Lurasidone Hydrochloride (Page 5 of 10)

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.

A dults

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

B ipolar Depression (Monotherapy)

The following findings are based on the adult short-term, placebo-controlled premarketing study for bipolar depression in which lurasidone hydrochloride tablets were 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 lurasidone hydrochloride tablets were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety.

Adverse Reactions Associated with Discontinuation of Treatment:A total of 6.0% (20/331) lurasidone hydrochloride tablets -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 lurasidone hydrochloride tablets that were at least 2% and at least twice the placebo rate.

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

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

Percentage of Patients Reporting Reaction
Body System or Organ Class Dictionary-derived Term Placebo (N= 168) (%) Lurasidone hydrochloride tablets 20-60 mg/day (N=164) (%) Lurasidone hydrochloride tablets 80- 120 mg/day (N=167) (%) All lurasidone hydrochloride tablets (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

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

Dose-Related Adverse Reactions in the Monotherapy Study:

In the adult short-term, placebo-controlled study (involving lower and higher lurasidone hydrochloride tablets dose ranges) [see Clinical Studies (14.2) ] the adverse reactions that occurred with a greater than 5% incidence in the patients treated with lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets 20 to 60 mg/day and lurasidone hydrochloride tablets 80 to 120 mg/day, respectively.

B ipolar Depression

A djunctive Therapy with Lithium or Valproate

The following findings are based on two adult short-term, placebo-controlled premarketing studies for bipolar depression in which lurasidone hydrochloride tablets 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 lurasidone hydrochloride tablets were akathisia and somnolence.

Adverse Reactions Associated with Discontinuation of Treatment:A total of 5.8% (21/360) lurasidone hydrochloride tablets -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 lurasidone hydrochloride tablets that were at least 2% and at least twice the placebo rate.

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

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

Percentage of Patients Reporting Reaction
Body System or Organ Class Dictionary-derived Term Placebo (N= 334) (%) Lurasidone Hydrochloride Tablets 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

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

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 Lurasidone hydrochloride 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 Lurasidone hydrochloride were nausea, weight increase, and insomnia.

Adverse Reactions Associated with Discontinuation of Treatment:The incidence of discontinuation due to adverse reactions between Lurasidone hydrochloride- 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 Lurasidone hydrochloride-Treated Patients:Adverse reactions associated with the use of Lurasidone hydrochloride (incidence of 2% or greater, rounded to the nearest percent and Lurasidone hydrochloride 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 Lurasidone hydrochloride-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)

Percentage of Patients Reporting Reaction
Body System or Organ Class Dictionary-derived Term Placebo(N=172) Lurasidone Hydrochloride 20 to 80mg/day(N=175)
GastrointestinalDisorders
Nausea 6 16
Vomiting 4 6
Abdominal PainUpper 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
DecreasedAppetite 2 4
Nervous SystemDisorders
Somnolence* 6 11
Extrapyramidalsymptoms** 5 6
Dizziness 5 6
PsychiatricDisorders
Insomnia 2 5
Abnormal Dreams 2 2
Respiratory, Thoracic and Mediastinal Disorders
OropharyngealPain 2 2

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

Extrapyramidal Symptoms

Bipolar Depression

Adults

M onotherapy

In the adult short-term, placebo-controlled monotherapy bipolar depression study, for lurasidone hydrochloride tablets — 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 lurasidone hydrochloride tablets -treated patients was 9.4% and 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 26.

T able 26: Incidence of EPS Compared to Placebo in the Adult Monotherapy Bipolar

Depression Study

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

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

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, placebo-controlled adjunctive therapy bipolar depression studies, for

lurasidone hydrochloride tablets -treated patients, the incidence of EPS, excluding akathisia and restlessness, was 13.9% and 8.7% for placebo. The incidence of akathisia for lurasidone hydrochloride tablets -treated patients was 10.8% and 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 27.

