Bipolar disorder, a mood disorder characterized by fluctuations

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1 Available at jfponline.com This promotional, non-cme content is intended only for healthcare professionals involved in the treatment of adult patients with bipolar disorder. first in a Series of 3 Newsletters MARCH 2015 A Supplement to This case newsletter series was developed and brought to you by Sunovion Pharmaceuticals Inc. It did not undergo peer review by The Journal of Family Practice. Newsletter content was developed in collaboration with the faculty. Faculty James Sloan Manning, MD Adjunct Associate Professor Department of Family Medicine University of North Carolina, Chapel Hill Co-Director Mood Disorders Clinic Moses Cone Family Practice Center Greensboro, North Carolina Larry Culpepper, MD, MPH Professor Department of Family Medicine Boston University School of Medicine Physician Division of Family Medicine Boston Medical Center Boston, Massachusetts DISCLOSURES Dr. Manning serves or has served as a consultant, speaker, and researcher for various pharmaceutical companies, including Sunovion Pharmaceuticals Inc. Dr. Culpepper serves or has served as a consultant for, and receives royalties and payment from, various pharmaceutical companies, including Sunovion Pharmaceuticals Inc. The clinical expert commentaries reflect the views of actual licensed clinicians, who have been engaged by Sunovion Pharmaceuticals Inc. to provide feedback on the hypothetical case studies. The information contained herein is intended for general informational purposes only and is not a substitute for your professional medical advice and judgment. This supplement is sponsored by in Primary Care: A Collaborative Approach Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. INDICATIONS and Usage LATUDA is indicated for treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate. The efficacy of LATUDA was established in a 6-week monotherapy study and a 6-week adjunctive therapy study 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 AND INDICATIONS FOR LATUDA Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older. In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. Advise families and caregivers of the need for close observation and communication with the prescriber. LATUDA is not approved for use in patients under the age of 18 years. Bipolar disorder, a mood disorder characterized by fluctuations between hypomania, depression, or mania, 1 may be present in patients in the primary care setting. A large study (N=1157) in a general medicine clinic found that 0.7% to 10% of adult patients screened positive for bipolar disorder, when screened using the Mood Disorder Questionnaire (MDQ). 2 The prevalence of bipolar disorder among depressed primary care patients is estimated to be nearly 28%. 3 LATUDA, SUNOVION, and are registered trademarks of Sumitomo Dainippon Pharma Co., Ltd. Sunovion Pharmaceuticals Inc. is a U.S. subsidiary of Sumitomo Dainippon Pharma Co., Ltd Sunovion Pharmaceuticals Inc. All rights reserved. LAT /15 Recognizing Bipolar depression is defined as the major depressive episodes associated with bipolar I disorder. It is important for primary care physicians (PCPs) to maintain an index of suspicion for bipolar Supplement to The Journal of Family Practice Vol 64, No 3 March 2015 S1

2 Bipolar DEPRESSION in PRimary Care: a Collaborative Approach Patient Profile: LISA* Lisa, a woman in her early 30s, has been referred to a PCP by a hospital psychiatrist who feels that she could benefit from regular follow-up with a PCP. During the initial consultation with her psychiatrist, it becomes clear that this young woman has endured a long and arduous road to her current diagnosis of bipolar I disorder, starting with a misdiagnosis of major depressive disorder at age 19. Over the course of the subsequent decade, Lisa was treated by 7 different mental health providers and received a range of diagnoses. Approximately 3 years ago, Lisa was diagnosed with bipolar I disorder after a psychiatrist uncovered a probable manic episode in her history. At that time, the psychiatrist prescribed a mood stabilizer. When discussing her recent discharge with her PCP, Lisa recounts that she presented to the emergency department with abrupt onset of severe depressive symptoms and was hospitalized. The hospital psychiatrist elected to continue treatment with a mood stabilizer and add adjunctive therapy with LATUDA for the treatment of bipolar depression. Lisa reports improvement in her depressive symptoms since her release from the hospital. The psychiatrist will continue to monitor her symptoms and any potential treatment-related side effects. At this juncture, the PCP initiates patient education on disease state and treatment, including the importance of specific pharmacologic interventions and the importance of multimodal treatment (ie, psychotherapy, lifestyle changes) to improve Lisa s awareness about her disorder and her new treatment regimen, to promote adherence to this regimen, and to improve her overall health. 