Latuda (lurasidone hydrochloride) tablet, film coated
Sumitomo Pharma America, Inc.

Sumitomo Pharma America, Inc.
Latuda
lurasidone hydrochloride
lurasidone hydrochloride
lurasidone
mannitol
starch, corn
croscarmellose sodium
hypromellose 2910 (6 MPA.S)
magnesium stearate
Carnauba Wax
white
ROUND
L;20
Latuda
lurasidone hydrochloride
lurasidone hydrochloride
lurasidone
mannitol
starch, corn
croscarmellose sodium
hypromellose 2910 (6 MPA.S)
magnesium stearate
Carnauba Wax
white
ROUND
L;40
Latuda
lurasidone hydrochloride
lurasidone hydrochloride
lurasidone
mannitol
starch, corn
croscarmellose sodium
hypromellose 2910 (6 MPA.S)
magnesium stearate
Carnauba Wax
white
OVAL
L;60
Latuda
lurasidone hydrochloride
lurasidone hydrochloride
lurasidone
mannitol
starch, corn
croscarmellose sodium
hypromellose 2910 (6 MPA.S)
magnesium stearate
ferric oxide yellow
FD&C blue No. 2
Carnauba Wax
green
OVAL
L;80
Latuda
lurasidone hydrochloride
lurasidone hydrochloride
lurasidone
mannitol
starch, corn
croscarmellose sodium
hypromellose 2910 (6 MPA.S)
magnesium stearate
Carnauba Wax
white
OVAL
L;120
Warnings and Precautions, Metabolic Changes, Hyperprolactinemia (5.6, 5.7) 12/2019

WARNING: 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. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Precautions ( 5.1)].

Suicidal Thoughts and Behaviors

Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adults in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and for emergence of suicidal thoughts and behaviors [see Warnings and Precautions (5.2)].

WARNING: 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).
  • Antidepressants increased the risk of suicidal thoughts and behavior in pediatric and young adult patients. Closely monitor for clinical worsening and emergence of suicidal thoughts and behaviors (5.2).

1 INDICATIONS AND USAGE

LATUDA is indicated for:

  • Treatment of adult and adolescent patients (13 to 17 years) with schizophrenia [see Clinical Studies (14.1)].
  • Monotherapy treatment of adult and pediatric patients (10 to 17 years) with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].
  • Adjunctive treatment with lithium or valproate in adult patients with major depressive episode associated with bipolar I disorder (bipolar depression) [see Clinical Studies (14.2)].

LATUDA is an atypical antipsychotic indicated for the treatment of:

  • Schizophrenia in adults and adolescents (13 to 17 years) ( 1, 14.1)
  • Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults and pediatric patients (10 to 17 years) as monotherapy (1, 14.2)
  • Depressive episode associated with Bipolar I Disorder (bipolar depression) in adults as adjunctive therapy with lithium or valproate (1, 14.2)

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 – adults (2.1) 40 mg per day 40 mg to 160 mg per day
Schizophrenia –adolescents (13 to 17 years) (2.1) 40 mg per day 40 mg to 80 mg per day
Bipolar Depression - adults (2.2) 20 mg per day 20 mg to 120 mg per day
Bipolar Depression –pediatric patients (10 to 17 years) (2.2) 20 mg per day 20 mg to 80 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 (2.5, 8.7).
  • 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 (2.6, 7.1).
  • Concomitant Use of a Moderate CYP3A4 Inducer:
    It may be necessary to increase the dose of LATUDA (2.6, 7.1).

2.1 Schizophrenia

Adults

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.

Adolescents (13 – 17 years)

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 80 mg per day [see Clinical Studies (14.1)]. The maximum recommended dose is 80 mg per day.

2.2 Depressive Episodes Associated with Bipolar I Disorder

Adults

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)].

Pediatric Patients (10 – 17 years)

The recommended starting dose of LATUDA is 20 mg given once daily as monotherapy. Initial dose titration is not required. The dose may be increased after one week based on clinical response. LATUDA has been shown to be effective in a dose range of 20 mg per day to 80 mg per day as monotherapy. At the end of the clinical study, most of the patients (67%) received 20 mg or 40 mg once daily [see Clinical Studies (14.2)]. The maximum recommended dose is 80 mg per day.

The efficacy of LATUDA in the treatment of mania associated with bipolar disorder has not been established.

2.3 Administration Information

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)].

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 and 2.2)].

2.4 Dose Modifications for 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)].

2.5 Dose Modifications for 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 per mg/day [see Use in Specific Populations (8.7)].

2.6 Dose Modifications Due to Drug Interactions of CYP3A4 Inhibitors and CYP3A4 Inducers

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 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.

3 DOSAGE FORMS AND STRENGTHS

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 Tablet Markings
20 mg white to off-white round L20
40 mg white to off-white round L40
60 mg white to off-white oblong L60
80 mg pale green oval L80
120 mg white to off-white oval L120

Tablets: 20 mg, 40 mg, 60 mg, 80 mg and 120 mg (3)

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)].
  • Known hypersensitivity to LATUDA or any components in the formulation (4).
  • Concomitant use with a strong CYP3A4 inhibitor (e.g., ketoconazole) (2.6, 4, 7.1).
  • Concomitant use with a strong CYP3A4 inducer (e.g., rifampin) (2.6, 4, 7.1).

