VA Class:CN709

ATC Class:N05AX16

AHFS Class:

• Atypical Antipsychotics 28:16.08.04

Generic Name(s):

• Brexpiprazole

Chemical Name:

• 7-[4-(4-Benzo[ b ]thien-4-yl-1-piperazinyl)butoxy]-2(1 H )-quinolinone

Molecular Formula:

• C₂₅H₂₇N₃O₂S

Brexpiprazole is considered an atypical or second-generation antipsychotic agent.1,6,7,8

Adjunctive Therapy of Major Depressive Disorder

Brexpiprazole is used orally as an adjunct to antidepressants for the treatment of major depressive disorder.1,2,3,6

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.1,2,3 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.1,2,3 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.1,2,3 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.1 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.1,2,3,6 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.1

The manufacturer states that the need for continued therapy and appropriate dosage of brexpiprazole should be reassessed periodically in patients with major depressive disorder.1 (See Dosage under Dosage and Administration.)

Schizophrenia

Brexpiprazole is used for the treatment of schizophrenia.1,4,5,6,96 Schizophrenia is a chronic major psychotic disorder that frequently has devastating effects on various aspects of the patient's life and is associated with an increased risk of suicide and increased overall mortality.28,30,69 The principal manifestations of schizophrenia usually are described in terms of positive, negative, and cognitive symptoms.28,33,34 Positive (i.e., psychotic) symptoms include hallucinations and delusions, while negative symptoms include decreases in emotional expression, initiation of goal-directed behavior (avolition), speech productivity (alogia), ability to experience pleasure from external stimuli (anhedonia), and apparent interest in social interactions (asociality).28,30,34 Cognitive symptoms include impairments in attention, concentration, and memory.30,33,34 Diagnostic criteria for schizophrenia also may include disorganized speech (e.g., frequent derailment or incoherence) or grossly disorganized or catatonic behavior.69

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.1,4,5,6 Both studies evaluated fixed brexpiprazole dosages of 2 or 4 mg once daily.1,4,5 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.1 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.1,4,5 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 3.1,4,5 An examination of population subgroups did not reveal any clear evidence of differential responsiveness to the drug based on age, gender, or race.1

Efficacy and safety of brexpiprazole in the maintenance treatment of schizophrenia have been established in a randomized, multicenter withdrawal study (study 5).1,96 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.1,96 The primary efficacy end point in this study was time from randomization to impending relapse during the double-blind phase.1,96 A prespecified interim analysis demonstrated a substantially longer time to relapse in patients randomized to brexpiprazole therapy compared with the placebo recipients.1,96 The study was therefore terminated early because maintenance of efficacy had been demonstrated.1,96 Long-term brexpiprazole therapy also was found to be well tolerated in this study.96

Antipsychotic therapy is integral to the management of patients with schizophrenia,28,29,31 both for management of acute psychotic symptoms and for maintenance treatment to prevent symptom recurrence.28,29,30,31,32 The American Psychiatric Association (APA) and other experts consider antipsychotic agents (i.e., first- and second-generation antipsychotic agents) to be first-line drugs for the management of schizophrenia (including first psychotic episodes).28,29,31,32 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 antipsychotic agent will have superior efficacy compared with another agent, although meaningful differences in response may be observed in individual patients.28 Therefore, initial choice of an antipsychotic agent should be individualized, and generally be made in the context of shared decision-making, taking into consideration multiple patient- and drug-related factors, including adverse effect profiles, concurrent medical conditions or risk factors, potential for drug interactions, and potential pharmacogenomic considerations, as well as the patient's preferences, prior responses to treatment, available formulations, and cost.28,29,30,31,32 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 another drug with different receptor binding or adverse effect profile.28,70,71,72

The APA recommends that patients with schizophrenia whose symptoms have improved with an antipsychotic agent continue to receive such therapy.28 The APA also suggests that patients whose symptoms have improved with an antipsychotic agent continue to be treated with the same antipsychotic agent; however, some circumstances (e.g., patient preferences, drug availability, adverse effects) may necessitate a change in antipsychotic agent.28 Drug therapy should be used as part of a comprehensive, patient-centered treatment plan that includes evidence-based nonpharmacologic and pharmacologic treatments for schizophrenia.28,30 Clinicians may consult APA's Practice Guideline for the Treatment of Patients with Schizophrenia (available at [Web]) for additional information on the treatment of schizophrenia.28

For additional information on the symptomatic management of schizophrenia, including treatment recommendations, see Schizophrenia and Other Psychotic Disorders under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Administration

Brexpiprazole is commercially available as tablets, which are administered orally once daily without regard to meals.1 (See Description.)

