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Brexpiprazole

Medically reviewed by Drugs.com. Last updated on Mar 25, 2020.

Pronunciation

(breks PIP ray zole)

Index Terms

  • OPC-34712

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Rexulti: 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg [contains corn starch]

Brand Names: U.S.

  • Rexulti

Pharmacologic Category

  • Second Generation (Atypical) Antipsychotic

Pharmacology

Brexpiprazole exhibits partial agonist activity for 5-HT1A and D2 receptors and antagonist activity for 5-HT2A receptors.

Distribution

Vd: IV: 1.56 L/kg

Metabolism

Hepatic, primarily by CYP3A4 and CYP2D6; major metabolite, DM-3411 (inactive)

Excretion

Feces (46%, ~14% of the total dose as unchanged drug); urine (25%, <1% of the total dose as unchanged drug)

Time to Peak

Plasma: Within 4 hours

Half-Life Elimination

Terminal: Brexpiprazole: 91 hours; DM-3411: 86 hours

Protein Binding

>99%, primarily to serum albumin and alpha1-acid glycoprotein

Special Populations: Renal Function Impairment

AUC was increased in patients with renal impairment (CrCl <60 mL/minute) compared to patients with normal renal function.

Special Populations: Hepatic Function Impairment

AUC increased in patients with moderate to severe hepatic impairment.

Special Populations Note

CYP2D6 poor metabolizers: Increased Cmax is observed in CYP2D6 poor metabolizers compared to normal CYP2D6 metabolizers.

Use: Labeled Indications

Major depressive disorder: Adjunctive treatment of major depressive disorder (MDD)

Schizophrenia: Treatment of schizophrenia

Off Label Uses

Agitation/aggression and psychosis associated with dementia, severe

Data from a randomized, control trial suggest that brexpiprazole may be beneficial for patients with Alzheimer disease and symptoms of agitation or aggression [Grossberg 2020].

Based on the American Psychiatric Association practice guideline on the use of antipsychotics to treat agitation or psychosis in patients with dementia, antipsychotics, such as brexpiprazole, may be considered for the treatment of agitation and psychosis in certain patients with dementia; however, evidence for efficacy is modest and use should be limited to patients whose symptoms are dangerous, severe, or cause significant patient distress due to safety risks associated with antipsychotic use.

Contraindications

Hypersensitivity (eg, anaphylaxis, facial swelling, rash, urticaria) to brexpiprazole or any component of the formulation

Dosing: Adult

Agitation/aggression and psychosis associated with dementia, severe (alternative agent) (off-label use):

Note: For short-term adjunctive use while addressing underlying cause(s) of severe symptoms. In patients without a clinically significant response after an adequate trial (eg, up to 4 weeks), taper and withdraw therapy. Only continue in patients with demonstrated benefit; attempt to taper and withdraw at regular intervals (eg, within 4 months of initiation). In severe agitation associated with dementia with Lewy bodies, antipsychotics are generally avoided (APA [Reus 2016]).

Oral: Initial: 0.25 mg once daily for 3 days, then 0.5 mg once daily for 10 days, then 1 mg once daily for 2 weeks, then increase to target dose of 2 mg once daily (Grossberg 2020).

Major depressive disorder (adjunct to antidepressants): Oral: Initial: 0.5 mg or 1 mg once daily; titrate at weekly intervals based on response and tolerability to 1 mg once daily (if initial dose is 0.5 mg), followed by 2 mg once daily; maximum daily dose: 3 mg.

Schizophrenia: Oral: Initial: 1 mg once daily for 4 days, titrate based on response and tolerability to 2 mg once daily for 3 days, followed by 4 mg on day 8; target dose: 2 to 4 mg/day; maximum daily dose: 4 mg.

Dosage adjustment for CYP2D6 poor metabolizers: Administer 1/2 of the usual dose; in patients also taking moderate/strong CYP3A4 inhibitors, administer 1/4 of the usual dose.