5 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) (5.3).
  • Neuroleptic Malignant Syndrome: Manage with immediate discontinuation and close monitoring (5.4).
  • Tardive Dyskinesia: Discontinue if clinically appropriate (5.5).
  • Metabolic Changes: Monitor for hyperglycemia/diabetes mellitus, dyslipidemia and weight gain (5.6).
  • 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: Monitor heart rate and blood pressure and warn patients with known cardiovascular or cerebrovascular disease, and risk of dehydration or syncope (5.9).

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. LATUDA is not approved for the treatment of patients with dementia-related psychosis [see Boxed Warning, Warnings and Precautions (5.3)].

5.2 Suicidal Thoughts and Behaviors in Pediatric and Young Adult Patients

In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in pediatric and young adult patients was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 2.

No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide.

Table 2: Risk Differences of the Number of Cases of Suicidal Thoughts or Behaviors in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Patients
Age Range Drug-Placebo Difference in Number of Patients of Suicidal Thoughts or Behaviors per 1000 Patients Treated
Increases Compared to Placebo
<18 14 additional patients
18-24 5 additional patients
Decreases Compared to Placebo
25-64 1 fewer patient
≥65 6 fewer patients

It is unknown whether the risk of suicidal thoughts and behaviors in pediatric and young adult patients extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.

Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behavior and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing LATUDA, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.

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 Boxed Warning, 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. Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.

If NMS is suspected, immediately discontinue LATUDA and provide intensive symptomatic treatment and monitoring.

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 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 or may even arise after discontinuation of treatment.

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 hyperglycemia-related adverse events in patients treated with the atypical antipsychotics.

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

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 3.

Table 3: Change in Fasting Glucose in Adult Schizophrenia Studies
LATUDA
Placebo 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 -0.0 -0.6 +2.6 -0.4 +2.5 + 2.5
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).

Adolescents

In studies of adolescents and adults with schizophrenia, changes in fasting glucose were similar. In the short-term, placebo-controlled study of adolescents, fasting serum glucose mean values were -1.3 mg/dL for placebo (n=95), +0.1 mg/dL for 40 mg/day (n=90), and +1.8 mg/dL for 80 mg/day (n=92).

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study are presented in Table 4.

Table 4: Change in Fasting Glucose in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=148 n=140 n=143
Serum Glucose +1.8 -0.8 +1.8
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)

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 adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 5.

Table 5: Change in Fasting Glucose in the Adult Adjunctive Therapy Bipolar Depression Studies

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

LATUDA
Placebo 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=302 n=319
Serum Glucose -0.9 +1.2
Proportion of Patients with Shifts to ≥ 126 mg/dL
Serum Glucose
(≥ 126 mg/dL)
1.0%
(3/290)
1.3%
(4/316)

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).

Pediatric Patients (10 to 17 years)

In studies of pediatric patients 10 to 17 years and adults with bipolar depression, changes in fasting glucose were similar. In the 6-week, placebo-controlled study of pediatric patients with bipolar depression, mean change in fasting glucose was +1.6 mg/dL for LATUDA 20 to 80 mg/day (n=145) and -0.5 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with schizophrenia, bipolar depression, or autistic disorder, 7% of patients with a normal baseline fasting glucose experienced a shift to high at endpoint while taking lurasidone.

Dyslipidemia

Undesirable alterations in lipids have been observed in patients treated with atypical antipsychotics.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 6.

Table 6: Change in Fasting Lipids in Adult Schizophrenia Studies
LATUDA
Placebo 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 -5.8 -12.3 -5.7 -6.2 -3.8 -6.9
Triglycerides -13.4 -29.1 -5.1 -13.0 -3.1 -10.6
Proportion of Patients with Shifts
Total Cholesterol (≥ 240 mg/dL) 5.3%
(30/571)
13.8%
(8/58)
6.2%
(25/402)
5.3%
(23/434)
3.8%
(9/238)
4.0%
(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 -15.1 (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.

Adolescents

In the adolescent short-term, placebo-controlled study, fasting serum cholesterol mean values were -9.6 mg/dL for placebo (n=95), -4.4 mg/dL for 40 mg/day (n=89), and +1.6 mg/dL for 80 mg/day (n=92), and fasting serum triglyceride mean values were +0.1 mg/dL for placebo (n=95), -0.6 mg/dL for 40 mg/day (n=89), and +8.5 mg/dL for 80 mg/day (n=92).

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled, monotherapy bipolar depression study are presented in Table 7.

Table 7: Change in Fasting Lipids in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=147 n=140 n=144
Total cholesterol -3.2 +1.2 -4.6
Triglycerides +6.0 +5.6 +0.4
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)

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 mg/dL (n=130) and -1.0 mg/dL (n=130) at week 24, respectively.

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled, adjunctive therapy bipolar depression studies are presented in Table 8.

Table 8: Change in Fasting Lipids in the Adult Adjunctive Therapy Bipolar Depression Studies

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

LATUDA
Placebo 20 to 120 mg/day
Mean Change from Baseline (mg/dL)
n=303 n=321
Total cholesterol -2.9 -3.1
Triglycerides -4.6 +4.6
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)

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.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, mean change in fasting cholesterol was -6.3 mg/dL for LATUDA 20 to 80 mg/day (n=144) and -1.4 mg/dL for placebo (n=145), and mean change in fasting triglyceride was -7.6 mg/dL for LATUDA 20 to 80 mg/day (n=144) and +5.9 mg/dL for placebo (n=145).

