Rexulti

Brexpiprazole (Rexulti) tablets have markings on one side, and are available in the following strengths and package configurations (see Table 1).

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Brexpiprazole, an atypical antipsychotic, is available as Brexpiprazole (Rexulti) tablets. Brexpiprazole is 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butoxy}quinolin-2(1H)-one. The empirical formula is C₂₅H₂₇N₃O₂S and its molecular weight is 433.57.
Brexpiprazole (Rexulti) tablets are for oral administration and are available in 500 mcg, 1 mg, 2 mg, 3 mg and 4 mg strengths.
Excipients/Inactive Ingredients: Lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, and talc.
For color: Titanium dioxide, iron oxide and ferrosoferric oxide.

Anti-psychotic.
Pharmacology: Mechanism of Action: The mechanism of action of Brexpiprazole (Rexulti) in the adjunctive treatment of major depressive disorder, treatment of agitation associated with dementia due to Alzheimer's disease, or treatment of schizophrenia is unknown. However, the efficacy of Brexpiprazole (Rexulti) may be mediated through a combination of partial agonist activity at serotonin 5-HT_1A and dopamine D₂ receptors, and antagonist activity at serotonin 5-HT_2A receptors.
Pharmacodynamics: Brexpiprazole has affinity (expressed as K_i) for multiple monoaminergic receptors including serotonin 5-HT_1A (0.12 nM), 5-HT_2A (0.47 nM), 5-HT_2B (1.9 nM), 5-HT₇ (3.7 nM), dopamine D₂ (0.30 nM), D₃ (1.1 nM), and noradrenergic α_1A (3.8 nM), α_1B (0.17 nM), α_1D (2.6 nM), and α_2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT_1A, D₂, and D₃ receptors and as an antagonist at 5-HT_2A, 5-HT_2B, 5-HT₇, α_1A, α_1B, α_1D, and α_2C receptors. Brexpiprazole also exhibits affinity for histamine H₁ receptor (19 nM) and for muscarinic M₁ receptor (67% inhibition at 10 μM).
Cardiac Electrophysiology: At a dose 3-times the MRHD for the treatment of schizophrenia and 4-times the MRHD for adjunctive therapy to antidepressants for the treatment of MDD, or agitation associated with dementia due to Alzheimer's disease, Brexpiprazole (Rexulti) does not prolong the QTc interval to any clinically relevant extent.
Clinical Studies: Adjunctive Treatment of Major Depressive Disorder: The efficacy of Brexpiprazole (Rexulti) in the adjunctive treatment of major depressive disorder (MDD) was evaluated in two 6-week, double-blind, placebo-controlled, fixed-dose studies of adult patients meeting DSM-IV-TR criteria for MDD, with or without symptoms of anxiety, who had an inadequate response to prior antidepressant therapy (1 to 3 courses) in the current episode and who had also demonstrated an inadequate response throughout the 8 weeks of prospective antidepressant treatment (with escitalopram, fluoxetine, paroxetine controlled-release, sertraline, duloxetine delayed release, or venlafaxine extended-release). Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of treatment.
Patients in Study 1 (NCT01360645) were randomized to Brexpiprazole (Rexulti) 2 mg once a day or placebo. Patients in Study 2 (NCT01360632) were randomized to Brexpiprazole (Rexulti) 1 or 3 mg once a day or placebo.
For patients randomized to Brexpiprazole (Rexulti), all patients initiated treatment at 500 mcg once daily during Week 1. At Week 2, the Brexpiprazole (Rexulti) dosage was increased to 1 mg in all treatment groups, and either maintained at 1 mg or increased to 2 mg or 3 mg once daily, based on treatment assignment, from Week 3 onwards. The dosages were then maintained for the 4 remaining weeks.
The primary endpoint was change from baseline to Week 6 in the Montgomery-Asberg Depression Rating Scale (MADRS), a 10-item clinician-related scale used to assess the degree of depressive symptomatology, with 0 representing no symptoms, and 60 representing worst symptoms.
At randomization, the mean MADRS total score was 27. In Studies 1 and 2, Brexpiprazole (Rexulti) (+ antidepressant (ADT)) 2 mg once daily and 3 mg once daily were superior to placebo + ADT in reducing mean MADRS total scores. Results from the primary efficacy parameters for both fixed dose studies are shown as follows in Table 2. Figure 1 as follows shows the time course of response based on the primary efficacy measure (MADRS) in Study 1. (See Table 2.)

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An examination of population subgroups did not suggest differential response based on age, gender, race or choice of prospective antidepressant. (See Figure 1.)

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Schizophrenia: The efficacy of Brexpiprazole (Rexulti) in the treatment of adults with schizophrenia was demonstrated in two 6-week, randomized, double-blind, placebo-controlled, fixed-dose clinical studies in patients who met DSM-IV-TR criteria for schizophrenia.
In both studies, Study 3 (NCT01396421) and Study 4 (NCT01393613), patients were randomized to Brexpiprazole (Rexulti) 2 or 4 mg once per day or placebo. Patients in the Brexpiprazole (Rexulti) groups initiated treatment at 1 mg once daily on Days 1 to 4. The Brexpiprazole (Rexulti) dosage was increased to 2 mg on Days 5 to 7. The dosage was then either maintained at 2 mg once daily or increased to 4 mg once daily, depending on treatment assignment, for the 5 remaining weeks.
The primary efficacy endpoint of both studies was the change from baseline to Week 6 in the Positive and Negative Syndrome Scale (PANSS) total score. The PANSS is a 30-item scale that measures positive symptoms of schizophrenia (7 items), negative symptoms of schizophrenia (7 items), and general psychopathology (16 items), each rated on a scale of 1 (absent) to 7 (extreme); the total PANSS scores range from 30 (best) to 210 (worst).
In Study 3, Brexpiprazole (Rexulti) at both 2 mg once daily and 4 mg once daily was superior to placebo on the PANSS total score. In Study 4, Brexpiprazole (Rexulti) 4 mg once daily was superior to placebo on the PANSS total score (Table 3). Figure 2 shows the time course of response based on the primary efficacy measure (change from baseline in PANSS total score) in Study 3.
Examination of population subgroups based on age, sex and race did not suggest differential responsiveness. (See Table 3 and Figure 2.)

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The safety and efficacy of Brexpiprazole (Rexulti) as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in the maintenance phase of a randomized withdrawal study (Study 5, (NCT01668797). Patients were stabilized for at least 12 weeks on 1 to 4 mg/day of Brexpiprazole (Rexulti) (N=202). They were then randomized in the double-blind treatment phase to either continue Brexpiprazole (Rexulti) at their achieved stable dose (N=97), or to switch to placebo (N=105).
The primary endpoint in Study 5 was time from randomization to impending relapse during the double-blind phase, defined as: 1) CGI-Improvement score of ≥5 (minimally worse) and an increase to a score >4 on PANSS conceptual disorganization, hallucinatory behavior, suspiciousness, or unusual thought content items, with either a ≥2 increase on a specific item or ≥4 point increase on the combined four PANSS items, 2) hospitalization due to worsening of psychotic symptoms, 3) current suicidal behavior, or 4) violent/aggressive behavior.
A pre-specified interim analysis demonstrated a statistically significantly longer time to relapse in patients randomized to the Brexpiprazole (Rexulti) group compared to placebo-treated patients. The study was subsequently terminated early because maintenance of efficacy had been demonstrated. The Kaplan-Meier curves of the cumulative proportion of patients with relapse during the double-blind treatment phase for Brexpiprazole (Rexulti) and placebo groups are shown in Figure 3. The key secondary endpoint, the proportion of subjects who met the criteria for impending relapse, was statistically significantly lower in Brexpiprazole (Rexulti)-treated patients compared with placebo group. (See Figure 3.)

