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Uses

Psychotic Disorders

Drug therapy is integral to the management of acute psychotic episodes in patients with schizophrenia and generally is required for long-term stabilization to sustain symptom remission or control and to minimize the risk of relapse. Antipsychotic agents are the principal class of drugs used for the management of all phases of schizophrenia. Patient response and tolerance to antipsychotic agents are variable, and patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.

Schizophrenia

Lurasidone hydrochloride is an atypical antipsychotic that is administered orally in the acute treatment of schizophrenia in adults. Schizophrenia is a major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and carries a high risk of suicide and other life-threatening behaviors. Manifestations of schizophrenia involve multiple psychologic processes, including perception (e.g., hallucinations), ideation, reality testing (e.g., delusions), emotion (e.g., flatness, inappropriate affect), thought processes (e.g., loose associations), behavior (e.g., catatonia, disorganization), attention, concentration, motivation (e.g., avolition, impaired intention and planning), and judgment. The principal manifestations of this disorder usually are described in terms of positive and negative (deficit) symptoms and, more recently, disorganized symptoms. Positive symptoms include hallucinations, delusions, bizarre behavior, hostility, uncooperativeness, and paranoid ideation, while negative symptoms include restricted range and intensity of emotional expression (affective flattening), reduced thought and speech productivity (alogia), anhedonia, apathy, and decreased initiation of goal-directed behavior (avolition). Disorganized symptoms include disorganized speech (thought disorder) and behavior and poor attention.

The short-term efficacy of oral lurasidone in the acute management of schizophrenia was supported in 5 placebo-controlled, fixed-dose clinical trials of 6 weeks' duration in adults who met DSM-IV criteria for schizophrenia. Two of these studies included an active-control arm (olanzapine or extended-release quetiapine) to assess assay sensitivity. The studies used either the Positive and Negative Syndrome Scale (PANSS) or the Brief Psychiatric Rating Scale derived (BPRSd) and the Clinical Global Impression severity scale (CGI-S) to assess the effects of drug treatment in improving clinical manifestations of schizophrenia. Studies 1 and 3 both evaluated 2 fixed dosages of lurasidone hydrochloride (40 or 120 mg daily), study 2 evaluated a fixed dosage of 80 mg daily, study 4 evaluated 3 fixed dosages (40, 80, or 120 mg daily), and study 5 evaluated 2 fixed dosages of the drug (80 or 160 mg daily). In all 5 studies, lurasidone was found to be more effective than placebo; however, in study 4 only the 80-mg daily dosage of lurasidone hydrochloride was found to be more effective than placebo, and neither 40 mg nor 120 mg could be distinguished from placebo. Thus, the efficacy of 40-, 80-, 120-, and 160-mg daily dosages of lurasidone hydrochloride was established in these studies as assessed by the change from baseline in the PANSS or BPRSd total scores and the CGI-S. An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.

The manufacturer states that if lurasidone is used for extended periods (i.e., longer than 6 weeks) in the treatment of schizophrenia, the long-term usefulness of the drug should be reassessed periodically on an individualized basis.(See Dosage and Administration: Dosage.)

The American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for the management of the acute phase of schizophrenia (including first psychotic episodes), principally because of the decreased risk of adverse extrapyramidal effects and tardive dyskinesia, with the understanding that the relative advantages, disadvantages, and cost-effectiveness of conventional and atypical antipsychotic agents remain controversial. The APA states that, with the possible exception of clozapine for the management of treatment-resistant symptoms, there currently is no definitive evidence that one atypical antipsychotic agent will have superior efficacy compared with another agent in the class, although meaningful differences in response may be observed in individual patients. Conventional antipsychotic agents also may be an appropriate first-line option for some patients, including those who have been treated successfully in the past with or who prefer conventional agents. The choice of an antipsychotic agent should be individualized, considering past response to therapy, current symptomatology, concurrent medical conditions, other medications and treatments, adverse effect profile, and the patient's preference for a specific drug, including route of administration.

For additional information on the symptomatic management of schizophrenia, including treatment recommendations and results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) research program, .

Bipolar Disorder

Depressive Episodes Associated with Bipolar Disorder

Lurasidone hydrochloride is used orally as monotherapy or adjunctive therapy with lithium or valproate for the treatment of major depressive episodes associated with bipolar I disorder (bipolar depression) in adults.

