Latuda: Adverse reactions

6.1. Overall Adverse Reaction Profile

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

• Use in Elderly Patients with Dementia-Related Psychosis [see Boxed Warning and Warnings and Precautions (5.1)]

• Cerebrovascular Adverse Reactions, Including Stroke [see Warnings and Precautions (5.2)]

• Neuroleptic Malignant Syndrome [see Warnings and Precautions (5.3)]

• Tardive Dyskinesia [see Warnings and Precautions (5.4)]

• Hyperglycemia and Diabetes Mellitus [see Warnings and Precautions (5.5)]

• Hyperprolactinemia [see Warnings and Precautions (5.6)]

• Leukopenia, Neutropenia, and Agranulocytosis [see Warnings and Precautions (5.7)]

• Orthostatic Hypotension and Syncope [see Warnings and Precautions (5.8)]

• Seizures [see Warnings and Precautions (5.9)]

• Potential for Cognitive and Motor Impairment [see Warnings and Precautions (5.10)]

• Body Temperature Regulation [see Warnings and Precautions (5.11)]

• Suicide [see Warnings and Precautions (5.12)]

• Dysphagia [see Warnings and Precautions (5.13)]

• Use in Patients with Concomitant Illness [see Warnings and Precautions (5.14)]

The information below is derived from a clinical study database for Latuda consisting of over 2096 patients with schizophrenia exposed to one or more doses with a total experience of 624 patient-years. Of these patients, 1004 participated in short-term placebo-controlled schizophrenia studies with doses of 20 mg, 40 mg, 80 mg or 120 mg once daily. A total of 533 Latuda-treated patients had at least 24 weeks and 238 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.

The stated frequencies of adverse reactions represent the proportion of individuals who experienced at least once, a treatment-emergent adverse event of the type listed. Treatment-emergent adverse events were defined as adverse experiences, which started or worsened on or after the date of the first dose through seven days after study medication discontinuation. There was no attempt to use investigator causality assessments; i.e., all events meeting the defined criteria, regardless of investigator causality are included. It is important to emphasize that, although the reactions occurred during treatment with Latuda, they were not necessarily caused by it. The label should be read in its entirety to gain an understanding of the safety profile of Latuda.

The figures in the tables and tabulations cannot be used to predict the incidence of side effects in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatment, uses and investigators. The cited figures, however, do provide the prescriber with some basis for estimating the relative contribution of drug and nondrug factors to the adverse reaction incidence in the population studied.

6.2. Clinical Studies Experience

The following findings are based on the short-term placebo-controlled premarketing studies for schizophrenia in which Latuda was administered at daily doses ranging from 20 to 120 mg (n = 1004).

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, nausea, parkinsonism and agitation.

Adverse Reactions Associated with Discontinuation of Treatment:

A total of 9.4% (94/1004) Latuda-treated patients and 5.9% (27/455) 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: Adverse Reaction in 2% or More of Latuda-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies.

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

	Percentage of Patients Reporting Reaction
Body System or Organ Class Dictionary-derived Term	Placebo (N = 455)	All Latuda (N = 1004)
Gastrointestinal Disorders
Nausea	6	12
Vomiting	6	8
Dyspepsia	6	8
Salivary hypersecretion	<1	2
General Disorders and Administration Site Conditions
Fatigue	3	4
Musculoskeletal and Connective Tissue Disorders
Back Pain	3	4
Nervous System Disorders
Somnolence*	10	22
Akathisia	3	15
Parkinsonism**	5	11
Dystonia***	<1	5
Dizziness	3	5
Psychiatric Disorders
Insomnia	7	8
Agitation	3	6
Anxiety	3	6
Restlessness	2	3

Note: Figures rounded to the nearest integer
* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence
** Parkinsonism includes adverse event terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor
*** Dystonia includes adverse event terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus

6.3. Dose-Related Adverse Reactions

Based on the pooled data from the placebo-controlled, short-term, fixed-dose studies, among the adverse reactions that occurred with a greater than 5% incidence in the patients treated with Latuda, the apparent dose-related adverse reactions were akathisia and somnolence (Table: Dose-Related Adverse Events).

Table: Dose-Related Adverse Events (%)

	Percentage of Subjects Reporting Reaction
Adverse Event Term	Placebo (N = 455)	Latuda 20 mg/day (N = 71)	Latuda 40 mg/day (N = 360)	Latuda 80 mg/day (N = 282)	Latuda 120 mg/day (N = 291)
Akathisia	3	6	11	15	22
Somnolence*	10	15	19	23	26

Note: Figures rounded to the nearest integer
* Somnolence includes adverse event terms: hypersomnia, hypersomnolence, sedation, and somnolence

6.4. Extrapyramidal Symptoms

In the short-term, placebo-controlled schizophrenia studies, for Latuda-treated patients, the incidence of reported EPS-related events, excluding akathisia and restlessness, was 14.7% versus 5.1% for placebo-treated patients; and the incidence of akathisia for Latuda-treated patients was 15.0% versus 3.3% for placebo-treated patients. Akathisia appeared to be dose-related and the greatest frequency of parkinsonism and dystonia occurred with the highest dose of Latuda, 120 mg/day (Table: Percentage of EPS Compared to Placebo).

