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Uses

Adjunctive Therapy of Major Depressive Disorder

Brexpiprazole is used orally as an adjunct to antidepressants for the treatment of major depressive disorder.

The adjunctive antidepressant efficacy of brexpiprazole was established in 2 short-term, double-blind, placebo-controlled, fixed-dose studies of 6 weeks' duration (studies 1 and 2) in adults who met DSM-IV-TR criteria for major depressive disorder with or without symptoms of anxiety and who had an inadequate response to previous antidepressant therapy (1-3 courses) in the current episode and had also demonstrated an inadequate response during an 8-week prospective treatment period of antidepressant therapy with delayed-release duloxetine, escitalopram, fluoxetine, extended-release paroxetine, sertraline, or extended-release venlafaxine. The primary efficacy end point in these studies was change from baseline to week 6 on the Montgomery-Asberg Depression Rating Scale (MADRS) total score. In study 1, patients were randomized to receive either brexpiprazole 2 mg once daily or placebo in addition to their antidepressant therapy; in study 2, patients were randomized to receive brexpiprazole 1 or 3 mg once daily or placebo as adjunctive therapy. Brexpiprazole therapy was initiated at a dosage of 0.5 mg once daily in all patients, then the dosage was increased to 1 mg once daily at week 2 in all treatments groups; the dosage was then either maintained at 1 mg once daily or increased to 2 or 3 mg once daily, based on treatment assignment, from week 3 onward. In studies 1 and 2, brexpiprazole at a dosage of 2 or 3 mg daily was superior to placebo in reducing mean MADRS total scores at week 6 and was generally well tolerated. An analysis of population subgroups did not reveal evidence of differential response to adjunctive brexpiprazole therapy based on age, gender, race, or choice of prospective antidepressant.

The manufacturer states that the need for continued therapy and appropriate dosage of brexpiprazole should be reassessed periodically in patients with major depressive disorder.(See Dosage and Administration: Dosage.)

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

Brexpiprazole is an atypical antipsychotic that is administered orally in the treatment of schizophrenia. 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.

Short-term efficacy of oral brexpiprazole monotherapy in the acute treatment of schizophrenia has been established in 2 randomized, multicenter, double-blind, placebo-controlled, fixed-dose studies of 6 weeks' duration (studies 3 and 4) in adults who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute exacerbation of psychotic symptoms. Both studies evaluated fixed brexpiprazole dosages of 2 or 4 mg once daily. Brexpiprazole therapy was initiated at a dosage of 1 mg once daily, given on days 1 through 4, then the dosage was increased to 2 mg once daily on days 5 to 7; the dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, based on treatment assignment, for 5 weeks. The primary efficacy end point in these studies was the change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) total score. In both studies, brexpiprazole 4 mg once daily was found to be more effective than placebo in improving the PANSS total score at week 6; the 2-mg daily dosage of brexpiprazole was more effective than placebo only in study 3. An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.

Efficacy and safety of brexpiprazole in the maintenance treatment of schizophrenia have been established in a randomized, multicenter withdrawal study (study 5). Adults with schizophrenia were stabilized for at least 12 weeks on 1-4 mg daily of brexpiprazole and were then randomized in the double-blind treatment phase to either continue brexpiprazole at their achieved stable dosage or to switch to placebo for up to 52 weeks. The primary efficacy end point in this study was time from randomization to impending relapse during the double-blind phase. A prespecified interim analysis demonstrated a substantially longer time to relapse in patients randomized to brexpiprazole therapy compared with the placebo recipients. The study was therefore terminated early because maintenance of efficacy had been demonstrated. Long-term brexpiprazole therapy also was found to be well tolerated in this study.

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, .

Dosage and Administration

Administration

Brexpiprazole is commercially available as tablets, which are administered orally once daily without regard to meals.(See Description.)

Patients receiving brexpiprazole 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

Adjunctive Therapy of Major Depressive Disorder

For adjunctive treatment of major depressive disorder in adults already receiving an antidepressant, the recommended initial dosage of brexpiprazole is 0.5 or 1 mg orally once daily. The dosage should be titrated to 1 mg once daily and then up to the target dosage of 2 mg once daily; dosage adjustments should be made at weekly intervals based on individual patient response and tolerability. The maximum recommended dosage of brexpiprazole for the adjunctive treatment of major depressive disorder is 3 mg daily.