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Note: A total of 202 subjects were randomized. Among them, one patient in the placebo group did not take investigational medicinal product and one patient in the Brexpiprazole (Rexulti) group did not have post-randomization efficacy evaluations. These two subjects were excluded from the efficacy analysis.
Agitation Associated with Dementia Due to Alzheimer's Disease: The efficacy of Brexpiprazole (Rexulti) in the treatment of agitation associated with dementia due to Alzheimer's disease was demonstrated in two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies (Study 6, NCT01862640 and Study 7, NCT03548584). In these studies, patients were required to: Have a diagnosis of probable Alzheimer's disease according to NINCDS-ADRDA criteria; Have a Mini-Mental State Examination (MMSE) score of ≥5 and ≤22 and have a total score of ≥4 by the agitation/aggression item of the NPI/NPI-NH, and; Exhibit sufficient agitation behaviors at time of entry to warrant use of pharmacotherapy, after excluding other factors.
Patients in: Study 6 were randomized to an oral dosage of either Brexpiprazole (Rexulti) 1 mg once a day, Brexpiprazole (Rexulti) 2 mg once a day, or placebo. Patients in both Brexpiprazole (Rexulti) groups started on 0.25 mg once daily for approximately three days, then received 0.5 mg once daily for approximately 12 days. Subsequently, patients in the 1 mg group received 1 mg once daily for the remainder of the 12-week study, and patients in the 2mg group received 1 mg once daily for approximately two weeks and then received 2 mg for the remainder of the study.
Study 7 were randomized to an oral dose of either Brexpiprazole (Rexulti) 2 mg or 3 mg once a day (combined treatment arm) or placebo. Patients in both Brexpiprazole (Rexulti) groups started on 0.5 mg once daily for 7 days, then received 1 mg once daily for 7 days and then 2 mg once daily for 14 days. Subsequently, patients in the 2 mg group received 2 mg once daily for the remainder of the 12-week study, and patients in the 3 mg group received 3 mg once daily for the remainder of the study.
Study 6 included 433 patients with a mean age of 74 years old, and a range of 51 and 90 years old; 45% were male; 96%, 3%, and 1%, were White, Black or African American, and Asian, respectively; and 16% and 83% were Latino/Hispanic and not Latino/Hispanic, respectively. Study 7 included 345 patients with a mean age of 74 years old, and a range of 56 and 90 years old; 44% were male; 95%, 4%, and 1% were White, Black or African American, and Asian, respectively; and 31% and 69% were Latino/Hispanic and not Latino/Hispanic, respectively.
The primary efficacy endpoint in these two studies was the change from baseline in the Cohen-Mansfield Agitation Inventory total (CMAI) score at Week 12. The CMAI is a clinician rated questionnaire consisting of 29 items, which assess the frequency of manifestations of agitated behaviors in elderly patients, based on caregiver input. Three specific factors can be derived from the CMAI scale: 1) Aggressive Behavior (e.g., screaming, throwing things, cursing/verbal aggression, kicking, pushing scratching, hurting self or others); 2) Physically Non-Aggressive Behavior (e.g., repetitive mannerisms, general restlessness, pacing); and 3) Verbally Agitated Behavior (e.g., complaining, repetitive questions, constant requests for attention). Each CMAI behavior was rated on a scale of 1 (never) to 7 (very frequent agitated behaviors); the total CMAI scores range from 29 (best) to 203 (worst). A negative change indicates improvement.
In Trial 6, patients in the Brexpiprazole (Rexulti) 2 mg group showed improved total CMAI scores compared to patients in the placebo group at Week 12. In Trial 7, patients in the Brexpiprazole (Rexulti) 2 mg/3 mg group showed improved total CMAI scores compared to patients in the placebo group at Week 12.
As shown in Table 4 and Figure 4, the mean change from baseline in the total CMAI score after 12 weeks in the 2 mg/or 3 mg Brexpiprazole (Rexulti) group was statistically significantly superior to the placebo group. The 1 mg Brexpiprazole (Rexulti) group did not demonstrate significantly greater mean changes at baseline from the placebo group in the total CMAI score in this patient population. The 1 mg once day Brexpiprazole (Rexulti) dosage is not approved and is not recommended for the treatment of agitation associated with dementia due to Alzheimer's disease [see Recommended Dosage for Agitation Associated with Dementia Due to Alzheimer's Disease under Dosage & Administration]. (See Table 4 and Figure 4.)

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Pharmacokinetics: Absorption: After single dose administration of Brexpiprazole (Rexulti) tablets, the peak plasma brexpiprazole concentrations occurred within 4 hours after administration; and the absolute oral bioavailability was 95%. Brexpiprazole steady-state concentrations were attained within 10 to 12 days of dosing.
Brexpiprazole (Rexulti) can be administered with or without food. Administration of a 4 mg Brexpiprazole (Rexulti) tablet with a standard high fat meal did not significantly affect the C_max or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (C_max and AUC) increased in proportion to the dose administered. In vitro studies of brexpiprazole did not indicate that brexpiprazole is a substrate of efflux transporters such as MDRI (P-gp) and BCRP.
Distribution: The volume of distribution of brexpiprazole following intravenous administration is high (1.56±0.42 L/kg), indicating extravascular distribution. Brexpiprazole is highly protein bound in plasma (greater than 99%) to serum albumin and α1-acid glycoprotein, and its protein binding is not affected by renal or hepatic impairment. Based on results of in vitro studies, brexpiprazole protein binding is not affected by warfarin, diazepam, or digitoxin.
Elimination: Metabolism: Based on in vitro metabolism studies of brexpiprazole using recombinant human cytochrome P450 (CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4), the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6.
In vivo brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes. After single- and multiple-dose administrations, brexpiprazole and its major metabolite, DM-3411, were the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represented 23% to 48% of brexpiprazole exposure (AUC) in plasma. DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.
Based on in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes.
Excretion: Following a single oral dose of [¹⁴C]-labeled brexpiprazole, approximately 25% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral clearance of a brexpiprazole oral tablet after once daily administration is 19.8 (±11.4) mL/h/kg. After multiple once daily administration of Brexpiprazole (Rexulti), the terminal elimination half-lives of brexpiprazole and its major metabolite, DM-3411, were 91 hours and 86 hours, respectively.
Studies In Specific Populations: Exposures of brexpiprazole in specific populations are summarized in Figure 5. Population PK analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function. (See Figure 5.)

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Pediatric Patients: A multiple dose PK study (0.5, 1, 2, 3 or 4 mg/day) has been conducted in 43 pediatric patients aged 13 years to 17 years old. Population PK analysis indicated systemic exposure (C_max and AUC) of brexpiprazole in pediatric patients (13 to 17 years of age) was comparable to that in adult patients across the dose range from 0.5 to 4 mg.
Drug Interaction Studies: Effects of other drugs on the exposures of brexpiprazole are summarized in Figure 6. Based on simulation, a 5.1-fold increase in AUC values at steady-state is expected when extensive metabolizers of CYP2D6 are administered with both strong CYP2D6 and CYP3A4 inhibitors. A 4.8-fold increase in mean AUC values at steady-state is expected in poor metabolizers of CYP2D6 administered with strong CYP3A4 inhibitors [see Drugs Having Clinically Important Interactions with Brexpiprazole (Rexulti) under Interactions]. (See Figure 6.)