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, shifts in baseline fasting cholesterol from normal to high at endpoint were reported in 12% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 27% (HDL cholesterol) of patients taking lurasidone. Of patients with normal baseline fasting triglycerides, 12% experienced shifts to high.

Weight Gain

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.

Schizophrenia

Adults

Pooled data from short-term, placebo-controlled schizophrenia studies are presented in Table 9. The mean weight gain was +0.43 kg for LATUDA-treated patients compared to -0.02 kg for placebo-treated patients. Change in weight from baseline for olanzapine was +4.15 kg and for quetiapine extended-release was +2.09 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 LATUDA-treated patients and 3.3% for placebo-treated patients.

Table 9: Mean Change in Weight (kg) from Baseline in Adult Schizophrenia Studies
LATUDA
Placebo
(n=696)
20 mg/day
(n=71)
40 mg/day
(n=484)
80 mg/day
(n=526)
120 mg/day
(n=291)
160 mg/day
(n=114)
All Patients -0.02 -0.15 +0.22 +0.54 +0.68 +0.60

In the uncontrolled, longer-term schizophrenia studies (primarily open-label extension studies), LATUDA was associated with a mean change in weight of -0.69 kg at week 24 (n=755), -0.59 kg at week 36 (n=443) and -0.73 kg at week 52 (n=377).

Adolescents

Data from the short-term, placebo-controlled adolescent schizophrenia study are presented in Table 10. The mean change in weight gain was +0.5 kg for LATUDA-treated patients compared to +0.2 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 3.3% for LATUDA-treated patients and 4.5% for placebo-treated patients.

Table 10: Mean Change in Weight (kg) from Baseline in the Adolescent Schizophrenia Study

Placebo
(n=111)
LATUDA
40 mg/day
(n=109)
80 mg/day
(n=104)
All Patients +0.2 +0.3 +0.7

Bipolar Depression

Adults

Monotherapy

Data from the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study are presented in Table 11. The mean change in weight gain was +0.29 kg for LATUDA-treated patients compared to -0.04 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 and 0.7% for placebo-treated patients.

Table 11: Mean Change in Weight (kg) from Baseline in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

LATUDA
Placebo
(n=151)
20 to 60 mg/day
(n=143)
80 to 120 mg/day
(n=147)
All Patients -0.04 +0.56 +0.02

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 -0.02 kg at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

Data from the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies are presented in Table 12. The mean change in weight gain was +0.11 kg for LATUDA-treated patients compared to +0.16 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 and 0.3% for placebo-treated patients.

Table 12: Mean Change in Weight (kg) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

LATUDA
Placebo
(n=307)
20 to 120 mg/day
(n=327)
All Patients +0.16 +0.11

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 +1.28 kg at week 24 (n=86).

Pediatric Patients (10 to 17 years)

Data from the 6-week, placebo-controlled bipolar depression study in patients 10 to 17 years are presented in Table 13. The mean change in weight gain was +0.7 kg for LATUDA-treated patients compared to +0.5 kg for placebo-treated patients. The proportion of patients with a ≥7% increase in body weight (at Endpoint) was 4.0% for LATUDA-treated patients and 5.3% for placebo-treated patients.

Table 13: Mean Change in Weight (kg) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)
LATUDA
Placebo
(n=170)
20 to 80 mg/day
(n=175)
All Patients +0.5 +0.7

Pediatric Patients (6 to 17 years)

In a long-term, open-label study that enrolled pediatric patients with schizophrenia, bipolar depression, or autistic disorder from three short-term, placebo-controlled trials, 54% (378/701) received lurasidone for 104 weeks. The mean increase in weight from open-label baseline to Week 104 was 5.85 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for the natural growth of children and adolescents by comparisons to age- and sex-matched population standards. A z-score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to Week 104 was -0.06 SD for body weight and -0.13 SD for body mass index (BMI), indicating minimal deviation from the normal curve for weight gain.

5.7 Hyperprolactinemia

As with other drugs that antagonize dopamine D2 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 carcinogenicity study conducted with lurasidone 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.

Schizophrenia

Adults

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 14.

Table 14: Median Change in Prolactin (ng/mL) from Baseline in Adult Schizophrenia Studies
LATUDA
Placebo 20 mg/day 40 mg/day 80 mg/day 120 mg/day 160 mg/day
All Patients -1.9
(n=672)
-1.1
(n=70)
-1.4
(n=476)
-0.2
(n=495)
+3.3
(n=284)
+3.3
(n=115)
Females -5.1
(n=200)
-0.7
(n=19)
-4.0
(n=149)
-0.2
(n=150)
+6.7
(n=70)
+7.1
(n=36)
Males -1.3
(n=472)
-1.2
(n=51)
-0.7
(n=327)
-0.2
(n=345)
+3.1
(n=214)
+2.4
(n=79)

The proportion of patients with prolactin elevations ≥5× upper limit of normal (ULN) was 2.8% for LATUDA-treated patients and = 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 5.7% for LATUDA-treated patients and = 2.0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 1.6% and 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), -5.3 ng/mL at week 36 (n=190) and -2.2 ng/mL at week 52 (n=307).

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.1 ng/mL and was +0.1 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +1.0 ng/mL and for females was +2.6 ng/mL. Median changes for prolactin by dose are shown in Table 15.