The manufacturer states that the need for continued therapy with brexpiprazole and the appropriate dosage of the drug should be reassessed periodically.

Schizophrenia

For the management of schizophrenia in adults, the recommended initial dosage of brexpiprazole is 1 mg orally once daily on days 1-4, followed by an increase in dosage to 2 mg once daily on days 5-7. Based on individual patient response and tolerability, the dosage may be increased to 4 mg once daily on day 8. The recommended target dosage of brexpiprazole for the treatment of schizophrenia is 2-4 mg once daily. The maximum recommended dosage of the drug for the treatment of schizophrenia is 4 mg daily.

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.

Special Populations

In patients with moderate, severe, or end-stage renal impairment (creatinine clearance less than 60 mL/minute), the maximum recommended dosage of brexpiprazole is 2 mg once daily for adjunctive treatment of major depressive disorder and 3 mg once daily for the treatment of schizophrenia.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The manufacturer does not provide any specific dosage recommendations for brexpiprazole in patients with mild hepatic impairment. In patients with moderate to severe hepatic impairment (Child-Pugh score of 7 or higher), the maximum recommended dosage of brexpiprazole is 2 mg once daily for adjunctive treatment of major depressive disorder and 3 mg once daily for the treatment of schizophrenia.(See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

In geriatric patients, the manufacturer states that dosage selection of brexpiprazole should be cautious, usually starting at the lower end of the recommended dosage range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and concomitant illness and other drug therapy in this population.(See Geriatric Use under Warnings/Precautions: Specific Populations, in Cautions.)

Dosage adjustment is not required based on gender, race, or smoking status.

Hepatic Microsomal Enzyme Considerations

Dosage adjustments of brexpiprazole are recommended in patients who are known poor metabolizers of the cytochrome P-450 (CYP) isoenzyme 2D6 and in patients concomitantly receiving CYP3A4 and/or CYP2D6 inhibitors or potent CYP3A4 inducers.(See Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Patients who are known poor metabolizers of CYP2D6 should receive 50% of the usual brexpiprazole dosage, since poor CYP2D6 metabolizers have higher concentrations of brexpiprazole than extensive metabolizers (see Description). Such patients who are also taking moderate or potent CYP3A4 inhibitors should receive 25% of the usual brexpiprazole dosage.

For the treatment of schizophrenia, brexpiprazole dosage should be reduced to 50% of the usual dosage when used concurrently with potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine). When the potent CYP2D6 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed. For adjunctive therapy of major depressive disorder, brexpiprazole dosage adjustment is not necessary when used concomitantly with potent CYP2D6 inhibitors because CYP-related considerations have already been taken into account for the general dosage recommendations. (See Adjunctive Therapy of Major Depressive Disorder under Dosage and Administration: Dosage and also see Drug Interactions: Drugs Affecting Hepatic Microsomal Enzymes.)

Brexpiprazole dosage should be reduced to 50% of the usual dosage when used concurrently with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole). When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed.

When used concurrently with a combination of moderate or potent CYP2D6 inhibitors and moderate or potent CYP3A4 inhibitors, brexpiprazole dosage should be reduced to 25% of the usual dosage. When the moderate or potent CYP2D6 inhibitor(s) and moderate or potent CYP3A4 inhibitor(s) are withdrawn from combined therapy, the original brexpiprazole dosage may be resumed.

If brexpiprazole is used concurrently with potent CYP3A4 inducers (e.g., rifampin, St. John's wort [Hypericum perforatum]), the usual brexpiprazole dosage should be doubled over 1-2 weeks, with further dosage adjustments based on clinical response. When the potent CYP3A4 inducer is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed over 1-2 weeks.

Cautions

Contraindications

Known hypersensitivity to brexpiprazole or any components in the formulation. Rash, facial swelling, urticaria, and anaphylaxis have been reported in patients receiving brexpiprazole.

