Rexulti

Rexulti

brexpiprazole

Manufacturer:

Lundbeck

Distributor:

Zuellig Pharma
Full Prescribing Info
Contents
Brexpiprazole.
Description
1 mg, 2 mg, 3 mg, and 4 mg film-coated tablets contain 1 mg, 2 mg, 3 mg, and 4 mg of brexpiprazole, respectively.
Brexpiprazole is a serotonin-dopamine activity modulator that is available as brexpiprazole film-coated tablets.
Brexpiprazole occurs as white to off-white crystals or crystalline powders.
Chemical Name: 7-{4-[4-(1-Benzothiophen-4-yl)piperazin-1-yl]butyloxy}quinolin-2(1H)-one.
Molecular Formula: C25H27N3O2S.
Molecular Weight: 433.57.
Pharmaceutical Form: See Table 1.

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Excipients/Inactive Ingredients: Lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, talc, titanium dioxide, iron oxide red (3 mg), iron oxide yellow (1 mg, 2 mg), ferrosoferric oxide (2 mg, 3mg).
Action
Pharmacotherapeutic group: Psycholeptics, other antipsychotics. ATC code: N05AX16.
Pharmacodynamics: Brexpiprazole has affinity (expressed as Ki) for multiple monoaminergic receptors including serotonin 5-HT1A (0.12 nM), 5-HT2A (0.47 nM), 5-HT2B (1.9 nM), 5-HT7 (3.7 nM), dopamine D2 (0.30 nM), D3 (1.1 nM), and noradrenergic α1A (3.8 nM), α1B (0.17 nM), α1D (2.6 nM), and α2C (0.59 nM) receptors. Brexpiprazole acts as a partial agonist at the 5-HT1A, D2, and D3 receptors and as an antagonist at 5-HT2A, 5-HT2B, 5-HT7, α1A, α1B, α1D, and α2C 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, REXULTI does not prolong the QTc interval to any clinically relevant extent.
Mechanism of Action: The mechanism of action of brexpiprazole in the treatment of major depressive disorder or schizophrenia is unknown. However, the efficacy of brexpiprazole may be mediated through a combination of partial agonist activity at serotonin 5-HT1A and dopamine D2 receptors, and antagonist activity at serotonin 5-HT2A receptors.
Clinical Studies: Adjunctive Treatment of Major Depressive Disorder: The efficacy of brexpiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in three 6-week, placebo-controlled, fixed-dose trials, and one flexible dose clinical trial with an active reference in 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 (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.
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 (apparent sadness, reported sadness, inner tension, reduced sleep, reduced appetite, concentration difficulties, lassitude, inability to feel, pessimistic thoughts and suicidal thoughts). The key secondary endpoint was the Sheehan Disability Scale (SDS), a 3-item self-rated instrument used to assess the impact of depression on three domains of functioning (work/school, social life, and family life) with each item scored from 0 (not at all) to 10 (extreme).
At randomization, the mean MADRS total score was 27. In the three 6-week, placebo-controlled trials, brexpiprazole +ADT 2 mg/day and 3 mg/day demonstrated efficacy over placebo +ADT in reducing mean MADRS total scores. Brexpiprazole +ADT 2 mg/day and 3 mg/day also demonstrated efficacy over placebo +ADT in improving functioning as measured by the SDS mean score. Brexpiprazole 2 to 3 mg/day +ADT also showed statistically significantly greater improvement on the MADRS total score than placebo+ADT in the flexible-dose trial. Results from the primary and key secondary efficacy parameters for both fixed dose and flexible dose trials are shown as follows. In the three, fixed-dose clinical trials, pooled analysis of response rate provided support for the efficacy of brexpiprazole+ADT 2 mg/day and 3 mg/day. The response rate was higher in the brexpiprazole+ADT 2 and 3 mg/day group (28.0%) compared to placebo+ADT (21.1%).
An examination of population subgroups did not reveal evidence of differential response based on age, gender, race or choice of prospective antidepressant. (See Table 2.)