The short-term efficacy of lurasidone monotherapy in the treatment of depressive episodes associated with bipolar I disorder was established in a randomized, double-blind, placebo-controlled, multicenter study of 6 weeks' duration in adults who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling and without psychotic features. The primary and key secondary end points were the change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) and the Clinical Global Impressions-Bipolar-Severity of Illness scale (CGI-BP-S) scores, respectively. Patients were randomized to receive lower-dose lurasidone hydrochloride (flexible dosage range of 20-60 mg daily), higher-dose lurasidone hydrochloride (flexible dosage range of 80-120 mg daily), or placebo. Lurasidone substantially reduced MADRS and CGI-BP-S scores at week 6 of therapy in both lurasidone dosage groups compared with placebo. The higher-dose range (80-120 mg daily) of lurasidone hydrochloride was not found to be more effective, on average, than the lower-dose regimen in this study.

The short-term efficacy of lurasidone as adjunctive therapy with lithium or valproate in the treatment of depressive episodes associated with bipolar I disorder was established in a randomized, double-blind, placebo-controlled, multicenter study of 6 weeks' duration in adults who met DSM-IV-TR criteria for major depressive episodes associated with bipolar I disorder, with or without rapid cycling and without psychotic features. Patients who remained symptomatic after lithium or valproate therapy were randomized to receive flexible-dose lurasidone hydrochloride (20-120 mg daily) or placebo. The primary end point was the change from baseline to week 6 in the MADRS score, and the secondary end point was the change from baseline to week 6 in the CGI-BP-S score. Lurasidone given as adjunctive therapy with lithium or valproate substantially reduced MADRS and CGI-BP-S scores at week 6 of therapy compared with placebo.

Clinical experience with lurasidone indicates that the drug is less likely to cause weight gain and to adversely affect metabolic parameters than some other atypical antipsychotic agents (e.g., olanzapine, quetiapine) that are used in the treatment of bipolar depression. Therefore, lurasidone may be a suitable alternative treatment for patients with bipolar depression who are at higher risk of metabolic abnormalities (e.g., those with diabetes mellitus or hyperlipidemia).

The manufacturer states that the efficacy of lurasidone for longer-term use (i.e., longer than 6 weeks) in bipolar depression has not been established in controlled studies. If lurasidone is used for extended periods, the long-term usefulness of the drug should be periodically reassessed on an individualized basis.(See Dosage and Administration: Dosage.)

The manufacturer states that the efficacy of lurasidone in the treatment of mania associated with bipolar disorder has not been established.

Dosage and Administration

Administration

Lurasidone hydrochloride is commercially available as tablets, which are administered orally once daily, usually in the morning or evening, and should be taken with food (containing at least 350 calories) to increase absorption. Food increases peak concentrations and areas under the plasma concentration-time curve (AUC) of lurasidone threefold and twofold, respectively; however, lurasidone exposure was not affected as meal size was increased from 350 to 1000 calories and was independent of meal fat content. Lurasidone was administered with food in the controlled clinical studies.

Patients receiving lurasidone should be monitored for possible worsening of depression, suicidality, or unusual changes in behavior, especially at the beginning of therapy or during periods of dosage adjustments.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Dosage

Dosage of lurasidone hydrochloride is expressed in terms of the hydrochloride salt.

Schizophrenia

For the acute management of schizophrenia in adults, the recommended initial dosage of lurasidone hydrochloride is 40 mg orally once daily. Initial dosage titration is not required. Dosages ranging from 40-160 mg daily were effective in 6-week controlled trials. The maximum recommended dosage of lurasidone hydrochloride for the treatment of schizophrenia is 160 mg daily.

The manufacturer states that efficacy of lurasidone in schizophrenia beyond 6 weeks has not been established in controlled studies. If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.

The American Psychiatric Association (APA) states that prudent long-term treatment options in patients with schizophrenia with remitted first or multiple episodes include either indefinite maintenance therapy or gradual discontinuance of the antipsychotic agent with close follow-up and a plan to reinstitute treatment upon symptom recurrence. Discontinuance of antipsychotic therapy should be considered only after a period of at least 1 year of symptom remission or optimal response while receiving the antipsychotic agent. In patients who have had multiple previous psychotic episodes or 2 psychotic episodes within 5 years, indefinite maintenance antipsychotic treatment is recommended.

Depressive Episodes Associated with Bipolar Disorder

For the management of depressive episodes associated with bipolar I disorder in adults, either as monotherapy or as adjunctive therapy with lithium or valproate, the recommended initial dosage of lurasidone hydrochloride is 20 mg orally once daily. Initial dosage titration is not required. Dosages ranging from 20-120 mg daily as monotherapy or as adjunctive therapy with lithium or valproate were effective in 6-week controlled studies. In the monotherapy study, the higher dosage range (80-120 mg daily) did not provide additional efficacy, on average, over the lower dosage range (20-60 mg daily). The maximum recommended dosage of lurasidone hydrochloride for the treatment of bipolar depression, either as monotherapy or as adjunctive therapy with lithium or valproate, is 120 mg daily.

