Side Effects of Latuda (lurasidone)

Latuda (lurasidone) is an atypical antipsychotic used to treat schizophrenia in adults and adolescents (13 to 17 years of age) and major depressive episodes in bipolar 1 disorder.

Atypical antipsychotics like Latuda are considered the standard of care for treating schizophrenia. Additionally, in clinical studies lurasidone was shown to be effective in improving mood in many people struggling with bipolar depression.

Latuda can be taken alone or with either lithium or valproate. The exact mechanism of action of Latuda is not known. It may work by blocking receptors for several neurotransmitters (chemicals that nerves use to communicate with each other) in the brain. It binds to dopamine and serotonin type 2 (5-HT2) receptors.

Common side effects of Latuda include

• sleepiness or drowsiness,
• restlessness or feeling a need to move around (akathisia),
• difficulty moving,
• slow movements,
• muscle stiffness,
• tremor, and
• nausea.

Serious side effects of Latuda include

• increased risk of stroke that can lead to death in elderly patients with dementia;
• increased risk of suicidal thoughts or actions especially in children, teenagers, and young adults within the first few months of treatment;
• neuroleptic malignant syndrome (rare);
• involuntary movements of the face, tongue, or other body parts (tardive dyskinesia);
• high blood sugar (hyperglycemia);
• increased cholesterol and triglycerides;
• weight gain;
• increased prolactin levels;
• reduced white blood cell count;
• decreased blood pressure especially when rising too quickly from a sitting or lying position;
• seizures; and
• difficulty swallowing.

Drug interactions of Latuda include medicines that interfere with the activity of CYP3A4 liver enzymes because co-administration with these medicines can alter the levels of Latuda in the blood.

Latuda should not be used concomitantly with strong CYP3A4 inhibitors such as ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, and many other drugs due to the risk of increased blood levels of lurasidone.

Grapefruit and grapefruit juice may also inhibit CYP3A4 enzymes and should be avoided in patients taking Latuda. Latuda should not be used concomitantly with strong CYP3A4 inducers such as rifampin, St. John's wort, phenytoin, and carbamazepine because blood levels of Latuda may decrease, resulting in poor treatment outcomes.

Use of Latuda in pregnant women has not been adequately evaluated. Due to the lack of conclusive safety data, Latuda should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Latuda is excreted in breast milk. Since many drugs are excreted in breast milk and have the potential of causing harm to the nursing infant, a decision should be made to either discontinue breastfeeding or taking Latuda.

The most common side effects of lurasidone include:

• sleepiness or drowsiness,
• akathesia (restlessness or feeling a need to move around),
• difficulty moving,
• slow movements,
• muscle stiffness,
• tremor, and
• nausea.

Lurasidone may increase the risk of stroke that can lead to death in elderly patients with dementia. It is associated with an increased risk of suicidal thoughts or actions especially in children, teenagers, and young adults within the first few months of treatment. Neuroleptic malignant syndrome or NMS, a rare but serious disorder caused by antipsychotic medicines can occur.

Other side effects include:

• Involuntary movements of the face, tongue, or other body parts called tardive dyskinesia;
• high blood sugar (hyperglycemia);
• increased cholesterol and triglycerides;
• weight gain;
• increases in prolactin levels;
• a drop in white blood cell count;
• a decrease in blood pressure especially when rising too quickly from a sitting or lying position;
• seizures; and
• difficulty swallowing.

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

• Increased Mortality in Elderly Patients with Dementia-Related Psychosis
• Suicidal Thoughts and Behaviors
• Cerebrovascular Adverse Reactions, Including Stroke, in Elderly Patients with Dementia-related Psychosis
• Neuroleptic Malignant Syndrome
• Tardive Dyskinesia
• Metabolic Changes
• Hyperprolactinemia
• Leukopenia, Neutropenia, and Agranulocytosis
• Orthostatic Hypotension and Syncope
• Falls
• Seizures
• Potential for Cognitive and Motor Impairment
• Body Temperature Dysregulation
• Activation of Mania/Hypomania
• Dysphagia
• Neurological Adverse Reactions in Patients with Parkinson’s Disease or Dementia with Lewy Bodies

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 17.

Table 17: 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

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 18.

Table 18: 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

Dose-Related Adverse Reactions in the Monotherapy Study

In the adult short-term, placebo-controlled study (involving lower and higher Latuda dose ranges) 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 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 the Adult Short-term Adjunctive Therapy Bipolar Depression Studies

Adolescents

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, 40mg only), vomiting, and rhinorrhea/rhinitis (80mg 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 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 Adolescent Short-term Schizophrenia Study

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% versus 5.8% for placebo-treated patients. The incidence of akathisia for Latuda-treated patients was 12.9% versus 3.0% for placebo-treated patients. Incidence of EPS by dose is provided in Table 21.

Table 21: Incidence of EPS Compared to Placebo in Adult Schizophrenia Studies

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 22.

Table 22: Incidence of EPS Compared to Placebo in the Adolescent Schizophrenia Study

Bipolar Depression

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% versus 2.4% for placebo-treated patients. The incidence of akathisia for Latuda-treated patients was 9.4% versus 2.4% for placebo-treated patients. Incidence of EPS by dose groups is provided in Table 23.

Table 23: Incidence of EPS Compared to Placebo in the Adult Monotherapy Bipolar Depression Study

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% versus 8.7% for placebo. The incidence of akathisia for Latuda-treated patients was 10.8% versus 4.8% for placebo-treated patients. Incidence of EPS is provided in Table 24.

Table 24: Incidence of EPS Compared to Placebo in the Adult Adjunctive Therapy Bipolar Depression Studies

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.

