Rexalti tablets 2 mg No. 28

Instructions for Rexalti tablets 2 mg No. 28

Composition

active ingredient: brexpiprazole;

1 tablet contains brexpiprazole 0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg, 3.0 mg or 4.0 mg;

excipients: lactose monohydrate, corn starch, microcrystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate

film coating: Opadry 03A465005 Brown (for 0.25 mg tablets), Opadry® 03A430000 Orange (for 0.5 mg tablets), Opadry 03A420002 Yellow (for 1.0 mg tablets), Opadry 03A410000 Green (for 2.0 mg tablets), Opadry 03A400000 Purple (for 3.0 mg tablets), Opadry 03A480004 White (for 4.0 mg tablets) (hypromellose 2910, titanium dioxide (E 171), talc, iron oxide yellow (E 172, for 0.25 mg, 0.5 mg, 1.0 mg and 2.0 mg tablets), iron oxide red (E 172, for 0.25 mg, 0.5 mg and 3.0 mg tablets) mg), iron oxide black (E 172, for tablets 0.25 mg, 2.0 mg and 3.0 mg)).

Dosage form

Film-coated tablets. Main physicochemical properties:

0.25 mg tablets: round, film-coated tablets, light brown in color, with the imprint “BRX” and “0.25” on one side;

0.5 mg tablets: round, film-coated tablets, light orange in color, with the imprint “BRX” and “0.5” on one side;

1 mg tablets: round, film-coated tablets, light yellow in color, with an imprint of “BRX” and “1” on one side;

2 mg tablets: round, film-coated tablets, light green in color, with "BRX" and "2" imprinted on one side;

3 mg tablets: round, film-coated tablets, light purple in color, imprinted with "BRX" and "3" on one side;

4 mg tablets: round, film-coated tablets, white to off-white, debossed with "BRX" and "4" on one side.

Pharmacotherapeutic group

Drugs acting on the nervous system. Psycholeptics. Other antipsychotics. ATC code N05A X16.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Brexpiprazole is an antipsychotic agent. The pharmacology of brexpiprazole is thought to be mediated by modulatory activity at the serotonin and dopamine systems, combining partial agonist activity at 5-HT1a and dopaminergic D2 receptors with antagonist activity at 5-HT2a receptors with similar high affinity for all of these receptors (inhibition constant (Ki): 0.1-0.5 nmol). Brexpiprazole also exhibits antagonistic activity at noradrenergic sivas receptors with affinities in the same subnanomolar Ki range (Ki: 0.2-0.6 nmol).

Pharmacodynamic effects

The effect of genetic variations on the pharmacodynamic response to brexpirazole has not been studied.

Effect on the OT interval

The effect of brexpiprazole on the QT interval was studied in patients with schizophrenia or schizoaffective disorder. In a pooled analysis, brexpiprazole did not cause clinically significant prolongation of the QTc interval after administration at therapeutic and supratherapeutic doses (4 mg/day; n = 62 or 12 mg/day; n = 53), and there was no correlation between brexpiprazole concentrations and QTc prolongation.

Subgroup analyses in the QT interval study demonstrated that QT prolongation was greater in women than in men. In the brexpiprazole 4 mg/day group, the maximum placebo-adjusted mean change from baseline in QT interval was 5.2 ms (90% CI: 1.5, 8.9) in men (n=48) and 15.0 ms (90% CI: 7.7, 22.3) in women (n=14) at 6 hours post-dose. In the brexpiprazole 12 mg/day group, the maximum placebo-adjusted mean change from baseline in QT interval was 2.9 ms (90% CI: -1.2, 6.9) in men (n=40) at 12 hours post-dose and 10.4 ms (90% CI: 2.7, 18.2) in women (n=13) at 24 hours post-dose. The smaller number of women than men included in the study does not allow for definitive conclusions.

Clinical efficacy and safety

The efficacy and safety of brexpiprazole in adults with schizophrenia were studied in two multinational and one regional (Japan), 6-week, randomised, double-blind, placebo-controlled, fixed-dose clinical trials (Studies 1-3), a multinational, 6-week, randomised, double-blind, placebo-controlled, active reference (quetiapine) flexible-dose clinical trial (Study 4), and one multinational, placebo-controlled, 52-week maintenance treatment trial (Study 5). These trials enrolled 2690 patients aged 18-65 years.

In Studies 1, 2, and 3, the dose of brexpiprazole was titrated as described in the Dosage and Administration section: 1 mg for 4 days, then 2 mg on days 5 through 7. On day 8, the dose was increased to 4 mg for some treatment groups.

Short-term studies

Study 4 evaluated the efficacy, safety, and tolerability of brexpiprazole with a flexible dose range of 2-4 mg/day and quetiapine extended-release (XR) doses of 400-800 mg to assess responsiveness. In these short-term studies, the primary efficacy endpoint was defined as the mean change from baseline at Week 6 in the total scores on the Positive and Negative Syndrome Scale (PANSS), a multi-item inventory consisting of five factors assessing positive symptoms, negative symptoms, disorganized thinking, uncontrolled hostility/agitation, and anxiety/depression.

The key secondary endpoint in Studies 1, 2, and 4 was the Clinical Global Illness Severity Score (CGI-S) for Schizophrenia, a 7-point clinician-rated measure of illness severity. The CGI-S was also assessed in Studies 3 and 5 as a secondary endpoint. The efficacy of brexpiprazole was also assessed on several pre-specified secondary endpoints; specific aspects of schizophrenia symptoms (PANSS positive subscale score, PANSS negative subscale score, PANSS excitement component score [PEC], Marder factors PANSS positive, negative, disorganized thinking, uncontrolled hostility/agitation, and anxiety/depression) and response analyses (defined as a 30% improvement from baseline in the PANSS total score or a CGI-I score of 1 [very much improved] or 2 [much improved]).