The manufacturer states that efficacy of lurasidone in bipolar depression beyond 6 weeks has not been established in controlled studies. If lurasidone is used for an extended period, the long-term usefulness of the drug for the individual patient should be reassessed periodically.

Special Populations

The manufacturer recommends dosage adjustment in patients with moderate (creatinine clearance from 30 to less than 50 mL/minute) or severe renal impairment (creatinine clearance less than 30 mL/minute). The recommended initial lurasidone hydrochloride dosage in these patients is 20 mg daily. The maximum recommended dosage in patients with moderate or severe renal impairment is 80 mg daily. The manufacturer makes no specific dosage recommendations for patients with mild renal impairment.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer recommends dosage adjustment in patients with moderate (Child-Pugh score 7-9) or severe hepatic impairment (Child-Pugh score 10-15). The recommended initial lurasidone hydrochloride dosage in these patients is 20 mg daily. The manufacturer states that lurasidone hydrochloride dosage in patients with moderate hepatic impairment should not exceed 80 mg daily and that dosage should not exceed 40 mg daily in patients with severe hepatic impairment. The manufacturer makes no specific dosage recommendations for patients with mild hepatic impairment.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In patients receiving lurasidone and in whom a moderate inhibitor of cytochrome P-450 (CYP) isoenzyme 3A4 (e.g., atazanavir, diltiazem, erythromycin, fluconazole, verapamil) will be added to therapy, the lurasidone dosage should be reduced to 50% of the original dosage. Similarly, in patients receiving a moderate CYP3A4 inhibitor in whom lurasidone hydrochloride is initiated, the recommended initial dosage of lurasidone hydrochloride is 20 mg daily and the maximum recommended dosage is 80 mg daily. If lurasidone is used concurrently with a moderate CYP3A4 inducer, it may be necessary to increase the lurasidone dosage after chronic therapy (i.e., 7 days or more) with the CYP3A4 inducer. Lurasidone should not be given concurrently with potent CYP3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, voriconazole) or potent CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]).(See Cautions: Contraindications and also see Drug Interactions.)

The manufacturer states that is not known whether dosage adjustment is necessary in geriatric patients on the basis of age alone.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not recommended based on gender or race.

Cautions

Contraindications

Known hypersensitivity to lurasidone hydrochloride or any components in the formulation. Angioedema has been reported.

Concurrent use of potent cytochrome P-450 (CYP) isoenzyme 3A4 inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, voriconazole) or potent CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]).(See Drug Interactions.)

Warnings/Precautions

Warnings

Increased Mortality in Geriatric Patients with Dementia-related Psychosis

Geriatric 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) revealed a 1.6- to 1.7-fold increase in mortality among geriatric patients who were mainly receiving atypical antipsychotic drugs (i.e., aripiprazole, olanzapine, quetiapine, risperidone) compared with that observed in patients receiving placebo. Over the course of a typical 10-week controlled trial, the rate of death in drug-treated patients was about 4.5% compared with a rate of about 2.6% in the placebo group. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Observational studies suggest that, similar to atypical antipsychotics, treatment with conventional (first-generation) antipsychotics may increase mortality; the extent to which the findings of increased mortality in observational studies may be attributed to the antipsychotic drug as opposed to some characteristic(s) of the patients remains unclear. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.(See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Worsening of Depression and Suicidality Risk

Worsening of depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior may occur in both adult and pediatric (see Pediatric Use under Warnings/Precautions: Specific Populations, in Cautions) patients with major depressive disorder or other psychiatric disorders, whether or not they are taking antidepressants. This risk may persist until clinically important remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. However, there has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term, placebo-controlled studies of antidepressants (i.e., selective serotonin-reuptake inhibitors [SSRIs] and other antidepressants) have shown an increased risk of suicidality in children, adolescents, and young adults (18-24 years of age) with major depressive disorder and other psychiatric disorders. An increased suicidality risk was not demonstrated with antidepressants compared with placebo in adults older than 24 years of age, and a reduced risk was observed in adults 65 years of age or older.

The US Food and Drug Administration (FDA) recommends that all patients being treated with antidepressants for any indication be appropriately monitored and closely observed for clinical worsening, suicidality, and unusual changes in behavior, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. Families and caregivers of patients being treated with antidepressants for major depressive disorder or other indications, both psychiatric and nonpsychiatric, also should be advised to monitor patients on a daily basis for the emergence of agitation, irritability, or unusual changes in behavior as well as the emergence of suicidality, and to report such symptoms immediately to a health-care provider.

Although a causal relationship between the emergence of symptoms such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia, hypomania, and/or mania and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consequently, consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or in patients experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, particularly if such manifestations are severe, abrupt in onset, or were not part of the patient's presenting symptoms. FDA also recommends that the drugs be prescribed in the smallest quantity consistent with good patient management, in order to reduce the risk of overdosage.