Dosage adjustment with concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Discontinuation of therapy: American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid withdrawal symptoms and minimize the risk of relapse (APA [Lehman 2004]; Cerovecki 2013; CPA 2005; WFSBP [Hasan 2012]); risk for withdrawal symptoms may be highest with highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). When stopping antipsychotic therapy in patients with schizophrenia, the CPA guidelines recommend a gradual taper over 6 to 24 months, and the APA guidelines recommend reducing the dose by 10% each month (APA [Lehman 2004]; CPA 2005). Continuing anti-parkinsonism agents for a brief period after discontinuation may prevent withdrawal symptoms (Cerovecki 2013). When switching antipsychotics, three strategies have been suggested: Cross-titration (gradually discontinuing the first antipsychotic while gradually increasing the new antipsychotic), overlap and taper (maintaining the dose of the first antipsychotic while gradually increasing the new antipsychotic, then tapering the first antipsychotic), and abrupt change (abruptly discontinuing the first antipsychotic and either increasing the new antipsychotic gradually or starting it at a treatment dose). Evidence supporting ideal switch strategies and taper rates is limited, and results are conflicting (Cerovecki 2013; Remington 2005).

Dosing: Geriatric

Refer to adult dosing.

Administration

Oral: Administer with or without food.

Storage

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abametapir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Acetylcholinesterase Inhibitors (Central): May enhance the neurotoxic (central) effect of Antipsychotic Agents. Severe extrapyramidal symptoms have occurred in some patients. Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Monitor therapy

Amisulpride (Oral): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk of neuroleptic malignant syndrome may be increased. Avoid combination

Amphetamines: Antipsychotic Agents may diminish the stimulatory effect of Amphetamines. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Anti-Parkinson Agents (Dopamine Agonist): Antipsychotic Agents (Second Generation [Atypical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Consider therapy modification

Aprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Azelastine (Nasal): May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Management: Use caution if coadministering blonanserin and CNS depressants; dose reduction of the other CNS depressant may be required. Strong CNS depressants should not be coadministered with blonanserin. Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

BuPROPion: Brexpiprazole may enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual dose with bupropion; reduce to 25% of usual if used with both bupropion and a strong or moderate CYP3A4 inhibitor. These recommendations do not apply if treating major depressive disorder. Monitor for seizures. Consider therapy modification

Cabergoline: May diminish the therapeutic effect of Antipsychotic Agents. Avoid combination

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Brexpiprazole. Management: If brexpiprazole is to be used together with both a moderate CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor, the brexpiprazole dose should be reduced to 25% of the usual dose when treating indications other than major depressive disorder. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder Consider therapy modification

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Brexpiprazole. Monitor therapy

CYP3A4 Inducers (Strong): May decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with a strong CYP3A4 inducer, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if the strong CYP3A4 inducer is discontinued. Consider therapy modification

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Brexpiprazole. Management: The brexpiprazole dose should be reduced to 25% of usual if used together with both a moderate CYP3A4 inhibitor and a strong or moderate CYP2D6 inhibitor, or if a moderate CYP3A4 inhibitor is used in a CYP2D6 poor metabolizer. Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose 50% with strong CYP3A4 inhibitors; reduce to 25% of usual if used with both a strong CYP3A4 inhibitor and a CYP2D6 inhibitor in patients not being treated for MDD, or strong CYP3A4 inhibitor used in a CYP2D6 poor metabolizer. Consider therapy modification

Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to concomitant therapy when possible. If concomitant therapy cannot be avoided, monitor for reduced clinical effects of the CYP3A4 substrate. Consider therapy modification

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Deutetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, the risk for akathisia, parkinsonism, or neuroleptic malignant syndrome may be increased. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Consider therapy modification

Duvelisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Management: Reduce the dose of CNS depressants when combined with flunitrazepam and monitor patients for evidence of CNS depression (eg, sedation, respiratory depression). Use non-CNS depressant alternatives when available. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fosnetupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Guanethidine: Antipsychotic Agents may diminish the therapeutic effect of Guanethidine. Monitor therapy