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The effects of Brexpiprazole (Rexulti) on the exposures of other drugs are summarized in Figure 7. (See Figure 7.)

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Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Lifetime carcinogenicity studies were conducted in ICR mice and SD rats. Brexpiprazole was administered orally for two years to male and female mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 to 6.1 times the oral MRHD of 4 mg/day based on mg/m² body surface area) and to male and female rats at doses of 1, 3, and 10 mg/kg and 3, 10, and 30 mg/kg/day, respectively (2.4 to 24 and 7.3 to 73 times the oral MRHD, males and females). In female mice, the incidence of mammary gland adenocarcinoma was increased at all doses and the incidence of adenosquamous carcinoma was increased at 2.4 and 6.1 times the MRHD. No increase in the incidence of tumors was observed in male mice. In the rat study, brexpiprazole was not carcinogenic in either sex at doses up to 73 times the MRHD.
Proliferative and/or neoplastic changes in the mammary and pituitary glands of rodents have been observed following chronic administration of antipsychotic drugs and are considered to be prolactin mediated. The potential for increasing serum prolactin level of brexpiprazole was shown in both mice and rats. The relevance for human risk of the findings of prolactin-mediated endocrine tumors in rodents is unknown.
Mutagenesis: Brexpiprazole was not mutagenic when tested in the in vitro bacterial reverse mutation assay (Ames test). Brexpiprazole was negative for clastogenic activity in the in vivo micronucleus assay in rats, and was not genotoxic in the in vivo/in vitro unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was clastogenic but only at doses that induced cytotoxicity. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans.
Impairment of Fertility: Female rats were treated with oral doses of 0.3, 3 or 30 mg/kg/day (0.7, 7.3, and 73 times the oral MRHD on a mg/m² basis) prior to mating with untreated males and continuing through conception and implantation. Estrus cycle irregularities and decreased fertility were observed at 3 and 30 mg/kg/day. Prolonged duration of pairing and increased preimplantation losses were observed at 30 mg/kg/day.
Male rats were treated with oral doses of 3, 10, or 100 mg/kg/day (7.3, 24 and 240 times the oral MRHD on a mg/m² basis) for 63 days prior to mating with untreated females and throughout the 14 days of mating. No differences were observed in the duration of mating or fertility indices in males at any dose of brexpiprazole.

Brexpiprazole (Rexulti) is indicated for: Adjunctive treatment of major depressive disorder (MDD) in adults [see Pharmacology: Pharmacodynamics: Clinical Studies: Adjunctive Treatment of Major Depressive Disorder under Actions].
Treatment of schizophrenia in adults and pediatric patients ages 13 years and older [see Pharmacology: Pharmacodynamics: Clinical Studies: Schizophrenia under Actions].
Treatment of agitation associated with dementia due to Alzheimer's disease.
Limitations of Use: Rexulti is not indicated as an as needed ("prn") treatment for agitation associated with dementia due to Alzheimer's disease [see Pharmacology: Pharmacodynamics: Clinical Studies: Agitation Associated with Dementia Due to Alzheimer's Disease under Actions].

Administration Information: Administer Brexpiprazole (Rexulti) orally, once daily with or without food (see Pharmacology: Pharmacokinetics under Actions).
Recommended Dosage for Adjunctive Treatment of Major Depressive Disorder (Adults): The recommended starting Brexpiprazole (Rexulti) dosage for the adjunctive treatment of MDD in adults is 500 mcg or 1 mg once daily (see Pharmacology: Pharmacokinetics under Actions).
Titrate to 1 mg once daily, then titrate to the target dosage of 2 mg once daily (based on the patient's clinical response and tolerability, increase the dosage at weekly intervals). The maximum recommended daily dosage is 3 mg.
Periodically reassess to determine the continued need and appropriate dosage for treatment.
Recommended Dosage for Schizophrenia (Adults and Pediatric Patients 13 to 17 Years): Adults: The recommended starting dosage for Brexpiprazole (Rexulti) for the treatment of schizophrenia in adult is 1 mg once daily on Days 1 to 4 (see Pharmacology: Pharmacokinetics under Actions).
Titrate to 2 mg once daily on Day 5 through Day 7. On Day 8, the dosage can be increased to the maximum recommended daily dosage of 4 mg based clinical response and tolerability. The recommended target dosage is 2 mg to 4 mg once daily.
Pediatric Patients (13 to 17 years of age): The recommended starting dosage for Brexpiprazole (Rexulti) for the treatment of schizophrenia in pediatric patients 13 to 17 years of age is 0.5 mg once daily on Days 1 to 4, taken orally with or without food (see Pharmacology: Pharmacokinetics under Actions). Titrate to 1 mg once daily on Day 5 through Day 7, then to 2 mg on Day 8 based on the patient's clinical response and tolerability. Weekly dose increases can be made in 1 mg increments. The recommended target Brexpiprazole (Rexulti) dosage is 2 mg to 4 mg once daily. The maximum recommended daily dosage is 4 mg.
Recommended Dosage for Agitation Associated with Dementia Due to Alzheimer's Disease: The recommended starting Brexpiprazole (Rexulti) dosage for the treatment of agitation associated with dementia due to Alzheimer's disease is 0.5 mg taken once daily on Days 1 to 7. Increase the dosage on Days 8 through 14 to 1 mg once daily, and on Day 15 to 2 mg once daily. The recommended target dose is 2 mg once daily. The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, based on clinical response and tolerability.
Recommended Dosage in Patients with Hepatic Impairment: The maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is [see Hepatic Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions]. 2 mg once daily for patients with MDD or agitation associated with dementia due to Alzheimer's disease, and 3 mg once daily in patients with schizophrenia (see Renal Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions).
Recommended Dosage in Patients with Renal Impairment: The maximum recommended dosage in patients with creatinine clearance CrCl <60 mL/minute) is [see Renal Impairment under Precautions, Pharmacology: Pharmacokinetics under Actions].
2 mg orally once daily in patients with MDD or agitation associated with dementia due to Alzheimer's disease and 3 mg orally once daily in patients with schizophrenia.
Dosage Modifications for CYP2D6 Poor Metabolizers and for Concomitant use with CYP Inhibitors or Inducers: Dosage modifications are recommended in patients who are known cytochrome P450 (CYP) 2D6 poor metabolizers and in patients taking concomitant CYP3A4 inhibitors, CYP2D6 inhibitors, or strong CYP3A4 inducers (see Table 5).
If the concomitant drug is discontinued, adjust the Brexpiprazole (Rexulti) dosage to its original level. If the concomitant CYP3A4 inducers is discontinued, reduce the Brexpiprazole (Rexulti) dosage to the original level over 1 to 2 weeks [see Drugs Having Clinically Important Interactions with Brexpiprazole (Rexulti) under Interactions, Pharmacology: Pharmacokinetics under Actions]. (See Table 5.)

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Patients with Lactose Intolerance: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should be aware that brexpiprazole tablets contain lactose.