T able 27: Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy

B ipolar Depression Studies

Adverse Event Term Placebo (N=334) (%) Lurasidone Hydrochloride Tablets 20 to 120 mg/day (N=360) (%)
A l l EPS events 13 24
A l l EPS events, excluding Akathisia/Restlessness 9 14
Akathisia 5 11
Dystonia* <1 1
Parkinsonism** 8 13
Restlessness <1 4

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

In the short-term, placebo-controlled 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 lurasidone hydrochloride tablets-treated patients was similar in the lurasidone hydrochloride tablets 20 to 80 mg/day (3.4%) treatment group vs. placebo (3.5%); and the incidence of akathisia-related events for lurasidone hydrochloride tablets-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)

Adverse Event Term Placebo (N=172) (%) Lurasidone Hydrochloride 20 to 80 mg/day (N=175) (%)
All EPS events * 5 6
All EPS events, excluding Akathisia/Restlessness 4 3
Akathisia 4 3
Parkinsonism** <1 <1
Dystonia*** 1 <1
Salivary hypersecretion <1 <1
Psychomotor hyperactivity 0 <1
Tardive Dyskinesia <1 0

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

Bipolar Depression

Adults

M onotherapy

The mean change from baseline for lurasidone-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone-treated patients and placebo for the BAS (lurasidone hydrochloride tablets, 8.4%; placebo, 5.6%), the SAS (lurasidone hydrochloride tablets, 3.7%; placebo, 1.9%) and the AIMS (lurasidone hydrochloride tablets, 3.4%; placebo, 1.2%).

Adjunctive Therapy with Lithium or Valproate

The mean change from baseline for lurasidone-treated adult patients for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone-treated patients and placebo for the BAS (lurasidone, 8.7%; placebo, 2.1%), the SAS (lurasidone, 2.8%; placebo, 2.1%) and the AIMS (lurasidone, 2.8%; placebo, 0.6%).

Pediatric Patients (10 to 17 years)

The mean change from baseline for lurasidone hydrochloride tablets- treated pediatric patients 10 to 17 years with bipolar depression for the SAS, BAS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in lurasidone hydrochloride tablets-treated patients and placebo for the BAS (lurasidone hydrochloride tablets, 4.6%; placebo, 2.4%), the SAS (lurasidone hydrochloride tablets, 0.6%; placebo, 0%) and was the same for the AIMS (lurasidone hydrochloride tablets, 0%; placebo, 0%).

Dystonia

Class Effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.

Bipolar Depression

Adults

M onotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of lurasidone hydrochloride tablets -treated subjects (0.0% and 1.8% for lurasidone hydrochloride tablets 20 to 60 mg/day and lurasidone hydrochloride tablets 80 to 120 mg/day, respectively) compared to 0.0% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Adjunctive Therapy with Lithium or Valproate

In the adult short-term, flexible-dose, placebo-controlled adjunctive therapy bipolar depression studies, dystonia occurred in 1.1% of lurasidone hydrochloride tablets -treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Pediatric Patients (10 to 17 years)

In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, dystonia occurred in 0.6% of Lurasidone Hydrochloride-treated patients compared to 1.2% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events.

Other Adverse Reactions Observed During the Premarketing Evaluation of Lurasidone Hydrochloride Tablets

Following is a list of adverse reactions reported by adult patients treated with lurasidone hydrochloride tablets at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with another indication. The reactions listed are those that could be of clinical importance, as well as reactions that are plausibly drug-related on pharmacologic or other grounds. Reactions listed those that appear elsewhere in the lurasidone hydrochloride tablets label are not included.

Reactions are further categorized by organ class and listed in order of decreasing frequency according to the following definitions: those occurring in at least 1/100 patients (frequent) (only those not already listed in the tabulated results from placebo-controlled studies appear in this listing); those occurring in 1/100 to 1/1000 patients (infrequent); and those occurring in fewer than 1/1000 patients (rare).