Schizophrenia

Adults

The mean change from baseline for Latuda-treated patients for the SAS, BAS and AIMS was comparable to placebo-treated patients, with the exception of the Barnes Akathisia Scale global score (Latuda, 0.1; 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, 14.4%; placebo, 7.1%), the SAS (Latuda, 5.0%; placebo, 2.3%) and the AIMS (Latuda, 7.4%; placebo, 5.8%).

Adolescents

The mean change from baseline for Latuda-treated patients with adolescent schizophrenia 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 Latuda-treated patients versus placebo for the BAS (Latuda, 7.0%; placebo, 1.8%), the SAS (Latuda, 8.3%; placebo, 2.7%) and the AIMS (Latuda, 2.8%; placebo, 0.9%).

Bipolar Depression

Monotherapy

The mean change from baseline for Latuda-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 Latuda-treated patients versus placebo for the BAS (Latuda, 8.4%; placebo, 5.6%), the SAS (Latuda, 3.7%; placebo, 1.9%) and the AIMS (Latuda, 3.4%; placebo, 1.2%).

Adjunctive Therapy with Lithium or Valproate

The mean change from baseline for Latuda-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 Latuda-treated patients versus placebo for the BAS (Latuda, 8.7%; placebo, 2.1%), the SAS (Latuda, 2.8%; placebo, 2.1%) and the AIMS (Latuda, 2.8%; placebo, 0.6%).

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.

Schizophrenia

Adults

In the short-term, placebo-controlled schizophrenia clinical studies, dystonia occurred in 4.2% of Latuda-treated subjects (0.0% Latuda 20 mg, 3.5% Latuda 40 mg, 4.5% Latuda 80 mg, 6.5% Latuda 120 mg and 2.5% Latuda 160 mg) compared to 0.8% of subjects receiving placebo. Seven subjects (0.5%, 7/1508) discontinued clinical trials due to dystonic events – four were receiving Latuda 80 mg/day and three were receiving Latuda 120 mg/day.

Adolescents

In the short-term, placebo-controlled, adolescent schizophrenia study, dystonia occurred in 1% of Latuda-treated patients (1% Latuda 40 mg and 1% Latuda 80 mg) compared to 0% of patients receiving placebo. No patients discontinued the clinical study due to dystonic events.

Bipolar Depression

Monotherapy

In the adult short-term, flexible-dose, placebo-controlled monotherapy bipolar depression study, dystonia occurred in 0.9% of Latuda-treated subjects (0.0% and 1.8% for Latuda 20 to 60 mg/day and Latuda 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 Latuda-treated subjects (20 to 120 mg) compared to 0.6% of subjects receiving placebo. No subject discontinued the clinical study due to dystonic events.

Other Adverse Reactions Observed During The Premarketing Evaluation Of Latuda

Following is a list of adverse reactions reported by adult patients treated with Latuda at multiple doses of ≥ 20 mg once daily within the premarketing database of 2905 patients with schizophrenia. 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 16 or those that appear elsewhere in the Latuda label are not included. Although the reactions reported occurred during treatment with Latuda, they were not necessarily caused by it.

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

Cardiac 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

Metabolism 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

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

Vascular Disorders: Frequent: hypertension

Clinical Laboratory Changes

Schizophrenia

Adults

Serum Creatinine: In short-term, placebo-controlled trials, the mean change from Baseline in serum creatinine was +0.05 mg/dL for Latuda-treated patients compared to +0.02 mg/dL for placebo-treated patients. A creatinine shift from normal to high occurred in 3.0% (43/1453) of Latuda-treated patients and 1.6% (11/681) on placebo. The threshold for high creatinine value varied from > 0.79 to > 1.3 mg/dL based on the centralized laboratory definition for each study (Table 25).

Table 25: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in Adult Schizophrenia Studies

Adolescents

Serum Creatinine: In the short-term, placebo-controlled, adolescent schizophrenia study, the mean change from Baseline in serum creatinine was −0.009 mg/dL for Latuda-treated patients compared to +0.017 mg/dL for placebo-treated patients. A creatinine shift from normal to high (based on the centralized laboratory definition) occurred in 7.2% (14/194) of Latuda-treated patients and 2.9% (3/103) on placebo (Table 26).

Table 26: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adolescent Schizophrenia Study

Bipolar Depression

Monotherapy

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 Latuda-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 Latuda-treated patients and 0.6% (1/162) on placebo (Table 27).

Table 27: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adult Monotherapy Bipolar Depression Study

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 Latuda-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 Latuda-treated patients and 1.6% (5/334) on placebo (Table 28).

Table 28: Serum Creatinine Shifts from Normal at Baseline to High at Study End-Point in the Adult Adjunctive Therapy Bipolar Depression Studies

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of Latuda. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Hypersensitivity Reactions: Urticaria, throat swelling, tongue swelling, and dyspnea.

Hyponatremia

Drugs Having Clinically Important Interactions With Latuda

Table 29: Clinically Important Drug Interactions with Latuda

Drugs Having No Clinically Important Interactions With Latuda

Based on pharmacokinetic studies, no dosage adjustment of Latuda is required when administered concomitantly with lithium, valproate, or substrates of P-gp or CYP3A4.

Drug Abuse And Dependence

Controlled Substance

Latuda is not a controlled substance.

Abuse

Latuda has not been systematically studied in humans for its potential for abuse or physical dependence or its ability to induce tolerance. While clinical studies with Latuda did not reveal any tendency for drug-seeking behavior, these observations were not systematic and it is not possible to predict the extent to which a CNS-active drug will be misused, diverted and/or abused once it is marketed.

Patients should be evaluated carefully for a history of drug abuse, and such patients should be observed carefully for signs of Latuda misuse or abuse (e.g., development of tolerance, drug-seeking behavior, increases in dose).