-----------------------DOSAGE FORMS AND STRENGTHS-------------------
`Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg (3)
`
`
`------------------------------CONTRAINDICATIONS-------------------------------
`
`Known hypersensitivity to LATUDA or any components in the
`
`formulation (4).
`
`Concomitant use with a strong CYP3A4 inhibitor (e.g.,
`
`ketoconazole) (2.5, 4, 7.1).
`
`Concomitant use with a strong CYP3A4 inducer (e.g., rifampin)
`
`(2.5, 4, 7.1).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`-----------------------------WARNINGS AND PRECAUTIONS------------------
`
`Cerebrovascular Adverse Reactions in Elderly Patients with
`
`Dementia-Related Psychosis: Increased incidence of
`
`cerebrovascular adverse events (e.g., stroke, transient ischemic
`
`attack) (5.2).
`
` Neuroleptic Malignant Syndrome: Manage with immediate
`
`discontinuation and close monitoring (5.4).
`
`Tardive Dyskinesia: Discontinue if clinically appropriate (5.5).
`
`
`
` Metabolic Changes: Atypical antipsychotic drugs have been
`associated with metabolic changes that may increase
`cardiovascular/cerebrovascular risk. These metabolic changes
`
`include hyperglycemia, dyslipidemia, and weight gain (5.6).
`
`
`Hyperglycemia and Diabetes Mellitus: Monitor patients for
`
`symptoms of hyperglycemia including polydipsia, polyuria,
`
`polyphagia, and weakness. Monitor glucose regularly in
`patients with diabetes or at risk for diabetes.
`Dyslipidemia: Undesirable alterations have been observed in
`patients treated with atypical antipsychotics.
`
` Weight Gain: Gain in body weight has been observed.
`
`
`Monitor weight.
`
`Hyperprolactinemia: Prolactin elevations may occur (5.7).
`Leukopenia, Neutropenia, and Agranulocytosis: Perform complete
`
`blood counts (CBC) in patients with a pre-existing low white blood
`cell count (WBC) or a history of leukopenia or neutropenia.
`
`
`Consider discontinuing LATUDA if a clinically significant decline
`in WBC occurs in the absence of other causative factors (5.8).
`Orthostatic Hypotension and Syncope: Dizziness, tachycardia or
`bradycardia, and syncope may occur, especially early in treatment.
`
`In patients with known cardiovascular or cerebrovascular disease,
`
`and in antipsychotic-naïve patients, consider a lower starting dose
`and slower titration (5.9).
`
`
`--------------------------------ADVERSE REACTIONS-----------------------------
`Commonly observed adverse reactions (incidence ≥ 5% and at least twice the
`rate for placebo) were (6.1):
`
`
`Schizophrenia: somnolence, akathisia, extrapyramidal symptoms,
`
`
`and nausea
`Bipolar depression: akathisia, extrapyramidal symptoms, and
`
`somnolence
`
`
`
`
`
`To report SUSPECTED ADVERSE REACTIONS, contact Sunovion
`
`Pharmaceuticals Inc. at 1-877-737-7226 or FDA at 1-800-FDA-1088 or
`www.fda.gov/medwatch.
`
`----------------------------USE IN SPECIFIC POPULATIONS-------------------
`
`Pregnancy: Use LATUDA during pregnancy only if the potential
`
`benefit justifies the potential risk (8.1).
`
`Nursing Mothers: Discontinue drug or nursing, considering risk of
`
`drug discontinuation to the mother (8.3).
`
`
`
`
`See 17 for PATIENT COUNSELING INFORMATION and Medication
`
`Guide
`
`Revised: 7/2013
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`LATUDA safely and effectively. See full prescribing information for
`LATUDA.
`
`LATUDA (lurasidone hydrochloride) tablets, for oral use
`
`Initial U.S. Approval: 2010
`
`
`
`WARNINGS:
`
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH
`
`
`DEMENTIA-RELATED PSYCHOSIS; AND SUICIDAL THOUGHTS
`
`AND BEHAVIORS
`
`See full prescribing information for complete boxed warning.
`
`
`
` Elderly patients with dementia-related psychosis treated with
`antipsychotic drugs are at an increased risk of death.
`
`
` LATUDA is not approved for the treatment of patients with dementia-
`
` related psychosis (5.1).