Table 15: Median Change in Prolactin (ng/mL) from Baseline in the Adolescent Schizophrenia Study

Placebo
LATUDA
40 mg/day
LATUDA
80 mg/day
All Patients +0.10
(n=103)
+0.75
(n=102)
+1.20
(n=99)
Females +0.70
(n=39)
+0.60
(n=42)
+4.40
(n=33)
Males 0.00
(n=64)
+0.75
(n=60)
+1.00
(n=66)

The proportion of patients with prolactin elevations ≥5x ULN was 0.5% for LATUDA-treated patients and 1.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 1.3% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% for LATUDA treated patients and 1.6% for placebo-treated male patients.

Bipolar Depression

Adults

Monotherapy

The median change from baseline to endpoint in prolactin levels, in the adult 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 16.

Table 16: Median Change in Prolactin (ng/mL) from Baseline in the Adult Monotherapy Bipolar Depression Study

Patients were randomized to flexibly dosed LATUDA 20 to 60 mg/day, LATUDA 80 to 120 mg/day, or placebo

LATUDA
Placebo 20 to 60 mg/day 80 to 120 mg/day
All Patients +0.3
(n=147)
+1.7
(n=140)
+3.5
(n=144)
Females 0.0
(n=82)
+1.8
(n=78)
+5.3
(n=88)
Males +0.4
(n=65)
+1.2
(n=62)
+1.9
(n=56)

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.4% for LATUDA-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0.6% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 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 -1.15 ng/mL at week 24 (n=130).

Adjunctive Therapy with Lithium or Valproate

The median change from baseline to endpoint in prolactin levels, in the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies was +2.8 ng/mL with LATUDA 20 to 120 mg/day 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 17.

Table 17: Median Change in Prolactin (ng/mL) from Baseline in the Adult Adjunctive Therapy Bipolar Depression Studies

Patients were randomized to flexibly dosed LATUDA 20 to 120 mg/day or placebo as adjunctive therapy with lithium or valproate.

LATUDA
Placebo 20 to 120 mg/day
All Patients 0.0
(n=301)
+2.8
(n=321)
Females +0.4
(n=156)
+3.2
(n=162)
Males -0.1
(n=145)
+2.4
(n=159)

The proportion of patients with prolactin elevations ≥5x upper limit of normal (ULN) was 0.0% for LATUDA-treated patients and 0.0% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 0% for placebo-treated female patients. The proportion of male patients with prolactin elevations ≥5x ULN was 0% and 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).

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study with pediatric patients 10 to 17 years, the median change from baseline to endpoint in prolactin levels for LATUDA-treated patients was +1.10 ng/mL and was +0.50 ng/mL for placebo-treated patients. For LATUDA-treated patients, the median change from baseline to endpoint for males was +0.85 ng/mL and for females was +2.50 ng/mL. Median changes for prolactin are shown in Table 18.

Table 18: Median Change in Prolactin (ng/mL) from Baseline in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)
LATUDA
Placebo 20 to 80 mg/day
All Patients +0.50
(n=157)
+1.10
(n=165)
Females +0.55
(n=78)
+2.50
(n=83)
Males +0.50
(n=79)
+0.85
(n=82)

The proportion of patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 0.6% for placebo-treated patients. The proportion of female patients with prolactin elevations ≥5x ULN was 0% for LATUDA-treated patients and 1.3% for placebo-treated female patients. No male patients in the placebo or LATUDA treatment groups had prolactin elevations ≥5x ULN.

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study of pediatric patients with schizophrenia, bipolar depression, or autistic disorder, the median changes from baseline to endpoint in serum prolactin levels were -0.20 ng/mL (all patients), -0.30 ng/mL (females), and -0.05 ng/mL (males). The proportions of patients with a markedly high prolactin level (≥5 times the upper limit of normal) at any time during open-label treatment were 2% (all patients), 3% (females), and 1% (males).

Adverse events among females in this trial that are potentially prolactin-related include galactorrhea (0.6%). Among male patients in this study, decreased libido was reported in one patient (0.2%) and there were no reports of impotence, gynecomastia, or galactorrhea.

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.

Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (absolute neutrophil count < 1000/mm3) should discontinue LATUDA and have their WBC followed until recovery.

5.9 Orthostatic Hypotension and Syncope

LATUDA may cause orthostatic hypotension and syncope, perhaps due to its α1-adrenergic receptor antagonism. Associated adverse reactions can include dizziness, lightheadedness, tachycardia, and bradycardia. Generally, these risks are greatest at the beginning of treatment and during dose escalation. Patients at increased risk of these adverse reactions or at increased risk of developing complications from hypotension include those with dehydration, hypovolemia, treatment with antihypertensive medication, history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history of cerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, consider using a lower starting dose and slower titration, and monitor orthostatic vital signs.

Orthostatic hypotension, as assessed by vital sign measurement, was defined by the following vital sign changes: ≥ 20 mm Hg decrease in systolic blood pressure and ≥10 bpm increase in pulse from sitting to standing or supine to standing position.

Schizophrenia

Adults

The incidence of orthostatic hypotension and syncope reported as adverse events from short-term, placebo-controlled schizophrenia studies was (LATUDA incidence, placebo incidence): orthostatic hypotension [0.3% (5/1508), 0.1% (1/708)] and syncope [0.1% (2/1508), 0% (0/708)].

In short-term schizophrenia clinical studies, orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.8% with LATUDA 40 mg, 2.1% with LATUDA 80 mg, 1.7% with LATUDA 120 mg and 0.8% with LATUDA 160 mg compared to 0.7% with placebo.