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The long-term efficacy and safety of REXULTI were evaluated in a phase 3, 24 week placebo-controlled trial (Study 5 (Study 14570A)). The adult patients in this trial fulfilled the DSM-IV-TR criteria for MDD, and demonstrated an inadequate response to 1-3 prior antidepressant therapy(ies) in the current episode and an inadequate response throughout 8 weeks of prospective antidepressant treatment.
Inadequate response during the prospective antidepressant treatment phase was defined as having persistent symptoms without substantial improvement throughout the course of the 8 weeks prospective treatment. The primary efficacy endpoint was full remission (defined as a MADRS total score ≤10 and a ≥50% decrease from randomisation in MADRS total score for at least 8 consecutive weeks during randomised treatment). This trial did not show efficacy of REXULTI over placebo.
Schizophrenia: The efficacy of REXULTI in adults with schizophrenia was demonstrated in four 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia who met DSM-IV-TR criteria for schizophrenia.
The primary efficacy endpoint of all trials was change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total score using MMRM analysis. The primary instrument for evaluating efficacy was the Positive and Negative Syndrome Scale, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. PANSS total score may range from 30 (absent symptoms) to 210 (extreme).
Efficacy was demonstrated in Study 6 (Study 231) for both brexpiprazole 2 mg/day and 4 mg/day and replicated in Study 7 (Study 230) only for brexpiprazole 4 mg/day and in Study 8 (Study 002) only for brexpiprazole 2 mg/day. The key secondary endpoint of both trials was change from baseline to Week 6 in Clinical Global Impression Severity of Illness Scale (CGI-S) total score, a validated clinician-related scale that measures the patient's current illness state and overall clinical state on a 1 (normal, not at all ill) to 7-point (extremely ill) scale.
In two fixed-dose clinical trials, REXULTI 4 mg/day demonstrated efficacy over placebo in the PANSS total score and showed greater improvement in CGI-S score compared to placebo. In two trials, REXULTI 2 mg/day demonstrated efficacy over placebo in the PANSS total score. Results from the primary and key secondary efficacy parameters for the fixed dose trials are shown as follows. In the three, fixed-dose clinical trials, pooled analysis of response rate provided support for the efficacy of REXULTI 2 mg/day and 4 mg/day. The response rate was higher in the REXULTI 4 mg/day group (42.5%) and 2 mg/day group (39.0%) compared to placebo (28.5%). In the flexible-dose Study 9 (Study 14644A), at week 6, subjects in the REXULTI group had numerically greater improvements on PANSS total score than the subjects in the placebo group, although, the difference at week 6 did not reach statistical significance for the primary efficacy analysis (p = 0.0560) (see Table 3). In the same study the active reference, quetiapine XR added for assay sensitivity only, separated from placebo.
The effects of REXULTI were evaluated across a number of pre-specified secondary endpoints; specific aspects of symptoms of schizophrenia (PANSS Positive Subscale score, PANSS Negative Subscale score, PANSS Excited Component (PEC) score, PANSS Marder factors Positive, Negative, Disorganized Thoughts, Uncontrolled Hostility/Excitement and Anxiety/Depression), improvement in Global Clinical Impression (CGI-I) and functioning (Personal and Social Performance scale and the Global Assessment of Functioning (GAF, maintenance Study 11 (Study 232) only)). Analyses of response (defined as 30 % improvement in PANSS total score compared to baseline and a CGI-I score of 1 (very much improved) or 2 (much improved)) and discontinuation for lack of efficacy were also performed. In Study 6 (Study 231), improvement in the change from baseline to week 6 for REXULTI compared to placebo was observed PANSS Positive (2 mg and 4 mg) and PANSS Negative Subscale scores (2 mg and 4 mg), PEC score (2 mg and 4 mg), PANSS Marder factors Positive, Negative, Disorganized Thought, and Uncontrolled Hostility/Excitement ( 2 mg and 4 mg); CGI-I score (2 mg and 4 mg) and in PSP score (2 mg); response rate for REXULTI at week 6 (2 mg and 4 mg) was larger, and discontinuation for lack of efficacy (4 mg/day) lower than for placebo. In Study 7 (Study 230), improvement in the change from baseline to week 6 for REXULTI compared to placebo in PANSS Positive and PANSS Negative Subscale scores, PEC score, PANSS Marder factors Negative, Disorganized Thought, and Uncontrolled Hostility/Excitement at 4 mg dose and PANSS Marder factor Anxiety/Depression at 2 mg and 4 mg doses; CGI-I (2 mg and 4 mg) and PSP score (4 mg); the response rate at week 6 was larger for REXULTI than for placebo for the 4 mg dose. In trial 3, improvement in the change from baseline at week 6 for REXULTI compared to placebo for the PANSS Negative Subscale score (2 mg and 4 mg), the PEC score (2 mg), the PANSS Marder Factors Negative Symptoms (2 mg and 4 mg), Disorganized Thought, and Anxiety/Depression scores (both 2 mg).
Examination of population subgroups based on age, gender and race did not show any statistical evidence of differential responsiveness. (See Table 3.)