`
`Increased risk of suicidal thinking and behavior in children, adolescents,
`
` and young adults taking antidepressants (5.2)
`
` Monitor for worsening and emergence of suicidal thoughts and
`behaviors (5.2)
`
`
`
`
`------------------------------RECENT MAJOR CHANGES-----------------------­
`Boxed Warnings, Suicidal Thoughts and Behaviors (5.2)
` 6/2013
`
`
`Indications and Usage, Bipolar Depression (1.2)
`6/2013
`Dosage and Administration, Bipolar Depression (2.1)
`6/2013
`
`
`
`Dosage Forms and Strengths (3)
`7/2013
`Warnings and Precautions (5.2, 5.6, 5.7, 5.9, 5.10, 5.11, 5.13, 5.14) 6/2013
`
`
`
`-----------------------------INDICATIONS AND USAGE--------------------------
`
`LATUDA is an atypical antipsychotic for the treatment of:
`
`
`Schizophrenia (1.1, 14.1)
`
`
`
`Depressive episodes associated with Bipolar I Disorder (bipolar
`
`
`
`
`depression), as monotherapy and as adjunctive therapy with lithium or
`valproate (1.2, 14.2).
`
`
`---------------------------DOSAGE AND ADMINISTRATION-------------------
`LATUDA should be taken with food (at least 350 calories). Administration
`with food substantially increases the absorption of LATUDA (2.3, 12.3).
`
`
` Indication
`
`Starting Dose
`
`Recommended Dose
`
`Schizophrenia (2.1)
`
`
`40 mg per day
`
`
`40 mg to 160 mg per day
`
`
`Bipolar Depression
`
`(2.2)
`
`20 mg per day
`
`
`20 mg to 120 mg per day
`
`
`
`
` Moderate and Severe Renal Impairment: Recommended starting
`dose is 20 mg per day, and the maximum recommended dose is 80
`
`
`mg per day (2.4, 8.6).
`
`
`
` Moderate and Severe Hepatic Impairment: Recommended starting
`dose is 20 mg per day. The maximum recommended dose is 80 mg
`
`
`
`
`per day in moderate hepatic impairment and 40 mg per day in
`
`severe hepatic impairment (2.4, 8.6).
`
`Concomitant Use of a Moderate CYP3A4 inhibitor (e.g.,
`
`diltiazem): LATUDA dose should be reduced to half of the
`original dose level. Recommended starting dose is 20 mg per day.
`
`Maximum recommended dose is 80 mg per day (2.5, 7.1)
`
`Concomitant Use of a Moderate CYP3A4 Inducer:
`
` It may be necessary to increase the dose of LATUDA (2.5, 7.1)
`
`
`
`
`
`
`
`
`
`
`
`1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3338948
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`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`WARNING:
`
`INCREASED MORTALITY IN ELDERLY PATIENTS WITH DEMENTIA-RELATED PSYCHOSIS
`
`
`1 INDICATIONS AND USAGE
`1.1
` Schizophrenia
`1.2 Depressive Episodes Associated with Bipolar I Disorder
`
`
`
`2 DOSAGE AND ADMINISTRATION
`2.1
` Schizophrenia
`2.2 Depressive Episodes Associated with Bipolar I Disorder
`
`
`2.3 Administration Instructions
`
`2.4 Dose Modifications in Special Populations
`
`2.5 Dose Modifications Due to Drug Interactions
`
`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
`5 WARNINGS AND PRECAUTIONS
`5.1
`Increased Mortality in Elderly Patients with Dementia-Related
`
`Psychosis
`
`5.2 Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`
`5.3 Cerebrovascular Adverse Reactions, Including Stroke in Elderly
`
`
`Patients with Dementia-Related Psychosis
`
`5.4 Neuroleptic Malignant Syndrome
`
`5.5 Tardive Dyskinesia
`
`5.6 Metabolic Changes
`
`5.7 Hyperprolactinemia
`
`
`5.8 Leukopenia, Neutropenia and Agranulocytosis
`
`5.9 Orthostatic Hypotension and Syncope
`
`
`5.10 Seizures
`
`5.11 Potential for Cognitive and Motor Impairment
`
`
`5.12 Body Temperature Dysregulation
`
`
`5.13 Suicide
`
`5.14 Activation of Mania/Hypomania
`
`
`5.15 Dysphagia
`
`5.16 Neurological Adverse Reactions in Patients with Parkinson's Disease
`
`
`or Dementia with Lewy Bodies
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
`
`7 DRUG INTERACTIONS
`Potential for Other Drugs to Affect LATUDA
`
`7.1
`
`7.2 Potential for LATUDA to Affect Other Drugs
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`
`
`8.3 Nursing Mothers
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Other Patient Factors
`
`
`9 DRUG ABUSE AND DEPENDENCE
`
`9.1 Controlled Substance
`
`9.2 Abuse
`
`10 OVERDOSAGE
`
`10.1 Human Experience
`
`10.2 Management of Overdosage
`
`11 DESCRIPTION
`12 CLINICAL PHARMACOLOGY
`12.1 Mechanism of Action
`
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`13 NONCLINICAL TOXICOLOGY
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`
`14 CLINICAL STUDIES
`14.1 Schizophrenia
`14.2 Depressive Episodes Associated with Bipolar I Disorder
`
`
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`17.1 Increased Mortality in Elderly Patients with Dementia-Related
`
`Psychosis
`
`17.2 Suicidal Thoughts and Behaviors; and Activation of Mania or
`
`
`
`Hypomania
`
`17.3 Neuroleptic Malignant Syndrome
`
`
`17.4 Metabolic Changes (Hyperglycemia and Diabetes Mellitus,
`
`
`
`Dyslipidemia, and Weight Gain)
`
`17.5 Orthostatic Hypotension
`17.6 Leukopenia/Neutropenia
`
`
`17.7 Interference with Cognitive and Motor Performance
`
`17.8 Pregnancy and Nursing
`
`17.9 Concomitant Medication and Alcohol
`
`
`17.10 Heat Exposure and Dehydration
`
`
`
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`
`listed .