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. The manufacturer states that brexpiprazole 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.

All patients being treated with antidepressants for any indication should be appropriately monitored 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. 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.

Other Warnings and Precautions

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

In placebo-controlled studies in geriatric patients with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of adverse cerebrovascular events (cerebrovascular accidents and transient ischemic attacks), including fatalities. The manufacturer states that brexpiprazole 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 characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, has been reported with antipsychotic agents. If NMS is suspected, antipsychotic therapy should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.(See Advice to Patients.) For additional information on NMS,

Tardive Dyskinesia

Because use of antipsychotic agents, including brexpiprazole, may be associated with tardive dyskinesia (a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements), brexpiprazole should be prescribed in a manner that is most likely to reduce the risk 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, 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 needed to achieve a satisfactory clinical response should be used, 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 brexpiprazole-treated patient, brexpiprazole 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, including brexpiprazole, have caused metabolic changes, including hyperglycemia and diabetes mellitus, 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. Hyperglycemia has been reported in patients treated with brexpiprazole. 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 suggest an increased risk of treatment-emergent hyperglycemia-related adverse events in patients treated with atypical antipsychotic agents. In short-term clinical studies, clinically important differences between brexpiprazole and placebo in the proportion of patients experiencing an increase in fasting glucose concentrations were not observed. In longer-term studies, 9-10% of brexpiprazole-treated patients with normal or borderline fasting glucose concentrations experienced shifts to high fasting glucose concentrations.

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 atypical antipsychotic; 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

Atypical antipsychotics cause adverse alterations in lipid parameters. In short-term clinical studies. a higher incidence of hypertriglyceridemia was reported with brexpiprazole than with placebo while changes in fasting total cholesterol, low-density lipoprotein (LDL)-cholesterol, and high-density lipoprotein (HDL)-cholesterol were similar between brexpiprazole-treated patients and those receiving placebo. In uncontrolled, longer-term depression studies, 14% of brexpiprazole-treated patients experienced a shift from normal baseline HDL-cholesterol concentrations to low HDL-cholesterol concentrations and 17% of brexpiprazole-treated patients with normal baseline triglyceride concentrations experienced shifts to high and 0.2% experienced shifts to very high triglyceride concentrations. In uncontrolled, longer-term schizophrenia studies, 13% of brexpiprazole-treated patients with normal baseline triglyceride concentrations experienced shifts to high and 0.4% experienced shifts to very high triglyceride concentrations.

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy. Monitoring of weight at baseline and frequently thereafter is recommended in patients receiving brexpiprazole.

Brexpiprazole generally appears to be associated with moderate weight gain. Mean weight gain during short-term studies in patients receiving brexpiprazole for depression or schizophrenia was 1-1.6 kg compared with 0.2-0.3 kg in those receiving placebo. In longer-term, open-label studies, 20-30% of brexpiprazole-treated patients gained 7% or more of their baseline body weight while 4-10% of patients receiving the drug lost 7% or more.

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.

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during therapy with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other antipsychotic agents.

Possible risk factors for leukopenia and neutropenia include preexisting low leukocyte count or absolute neutrophil count (ANC) or a history of drug-induced leukopenia or neutropenia. Patients with a preexisting low leukocyte count or ANC or a history of drug-induced leukopenia or neutropenia should have their complete blood count monitored frequently during the first few months of therapy. Brexpiprazole should be discontinued at the first sign of a clinically important 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 (ANC less than 1000/mm), brexpiprazole 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

Atypical antipsychotic agents cause orthostatic hypotension and syncope, perhaps because of their α1-adrenergic blocking activity. The risk of these adverse effects generally is greatest during initial dosage titration and when the dosage is increased.

In short-term depression studies, dizziness and orthostatic hypotension were reported as adverse events in 2 and 0.1%, respectively, of patients receiving brexpiprazole with an antidepressant compared with 2% and none, respectively, of patients receiving placebo with an antidepressant. In short-term schizophrenia studies, dizziness, orthostatic hypotension, and syncope were reported in 2 and 2%, 0.4 and 0.2%, and 0.1% and none of the patients receiving brexpiprazole or placebo, respectively.

