to 17 years) with bipolar depression Efficacy of LATUDA in Pediatric Patients (10 to 17 years): CDRS-R Total Score 18,19 LS Mean Change From Baseline Baseline Effect size: *P<.05 **P<.001 ***P<.0001 Baseline mean = * LATUDA mg/day (n=173) Time (Weeks) ** *** Placebo (n=170) *** *** Back Click here to see Important Safety Information, including BOXED WARNING Next

11 Newsletter 3 Page 11 Safety and Tolerability of LATUDA (lurasidone HCl) in Pediatric Patients (10 to 17 Years) With Bipolar Depression The most commonly observed adverse events ( 5% and at least twice the placebo rate) with LATUDA as a monotherapy in pediatric patients (10 to 17 years) with bipolar depression were: nausea, weight increase, and insomnia 18 Atypical antipsychotics have been associated with metabolic changes, including changes in lipids, glucose, and body weight. 18 Monitoring of weight and symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness, are recommended 18 The proportion of patients with 7% weight gain at Week 6 was 4.0% for LATUDA-treated patients versus 5.3% for placebo-treated patients 18 Mean Change in Metabolic Parameters From Baseline to Week 6 *18 Total Cholesterol (mg/dl) Triglycerides (mg/dl) Glucose (mg/dl) Weight (lb) LATUDA mg -6.3 (n=144) -7.8 (n=144) 1.6 (n=145) 1.5 (n=175) Placebo *Last observation carried forward (LOCF) analysis (n=145) 5.9 (n=145) -0.5 (n=145) 1.1 (n=170) Adverse Reactions in 2% of LATUDA-Treated Pediatric Patients (10 to 17 Years) and at Greater Incidence Than Placebo Patients (%) Nausea Somnolence Weight increased Vomiting LATUDA mg (n=175) Placebo (n=172) EPS Dizziness Insomnia Decreased appetite Oropharyngeal pain Upper abdominal pain Fatigue Diarrhea Abdominal pain Abnormal dreams Note: Figures rounded to the nearest integer. Safety population. Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence. EPS=extrapyramidal symptoms; EPS includes adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor. Back Click here to see Important Safety Information, including BOXED WARNING Next

12 Newsletter 3 Page 12 LATUDA (lurasidone HCl) Dosage and Administration in Pediatric Patients (10 to 17 Years) With Bipolar Depression LATUDA has once-daily flexible dosing, with a recommended starting dose of 20 mg/day in pediatric patients with bipolar disorder 18 Initial does titration is not required for LATUDA 18 Dosing may be increased after 1 week, as needed, up to a maximum recommended dose of 80 mg/ day 18 LATUDA should be taken with food (at least 350 calories); Administration with food substantially increases the absorption of LATUDA 18 At the end of the clinical study in pediatric patients (10 to 17 years) with bipolar depression, most of the patients (67%) received 20 mg or 40 mg LATUDA once daily 18 The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. Therefore, the physician who elects to use LATUDA for extended periods should periodically reevaluate the longterm usefulness of the drug for the individual patient 18 The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established 18 LATUDA Dose Modification in Special Populations For patients with moderate renal impairment (creatinine clearance of 30 ml/min to >50 ml/ min) as well as for those with severe renal impairment (creatinine clearance of >30 ml/min), the recommended starting dose is 20 mg/day, and the dose should not exceed 80 mg/day 18 For patients with moderate hepatic impairment (Child-Pugh score=7 to 9), the dose should not exceed 80 mg/day. 18 For patients with severe hepatic impairment (Child-Pugh score=10 to 15), the dose should not exceed 40 mg/day 18 LATUDA Dose Modifications Due to Drug Interactions LATUDA should not be administered with strong CYP3A4 inhibitors (eg, ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc) or strong CYP3A4 inducers (eg, rifampin, avasimibe, St. John s wort, phenytoin, carbamazepine, etc) 18 When a moderate CYP3A4 inhibitor (eg, diltiazem, atazanavir, erythromycin, fluconazole, verapamil, etc) is added to therapy with LATUDA, the LATUDA dose should be reduced to half of the original dose level 18 When LATUDA is added to therapy with a moderate CYP3A4 inhibitor, the recommended starting dose is 20 mg/day and the maximum recommended dose is 80 mg/day 18 If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may be necessary to increase the LATUDA dose after chronic treatment (at least 7 days) with the CYP3A4 inducer 18 Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may inhibit CYP3A4 and alter LATUDA concentrations mg 40 mg 60 mg 80 mg Pills shown are not actual size. Back Click here to see Important Safety Information, including BOXED WARNING Next