Adolescents

The incidence of orthostatic hypotension reported as adverse events from the short-term, placebo-controlled adolescent schizophrenia study was 0.5% (1/214) in LATUDA-treated patients and 0% (0/112) in placebo-treated patients. No syncope event was reported.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0% with LATUDA 40 mg and 2.9% with LATUDA 80 mg, compared to 1.8% with placebo.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, there were no reported adverse events of orthostatic hypotension and syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 0.6% with LATUDA 20 to 60 mg and 0.6% with LATUDA 80 to 120 mg compared to 0% with placebo.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression therapy studies, there were no reported adverse events of orthostatic hypotension and syncope. Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 120 mg compared to 0.9% with placebo.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, there were no reported adverse events of orthostatic hypotension or syncope.

Orthostatic hypotension, as assessed by vital signs, occurred with a frequency of 1.1% with LATUDA 20 to 80 mg/day, compared to 0.6% with placebo.

5.10 Falls

LATUDA may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.

5.11 Seizures

As with other antipsychotic drugs, LATUDA should be used cautiously in patients with a history of seizures or with conditions that lower the seizure threshold, e.g., Alzheimer's dementia. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Schizophrenia

In adult short-term, placebo-controlled schizophrenia studies, seizures/convulsions occurred in 0.1% (2/1508) of patients treated with LATUDA compared to 0.1% (1/708) placebo-treated patients.

Bipolar Depression

Monotherapy

In the adult and pediatric 6-week, flexible-dose, placebo-controlled monotherapy bipolar depression studies, no patients experienced seizures/convulsions.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, no patient experienced seizures/convulsions.

5.12 Potential for Cognitive and Motor Impairment

LATUDA, like other antipsychotics, has the potential to impair judgment, thinking or motor skills. Caution patients about operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy with LATUDA does not affect them adversely.

In clinical studies with LATUDA, somnolence included: hypersomnia, hypersomnolence, sedation and somnolence.

Schizophrenia

Adults

In short-term, placebo-controlled schizophrenia studies, somnolence was reported by 17.0% (256/1508) of patients treated with LATUDA (15.5% LATUDA 20 mg, 15.6% LATUDA 40 mg, 15.2% LATUDA 80 mg, 26.5% LATUDA 120 mg and 8.3% LATUDA 160 mg/day) compared to 7.1% (50/708) of placebo patients.

Adolescents

In the short-term, placebo-controlled adolescent schizophrenia study, somnolence was reported by 14.5% (31/214) of patients treated with LATUDA (15.5% LATUDA 40 mg and 13.5% LATUDA 80 mg,/day) compared to 7.1% (8/112) of placebo patients.

Bipolar Depression

Adults

Monotherapy

In the adult short-term, flexible-dosed, placebo-controlled monotherapy bipolar depression study, somnolence was reported by 7.3% (12/164) and 13.8% (23/167) with LATUDA 20 to 60 mg and 80 to 120 mg, respectively compared to 6.5% (11/168) of placebo patients.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dosed, placebo-controlled adjunctive therapy bipolar depression studies, somnolence was reported by 11.4% (41/360) of patients treated with LATUDA 20-120 mg compared to 5.1% (17/334) of placebo patients.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, somnolence was reported by 11.4% (20/175) of patients treated with LATUDA 20 to 80 mg/day compared to 5.8% (10/172) of placebo treated patients.

5.13 Body Temperature Dysregulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing LATUDA for patients who will be experiencing conditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

5.14 Activation of Mania/Hypomania

Antidepressant treatment can increase the risk of developing a manic or hypomanic episode, particularly in patients with bipolar disorder. Monitor patients for the emergence of such episodes.

In the adult bipolar depression monotherapy and adjunctive therapy (with lithium or valproate) studies, less than 1% of subjects in the LATUDA and placebo groups developed manic or hypomanic episodes.

5.15 Dysphagia

Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. LATUDA and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

5.16 Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies

Patients with Parkinson's Disease or Dementia with Lewy Bodies are reported to have an increased sensitivity to antipsychotic medication. Manifestations of this increased sensitivity include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and clinical features consistent with the neuroleptic malignant syndrome.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more detail in other sections of the labeling:

  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)]
  • Suicidal Thoughts and Behaviors [see Boxed Warning and Warnings and Precautions (5.2)]
  • Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis [see Warnings and Precautions (5.3)]
  • Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.4)]
  • Tardive Dyskinesia [see Warnings and Precautions (5.5)]
  • Metabolic Changes [see Warnings and Precautions (5.6)]
  • Hyperprolactinemia [see Warnings and Precautions (5.7)]
  • Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.8)]
  • Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.9)]
  • Falls [see Warnings and Precautions (5.10)]
  • Seizures [see Warnings and Precautions (5.11)]
  • Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.12)]
  • Body Temperature Dysregulation [see Warnings and Precautions (5.13)]
  • Activation of Mania/Hypomania [see Warnings and Precautions (5.14)]
  • Dysphagia [see Warnings and Precautions (5.15)]
  • Neurological Adverse Reactions in Patients with Parkinson's Disease or Dementia with Lewy Bodies [see Warnings and Precautions (5.16)]

Commonly observed adverse reactions (incidence ≥ 5% and at least twice the rate for placebo) were (6.1):

  • Adult patients with schizophrenia: somnolence, akathisia, extrapyramidal symptoms, and nausea
  • Adolescent patients (13-17 years) with schizophrenia: somnolence, nausea, akathisia, EPS (non-akathisia), rhinitis (80 mg only), and vomiting
  • Adult patients with bipolar depression: akathisia, extrapyramidal symptoms, and somnolence
  • Pediatric patients (10-17 years) with bipolar depression: nausea, weight increase, and insomnia.

