real looking [60:<60 mL/minute): Do not exceed 3 mg once daily. 1 Geriatric Patients Cautious dosage selection recommended, usually starting at the lower end of the recommended dosage range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function and concomitant illnesses and other drug therapy in this population. 1 Gender, Race, or Smoking Status Dosage adjustment not required based on gender, race, or smoking status. 1 Poor Metabolizers of CYP2D6 Reduce brexpiprazole dosage by 50%. 1 (See Special Populations under Pharmacokinetics.) In poor CYP2D6 metabolizers who are also taking moderate or potent CYP3A4 inhibitors, reduce brexpiprazole dosage to 25% of the usual dosage. 1 (See Interactions.) Cautions for Rexulti Contraindications Known hypersensitivity to brexpiprazole or any components in the formulation. 1 Rash, facial swelling, urticaria, and anaphylaxis reported. 1 Warnings/Precautions Warnings Increased Mortality in Geriatric Patients with Dementia-related Psychosis Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis. 1 28 39 73 75 Antipsychotic agents, including brexpiprazole, are not approved for the treatment of dementia-related psychosis. 1 39 73 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning, see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions, and see Dysphagia under Cautions.) Worsening of Depression and Suicidality Risk Possible worsening of depression and/or emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior in both adult and pediatric patients with major depressive disorder, whether or not they are taking antidepressants; may persist until clinically important remission occurs. 93 94 95 (See Suicidality in Boxed Warning.) However, suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. 92 93 94 Appropriately monitor and closely observe patients receiving antidepressants for any reason, particularly during initiation of therapy (i.e., the first few months) and during periods of dosage adjustments. 1 93 Consider changing or discontinuing therapy in patients whose depression is persistently worse or in those with emerging suicidality. 1 Other Warnings and Precautions Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis Increased incidence of adverse cerebrovascular events (cerebrovascular accidents and TIAs), including fatalities, observed in geriatric patients with dementia treated with risperidone, aripiprazole, or olanzapine in placebo-controlled studies. 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 in Boxed Warning.) Neuroleptic Malignant Syndrome Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, reported with antipsychotic agents. 1 If NMS is suspected, immediately discontinue therapy and provide intensive symptomatic treatment and monitoring. 1 Tardive Dyskinesia Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents. 1 Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. 1 In patients requiring chronic treatment, use lowest dosage and shortest duration of treatment needed to achieve a satisfactory clinical response; periodically reassess need for continued therapy. 1 APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months. 28 Consider discontinuance of brexpiprazole if signs and symptoms of tardive dyskinesia appear. 1 However, some patients may require treatment despite presence of the syndrome. 1 Metabolic Changes Atypical antipsychotic agents, including brexpiprazole, have caused metabolic changes, including hyperglycemia and diabetes mellitus, dyslipidemia, and weight gain. 1 While all atypical antipsychotics 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, reported in patients receiving atypical antipsychotic agents. 1 Hyperglycemia reported in patients treated with brexpiprazole. 1 In short-term clinical trials, clinically important differences between brexpiprazole and placebo in the proportion of patients experiencing an increase in fasting glucose concentrations from baseline to end point not observed. 1 In longer-term clinical studies, 9 10% of patients with normal or borderline fasting glucose concentrations treated with brexpiprazole experienced shifts to high fasting glucose concentrations. 1 Periodically monitor patients with an established diagnosis of diabetes mellitus for worsening of glucose control and perform fasting blood glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes). 1 If manifestations of hyperglycemia occur in any brexpiprazole-treated patient, perform fasting blood glucose testing. 