The manufacturer recommends monitoring orthostatic vital signs in patients who are susceptible to hypotension (e.g., geriatric patients, patients with dehydration or hypovolemia, patients receiving concomitant antihypertensive therapy), patients with known cardiovascular disease (e.g., history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. The manufacturer states that brexpiprazole has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from premarketing clinical trials.

Falls

Brexpiprazole therapy may cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls; as a consequence, fractures or other injuries may occur. For patients with diseases or conditions or receiving other drugs that could exacerbate these effects, fall risk assessments should be completed when initiating antipsychotic treatment and periodically during long-term therapy.

Seizures

As with other antipsychotic agents, brexpiprazole may cause seizures. The risk of seizures is greatest in patients with a history of seizures or with conditions that lower the seizure threshold; such conditions may be more prevalent in older patients.

Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. The manufacturer recommends using brexpiprazole with caution in patients who may experience conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, dehydration, concomitant use of agents with anticholinergic activity).(See Advice to Patients.)

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents. Brexpiprazole should be used with caution in patients at risk for aspiration pneumonia.

Cognitive and Motor Impairment

Like other antipsychotic agents, brexpiprazole potentially may impair judgment, thinking, or motor skills. In short-term major depressive disorder studies, somnolence (including sedation and hypersomnia) was reported in 4% of patients receiving brexpiprazole with an antidepressant compared with 1% of patients receiving placebo with an antidepressant. In short-term, placebo-controlled schizophrenia studies, somnolence (including sedation and hypersomnia) was reported in 5% of patients receiving brexpiprazole compared with 3% of placebo recipients.(See Advice to Patients.)

Specific Populations

Pregnancy

There are no adequate and well-controlled studies to date of brexpiprazole use in pregnant women. In animals, brexpiprazole was not teratogenic but increased perinatal death in pups at dosages much higher than the maximum recommended human dosage.

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, 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.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and http://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/atypicalantipsychotic/.

Lactation

It is not known whether brexpiprazole is distributed into milk in humans. The drug is distributed into milk in rats. The effects of brexpiprazole on nursing infants and on milk production also are unknown. The benefits of brexpiprazole therapy to the woman as well as the benefits of breast-feeding to the infant should be weighed against the potential risk to the infant resulting from exposure to the drug or from the underlying maternal condition.

Pediatric Use

Safety and efficacy of brexpiprazole 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 brexpiprazole 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 trials of the efficacy of brexpiprazole did not include any patients 65 years of age and older to determine whether they respond differently than younger adults. In a safety, tolerability, and pharmacokinetics study in geriatric patients (70-85 years of age) with major depressive disorder, the pharmacokinetics of brexpiprazole were similar to those observed in younger adults.

The manufacturer of brexpiprazole states that dosage selection for geriatric patients should be cautious, usually starting at the lower end of the dosage range, reflecting the greater incidence of decreased hepatic, renal, and cardiac function and concomitant illness and other drug therapy in this population.

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death. 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. Brexpiprazole 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 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

Brexpiprazole is extensively metabolized in the liver. In individuals with mild, moderate, or severe hepatic impairment, brexpiprazole exposures were 26, 73, or 4% higher, respectively, than those in patients with normal hepatic function. Because greater exposure to the drug may increase the risk of adverse effects, a reduction in the maximum recommended dosage of brexpiprazole is recommended for patients with moderate or severe hepatic impairment (Child-Pugh score of 7 or higher).(See Dosage and Administration: Special Populations.)

Renal Impairment

Following a single 3-mg dose, brexpiprazole exposure was 72% higher in patients with severe renal impairment than in patients with normal renal function. In a population pharmacokinetic analysis, brexpiprazole exposures were similar between patients with mild renal impairment and those with normal renal function but exposure to the drug was 71% higher in patients with moderate renal impairment. Because greater exposure to the drug may increase the risk of adverse effects, a reduction in the maximum recommended dosage of brexpiprazole is recommended in patients with moderate or severe renal impairment (creatinine clearance less than 60 mL/minute) or end-stage renal disease.(See Dosage and Administration: Special Populations.)