Patients receiving brexpiprazole should be monitored for possible worsening of depression and emergence of suicidal thoughts or behaviors, especially at the beginning of therapy or during periods of dosage adjustments.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under 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.1 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.1 The maximum recommended dosage of brexpiprazole for the adjunctive treatment of major depressive disorder is 3 mg daily.1

The manufacturer states that the need for continued therapy with brexpiprazole and the appropriate dosage of the drug should be reassessed periodically.1

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 5-7.1 Based on individual patient response and tolerability, the dosage may be increased to 4 mg once daily on day 8.1 The recommended target dosage of brexpiprazole for the treatment of schizophrenia is 2-4 mg once daily.1 The maximum recommended dosage of the drug for the treatment of schizophrenia is 4 mg daily.1

In patients with schizophrenia whose symptoms have improved with an antipsychotic agent, continued treatment (i.e., maintenance therapy) with an antipsychotic agent is recommended to reduce the risk of relapse.28,29,30,31 The APA suggests that such patients continue to be treated with the same antipsychotic agent that was effective during acute treatment.28 Some experts have recommended maintenance antipsychotic therapy for at least 1-2 years after the first psychotic episode29,30,31 and for 2-5 years or longer following recurrent episodes.30,31,32 Indefinite maintenance antipsychotic treatment may be necessary in many cases; however, the benefits and risks of continued antipsychotic therapy should be assessed periodically in the context of shared decision-making, taking into consideration each patient's risk of relapse, drug-associated adverse effects, course of disease, and the specific goals and needs of each patient.28,29,30,32

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.1 (See Renal Impairment under Cautions.)

The manufacturer does not provide any specific dosage recommendations for brexpiprazole in patients with mild hepatic impairment.1 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.1 (See Hepatic Impairment under 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.1 (See Geriatric Use under Cautions.)

Dosage adjustment is not required based on gender, race, or smoking status.1

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.1 (See Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions.)

Patients who are known CYP2D6 poor metabolizers should receive 50% of the usual brexpiprazole dosage, since CYP2D6 poor metabolizers have higher concentrations of brexpiprazole than extensive metabolizers (see Description).1 Such patients who are also taking moderate or potent CYP3A4 inhibitors should receive 25% of the usual brexpiprazole dosage.1

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).1 When the potent CYP2D6 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed.1 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.1 (See Adjunctive Therapy of Major Depressive Disorder under Dosage and Administration and also see Drugs Affecting Hepatic Microsomal Enzymes under Drug Interactions.)

Brexpiprazole dosage should be reduced to 50% of the usual dosage when used concurrently with potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole).1 When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed.1

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.1 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.1

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.1,10 When the potent CYP3A4 inducer is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed over 1-2 weeks.1

Contraindications

Known hypersensitivity to brexpiprazole or any components in the formulation.1 Rash, facial swelling, urticaria, and anaphylaxis have been reported in patients receiving brexpiprazole.1

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.1 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.1 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.1 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.1 The manufacturer states that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Adverse Cerebrovascular Events, including Stroke, in Geriatric Patients with Dementia-related Psychosis, and also see Geriatric Use under Cautions.)

Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Antidepressants may increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults.1,95 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 suicidal thoughts and behaviors in children, adolescents, and young adults (24 years of age or younger) receiving antidepressants for major depressive disorder and other indications.1 Although the risk varied considerably between drugs, an increased risk was identified for most antidepressants studied.1 Differences in absolute risk of suicidal thoughts and behaviors were seen across the different indications, with the highest incidence in patients with major depressive disorder.1 An increased risk of suicidal thoughts and behaviors 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.1 Because the studies analyzed were short-term, it is not known whether the increased risk of suicidal thoughts or behaviors in such patients continues with longer-term antidepressant treatment (i.e., beyond 4 months).1 However, substantial evidence from placebo-controlled maintenance studies in adults with major depressive disorder indicates that antidepressants delay the recurrence of depression.1 Safety and efficacy of brexpiprazole have not been established in pediatric patients.1