Table: Percentage of EPS Compared to Placebo

Adverse Event Term	Placebo (N = 455) (%)	Latuda 20 mg/day (N = 71) (%)	Latuda 40 mg/day (N = 360) (%)	Latuda 80 mg/day (N = 282) (%)	Latuda 120 mg/day (N = 291) (%)
All EPS events	9	10	24	26	39
All EPS events, excluding Akathisia/Restlessness	5	6	13	11	22
Akathisia	3	6	11	15	22
Dystonia*	1	0	4	5	7
Parkinsonism**	5	6	10	7	17
Restlessness	2	1	4	1	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, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

In the short-term, placebo-controlled schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale for extrapyramidal symptoms (EPS), the Barnes Akathisia Scale (for akathisia) and the Abnormal Involuntary Movement Scale (for dyskinesias). The mean change from baseline for Latuda-treated patients was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (Latuda, 0.2; placebo, 0.0). The percentage of patients who shifted from normal to abnormal was greater in Latuda-treated patients versus placebo for the BAS (Latuda, 16.0%; placebo, 7.6%) and the SAS (Latuda, 5.3%; placebo, 2.5%).

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.

In the short-term, placebo-controlled clinical trials, dystonia occurred in 4.7% of Latuda-treated subjects (0.0% Latuda 20 mg, 4.2% Latuda 40 mg, 4.6% Latuda 80 mg and 6.5% Latuda 120 mg) compared to 0.7% of subjects receiving placebo. Seven subjects (0.7%, 7/1004) discontinued clinical trials due to dystonic events – 4 were receiving Latuda 80 mg/day and 3 were receiving Latuda 120 mg/day.

6.5. Laboratory Test Abnormalities and ECG Changes in Clinical Studies

Laboratory Test Abnormalities

In a between-group comparison of the pooled data from short-term, placebo-controlled studies, there were no clinically important changes in total cholesterol measurements; triglycerides or glucose from Baseline to Endpoint [see Warnings and Precautions [5.5)]. There were also no clinically important differences between Latuda and placebo in mean change from baseline to endpoint in routine hematology, urinalysis, or serum chemistry. Latuda was associated with a dose-related increase in prolactin concentration [see Warnings and Precautions [5.6)]

Creatinine:

In short-term, placebo-controlled trials, the mean change from Baseline in creatinine was 0.06 mg/dL for Latuda-treated patients compared to 0.03 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.1% (30/977) of Latuda-treated patients and 1.4% (6/439) on placebo. The threshold for high creatinine value varied from > 1.1 to > 1.3 mg/dL based on the centralized laboratory definition for each study [see Dosage in Special Population (2.3); Use in Specific Populations (8)]

Transaminases: The mean changes in AST and ALT for Latuda- and placebo-treated patients were similar. The proportion of patients with transaminases (AST and ALT) elevations > 3 times ULN was similar for all Latuda-treated patients (0.8% and 0.8%, respectively) to placebo-treated patients (0.9% and 1.1%, respectively).

ECG Changes

Electrocardiogram (ECG) measurements were taken at various time points during the Latuda clinical trial program. No post-baseline QT prolongations exceeding 500 msec were reported in patients treated with Latuda. Within a subset of patients defined as having an increased cardiac risk, no potentially important changes in ECG parameters were observed. No cases of torsade de pointes or other severe cardiac arrhythmias were observed in the pre-marketing clinical program.

The effects of Latuda on the QT/QTc interval were evaluated in a dedicated QT study involving 87 clinically stable patients with schizophrenia or schizoaffective disorder, who were treated with Latuda doses of 120 mg daily, 600 mg daily, or ziprasidone 160 mg daily. Holter monitor-derived electrocardiographic assessments were obtained over an eight hour period at baseline and steady state. No patients treated with Latuda experienced QTc increases > 60 msec from baseline, nor did any patient experience a QTc of > 500 msec.

6.6. Other Adverse Reactions Observed During the Premarketing Evaluation of Latuda

Following is a list of MedDRA terms that reflect adverse reactions reported by patients treated with Latuda at multiple doses of > 20 mg once daily during any phase of a study within the database of 2096 patients. 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 in Table: Adverse Reaction in 2% or More of Latuda-Treated Patients and That Occurred at Greater Incidence than in the Placebo-Treated Patients in Short-term Schizophrenia Studies are not included. Although the reactions reported occurred during treatment with Latuda, they were not necessarily caused by it.

Reactions are further categorized by MedDRA system organ class and listed in order of decreasing frequency according to the following definitions:

1. 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);
2. those occurring in 1/100 to 1/1000 patients (infrequent);
3. and those occurring in fewer than 1/1000 patients (rare).

Blood and Lymphatic System Disorders:

• Infrequent: anemia;
  
• Rare: leucopenia, neutropenia

Cardiac Disorders:

• Frequent: tachycardia;
• Infrequent: AV block 1st degree, angina pectohs, bradycardia

Ear and Labyrinth Disorders:

• Infrequent: vertigo

Eye disorders:

• Frequent: blurred vision

Gastrointestinal Disorders:

• Frequent: abdominal pain, diarrhea;
  
• Infrequent: gastritis, dysphagia

General Disorders and Administrative Site Conditions:

• Rare: Sudden death

Investigations:

• Frequent: CPK increased

Metabolic and Nutritional System Disorders:

• Frequent: decreased appetite

Musculoskeletal and Connective Tissue Disorders:

• Rare: rhabdomyolysis

Nervous System Disorders:

• Infrequent tardive dyskinesia, cerebrovascular accident, dysarthria, syncope;
  
• Rare: neuroleptic malignant syndrome, seizure

Psychiatric Disorders:

• Infrequent: abnormal dreams, panic attack, sleep disorder;
  
• Rare: suicidal behavior

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

Skin and Subcutaneous Tissue Disorders:

• Frequent: rash, pruritus;
  
• Rare: angioedema

Vascular Disorders:

• Infrequent: hypertension, orthostatic hypotension