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Maintenance: The safety and efficacy of REXULTI as maintenance treatment in adults with schizophrenia aged 18 to 65 years were demonstrated in a 52-week maintenance phase of a randomized withdrawal trial (Study 232). A pre-specified interim analysis demonstrated a statistically significantly longer time to impending relapse in patients randomized to the REXULTI group (1 mg/day to 4 mg/day) compared to placebo-treated patients and the trial was subsequently terminated early because maintenance of efficacy had been demonstrated. The final analysis demonstrated a longer time to impending relapse in patients randomized to the REXULTI group compared to placebo. The key secondary endpoint, the proportion of patients who met the criteria for impending relapse, was lower in REXULTI -treated patients (13.5%) compared with placebo group (38.5%). REXULTI reduced the risk of impending relapse by 71% compared to placebo. REXULTI improved clinical symptomology (as assessed by PANSS, CGI-S and GGI-I [LOCF]) and functioning (as assessed by GAF [LOCF]) during the stabilization phase. These improvements were maintained during the 52-week double-blind maintenance phase in patients on REXULTI whereas patients randomized to placebo showed deterioration in PANSS, CGI-S and GGI-I, and GAF scores [LOCF]). REXULTI maintained symptom control and functioning compared to placebo.
Pharmacokinetics: Absorption: After single dose administration of 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 10-12 days of dosing.
REXULTI can be administered with or without food. Administration of a 4 mg REXULTI tablet with a standard high fat meal did not significantly affect the Cmax or AUC of brexpiprazole. After single and multiple once daily dose administration, brexpiprazole exposure (Cmax 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 REXULTI oral tablet after once daily administration is 19.8 (±11.4) mL/h/kg. After multiple once daily administration of 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 1. Population PK analysis indicated exposure of brexpiprazole in patients with moderate renal impairment was higher compared to patients with normal renal function. (See Figure 1.)

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Drug Interaction Studies: Effects of other drugs on the exposures of brexpiprazole are summarized in Figure 2. 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 Interactions]. (See Figure 2.)

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The effects of REXULTI on the exposures of other drugs are summarized in Figure 3. (See Figure 3.)

