`
` Latuda
`(urasidone HC)tablets
`20mg | 40mg | 60mg | 80mg | 120mg
`
`Please see Important Safety Information, including Boxed Warnings,
`on pages 66-67 and enclosed full Prescribing Information.
`
`Look inside to learn more about an
`FDA-approved atypical antipsychotic
`
`Product Monograph
`
`INDICATIONS
`
`LATUDAis indicated for treatment of adult and adolescent patients age 13 to 17 years with schizophrenia and in adult
`patients with major depressive episodes associated with bipolar | disorder (bipolar depression) as monotherapy and
`as adjunctive therapy with lithium or valproate.
`
`IMPORTANT SAFETY INFORMATION FOR LATUDA
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS;
`and SUICIDAL THOUGHTS AND BEHAVIORS
`
`increased Mortality in Elderly Patients with Dementia-Related Psychosis
`Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an
`increased risk of death. LATUDAis not approved for the treatment of patients with dementia-
`related psychosis.
`
`Suicidal Thoughts and Behaviors
`Antidepressants increased the risk of suicidal thoughts and behaviors in patients aged 24 years
`and younger. Monitor for clinical worsening and emergence of suicidal thoughts and behavior.
`LATUDAis not approved for use in pediatric patients with depression.
`
`Please see additional Important Safety Information, including Boxed Warnings,
`on pages 66-67 and enclosedfull Prescribing Information.
`
`CONFIDENTIAL
`
`1
`
`Exhibit 2070
`Slayback v. Sumitomo
`IPR2020-01053
`
`

`

`IMPORTANT SAFETY INFORMATION FOR LATUDA
`
`Contraindications: LATUDA is contraindicated in the following:
`
`* Known hypersensitivity to lurasidone HCI or any components in the formulation.
`Angioedema has been observed with lurasidone
`
`* Strong CYP3A4inhibitors (e.g., ketoconazole)
`
`* Strong CYP3A4 inducers(e.g., rifampin)
`
`For more information please visit us at: www.LATUDAhcp.com
`
`Please see additional Important Safety Information, including Boxed Warnings,
`on pages 66-67 and enclosed fuil Prescribing information.
`
`CONFIDENTIAL
`
`LATUDA04006171
`
`2
`
`

`

`Bipolar Disorder Clinical and Economic Burden ......... 00. ccc cece cee eee eer eevee renves 6
`
`Summaryof Bipolar | Disorder 2.2.2.2... cece eee cee ee eee eee nee eee eee eeeeenees 8
`
`a ermmies eemceenecasate'e gue 4
`
`aymun
`
` BIPOLAR. DISORDER OVERVIEW 0.0 cen ermseue ey oesareuereie a) slavelie gustaria anes e!werene gs
`
`SCHIZOPRRENIAPOVERVIEW sissies su Geis acer aaa e ah tal owetieueas Gullo chinensis WR eA mi 10
`
`Schizophrenia Cilical and! ECOHGMIG BUBEM « ax wesc wre acernarmanerew a ace ne euoncenle aOR ANNE 1
`
`Summary:oFSchizophrenla osc ssew ances oeesere se ewes ove eens cee ous a Sua 15
`
`LATUDA PRODUCT PROFILE wisescuceerecaun naan eine ee ee eT 16
`
`Indications. 2.2...2.ee eee eee tee tebe eee eee eee 16
`
`Dosade atid AGMIMSHSEGN cavcmcsnw cere en iew aise w
`
`a Weta we alee ee RaW eS 7
`
`Clinical Pharmacology... 2.0.0... eee eee tenet etter ent ete e eens 18
`
`LATUDMEMICRCY scnivscs cascaneanmewe neta Ee eee cS TR Ee eT 20
`
`Major Depressive Episodes Associated With Bipolar | Disorder (Bipolar Depression) ..... 20
`
`SCHIZODHEEMIA ssiscesiaseeeaieas ene iies Wadiete oe ee EO Sdee 23
`
`LATUDA Satety GTOISR AB HEY Swe uce teres seseererse year ecn aurea ie cas oer ace nraree wean ce macECEM areas 40
`
`LATUDA Safety Database: Adults With Bipolar Depression and Schizophrenia........... 40
`
`Major Depressive Episodes Associated With Bipolar | Disorder (Bipolar Depression) ...... 4
`
`SCHIZOPRFENIA Facies pane Sis Seek see So Se Se ae 50
`
`Summary of the Efficacy and Tolerability of LATUDA.. 0... cee cee eee ees 65
`
`IMPORTANT SAFETY INFORMATION AND INDICATIONS FOR LATUDA...............-....5. 66
`
`REFERENCES scccenwancita mace vat awe wien aaenliee alts mea eS madi oe eTE 68
`
`CON TACE INFORMATION o.-0:6:c:0e wisn renin eereiew seine sien WINS ae ee ee eee 10
`
`FULL PRESCRIBING INFORMATION .......0:.0 cee cee cece ee se seneneeeeeeeereeenens Enclosed
`
`CONFIDENTIAL
`
`LATUDA04006172
`
`
`
`
`lurasidone HC)tablets