All patients being treated with antidepressants for any indication should be closely monitored for worsening of depression and emergence of suicidal thoughts and behaviors, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments.1 Family members and caregivers of patients being treated with antidepressants also should be advised to monitor patients for changes in behavior and to alert a health-care provider if such changes occur.1 Consideration should be given to changing the therapeutic regimen or discontinuing therapy in patients whose depression is persistently worse or who are experiencing emergent suicidal thoughts or behaviors.1

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.1 The manufacturer states that brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis and also see Geriatric Use under 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, including brexpiprazole.1 If NMS is suspected, antipsychotic therapy should be immediately discontinued and intensive symptomatic treatment and monitoring should be provided.1 (See Advice to Patients.) For additional information on NMS, see Neuroleptic Malignant Syndrome under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

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.1 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.1 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.1

The American Psychiatric Association (APA) currently recommends that patients with schizophrenia who are receiving antipsychotic agents be assessed clinically for abnormal involuntary movements at baseline and at each follow-up visit and that assessment with a structured instrument (e.g., the Abnormal Involuntary Movement Scale [AIMS], Dyskinesia Identification System: Condensed User Scale [DISCUS]) occur at least every 6 months in patients considered at high risk for tardive dyskinesia (including patients older than 55 years of a women; individuals with a mood disorder, substance use disorder, intellectual disability, or CNS injury; individuals with high cumulative exposure to antipsychotic medications, particularly high-potency dopamine D₂ receptor antagonists; and patients who experience acute dystonic reactions, clinically significant parkinsonism, or akathisia) or at least every 12 months in other patients as well as if a new onset or exacerbation of preexisting movements is observed at any follow-up visit.28 In some jurisdictions, the frequency of monitoring for involuntary movements in individuals receiving antipsychotic agents may also be subject to local regulations.28

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.1

APA recommends that patients who have moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy be treated with a vesicular monoamine transporter 2 (VMAT2) inhibitor (e.g., deutetrabenazine, valbenazine, tetrabenazine); such treatment may also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial functioning.28 (See Deutetrabenazine 28:56, Tetrabenazine 28:56, and Valbenazine 28:56.)

For additional information on tardive dyskinesia, see Tardive Dyskinesia under Cautions: Nervous System Effects, in the Phenothiazines General Statement 28:16.08.24.

Metabolic Changes

Atypical antipsychotic agents, including brexpiprazole, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and body weight gain.1 While all of these drugs produce some metabolic changes, each drug has its own specific risk profile.1 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under 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.1 Hyperglycemia has been reported in patients treated with brexpiprazole.1 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.1,26,27,64 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.1 In longer-term studies, 9-10% of brexpiprazole-treated patients with normal or borderline fasting glucose concentrations experienced shifts to high fasting glucose concentrations.1

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.1 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.1 (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.1

For further information on managing the risk of hyperglycemia and diabetes mellitus associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions, in Clozapine 28:16.08.04.

Dyslipidemia

Atypical antipsychotics cause adverse alterations in lipid parameters.1 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.1,11 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.1 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.1

Weight Gain

Weight gain has been observed with atypical antipsychotic therapy.1 Monitoring of weight at baseline and frequently thereafter is recommended in patients receiving brexpiprazole.1

Brexpiprazole generally appears to be associated with moderate weight gain.1,11 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.1 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.1

For additional information on metabolic effects associated with atypical antipsychotic agents, see Hyperglycemia and Diabetes Mellitus under Cautions.

Pathological Gambling and Other Compulsive Behaviors

Postmarketing case reports have suggested that patients receiving brexpiprazole may experience intense urges, particularly for gambling, and the inability to control these urges.1 Other compulsive urges reported include sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors.1 In some, but not all, cases, these uncontrollable urges reportedly stopped when the brexpiprazole dosage was reduced or the drug was discontinued.1

Brexpiprazole-associated compulsive behaviors may result in harm to the patient or others if not recognized.1 Because patients may not recognize such behaviors as abnormal, clinicians should specifically ask patients or caregivers whether any new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges have developed during treatment with the drug.1 If a patient develops such urges or other compulsive behaviors while receiving brexpiprazole, consideration should be given to reducing the dosage or discontinuing the drug.1 (See Advice to Patients.)