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Special Population: Age/Gender: After single dose administration of brexpiprazole (2 mg), elderly subjects (older than 65 years old) exhibited similar brexpiprazole systemic exposure (Cmax and AUC) in comparison with the adult subjects (18-45 years old) and female subjects exhibited approximately 40-50% higher brexpiprazole systemic exposure (Cmax and AUC) in comparison to the male subjects. Population pharmacokinetic evaluation identified age and female sex as statistically significant covariates affecting brexpiprazole PK but the effects on PK were not considered clinically relevant.
Race: Although no specific pharmacokinetic study was conducted to investigate the effects of race on the disposition of brexpiprazole, population pharmacokinetic evaluation revealed no evidence of clinically significant race-related differences in the pharmacokinetics of brexpiprazole.
CYP2D6 Poor Metabolisers: Approximately 8% of whites and 3-8% of blacks/African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PM), whereas the rest are extensive metabolizers (EM). Population pharmacokinetic evaluation shows that CYP2D6 PMs have 47% higher exposure to brexpiprazole compared to EMs.
Smoking: Based on studies utilizing human liver enzymes in vitro, brexpiprazole is not a substrate for CYP1A2. Smoking should, therefore, not have an effect on the pharmacokinetics of brexpiprazole.
Non-Clinical Safety: Abuse/liability: Brexpiprazole showed neither a potential to produce physical dependence in rats nor a reinforcing effect in rhesus monkeys. In a drug abuse liability study in rats, no withdrawal signs suggestive of physical dependence were evident. Brexpiprazole is not considered to have potential to produce physical dependence.
Carcinogenicity, mutagenesis, and impairment of fertility: The lifetime carcinogenic potential of brexpiprazole was evaluated in a two year study in ICR mice and Sprague-Dawley rats. Brexpiprazole was administered orally (gavage) for two years to mice at doses of 0.75, 2 and 5 mg/kg/day (0.9 to 6.1-fold the 4 mg oral maximum recommended human dose [MRHD] for a 60 kg patient based on body surface area). There was no increase in the incidence of tumors in males at any dose group. In female mice, there was an increased incidence of mammary gland adenocarcinoma and adenosquamous carcinoma, and pars distalis adenoma of the pituitary gland. Brexpiprazole was administered orally (gavage) for two years to rats at doses of 1, 3 and 10 mg/kg/day in male rats or 3, 10 and 30 mg/kg/day in female rats (for males 2.4 to 24.3-fold and for females 7.3 to 72.9-fold the 4 mg oral MRHD for a 60 kg patient based on body surface area). Long-term administration of brexpiprazole to rats did not induce neoplastic lesions.
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.
The mutagenic potential of brexpiprazole was tested in the in vitro bacterial reverse mutation assay, the in vitro forward gene mutation assay in mouse lymphoma cells, the in vitro chromosomal aberration assay in Chinese hamster ovary (CHO) cells, the in vivo micronucleus assay in rats, and the unscheduled DNA synthesis assay in rats. In vitro with mammalian cells brexpiprazole was mutagenic and clastogenic but occurred at doses that induced cytotoxicity. No mutagenicity or genotoxicity was observed in other studies. Based on a weight of evidence, brexpiprazole is not considered to present a genotoxic risk to humans at therapeutic doses and exposures.
Brexpiprazole was given once daily by oral gavage to female rats at doses of 0, 0.3, 3 or 30 mg/kg/day prior to mating with untreated males and continuing through conception and implantation. Prolonged diestrus and decreased fertility were observed at 3 and 30 mg/kg/day. At 30 mg/kg/day a slight prolongation of the mating phase was observed and significantly increased preimplantation losses were seen. The no observed adverse effect level in brexpiprazole was 0.3 mg/kg/day (0.7-fold the 4 mg oral MRHD for a 60 kg patient based on body surface area).
Brexpiprazole was given once daily by oral gavage to male rats at 0, 3, 10 or 100 mg/kg/day. Following 63 days of dosing, treated males were cohabited with untreated females for a maximum of 14 days. No noticeable differences were noted in the duration of mating or fertility indices in any brexpiprazole treated group.
Teratogenic effects: Brexpiprazole was not teratogenic and did not cause adverse developmental effects in developmental toxicity studies in which pregnant rats and rabbits were given brexpiprazole during the period of organogenesis at doses up to 30 mg/kg/day (73-fold and 146-fold for rats and rabbits, respectively of the 4 mg/day oral MRHD for a 60 kg patient based on body surface area, with respective rat and rabbit exposures (plasma AUC) 3.3-fold and 5.9-fold the clinical exposure at the 4mg/day MRHD).
In a rabbit embryo-fetal development study (at 150 mg/kg/day, a dose that induced maternal toxicity), decreased body weight, retarded ossification, and increased incidences of visceral and skeletal variations were observed in fetuses.
Cardiovascular Toxicity: Decreased blood pressure and prolonged QT interval and QTc were noted in the conscious dog in the safety pharmacology study in the 13-week repeat-dose toxicity study with monkeys and in the juvenile toxicity study with dogs. The effect of brexpiprazole on decreased blood pressure was suggested to be due to a blockade of α1- adrenoceptors in peripheral blood vessels, which is consistent with the pharmacological profile for this compound.
Indications/Uses
Brexpiprazole is indicated in adult patients for: Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD). Efficacy was demonstrated in 6-week trials in adults with MDD who had an inadequate response to antidepressant therapy during the current episode. The long-term efficacy of brexpiprazole as adjunctive treatment in MDD has not been established.
Treatment of schizophrenia.
Dosage/Direction for Use
For oral use once daily with or without food.
Dosage and Method of Administration: Adjunctive Treatment of Major Depressive Disorder: The recommended starting dose for REXULTI as adjunctive treatment is 0.5 mg or 1 mg once daily. Dose titration to 1 mg/day and up to the target dose of 2 mg/day should occur at intervals of up to 1 week based on the patient's clinical response and tolerability. Doses up to 3 mg/day have been studied in clinical trials. The benefit of the 3 mg dose has not been clearly established. Periodically reassess to determine the continued need and appropriate dose for treatment.
The long-term efficacy of REXULTI as adjunctive treatment in MDD has not been established.
Schizophrenia: The recommended starting dose for REXULTI in the treatment of patients with schizophrenia is 1 mg once daily on days 1 to 4. The recommended target dose range is 2 mg to 4 mg once daily. Titrate to 2 mg once daily on Day 5 through Day 7, then to 4 mg on Day 8 based on the patient's clinical response and tolerability. The maximum recommended daily dosage is 4 mg.
Maintenance treatment: The recommended maintenance dose range is 2 mg/day to 4 mg/day. Periodically reassess to determine the continued need for maintenance treatment.
Dosing Precautions: Dosing Adjustment for Hepatic Impairment: For patients with moderate to severe hepatic impairment (Child-Pugh score ≥7), the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia.
Dosing Adjustment for Renal Impairment: For patients with moderate, severe or end-stage renal impairment (creatinine clearance CLcr<60 mL/minute), the maximum recommended dosage is 2 mg once daily for patients with MDD and 3 mg once daily for patients with schizophrenia. (See Table 4.)

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Overdosage
No specific information is available on the treatment of overdose with REXULTI. Gastric lavage and treatment with an emetic may be useful immediately after overdose. An electrocardiogram should be obtained in case of overdosage and if QT interval prolongation is present, cardiac monitoring should be instituted. Otherwise, management of 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.
Consult a certified POISON CONTROL CENTER for up to date guidance and advice.
Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting oral brexpiprazole, decreased brexpiprazole Cmax and 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. Although there is no information on the effect of hemodialysis in treating an overdose with REXULTI, hemodialysis is unlikely to be useful in overdose management since brexpiprazole is highly bound to plasma proteins.
Contraindications
Hypersensitivity to the active substance or to any of the excipients. Reactions have included rash, facial swelling, urticaria, and anaphylaxis.
Special Precautions
Product Specific Warnings and 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 compared to placebo. Analyses of 17 placebo-controlled trials (modal duration of 10 weeks), in patients taking atypical antipsychotic drugs (including risperidone, aripiprazole, olanzapine, and quetiapine), revealed a risk of death in 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 varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature. Brexpiprazole is not approved for the treatment of dementia-related psychosis.
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. REXULTI is not approved for the treatment of patients with dementia-related psychosis.
Suicidal Risk: The possibility of a suicide attempt is inherent in psychotic illnesses and major depressive disorder (MDD). Close supervision and appropriate clinical management of high-risk patients should accompany drug therapy.
Suicidal Thoughts and Behaviours 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 paediatric patients, the incidence of suicidal thoughts and behaviours in patients age 24 years 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 behaviours per 1000 patients treated are provided in Table 5. No suicides occurred in any of the paediatric 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 5.)