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 .

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adults

The information below is derived from an integrated clinical study database for LATUDA consisting of 3799 adult patients exposed to one or more doses of LATUDA for the treatment of schizophrenia, and bipolar depression in placebo-controlled studies. This experience corresponds with a total experience of 1250.9 patient-years. A total of 1106 LATUDA-treated patients had at least 24 weeks and 371 LATUDA-treated patients had at least 52 weeks of exposure.

Adverse events during exposure to study treatment were obtained by general inquiry and voluntarily reported adverse experiences, as well as results from physical examinations, vital signs, ECGs, weights and laboratory investigations. Adverse experiences were recorded by clinical investigators using their own terminology. In order to provide a meaningful estimate of the proportion of individuals experiencing adverse events, events were grouped in standardized categories using MedDRA terminology.

Schizophrenia

The following findings are based on the short-term, placebo-controlled premarketing adult studies for schizophrenia in which LATUDA was administered at daily doses ranging from 20 to 160 mg (n=1508).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥ 5% and at least twice the rate of placebo) in patients treated with LATUDA were somnolence, akathisia, extrapyramidal symptoms, and nausea.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 9.5% (143/1508) LATUDA-treated patients and 9.3% (66/708) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with schizophrenia) are shown in Table 19.

Table 19: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Adult Short-term Schizophrenia Studies

Note: Figures rounded to the nearest integer

* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

** Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

Percentage of Patients Reporting Reaction
LATUDA
Body System or
Organ Class
Placebo
(N=708)
(%)
20
mg/day
(N=71)
(%)
40
mg/day
(N=487)
(%)
80
mg/day
(N=538)
(%)
120
mg/day
(N=291)
(%)
160
mg/day
(N=121)
(%)
All
LATUDA
(N=1508)
(%)
Gastrointestinal Disorders
     Nausea 5 11 10 9 13 7 10
     Vomiting 6 7 6 9 9 7 8
     Dyspepsia 5 11 6 5 8 6 6
     Salivary
     Hypersecretion
<1 1 1 2 4 2 2
Musculoskeletal and Connective Tissue Disorders
     Back Pain 2 0 4 3 4 0 3
Nervous System Disorders
     Somnolence* 7 15 16 15 26 8 17
     Akathisia 3 6 11 12 22 7 13
     Extrapyramidal
     Disorder**
6 6 11 12 22 13 14
     Dizziness 2 6 4 4 5 6 4
Psychiatric Disorders
     Insomnia 8 8 10 11 9 7 10
     Agitation 4 10 7 3 6 5 5
     Anxiety 4 3 6 4 7 3 5
     Restlessness 1 1 3 1 3 2 2

Dose-Related Adverse Reactions in the Schizophrenia Studies

Akathisia and extrapyramidal symptoms were dose-related. The frequency of akathisia increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 10.7% for LATUDA 40 mg, 12.3% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg). Akathisia was reported by 7.4% (9/121) of patients receiving 160 mg/day. Akathisia occurred in 3.0% of subjects receiving placebo. The frequency of extrapyramidal symptoms increased with dose up to 120 mg/day (5.6% for LATUDA 20 mg, 11.5% for LATUDA 40 mg, 11.9% for LATUDA 80 mg, and 22.0% for LATUDA 120 mg).

Bipolar Depression (Monotherapy)

The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg (n=331).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5%, in either dose group, and at least twice the rate of placebo) in patients treated with LATUDA were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 6.0% (20/331) LATUDA-treated patients and 5.4% (9/168) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 20.

Table 20: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Monotherapy Bipolar Depression Study

Note: Figures rounded to the nearest integer

*Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Percentage of Patients Reporting Reaction
Body System or Organ Class
     Dictionary-derived Term
Placebo
(N=168)
(%)
LATUDA
20-60 mg/day
(N=164)
(%)
LATUDA
80-120 mg/day
(N=167)
(%)
All LATUDA(N=331)
(%)
Gastrointestinal Disorders
     Nausea 8 10 17 14
     Dry Mouth 4 6 4 5
     Vomiting 2 2 6 4
     Diarrhea 2 5 3 4
Infections and Infestations
     Nasopharyngitis 1 4 4 4
     Influenza 1 <1 2 2
     Urinary Tract Infection <1 2 1 2
Musculoskeletal and Connective Tissue
Disorders
     Back Pain <1 3 <1 2
Nervous System Disorders
     Extrapyramidal Symptoms* 2 5 9 7
     Akathisia 2 8 11 9
     Somnolence** 7 7 14 11
Psychiatric Disorders
     Anxiety 1 4 5 4

Dose-Related Adverse Reactions in the Monotherapy Study:

In the adult short-term, placebo-controlled study (involving lower and higher LATUDA dose ranges) [see Clinical Studies (14.2)] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with LATUDA in any dose group and greater than placebo in both groups were nausea (10.4%, 17.4%), somnolence (7.3%, 13.8%), akathisia (7.9%, 10.8%), and extrapyramidal symptoms (4.9%, 9.0%) for LATUDA 20 to 60 mg/day and LATUDA 80 to 120 mg/day, respectively.