`
`
`
`
`
`
`
`
`
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`Reference ID: 3338948
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`

`

`
`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 )].
`
`
` LATUDA 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)].
`
`
`
`
`
`INDICATIONS AND USAGE
`
`
`1
`
`Schizophrenia
`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)].
`
`Depressive Episodes Associated with Bipolar I Disorder
`1.2
` Monotherapy: 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)].
`Adjunctive Therapy with Lithium or Valproate: 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.
`
`
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`DOSAGE AND ADMINISTRATION
`
`
`2
`
`Schizophrenia
`2.1
`The recommended starting dose of LATUDA is 40 mg once daily. Initial dose titration is not
`required. LATUDA has been shown to be effective in a dose range of 40 mg per day to 160 mg
`
`per day [see Clinical Studies (14.1)]. The maximum recommended dose is 160 mg per day.
`
`Depressive Episodes Associated with Bipolar I Disorder
`2.2
`The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy or as
`adjunctive therapy with lithium or valproate. Initial dose titration is not required. LATUDA has
`been shown to be effective in a dose range of 20 mg per day to 120 mg per day as monotherapy
`or as adjunctive therapy with lithium or valproate [see Clinical Studies (14.2)]. The maximum
`recommended dose, as monotherapy or as adjunctive therapy with lithium or valproate, is 120
`mg per day. In the monotherapy study, the higher dose range (80 mg to 120 mg per day) did not
`provide additional efficacy, on average, compared to the lower dose range (20 to 60 mg per day)
`[see Clinical Studies (14.2).
`
`Administration Instructions
`2.3
`LATUDA should be taken with food (at least 350 calories). Administration with food
`substantially increases the absorption of LATUDA. Administration with food increases the AUC
`approximately 2-fold and increases the Cmax approximately 3-fold. In the clinical studies,
`LATUDA was administered with food [see Clinical Pharmacology (12.3)].
`
`
`Dose Modifications in Special Populations
`2.4
`
` Renal Impairment
`Dose adjustment is recommended in moderate (creatinine clearance: 30 to <50 mL/min) and
`
` severe renal impairment (creatinine clearance <30 mL/min) patients. The recommended starting
`
` dose is 20 mg per day. The dose in these patients should not exceed 80 mg per day [see Use in
`
` Specific Populations (8.6)].
`Hepatic Impairment
`
`Dose adjustment is recommended in moderate (Child-Pugh Score = 7 to 9) and severe hepatic
`impairment (Child-Pugh Score = 10 to 15) patients. The recommended starting dose is 20 mg per
`day. The dose in moderate hepatic impairment patients should not exceed 80 mg per day and the
`dose in severe hepatic impairment patients should not exceed 40 mg/day [see Use in Specific
`Populations (8.6)].
`
`
` Dose Modifications Due to Drug Interactions
`
`2.5
`
` Concomitant Use with CYP3A4 Inhibitors
`LATUDA should not be used concomitantly with a strong CYP3A4 inhibitor (e.g., ketoconazole,
`clarithromycin, ritonavir, voriconazole, mibefradil, etc.) [see Contraindications (4)].