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It is unknown whether the risk of suicidal thoughts and behaviours 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 behaviours, especially during the initial few months of drug therapy and at times of dosage changes. Counsel family members or caregivers of patients to monitor for changes in behaviour and to alert the healthcare provider. Consider changing the therapeutic regimen, including possibly discontinuing REXULTI, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviours.
Neuroleptic Malignant Syndrome (NMS): A potentially fatal symptom complex, referred to as Neuroleptic Malignant Syndrome (NMS), has been reported in association with administration of antipsychotic drugs including 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 creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotic drugs including REXULTI must be discontinued. If a patient requires antipsychotic drug treatment after recovery from NMS, the potential reintroduction of drug therapy should be carefully considered.
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 the elderly, especially elderly women, but it is not possible to predict which patients are likely to 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 increase with the duration of treatment and the cumulative dose. The syndrome can develop after a relatively brief treatment period, even at low doses. It may also occur after discontinuation of treatment.
There is no known treatment for established cases of tardive dyskinesia, although the syndrome may remit, partially or completely, if antipsychotic treatment is discontinued. Antipsychotic treatment itself, however, may suppress (or partially suppress) the signs and symptoms of the syndrome, possibly masking the underlying process. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown.
Given these considerations, REXULTI should be prescribed in a manner most likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment should generally be reserved for patients: who suffer from a chronic illness that is known to respond to antipsychotic drugs; and for whom alternative, effective, but potentially less harmful treatments are not available or appropriate. In patients who do require chronic treatment, use the lowest dose and the shortest duration of treatment needed to produce a satisfactory clinical response. Periodically reassess the need for continued treatment.
If signs and symptoms of tardive dyskinesia appear in a patient on REXULTI, drug discontinuation should be considered. However, some patients may require treatment with REXULTI despite the presence of the syndrome.
Metabolic Changes: Atypical antipsychotic drugs, including 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, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotics. Assessment of the relationship between atypical antipsychotics use and glucose abnormalities is complicated by the possibility of an increased background risk of diabetes mellitus in patients with schizophrenia and the increasing incidence of diabetes mellitus in the general population. Given these confounders, the relationship between atypical antipsychotic use and hyperglycaemia-related adverse events is not completely understood. However, epidemiological studies suggest an increased risk of treatment-emergent hyperglycaemia-related adverse events in patients treated with the atypical antipsychotics. Precise risk estimates for hyperglycaemia-related adverse events in patients treated with atypical antipsychotics are not available.
Patients with an established diagnosis of diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) who are starting treatment with atypical antipsychotics should undergo fasting blood glucose testing in the beginning of treatment and periodically during treatment. Any patient treated with atypical antipsychotics should be monitored for symptoms of hyperglycaemia including polydipsia, polyuria, polyphagia, and weakness. Patients who develop symptoms of hyperglycaemia during treatment with atypical antipsychotics should undergo fasting blood-glucose testing. In some cases, hyperglycaemia has resolved when the atypical antipsychotic was discontinued; however, some patients required continuation of anti-diabetic treatment despite discontinuation of the suspect drug.
There have been reports of hyperglycemia in patients treated with REXULTI. (see Adverse Reactions).
Dyslipidemia: Atypical antipsychotics cause adverse alterations in lipids. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment (see Adverse Reactions).
Weight Gain: Weight gain has been observed in patients treated with atypical antipsychotics, including REXULTI. Monitor weight at baseline and frequently thereafter.
For more details related to metabolic changes and weight gain see Adverse Reactions.
Prolactin: REXULTI can elevate prolactin levels. Elevations associated with REXULTI treatment are generally mild and may decline during administration, however, in some infrequent cases the effect may persist during administration.
Genitourinary: Although no cases of priapism were reported in clinical trials with REXULTI, rare cases of priapism have been reported with antipsychotic use. With other psychotropic drugs, this adverse reaction did not appear to be dose-dependent and did not correlate with the duration of treatment.
Venous thromboembolism: Venous thromboembolism (VTE), including fatal pulmonary embolism, has been reported with antipsychotic drugs including REXULTI, in case reports and/or observational studies. When prescribing REXULTI all potential risk factors for VTE should be identified and preventative measures undertaken.
Immune: Hypersensitivity: Spontaneous post-market reports of serious hypersensitivity reactions, such as anaphylaxis, angioedema and facial swelling, rash and urticaria, have been reported with REXULTI.
Cardiovascular disorders: REXULTI has not been evaluated in patients with a history of myocardial infarction/ischaemic heart disease or clinically significant cardiovascular disease since such patients were excluded from clinical trials.
REXULTI should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension (including accelerated or malignant).
Leukopenia, Neutropenia and Agranulocytosis: Leukopenia and neutropenia have been reported during treatment with antipsychotic agents. Agranulocytosis (including fatal cases) has been reported with other agents in this class.
Possible risk factors for leukopenia and neutropenia include pre-existing low white blood cell count (WBC) or absolute neutrophil count (ANC) and history of drug-induced leukopenia or neutropenia. In patients with a pre-existing low WBC or ANC or a history of drug-induced leukopenia or neutropenia, perform a complete blood count (CBC) frequently during the first few months of therapy. In such patients, consider discontinuation of 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 REXULTI in patients with 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 two short-term, placebo-controlled clinical studies of REXULTI+ADT in patients with MDD Studies 1 (Study 228) and 2 (Study 227), the incidence of orthostatic hypotension-related adverse reactions in REXULTI+ADT-treated patients compared to placebo+ADT patients included: dizziness (2% vs. 2%) and orthostatic hypotension (0.1% vs. 0%). In two short-term, placebo-controlled clinical studies of REXULTI in patients with schizophrenia Studies 6 (Study 231) and 7 (Study 230) the incidence of orthostatic hypotension-related adverse reactions in 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%).
