Research suggests that as many as 1 in 5 primary care patients

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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. SECOND IN A SERIES OF 3 NEWSLETTERS APRIL 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 Robert L. Grieco, MD Heritage Valley Family Practice Heritage Valley Medical Group Beaver Falls, Pennsylvania 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. Grieco 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 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 in Primary Care: Treatment With LATUDA 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. Research suggests that as many as 1 in 5 primary care patients who have clinically significant depressive symptoms and are receiving antidepressant treatment may actually have bipolar disorder. 1 Although a lifetime history of at least 1 manic episode is required for a diagnosis of bipolar I disorder, 2 it is important to recognize that depressive symptoms usually predominate. Patients with bipolar disorder are more likely to initially present with depressive symptoms than with mania, 3 and over the long-term course of the disease, they spend approximately twice as much time with depressive symptoms as with mania, hypomania, rapid cycling, or mixed features combined. 4 Supplement to The Journal of Family Practice Vol 64, No 4 April 2015 S1

2 BIPOLAR DEPRESSION IN PRIMARY CARE: TREATMENT WITH LATUDA MONOTHERAPY PATIENT PROFILE: DAVE* Dave is a 32-year-old man who was diagnosed with bipolar I disorder at age 22 and is currently seeking treatment for continued major depressive episodes associated with bipolar I disorder. Dave has initiated and discontinued treatment several times since his bipolar disorder diagnosis, due to either persistent depressive symptoms or adverse effects such as fatigue or weight gain. Dave first sought care for depression at age 19, during his freshman year of college, and he was initially treated by a primary care physician at his university s student health center. In addition to having depressive symptoms, Dave also admitted to frequent episodes of binge drinking, sexual promiscuity, and excessive gambling and fast driving. The university health center physician prescribed a selective serotonin reuptake inhibitor for Dave s depression, but Dave reported increased feelings of anger, agitation, and sleep problems, and he discontinued treatment after a few months. Dave sought treatment for depressive symptoms again during his senior year of college, at age 23, and was seen by a family physician who recognized that Dave s history of poor response to antidepressant therapy, as well as his previous episodes of high-risk behavior, suggested the possibility of bipolar disorder. The family physician administered a bipolar disorder screening instrument, which yielded a positive result. Dave was then referred to a psychiatrist, who conducted a complete clinical assessment and diagnosed Dave with bipolar I disorder. Since then, Dave has been treated by a psychiatrist for depressive episodes on a total of 3 occasions (including his initial diagnosis with bipolar I disorder and 2 subsequent major depressive episodes at ages 26 and 31). During the first 2 episodes, he was treated with mood stabilizers either alone or in combination with antidepressants. Although he reported some improvement in mood symptoms, he discontinued treatment because of persistent depressive symptoms and fatigue. During his most recent depressive episode, about 1 year ago, he achieved better symptom control with a revised treatment regimen that included a mood stabilizer plus an atypical antipsychotic, but he discontinued treatment after 8 months because he had gained a significant amount of weight. Now Dave is once again seeking treatment for depression. In addition to his diagnosis of bipolar I disorder, Dave s current medical history is notable for hypertension, for which he is not currently taking medication. Dave is clinically obese, and he was also recently diagnosed with type 2 diabetes mellitus. After reviewing Dave s current symptoms, medical history, and responses to previous medication regimens, his psychiatrist elects to initiate monotherapy with Latuda (lurasidone HCl), which is indicated for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) as monotherapy and as adjunctive therapy with lithium or valproate in adults. The psychiatrist also refers Dave to a primary care nurse practitioner (NP) and requests frequent visits to monitor mood symptoms, weight, body mass index, cholesterol, triglycerides, and glucose. The NP will regularly update Dave s psychiatrist about his progress, adverse events, and any metabolic changes. *Hypothetical case representing a fictional patient. Bipolar disorder is also associated with a high rate of comorbid psychiatric and general medical conditions. In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, 5 approximately 70% of patients with bipolar disorder met diagnostic criteria for at least 1 comorbid psychiatric disorder, including anxiety disorder, substance use disorder, attention deficit/ hyperactivity disorder, or eating disorder. 6 Bipolar disorder is also associated with increased risk of several comorbid medical conditions, including endocrine/ metabolic disorders (eg, metabolic syndrome and diabetes), vascular disease (eg, hypertension), obesity, and dyslipidemia. 