There is limited clinical trial experience regarding human overdosage with Brexpiprazole (Rexulti).
Management of Brexpiprazole (Rexulti) overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.
Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral Brexpiprazole (Rexulti), decreased brexpiprazole C_max and area under the curve (AUC) by approximately 5% to 23% and 31% to 39% respectively; however, there is insufficient information available on the therapeutic potential of activated charcoal in treating an overdose with Brexpiprazole (Rexulti).
There is no information on the effect of hemodialysis in treating an overdose with Brexpiprazole (Rexulti); hemodialysis is unlikely to be useful because brexpiprazole is highly bound to plasma proteins.

Brexpiprazole (Rexulti) is contraindicated in patients with a known hypersensitivity to Brexpiprazole (Rexulti) or any of its components. Reactions have included rash, angioedema, facial swelling, urticaria, and anaphylaxis.

Increased Mortality in Elderly Patients with Dementia-Related Psychosis; and Suicidal Thoughts and Behaviors.
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 (Rexulti) is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease [see Increased Mortality in Elderly Patients with Dementia-Related Psychosis under Precautions].
Suicidal Thoughts and Behaviors: Antidepressants increased the risk of suicidal thoughts and behaviors in patients 24 years of age 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 (Rexulti) has not been established in pediatric patients with MDD [see Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults and Use in Children under Precautions].

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. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk of death in the drug-treated patients of between 1.6 to 1.7 times the risk of death in placebo-treated patients. Over the course of a typical 10-week controlled trial, the rate of death in drug treated patients was about 4.5%, compared to a rate of about 2.6% in the placebo group.
Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease [see Warnings and Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis as follows].
Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults: In pooled analyses of placebo-controlled trials of antidepressant drugs (SSRIs and other antidepressant classes) that included approximately 77,000 adult patients, and over 4,400 pediatric patients, the incidence of suicidal thoughts and behaviors in patients 24 years of age and younger was greater in antidepressant-treated patients than in placebo-treated patients. The drug-placebo differences in the number of cases of suicidal thoughts and behaviors per 1000 patients treated are provided in Table 6.
No suicides occurred in any of the pediatric studies. There were suicides in the adult studies, but the number was not sufficient to reach any conclusion about antidepressant drug effect on suicide. (See Table 6.)

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It is unknown whether the risk of suicidal thoughts and behaviors in children, adolescents, and young adults extends to longer-term use, i.e., beyond four months. However, there is substantial evidence from placebo-controlled maintenance studies in adults with MDD that antidepressants delay the recurrence of depression.
Monitor all antidepressant-treated patients for clinical worsening and emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy and at times of dosage changes. Consider changing the therapeutic regimen, including possibly discontinuing Brexpiprazole (Rexulti), in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors.
As with other products of this class, suicidal ideation and attempt have been reported during use of brexpiprazole.
Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis: In placebo-controlled trials in elderly subjects with dementia, patients randomized to risperidone, aripiprazole, and olanzapine had a higher incidence of stroke and transient ischemic attack, including fatal stroke. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis without agitation associated with dementia due to Alzheimer's disease [see Warnings and Increased Mortality in Elderly Patients with Dementia-Related Psychosis previously].
Neuroleptic Malignant Syndrome (NMS): Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex, has been reported in association with administration of antipsychotic drugs, including Brexpiprazole (Rexulti).
Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
If NMS is suspected, immediately discontinue Brexpiprazole (Rexulti) and provide intensive symptomatic treatment and monitoring.
Tardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. The risk appears to be highest among elderly, especially elderly women, but it is impossible to predict which patients will develop the syndrome. Whether antipsychotic drugs differ in their potential to cause tardive dyskinesia is unknown.
The risk of tardive dyskinesia and the likelihood that it will become irreversible appear to increase as the duration of treatment and the total cumulative dose increases. The syndrome can develop, although much less commonly, after relatively brief treatment periods at low doses. It may also occur after discontinuation of treatment.
Tardive dyskinesia may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment, itself may suppress (or partially suppress) the signs and symptoms of the syndrome and thereby may possibly mask the underlying process. The effect that symptomatic suppression has upon the long-term course of tardive dyskinesia is unknown.
Given these considerations, Brexpiprazole (Rexulti) should be prescribed in a manner that is most likely to reduce the occurrence of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients who appear to suffer from a chronic illness that (1) is known to respond to antipsychotic drugs, and (2) for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, the smallest dose and the shortest duration of treatment needed to produce a satisfactory clinical response. The need for continued treatment should be reassessed periodically.
If signs and symptoms of tardive dyskinesia appear in a patient treated with Brexpiprazole (Rexulti), drug discontinuation should be considered. However, some patients may require treatment with Brexpiprazole (Rexulti) despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs including Brexpiprazole (Rexulti) have caused metabolic changes, including hyperglycemia, diabetes mellitus, dyslipidemia, and body weight gain. Although all of the drugs in the class to date have been shown to produce some metabolic changes, each drug has its own specific risk profile.
Hyperglycemia and Diabetes Mellitus: Hyperglycemia and diabetes mellitus, in some cases extreme and associated with diabetic ketoacidosis or hyperosmolar coma or death, have been reported in patients treated with atypical antipsychotics. There have been reports of hyperglycemia in patients treated with Brexpiprazole (Rexulti) [see Clinical Trials Experience under Adverse Reactions]. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment.
Adjunctive Treatment of Major Depressive Disorder: In the 6-week, placebo-controlled, fixed-dose clinical studies in patients with MDD, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 mg/dL and <126 mg/dL) to high were similar in patients treated with Brexpiprazole (Rexulti) and placebo.
In the long-term, open-label depression studies, 5% of adult patients with normal baseline fasting glucose experienced a shift to high while taking Brexpiprazole (Rexulti)+Antidepressant (ADT); 25% of subjects with borderline fasting glucose experienced shifts to high. Combined, 9% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term depression studies.
Schizophrenia: Adult: In the 6-week, placebo-controlled, fixed-dose clinical studies in adult patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) and borderline (≥100 mg/dL and <126 mg/dL) to high were similar in patients treated with Brexpiprazole (Rexulti) and placebo.
In the long-term, open-label schizophrenia studies, 8% of adult patients with normal baseline fasting glucose experienced a shift from normal to high while taking Brexpiprazole (Rexulti), 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 10% of subjects with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies.
Pediatric Patients (13 to 17 years of age): In the long-term, open-label study in pediatric patients with schizophrenia, 2.7% of pediatric patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) while taking Brexpiprazole (Rexulti).
Agitation Associated with Dementia Due to Alzheimer's Disease: In the 12-week placebo-controlled, fixed-dose studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or impaired (≥100 and <126 mg/dL) to high were similar in patients treated with Brexpiprazole (Rexulti) (14%) and patients treated with placebo (16%).
Of the patients who were previously treated with Brexpiprazole (Rexulti) for 12-weeks and continued into a 12-week, active-treatment extension study, 15% of patients with normal baseline fasting glucose experienced a shift from normal (<100 mg/dL) to high (≥126 mg/dL) fasting glucose while taking Brexpiprazole (Rexulti); 30% of patients with impaired fasting glucose experienced shifts from impaired fasting glucose (≥100 and <126 mg/dL) to high fasting glucose. Combined, 20% of patients with normal or impaired fasting glucose experienced shifts to high fasting glucose.
Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a sating lipid profile at baseline and monitor periodically during treatment. Clinical monitoring of fasting lipid profile at baseline and during treatment is recommended.
Adjunctive Treatment of Major Depressive Disorder: In the 6-week, placebo-controlled, fixed-dose clinical studies in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Brexpiprazole (Rexulti)- and placebo-treated patients. Table 7 shows the proportions of patients with changes in fasting triglycerides. (See Table 7.)