Bipolar Depression

Adjunctive Therapy with Lithium or Valproate

The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which LATUDA was administered at daily doses ranging from 20 to 120 mg as adjunctive therapy with lithium or valproate (n=360).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in subjects treated with LATUDA were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment: A total of 5.8% (21/360) LATUDA-treated patients and 4.8% (16/334) of placebo-treated patients discontinued due to adverse reactions. There were no adverse reactions associated with discontinuation in subjects treated with LATUDA that were at least 2% and at least twice the placebo rate.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in patients with bipolar depression) are shown in Table 21.

Table 21: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adult Short-term Adjunctive Therapy Bipolar Depression Studies

Note: Figures rounded to the nearest integer

*Extrapyramidal symptoms include adverse event terms: bradykinesia, cogwheel rigidity, drooling, dystonia, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, oculogyric crisis, oromandibular dystonia, parkinsonism, psychomotor retardation, tongue spasm, torticollis, tremor, and trismus

** Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

Percentage of Patients Reporting Reaction
Body System or Organ Class
     Dictionary-derived Term
Placebo
(N=334)
(%)
LATUDA
20 to 120 mg/day

(N=360)
(%)
Gastrointestinal Disorders
     Nausea 10 14
     Vomiting 1 4
General Disorders
     Fatigue 1 3
Infections and Infestations
     Nasopharyngitis 2 4
Investigations
     Weight Increased <1 3
Metabolism and Nutrition Disorders
     Increased Appetite 1 3
Nervous System Disorders
     Extrapyramidal Symptoms* 9 14
     Somnolence** 5 11
     Akathisia 5 11
Psychiatric Disorders
     Restlessness <1 4

Adolescents

Schizophrenia

The following findings are based on the short-term, placebo-controlled adolescent study for schizophrenia in which LATUDA was administered at daily doses ranging from 40 (N=110) to 80 mg (N=104).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5% and at least twice the rate of placebo) in adolescent patients (13 to 17 years) treated with LATUDA were somnolence, nausea, akathisia, extrapyramidal symptoms (non-akathisia, 40 mg only), vomiting, and rhinorrhea/rhinitis (80 mg only).

Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between LATUDA- and placebo-treated adolescent patients (13 to 17 years) was 4% and 8%, respectively.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6-weeks in adolescent patients with schizophrenia) are shown in Table 22.

Table 22: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the Adolescent Short-term Schizophrenia Study

Note: Figures rounded to the nearest integer

* Somnolence includes adverse event terms: hypersomnia, sedation, and somnolence

** Viral Infection includes adverse event terms: nasopharyngitis, influenza, viral infection, upper respiratory tract infection

*** Rhinitis incudes adverse event terms: rhinitis, allergic rhinitis, rhinorrhea, and nasal congestion

Percentage of Patients Reporting Reaction

Body System or Organ Class
     Dictionary-derived Term

Placebo
(N=112)
LATUDA
40 mg/day
(N=110)
LATUDA
80 mg/day
(N=104)

All LATUDA
(N=214)
Gastrointestinal Disorders
     Nausea 3 13 14 14
     Vomiting 2 8 6 8
     Diarrhea 1 3 5 4
     Dry Mouth 0 2 3 2
Infections and Infestations
     Viral Infection** 6 11 10 10
     Rhinitis*** 2 <1 8 4
     Oropharyngeal pain 0 <1 3 2
     Tachycardia 0 0 3 1
Nervous System Disorders
     Somnolence* 7 15 13 15
     Akathisia 2 9 9 9
     Dizziness 1 5 5 5

Pediatric Patients (10 to 17 years)

Bipolar Depression

The following findings are based on the 6-week , placebo-controlled study for bipolar depression in pediatric patients 10 to 17 years in which LATUDA was administered at daily doses ranging from 20 to 80 mg (N=175).

Commonly Observed Adverse Reactions: The most common adverse reactions (incidence ≥5%, and at least twice the rate of placebo) in pediatric patients (10 to 17 years) treated with LATUDA were nausea, weight increase, and insomnia.

Adverse Reactions Associated with Discontinuation of Treatment: The incidence of discontinuation due to adverse reactions between LATUDA- and placebo-treated pediatric patients 10 to 17 years was 2% and 2%, respectively.

Adverse Reactions Occurring at an Incidence of 2% or More in LATUDA-Treated Patients: Adverse reactions associated with the use of LATUDA (incidence of 2% or greater, rounded to the nearest percent and LATUDA incidence greater than placebo) that occurred during acute therapy (up to 6 weeks in pediatric patients with bipolar depression) are shown in Table 23.

Table 23: Adverse Reactions in 2% or More of LATUDA-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in the 6-Week Bipolar Depression Study in Pediatric Patients (10 to 17 years)

Note: Figures rounded to the nearest integer

*Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

**EPS includes adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor

Percentage of Patients Reporting Reaction
Body System or Organ Class
     Dictionary-derived Term
Placebo
(N=172)
LATUDA
20 to 80 mg/day
(N=175)
Gastrointestinal Disorders
     Nausea 6 16
     Vomiting 4 6
     Abdominal Pain Upper 2 3
     Diarrhea 2 3
     Abdominal Pain 1 3
General Disorders And Administration Site Conditions
     Fatigue 2 3
Investigations
     Weight Increased 2 7
Metabolism and Nutrition Disorders
     Decreased Appetite 2 4
Nervous System Disorders
     Somnolence* 6 11
     Extrapyramidal symptoms** 5 6
     Dizziness 5 6
Psychiatric Disorders
     Insomnia 2 5
     Abnormal Dreams 2 2
Respiratory, Thoracic and Mediastinal Disorders
     Oropharyngeal Pain 2 2

Extrapyramidal Symptoms

Schizophrenia

Adults

In the short-term, placebo-controlled schizophrenia studies, for LATUDA-treated patients, the incidence of reported events related to extrapyramidal symptoms (EPS), excluding akathisia and restlessness, was 13.5% and 5.8% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 12.9% and 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 24.