Sensitivity Reactions

Rash and pruritus have been reported frequently and angioedema has been reported rarely in patients receiving lurasidone.(See Contraindications under Cautions.)

Other Warnings and Precautions

Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis

An increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis.(See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, and also see Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome requiring immediate discontinuance of the drug and intensive symptomatic treatment, has been reported in patients receiving antipsychotic agents, including lurasidone.(See Advice to Patients.) For additional information on NMS,

Tardive Dyskinesia

Because use of antipsychotic agents, including lurasidone, may be associated with tardive dyskinesia (a syndrome of potentially irreversible, involuntary, dyskinetic movements), lurasidone should be prescribed in a manner that is most likely to minimize the occurrence of this syndrome. Chronic antipsychotic treatment generally should be reserved for patients who suffer from a chronic illness that is known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the lowest dosage and the shortest duration of treatment producing a satisfactory clinical response should be sought, and the need for continued treatment should be reassessed periodically.

The American Psychiatric Association (APA) currently recommends that patients receiving atypical antipsychotic agents be assessed clinically for abnormal involuntary movements every 12 months and that patients considered to be at increased risk for tardive dyskinesia be assessed every 6 months. If signs and symptoms of tardive dyskinesia appear in a lurasidone-treated patient, lurasidone discontinuance should be considered; however, some patients may require continued treatment with the drug despite the presence of the syndrome. For additional information on tardive dyskinesia,

Metabolic Changes

Atypical antipsychotic agents have been associated with metabolic changes that may increase cardiovascular and cerebrovascular risk, including hyperglycemia, dyslipidemia, and body weight gain. While all of these drugs produce some metabolic changes, each drug has its own specific risk profile. (See Hyperglycemia and Diabetes Mellitus,see Dyslipidemia, and also see Weight Gain under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, has been reported in patients receiving atypical antipsychotic agents. In short- and longer-term clinical trials in patients with schizophrenia or bipolar depression, clinically important differences between lurasidone and placebo in mean change from baseline to end point in serum glucose concentrations were not observed. While confounding factors such as an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population make it difficult to establish with certainty the relationship between use of agents in this drug class and glucose abnormalities, epidemiologic studies (which did not include lurasidone) suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with the atypical antipsychotic agents included in the studies (e.g., clozapine, olanzapine, quetiapine, risperidone). It remains to be determined whether lurasidone also is associated with this increased risk.

Precise risk estimates for hyperglycemia-related adverse events in patients treated with atypical antipsychotics currently are not available. While some evidence suggests that the risk for diabetes may be greater with some atypical antipsychotics (e.g., clozapine, olanzapine) than with others (e.g., aripiprazole, asenapine, iloperidone, lurasidone, quetiapine, risperidone, ziprasidone) in the class, available data are conflicting and insufficient to provide reliable estimates of relative risk associated with use of the various atypical antipsychotics.

The manufacturers of atypical antipsychotic agents state that patients with preexisting diabetes mellitus in whom therapy with an atypical antipsychotic is initiated should be periodically monitored for worsening of glucose control; those with risk factors for diabetes (e.g., obesity, family history of diabetes) should undergo fasting blood glucose testing upon therapy initiation and periodically throughout treatment. Any patient who develops manifestations of hyperglycemia (including polydipsia, polyuria, polyphagia, and weakness) during treatment with an atypical antipsychotic should undergo fasting blood glucose testing.(See Advice to Patients.) In some cases, patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other cases, hyperglycemia resolved with discontinuance of the antipsychotic.

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents,

Dyslipidemia

Undesirable changes in lipid parameters have been observed in patients treated with some atypical antipsychotic agents; however, lurasidone generally does not appear to adversely affect the lipid profile in patients receiving the drug. In a between-group comparison of pooled data from short-term, placebo-controlled studies, there were no clinically important changes in mean fasting total cholesterol and triglyceride concentrations from baseline to end point in the lurasidone-treated patients. In uncontrolled, longer-term schizophrenia studies, lurasidone was associated with decreases from baseline in mean total cholesterol and triglyceride concentrations of 3.8 and 15.1 mg/dL at week 24, 3.1 and 4.8 mg/dL at week 36, and 2.5 and 6.9 mg/dL at week 52, respectively. In an uncontrolled, longer-term bipolar depression study, lurasidone monotherapy was associated with decreases from baseline in mean total cholesterol and triglyceride concentrations of 0.5 and 1 mg/dL at week 24, respectively. In an uncontrolled, longer-term bipolar depression study of lurasidone given as adjunctive therapy with lithium or valproate, lurasidone was associated with a decrease in mean total cholesterol concentrations of 0.9 mg/dL and a mean increase in triglyceride concentrations of 5.3 mg/dL at week 24.