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In the long-term, open-label depression studies, shifts in baseline fasting cholesterol from normal to high were reported in 9% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 14% (HDL cholesterol) of patients taking Brexpiprazole (Rexulti). Of patients with normal baseline triglycerides, 17% experienced shifts to high, and 0.2% experienced shifts to very high. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term depression studies.
Schizophrenia: Adult: In the 6-week, placebo-controlled, fixed-dose clinical studies in patients with schizophrenia, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Brexpiprazole (Rexulti)- and placebo-treated patients. Table 8 shows the proportions of patients with changes in fasting triglycerides. (See Table 8.)

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In the long-term, open-label schizophrenia studies, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 2% (LDL cholesterol), and shifts in baseline from normal to low were reported in 17% (HDL cholesterol) of patients taking Brexpiprazole (Rexulti). Of patients with normal baseline triglycerides, 13% experienced shifts to high, and 0.4% experienced shifts to very high triglycerides. Combined, 0.6% of subjects with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies.
Pediatric Patients (13 to 17 years of age): In the long-term, open-label study in pediatric patients with schizophrenia, shifts in baseline fasting total cholesterol from normal to high (<170 to ≥200 mg/dL) were reported in 7% of patients taking Brexpiprazole (Rexulti) and shifts in baseline HDL cholesterol from normal baseline triglycerides, 8.5% experienced shifts from normal to high (<150 to ≥200 mg/dL).
Agitation Associated with Dementia Due to Alzheimer's Disease: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (55 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, changes in total cholesterol, LDL cholesterol, and HDL cholesterol were similar in Brexpiprazole (Rexulti) and placebo-treated patients.
Table 9 shows the proportions of patients with changes in fasting triglycerides in Brexpiprazole (Rexulti) and placebo-treated patients. (See Table 9.)

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Of the patients who were previously treated with Brexpiprazole (Rexulti) for 12 weeks and continued into a 12-week, active-treatment extension study, 9% of patients taking Brexpiprazole (Rexulti) showed shifts in baseline fasting total cholesterol from normal (<200 mg/dL) to high (≥240 mg/dL), and 16% of patients taking Brexpiprazole (Rexulti) showed shifts in baseline HDL cholesterol from normal to low (≥40 to <40 mg/dL). Of the patients with normal baseline triglycerides, 18% experienced shifts from normal (<150 mg/dL) to high (200 to <500 mg/dL).
Weight Gain: Weight gain has been observed in patients treated with atypical antipsychotics including Brexpiprazole (Rexulti). Monitor weight at baseline and frequently thereafter.
Adjunctive Treatment of Major Depressive Disorder: Table 10 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with MDD. (See Table 10.)

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In the long-term, open-label depression studies, 4% of patients discontinued due to weight increase. Brexpiprazole (Rexulti) was associated with mean change from baseline in weight of 2.9 kg at week 26 and 3.1 kg at week 52. In the long-term, open label depression studies, 30% of patients demonstrated a ≥7% increase in body weight and 4% demonstrated a ≥7% decrease in body weight.
Schizophrenia: Adult: Table 11 shows weight gain data at last visit and percentage of adult patients with ≥7% increase in body weight at endpoint from the 6-week, placebo-controlled, fixed-dose clinical studies in patients with schizophrenia. (See Table 11.)