`20mg | 40mg] 60mg] 80mg! 120mg
`
`3
`
`3
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`

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`
`
`4
`
`CONFIDENTIAL
`
`BIPOLAR DISORDER OVERVIEW
`
`Bipolar disorder is a mental illness characterized by debilitating mood swings.' The lifetime
`prevalence estimate for bipolar disorder has been estimated to be approximately 4% to 5%of
`Americans over the age of 18.* Therefore, it is estimated that as many as 12.3 million peaple in the
`United States are affected by bipolar disorder.* Bipolar disorder is among the top 10 leading causes
`of disability in the United States.?
`
`Bipolar disorder shows different patternsof illness and is suggested to be a spectrum of disorders.
`However, the main categories of bipolar disorder are bipolar | disorder and bipolar || disorder. The
`fifth edition of the Diagnostic and Statistical Manual of Menta! Disorders (DSM-5)criteria for a
`diagnosis of bipolar | disorder includes a history of | or more major depressive episodes and at least
`J episode of mania. DSM-5 criteria for bipolar Ii disorder includes a history of 1 or more major
`depressive episodes and hypomanic episodes, without true manic episodes.4
`
`Mania is defined as a distinct period of abnormally and persistently elevated, expansive, or irritable
`mood and abnormally and persistently increased goal-directed activity or energy, lasting at least 1
`week and present most of the day, nearly every day (or any duration if hospitalization is necessary),
`should be present.4 During this period of mood disturbance and increased energy oractivity, 23 of
`the following symptoms (4 if the mood is only irritable) need to be present to a significant degree
`and noticeable*:
`
`1. Inflated self-esteem or grandiosity
`
`2. Decreased need for sleep (eg, feels rested after only 3 hours of sleep)
`
`3. More talkative than usual or pressured to keep talking
`
`4. Flight of ideas or subjective experience that thoughts are racing
`
`5. Distractibility
`&, increase in goaldirected activity or psychomotor agitation
`7. Excessive involvementin activities that have a high potential for painful consequences
`
`In general, the mood disturbanceis sufficiently severe to cause marked impairment in social or
`occupational functioning or to necessitate hospitalization to prevent harm to self or others, or
`psychotic features are present.’ The episode should not be attributable to the physiologic effects of
`a substance of abuse, medication, or other medical condition.
`
`Hypomania is defined as a distinct period of abnormally and persistently elevated, expansive,
`orirritable mood and abnormally and persistently increased activity or energy, lasting at least
`4 consecutive days and present mostof the day, nearly every day.4
`
`A major depressive episode is defined by the presence of 25 of the following symptoms during the
`same 2-week period, and represents a change from previous functioning. At least one of the
`symptoms ts either (1) depressed mood or (2) loss of interest or pleasure.
`
`i. Depressed mood most of the day, nearly every day, as indicated by either subjective report or
`observation made by others
`
`2. Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly
`every day
`3. Significant weight loss when not dieting or weight gain
`
`4, Insomnia or hypersomnia nearly every day
`
`§. Psychomotor agitation or retardation nearly every day
`&. Fatigue or loss of energy nearly every day
`7. Feelings of worthiessness or excessive or inappropriate guilt nearly every day
`
`8. Diminished ability to think or concentrate, or indecisiveness, nearly every day
`
`9%, Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a
`specific plan, or a suicide attempt or a specific plan for committing suicide
`
`Symptoms of a major depressive episode cause clinically significant distress or impairment in social,
`occupational, or ether important areas of functioning.4 The episode should not be attributable to
`the physiologic effects of a substance of abuse, medication, or other medical condition.