1 Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the atypical antipsychotic; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic. 1 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, LDL-cholesterol, and HDL-cholesterol were similar between brexpiprazole-treated patients and those receiving placebo. 1 11 In uncontrolled, longer-term depression and schizophrenia studies, shifts to high or very high triglyceride concentrations reported in 13 17 or 0.2 0.4%, respectively, of brexpiprazole-treated patients with normal baseline triglyceride concentrations and shifts from normal to low HDL-cholesterol concentrations reported in 14% of patients in the depression studies. 1 Weight Gain Weight gain observed with atypical antipsychotic therapy. 1 Brexpiprazole generally appears to be associated with moderate weight gain; mean weight gain of 1 1.6 kg reported during short-term studies. 1 Weight gain was 7% of baseline body weight in 20 30% of brexpiprazole-treated patients during longer-term studies. 1 11 Manufacturer recommends monitoring of weight at baseline and frequently thereafter during therapy. 1 Leukopenia, Neutropenia, and Agranulocytosis Leukopenia and neutropenia reported during therapy with antipsychotic agents. 1 78 Agranulocytosis (including fatal cases) reported with other antipsychotic agents. 1 Possible risk factors for leukopenia and neutropenia include preexisting low WBC count or ANC or a history of drug-induced leukopenia or neutropenia. 1 78 Monitor CBC frequently during the first few months of therapy in patients with such risk factors. 1 Discontinue brexpiprazole at the first sign of a decline in WBC count in the absence of other causative factors. 1 Carefully monitor patients with neutropenia for signs and symptoms of infection (e.g., fever) and treat promptly if they occur. 1 Discontinue brexpiprazole if severe neutropenia (ANC> <1000/mm 3 ) occurs; monitor WBC until recovery occurs. 1 Orthostatic Hypotension and Syncope Risk of orthostatic hypotension and syncope with atypical antipsychotics, particularly during initial dosage titration and when dosage is increased, because of brexpiprazole's α 1 -adrenergic blocking activity. 1 Dizziness (2%), orthostatic hypotension (0.4%), and syncope (0.1%) reported in brexpiprazole-treated patients in short-term schizophrenia studies; dizziness (2%) and orthostatic hypotension (0.1%) reported in brexpiprazole-treated patients in short-term depression trials. 1 Monitor orthostatic vital signs in patients 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 MI, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. 1 Brexpiprazole has not been evaluated in patients with a recent history of MI or unstable cardiovascular disease; such patients were excluded from premarketing clinical trials. 1 Falls May cause somnolence, postural hypotension, and motor and sensory instability, which may lead to falls and, consequently, fractures or other injuries. 1 In patients with diseases or conditions or receiving other drugs that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic therapy and repeat such testing periodically during long-term therapy. 1 Seizures Brexpiprazole may cause seizures. 1 Higher risk of seizures in patients with a history of seizures or with conditions that lower the seizure threshold; conditions that lower seizure threshold may be more prevalent in older patients. 1 Body Temperature Dysregulation Atypical antipsychotic agents may disrupt body's ability to reduce core body temperature. 1 Use 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 Dysphagia Esophageal dysmotility and aspiration associated with the use of antipsychotic agents. 1 Use with caution in patients at risk for aspiration pneumonia. 1 Cognitive and Motor Impairment Judgment, thinking, or motor skills may be impaired. 1 Somnolence (including sedation and hypersomnia) reported in 4 5% of brexpiprazole-treated patients in short-term depression and schizophrenia trials. 1 (See Advice to Patients.) Specific Populations Pregnancy No adequate and well-controlled studies to date in pregnant women. 1 No teratogenicity observed in animal studies, but increased perinatal deaths observed in pups at supratherapeutic dosages. 1 Risk for extrapyramidal and/or withdrawal symptoms (e.g., agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, feeding disorder) in neonates exposed to antipsychotic agents during the third trimester; monitor neonates exhibiting such symptoms. 