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In the long-term, open-label schizophrenia studies, 0.6% of patients discontinued due to weight increase. Brexpiprazole (Rexulti) was associated with mean change from baseline in weight of 1.3 kg at week 26 and 2.0 kg at week 52. In the long-term, open label schizophrenia studies, 20% of patients demonstrated a ≥7% increase in body weight and 10% demonstrated a ≥7% decrease in body weight.
Pediatric Patients (13 to 17 years of age): In the long-term, open label study in pediatric patients with schizophrenia, 0.5% of patients discontinued due to weight increase. The mean increase in weight from the open-label study baseline to last visit was 3.8 kg. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents by comparisons to age- and gender-matched population standards. A z score change <0.5 SD is considered not clinically significant. In this trial, the mean change in z-score from open-label baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age-and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. When treating pediatric, weight gain should be monitored and assessed against that expected for normal growth.
Agitation Associated with Dementia Due to Alzheimer's Disease: In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, the proportion of the patients with a ≥7% increase in body weight (kg) at any visit were 2% in Brexpiprazole (Rexulti) compared to 0% in placebo group.
In patients who were previously treated with Brexpiprazole (Rexulti) for 12 weeks and who continued into a 12-week, active-treatment extension study, there was no mean change in weight (kg) from baseline to last visit in association with Brexpiprazole (Rexulti). In this extension study, 4% of patients demonstrated ≥7% increase in body weight, and 5% demonstrated a ≥7% decrease in body weight from baseline to last visit.
Pathological Gambling and Other Compulsive Behaviors: Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking Brexpiprazole (Rexulti). Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviors. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to ask patients or their caregivers specifically about the development of new or intense gambling urges, compulsive sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with Brexpiprazole (Rexulti). In some cases, although not all, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviors may result in harm to the patient and others if not recognized. Consider dose reduction or stopping the medication if a patient develops such urges.
Leukopenia, Neutropenia, and Agranulocytosis: Leukopenia and neutropenia have been reported treatment of antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class.
Possible risk factors for leukopenia/neutropenia include pre-existing low white blood cell count (WBC)/absolute neutrophil count (ANC) and history of drug-induced leukopenia/neutropenia. In patients with a history of a clinically significant low WBC/ANC or drug-induced leukopenia/neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of Brexpiprazole (Rexulti) at the first sign of a clinically significant decline in WBC in the absence of other causative factors.
Monitor patients with clinically significant neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur. Discontinue Brexpiprazole (Rexulti) in patients with severe neutropenia (absolute neutrophil count <1000/mm³) and follow their WBC until recovery.
Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic hypotension and syncope. Generally, the risk is greatest during initial dose titration and when increasing the dose. In the short-term, placebo-controlled clinical studies of Brexpiprazole (Rexulti)+ADT in patients with MDD, the incidence of orthostatic hypotension-related adverse reactions in Brexpiprazole (Rexulti)+ADT-treated patients compared to placebo+ADT patients included: dizziness (2% vs. 2%) and orthostatic hypotension (0.1% vs. 0%). In the short-term, placebo-controlled clinical studies of Brexpiprazole (Rexulti) in patients with schizophrenia, the incidence of orthostatic hypotension-related adverse reactions in Brexpiprazole (Rexulti)-treated patients compared to placebo patients included: dizziness (2% versus 2%), orthostatic hypotension (0.4% versus 0.2%), and syncope (0.1% versus 0%). In 12-week, placebo-controlled clinical studies of Brexpiprazole (Rexulti) in patients with agitation associated with dementia due to Alzheimer's disease, the incidence of orthostatic hypotension-related adverse reactions in patients treated with Brexpiprazole (Rexulti) compared to patients treated with placebo included: dizziness (3% versus 3%), orthostatic hypotension (1% versus 1%), and syncope (0.2% versus 0.8%).
Orthostatic vital signs should be monitored in patients who are vulnerable to hypotension, (e.g., elderly patients, patients with dehydration, hypovolemia, concomitant treatment with antihypertensive medication), patients with known cardiovascular disease (history of myocardial infarction, ischemic heart disease, heart failure, or conduction abnormalities), and patients with cerebrovascular disease. Brexpiprazole (Rexulti) has not been evaluated in patients with a recent history of myocardial infarction or unstable cardiovascular disease. Such patients were excluded from pre-marketing clinical studies.
Falls: Antipsychotics, including Brexpiprazole (Rexulti), may cause somnolence, postural hypotension, motor, and sensory instability, which may lead to falls and, consequently, fractures or other injuries. For patients with diseases, conditions, or medications that could exacerbate these effects, complete fall risk assessments when initiating antipsychotic treatment and recurrently for patients on long-term antipsychotic therapy.
Seizures: Like other antipsychotic drugs, Brexpiprazole (Rexulti) should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Seizures have been reported during use of brexpiprazole. Conditions that lower the seizure threshold may be more prevalent in older patients.
Body Temperature Dysregulation: Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature, use Brexpiprazole (Rexulti) with caution in patients who may experience these conditions.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Antipsychotic drugs, including Brexpiprazole (Rexulti), should be used cautiously in patients at risk for aspiration.
Potential for Cognitive and Motor Impairment: Brexpiprazole (Rexulti), like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 6-week, placebo-controlled clinical studies in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for Brexpiprazole (Rexulti)+ADT-treated patients compared to 1% of placebo+ADT patients.
In 6-week, placebo-controlled clinical studies in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of Brexpiprazole (Rexulti)-treated patients compared to 3% of placebo-treated patients.
In the 12-week placebo-controlled, fixed-dose clinical studies in patients (51 to 90 years of age) with agitation associated with dementia due to Alzheimer's disease, somnolence (including sedation) was reported in 3% of patients treated with Brexpiprazole (Rexulti) compared to 1% of patients treated with placebo.
Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that Brexpiprazole (Rexulti) therapy does not affect them adversely.
Prolactin: Brexpiprazole (Rexulti) can elevate prolactin levels. Elevations associated with brexpiprazole treatment are generally mild and may decline during administration, however, in some infrequent cases the effect may persist during administration.
CYP2D6 Poor Metabolizers: Dosage adjustment is recommended in known CYP2D6 poor metabolizers, because these patients have higher brexpiprazole concentrations than normal metabolizers of CYP2D6. Approximately 8% of Caucasians and 3-8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as poor metabolizers (PM) [see Recommended Dosage in Patients with Hepatic Impairment under Dosage and Administration, Pharmacology: Pharmacokinetics under Actions].
Hepatic Impairment: The maximum recommended dosage in patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) is lower than those with mild hepatic impairment and those with normal hepatic function [see Recommended Dosage for Agitation Associated with Dementia Due to Alzheimer's Disease under Dosage & Administration]. Patients with moderate to severe hepatic impairment generally had higher exposure to brexpiprazole than patients with normal hepatic function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of Brexpiprazole (Rexulti)-associated adverse reactions.
Renal Impairment: The maximum recommended dosage in patients with CrCl <60 mL/minute is lower than those with mild renal impairment and those with normal renal function [see Dosage Adjustments for Renal Impairment under Dosage & Administration]. Patients with renal impairment had higher exposure to brexpiprazole than patients with normal renal function [see Pharmacology: Pharmacokinetics under Actions]. Greater exposure may increase the risk of Brexpiprazole (Rexulti)-associated adverse reactions.
Other Specific Populations: The recommended dosage for Brexpiprazole (Rexulti) is the same in males and females, in different racial groups, and in smokers and nonsmokers [see Pharmacology: Pharmacokinetics under Actions].
Drug Abuse and Dependence: Controlled Substance: Brexpiprazole (Rexulti) is not a controlled substance.
Abuse: Animals given access to Brexpiprazole (Rexulti) did not self-administer the drug, suggesting that Brexpiprazole (Rexulti) does not have rewarding properties.
Dependence: Humans and animals that received chronic Brexpiprazole (Rexulti) administration did not demonstrate any withdrawal signs upon drug discontinuation. This suggests that Brexpiprazole (Rexulti) does not produce physical dependence.
Use in Children: Schizophrenia: Safety and effectiveness of Brexpiprazole (Rexulti) for treatment of schizophrenia have been established in pediatric patients 13 years of age and older. Use of Brexpiprazole (Rexulti) in this population is supported by evidence from adequate and well-controlled studies in adults with schizophrenia, pharmacokinetic data from adults and pediatric patients, and safety data in pediatric patients 13 to 17 years of age [see Metabolic Changes as mentioned previously, Clinical Trials Experience under Adverse Reactions & Pharmacology: Pharmacokinetics under Actions].
Major Depressive Disorder: Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric patients [see Warnings, Suicidal Thoughts and Behaviors in Children Adolescents and Young Adults under Precautions].
Use in the Elderly: Antipsychotic drugs increase the risk of death in elderly patients with dementia-related psychosis. Brexpiprazole (Rexulti) is not approved for the treatment of patients with dementia-related psychosis [see Warnings and Increased Mortality in Elderly Patients with Dementia-Related Psychosis previously].
Adjunctive Treatment of Major Depressive Disorder (MDD) and Schizophrenia: Of the total number of Brexpiprazole (Rexulti)-treated patients in the clinical studies for the adjunctive therapy to antidepressants for MDD and for schizophrenia, 248 (3%) were 65 years of age and older (which included 45 (18%) patients who were 75 years of age and older). Clinical studies of Brexpiprazole (Rexulti) in these patients did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger adult patients. In general, dosage selection for the treatment of MDD or schizophrenia in a geriatric patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, and cardiac function, concomitant diseases, and other drug therapy.
Agitation Associated with Dementia Due to Alzheimer's Disease: The total number of Brexpiprazole (Rexulti)-treated patients 65 years of age and older in the clinical studies for agitation associated with dementia due to Alzheimer's disease (Studies 6 and 7) was 448 (86%) including 170 (33%) patients 65 to 74 years of age, 228 (44%) patients 75 to 84 years of age, and 50 (10%) patients 85 years of age and older [see Pharmacology: Pharmacodynamics: Clinical Studies: Agitation Associated with Dementia Due to Alzheimer's Disease under Actions].
In clinical studies of Brexpiprazole (Rexulti) for the treatment of agitation associated with dementia due to Alzheimer's disease did not include sufficient numbers of younger adult patients to determine if patients 65 years of age and older respond differently than younger adult patients.

Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Brexpiprazole (Rexulti) during pregnancy.
Risk Summary: Adequate and well-controlled studies have not been conducted with Brexpiprazole (Rexulti) in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like Brexpiprazole (Rexulti), during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms. In animal reproduction studies, no teratogenicity was observed with oral administration of brexpiprazole to pregnant rats and rabbits during organogenesis at doses up to 73 and 146 times, respectively, of maximum recommended human dose (MRHD) of 4 mg/day on a mg/m² basis. However, when pregnant rats were administered brexpiprazole during the period of organogenesis through lactation, the number of perinatal deaths of pups was increased at 73 times the MRHD [see Data as follows]. The background risk of major birth defects and miscarriage for the indicated population(s) is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Clinical Considerations: Fetal/Neonatal Adverse Reactions: Extrapyramidal and/or withdrawal symptoms, including agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder have been reported in neonates whose mothers were exposed to antipsychotic drugs during the third trimester of pregnancy. These symptoms have varied in severity. Some neonates recovered within hours or days without specific treatment; others required prolonged hospitalization. Monitor neonates for extrapyramidal and/or withdrawal symptoms and manage symptoms appropriately.
Data: Animal Data: Pregnant rats were treated with oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD on a mg/m² basis) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 73 times the MRHD.
Pregnant rabbits were treated with oral doses of 10, 30, and 150 mg/kg/day (49, 146, and 730 times the MRHD) of brexpiprazole during the period of organogenesis. Brexpiprazole was not teratogenic and did not cause adverse developmental effects at doses up to 146 times the MRHD. Findings of decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses at 730 times the MRHD, a dose that induced maternal toxicity.
In a study in which pregnant rats were administered oral doses of 3, 10, and 30 mg/kg/day (7.3, 24, and 73 times the MRHD) during the period of organogenesis and through lactation, the number of live-born pups was decreased and early postnatal deaths increased at a dose 73 times the MRHD. Impaired nursing by dams, and low birth weight and decreased body weight gain in pups were observed at 73 times, but not at 24 times, the MRHD.
Lactation: Risk Summary: Lactation studies have not been conducted to assess the presence of brexpiprazole in human milk, the effects of brexpiprazole on the breastfed infant, or the effects of brexpiprazole on milk production. Brexpiprazole is present in rat milk. The development and health benefits of breastfeeding should be considered along with the mother's clinical need for Brexpiprazole (Rexulti) and any potential adverse effects on the breastfed infant from Brexpiprazole (Rexulti) or from the underlying maternal condition.

The following adverse reactions are discussed in more detail in other sections of the monograph: Increased Mortality in Elderly Patients with Dementia-Related Psychosis [see Warnings and Precautions].
Suicidal Thoughts and Behaviors in Adolescents and Young Adults [see Warnings and Precautions].
Cerebrovascular Adverse Reactions Including Stroke in Elderly Patients with Dementia-Related Psychosis [see Precautions].
Neuroleptic Malignant Syndrome (NMS) [see Precautions].
Tardive Dyskinesia [see Precautions].
Metabolic Changes [see Precautions].
Pathological Gambling and Other Compulsive Behaviors [see Precautions].
Leukopenia, Neutropenia, and Agranulocytosis [see Precautions].
Orthostatic Hypotension and Syncope [see Precautions].
Falls [see Precautions].
Seizures [see Precautions].
Body Temperature Dysregulation [see Precautions].
Dysphagia [see Precautions].
Potential for Cognitive and Motor Impairment [see Precautions].
Prolactin [see Precautions].
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adjunctive Treatment in Major Depressive Disorder (MDD): The safety of Brexpiprazole (Rexulti) was evaluated 1,054 patients (18 to 65 years of age) diagnosed with MDD who participated in two 6-week, placebo-controlled, fixed-dose clinical studies in patients with major depressive disorder in which Brexpiprazole (Rexulti) was administered at doses of 1 mg to 3 mg daily as adjunctive treatment to continued antidepressant therapy; patients in the placebo group continued to receive antidepressant therapy [see Pharmacology: Pharmacodynamics: Clinical Studies: Adjunctive Treatment of Major Depressive Disorder under Actions].
Adverse Reactions Reported as Reasons for Discontinuation of Treatment: A total of 3% (17/643) of Brexpiprazole (Rexulti)-treated patients and 1% (3/411) of placebo-treated patients discontinued due to adverse reactions.
Adverse Reactions in Brexpiprazole (Rexulti) Studies for Adjunctive MDD in Adults: Adverse reactions associated with the adjunctive use of Brexpiprazole (Rexulti) (incidence of 2% or greater and adjunctive Brexpiprazole (Rexulti) incidence greater than adjunctive placebo) that occurred during acute therapy (up to 6-weeks in patients with MDD) are shown in Table 12. (See Table 12.)

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Dose-Related Adverse Reactions in the MDD trials: In Studies 1 and 2, among the adverse reactions that occurred at ≥2% incidence in the patients treated with Brexpiprazole (Rexulti)+ADT, the incidences of akathisia and restlessness increased with increases in dose.
Schizophrenia: The safety of Brexpiprazole (Rexulti) was evaluated 852 patients (18 to 65 years of age) diagnosed with schizophrenia who participated in two 6-week, placebo-controlled, fixed-dose clinical trials in which Brexpiprazole (Rexulti) was administered at daily doses of 1 mg, 2 mg and 4 mg [see Pharmacology: Pharmacodynamics: Clinical Studies: Schizophrenia under Actions].
Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with Brexpiprazole (Rexulti) for Schizophrenia: Adverse reactions associated with Brexpiprazole (Rexulti) (incidence of 2% or greater and Brexpiprazole (Rexulti) incidence greater than placebo) during short-term (up to 6 weeks) trials in patients with schizophrenia are shown in Table 13. (See Table 13.)

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Agitation Associated with Dementia Due to Alzheimer's Disease: The safety of Brexpiprazole (Rexulti) was evaluated in 503 patients (51 to 90 years of age), with a probable diagnosis of agitation associated with dementia due to Alzheimer's disease, who participated in two 12-week placebo-controlled, fixed-dose clinical studies in which Brexpiprazole (Rexulti) was administered at daily doses of 2 mg to 3 mg [see Pharmacology: Pharmacodynamics: Clinical Studies: Agitation Associated with Dementia Due to Alzheimer's Disease under Actions].
Discontinuation of Treatment Due to Adverse Reactions: In two 12-week placebo-controlled, fixed-dose, clinical studies, a total of 5.6% (28/503) of patients treated with Brexpiprazole (Rexulti) and 4.8% (12/251) of patients treated with placebo discontinued due to adverse reactions.
Adverse Reactions Occurring at an Incidence of 2% or More in Patients Treated with Brexpiprazole (Rexulti) for Agitation Associated with Dementia Due to Alzheimer's Disease: Adverse reactions associated with Brexpiprazole (Rexulti) (incidence ≥2% and greater than placebo) during the 12-week fixed-dose clinical studies in geriatric patients for treatment of agitation associated with dementia due to Alzheimer's disease are shown in Table 14. (See Table 14.)