`
`LATUDA04006173
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`An example of a bipolar | disorder cycle is shown in Figure 1. Diagnosis of bipolar | disorder ts differentiated from
`bipolar ll disorder by determining whether there have been any past episodes of mania.
`
`Upper limit of “normal” mood
`{happiness, joy}
`
`“Good times”
`ee ee
`
`See
`
`“Bad times”
`
`Lower fimif of “normal” mood
`
`Men and women are equally likely to develop bipolar disorder over their lifetime and the disease tends to have an
`onset in early adulthood.® Figure 2 showsthe proportion of time spentill during clinical visits for bipolar | disorder
`(N = 572) from one study. As for differences between genders, this study showed that women had a significantly
`greater numberof prior depressive episodes and hospitalizations for depression.® Although there was no difference
`in time spent in mania between the 2 groups in this study, there was a trend showing that men had a greater number
`oflifetime hospitalizations for mania.>
`
`(sadness, grief}
`4 @B Severedepression Men
`
`Severe mania
`
`88 Mild mania
`2 Euthymia
`‘Mild depression
`i 88 Moderate depression :
`
`-
`
`(n = 245)
`
`Women (35.4%) vs men (29.3%) for depressed visits; women (49.3%) vs men (56.1%) for euthymic visits;
`women (15.1%) vs men (14.6%) for hypomanic or manic visits.
`
`A common misconception about the disease course of bipolar disorder is that patients spend an equal amount of
`time, when ill, either manic or depressed. Contrary to this belief, a longitudinal study (approximately 13 years of
`follow-up) of patients with bipolar | disorder demonstrated that depressive symptoms (32% of total follow-up weeks)
`seem to predominate over manic/hypomanic symptoms (9% of weeks) or cycling/mixed symptoms (6% of weeks).®
`This is termed bipolar depression and refers to the depressive phase of bipolar disorder. Symptoms of bipolar
`depression include: extreme sadness, anxiety, fatigue, hopelessness, inactivity and disinterest in usual activities,
`disruptions to sleeping and eating patterns, and thoughts of death or suicide.’ This sometimes prevents early
`diagnosis of bipolar disorder since, when symptomatic, most people with bipolar | disorder tend to spend about 70%
`of the time in the depressed state.®
`
`Furthermore, monitoring for symptoms consistent with bipolar disorder is important since approximately 15% of
`people diagnosed with unipolar depression, and who self-report episodes consistent with mania, may be at risk for
`undiagnosed bipolar disorder.’
`
`CONFIDENTIAL
`
`LATUDA04006174
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`5
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`

`

`Bipolar Disorder Clinical and Economic Burden
`
`Disease Burden
`
`Bipolar disorder is a burdensome illness characterized by recurrent episodes of major depressive
`episodes and mania (or mixed episodes of the 2) or hypomania. In a longitudinal study
`{approximately 13 years of follow-up) of patients with bipolar | disorder (N = 146), patients were
`symptomatically ill nearly half of all of the weeks they were followed.® Additionally, patients with
`bipolar | disorder changed symptom status an average of 6 times per year and polarity more than
`3 times per year.® These events take a heavy toll on a patient’s health status and affect family,
`social, and work relationships.
`
`Mortality Risk From General Medical Conditions and Life Expectancy
`
`Bipolar disorder can also double a person’s risk of early death from a range of medical conditions.®
`Patients with bipolar disorder have increased risk for metabolic syndrome, high blood glucose and
`cholesterol, high blood pressure, and obesity? These factors are closely associated with the risk for
`cardiovascular disease (CVD),
`
`Mortality ratios for death from general medical conditions, such as cardiovascular, respiratory,
`cerebrovascular, and endocrine disorders, are significantly higher among patients with bipolar
`disorder compared with persons with no psychiatric illness.? Recently, in a large population-based
`study of 17,101 patients with bipolar disorder it was shown that mortality from CVD was 2-fold higher
`in this population compared with the genera! population, and 38% of all deaths in persons with
`bipolar disorder were caused by CVD.? Furthermore, patients with bipolar disorder died of CVD
`approximately 10 years earlier than the general population and 5-year survival rates (by patient age)
`after first hospital admission for CVD were significantly lower among patients with bipolar disorder
`than individuals in the general population (Figure 3).?