1,2 Specifically, the PCP and Lisa work together to develop a personalized treatment plan, including patient responsibilities (ie, taking medication as prescribed, and maintaining a healthy lifestyle with diet and exercise), clinician responsibilities (ie, tracking clinical improvement using metrics such as the Patient Health Questionnaire [depression module], monitoring various laboratory parameters, and listening to patient concerns), and shared responsibilities (ie, communication and collaborative decisions). Lisa and her PCP revisit this personalized treatment plan at each subsequent appointment. Communication is maintained with a consulting psychiatrist, who can be called upon to provide specialized input for the PCP or psychotherapy for Lisa, if needed. *Hypothetical case representing a fictional patient. References 1. Davies MA, McBride L, Sajatovic M. The collaborative care practice model in the long-term care of individuals with bipolar disorder: a case study. J Psychiatr Ment Health Nurs. 2008;15(8): Cardoso TD, Farias CD, Mondin TC, et al. Brief psychoeducation for bipolar disorder: Impact on quality of life in young adults in a 6-month follow-up of a randomized controlled trial. Psychiatry Res. 2014;220(3): depression in anyone presenting with a major depressive episode. 4 A number of authors have identified clinical indicators that may suggest bipolarity in individuals presenting with depression. Some of these indicators are relatively strong, such as an established family history of bipolar disorder in a first-degree relative, history of antidepressant-induced mania or hypomania, and early age of onset. Others are more suggestive, such as psychotic features manifesting during depression. 4 If a patient is receiving antidepressant treatment for depressive symptoms, the nature of response to that treatment may help to distinguish bipolar depression from major depressive disorder: Patients with erratic, unexpected, or no response to therapy should be strongly considered for a diagnosis of bipolar disorder. 5 In a study of patients in a primary care clinic who were receiving antidepressants for depression, about 21% screened positive for bipolar disorder on the MDQ. 6 Importance of Patient Education Initiating patient education is a component of the PCP s management strategy in the hypothetical case above. Patient education on bipolar disorder aims to improve patient awareness about the disorder, increase treatment adherence, 6 potentially reduce new mood episodes, and improve quality oflife. 6 In a recent study of young adult patients with bipolar disorder, patient education was associated with a significant improvement indepressive symptoms, and that improvement was maintained through 3- and 6-month follow-up. 7 Collaborative Care Although PCPs see psychiatric patients on a regular basis, they may benefit from collaboration with the individual patient and a consulting psychiatrist, when appropriate. Collaborative care treatment models have been shown to improve outcomes over those of usual care (ie, pharmacologic intervention only), 8 with studies showing benefits for up to 5 years. 9 These studies included models of collaboration not only between the physician and patient but also among PCPs, specialists, and other healthcare professionals. 9 Clinician strategies for collaborative care include educating the patient about bipolar disorder and related treatment (ie, patient education, as mentioned previously); encouraging the patient to participate in identifying symptoms, treatment goals, and progress; maximizing easy access to care and continuity of care; and providing psychotherapy. 9 LATUDA: A Treatment Option for In our patient case above, Lisa has recently initiated adjunctive treatment with LATUDA in addition to a mood stabilizer. The efficacy of LATUDA for the adjunctive treatment of bipolar depression was evaluated in a phase 3, randomized, multicenter, double-blind, placebo-controlled clinical trial of 348 patients with bipolar I disorder. 10 The results of this pivotal trial were Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S2 March 2015 Vol 64, No 3 Supplement to The Journal of Family Practice

3 Figure 1. Primary Efficacy Endpoint: MADRS Score 9 LS Mean Change From Baseline Baseline Baseline mean = 1 2 LATUDA mg + Li/VPA (n=179) Adjunctive Therapy Time (Weeks) Effect size: 0.34 *** *** * ** + Li/VPA (n=161) published in the February 2014 issue of The American Journal of Psychiatry. 10 All psychotropic medications other than lithium or valproate were tapered off during the screening phase, and a therapeutic range of lithium ( meq/l) or valproate ( µg/ml) was maintained for at least 28 days. The patients were then randomized to receive flexibly dosed adjunctive LATUDA 20 mg/day to 120 mg/day plus lithium or valproate (n=183) or placebo plus lithium or valproate (n=165) for 6 weeks. Study medication was taken once daily in the evening by mouth with a meal (eg, dinner) or within 30 minutes after eating. 