`If LATUDA is being prescribed and a moderate CYP3A4 inhibitor (e.g. diltiazem, atazanavir,
`erythromycin, fluconazole, verapamil etc.) is added to the therapy, the LATUDA dose should be
`reduced to half of the original dose level. Similarly, if a moderate CYP3A4 inhibitor is being
`
`4
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`prescribed and LATUDA is added to the therapy, the recommended starting dose of LATUDA is
`20 mg per day, and the maximum recommended dose of LATUDA is 80 mg per day [see
`Contraindications (4); Drug Interactions (7.1)].
`
`Grapefruit and grapefruit juice should be avoided in patients taking LATUDA, since these may
`inhibit CYP3A4 and alter LATUDA concentrations [see Drug Interactions (7.1)].
`Concomitant Use with CYP3A4 Inducers
`
`LATUDA should not be used concomitantly with a strong CYP3A4 inducer (e.g., rifampin,
`avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.) [see Contraindications (4); Drug
`Interactions (7.1)]. If LATUDA is used concomitantly with a moderate CYP3A4 inducer, it may
`
`be necessary to increase the LATUDA dose after chronic treatment (7 days or more) with the
`CYP3A4 inducer.
`
`
`DOSAGE FORMS AND STRENGTHS
`3
`LATUDA tablets are available in the following shape and color (Table 1) with respective one-
`sided debossing:
`Table 1:
`LATUDA Tablet Presentations
`Tablet Strength
`Tablet Color/Shape
`
`20 mg
`white to off-white round
`
`40 mg
`white to off-white round
`
`
`60 mg
`white to off white oblong
`
`80 mg
`pale green oval
`
`120 mg
`white to off-white oval
`
`Tablet Markings
`L20
`L40
`L60
`L80
`L120
`
`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)].
`
`
`WARNINGS AND PRECAUTIONS
`
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`5
`
`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),
`
`
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`Suicidal Thoughts and Behaviors in Adolescents and Young Adults
`
`
`
`
`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
`
`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 2.
`
`
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`Age Range
`
`
`<18
`18-24
`
`25-64
`≥65
`
`Table 2
`Drug-Placebo Difference in Number of
`Cases of Suicidality per 1000 Patients
`Treated
`Increases Compared to Placebo
`14 additional cases
`5 additional cases
`Decreases Compared to Placebo
`1 fewer case
`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 LATUDA should be written for the smallest quantity of capsules
`
`consistent with good patient management, in order to reduce the risk of overdose.
`
`
`
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`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)].
`
`
`Neuroleptic Malignant Syndrome
`5.4
` 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.
`
` Tardive Dyskinesia
`5.5
`
`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 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
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`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.
`
` Metabolic Changes
`5.6
`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 treatment-emergent 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.
`Schizophrenia
`Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3.
`
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`Table 3:
`
`
`
`Change in Fasting Glucose in Schizophrenia Studies
`
`
`LATUDA
`Placebo
`20 mg/day
`40 mg/day
`80 mg/day
`
`
`120 mg/day
`
`
`
`160 mg/day
`
`
`n=680
`-0.0
`
`Serum Glucose
`
`Serum Glucose
`(≥ 126 mg/dL)
`
`
`
`Mean Change from Baseline (mg/dL)
`n=71
`n=478
`n=508
`-0.6
`+2.6
`-0.4
`Proportion of Patients with Shifts to ≥ 126 mg/dL
`
`11.7%
`12.7%
`6.8%
`
`
`
`(7/60)
`( 57/449)
`(32/472)
`
`8.3%
`
`(52/628)
`
`n=283
`+2.5
`
`n=113
`+2.5
`
`
`
`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).
`Bipolar Depression
`Monotherapy
`Data from the short-term, flexible-dose, placebo-controlled monotherapy bipolar depression
`study are presented in Table 4.
`
`Change in Fasting Glucose in the Monotherapy Bipolar Depression Study
`Table 4:
`
`
`LATUDA
`Placebo
`20 to 60 mg/day
`80 to 120 mg/day
`
`
`n=143
`+1.8
`
`
`Serum Glucose
`
`Mean Change from Baseline (mg/dL)
`n=148
`n=140
`+1.8
`-0.8
`Proportion of Patients with Shifts to ≥ 126 mg/dL
`
`
`
`
`6.4%
`4.3%
`2.2%
`Serum Glucose
`(9/141)
`(6/141)
`(3/138)
`(≥ 126 mg/dL)
` 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).
`Adjunctive Therapy with Lithium or Valproate
`
` Data from the short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar
`depression studies are presented in Table 5.
`
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