`
`.
`BVO er
`By SABE EC RK ORNS SN ERR R eee NEE MK Ee eR wa
`
`an
`
`ame ae
`
`=
`SOO eM Oe
`
`= 2=h
`
`n]
`wa
`
`+v«s+ Population
`
`2
`
`3
`
`Time Since Diagnosis, y
`
`~wwwe Bipolar
`
`Biological factors, unhealthy lifestyle (eg, smoking and unhealthy diet), adverse medication effects,
`and disparities in healthcare are all possible underlying contributors to increased mortality in
`bipolar disorder.® It has been shownthat life expectancy in patients with bipolar disorder is reduced
`by nearly 14 years in men and by 12 years in women.
`
`LATUDA has not been shownor indicated to impact mortality
`in prospective, randomized, placebo-controlled triats.
`
`LATUDA04006175
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`
`:ee
`:ss
`iaS
`.
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`CONFIDENTIAL
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`Economic Burden
`
`Estimates of healthcare utilization costs for patients with bipolar disorder are 2.5 times greater than for general
`medical outpatients." In 2002, a US population-based survey of people with bipolar depression showed higher
`healthcare utilization patterns over 12 months compared with people who had unipolar depression.'* More frequent
`office visits, emergency care visits, hospitalizations, and use of social services were reported by patients with
`bipolar depression compared with patients with unipolar depression (Figure 4).'¢ For example, patients with bipolar
`depression were twice as likely to seek counseling and 3.5 times as likely to need a psychiatric hospital stay than
`patients with unipolar depression.
`
`40
`
`#2 Unipolar depression
`
`30
`
`20
`
` a RO i
`
`Psychiatric
`Emergency Room/
`Primary
`Psychiatrist
`Psychologist/
`Substance Abuse/
`Hospital Stay
`Urgent Care Visit
`Care Visit
`Visit
`Counselor Visit
`Social Services
`
`
`
`
`
`oe!
`
` 88 Bipolar depression
`
`©© Control subjects
`
`PercentofPatientsReporting
`
`
`
`
`
`LATUDA has not been shown or indicated to impact healthcare costs in prospective, randomized, placebo-controlledtrials.
`
`Residual Symptoms and Medication Nonadherence Are Factors Associated With the Continued
`Burden of Bipolar Depression
`
`in the large Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, patients with bipolar
`disorder were followed for up to 2 years.'? Two observations were made about patients who had yet to recover from
`their symptoms in this study. The first was that, despite appropriate clinical treatment based on available guidelines,
`nearly 50%of the participants experienced a recurrence of their symptoms by the end of the 2-year follow-up
`period."? The second observation was that 70% of recurrence episodes were to a depressed state and the risk for
`recurrent depressive episodes increased by 14%for every depressive symptom present at recovery.This study
`confirmed that residual symptoms early in recovery predict recurrence, particularly for the depression associated
`with bipolar disorder.'3 In one other study, patients recovering with residual symptoms experienced a subsequent
`major episode approximately 3 times faster than patients recovering without residual symptoms.'4
`
`Treatment nonadherencein bipolar disorder is a common occurrence. A study evaluated adherence to antipsychotic
`therapy with aripiprazole, quetiapine, and ziprasidone in the 6 months following hospitalization of 84 patients with
`bipolar disorder.*® in the 6 months following hospitalization, patients with bipolar disorder received medication
`enough to cover only 37%of their follow-up days.Several reasons for poor adherence were discussed including
`symptoms of the disease itself, medication side effects, substance abuse, lack of support systems, stress, and
`inadequate patient-healthcare provider relationships.'> Clinical features that have been shownto be significantly
`associated with poor adherence included rapid bipolar cycling, suicide attempts, earlier onset of illness, and current
`anxiety or alcohol use disorder (P<0.05).'°
`
`These data suggest that there is a need to appropriately treat the depressive episodes associated with bipolar
`disorder and to provide education to patients and their caregivers on the importance of medication adherence
`to maintain disease stability.