10 Short-term Efficacy Figure 1 shows the improvement in depressive symptoms for the LATUDA and placebo groups from baseline to Week 6 as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) total score, which was the study s primary efficacy endpoint. 10 The MADRS is a 10-item, clinician-rated scale with total scores ranging from 0 to At Week 6, LATUDA added to lithium or valproate was associated with significantly greater reduction from baseline MADRS total score than was placebo added to lithium or valproate (-17.1 vs points; P<0.01). LATUDA was also associated with significantly *P<0.05; **P<0.01; ***P< Abbreviations: Li, lithium; LS, least squares; MADRS, Montgomery-Åsberg Depression Rating Scale; VPA, valproate. MADRS scale range, Reduction in severity of depression greater reduction in the key secondary end-point of the Clinical Global Impression- Bipolar Version-Severity scale score. 11 Short-term Safety The safety of LATUDA as adjunctive therapy with lithium or valproate was also established in a second short-term, randomized, placebocontrolled study for bipolar depression. Together, these 2 studies enrolled 360 patients who received LATUDA at daily doses of 20 mg to 120 mg as adjunctive therapy with lithium or valproate. 10 Adverse events that occurred in at least 2% of LATUDAtreated patients and more often than in the placebo group are shown in Figure In the 2 short-term studies of LATUDA as adjunctive therapy, the mean increase in body weight from baseline to Week 6 was 0.2 pounds for patients who received LATUDA plus lithium or valproate versus 0.4 pounds for patients who received placebo plus lithium or valproate. An increase of body Patients weight of at least 7.0% was noted for 3.1% of patients who received LATUDA versus 0.3% of patients who received placebo. 11 Patients in the LATUDA group exhibited a mean increase in blood glucose concentration of 1.2 mg/dl, compared with a mean decrease of 0.9 mg/dl for patients who received placebo. 11 Total cholesterol concentration decreased by a mean of 3.1 mg/dl in the LATUDA group versus a decrease of 2.9 mg/dl in the placebo group. The mean triglyceride concentration increased by 4.6 mg/dl in the LATUDA group and decreased by 4.6 mg/dl in the placebo group. 11 In these 2 studies, the median prolactin concentration increased by 2.8 ng/ml between baseline and Week 6 for patients in the LATUDA group and remained unchanged for patients in the placebo group. For male patients, the change from baseline to Week 6 was +2.4 ng/ml with LATUDA and -0.1 ng/ml with placebo; for female patients, the median change from baseline was +3.2 ng/ml with LATUDA versus +0.4 ng/ml with placebo. 11 EPS, akathisia, and tardive dyskinesia were examined using the Simpson- Angus Scale, the Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS), respectively. A shift from normal at baseline to abnormal findings at Week 6 (or at last observation carried forward for patients who FIGURE 2. ADVERSE REACTIONS IN 2% OF LATUDA-TREATED PATIENTS AND AT GREATER INCIDENCE THAN PLACEBO 11 LATUDA mg + Li/VPA (N=360) Li/VPA (N=334) <1 1 1 <1 Nauseaa EPS* Somnolence e Akathisia ia Nasopharyngitis is Vomiting Restlessnesss Fatigue Increased Appetitete Weight Increased Abbreviations: EPS, extrapyramidal symptoms; Li, lithium; VPA, valproate. Note: Figures rounded to the nearest integer. *EPS includes bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus. Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence. Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. Supplement to The Journal of Family Practice Vol 64, No 3 March 2015 S3

4 Bipolar DEPRESSION in PRimary Care: a Collaborative Approach AN EXPERT s PERSPECTIVE Case Commentary by Larry Culpepper, MD, MPH To optimally treat patients with bipolar disorder, a collaborative care approach is essential. PCPs hold the key to early recognition of bipolar disorder. For prompt diagnosis, attention to early warning signs is critical as is understanding that the initial manic episode may not emerge until after several depressive episodes, often treated in the primary care setting. Repeated use of screening tools can alert the clinician to a lifetime history of mania, but it does not replace the clinician interview in confirming diagnosis, as many patients who screen positive are false positives. Interviewing a family member or a trusted friend can be very helpful in understanding a patient s symptoms. Psychiatrists often have greater expertise in clarifying a suspected diagnosis and the experience to tailor education for the patient, refine a treatment plan that is individualized, and modify treatment to attain maximum benefit. Psychiatric involvement also is essential in managing patients during manic and mixed episodes, and in carefully monitoring and adjusting treatment for the severely depressed and suicidal patient. Bipolar disorder carries with it both disease- and treatment-related increased risk for chronic medical disease. These