1 79 80 81 Symptoms were self-limiting in some neonates but varied in severity; some infants required intensive support and prolonged hospitalization. 1 79 80 81 National Pregnancy Registry for Atypical Antipsychotics: 866-961-2388 and . 1 Lactation Distributes into milk in rats; not known whether distributes into human milk. 1 Effects on nursing infants and on milk production also not known. 1 Weigh benefits of brexpiprazole therapy to the woman and benefits of breast-feeding against potential risks of infant drug exposure. 1 Pediatric Use Safety and efficacy not established in pediatric patients. 1 FDA warns that a greater risk of suicidal thinking or behavior (suicidality) occurred during the first few months of antidepressant treatment compared with placebo in children and adolescents with major depressive disorder, obsessive-compulsive disorder (OCD), or other psychiatric disorders based on pooled analyses of 24 short-term, placebo-controlled trials of 9 antidepressants (SSRIs and others). 1 93 However, a later meta-analysis of 27 placebo-controlled trials of 9 antidepressants (SSRIs and others) in patients> <19 years of age with major depressive disorder, OCD, or non-OCD anxiety disorders suggests that the benefits of antidepressant therapy in treating these conditions may outweigh the risks of suicidal behavior or suicidal ideation. 95 No suicides occurred in these pediatric trials. 1 93 95 Geriatric Use Clinical efficacy trials of brexpiprazole did not include any patients 65 years of age to determine whether they respond differently than younger adults. 1 Pharmacokinetics of the drug in geriatric patients (70 85 years of age) with depression were similar to those observed in younger adults. 1 Manufacturer recommends cautious dosage selection in geriatric patients (see Geriatric Patients under Dosage and Administration). 1 Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death; 1 39 73 75 increased incidence of cerebrovascular events also observed with certain atypical antipsychotic agents. 1 Brexpiprazole is not approved for the treatment of patients with dementia-related psychosis. 1 (See Boxed Warning and also see Cerebrovascular Events in Geriatric Patients with Dementia-related Psychosis under Cautions.) In pooled data analyses, a reduced risk of suicidality was observed in adults 65 years of age with antidepressant therapy compared with placebo. 1 92 93 (See Boxed Warning and also see Worsening of Depression and Suicidality Risk under Cautions.) Hepatic Impairment Patients with moderate to severe hepatic impairment generally have higher brexpiprazole exposure than patients with normal hepatic function, which may increase the risk of adverse effects. 1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe hepatic impairment (Child-Pugh score 7). 1 10 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.) Renal Impairment Patients with moderate to severe renal impairment or end-stage renal disease generally have higher brexpiprazole exposure than patients with normal renal function, which may increase the risk of adverse effects. 1 10 Manufacturer recommends a reduction in the maximum recommended dosage in patients with moderate or severe renal impairment (Cl cr> <60 mL/minute) or end-stage renal disease. 1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.) Poor CYP2D6 Metabolizers Dosage adjustment is recommended in patients known to be poor metabolizers of CYP2D6. 1 (See Poor Metabolizers of CYP2D6 under Dosage and Administration and also see Special Populations under Pharmacokinetics.) Common Adverse Effects Major depressive disorder (adjunctive therapy with antidepressants): 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 decreased blood cortisol concentration. 1 Akathisia and restlessness were dose related. 1 Schizophrenia: Akathisia, 1 4 5 extrapyramidal symptoms (excluding akathisia), 1 weight gain, 1 4 5 diarrhea, 1 4 dyspepsia, 1 5 tremor, 1 increased CK concentrations, 1 5 sedation. 1 4 5 Interactions for Rexulti Principally metabolized by CYP3A4 and CYP2D6. 1 In vitro, not a potent inhibitor or inducer of CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4/5. 1 10 In vitro, neither a clinically relevant substrate nor inhibitor 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 CYP3A4 and/or CYP2D6 inhibitors: Potential pharmacokinetic interaction (inhibition of brexpiprazole clearance resulting in increased systemic exposure). 