Leukopenia, Neutropenia, and Agranulocytosis

Leukopenia and neutropenia have been reported during therapy with antipsychotic agents.1,78 Agranulocytosis (including fatal cases) has been reported with other antipsychotic agents.1

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.1,78 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.1 Brexpiprazole should be discontinued at the first sign of a clinically important decline in leukocyte count in the absence of other causative factors.1

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.1 In patients with severe neutropenia (ANC less than 1000/mm³), brexpiprazole should be discontinued and the leukocyte count monitored until recovery occurs.1 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.78

Orthostatic Hypotension and Syncope

Atypical antipsychotic agents cause orthostatic hypotension and syncope, perhaps because of their α₁-adrenergic blocking activity.1 The risk of these adverse effects generally is greatest during initial dosage titration and when the dosage is increased.1

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.1 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.1

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.1 The manufacturer states that brexpiprazole has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease.1 Such patients were excluded from premarketing clinical trials.1

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.1 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.1

Seizures

As with other antipsychotic agents, brexpiprazole may cause seizures.1 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.1

Body Temperature Dysregulation

Atypical antipsychotics may disrupt the body's ability to reduce core body temperature.1 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).1 (See Advice to Patients.)

Dysphagia

Esophageal dysmotility and aspiration have been associated with the use of antipsychotic agents.1 Brexpiprazole should be used with caution in patients at risk for aspiration pneumonia.1

Cognitive and Motor Impairment

Like other antipsychotic agents, brexpiprazole potentially may impair judgment, thinking, or motor skills.1 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.1 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.1 (See Advice to Patients.)

Specific Populations

Pregnancy

There are no adequate and well-controlled studies to date of brexpiprazole use in pregnant women.1 In animals, brexpiprazole was not teratogenic but increased perinatal death in pups at dosages much higher than the maximum recommended human dosage.1

Neonates exposed to antipsychotic agents during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery.1,79,80,81 Symptoms reported to date have included agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorder.1,79,80,81 Neonates exhibiting such symptoms should be monitored.81 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.1,79,80,81 For further information on extrapyramidal and withdrawal symptoms in neonates, see Cautions: Pregnancy, Fertility, and Lactation, in the Phenothiazines General Statement 28:16.08.24.

National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and [Web].1

Lactation

It is not known whether brexpiprazole is distributed into milk in humans.1 The drug is distributed into milk in rats.1 The effects of brexpiprazole on nursing infants and on milk production also are unknown.1 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.1

Pediatric Use

Safety and efficacy of brexpiprazole in pediatric patients have not been established.1

Antidepressants may increase the risk of suicidal thoughts and behaviors in children, adolescents, and young adults.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under 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.1 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.1

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.1

Geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1 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.1 Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis (see Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions).1 For additional information on the use of antipsychotic agents in the management of dementia-related psychosis, see Geriatric Considerations under Uses: Psychotic Disorders, in the Phenothiazines General Statement 28:16.08.24.

Hepatic Impairment

Brexpiprazole is extensively metabolized in the liver.1,10 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.1,10 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).1,10 (See Special Populations under Dosage and Administration.)

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.1,10 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.1,10 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.1,10 (See Special Populations under Dosage and Administration.)

Hemodialysis is not expected to affect plasma concentrations of brexpiprazole because the drug is highly bound to plasma proteins.1

CYP2D6 Poor 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 CYP2D6 poor metabolizers.1 Approximately 8% of Caucasians and 3-8% of Blacks/African Americans cannot metabolize CYP2D6 substrates and are classified as CYP2D6 poor metabolizers.1 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration.)

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,1,2,3 headache, 1,2,3 weight gain,1,2,3 extrapyramidal symptoms (excluding akathisia),1,2,3 somnolence,1,2,3 nasopharyngitis,1,3 tremor,1,3 anxiety,1,2,3 increased appetite,1 dizziness,1 fatigue,1,2,3 restlessness,1,2,3 constipation,1 and decreased blood cortisol concentration.1 Akathisia and restlessness were found to be dose related in placebo-controlled studies.1

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,1,4,5 extrapyramidal symptoms (excluding akathisia),1 weight gain,1,4,5 diarrhea,1,4 dyspepsia,1,5 tremor,1 increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations,1,5 and sedation.1,4,5

Brexpiprazole is metabolized principally by cytochrome P-450 (CYP) isoenzymes 3A4 and 2D6.1

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 3A4/5.1,10

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.1,10

Drugs Affecting Hepatic Microsomal Enzymes

Clinically important pharmacokinetic interactions with brexpiprazole are possible with drugs that inhibit or induce CYP3A4 or CYP2D6.1

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.1 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.1,10

Brexpiprazole dosage should be reduced by 50% of the usual dosage when used concurrently with potent CYP3A4 inhibitors.1 When the potent CYP3A4 inhibitor is withdrawn from combined therapy, the original brexpiprazole dosage may be resumed.1 Brexpiprazole dosage should be reduced to 25% of the usual dosage when used concurrently with moderate or potent CYP3A4 inhibitors in patients who are CYP2D6 poor metabolizers.1 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.1 Brexpiprazole dosage should be increased back to the original dosage when the CYP2D6 and CYP3A4 inhibitors are discontinued.1 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration.)