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. 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 trials.
QT Interval: QT prolongation can develop in patients treated with antipsychotics. In clinical trials, only a few, nonserious, QT prolongations have been reported with REXULTI. Caution should be exercised when REXULTI is prescribed in patients with known cardiovascular disease, family history of QT prolongation, electrolyte imbalance or in concomitant use with other medicinal products thought to prolong the QT interval.
Falls: Antipsychotics, including 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, REXULTI may cause seizures. This risk is greatest in patients with a history of seizures or with conditions that lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in older patients.
Body Temperature Regulation: Atypical antipsychotics may disrupt the body's ability to reduce core body temperature. Strenuous exercise, exposure to extreme heat, dehydration, and anticholinergic medications may contribute to an elevation in core body temperature; use REXULTI with caution in patients who may experience these conditions.
Dysphagia: Esophageal dysmotility and aspiration have been associated with antipsychotic drug use. Aspiration pneumonia is a common cause of morbidity and mortality in elderly patients, in particular those with advanced Alzheimer's dementia. Brexpiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.
Pathological Gambling and Other Compulsive Behaviours: Post-marketing case reports suggest that patients can experience intense urges, particularly for gambling, and the inability to control these urges while taking REXULTI. Other compulsive urges, reported less frequently, include: sexual urges, shopping, eating or binge eating, and other impulsive or compulsive behaviours. Because patients may not recognize these behaviours 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 REXULTI. In some cases, although not all, urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Compulsive behaviours 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.
Lactose: REXULTI film-coated tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.
Potential for Cognitive and Motor Impairment: REXULTI, like other antipsychotics has the potential to impair judgment, thinking or motor skills. In two 6-week, placebo-controlled clinical trials in patients with MDD, somnolence (including sedation and hypersomnia) was reported in 4% for REXULTI+ADT-treated patients compared to 1% of placebo+ADT patients Studies 1 (Study 228) and 2 (Study 227).
In two 6-week, placebo-controlled clinical trials in patients with schizophrenia, somnolence (including sedation and hypersomnia) was reported in 5% of REXULTI-treated patients compared to 3% of placebo-treated patients Studies 6 (Study 231) and 7 (Study 230).
Patients should be cautioned about operating hazardous machinery including motor vehicles until they are reasonably certain that REXULTI therapy does not affect them adversely.
Special Population: Hepatic Impairment: Patients with moderate to severe hepatic impairment (Child-Pugh score ≥7) generally had higher exposure to brexpiprazole than patients with normal hepatic function; therefore, the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia. In subjects with varying degrees of hepatic impairment (Child-Pugh Classes A, B, and C), the AUC of oral brexpiprazole (2 mg single dose), compared to matched healthy subjects, increased 24% in mild hepatic impairment, increased 60% in moderate hepatic impairment, and did not change in severe hepatic impairment.
Renal Impairment: Patients with impaired renal function (CLcr<60 mL/minute) had higher exposure to brexpiprazole than patients with normal renal function; therefore, the maximum recommended dosage is 2 mg once daily for patients with MDD, and 3 mg once daily for patients with schizophrenia . In subjects with severe renal impairment (CLcr <30 mL/min), AUC of oral brexpiprazole (2 mg single dose) compared to matched healthy subjects was increased by 68% while its Cmax was not changed.
Other Special Populations: No dosage adjustment for brexpiprazole is required on the basis of a patient's sex, race, or smoking status (see Pharmacology: Pharmacokinetics: Special Population under Actions).
Use in Children: Safety and effectiveness in pediatric patients have not been established. Antidepressants increased the risk of suicidal thoughts and behaviours in paediatric patients (See Precautions).
Use in Elderly: Clinical studies of brexpiprazole did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. In long-term trials, no new safety concerns were identified in patients 65 years of age or older with MDD (N=132) treated with 1-3 mg of REXULTI as adjunctive treatment to continued antidepressant therapy during 26 weeks In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
Based on the results of a safety, tolerability and pharmacokinetics (PK) trial, once daily oral administration of brexpiprazole (up to 3 mg/day for 14 days) as an adjunct therapy in the treatment of elderly subjects (70 to 85 years old, N=11) with MDD were comparable to that of the adult subjects with MDD.
Elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death compared to placebo. REXULTI is not approved for the treatment of patients with dementia related psychosis.
Use In Pregnancy & Lactation
Pregnancy: Risk Summary: Adequate and well-controlled studies have not been conducted with REXULTI in pregnant women to inform drug-associated risks. However, neonates whose mothers are exposed to antipsychotic drugs, like 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.
Clinical Considerations: Foetal/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.
REXULTI should be used during pregnancy only if the potential benefit justifies the risk to the foetus.
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 REXULTI on the breastfed infant, or the effects of REXULTI 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 REXULTI and any potential adverse effects on the breastfed infant from REXULTI or from the underlying maternal condition.
Adverse Reactions
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.
As with other drugs belonging to the therapeutic class of atypical antipsychotics, cases of restless legs syndrome and urinary retention have been reported for REXULTI.
Atypical antipsychotic drugs, such as REXULTI, have been associated with cases of sleep apnea, with or without concomitant weight gain. In patients who have a history of or are at risk for sleep apnea, REXULTI should be prescribed with caution.
CLINICAL TRIAL DATA FOR MAJOR DEPRESSIVE DISORDER: Table 6 shows the incidence of treatment-emergent adverse events (TEAEs) that occurred in at least 2% of patients treated with REXULTI and observed more frequently than with placebo. (See Table 6.)