1 Reduce usual brexpiprazole dosage by 50% if used concomitantly with a potent inhibitor of CYP3A4 or CYP2D6; may resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 or CYP2D6 inhibitor. 1 Dosage adjustment not necessary when potent CYP2D6 inhibitors are used in the adjunctive treatment of major depressive disorder. 1 In known poor CYP2D6 metabolizers, reduce usual brexpiprazole dosage by 75% if used concurrently with moderate or potent CYP3A4 inhibitors. 1 Also reduce usual brexpiprazole dosage by 75% when given in combination with both moderate or potent CYP2D6 inhibitors and moderate or potent CYP3A4 inhibitors. 1 May resume previous brexpiprazole dosage upon discontinuance of the CYP3A4 and/or CYP2D6 inhibitors. 1 Potent CYP3A4 inducers: Potential pharmacokinetic interaction (increased brexpiprazole clearance resulting in decreased systemic exposure). 1 Double brexpiprazole dosage over 1 2 weeks during concurrent therapy. 1 May resume usual brexpiprazole dosage over 1 2 weeks upon discontinuance of the CYP3A4 inducer. 1 Drugs Metabolized by Hepatic Microsomal Enzymes Substrates of CYP3A4, CYP2B6, or CYP2D6: Dosage adjustment of the CYP substrate not necessary during concurrent use. 1 10 Drugs Affecting Gastric pH Clinically important pharmacokinetic interaction unlikely; dosage adjustment of brexpiprazole not necessary. 1 10 Protein-bound Drugs In vitro studies suggest that protein binding of brexpiprazole not affected by concurrent administration of other highly protein-bound drugs; clinically important drug interactions because of protein displacement unlikely. 1 10 Specific Drugs Drug Interaction Comments Antacids Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH 1 10 Dosage adjustment of brexpiprazole not necessary 1 10 Anticholinergic agents Possible disruption of body temperature regulation 1 Use with caution 1 Antifungals, azoles (e.g., fluconazole, itraconazole, ketoconazole) CYP3A4 inhibitors: Possible increased brexpiprazole exposure 1 Ketoconazole (potent CYP3A4 inhibitor) increased brexpiprazole peak concentrations and AUC by approximately 1.2-fold and twofold, respectively 1 10 Potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 50% of usual dosage (or 25% of usual dosage in patients who are poor CYP2D6 metabolizers) 1 In combination with moderate or potent CYP2D6 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Bupropion No clinically important effect on pharmacokinetics of bupropion (CYP2B6 substrate) 1 10 Dosage adjustment of bupropion not necessary 1 10 Clarithromycin Possible increased brexpiprazole exposure with clarithromycin (potent CYP3A4 inhibitor) 1 Reduce brexpiprazole dosage to 50% of usual dosage (or 25% of usual dosage in patients who are poor CYP2D6 metabolizers) 1 In combination with moderate or potent CYP2D6 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Dextromethorphan No clinically important effect on pharmacokinetics of dextromethorphan (CYP2D6 substrate) 1 10 Dosage adjustment of dextromethorphan not necessary 1 10 Diazepam Clinically important interaction due to protein binding displacement of brexpiprazole unlikely 1 10 Duloxetine Possible increased brexpiprazole exposure with duloxetine (moderate CYP2D6 inhibitor) 1 In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Fexofenadine No clinically important effect on fexofenadine pharmacokinetics 1 10 Fluoxetine Possible increased brexpiprazole exposure with fluoxetine (potent CYP2D6 inhibitor) 1 Reduce brexpiprazole dosage to 50% of usual dosage; 1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder 1 In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Histamine H 2 -receptor antagonists Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH 1 10 Dosage adjustment of brexpiprazole not necessary 1 10 Hypotensive agents Possible additive hypotensive effects; may result in orthostatic hypotension and syncope 1 Monitor orthostatic vital signs 1 Lovastatin No clinically important effect on lovastatin pharmacokinetics 1 10 Dosage adjustment of lovastatin not necessary 1 10 Paroxetine Possible increased brexpiprazole exposure with paroxetine (potent CYP2D6 inhibitor) 1 Reduce brexpiprazole dosage to 50% of usual dosage; 1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder 1 In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Proton-pump inhibitors (e.g., omeprazole) Clinically important pharmacokinetic interaction unlikely with drugs that increase gastric pH 1 10 Omeprazole: No clinically important effect on