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic anticonvulsants. Consider therapy modification

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lithium: May enhance the neurotoxic effect of Antipsychotic Agents. Lithium may decrease the serum concentration of Antipsychotic Agents. Specifically noted with chlorpromazine. Monitor therapy

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mequitazine: Antipsychotic Agents may enhance the arrhythmogenic effect of Mequitazine. Management: Consider alternatives to one of these agents when possible. While this combination is not specifically contraindicated, mequitazine labeling describes this combination as discouraged. Consider therapy modification

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce the usual dose of CNS depressants by 50% if starting methotrimeprazine until the dose of methotrimeprazine is stable. Monitor patient closely for evidence of CNS depression. Consider therapy modification

Methylphenidate: Antipsychotic Agents may enhance the adverse/toxic effect of Methylphenidate. Methylphenidate may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Metoclopramide: May enhance the adverse/toxic effect of Antipsychotic Agents. Avoid combination

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

MetyroSINE: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

MiFEPRIStone: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Minimize doses of CYP3A4 substrates, and monitor for increased concentrations/toxicity, during and 2 weeks following treatment with mifepristone. Avoid cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. Consider therapy modification

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Netupitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Oxybate Salt Products: CNS Depressants may enhance the CNS depressant effect of Oxybate Salt Products. Management: Consider alternatives to this combination when possible. If combined, dose reduction or discontinuation of one or more CNS depressants (including the oxybate salt product) should be considered. Interrupt oxybate salt treatment during short-term opioid use Consider therapy modification

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Piribedil: Antipsychotic Agents may diminish the therapeutic effect of Piribedil. Piribedil may diminish the therapeutic effect of Antipsychotic Agents. Management: Use of piribedil with antiemetic neuroleptics is contraindicated, and use with antipsychotic neuroleptics, except for clozapine, is not recommended. Avoid combination

Quinagolide: Antipsychotic Agents may diminish the therapeutic effect of Quinagolide. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Serotonergic Agents (High Risk): May enhance the adverse/toxic effect of Antipsychotic Agents. Specifically, serotonergic agents may enhance dopamine blockade, possibly increasing the risk for neuroleptic malignant syndrome. Antipsychotic Agents may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

St John's Wort: May decrease the serum concentration of Brexpiprazole. Management: If brexpiprazole is used together with St John's wort, the brexpiprazole dose should gradually be doubled over the course of 1 to 2 weeks. Decrease brexpiprazole to original dose over 1 to 2 weeks if St John's wort is discontinued. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Sulpiride: Antipsychotic Agents may enhance the adverse/toxic effect of Sulpiride. Avoid combination

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tetrabenazine: May enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.

>10%:

Endocrine & metabolic: Increased serum triglycerides (<500 mg/dL: 8% to 13%; ≥500 mg/dL: <1%), weight gain (3% to 11%)

Nervous system: Akathisia (4% to 14%; dose related)

1% to 10%:

Dermatologic: Hyperhidrosis (≥1%)

Endocrine & metabolic: Decreased cortisol (major depressive disorder: 3% to 4%), increased serum prolactin (≥1%)

Gastrointestinal: Abdominal pain (≥1%), constipation (major depressive disorder: 2% to 3%), diarrhea (schizophrenia: 3%), dyspepsia (schizophrenia: 3% to 6%), flatulence (≥1%), increased appetite (major depressive disorder: 3%), nausea (≥1%), sialorrhea (≥1%), xerostomia (≥1%)

Genitourinary: Urinary tract infection (≥1%)

Nervous system: Abnormal dreams (≥1%), anxiety (major depressive disorder: 2% to 4%), dizziness (major depressive disorder: 2% to 5%), drowsiness (4% to 6%), drug-induced extrapyramidal reaction (5% to 6%), fatigue (major depressive disorder: 3% to 5%), headache (major depressive disorder: 9%), insomnia (≥1%), restlessness (major depressive disorder: 2% to 4%; dose-related), sedated state (schizophrenia: 2% to 3%)

Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen (schizophrenia: 2% to 4%), myalgia (≥1%), tremor (2% to 5%)

Ophthalmic: Blurred vision (≥1%)

Respiratory: Nasopharyngitis (major depressive disorder: 3% to 7%)

<1%: Cardiovascular: Orthostatic hypotension, syncope

Frequency not defined:

Endocrine & metabolic: Hyperglycemia

Nervous system: Dystonia (excluding akathisia, occur more frequently with higher dosing), suicidal ideation, suicidal tendencies

Postmarketing:

Endocrine & metabolic: Diabetes mellitus, dyslipidemia

Nervous system: Impulse control disorder (including pathological gambling, increased libido, shopping, eating), neuroleptic malignant syndrome

ALERT: U.S. Boxed Warning

Increased mortality in elderly patients with dementia-related psychosis:

Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death. Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis.

Suicidal thoughts and behaviors:

Antidepressants increased the risk of suicidal thoughts and behavior in patients aged 24 years and younger in short-term studies. Monitor closely for clinical worsening and for emergence of suicidal thoughts and behaviors. The safety and efficacy of brexpiprazole have not been established in pediatric patients.

Warnings/Precautions

Concerns related to adverse reactions:

• Blood dyscrasias: Leukopenia, neutropenia, and agranulocytosis (sometimes fatal) have been reported in clinical trials and postmarketing reports with antipsychotic use; presence of risk factors (eg, preexisting low WBC/ANC or history of drug-induced leuko-/neutropenia) should prompt periodic blood count assessment. Discontinue therapy at first signs of blood dyscrasias or if absolute neutrophil count <1,000/mm3.

• Cerebrovascular effects: An increased incidence of cerebrovascular effects (eg, transient ischemic attack, stroke), including fatalities, has been reported in placebo-controlled trials of antipsychotics for the unapproved use in elderly patients with dementia-related psychosis.

• CNS depression: May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery, driving).

• Dyslipidemia: Has been reported with atypical antipsychotics; risk profile may differ between agents. In clinical trials, the incidence of hypertriglyceridemia observed with brexpiprazole was greater than observed with placebo, while changes in fasting total cholesterol, LDL, and HDL were similar.

• Esophageal dysmotility/aspiration: Antipsychotic use has been associated with esophageal dysmotility and aspiration; risk increases with age. Use with caution in patients at risk for aspiration pneumonia (eg, Alzheimer disease), particularly in patients >75 years (Herzig 2017; Maddalena 2004).

• Extrapyramidal symptoms: May cause extrapyramidal symptoms (EPS), including pseudoparkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia (risk of these reactions is generally much lower relative to typical/conventional antipsychotics; frequencies reported are similar to placebo). Risk of dystonia (and probably other EPS) may be greater with increased doses, use of conventional antipsychotics, males, and younger patients. Factors associated with greater vulnerability to tardive dyskinesia include older in age, female gender combined with postmenopausal status, Parkinson disease, pseudoparkinsonism symptoms, affective disorders (particularly major depressive disorder), concurrent medical diseases such as diabetes, previous brain damage, alcoholism, poor treatment response, and use of high doses of antipsychotics (APA [Lehman 2004]; Soares-Weiser 2007). Consider therapy discontinuation with signs/symptoms of tardive dyskinesia.

• Falls: May increase the risk for falls due to somnolence, orthostatic hypotension, and motor or sensory instability.

• Hyperglycemia: Atypical antipsychotics have been associated with development of hyperglycemia; in some cases, may be extreme and associated with ketoacidosis, hyperosmolar coma, or death. All patients should be monitored for symptoms of hyperglycemia (eg, polydipsia, polyuria, polyphagia, weakness). Use with caution in patients with diabetes or other disorders of glucose regulation; monitor for worsening of glucose control. Patients with risk factors for diabetes (eg, obesity or family history) should have a baseline fasting blood sugar (FBS) and periodic assessment of glucose regulation. Hyperglycemia may resolve with discontinuation of antipsychotic; some patients may require treatment of diabetes after discontinuation of therapy.

• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, uncontrolled sexual urges, uncontrolled spending, binge or compulsive eating, and/or other intense urges. Patients with prior history of impulse control issues may be at increased risk. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in most, but not all, cases.

• Neuroleptic malignant syndrome: Neuroleptic malignant syndrome (NMS) has been associated with use of antipsychotic agents, including brexpiprazole; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability, elevated creatinine phosphokinase, rhabdomyolysis, and/or acute renal failure. Discontinue treatment immediately if NMS is suspected and initiate symptomatic treatment and monitoring.

• Orthostatic hypotension: May cause orthostatic hypotension; increased risk at initiation of therapy or during dose escalation. Use with caution in patients at risk of this effect or in those who would not tolerate transient hypotensive episodes (patients who are antipsychotic-naive or have cerebrovascular disease, cardiovascular disease, hypovolemia, dehydration, or are taking concurrent medication use which may predispose to hypotension/bradycardia). Consider using lower starting dosages and slower titrations in these patients.

• Suicidal thinking/behavior: [US Boxed Warning]: Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (≤24 years of age). Short-term studies did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening and suicidality particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Safety and efficacy have not been established in pediatric patients.

• Temperature regulation: Antipsychotic use has been associated with impaired core body temperature regulation; caution with strenuous exercise, heat exposure, dehydration, and concomitant medication possessing anticholinergic effects.

• Weight gain: Significant weight gain has been observed with antipsychotic therapy; incidence varies with product. Monitoring of weight is recommended.

Disease-related concerns:

• Dementia: [US Boxed Warning]: Elderly patients with dementia-related psychosis treated with antipsychotics are at an increased risk of death compared to placebo. Most deaths appeared to be either cardiovascular (eg, heart failure, sudden death) or infectious (eg, pneumonia) in nature. Use with caution in patients with Lewy body dementia or Parkinson disease dementia due to greater risk of adverse effects, increased sensitivity to extrapyramidal effects, and association with irreversible cognitive decompensation or death. (APA [Reus 2016]). Brexpiprazole is not approved for the treatment of dementia-related psychosis.

• Seizures: Use with caution in patients at risk of seizures or with conditions that potentially lower the seizure threshold. Elderly patients may be at increased risk of seizures due to an increased prevalence of predisposing factors.

Special populations:

• Elderly: Use in patients with dementia-related psychosis is associated with an increased risk of mortality and cerebrovascular accidents. Brexpiprazole is not approved for the treatment of dementia-related psychosis.

Dosage form specific issues:

• Lactose: Tablets may contain lactose; avoid use in patients with galactose intolerance or glucose-galactose malabsorption.

Other warnings/precautions:

• Discontinuation of therapy: When discontinuing antipsychotic therapy, the American Psychiatric Association (APA), Canadian Psychiatric Association (CPA), and World Federation of Societies of Biological Psychiatry (WFSBP) guidelines recommend gradually tapering antipsychotics to avoid physical withdrawal symptoms, including anorexia, anxiety, diaphoresis, diarrhea, dizziness, dyskinesia, headache, myalgia, nausea, paresthesia, restlessness, tremulousness, and vomiting (APA [Lehman 2004]; CPA 2005]; Lambert 2007; WFSBP [Hasan 2012]). The risk of withdrawal symptoms is highest following abrupt discontinuation of highly anti-cholinergic or dopaminergic antipsychotics (Cerovecki 2013). Additional factors such as duration of antipsychotic exposure, the indication for use, medication half-life and risk for relapse should be considered. In schizophrenia, there is no reliable indicator to differentiate the minority who will not from the majority who will relapse with drug discontinuation. However, studies in which the medication of well-stabilized patients were discontinued indicate that 75% of patients relapse within 6 to 24 months. Indefinite maintenance antipsychotic medication is generally recommended, and especially for patients who have had multiple prior episodes or 2 episodes within 5 years (APA [Lehman 2004]).