7,8 In addition, Individuals with bipolar disorder are at increased risk of cardiovascular mortality compared with the general population, and cardiovascular disease is a greater cause of excess mortality than suicide in this patient population. 8 Patients with bipolar disorder using atypical antipsychotics should be monitored for various cardiometabolic indicators, such as weight, waist circumference, blood pressure, fasting plasma glucose, and fasting lipid profile. 9 Further, as reported in the STEP-BD study, 22.4% of patients who attained recovery from an episode of bipolar disorder experienced a recurrence of depressive symptoms during 1 year of follow-up, compared with 6.4% of patients who had recurrent mania, hypomania, or mixed features. 5 It should also be noted that some patients exhibit bipolar disorder with mixed features in that the symptoms of depression occur together with mania but do not predominate the clinical picture. 2 LATUDA: A Treatment Option for 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 has not been established for longer-term use (more than 6 weeks) or for the treatment of mania associated with bipolar disorder. 10 The results of a phase 3, randomized, multicenter, double-blind, placebo-controlled clinical trial that examined the efficacy and safety of LATUDA monotherapy for patients with bipolar I depression were published in the February 2014 issue of The American Journal of Psychiatry. 11 Adult patients (N=505) with major depressive episodes associated with bipolar I disorder, with or without rapid cycling, and without psychotic features, were evaluated for eligibility. 11 All psychotropic medications were tapered off, and patients were randomly assigned to 1 of 3 treatment groups: flexibly dosed LATUDA mg/day (N=166), flex- Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S2 April 2015 Vol 64, No 4 Supplement to The Journal of Family Practice

3 FIGURE 1. PRIMARY EFFICACY ENDPOINT: MADRS SCORE 11 LS Mean Change From Baseline Baseline Baseline mean = LATUDA mg (n=161) ibly dosed LATUDA mg/day (N=169), or placebo (N=170). 11 LATUDA dosing adjustments were permitted for patients in both LATUDA groups to optimize efficacy and tolerability. 11 Study medication was taken once daily in the evening by mouth with a meal (eg, dinner) or within 30 minutes after eating. 11 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. 11 The MADRS is a 10-item, clinician-rated scale with total scores ranging from 0 to At Week 6, LATUDA mg/day and mg/day were associated with statistically significant improvement in MADRS score from baseline to the 6-week endpoint than placebo (-15.4 for both LATUDA treatment groups vs for the placebo group; P<.001 for each LATUDA group vs placebo). 11 The higher dose range ( mg/day) did not provide additional efficacy, on average, compared with the lower dose range (20-60 mg/day). 10 * ** Time (Weeks) Effect size: LATUDA mg: 0.51 LATUDA mg: 0.51 * ** LATUDA mg (n=162) ** *** *** *** *** *** (n=162) *P<.05; **P<.01; ***P<.001. Abbreviations: LS, least squares; MADRS, Montgomery-Åsberg Depression Rating Scale. MADRS scale range, of patients in either LATUDA group and at greater incidence than placebo during acute therapy (up to 6 weeks in patients with bipolar depression). 10 Treatment was discontinued prematurely due to adverse events in 20 of 331 patients (6.0%) who received LATUDA mg/day and in 9 of 168 patients (5.4%) who received placebo. 10 In the short-term study of LATUDA as monotherapy, the mean change in body weight from baseline to Week 6 was +1.2 pounds for patients who received LATUDA mg/day, 0.0 pounds for patients who received LATUDA mg/day, and -0.1 pound for patients who Patients Reduction in severity of depression received placebo. 10 Increase of body weight of at least 7% was noted for 2.4% of patients who received LATUDA vs 0.7% of patients who received placebo. 10 Changes in fasting glucose and lipids for the LATUDA and placebo groups are shown in the Table. 10 The median prolactin concentration increased by 1.7 ng/ml for the LATUDA mg group, 3.5 ng/ml for the LATUDA mg group, and 0.3 ng/ml for the placebo group. For male patients, the median change from baseline to Week 6 was +1.2 ng/ml, +1.9 ng/ml, and +0.4 ng/ml for the low-dose LATUDA, high-dose LATUDA, and placebo groups, respectively; for female patients, the corresponding median changes from baseline were +1.8 ng/ml, +5.3 ng/ml, and 0.0 ng/ml, respectively. 10 Extrapyramidal symptoms (EPS) observed during the 6-week LATUDA monotherapy study included akathisia (noted for 8%, 11%, and 2% of patients in the LATUDA mg, FIGURE 2. ADVERSE REACTIONS IN 2% OF LATUDA-TREATED PATIENTS AND AT GREATER INCIDENCE THAN PLACEBO LATUDA mg (N=164) Nausea Akathisia Somnolence* Dry Mouth LATUDA mg (N=167) <1<1 1 <1 <1 1 EPS Diarrhea Anxiety Nasopharyngitis Back Pain Vomiting (N=168) UTI Influenza Abbreviations: EPS, extrapyramidal symptoms; UTI, urinary tract infection. *Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence. 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. TABLE. CHANGE IN LABORATORY PARAMETERS FROM BASELINE TO WEEK 6 IN PATIENTS RANDOMIZED TO TREATMENT WITH LATUDA MONOTHERAPY OR PLACEBO 10 Parameter LATUDA mg LATUDA mg Glucose (mean) -0.8 mg/dl (n=140)) +1.8 mg/dl (n=143) +1.8 mg/dl (n=148) Short-term Safety Figure 2 shows the incidence of adverse reactions occurring in 2% Total cholesterol (mean) +1.2 mg/dl (n=140) -4.6 mg/dl (n=144) -3.2 mg/dl (n=147) Triglycerides (mean) +5.6 mg/dl (n=140) +0.4 mg/dl (n=144) +6.0 mg/dl (n=147) Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. Supplement to The Journal of Family Practice Vol 64, No 4 April 2015 S3