brexpiprazole pharmacokinetics 1 10 Dosage adjustment of brexpiprazole not necessary 1 10 Quinidine Quinidine (potent CYP2D6 inhibitor) increased peak concentration and AUC of brexpiprazole by approximately 1.1- and 1.9-fold, respectively 10 Reduce brexpiprazole dosage to 50% of usual dosage; 1 dosage adjustment not necessary when used as adjunctive therapy for major depressive disorder 1 In combination with moderate or potent CYP3A4 inhibitors: Reduce brexpiprazole dosage to 25% of usual dosage 1 Increase back to original brexpiprazole dosage when the CYP2D6 and/or CYP3A4 inhibitors are discontinued 1 Rifampin Rifampin (potent CYP3A4 inducer) decreased peak concentration and AUC of brexpiprazole by 40 and 73%, respectively 1 10 Double usual brexpiprazole dosage over 1 2 weeks during concomitant use, then adjust dosage based on clinical response 1 10 Reduce brexpiprazole dosage back to original dosage over 1 2 weeks when rifampin is discontinued 1 Rosuvastatin No clinically important effect on rosuvastatin pharmacokinetics 1 10 Smoking Pharmacokinetic interaction unlikely 1 Dosage adjustment of brexpiprazole in smokers not necessary 1 St. John's wort ( Hypericum perforatum ) St. John's wort (potent CYP3A4 inducer) potentially can decrease peak concentration and AUC of brexpiprazole 1 Double usual brexpiprazole dosage over 1 2 weeks during concomitant use, then adjust dosage based on clinical response 1 10 Reduce brexpiprazole dosage back to previous dosage over 1 2 weeks when St. John's wort is discontinued 1 Ticlopidine No clinically important effect on brexpiprazole pharmacokinetics 1 10 Warfarin Clinically important interaction due to protein binding displacement of brexpiprazole unlikely 1 10 Rexulti Pharmacokinetics Absorption Bioavailability Peak plasma concentrations achieved within 4 hours following single-dose, oral administration. 1 Exhibits dose-proportional pharmacokinetics. 1 Absolute oral bioavailability of tablets is 95%. 1 Steady-state concentrations achieved within 10 12 days. 1 Food Administration with a high-fat meal does not substantially affect peak plasma concentration or AUC. 1 Special Populations In patients with mild, moderate or severe renal impairment, brexpiprazole exposure was approximately 7, 71, or 72% higher, respectively, than in patients with normal renal function. 1 10 Hemodialysis not expected to affect plasma concentrations of brexpiprazole because drug is highly bound to plasma proteins. 1 In patients with mild, moderate, or severe hepatic impairment, brexpiprazole exposures were 26, 73, or 4% higher, respectively, than in patients with normal hepatic function. 1 10 In geriatric patients (70 85 years of age) with depression, brexpiprazole pharmacokinetics were similar to those observed in younger adults. 1 Higher plasma concentrations observed in poor CYP2D6 metabolizers compared with extensive CYP2D6 metabolizers. 1 Distribution Extent Large volume of distribution following IV administration indicates extravascular distribution. 1 Brexpiprazole distributes into milk in rats; not known whether distributes into human milk. 1 Plasma Protein Binding Brexpiprazole: Highly bound (> 99%) to albumin and α 1 -acid glycoprotein. 1 10 Not affected by renal or hepatic impairment. 10 DM-3411 (principal metabolite): >90%. 10 Elimination Metabolism Extensively metabolized mainly by CYP3A4 and CYP2D6. 1 Principal metabolite (DM-3411) not likely to contribute to therapeutic effects of brexpiprazole. 1 Elimination Route Following administration of a single radiolabeled dose, approximately 46% recovered in feces and 25% in urine. 1 Approximately 14% and <1% excreted unchanged in feces and urine, respectively. 1 Half-life Brexpiprazole: 91 hours. 1 DM-3411 (principal metabolite): 86 hours. 1 Stability Storage Oral Tablets 20 25 C (may be exposed to 15 30 C). 1 Actions Exact mechanism of action in major depressive disorder and schizophrenia unknown; efficacy may be mediated through a combination of partial agonist activity at dopamine type 2 (D 2 ) and serotonin type 1 (5-hydroxytryptamine [5-HT 1A ]) receptors and antagonist activity at serotonin type 2 (5-HT 2A ) receptors. 1 Demonstrates partial agonist activity at D 2 and D 3 receptors and 5-HT 1A receptors and antagonist activity at 5-HT 2A , 5-HT 2B , and 5-HT 7 receptors and α 1A -, α 1B -, α 1D -, and α 2C -adrenergic receptors. 