Monitoring Parameters

Mental status; vital signs (as clinically indicated); blood pressure (baseline; repeat 3 months after antipsychotic initiation, then yearly); weight, height, BMI, waist circumference (baseline; repeat at 4, 8, and 12 weeks after initiating or changing therapy, then quarterly; consider switching to a different antipsychotic for a weight gain ≥5% of initial weight); CBC (as clinically indicated; monitor frequently during the first few months of therapy in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia); electrolytes and liver function (annually and as clinically indicated); personal and family history of obesity, diabetes, dyslipidemia, hypertension, or cardiovascular disease (baseline; repeat annually); fasting plasma glucose level/HbA1c (baseline; repeat 3 months after starting antipsychotic, then yearly); fasting lipid panel (baseline; repeat 3 months after initiation of antipsychotic; if LDL level is normal repeat at 2- to 5-year intervals or more frequently if clinical indicated); changes in menstruation, libido, development of galactorrhea, erectile and ejaculatory function (yearly); abnormal involuntary movements or parkinsonian signs (baseline; repeat weekly until dose stabilized for at least 2 weeks after introduction and for 2 weeks after any significant dose increase); tardive dyskinesia (every 12 months; high-risk patients every 6 months); ocular examination (yearly in patients >40 years; every 2 years in younger patients) (ADA 2004; Lehman 2004; Marder 2004); fall risk (baseline and periodically during treatment in patients with diseases or on medications that may also increase fall risk).

Pregnancy Considerations

Antipsychotic use during the third trimester of pregnancy has a risk for abnormal muscle movements (extrapyramidal symptoms [EPS]) and/or withdrawal symptoms in newborns following delivery. Symptoms in the newborn may include agitation, feeding disorder, hypertonia, hypotonia, respiratory distress, somnolence, and tremor; these effects may be self-limiting or require hospitalization.

Treatment algorithms have been developed by the ACOG and the APA for the management of depression in women prior to conception and during pregnancy (Yonkers 2009). The ACOG recommends that therapy during pregnancy be individualized; treatment with psychiatric medications during pregnancy should incorporate the clinical expertise of the mental health clinician, obstetrician, primary health care provider, and pediatrician. Safety data related to atypical antipsychotics during pregnancy is limited and routine use is not recommended. However, if a woman is inadvertently exposed to an atypical antipsychotic while pregnant, continuing therapy may be preferable to switching to a typical antipsychotic that the fetus has not yet been exposed to; consider risk:benefit (ACOG 2008).

Health care providers are encouraged to enroll women exposed to brexpiprazole during pregnancy in the National Pregnancy Registry for Atypical Antipsychotics (866-961-2388 or http://www.womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/).

Patient Education

What is this drug used for?

• It is used to treat schizophrenia or low mood (depression). It may be given for other reasons. Talk with the doctor.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Fatigue

• Loss of strength and energy

• Restlessness

• Headache

• Weight gain

• Stuffy nose

• Sore throat

• Tremors

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• High blood sugar like confusion, fatigue, increased thirst, increased hunger, passing a lot of urine, flushing, fast breathing, or breath that smells like fruit

• Weakness on 1 side of the body, trouble speaking or thinking, change in balance, drooping on one side of the face, or blurred eyesight

• Neuroleptic malignant syndrome like fever, muscle cramps or stiffness, dizziness, severe headache, confusion, change in thinking, fast heartbeat, abnormal heartbeat, or sweating a lot

• Tardive dyskinesia like unable to control body movements; tongue, face, mouth, or jaw sticking out; mouth puckering; or puffing cheeks

• Infection

• Depression like thoughts of suicide, anxiety, emotional instability, agitation, irritability, panic attacks, mood changes, behavioral changes, or confusion

• Abnormal movements

• Twitching

• Change in balance

• Trouble swallowing

• Trouble speaking

• Severe dizziness

• Passing out

• Seizures

• Uncontrollable urges

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine’s uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Frequently Asked Questions