`
`LATUDA has not been shown or indicated to impact adherence
`in prospective, randomized, placebo-controlledtrials
`
`CONFIDENTIAL
`
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`LATUDA04006176
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`

`Summary of Bipolar | Disorder
`
`Bipolar | disorder is a chronic mood disorder associated with high rates of disability and medical
`comorbidities, premature mortality from general medical conditions, in particular CVD, and risk of
`suicide. Although manic episodes are a key diagnostic factor of bipolar | disorder, patients will spend
`a high proportion of their symptomatic days in a depressed state and these symptoms tend to recur
`if inadequately treated.
`
`Furthermore, since definitive diagnosis is sometimes delayed, information from previous medical
`records as well as family, friends, and coworkers may aid in the more timely diagnosis of bipolar
`disorder. In turn, bipolar disorder is an important consideration in the differential diagnosis of
`major depressive disorder.
`
`LATUDBA has not been shown or indicated to impact mortality
`in prospective, randomized, placebo-controlled trials.
`
` 8
`
`CONFIDENTIAL
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`LATUDA04006177
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`

`ss 9
`
`eit echae neha Sienaanc
`Seticiniaehiencomagar
`Seresearaes
`secoeceee
`Pope
`eee cee
`
`=-
`
`ee
`
`ae eee
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`CONFIDENTIAL
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`LATUDA04006178
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`

`SCHIZOPHRENIA OVERVIEW
`
`Adults
`
`Schizophrenia is a widespread mental illness affecting more than 2 million Americans.'"® |t affects
`both men and women, with symptoms typically beginning in adolescence and early adulthood.”
`The etiology of schizophrenia is multifactorial and poorly understood.?° Although a direct biological
`cause has not been determined, genetic and environmental factors appear to play a role.©° Evidence
`suggests that patients with schizophrenia have multiple abnormalities in brain anatomy.?°
`
`Schizophrenia has 4 recognized clinical stages based on a patient's overall level of functioning:
`premorbid, prodromal, progressive, and residual.*°@! The mean age range of these stages and the
`associated decline in functioning are presented in Figure 5.
`
`Functioning
`
`&
`
`ae
`
`_2.
`
`ee
`
`© Premorbid
`“— Prodromal
`as
`_.Progressive
`Residual
`
`Se
`
`
`
`
`
`sibsheiratchttates
`
`10
`
`CONFIDENTIAL
`
`30 Age (Years)
`
`iia
`
`ESSSSeS
`
`ee
`:
`
`ee
`a—
`
`Adapted from Lewis DA, Lieberman JA. Neuron, 2000;28(2):325-334,
`
`The characteristic symptoms of schizophrenia involve a range of cognitive, behavioral, and
`emotional dysfunctions, but no single symptom is pathognomonic of the disorder. The diagnosis
`involves the recognition of a constellation of signs and symptoms associated with impaired
`occupational or social functioning. Individuals with the disorder will vary substantially on most
`features, as schizophrenia is a heterogeneous clinical syndrome.'® DSM-5 diagnostic criteria for
`schizophrenia require that two or more of the following are each present for a significant portion
`of time during a 1-month period (or less if successfully treated). At least one of these must be (1),
`(2), or (3)'8:
`
`1. Delusions
`2. Hallucinations
`
`3. Disorganized speech (eq, frequent derailment or incoherence)
`4. Grossly disorganized or catatonic behavior
`5, Negative symptoms (ie, diminished emotional expression or avolition)
`
`Furthermore, for a significant portion of the time since the onset of the disturbance, level of
`functioning in one or more major areas, such as work, interpersonal relations, or self-care, is
`markedly below the level achieved prior to the onset (or when the onsetis in childhood or
`adolescence, there is failure to achieve expected level of interpersonal, academic, or occupational
`functioning).'® Continuous signs of the disturbance persist for at least 6 months. This 6-month
`
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`period must include at least one month of symptoms (or less if successfully treated) that meet the criteria listed