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy. Although lurasidone generally appears to be associated with minimal weight gain and less weight gain than some other atypical antipsychotic agents (e.g., olanzapine, quetiapine, risperidone), the manufacturer recommends clinical monitoring of weight in patients receiving the drug.

Differences in mean weight gain between lurasidone-treated patients and placebo recipients were reported in short-term schizophrenia clinical studies. A mean weight gain of 0.43 kg was reported in lurasidone-treated patients compared with a loss of 0.02 kg in those receiving placebo; 4.8% of lurasidone-treated patients gained 7% or more of their baseline body weight compared with 3.3% of those receiving placebo. During uncontrolled, longer-term schizophrenia studies, lurasidone therapy was associated with a mean weight loss of 0.69 kg at week 24, 0.59 kg at week 36, and 0.73 kg at week 52.

The mean weight gain during a short-term study in patients receiving lurasidone as monotherapy for bipolar depression was 0.29 kg compared with a loss of 0.04 kg in those receiving placebo; 2.4% of lurasidone-treated patients gained 7% or more of their baseline body weight compared with 0.7% of those receiving placebo. During an uncontrolled, longer-term extension of this study, lurasidone monotherapy was associated with a mean weight loss of 0.02 kg at week 24. In the short-term studies of lurasidone as adjunctive therapy with lithium or valproate, lurasidone was associated with a mean weight gain of 0.11 kg compared with a gain of 0.16 kg in those receiving placebo. During an uncontrolled, longer-term bipolar depression study, lurasidone, given as adjunctive therapy with lithium or valproate, was associated with a mean weight gain of 1.28 kg at week 24.

For additional information on metabolic effects associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Warnings/Precautions: Other Warnings and Precautions, in Cautions.

Hyperprolactinemia

Similar to other antipsychotic agents and drugs with dopamine D2 antagonistic activity, lurasidone can elevate serum prolactin concentrations.

In short-term schizophrenia clinical trials, the median change from baseline to end point in prolactin concentrations for lurasidone-treated patients was an increase of 0.4 ng/mL compared with a decrease of 1.9 ng/mL in the placebo group. The proportion of patients with prolactin elevations 5 or more times the upper limit of normal was 2.8% for lurasidone-treated patients compared with 1% for placebo recipients. In short-term bipolar depression trials, the median increase from baseline to end point in prolactin concentrations was 1.7 and 3.5 ng/mL in the lower- and higher-dosage lurasidone monotherapy groups, respectively, compared with an increase of 0.3 ng/mL in the placebo group. In the clinical study of lurasidone as adjunctive therapy with lithium or valproate, the median increase in prolactin was 2.8 ng/mL in the lurasidone-treated patients compared with no change in the placebo recipients. The increase in prolactin was generally greater in female patients than male patients. Clinical disturbances such as galactorrhea, amenorrhea, gynecomastia, and impotence have been associated with prolactin-elevating drugs. In addition, chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density in both female and male patients.

If lurasidone therapy is considered in a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.

Leukopenia, Neutropenia, and Agranulocytosis

In clinical trial and/or postmarketing experience, leukopenia and neutropenia have been temporally related to antipsychotic agents, including lurasidone. Agranulocytosis (including fatal cases) also has been reported with other antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count and a history of drug-induced leukopenia and neutropenia. Patients with a preexisting low leukocyte count or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy. Lurasidone should be discontinued at the first sign of a decline in leukocyte count in the absence of other causative factors.

Patients with neutropenia should be carefully monitored for fever or other signs or symptoms of infection and promptly treated if such signs and symptoms occur. In patients with severe neutropenia (absolute neutrophil count [ANC] less than 1000/mm), lurasidone should be discontinued and the leukocyte count monitored until recovery occurs. Lithium reportedly has been used successfully in the treatment of several cases of leukopenia associated with aripiprazole, clozapine, and some other drugs; however, further clinical experience is needed to confirm these anecdotal findings.

Orthostatic Hypotension and Syncope

Orthostatic hypotension, dizziness, lightheadedness, tachycardia or bradycardia, and syncope may occur during lurasidone therapy in some patients, particularly early in treatment and when dosage is increased, perhaps because of the drug's α1-adrenergic blocking activity. Patients at increased risk of these adverse reactions or of developing complications from hypotension include those with dehydration, hypovolemia, a history of cardiovascular disease (e.g., heart failure, myocardial infarction, ischemic heart disease, conduction abnormalities), or a history of cerebrovascular disease, as well as patients receiving concomitant antihypertensive therapy and those who are antipsychotic-naive.