1 6 7 8 9 Compared with aripiprazole, brexpiprazole appears to have lower intrinsic activity at D 2 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 Exhibits moderate affinity for histamine (H 1 ) receptors, which are associated with sedation, and very low affinity for muscarinic (M 1 ) receptors. 1 4 9 Advice to Patients Importance of providing a copy of written patient information (medication guide) each time brexpiprazole is dispensed. 1 92 93 94 Importance of advising patients to read the patient information before taking brexpiprazole and each time the prescription is refilled. 92 Importance of advising patients that brexpiprazole tablets may be taken with or without food. 1 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 39 73 Inform patients and caregivers that brexpiprazole is not approved for treating geriatric patients with dementia-related psychosis. 1 73 Risk of suicidality; importance of patients, family, and caregivers being alert to and immediately reporting emergence of suicidality, worsening depression, manic or hypomanic symptoms, irritability, agitation, or unusual changes in behavior, especially during the first few months of therapy or during periods of dosage adjustment. 1 92 93 94 (See Worsening of Depression and Suicidality Risk under Cautions.) Importance of informing patients and caregivers about the risk of 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 BP, 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) and the need for specific monitoring for such changes. 1 Importance of patients and caregivers being aware of the symptoms of hyperglycemia (e.g., increased thirst, increased urination, increased appetite, weakness). 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; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed. 1 Risk of leukopenia, neutropenia, and agranulocytosis. 1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia that their CBC count should be monitored during brexpiprazole therapy. 1 Risk of orthostatic hypotension and syncope, especially when initiating or reinitiating treatment or increasing the dosage. 1 Importance of avoiding overheating and dehydration. 1 Risk of somnolence and impairment of judgment, thinking, or motor skills. 1 Importance of advising patients to exercise caution when performing activities requiring mental alertness (e.g., driving, operating hazardous machinery) 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 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 about the benefits and risks of breast-feeding during brexpiprazole therapy. 1 Importance of informing patients of other important precautionary information. 1 (See Cautions.) Preparations Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details. Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations. Brexpiprazole Routes Dosage Forms Strengths Brand Names Manufacturer Oral Tablets 0.25 mg Rexulti Otsuka (also promoted by Lundbeck) 0.5 mg Rexulti Otsuka (also promoted by Lundbeck) 1 mg Rexulti Otsuka (also promoted by Lundbeck) 2 mg Rexulti Otsuka (also promoted by Lundbeck) 3 mg Rexulti Otsuka (also promoted by Lundbeck) 4 mg Rexulti Otsuka (also promoted by Lundbeck) AHFS DI Essentials. Copyright 2017, Selected Revisions June 19, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814. References 1. Otsuka America Pharmaceutical, Inc. Rexulti (brexpiprazole) tablets prescribing information. Rockville, MD; 2017 Feb. 2. Thase ME, Youakim JM, Skuban A et al. Efficacy and safety of adjunctive brexpiprazole 2 mg in major depressive disorder: a phase 3, randomized, placebo-controlled study in patients with inadequate response to antidepressants. J Clin Psychiatry . 2015; 76:1224-31. [PubMed 26301701] 3. Thase ME, Youakim JM, Skuban A et al. Adjunctive brexpiprazole 1 and 3 mg for patients with major depressive disorder following inadequate response to antidepressants: a phase 3, randomized, double-blind study. J Clin Psychiatry . 2015; 76:1232-40. [PubMed 26301771] 4. Correll CU, Skuban A, Ouyang J et al. Efficacy and safety of brexpiprazole for the treatment of acute schizophrenia: a 6-week randomized, double-blind, placebo-controlled trial. Am J Psychiatry . 2015; 172:870-80. [PubMed 25882325] 5. Kane JM, Skuban A, Ouyang J et al. A multicenter, randomized, double-blind, controlled phase 3 trial of fixed-dose brexpiprazole for the treatment of adults with acute schizophrenia. Schizophr Res . 2015; 164:127-35. [PubMed 25682550] 6. Greig SL. Brexpiprazole: first global approval. Drug various
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