`above (ie, active-phase symptoms) and may include periods of prodromal or residual symptoms. During these
`prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or by two
`or more symptoms listed above if they present in an attenuated form (eq, odd beliefs, unusual perceptual
`experiences).'® Other symptoms of schizophrenia may include hostility, excitement, emotional and social withdrawal,
`uncooperativeness, as well as impaired attention, executive functioning, and verbal fluency.** Schizoaffective
`disorder and depressive or bipolar disorder with psychotic features should be ruled out, as well as disturbances
`attributable to a drug of abuse or medication, or another medical condition.'* If there is a history of autism or
`communication disorder in childhood, then a diagnosis of schizophrenia is made only if prominent delusions or
`hallucinations, in addition to other required symptoms of schizophrenia, are also present for at least one month.'®
`
`Adolescents
`
`Approximately one-third of individuals develop schizophrenia before the age of 18.°7 Adolescents age 13 to 17 years
`with schizophrenia are diagnosed according to the samecriteria as adults, though it is important to note that the
`disorder presents differently in these younger individuals, making its recognition more difficult. Adolescent-onset
`schizophrenia is characterized by a more insidious onset with a relative lack of symptom specificity in the early
`stages of the disease, the potential for more prominent negative symptoms, frequently disorganized behavior or
`dysfunctional ways of thinking, and less complex delusions and hallucinations. The duration of untreated psychosis
`can be 3.5 times longer in patients with early-onset schizophrenia versus those with adult-onset schizophrenia.**
`
`Short-term outcomes appear worse for adolescents with schizophrenia than for their adult counterparts. Over time,
`patients can typically expect a chronic, unremitting course with severe impairment as adults. However, this path can
`vary considerably in terms of impairment level and social and psychiatric support needed.2°
`
`Additional clinical resources are needed to assist healthcare professionals with identifying schizophrenia in
`adolescents. The stigma associated with the illness can delay communication of an actual diagnosis to the patient
`and family.*46 The severe and extended clinical course and poor outcomes associated with adolescent
`schizophrenia highlight the need for early recognition, diagnosis, and intervention.24.25
`
`Schizophrenia Clinical and Economic Burden
`
`Disease Burden and Life Expectancy
`
`Although schizophrenia is a brain disorder, it has been shown to adversely affect not only mental, but also overall
`physical health, leading to increased morbidity and mortality.2°2’
`
`
`
`The life expectancy of people with mental illness is, on average, 13 to 30 years shorter than that of the general
`population.2’ The cause of premature mortality is largely attributed to coronary heart disease (Figure 6).2°
`
`ith
`
`schizophrenia
`
`#2 Without schizophrenia 30
`
`40
`
`50
`
`Life Expectancy (years)
`
`LATUDA has not been shown or indicated to impact mortality or life expectancy
`in prospective, randomized, placebo-controlledtrials.
`
`CONFIDENTIAL
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`Cardiovascular Risk
`
`Coronary heart disease accounts for one-half to three-fourths of deaths in patients with
`schizophrenia as compared with about one-third of deaths in the general population.@® Rates of
`cardiovascular risk factors, including obesity, cigarette smoking, diabetes, hypertension,
`dyslipidemia, and metabolic syndrome, are up to 4 times higher in patients with schizophrenia than
`in the general population (Table 1).293?
`
`
`| Cardiovascular
`Prevalencein
`prevalence iH
`:
`;
`| Risk Factors
`General Population
`Schizophrenia
`Relative Risk (RR)
`
`Obesity
`
`Smoking
`
`Diabetes
`
`| Hypertension
`| Dyslipidemia
`
`Population??
`
`B4%30
`
`21%?!
`
`B%"!
`
`24%?!
`16%
`
`45%-55%
`
`50%-80%
`
`10%-15%
`
`19%-58%
`25%-69%
`
`37%-63%
`34%
`Metabolic syndrome
`sreativerisk (RR) = rtrisk oii eventrelativeto ese value above 1 cleats Wicraase risk.