In short-term schizophrenia trials, orthostatic hypotension was reported as an adverse event in 0.3% of patients receiving lurasidone compared with 0.1% of placebo recipients, and syncope was reported in 0.1% of patients receiving lurasidone compared with none of the placebo recipients. Orthostatic hypotension, as assessed by vital signs, was reported in 0.8, 2.1, 1.7, and 0.8% of patients receiving lurasidone hydrochloride 40, 80, 120, and 160 mg daily, respectively, compared with 0.7% of patients receiving placebo in short-term schizophrenia trials.

There were no reports of orthostatic hypotension or syncope as adverse events in short-term bipolar depression clinical trials. Orthostatic hypotension, as assessed by vital signs, occurred in 0.6-1.1% of lurasidone-treated patients compared with 0-0.9% of the placebo recipients in these trials.

The manufacturer recommends considering use of a lower initial lurasidone dosage and more gradual dosage titration in patients with a history of cardiovascular disease (e.g., heart failure, history of myocardial infarction, ischemic heart disease, conduction abnormalities) or cerebrovascular disease or with conditions that would predispose patients to hypotension (e.g., dehydration, hypovolemia, concomitant antihypertensive therapy) and in antipsychotic-naive patients. In addition, orthostatic vital signs should be monitored in such patients.

Seizures

In short-term schizophrenia trials, seizures occurred in 0.1% of patients receiving lurasidone compared with 0.1% of patients receiving placebo. There were no reports of seizures or convulsions in lurasidone-treated patients in short-term bipolar depression trials.

As with other antipsychotic agents, lurasidone should be used with caution in patients with a history of seizures or with conditions that lower the seizure threshold (e.g., dementia of the Alzheimer's type); conditions that lower the seizure threshold may be more prevalent in patients 65 years of age or older.

Cognitive and Motor Impairment

Like other antipsychotic agents, lurasidone potentially may impair judgment, thinking, or motor skills. In short-term, placebo-controlled schizophrenia trials, somnolence (including hypersomnia, hypersomnolence, and sedation) was reported in 17% of patients receiving lurasidone compared with 7.1% of placebo recipients. In a short-term bipolar depression trial, somnolence was reported in 7.3 and 13.8% of patients who received lower-dose (20-60 mg daily) and higher-dose (80-120 mg daily) lurasidone hydrochloride monotherapy, respectively, compared with 6.5% of placebo recipients. Frequency of somnolence was found to be dose related in the monotherapy study.(See Advice to Patients.)

Body Temperature Regulation

Disruption of the body's ability to reduce core body temperature has been attributed to antipsychotic agents. The manufacturer recommends appropriate caution when lurasidone is used in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).(See Advice to Patients.)

Suicide

There is an attendant risk of suicide in patients with psychotic illnesses; high-risk patients should be closely supervised. Lurasidone should be prescribed in the smallest quantity consistent with good patient management to reduce the risk of overdosage.

Activation of Mania/Hypomania

Antidepressants can increase the risk of developing manic or hypomanic episodes, particularly in patients with bipolar disorder. Manic or hypomanic episodes were reported in less than 1% of patients receiving lurasidone and in less than 1% of patients receiving placebo in the bipolar depression monotherapy and adjunctive therapy studies. Patients should be monitored for the emergence of manic or hypomanic episodes during lurasidone therapy.

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia. Lurasidone is not approved for the treatment of patients with dementia-related psychosis and should be used with caution in patients at risk for aspiration pneumonia.(See Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions.)

Neurologic Adverse Reactions in Patients with Parkinsonian Syndrome or Dementia with Lewy Bodies

Patients with parkinsonian syndrome or dementia with Lewy bodies reportedly have an increased sensitivity to antipsychotic agents. Clinical manifestations of this increased sensitivity have been reported to include confusion, obtundation, postural instability with frequent falls, extrapyramidal symptoms, and features consistent with NMS. For additional information on extrapyramidal adverse effects and NMS,

Specific Populations

Pregnancy

Category B.

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. Symptoms reported to date have included agitation, hypertonia, hypotonia, tardive dyskinetic-like symptoms, tremor, somnolence, respiratory distress, and feeding disorder. Neonates exhibiting such symptoms should be monitored. The complications have varied in severity; some neonates recovered within hours to days without specific treatment while others have required intensive care unit support and prolonged hospitalization.

The effect of lurasidone on labor and delivery is unknown.

Lactation

Lurasidone is distributed into milk in rats. It is not known whether lurasidone and/or its metabolites are distributed into milk in humans. Because of the potential for serious adverse reactions to lurasidone in nursing infants, the manufacturer states that a decision should be made whether to discontinue nursing or lurasidone, taking into consideration the risk of drug discontinuance to the woman.