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.1,10 Brexpiprazole dosage should be reduced by 50% when used concurrently with ketoconazole.1,10

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.1 Brexpiprazole dosage should be reduced by 50% when used concurrently with potent CYP2D6 inhibitors.1 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.1 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.1 Brexpiprazole dosage should be increased back to the original dosage when the CYP2D6 and CYP3A4 inhibitors are discontinued.1 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration.)

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.10 Except when used in the adjunctive treatment of major depressive disorder, brexpiprazole dosage should be reduced by 50% when used concurrently with quinidine.1,10

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.1,10 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.1,10 If the potent CYP3A4 inducer is discontinued, the brexpiprazole dosage should be reduced back to the original dosage over 1-2 weeks.1 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration.)

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.10 Brexpiprazole dosage should be doubled when used concomitantly with potent CYP3A4 inducers.1,10 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration.)

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 2D6.1,10

Bupropion

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP2B6 substrate bupropion did not substantially affect the pharmacokinetics of bupropion.1,10

Dextromethorphan

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP2D6 substrate dextromethorphan did not substantially affect the metabolism of dextromethorphan.1,10

Lovastatin

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the CYP3A4 substrate lovastatin did not substantially affect the pharmacokinetics of lovastatin.1,10

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.1,10

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.1,10

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.1 (See Orthostatic Hypotension and Syncope under 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.1,10 Therefore, clinically important drug interactions based on protein binding displacement appear to be unlikely with brexpiprazole.1,10

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.1 (See Body Temperature Dysregulation under 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.1,10 No dosage adjustment is necessary when brexpiprazole is used concomitantly with fexofenadine.1

Rosuvastatin

Concomitant administration of brexpiprazole (2 mg daily for 11 days) with the BCRP substrate rosuvastatin did not affect the pharmacokinetics of rosuvastatin.1,10 No dosage adjustment is necessary when brexpiprazole is used concomitantly with rosuvastatin.1

Ticlopidine

Concomitant administration of brexpiprazole (single 2-mg dose) with the potent CYP2B6 inhibitor ticlopidine did not affect the pharmacokinetics of brexpiprazole.1,10 No dosage adjustment is necessary when brexpiprazole is used concomitantly with ticlopidine or other CYP2B6 inhibitors.1

Description

Brexpiprazole is considered an atypical or second-generation antipsychotic agent; the drug is structurally similar to aripiprazole.1,6,7,8 The exact mechanism of action of brexpiprazole in major depressive disorder and schizophrenia has not been fully elucidated but is thought to be mediated through a combination of partial agonist activity at dopamine type 2 (D₂) and serotonin type 1A (5-HT_1A) receptors and antagonist activity at serotonin type 2A (5-HT_2A) receptors.1,6

Brexpiprazole, like aripiprazole, differs from many other atypical antipsychotic agents (which primarily antagonize D₂ receptors) because it is a D₂ partial agonist; these drugs also are partial agonists at 5-HT_1A receptors and antagonists at 5-HT_2A receptors.4,6,7,8,9 Compared with aripiprazole, brexpiprazole appears to have lower intrinsic activity at D₂ receptors and higher activity at 5-HT_1A and 5-HT_1B receptors and demonstrates stronger antagonism at 5-HT_2A receptors.2,4,7,8,9 Brexpiprazole also is a partial agonist at D₃ receptors and an antagonist at 5-HT_2B, 5-HT₇, and α_1A-, α_1B-, α_1D-, and α_2C-adrenergic receptors.1,6,7,8,9 It has been suggested that the lower activity of brexpiprazole compared with aripiprazole at D₂ receptors may reduce the potential for certain D₂ partial agonist-mediated adverse effects (e.g., akathisia, insomnia, restlessness, nausea).4 In addition, brexpiprazole exhibits moderate affinity for histamine (H₁) receptors, which are associated with sedation, and very low affinity for muscarinic (M₁) receptors.1,4,9