`
`
`
`
`
`15-2
`
`2-4
`
`1-1.5
`
`1-2
`1-4
`
`1-2
`
`
`
`The term “metabolic syndrome" refers to a group of abnormalities that is widely considered to be
`a precursor of diabetes and CVD. Metabolic syndrome can be constituted by changes in several
`cardiometabolic risk categories, including elevated fasting blood glucose, altered lipid profile,
`elevated blood pressure, being overweight or obese, and central adiposity. Patients with
`schizophrenia may be more susceptible to changesin these parameters than the general population
`and, therefore, may have a higher risk of metabolic syndrome and cardiovascular comorbidities.24.35
`
`According to a meta-analysis including over 25,000 patients with schizophrenia, the rate of
`metabolic syndrome in these patients approached 50%, compared with 33%in the general
`population.*° Additionally, atypical antipsychotic medications are associated with changesin
`metabolic parameters.2”3° Other contributing factors that may affect metabolic risk in patients
`with schizophrenia are that they receive less frequent or no screening and fewer treatments for
`cardiometabolic risk factors.2%4°
`
`In addition to the higher prevalence of CVD, schizophrenia is often associated with higher rates of
`comorbid mental illnesses as well as respiratory and infectious diseases.4!4¢
`
`Economic Burden
`
`Onset of symptoms of schizophrenia frequently occurs during the most productive years of
`adulthood (males: late teens to early 20s; females: 20s to early 30s). Therefore, the disease can
`lead to substantial losses in productivity and increased costs to both the patient and society.2°4?
`
`Schizophrenia has been shown to have a substantial economic impact. in a 2005 study, overall
`spending on schizophrenia was estimated at $62.7 billion a year (2002 data; Figure 7).*4
`
`Indirect costs (losses resulting from decreased productivity) made up the largest portion of
`spending, amounting to an estimated total of $32.4 billion. Of these, unemployment was the
`greatest cost, followed by caregiver expenses, reduced productivity, and suicide.44
`
`Direct healthcare-related costs, Including long-term care, outpatient and inpatient care, and
`pharmacy expenses, accounted for the second largest proportion of spending, estimated at
`$22.7 billion.44 Direct non-healthcare costs, including law enforcement, homeless shelters,
`and research and training, accounted for an estimated $7.6 billion.44
`
`12
`
`LATUDA has not been shownor indicated to impact healthcare costs
`in prospective, randomized, placebo-controlled triats.
`
`CONFIDENTIAL
`
`LATUDA04006181
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` Cost
`
`
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`=§
`
`1000
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`
`
`Schizophrenia + Diabetes
`(N = 83,000)
`
`Schizophrenia + Dyslipidemia’
`(N= 79,000)
`
`
`"Schizophrenia + Hypertension Schizophrenia + Heart Disease
`(N = 165,000)
`(N = 130,000)
`
`
`
`Note: Persons with >1 comorbidity appear in muitinie categories and their expenses are doubie counted.
`“Comorbid categories are limited to diabetes, dystipidemia, hypertension. and heart disease,
`‘Costs of persons with dyslipidemia should be treated with caution because relative standard error (SE) is 30%.
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`$7.97
`| Long-term care
`Outpatientcare
`| $6.95
`
`| Pharmacy cost
`| $5.04
`
`i inpatient care
`| $2.76
`
`
`
`
`
` Direct Non-Healthcare Costs
`
`
`
`
`Percentage
`5%
`
`31%
`|
`|
`22%
`|
`12%
`
`
`| 3
`
`
`
`About two-thirds of patients with schizophrenia also suffer from diabetes, dyslipidemia, hypertension, and/or
`heart disease, adding substantially to the economic burden of their mental illness (Figure 8).45 Approximately
`2 of 3 patients with schizophrenia have at least 1 of 4 associated comorbidities.