account for the majority of morbidity leading to premature mortality. The primary care team working collaboratively with a psychiatrist can keep patients in care for all of their conditions. A key to success in treating bipolar depression is continuation of effective medication, effective both in treating and decreasing the frequency of symptoms related to bipolar depression. Patients are likely to adhere to treatment long-term using medication that can be used continuously, rather than switching medication depending on the phase of illness. This also facilitates developing a stable medication regimen for comorbid medical illnesses integrated with the bipolar disorder treatment. Carefully selecting treatment and integrating the skills of primary care and psychiatric clinicians can be transformative for patients with bipolar disorder. Larry Culpepper, MD, MPH discontinued prematurely) was noted for 2.8% of patients who received LATUDA plus lithium or valproate versus 2.1% of patients receiving placebo plus lithium or valproate. On the BAS, worsening from baseline to endpoint was noted for 8.7% versus 2.1% of patients who received LATUDA or placebo, respectively, whereas on the AIMS, worsening from baseline was noted for 2.8% of patients who received LATUDA versus 0.6% of those receiving placebo. 11 EPS observed during the 6-week study included akathisia (11% vs 5% for LATUDA and placebo groups, respectively), dystonia (1% vs <1%), parkinsonism (13% vs 8%), and restlessness (4% vs <1%). 11 Longer-term Safety* Patients with bipolar depression who completed the two 6-week trials of LATUDA as adjunctive therapy with lithium or valproate were eligible to continue into a 6-month, uncontrolled, open-label, flexible-dose extension study. Eligible patients who received placebo in the short-term studies were switched to LATUDA in the longer-term extension study. Adverse events that occurred in at least 5% of patients who continued on LATUDA adjunctive therapy plus lithium or valproate (n=254) included parkinsonism (14.2%), somnolence (9.1%), akathisia (8.7%), insomnia (7.1%), nausea (5.5%), and headache (5.5%). Changes in weight and laboratory parameters from open-label baseline to Week 24 were as follows: mean change in weight, 1.7 pounds; mean change in glucose, -0.5 mg/dl; mean change in cholesterol, 0.4 mg/dl; mean change in triglycerides, 1.6 mg/dl; and median change in prolactin levels, -1.3 ng/dl. 12 *The effectiveness of LATUDA for longer-term use, that is, for more than 6 weeks, has not been established in controlled studies. References 1. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association; Das AK, Olfson M, Gameroff MJ, et al. Screening for bipolar disorder in a primary care practice. JAMA. 2005;293(8): Dubovsky SL, Leonard K, Griswold K, et al. Bipolar disorder is common in depressed primary care patients. Postgrad Med. 2011;123(5): Berk M, Berk L, Moss K, Dodd S, Malhi GS. Diagnosing bipolar disorder: how can we do it better? Med J Aust. 2006;184(9): Hirschfeld RM, Cass AR, Holt DCL, Carlson CA. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18(4): Muzina DJ, Colangelo E, Manning JS, Calabrese JR. Differentiating bipolar disorder from depression in primary care. Cleve Clin J Med. 2007; 74(2): Davies MA, McBride L, Sajatovic M. The collaborative care practice model in the long-term care of individuals with bipolar disorder: a case study. J Psychiatr Ment Health Nurs. 2008;15(8): Cardoso TD, Farias CD, Mondin TC, et al. Brief psychoeducation for bipolar disorder: Impact on quality of life in young adults in a 6-month followup of a randomized controlled trial. Psychiatry Res. 2014;220(3): Susman JL. Improving outcomes in patients with bipolar disorder through establishing an effective treatment team. Prim Care Companion J Clin Psychiatry. 2010;12(suppl 1): Loebel A, Cucchiaro J, Silva R, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression: a randomized, double-blind, placebo-controlled study. Am J Psychiatry. 2014;171(2): LATUDA [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc.; Data on file. Sunovion Pharmaceuticals Inc. Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S4 March 2015 Vol 64, No 3 Supplement to The Journal of Family Practice

5 Brief Summary of full PreSCriBiNG information WarNiNGS: increased mortality in elderly PatieNtS WitH dementia-related PSyCHoSiS; and SuiCidal thoughts and BeHaViorS elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death [see Warnings and Precautions (5.1)]. is not approved for use in patients with dementia-related psychosis [see Warnings and Precautions (5.1)]. antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term studies. these studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older [see Warnings and Precautions (5.2)]. in patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors. advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.2)]. 