13 Newsletter 3 Page 13 IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR LATUDA Suicidal Thoughts and Behaviors Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressanttreated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors. Contraindications: LATUDA is contraindicated in the following: Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone Strong CYP3A4 inhibitors (e.g., ketoconazole) Strong CYP3A4 inducers (e.g., rifampin) Cerebrovascular Adverse Reactions, Including Stroke: In clinical trials, elderly patients with dementia randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. LATUDA is not approved for the treatment of patients with dementia-related psychosis. Neuroleptic Malignant Syndrome (NMS): NMS is a potentially fatal symptom complex reported with administration of antipsychotic drugs. Clinical signs of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. Manage NMS with immediate discontinuation of antipsychotic drugs, including LATUDA, intensive symptomatic treatment and monitoring. Tardive Dyskinesia (TD): The risk of developing TD (a syndrome of abnormal involuntary movements) and the potential for it to become irreversible are believed to increase as the duration of treatment and total cumulative dose of antipsychotic increase. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses or may even arise after discontinuation of treatment. The syndrome may remit, partially or completely, if antipsychotic treatment is withdrawn. Metabolic Changes: Atypical antipsychotic drugs have caused metabolic changes, including: Hyperglycemia and Diabetes Mellitus: Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Patients with diabetes should be regularly monitored for worsening of glucose control; those with risk factors for diabetes should undergo fasting blood glucose testing at the beginning of and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycemia, including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycemia should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug. Dyslipidemia: Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Weight Gain: Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Hyperprolactinemia: As with other drugs that antagonize dopamine D2 receptors, LATUDA elevates prolactin levels. Galactorrhea, amenorrhea, gynecomastia, and impotence have been reported in patients receiving prolactin-elevating compounds. Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia/neutropenia has been reported with antipsychotics. Agranulocytosis (including fatal cases) has been reported with other agents in the class. Monitor complete blood count in patients with a pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) or a history of drug-induced leukopenia/neutropenia. Discontinue LATUDA at the first sign of a decline in WBC in the absence of other causative factors. Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest at the beginning of treatment and when increasing dose. Monitor patients vulnerable to hypotension and those with cardiovascular and cerebrovascular disease. Falls: Antipsychotics may cause somnolence, postural hypotension, or motor and sensory instability, which may lead to falls, causing fractures or other injuries. For patients with disease, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating treatment and recurrently during therapy. Seizures: LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower seizure threshold. Potential for Cognitive and Motor Impairment: Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely. Body Temperature Regulation: Use LATUDA with caution in patients who may experience conditions that increase body temperature (e.g., exercising strenuously, exposure to