Hemodialysis is not expected to affect plasma concentrations of brexpiprazole because the drug is highly bound to plasma proteins.

Poor CYP2D6 Metabolizers

Because higher concentrations of brexpiprazole have been observed in poor metabolizers of cytochrome P-450 (CYP) isoenzyme 2D6 than in extensive metabolizers, dosage adjustment of the drug is recommended in patients known to be poor metabolizers of CYP2D6. Approximately 8% of Caucasians and 3-8% of Blacks/African Americans cannot metabolize CYP2D6 substrates and are classified as poor CYP2D6 metabolizers.(See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving brexpiprazole as adjunctive therapy for major depressive disorder and at a higher frequency than reported with placebo include akathisia, headache, weight gain, extrapyramidal symptoms (excluding akathisia), somnolence, nasopharyngitis, tremor, anxiety, increased appetite, dizziness, fatigue, restlessness, constipation, and decreased blood cortisol concentration. Akathisia and restlessness were found to be dose related in placebo-controlled studies.

Adverse effects occurring in 2% or more of patients receiving brexpiprazole for treatment of schizophrenia and at a higher frequency than reported with placebo include akathisia, extrapyramidal symptoms (excluding akathisia), weight gain, diarrhea, dyspepsia, tremor, increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, and sedation.

Drug Interactions

Brexpiprazole is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6.

In vitro studies indicate that brexpiprazole and its principal major metabolite, DM-3411, are not potent inhibitors and/or inducers of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5.

In vitro studies indicate that brexpiprazole and its principal metabolite, DM-3411, are not clinically relevant substrates or inhibitors of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), organic anion transport proteins (OATP) 1B1 and 1B3, organic anion transporter 3 (OAT3), organic cation transporter 2 (OCT2), and multidrug and toxic compound extrusion (MATE) 1 and MATE2K.

Drugs Affecting Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions with brexpiprazole are possible with drugs that inhibit or induce CYP3A4 or CYP2D6.

Inhibitors of CYP3A4

Concomitant use of brexpiprazole with potent inhibitors of CYP3A4 (e.g., clarithromycin, itraconazole, ketoconazole) may result in substantially increased systemic exposure (area under the concentration-time curve [AUC]) of brexpiprazole. When the potent CYP3A4 inhibitor ketoconazole was administered concomitantly with brexpiprazole (single 2-mg dose), peak plasma concentrations and AUC of brexpiprazole were increased by approximately 1.2-fold and twofold, respectively.

Brexpiprazole dosage should be reduced by 50% of the usual dosage when used concurrently with potent CYP3A4 inhibitors. When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed. Brexpiprazole dosage should be reduced to 25% of the usual dosage when used concurrently with moderate or potent CYP3A4 inhibitors in patients who are poor metabolizers of CYP2D6. In patients taking moderate or potent CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, itraconazole) and moderate or potent CYP2D6 inhibitors (e.g., duloxetine, paroxetine, quinidine), brexpiprazole dosage also should be reduced to 25% of the usual dosage. Brexpiprazole dosage should be increased back to the original dosage when the CYP2D6 and CYP3A4 inhibitors are discontinued.(See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.)

Ketoconazole

Concomitant administration of ketoconazole, a potent CYP3A4 inhibitor, and brexpiprazole (single 2-mg dose) increased peak plasma concentrations and AUC of brexpiprazole by approximately 1.2-fold and twofold, respectively, compared with administration of brexpiprazole alone. Brexpiprazole dosage should be reduced by 50% when used concurrently with ketoconazole.

Inhibitors of CYP2D6

Concomitant use of brexpiprazole with potent CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine) may result in substantially increased systemic exposure to brexpiprazole. Brexpiprazole dosage should be reduced by 50% when used concurrently with potent CYP2D6 inhibitors. This dosage reduction is not necessary in patient receiving brexpiprazole for adjunctive treatment of major depressive disorder because CYP considerations have been taken into account for the general dosage recommendations. In patients taking moderate or potent CYP3A4 inhibitors (e.g., clarithromycin, fluconazole, itraconazole) and moderate or potent CYP2D6 inhibitors (e.g., duloxetine, paroxetine, quinidine), brexpiprazole dosage should be reduced to 25% of the usual dosage. Brexpiprazole dosage should be increased back to the original dosage when the CYP2D6 and CYP3A4 inhibitors are discontinued.(See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.)