1 indications and usage 1.1 LATUDA is indicated for the treatment of patients with schizophrenia. The efficacy of LATUDA in schizophrenia was established in five 6-week controlled studies of adult patients with schizophrenia [see Clinical Studies (14.1)]. 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 [see Dosage and Administration (2)]. 1.2 depressive episodes associated with Bipolar i disorder : LATUDA is indicated as monotherapy for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA was established in a 6-week monotherapy study in adult patients with bipolar depression [see Clinical Studies (14.2)]. : LATUDA is indicated as adjunctive therapy with either lithium or valproate for the treatment of patients with major depressive episodes associated with bipolar I disorder (bipolar depression). The efficacy of LATUDA as adjunctive therapy was established in a 6-week study in adult patients with bipolar depression who were treated with lithium or valproate [see Clinical Studies (14.2)]. 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 [see Dosage and Administration (2.2)]. The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established. 4 CoNtraiNdiCatioNS Known hypersensitivity to lurasidone HCl or any components in the formulation. Angioedema has been observed with lurasidone [see Adverse Reactions (6.1)]. Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Drug Interactions (7.1)]. Strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John s wort, phenytoin, carbamazepine, etc.) [see Drug Interactions (7.1)]. 5 WarNiNGS and PreCautioNS 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 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. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning]. 5.2 Suicidal thoughts and Behaviors in adolescents and young adults Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1. table 1 drug- difference in Number of Cases of age range Suicidality per 1000 Patients treated Increases Compared to <18 14 additional cases additional cases Decreases Compared to fewer case 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. all patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient s presenting symptoms. families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidal thoughts and behaviors, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for should be written for the smallest quantity of capsules consistent with good patient management, in order to reduce the risk of overdose. 5.3 Cerebrovascular adverse reactions, including Stroke in elderly Patients with dementia-related Psychosis In placebo-controlled trials with risperidone, aripiprazole, and olanzapine in elderly subjects with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated subjects. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see also Boxed Warning and Warnings and Precautions (5.1)]. 5.4 Neuroleptic malignant Syndrome A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs, including LATUDA. 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. The diagnostic evaluation of patients with this syndrome is complicated. It is important to exclude cases where the clinical presentation includes both serious medical illness (e.g., pneumonia, systemic infection) 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 NMS. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered. If reintroduced, the patient should be carefully monitored, since recurrences of NMS have been reported. 5.5 tardive dyskinesia Tardive dyskinesia is a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements that can 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 Supplement to The Journal of Family Practice Vol 64, No 3 March 2015 S5

6 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, LATUDA 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 on LATUDA, drug discontinuation should be considered. However, some patients may require treatment with LATUDA despite the presence of the syndrome. 5.6 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 of the 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, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. 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 treatmentemergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotics. Because LATUDA was not marketed at the time these studies were performed, it is not known if LATUDA is associated with this increased risk. Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics 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 should undergo fasting blood glucose testing at the beginning of treatment 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 during treatment with atypical antipsychotics 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. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 2. table 2: Change in fasting Glucose in Studies 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day mean Change from Baseline (mg/dl) n=680 n=71 n=478 n=508 n=283 n=113 Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 8.3% (52/628) 11.7% (7/60) 12.7% (57/449) 6.8% (32/472) 10.0% (26/260) 5.6% (6/108) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in glucose of +1.8 mg/dl at week 24 (n=355), +0.8 mg/dl at week 36 (n=299) and +2.3 mg/dl at week 52 (n=307). Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 3. table 3: Change in fasting Glucose in the monotherapy Bipolar depression Study 20 to 60 mg/day 80 to 120 mg/day n=148 n=140 n=143 mean Change from Baseline (mg/dl) Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 4.3% (6/141) 2.2% (3/138) 6.4% (9/141) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.2 mg/dl at week 24 (n=129). Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 4. table 4: Change in fasting Glucose in the adjunctive therapy Bipolar depression Studies mean Change from Baseline (mg/dl) n=302 n=319 Serum Glucose Proportion of Patients with Shifts to 126 mg/dl Serum Glucose ( 126 mg/dl) 1.0% (3/290) 1.3% (4/316) Patients were randomized to flexibly dosed LATUDA or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in glucose of +1.7 mg/dl at week 24 (n=88). Dyslipidemia Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 5. table 5: Change in fasting lipids in Studies 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day mean Change from Baseline (mg/dl) n=660 n=71 n=466 n=499 n=268 n=115 Total Cholesterol Triglycerides Proportion of Patients with Shifts Total Cholesterol 5.3% 13.8% 6.2% 5.3% 3.8% 4.0% ( 240 mg/dl) (30/571) (8/58) (25/402) (23/434) (9/238) (4/101) Triglycerides ( 200 mg/dl) 10.1% (53/526) 14.3% (7/49) 10.8% (41/379) 6.3% (25/400) 10.5% (22/209) 7.0% (7/100) In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in total cholesterol and triglycerides of -3.8 (n=356) and (n=357) mg/dl at week 24, -3.1 (n=303) and -4.8 (n=303) mg/dl at week 36 and -2.5 (n=307) and -6.9 (n=307) mg/dl at week 52, respectively. Data from the short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 6. table 6: Change in fasting lipids in the monotherapy Bipolar depression Study 20 to 60 mg/day 80 to 120 mg/day mean Change from Baseline (mg/dl) n=147 n=140 n=144 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) 4.2% (5/118) 4.4% (5/113) 4.4% (5/114) Triglycerides ( 200 mg/dl) 4.8% (6/126) 10.1% (12/119) 9.8% (12/122) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in total cholesterol and triglycerides of -0.5 (n=130) and -1.0 (n=130) mg/dl at week 24, respectively. Data from the short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 7. table 7: Change in fasting lipids in the adjunctive therapy Bipolar depression Studies mean Change from Baseline (mg/dl) n=303 n=321 Total cholesterol Triglycerides Proportion of Patients with Shifts Total cholesterol ( 240 mg/dl) 5.7% (15/263) 5.4% (15/276) Triglycerides ( 200 mg/dl) 8.6% (21/243) 10.8% (28/260) Patients were randomized to flexibly dosed LATUDA or placebo as adjunctive therapy with lithium or valproate. S6 March 2015 Vol 64, No 3 Supplement to The Journal of Family Practice

7 In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA, as adjunctive therapy with either lithium or valproate in the short-term study and continued in the longer-term study, had a mean change in total cholesterol and triglycerides of -0.9 (n=88) and 5.3 (n=88) mg/dl at week 24, respectively. Weight Gain Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended. Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 8. The mean weight gain was kg for LATUDA-treated patients compared to kg for placebotreated patients. Change in weight from baseline for olanzapine was kg and for quetiapine extended-release was kg in Studies 3 and 5 [see Clinical Studies (14.1)], respectively. The proportion of patients with a 7% increase in body weight (at Endpoint) was 4.8% for LATUDAtreated patients versus 3.3% for placebo-treated patients. table 8: mean Change in Weight (kg) from Baseline in Studies 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day (n=696) (n=71) (n=484) (n=526) (n=291) (n=114) All Patients In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of kg at week 24 (n=755), kg at week 36 (n=443) and kg at week 52 (n=377). Data from the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 9. The mean weight gain was kg for LATUDA-treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 2.4% for LATUDA-treated patients versus 0.7% for placebo-treated patients. table 9: mean Change in Weight (kg) from Baseline in the monotherapy Bipolar depression Study 20 to 60 mg/day 80 to 120 mg/day (n=151) (n=143) (n=147) All Patients Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo In the uncontrolled, open-label, longer-term bipolar depression study, patients who received LATUDA as monotherapy in the short-term and continued in the longer-term study had a mean change in weight of kg at week 24 (n=130). Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 10. The mean weight gain was kg for LATUDA-treated patients compared to kg for placebo-treated patients. The proportion of patients with a 7% increase in body weight (at Endpoint) was 3.1% for LATUDA-treated patients versus 0.3% for placebo-treated patients. table 10: mean Change in Weight (kg) from Baseline in the adjunctive therapy Bipolar depression Studies (n=307) (n=327) All Patients Patients were randomized to flexibly dosed LATUDA or placebo as adjunctive therapy with lithium or valproate. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate in the short-term and continued in the longer-term study, had a mean change in weight of kg at week 24 (n=86). 5.7 Hyperprolactinemia As with other drugs that antagonize dopamine D 2 receptors, LATUDA elevates prolactin levels. Hyperprolactinemia may suppress hypothalamic GnRH, resulting in reduced pituitary gonadotrophin 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 with prolactin-elevating compounds. Long-standing hyperprolactinemia, when associated with hypogonadism, may lead to decreased bone density in both female and male patients [see Adverse Reactions (6)]. 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 considered in a patient with previously detected breast cancer. As is common with compounds which increase prolactin release, an increase in mammary gland neoplasia was observed in a LATUDA carcinogenicity study conducted in rats and mice [see Nonclinical Toxicology (13)]. 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, but the available evidence is too limited to be conclusive. In short-term, placebo-controlled schizophrenia studies, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +0.4 ng/ml and was -1.9 ng/ml in the placebo-treated patients. The median change from baseline to endpoint for males was +0.5 ng/ml and for females was -0.2 ng/ml. Median changes for prolactin by dose are shown in Table 11. table 11: median Change in Prolactin (ng/ml) from Baseline in Studies 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day All Patients (n=672) (n=70) (n=476) (n=495) (n=284) (n=115) Females (n=200) (n=19) (n=149) (n=150) (n=70) (n=36) Males (n=472) (n=51) (n=327) (n=345) (n=214) (n=79) The proportion of patients with prolactin elevations 5 upper limit of normal (ULN) was 2.8% for LATUDA-treated patients versus 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 5.7% for LATUDA-treated patients versus 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 1.6% versus 0.6% for placebo-treated male patients. In the uncontrolled longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a median change in prolactin of -0.9 ng/ml at week 24 (n=357), -5.3ng/mL at week 36 (n=190) and -2.2 ng/ml at week 52 (n=307). The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, was +1.7 ng/ml and +3.5 ng/ml with LATUDA 20 to 60 mg/day and 80 to 120 mg/day, respectively compared to +0.3 ng/ml with placebo-treated patients. The median change from baseline to endpoint for males was +1.5 ng/ml and for females was +3.1 ng/ml. Median changes for prolactin by dose range are shown in Table 12. table 12: median Change in Prolactin (ng/ml) from Baseline in the monotherapy Bipolar depression Study 20 to 60 mg/day 80 to 120 mg/day All Patients (n=147) (n=140) (n=144) Females (n=82) (n=78) (n=88) Males +0.4 (n=65) +1.2 (n=62) +1.9 (n=56) Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0.6% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA as monotherapy in the short-term and continued in the longer-term study, had a median change in prolactin of ng/ml at week 24 (n=130). The median change from baseline to endpoint in prolactin levels, in the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/ml with LATUDA compared to 0.0 ng/ml with placebo-treated patients. The median change from baseline to endpoint for males was +2.4 ng/ml and for females was +3.2 ng/ml. Median changes for prolactin across the dose range are shown in Table 13. table 13: median Change in Prolactin (ng/ml) from Baseline in the adjunctive therapy Bipolar depression Studies All Patients (n=301) (n=321) Females (n=156) (n=162) Males (n=145) (n=159) Patients were randomized to flexibly dosed LATUDA or placebo as adjunctive therapy with lithium or valproate. The proportion of patients with prolactin elevations 5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients versus 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations 5x ULN was 0% for LATUDA-treated patients versus 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations 5x ULN was 0% versus 0% for placebo-treated male patients. In the uncontrolled, open-label, longer-term bipolar depression study, patients who were treated with LATUDA, as adjunctive therapy with either lithium or valproate, in the short-term and continued in the longer-term study, had a median change in prolactin of -2.9 ng/ml at week 24 (n=88). 5.8 leukopenia, Neutropenia and agranulocytosis Leukopenia/neutropenia has been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in the class. 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 pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and LATUDA should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Supplement to The Journal of Family Practice Vol 64, No 3 March 2015 S7