Pediatric Use

Safety and effectiveness of lurasidone in pediatric patients have not been established.

FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressant drugs (SSRIs and other antidepressants). However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients younger than 19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. No suicides occurred in these pediatric trials. These findings should be carefully considered when assessing potential benefits and risks of lurasidone in a child or adolescent for any clinical use.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Geriatric Use

Clinical trial experience with lurasidone in patients with schizophrenia who are 65 years of age and older is insufficient to determine whether they respond differently than younger adults.

In geriatric patients (65-85 years of age) with psychosis, serum lurasidone concentrations were similar to those observed in younger adults. The manufacturer states that it is unknown whether dosage adjustment is necessary in geriatric patients on the basis of age alone.

Geriatric patients with dementia-related psychosis treated with lurasidone are at an increased risk of death compared with those treated with placebo. In addition, an increased incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities, has been observed in geriatric patients with dementia-related psychosis treated with certain atypical antipsychotic agents (aripiprazole, olanzapine, risperidone) in placebo-controlled studies. The manufacturer states that lurasidone is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Warnings/Precautions: Warnings, in Cautions and see also Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis and see Dysphagia under Warnings/Precautions: Other Warnings and Precautions, in Cautions). For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, .

In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age or older with antidepressant therapy compared with placebo.(See Worsening of Depression and Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Hepatic Impairment

In a single-dose study, mean areas under the serum concentration-time curve (AUCs) of lurasidone were 1.5, 1.7, and 3 times higher in individuals with mild (Child-Pugh score 5-6), moderate (Child-Pugh score 7-9), and severe hepatic impairment (Child-Pugh score 10-15), respectively, compared with values in healthy matched individuals. Mean peak serum concentrations of lurasidone were 1.3, 1.2, and 1.3 times higher for patients with mild, moderate, and severe hepatic impairment, respectively, compared with values for healthy matched individuals. Dosage adjustment is recommended for patients with moderate or severe hepatic impairment.(See Dosage and Administration: Special Populations.)

Renal Impairment

After administration of a single 40-mg dose of lurasidone hydrochloride to patients with mild, moderate, or severe renal impairment, mean peak serum concentrations increased by 40, 92, and 54%, respectively, and mean AUCs increased by 53%, 91%, and twofold, respectively, compared with healthy matched individuals. Dosage adjustment is recommended for patients with moderate or severe renal impairment (creatinine clearance from 10 to less than 50 mL/minute).(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 5% or more of patients receiving lurasidone for schizophrenia and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, extrapyramidal symptoms (including parkinsonian symptoms and dyskinesia), and nausea. Akathisia and extrapyramidal symptoms were found to be dose related in these studies.

Adverse effects occurring in 5% or more of patients receiving lurasidone for bipolar depression as monotherapy or as adjunctive therapy with lithium or valproate and at a frequency at least twice that reported with placebo include somnolence (including hypersomnia, hypersomnolence, and sedation), akathisia, nausea, extrapyramidal symptoms (including parkinsonian symptoms and dyskinesia), vomiting, diarrhea, and anxiety. Nausea, somnolence, akathisia, and extrapyramidal symptoms were found to be dose related in the monotherapy study.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

CYP3A4 Inhibitors and Inducers

Lurasidone is predominantly metabolized by cytochrome P-450 (CYP) isoenzyme 3A4. Pharmacokinetic interactions of lurasidone with potent and moderate inhibitors or potent inducers of CYP3A4 have been observed.

Lurasidone should not be used in combination with potent inhibitors (e.g., clarithromycin, ketoconazole, ritonavir, voriconazole) or potent inducers (e.g., carbamazepine, phenytoin, rifampin, St. John's wort [Hypericum perforatum]) of CYP3A4. (See Contraindications and also see Drug Interactions: Ketoconazole and Drug Interactions: Rifampin.) Lurasidone dosage should be adjusted when used concurrently with moderate CYP3A4 inhibitors (e.g., atazanavir, diltiazem, erythromycin, fluconazole, verapamil). (See Dosage and Administration: Special Populations and also see Drug Interactions: Diltiazem.)

If lurasidone is used concurrently with a moderate CYP3A4 inducer, an increase in lurasidone dosage may be necessary after chronic therapy (i.e., 7 days or more) with the CYP3A4 inducer.

Inhibitors and Inducers of Other CYP Isoenzymes

Lurasidone is not a substrate of CYP isoenzymes 1A1, 1A2, 2A6, 4A11, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1; therefore, clinically important pharmacokinetic interactions between lurasidone and drugs that are either inhibitors or inducers of these enzymes are unlikely.