Blood and Lymphatic System Disorders: Infrequent: anemia

C ardiac Disorders: Frequent: tachycardia; Infrequent: AV block 1st degree, angina pectoris, bradycardia

Ear and Labyrinth Disorders: Infrequent: vertigo

Eye Disorders: Frequent: blurred vision

Gastrointestinal Disorders: Frequent: abdominal pain, diarrhea; Infrequent: gastritis General Disorders and Administrative Site Conditions: Rare: sudden death Investigations: Frequent: CPK increased

Me tabolism and Nutritional System Disorders: Frequent: decreased appetite Musculoskeletal and Connective Tissue Disorders: Rare: rhabdomyolysis Nervous System Disorders: Infrequent: cerebrovascular accident, dysarthria

Psychiatric Disorders: Infrequent: abnormal dreams, panic attack, sleep disorder

Renal and Urinary Disorders: Infrequent: dysuria; Rare: renal failure

Reproductive System and Breast Disorders: Infrequent: amenorrhea, dysmenorrhea; Rare: breast enlargement, breast pain, galactorrhea, erectile dysfunction, priapism

Skin and Subcutaneous Tissue Disorders: Frequent: rash, pruritus; Rare: angioedema

Vascular Disorders: Frequent: hypertension

Clinical Laboratory Changes

Bipolar Depression

Adults

M onotherapy

Serum Creatinine: In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, the mean change from Baseline in serum creatinine was +0.01 mg/dL for lurasidone hydrochloride tablets-treated patients compared to -0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 2.8% (9/322) of Lurasidone hydrochloride tablets-treated patients and 0.6% (1/162) on placebo (Table 31).

T able 31: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Monotherapy Bipolar Depression Study

L aboratory Parameter Placebo Lurasidone hydrochloride tablets Lurasidone hydrochloride tablets
( N= 168) 20 to 60 mg/day 80 to 120 mg/day
( N= 164) ( N= 167)
Serum Creatinine <1% 2% 4%
E l evated

Adjunctive Therapy with Lithium or Valproate

Serum Creatinine: In adult short-term, placebo-controlled premarketing adjunctive studies for bipolar depression, the mean change from Baseline in serum creatinine was +0.04 mg/dL for lurasidone hydrochloride tablets-treated patients compared to -0.01 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 4.3% (15/360) of lurasidone hydrochloride tablets-treated patients and 1.6% (5/334) on placebo (Table 32).

T able 32: Serum Creatinine Shifts from Normal at Baseline to High at Study End- Point in the Adult Adjunctive Therapy Bipolar Depression Studies

L aboratory Parameter Placebo Lurasidone hydrochloride tablets
( N= 334) 20 to 120 mg/day ( N= 360)
Serum Creatinine E l evated 2% 4%

Pediatric Patients (10 to 17 years)

Serum Creatinine: In the 6-week, placebo-controlled bipolar depression study in pediatric patients 10 to 17 years, the mean change from Baseline in serum creatinine was +0.021 mg/dL for lurasidone hydrochloride tablets-treated patients compared to +0.009 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 6.7% (11/163) of lurasidone hydrochloride tablets-treated patients and 4.5% (7/155) on placebo (Table 33).

Table 33: Serum Creatinine Shifts from Normal at Baseline to High at Study

End-Point in the Bipolar Depression Study in Pediatric Patients (10 to 17 years)

Laboratory Parameter Placebo Lurasidone Hydrochloride Tablets
(N=163) (N=155) 20 to 80 mg/day
Serum Creatinine Elevated 4.5% 6.7%

Pediatric Patients (6 to 17 years)

In a 104-week, open-label study in pediatric patients with bipolar depression, autistic disorder or another indication, the mean change from baseline to Week 104 in serum creatinine was +0.07 mg/dL. In patients with a normal serum creatinine at baseline, 6% experienced a shift to high at endpoint.

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