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Extrapyramidal Symptoms: Adjunctive Treatment of Major Depressive Disorder: The incidence of reported EPS-related adverse reactions, excluding akathisia, was 6% for Brexpiprazole (Rexulti)+ADT-treated patients versus 3% for placebo+ADT-treated patients. The incidence of akathisia events for Brexpiprazole (Rexulti)+ADT-treated patients was 9% versus 2% for placebo+ADT-treated patients.
In the 6-week, placebo-controlled MDD studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Score (AIMS) for dyskinesia. The mean change from baseline at last visit for Brexpiprazole (Rexulti)+ADT-treated patients for the SAS, BARS and AIMS was comparable to placebo treated patients. The percentage of patients who shifted from normal to abnormal was greater in Brexpiprazole (Rexulti)+ADT-treated patients versus placebo+ADT for the BARS (4% versus 0.6%) and the SAS (4% versus 3%).
Schizophrenia: The incidence of reported EPS-related adverse reactions, excluding akathisia, was 5% for Brexpiprazole (Rexulti)-treated patients versus 4% for placebo-treated patients. The incidence of akathisia events for Brexpiprazole (Rexulti)-treated patients was 6% versus 5% for placebo-treated patients.
In the 6-week, placebo-controlled, fixed-dose schizophrenia studies, data was objectively collected on the Simpson Angus Rating Scale (SAS) for extrapyramidal symptoms (EPS), the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for Brexpiprazole (Rexulti)-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Brexpiprazole (Rexulti)-treated patients versus placebo for the BARS (2% versus 1%) and the SAS (7% versus 5%).
Agitation Associated with Dementia Due to Alzheimer's Disease: The incidence of reported EPS-related adverse reactions, excluding akathisia, was 3% for Brexpiprazole (Rexulti)-treated patients versus 2% for placebo-treated patients. The incidence of akathisia events for Brexpiprazole (Rexulti)-treated patients was 1% versus 0% for placebo-treated patients.
In the 12-week placebo-controlled, fixed-dose studies in agitation associated with dementia due to Alzheimer's disease, data was objectively collected on the Simpson-Angus Rating Scale (SAS) for EPS, the Barnes Akathisia Rating Scale (BARS) for akathisia and the Abnormal Involuntary Movement Scale (AIMS) for dyskinesia. The mean change from baseline at last visit for Brexpiprazole (Rexulti)-treated patients for the SAS, BARS and AIMS was comparable to placebo-treated patients. The percentage of patients who shifted from normal to abnormal was greater in Brexpiprazole (Rexulti)-treated patients versus placebo for the SAS (6% versus 2%).
Dystonia: Symptoms of dystonia may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first-generation antipsychotic drugs. An elevated risk of acute dystonia is observed in males and younger age groups.
Other Adverse Reactions Observed During the Premarketing Evaluation of Brexpiprazole (Rexulti): Other adverse reactions (≥1% frequency and greater than placebo) within the short-term, placebo-controlled trials in patients with MDD and schizophrenia are shown as follows. The following listing does not include adverse reactions: 1) already listed in previous tables or elsewhere in the labeling, 2) for which a drug cause was remote, 3) which were so general as to be uninformative, 4) which were not considered to have clinically significant implications, or 5) which occurred at a rate equal to or less than placebo.
Eye Disorders: Vision Blurred.
Gastrointestinal Disorders: Nausea, Dry Mouth, Salivary Hypersecretion, Abdominal Pain, Flatulence.
Investigations: Blood Prolactin Increased.
Musculoskeletal and Connective Tissue Disorders: Myalgia.
Psychiatric Disorders: Abnormal Dreams.
Skin and Subcutaneous Tissue Disorders: Hyperhidrosis.
Pediatric Patients (13 to 17 years of age): In an on-going, 2 year, open-label study in pediatric patients 13 to 17 years of age with schizophrenia, in which safety was assessed in 194 patients of which 140 received Brexpiprazole (Rexulti) for at least 6 months. Adverse reactions reported in clinical studies for this age group were generally similar to those observed in adult patients.
Postmarketing Experience: The following adverse reaction has been identified during post-approval use of Brexpiprazole (Rexulti). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Nervous System disorders: Neuroleptic Malignant Syndrome.

Drugs Having Clinically Important Interactions with Brexpiprazole (Rexulti): See Table 15 for clinically important drug interactions with Brexpiprazole (Rexulti). (See Table 15.)

Click on icon to see table/diagram/image

Drugs Having No Clinically Important Interactions with Brexpiprazole (Rexulti): Based on pharmacokinetic studies, no dosage adjustment of Brexpiprazole (Rexulti) is required when administered concomitantly with CYP2B6 inhibitors (e.g., ticlopidine) or gastric pH modifiers (e.g., omeprazole). Additionally, no dosage adjustment for substrates of CYP2D6 (e.g., dextromethorphan), CYP3A4 (e.g., lovastatin), CYP2B6 (e.g., bupropion), BCRP (e.g., rosuvastatin), or P-gp (e.g., fexofenadine) is required when administered concomitantly with Brexpiprazole (Rexulti).

Store at temperatures not exceeding 30°C.

Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide).
Suicidal Thoughts and Behaviors: Advise patients and caregivers to look for the emergence of suicidality, especially early during treatment and when the dosage is adjusted up or down and instruct them to report such symptoms to the healthcare provider [see Warnings and Suicidal Thoughts and Behaviors in Children, Adolescents and Young Adults under Precautions].
Dosage and Administration: Advise patients that Brexpiprazole (Rexulti) can be taken with or without food. Advise patients regarding importance of following dosage escalation instructions [see Dosage & Administration].
Neuroleptic Malignant Syndrome (NMS): Counsel patients about a potentially fatal adverse reaction - Neuroleptic Malignant Syndrome (NMS) that has been reported in association with administration of antipsychotic drugs. Advise patients to contact a health care provider or report to the emergency room if they experience signs or symptoms of NMS [see Neuroleptic Malignant Syndrome (NMS) under Precautions].
Tardive Dyskinesia: Counsel patients on the signs and symptoms of tardive dyskinesia and to contact their health care provider if these abnormal movements occur [see Tardive Dyskinesia under Precautions].
Metabolic Changes: Educate patients about the risk of metabolic changes, how to recognize symptoms of hyperglycemia and diabetes mellitus, and the need for specific monitoring, including blood glucose, lipids, and weight [see Metabolic Changes under Precautions].
Pathological Gambling and Other Compulsive Behaviors: Advise patients and their 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 while taking Brexpiprazole (Rexulti). In some cases, but not all, the urges were reported to have stopped when the dose was reduced or stopped [see Pathological Gambling and Other Compulsive Behaviors under Precautions].
Leukopenia, Neutropenia and Agranulocytosis: Advise patients with a pre-existing low WBC or a history of drug induced leukopenia/neutropenia that they should have their CBC monitored while taking Brexpiprazole (Rexulti) [see Leukopenia, Neutropenia and Agranulocytosis under Precautions].
Orthostatic Hypotension and Syncope: Educate patients about the risk of orthostatic hypotension and syncope especially early in treatment, and also at times of re-initiating treatment or increases in dosage [see Orthostatic Hypotension and Syncope under Precautions].
Heat Exposure and Dehydration: Counsel patients regarding appropriate care in avoiding overheating and dehydration [see Body Temperature Dysregulation under Precautions].
Potential for Cognitive and Motor Impairment: Caution patients about performing activities requiring mental alertness, such as operating hazardous machinery or operating a motor vehicle, until they are reasonably certain that Brexpiprazole (Rexulti) therapy does not adversely affect their ability to engage in such activities [see Potential for Cognitive and Motor Impairment under Precautions].
Concomitant Medications: Advise patients to inform their health care providers of any changes to their current prescription or over-the-counter medications because there is a potential for clinically significant interactions [see Drugs Having Clinically Important Interactions with Brexpiprazole (Rexulti) under Interactions].
Pregnancy: Advise patients that third trimester use of Brexpiprazole (Rexulti) may cause extrapyramidal and/or withdrawal symptoms in a neonate and to notify their healthcare provider with a known or suspected pregnancy. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Brexpiprazole (Rexulti) during pregnancy [see Pregnancy under Use in Pregnancy & Lactation].

Antipsychotics

N05AX16 - brexpiprazole ; Belongs to the class of other antipsychotics.

Rx