Anticholinergic Agents

Potential pharmacologic interaction (possible disruption of body temperature regulation); use lurasidone with caution in patients concurrently receiving drugs with anticholinergic activity. (See Body Temperature Regulation under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

CNS Agents or Alcohol

Potential pharmacologic interaction (additive CNS effects). Use with caution with other CNS agents and avoid use of alcohol during lurasidone therapy.

Digoxin

Concomitant administration of lurasidone hydrochloride (120 mg daily at steady state) with a single 0.25-mg dose of digoxin, a P-glycoprotein substrate, increased peak plasma concentrations and areas under the serum concentration-time curve (AUCs) of digoxin by approximately 9 and 13%, respectively. Digoxin dosage adjustment is not required in patients receiving these drugs concurrently.

Diltiazem

Concomitant administration of diltiazem (240 mg daily for 5 days), a moderate CYP3A4 inhibitor, and lurasidone hydrochloride (single 20-mg dose) increased peak serum lurasidone concentrations and AUCs by 2.1 and 2.2 times, respectively, compared with administration of lurasidone alone. If diltiazem is initiated in patients receiving lurasidone, the manufacturer states that lurasidone dosage should be reduced to 50% of the original dosage. If lurasidone is initiated in patients receiving diltiazem, the manufacturer recommends that lurasidone hydrochloride therapy be initiated at 20 mg daily and that dosage not exceed 80 mg daily.

Grapefruit

Grapefruit and grapefruit juice should be avoided in patients receiving lurasidone since they may inhibit CYP3A4 and increase plasma concentrations of lurasidone.(See Advice to Patients.)

Hypotensive Agents

Because of its α1-adrenergic blocking activity, the manufacturer states that patients receiving lurasidone may be at increased risk of orthostatic hypotension and syncope and related adverse effects. A lower initial dosage of lurasidone and more gradual dosage titration should therefore be considered in patients concomitantly receiving antihypertensive agents; in addition, monitoring of orthostatic vital signs is recommended in such patients.(See Orthostatic Hypotension and Syncope under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Advice to Patients.)

Ketoconazole

Concomitant administration of ketoconazole (400 mg daily), a potent CYP3A4 inhibitor, and lurasidone hydrochloride (single 10-mg dose) increased peak serum concentrations and AUCs of lurasidone by 6.8 and 9.3 times, respectively, compared with administration of lurasidone alone. Ketoconazole should therefore not be used concurrently with lurasidone.

Lithium

Concomitant administration of lithium (600 mg twice daily for 8 days) and lurasidone hydrochloride (120 mg daily for 8 days) decreased peak serum lurasidone concentrations by 8% and increased lurasidone AUC by 7% compared with lurasidone administration alone; these changes were not considered clinically important. In bipolar depression studies evaluating lurasidone and adjunctive lithium therapy, there was no evidence of additive CNS toxicity in patients receiving lurasidone and lithium in combination. Lurasidone dosage adjustment is not required in patients receiving lithium concurrently. In addition, lithium dosage adjustment is not necessary during concurrent use of lurasidone.

Midazolam

Concomitant administration of lurasidone hydrochloride (120 mg daily at steady state) with a single 5-mg dose of midazolam, a CYP3A4 substrate, increased peak plasma concentrations and AUCs of midazolam by approximately 21 and 44%, respectively. Midazolam dosage adjustment is not required in patients receiving lurasidone concurrently.

Oral Contraceptives

Concomitant administration of lurasidone hydrochloride (40 mg daily at steady state) with an oral contraceptive containing ethinyl estradiol and norgestimate resulted in equivalent peak plasma concentrations and AUCs of ethinyl estradiol and norgestimate relative to oral contraceptive administration alone. Sex hormone binding globulin concentrations also were not substantially affected by concurrent administration of the drugs. Oral contraceptive dosage adjustment is not required in patients receiving lurasidone concurrently.

Rifampin

Concomitant administration of rifampin (600 mg daily for 8 days), a strong CYP3A4 inducer, and lurasidone hydrochloride (single 40-mg dose) decreased peak serum lurasidone concentrations and AUCs by approximately 85 and 82%, respectively. Rifampin should not be concurrently administered with lurasidone.

Smoking

Lurasidone is not a substrate for CYP1A2 in vitro; therefore, smoking should not alter the pharmacokinetics of the drug.

St. John's Wort

Lurasidone should not be used concurrently with St. John's wort (Hypericum perforatum), a potent inducer of CYP3A4.

Valproate

The manufacturer states that a dedicated drug interaction study has not been conducted with lurasidone and valproate. However, pharmacokinetic data obtained from the bipolar depression studies indicate that valproate concentrations are not affected by concomitant use of lurasidone, and that lurasidone concentrations are not affected by concomitant use of valproate. Therefore, dosage adjustments are not required in patients receiving valproate and lurasidone concurrently.

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