extreme heat, concomitant medication with anticholinergic activity, or being subject to dehydration). Dysphagia: Antipsychotics, including LATUDA, have been associated with esophageal dysmotility and aspiration, and should be used with caution in patients at risk for aspiration pneumonia. Most Commonly Observed Adverse Reactions: The most commonly observed adverse reactions ( 5% incidence and at least twice the rate of placebo) for LATUDA. In adult patients: akathisia, extrapyramidal symptoms, and somnolence In pediatric patients (10 to 17 years): nausea, weight increase, and insomnia To report SUSPECTED ADVERSE REACTIONS, contact Sunovion Pharmaceuticals Inc. at or FDA at FDA-1088 ( INDICATIONS LATUDA is indicated for monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) and adjunctive treatment with lithium or valproate in adult patients with bipolar depression. Before prescribing LATUDA, please read the full Prescribing Information, including Boxed Warning. Back Next

14 Newsletter 3 Page 14 References 1. Leverich GS, Post RM, Keck PE Jr, et al. The poor prognosis of childhood-onset bipolar disorder. J Pediatr. 2007;150(5): Perlis RH, Miyahara S, Marangell LB, et al. STEP-BD Investigators. Sponsored Long-term by Sunovion implications Pharmaceuticals of early onset Inc. in bipolar disorder: data from the first 1000 participants in the systematic treatment enhancement program for bipolar disorder (STEP-BD). Biol Psychiatry. 2004;55(9): Joslyn C, Hawes DJ, Hunt C, Mitchell PB. Is age of onset associated with severity, prognosis, and clinical features in bipolar disorder? A meta-analytic review. Bipolar Disord. 2016;18(5): Post RM, Leverich GS, Kupka RW, et al. Early-onset bipolar disorder and treatment delay are risk factors for poor outcome in adulthood. J Clin Psychiatry. 2010;71(7): LATUDA Prescribing Information. Marlborough, MA; Sunovion Pharmaceuticals Inc.; March DelBello MP, Goldman R, Phillips D, Deng L, Cucchiaro J, Loebel A. Efficacy and safety of lurasidone in children and adolescents with bipolar I depression: a double-blind, placebo-controlled study. J Am Acad Child Adolesc Psychiatry. 2017;56(12): Van Meter AR, Moreira AL, Youngstrom EA. Meta-analysis of epidemiologic studies of pediatric bipolar disorder. J Clin Psychiatry. 2011;72(9): Moreno C, Laje G, Blanco C, Jiang H, Schmidt AB, Olfson M. National trends in the outpatient diagnosis and treatment of bipolar disorder in youth. Arch Gen Psychiatry. 2007;64(9): Blader JC, Carlson GA. Increased rates of bipolar disorder diagnoses among U.S. child, adolescent, and adult inpatients, Biol Psychiatry. 2007;62(2): American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; Birmaher B, Axelson D, Strober M, et al. Comparison of manic and depressive symptoms between children and adolescents with bipolar spectrum disorders. Bipolar Disord. 2009;11(1): Chilakamarri JK, Filkowski MM, Ghaemi SN. Misdiagnosis of bipolar disorder in children and adolescents: a comparison with ADHD and major depressive disorder. Ann Clin Psychiatry. 2011;23(1): Kowatch RA, DelBello MP. Pediatric bipolar disorder: emerging diagnostic and treatment approaches. Child Adolesc Psychiatry Clin N Am. 2006;15(1): Birmaher B, Axelson D, Monk K, et al. Lifetime psychiatric disorders in school-aged offspring of parents with bipolar disorder: the Pittsburgh Bipolar Offspring study. Arch Gen Psychiatry. 2009;66(3): Henin A, Biederman J, Mick E, et al. Psychopathology in the offspring of parents with bipolar disorder: a controlled study. Biol Psychiatry. 2005;58(7): Wagner KD, Hirschfeld RM, Emslie GJ, Findling RL, Gracious BL, Reed ML. Validation of the Mood Disorder Questionnaire for bipolar disorders in adolescents. J Clin Psychiatry. 2006;67(5): Hirschfeld RM, Williams JB, Spitzer RL, et al. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157: Post RM, Altshuler LL, Kupka R, et al. Verbal abuse, like physical and sexual abuse, in childhood is associated with an earlier onset and more difficult course of bipolar disorder. Bipolar Disord. 2015;17(3): Romero S, Birmaher B, Axelson DA, et al. Negative life events in children and adolescents with bipolar disorder. J Clin Psychiatry. 2009;70(10):