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Adverse reactions that occurred <2% and the difference between REXULTI and placebo ≥0.5% in the short-term; placebo-controlled MDD adjunctive therapy clinical trials included palpitations, blepharospasm, toothache, salivary hypersecretion, urinary tract infection, blood prolactin increased, blood cortisol decreased, aspartate aminotransferase increased, muscle spasms, tension, night sweats and hypertension.
Selected Adverse Reactions: Extrapyramidal Symptoms: In the three 6-week, placebo-controlled, fixed-dose and one 6-week, placebo-controlled, flexible-dose MDD studies for REXULTI-treated patients, the incidence of reported EPS-related events, excluding akathisia events, was 5% versus 3% for placebo-treated patients. The incidence of akathisia events for REXULTI-treated patients was 8% versus 3% for placebo-treated patients.
Clinical Chemistry Findings: Weight Gain: In the long-term, placebo-controlled MDD study, the mean change in body weight from baseline at week 24 was 2.2 kg (N=349) for brexpiprazole and 0.8 kg (N=380) for placebo. The proportion of patients with a ≥ 7% increase in body weight was 19% (84/440) in the REXULTI group and 8.3% (36/436) in the placebo group and with a ≥ 7% decrease in body weight it was 1.4% (6/441) in the REXULTI group and 4.1% (18/436) in placebo. Weight increased led to discontinuation in 0.7% and 0.2% of patients in the REXULTI and placebo groups, respectively.
In the long-term, open-label MDD studies, the mean change in body weight from baseline to last visit was 2.6 kg (N=2232). The proportion of patients with a ≥7% increase in body weight at last visit was 22.12% (494/2232) and with a ≥7% decrease in body weight was 3.2% (72/2232). At 52 weeks, the proportion of patients with a ≥7% increase in body weight was 28.2 % (286/1013) and with a ≥7% decrease in body weight was 3.7% (37/1013). Weight gain led to discontinuation of study medication in 3.8% (84/2240) of patients.
Fasting Glucose: In the long-term, placebo-controlled MDD study, 7.1% of patients in the REXULTI group and 3.4% of patients in the placebo group had shifts from normal or impaired to high in fasting glucose. The mean change from baseline for fasting glucose to last visit was 1.74 mg/dL and 0.21 mg/dL for REXULTI and placebo, respectively.
In the long-term, open-label MDD studies, 5.22% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking REXULTI, 24.35% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 9.06% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term MDD studies. The mean change from baseline for fasting glucose to last visit in the long-term, open label trials was 3.53 [2.00] mg/dL.
Fasting Lipids: In the long-term, placebo-controlled study mean changes from baseline and shifts in lipids are presented in Table 7. (See Table 7.)