Following oral administration of brexpiprazole tablets, peak plasma concentrations of the drug occur within 4 hours.1 Administration of the tablets with a high-fat meal does not substantially affect peak plasma concentration or systemic exposure of brexpiprazole.1 The absolute oral bioavailability of brexpiprazole tablets is 95%.1 Steady-state plasma concentrations of the drug are achieved within 10-12 days.1 Higher concentrations of brexpiprazole have been observed in cytochrome P-450 (CYP) isoenzyme 2D6 poor metabolizers compared with CYP2D6 extensive metabolizers.1 (See Hepatic Microsomal Enzyme Considerations under Dosage and Administration: Special Populations.) Brexpiprazole has a large volume of distribution, which suggests extravascular distribution, and the drug is highly bound (greater than 99%) to plasma proteins (albumin and α₁-acid glycoprotein).1 The drug is extensively metabolized, principally by CYP3A4 and CYP2D6, to its principal metabolite, DM-3411.1 DM-3411 does not appear to contribute to the therapeutic effects of brexpiprazole.1 The elimination half-lives of brexpiprazole and DM-3411 are approximately 91 and 86 hours, respectively.1 Following administration of a single radiolabeled dose of brexpiprazole, approximately 46 and 25% of the dose is recovered in feces and urine (approximately 14% and less than 1% excreted unchanged), respectively.1

Advice to Patients

Importance of advising patients and/or caregivers to read the patient information (medication guide).1

Importance of advising patients that brexpiprazole tablets may be taken with or without food.1 Importance of also advising patients of the importance of following dosage escalation instructions.1

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1,28 Patients and caregivers also should be informed that brexpiprazole is not approved for treating geriatric patients with dementia-related psychosis.1

Risk of suicidal thoughts and behaviors; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, especially during the first few months of therapy or during periods of dosage adjustment.1 (See Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults under Cautions.)

Importance of informing patients and caregivers about the risk of neuroleptic malignant syndrome (NMS); importance of immediately contacting clinician or seeking emergency medical attention if signs and symptoms of this rare but potentially life-threatening syndrome develop (e.g., high fever, muscle stiffness, sweating, fast or irregular heart beat, change in blood pressure, confusion, kidney damage).1

Importance of advising patients about the signs and symptoms of tardive dyskinesia.1 Importance of contacting a healthcare professional if abnormal muscle movements occur.1

Importance of informing patients and caregivers about the risk of metabolic changes (e.g., hyperglycemia and diabetes mellitus, dyslipidemia, weight gain) with brexpiprazole and the need for specific monitoring for such changes during therapy.1 Importance of patients and caregivers being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness) and monitoring all patients receiving brexpiprazole for these symptoms.1 Importance of informing patients who are diagnosed with diabetes or those with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during brexpiprazole therapy.1 Importance of informing patients that clinical monitoring of weight is recommended during brexpiprazole therapy.1

Risk of pathological gambling and other compulsive behaviors.1 Importance of advising patients and caregivers of the possibility that they may experience compulsive urges to shop, intense urges to gamble, compulsive sexual urges, binge eating and/or other compulsive urges and the inability to control these urges during brexpiprazole therapy.1 In some cases, but not all, the urges reportedly stopped when the dosage was reduced or the drug was discontinued.1

Risk of leukopenia, neutropenia, and agranulocytosis.1 Importance of advising patients with a preexisting low leukocyte count or a history of drug-induced leukopenia/neutropenia that they should have their complete blood cell (CBC) count monitored during brexpiprazole therapy.1

Importance of informing patients about the risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage.1

Importance of avoiding overheating or dehydration.1

Because somnolence and impairment of judgment, thinking, or motor skills may be associated with brexpiprazole, patients should be cautioned about performing activities requiring mental alertness, such as driving or operating hazardous machinery, while taking brexpiprazole until they gain experience with the drug's effects.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs or herbal supplements (see Drug Interactions), as well as any concomitant illnesses (e.g., cardiovascular disease, diabetes mellitus, seizures).1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1,81 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy, and encouraging enrollment in the pregnancy registry (see Pregnancy under Cautions).1,81 Importance of advising patients not to stop taking brexpiprazole if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.81

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Otsuka America Pharmaceutical, Inc. Rexulti^® (brexpiprazole) tablets prescribing information. Rockville, MD; 2020 Mar

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