Quinidine

Concomitant administration of quinidine, a potent CYP2D6 inhibitor, and brexpiprazole (single 2-mg dose) increased peak plasma concentration and AUC of brexpiprazole by approximately 1.1- and 1.9-fold, respectively, compared with administration of brexpiprazole alone. Except when used in the adjunctive treatment of major depressive disorder, brexpiprazole dosage should be reduced by 50% when used concurrently with quinidine.

Inducers of CYP3A4

Concomitant use of brexpiprazole with potent CYP3A4 inducers (e.g., rifampin, St. John's wort [Hypericum perforatum]) may result in substantially decreased systemic exposure of brexpiprazole. The usual brexpiprazole dosage should therefore be doubled over 1-2 weeks during concurrent therapy with potent CYP3A4 inducers; further dosage adjustment should be based on clinical response. If the potent CYP3A4 inducer is discontinued, the brexpiprazole dosage should be reduced back to the original dosage over 1-2 weeks.(See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.)

Rifampin

Concomitant administration of rifampin, a potent CYP3A4 inducer, and brexpiprazole (single 4-mg dose) decreased peak serum concentration and AUC of brexpiprazole by 40 and 73%, respectively. Brexpiprazole dosage should be doubled when used concomitantly with potent CYP3A4 inducers.(See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.)

Drugs Metabolized by Hepatic Microsomal Enzymes

The manufacturer states that no dosage adjustments are necessary if brexpiprazole is used concomitantly with substrates of CYP isoenzymes 3A4, 2B6, or 2D6.

Bupropion

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP2B6 substrate bupropion did not substantially affect the pharmacokinetics of bupropion.

Dextromethorphan

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP2D6 substrate dextromethorphan did not substantially affect the metabolism of dextromethorphan.

Lovastatin

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP3A4 substrate lovastatin did not substantially affect the pharmacokinetics of lovastatin.

Drugs Affecting Gastric pH

Concomitant administration of brexpiprazole (single 4-mg dose) with omeprazole did not have a clinically important effect on the pharmacokinetics of brexpiprazole.

Drugs that increase gastric pH (e.g., antacids, histamine H2-receptor antagonists, proton-pump inhibitors) are not expected to substantially affect the absorption of brexpiprazole following oral administration; therefore, dosage adjustment of brexpiprazole is not necessary during concomitant use of such drugs.

Hypotensive Agents

Because patients receiving brexpiprazole are at increased risk of orthostatic hypotension and syncope, monitoring of orthostatic vital signs is recommended in patients concomitantly receiving antihypertensive agents.(See Orthostatic Hypotension and Syncope under Warnings/Precautions: Other Warnings and Precautions, in Cautions and also see Advice to Patients.)

Protein-bound Drugs

Based on the results of in vitro studies, brexpiprazole protein binding does not appear to be affected by concurrent administration of other highly protein-bound drugs such as diazepam, digitoxin (no longer commercially available in the US), or warfarin. Therefore, clinically important drug interactions based on protein binding displacement appear to be unlikely with brexpiprazole.

Anticholinergic Agents

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

Fexofenadine

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the P-gp substrate fexofenadine did not affect the pharmacokinetics of fexofenadine. No dosage adjustment is necessary when brexpiprazole is used concomitantly with fexofenadine.

Rosuvastatin

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the BCRP substrate rosuvastatin did not affect the pharmacokinetics of rosuvastatin. No dosage adjustment is necessary when brexpiprazole is used concomitantly with rosuvastatin.

Ticlopidine

Concomitant administration of brexpiprazole (single 2-mg dose) with the potent CYP2B6 inhibitor ticlopidine did not affect the pharmacokinetics of brexpiprazole. No dosage adjustment is necessary when brexpiprazole is used concomitantly with ticlopidine or other CYP2B6 inhibitors.

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