Table 24: Incidence of EPS Compared to Placebo in Adult Schizophrenia Studies

Note: Figures rounded to the nearest integer

* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

LATUDA
Adverse Event Term Placebo
(N=708)
(%)
20 mg/day
(N=71)
(%)
40 mg/day
(N=487)
(%)
80 mg/day
(N=538)
(%)
120 mg/day
(N=291)
(%)
160 mg/day
(N=121)
(%)
All EPS events 9 10 21 23 39 20
All EPS events, excluding Akathisia/Restlessness 6 6 11 12 22 13
     Akathisia 3 6 11 12 22 7
     Dystonia* <1 0 4 5 7 2
     Parkinsonism** 5 6 9 8 17 11
     Restlessness 1 1 3 1 3 2

Adolescents

In the short-term, placebo-controlled, study of schizophrenia in adolescents, the incidence of EPS, excluding events related to akathisia, for LATUDA-treated patients was higher in the 40 mg (10%) and the 80 mg (7.7%) treatment groups vs. placebo (3.6%); and the incidence of akathisia-related events for LATUDA-treated patients was 8.9% vs. 1.8% for placebo-treated patients. Incidence of EPS by dose is provided in Table 25.

Table 25: Incidence of EPS Compared to Placebo in the Adolescent Schizophrenia Study

Note: Figures rounded to the nearest integer

* Dystonia includes adverse event terms: dystonia, trismus, oculogyric crisis, oromandibular dystonia, tongue spasm, and torticollis

** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation

LATUDA
Adverse Event Term Placebo
(N=112)
(%)
40 mg/day
(N=110)
(%)
80 mg/day
(N=104)
(%)
All EPS events 5 14 14
All EPS events, excluding Akathisia/Restlessness 4 7 7
Akathisia 2 9 9
Parkinsonism** <1 4 0
Dyskinesia <1 <1 1
Dystonia* 0 <1 1

Bipolar Depression

Adults

Monotherapy

In the adult short-term, placebo-controlled monotherapy bipolar depression study, for LATUDA-treated patients, the incidence of reported events related to EPS, excluding akathisia and restlessness was 6.9% and 2.4% for placebo-treated patients. The incidence of akathisia for LATUDA-treated patients was 9.4% and 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 26.

Table 26: Incidence of EPS Compared to Placebo in the Adult Monotherapy Bipolar Depression Study

Note: Figures rounded to the nearest integer

* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

LATUDA
Adverse Event Term Placebo
(N=168)
(%)
20 to 60 mg/day
(N=164)
(%)
80 to 120 mg/day
(N=167)
(%)
All EPS events 5 12 20
All EPS events, excluding Akathisia/Restlessness 2 5 9
     Akathisia 2 8 11
     Dystonia* 0 0 2
     Parkinsonism** 2 5 8
     Restlessness <1 0 3

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for LATUDA-treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% and 8.7% for placebo. The incidence of akathisia for LATUDA-treated patients was 10.8% and 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 27.

Table 27: Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy Bipolar Depression Studies

Note: Figures rounded to the nearest integer

* Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

Adverse Event Term Placebo
(N=334)
(%)
LATUDA
20 to 120 mg/day
(N=360)

(%)
All EPS events 13 24
All EPS events, excluding Akathisia/Restlessness 9 14
     Akathisia 5 11
     Dystonia* <1 1
     Parkinsonism** 8 13
     Restlessness <1 4

In the short-term, placebo-controlled schizophrenia and bipolar depression studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (BAS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesias.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled study of bipolar depression in pediatric patients 10 to 17 years, the incidence of EPS, excluding events related to akathisia, for LATUDA-treated patients was similar in the LATUDA 20 to 80 mg/day (3.4%) treatment group vs. placebo (3.5%); and the incidence of akathisia-related events for LATUDA-treated patients was 2.9% vs. 3.5% for placebo-treated patients. Incidence of EPS by dose is provided in Table 28.

Table 28: Incidence of EPS Compared to Placebo in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)

Note: Figures rounded to the nearest integer

* EPS include adverse event terms: akathisia, cogwheel rigidity, dyskinesia, dystonia, hyperkinesia, joint stiffness, muscle rigidity, muscle spasms, musculoskeletal stiffness, oculogyric crisis, parkinsonism, tardive dyskinesia, and tremor

** Parkinsonism includes adverse event terms: bradykinesia, drooling, extrapyramidal disorder, glabellar reflex abnormal, hypokinesia, parkinsonism, and psychomotor retardation

***Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

Adverse Event Term Placebo
(N=172)
(%)
LATUDA
20 to 80 mg/day
(N=175)
(%)
All EPS events* 5 6
All EPS events, excluding Akathisia/Restlessness 4