`
`
`
`#8 For schizophrenia only
`
`Ei For schizophrenia and comorbidity
`
`-—~ 5000
`<=
`
`22
`
`4000
`few
`é 3000
`=a
`z& 2000
`ww
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`Factors Associated With Clinical and Economic Burden
`
`Two factors that often play a substantial role in the high clinical and economic costs associated with
`schizophrenia are hospitalization and treatment nonadherence.4>48
`
`A study of medical and pharmacy claims for the years 1998 to 2007 found that newly diagnosed
`patients (<1 year since diagnosis) had significantly higher medical expensesin their first year of
`treatment than those diagnosed for 3 or more years.*® Newly diagnosed patients were hospitalized
`twice as often (22.3%vs 12.4%; P<0.0001), spent an average of 2 more days in the hospital, and
`cost approximately $5000 more than chronic patients.“®
`
`Nonadherence to treatment is an important contributor to relapse that increases the healthcare
`burden of schizophrenia. One study found that continuous treatment reduced the risk of relapse by
`about 70%.*?
`
`A study of 213 patients found that discontinuation of antipsychotic medication doubled the risk of
`rehospitalization within the first 3 months of hospital discharge.*®
`
`Patient-related, treatment-related, and environmental factors may all play a contributing role in the
`nonadherence of patients with schizophrenia (Table 2).2°
`
`Treatment-Related Factors
`
`Patient-Related Factors
`
`Environmental
`Psychosocial Factors
`
`importance of treatment Lack of family support
`
`in Figure 9.
`
`Lackotetiiva:
`
`Side effects
`
`y
`
`Lack of insight about
`illness severity
`
`Breakdownof
`therapeutic alliance
`
`Misconceptions about the
`
`LATUDA has not been shown or indicated to impact hospitalization rates or treatment adherence in
`prospective, randomized, placebo-controlled trials.
`
`Continuing Need for Additional Antipsychotics
`
`The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Study compared the relative
`effectiveness of one first-generation (typical) antipsychotic (perphenazine) and 4 second-generation
`(atypical) antipsychotics (olanzapine, quetiapine, risperidone, and ziprasidone) for treatment of
`patients with schizophrenia.*?
`
`The CATIE Study indicated that 74% (1061/1432) of patients discontinued antipsychotic treatment
`before the 18-month study endpoint. Analysis of the reasons for discontinuation indicated that over
`one-half of patients discontinued treatment due to either lack of efficacy (32%) or being unable to
`tolerate the prescribed drug (20%).4? The reasons given for treatment intolerance are described
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`Reasonsfor Intolerability
`
`
`
`Weight gain or metabolic effects
`Extrapyramidal symptoms
`| |Sedation
`
`Other effects
`
`
`
`
`
`
`conducted and therefore is not included in this analysis.
`
`
` psychot
`
`LATUDA was not available at the time the CATIE Study was
`
`Considerations When Choosing an Antipsychotic for Schizophrenia
`
`Having a variety of available antipsychotic drugs allows for individualization of therapy for adult patients with
`schizophrenia. Important considerations when choosing the appropriate antipsychotic for each patient include the
`patient's past responses to treatment, medication side-effect profiles, patient preferences, route of administration,
`presence of comorbid medical conditions, and potential interactions with other prescribed medications.°°
`
`Summary of Schizophrenia
`
`Schizophrenia is a serious chronic and disabling mental illness with a substantial clinical burden that includes poor
`overall physical health and higher rates of comorbid mental illnesses as well as cardiovascular, respiratory, and
`infectious diseases; all of which can contribute to a reduced life expectancy.!*20.27.28
`
`Schizophrenia is associated with significant costs due to lost productivity and other direct and indirect healthcare-
`and non-healthcare-related expenses.42.44
`
`Treatment nonadherence can result in poorer outcomes and may contribute to increased medical costs. Lack of
`treatment efficacy and/or poortolerability and patient and environmental factors may also all contribute
`to nonadherence.*?
`
`Adolescents age 13 to 17 are diagnosed with the same criteria as adults, but schizophrenia can be harderto
`recognize in this population.** The clinical severity, impact on development, and poor prognosis of adolescent
`schizophrenia underscore the importance of early detection, prompt diagnosis, and effective treatment.2°
`
`LATUDA has not been shown or indicated to impact adherence or healthcare costs
`in prospective, randomized, placebo-controlledtrials.
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`Tablet images shown are not actualsize,
`
`LATUDA PRODUCT PROFILE
`
`INDICATIONS*
`
`LATUDAis indicated for treatment of adult and adolescent patients age 13 to 17 years with
`schizophrenia and in adult patients with major d