4 BIPOLAR DEPRESSION IN PRIMARY CARE: TREATMENT WITH LATUDA MONOTHERAPY AN EXPERT S PERSPECTIVE Case Commentary by Larry Culpepper, MD, MPH Bipolar disorder is a chronic disease that, for some patients, can be associated with comorbid conditions. In the case of Dave,* a 32-year-old man who was diagnosed with bipolar I disorder at age 23, those comorbid conditions include clinical obesity, hypertension, and type 2 diabetes. Cardiovascular conditions are not to be considered lightly. In fact, comorbid cardiovascular disease is a greater contributor to mortality than suicide in patients with bipolar disorder. 1 As such, it is important for patients particularly those with cardiovascular conditions to be followed regularly by a primary care provider. Dave is referred to an NP to monitor for mood symptoms, weight, body mass index, cholesterol, triglycerides, and glucose. The NP and psychiatrist should be sure to keep their lines of communication open. As medications are initiated, full and repeated disclosure that initial treatment may need to be altered either to increase symptom control or to minimize side effects is essential. Emphasizing that medication is a tool that can help patients stay in control of their lives, rather than a cause of relinquishing control to their chronic disease, can be a positive message for patients. Selection of initial medications with strong evidence for effectiveness, including minimal side effects, is a key consideration in helping patients choose an effective treatment option. Even with these steps, patients often discontinue treatment during early years for a variety of reasons. Patients may not come to recognize and accept the chronic nature of bipolar disease until they have lived through the consequences of multiple episodes. For such patients, continued professional engagement, repeated education, and counseling are critical, not only to intervene early in any single episode, but also to support acceptance of treatment and control. *Hypothetical case representing a fictional patient. Larry Culpepper, MD, MPH Reference: 1. Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011;23(1): LATUDA mg, and placebo groups, respectively), dystonia (0%, 2%, and 0%), parkinsonism (5%, 8%, and 2%), and restlessness (0%, 3%, and <1%). 10 EPS, akathisia, and dyskinesia were also examined using the Simpson-Angus Scale (SAS), the Barnes Akathisia Scale (BAS), and the Abnormal Involuntary Movement Scale (AIMS), respectively. 10 On the SAS, a shift from normal at baseline to an abnormal score at Week 6 (or at last observation carried forward for patients who discontinued prematurely) was noted for 3.7% of patients who received LATUDA mg/day versus 1.9% of patients receiving placebo. On the BAS, worsening from baseline to endpoint was noted for 8.4% versus 5.6% of patients who received LATUDA or placebo, respectively, whereas on the AIMS, worsening from baseline was noted for 3.4% of patients who received LATUDA versus 1.2% of those receiving placebo. 10 References 1. 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): American Psychiatric Association. Bipolar and related disorders Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. Arlington, VA: American Psychiatric Association; Suppes T, Leverich GS, Keck PE, et al. The Stanley Foundation Bipolar Treatment Outcome Network. II. Demographics and illness characteristics of the first 261 patients. J Affect Disord. 2001;67(1-3): Judd LL, Akiskal HS, Schettler PJ, et al. The longterm natural history of the weekly symptomatic status of bipolar I disorder. Arch Gen Psychiatry. 2002;59(6): Perlis RH, Ostacher MJ, Patel JK, et al. Predictors of recurrence in bipolar disorder: primary outcomes from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Am J Psychiatry. 2006;163(2): Simon NM, Otto MW, Weiss RD, et al. Pharmacotherapy for bipolar disorder and comorbid conditions: baseline data from STEP-BD. J Clin Psychopharmacol. 2004;24(5): Maina G, Bechon E, Rigardetto S, Salvi V. General medical conditions are associated with delay to treatment in patients with bipolar disorder. Psychosomatics. 2013;54(5): Weiner M, Warren L, Fiedorowicz JG. Cardiovascular morbidity and mortality in bipolar disorder. Ann Clin Psychiatry. 2011;23(1): American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004;27(2): LATUDA [prescribing information]. Marlborough, MA: Sunovion Pharmaceuticals Inc.; Loebel A, Cucchiaro J, Silva R, et al. Lurasidone monotherapy in the treatment of bipolar I depression: a randomized, double-blind, placebocontrolled study. Am J Psychiatry. 2014;171(2): Please see Brief Summary of full Prescribing Information, including Boxed Warning, on page S5. S4 April 2015 Vol 64, No 4 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 4 April 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 April 2015 Vol 64, No 4 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 4 April 2015 S7