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In the long-term open-label studies, shifts in fasting cholesterol from normal to high were reported in 8.65% (total cholesterol), 3.20% (LDL cholesterol), and shifts from normal to low were reported in 13.30% (HDL cholesterol) of patients taking REXULTI. Of patients with normal baseline triglycerides, 17.26% experienced shifts to high, and 0.22% experienced shifts to very high triglycerides. Combined, 0.61% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term MDD studies. The mean changes from baseline for fasting HDL cholesterol, fasting LDL cholesterol, fasting cholesterol and fasting triglycerides to last visit in the longterm, open label trials were -2.13 [-2.00] mg/dL, 1.36 [1.00] mg/dL, 0.05 [0.00] mg/dL and 11.46 [8.00] mg/dL, respectively.
CLINICAL TRIAL DATA FOR SCHIZOPHRENIA: Table 8 shows the incidence of treatment-emergent adverse events (TEAEs) that occurred in at least 2% of patients treated with REXULTI and observed more frequently than placebo. (See Table 8.)

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Adverse reactions that occurred <2% and the difference between REXULTI and placebo ≥0.5% in the short-term; placebo-controlled schizophrenia clinical trials included abdominal pain upper, dental caries, flatulence, pain, blood pressure increased, blood triglycerides increased, pain in extremity, myalgia, sedation, cough and rash.
Extrapyramidal Symptoms: In the 6-week, placebo-controlled, fixed-dose schizophrenia studies for 2-4 mg REXULTI -treated patients, the incidence of reported EPS-related events, excluding akathisia events, was 12% versus 10% for placebo-treated patients. The incidence of akathisia events for REXULTI -treated patients was 6% versus 5% for placebo treated patients.
Clinical Chemistry Findings: Weight Gain: In the long-term, open-label schizophrenia studies, the mean change in body weight from baseline to last visit was 1.0 kg (N=1468). The proportion of patients with a ≥7% increase in body weight at any visit was 17.9% (226/1257) and with a ≥7% decrease in body weight at any visit was 8.2% (104/1257). Weight gain led to discontinuation of study medication in 0.4% (5/1265) of patients.
Fasting Glucose: In the long-term, open-label schizophrenia studies, 7% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking brexpiprazole, 17% of subjects with borderline fasting glucose experienced shifts from borderline to high. Combined, 9% of patients with normal or borderline fasting glucose experienced shifts to high fasting glucose during the long-term schizophrenia studies. The mean change from baseline for fasting glucose to last visit in the long-term, open label trials was 2.35 [2.00] mg/dL.
Fasting Lipids: In the long-term open-label studies, shifts in baseline fasting cholesterol from normal to high were reported in 6% (total cholesterol), 3% (LDL cholesterol), and shifts in baseline from normal to low were reported in 20% (HDL cholesterol) of patients taking brexpiprazole. Of patients with normal baseline triglycerides, 14% experienced shifts to high, and 0.3% experienced shifts to very high triglycerides. Combined, 0.5% of patients with normal or borderline fasting triglycerides experienced shifts to very high fasting triglycerides during the long-term schizophrenia studies. The mean changes from baseline for fasting HDL cholesterol, fasting LDL cholesterol, fasting cholesterol and fasting triglycerides to last visit in the long-term, open label trials were 0.89 [1.00] mg/dL, -0.97 [-1.00] mg/dL, 0.05 [0.00] mg/dL and -0.40 [-2.00] mg/dL, respectively.
Additional Findings Observed in Schizophrenia Clinical Trials: The adverse reactions reported in a 52-week maintenance phase of a randomized, placebo-controlled withdrawal trial in adults with schizophrenia were comparable with those reported in short-term, fixeddose trials for schizophrenia.
Drug Interactions
Drugs Having Clinically Important Interactions with REXULTI: (See Table 9.)

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Drugs Having No Clinically Important Interactions with REXULTI: Based on pharmacokinetic studies, no dosage adjustment of 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 REXULTI.
As with other antipsychotics, caution should be used if REXULTI is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance.
Food: Intake of food has no effect on the pharmacokinetics of REXULTI.
Caution For Usage
Special Instructions for Use, Handling and Disposal: No special requirements.
Incompatibilities: Not applicable.
Storage
Store below 30°C.
Shelf-Life: 3 years.
MIMS Class
ATC Classification
N05AX16 - brexpiprazole ; Belongs to the class of other antipsychotics.
Presentation/Packing
FC tab 1 mg (round, light yellow, marking "BRX" and "1") x 28's. 2 mg (round, light green, marking "BRX" and "2") x 28's. 3 mg (round, light purple, marking "BRX" and "3") x 28's. 4 mg (round, white, marking "BRX" and "4") x 28's.
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