Efficacy was demonstrated in Study 1 for both brexpiprazole doses of 2 mg/day and 4 mg/day and was replicated in Study 2 for brexpiprazole dose of 4 mg/day only and in Study 3 for brexpiprazole dose of 2 mg/day only.

In flexible-dose study 4, patients in the brexpiprazole group had a numerically greater improvement in PANSS total score than patients in the placebo group, but the difference at week 6 did not reach statistical significance for the primary efficacy analysis (p=0.0560; see Table 1). In this study, the active reference drug (quetiapine XR) was added only for sensitivity assessment, separate from placebo.

Table 1. Main efficacy results from 6-week schizophrenia studies

SD - Standard Deviation

SD - Standard Error

LS Mean Least Squares Mean

CI - Confidence Interval

* - Treatment is statistically significantly more effective than placebo

a - Difference (brexpiprazole minus placebo) in least squares means, change from baseline to week 6

b - LS mean, 95% CI, and p-values for individual studies were obtained in a mixed effects model for multiple measurements (MMRM) analysis as follows: study center, treatment, visit, and the relationship between visit and treatment effect were fixed effects, and baseline and change from baseline at a given visit were covariates. An unstructured variance-covariance matrix structure was used.

The primary analysis was performed using the MMRM model with random imputation for missing data. The results of the sensitivity analysis using placebo-based multiple imputation for missing data (PMI) were consistent with the primary analysis. The results for the (key) secondary outcomes and secondary endpoints supported the data for the primary endpoint.

Table 2. Key secondary efficacy outcomes from 6-week schizophrenia studies

CB - Standard deviation

SD - Standard Error

LS Mean Least Squares Mean

CI - Confidence Interval

* Treatment is statistically significantly more effective than placebo

a- Difference (brexpiprazole minus placebo) in least squares means, change from baseline to week 6

b- Average dose 3.5 mg/day

Research on maintaining effectiveness

In Study 5, a long-term study designed to assess the maintenance of brexpiprazole by assessing the time delay to future relapse of schizophrenia, patients with schizophrenia who responded to treatment with brexpiprazole 1-4 mg/day were stabilized for 12-36 weeks and then randomized in a double-blind fashion to continue treatment with a stabilizing dose of brexpiprazole (n=96) or receive placebo (n=104) for 52 weeks or until relapse.

In the primary analysis of time to future relapse, patients treated with brexpiprazole demonstrated a significantly longer time to relapse compared with patients treated with placebo (p < 0.0001). At week 52, brexpiprazole (13.5%) reduced the risk of future relapse by 71% compared with placebo (38.5%). During stabilization, brexpiprazole improved clinical symptoms (PANSS, CGI-S, and CGI- [analysis of covariance - ANCOVA, last observation carried forward LOCF]) and function (Global Assessment of Functional Status (GAF) scale score (ANCOVA LOCF)). These improvements were maintained during the 52-week double-blind maintenance phase in patients treated with brexpiprazole, whereas patients randomized to placebo experienced worsening of PANSS, CGI-S, CGI-I, and GAF scores [ANCOVA LOCF]). Compared with placebo, brexpiprazole maintained symptom control and function.

Children

The European Medicines Agency has deferred the obligation to provide the results of studies on the efficacy and safety of brexpiprazole in children aged 13 to 18 years (for information on use in children, see the section “Method of administration and dosage”).

Pharmacokinetics

Absorption

Brexpiprazole is absorbed after tablet administration, reaching peak plasma concentrations 4 hours after a single dose, with an absolute oral bioavailability of 95.1%. Steady-state concentrations of brexpiprazole are achieved within 10-12 days of dosing. Administration of a 4 mg brexpiprazole tablet with a standard high-fat meal had no significant effect on Cmax or AUC of brexpiprazole. After single and multiple once-daily dosing, brexpiprazole exposure (Cmax and AUC) increased in proportion to the dose administered. Based on in vivo studies, brexpiprazole is not a substrate or inhibitor of efflux transporters such as multidrug resistance protein (MDR) 1, P-gp, and BCRP. Distribution

The volume of distribution of brexpiprazole after intravenous administration is high (1.56 l/kg ± 0.418 l/kg), indicating extravascular distribution. Brexpiprazole is highly bound to plasma proteins (greater than 99%), to serum albumin and α1-acid glycoprotein, and protein binding is not affected by renal or hepatic impairment. Based on in vitro studies, the protein binding of brexpiprazole is not affected by warfarin, diazepam and digitoxin.

Based on in vitro metabolism studies using recombinant human cytochrome P450, the metabolism of brexpiprazole is primarily mediated by CYP3A4 and CYP2D6 to form oxidative metabolites. Based on in vitro data, brexpiprazole does not inhibit or only slightly inhibits other CYP450 enzymes. In vivo, the metabolism of brexpiprazole is primarily mediated by CYP3A4 and CYP2D6 to form oxidative metabolites, of which only one metabolite, DM-3411, accounts for more than 10% of the blood. Detectable in plasma

TOB At steady state, DM-3411 accounts for 23.1% to 47.7% of the exposure (AUC) of brexpiprazole in plasma. It should be noted that in preclinical studies in vivo, the apparent AUC was significantly lower, but at clinically relevant plasma exposures of brexpiprazole, the exposure of DM-3411 in the brain was below the limit of detection. Thus, DM-3411 is not considered to contribute to the therapeutic effects of brexpiprazole.

Breeding

Following a single oral dose of [14C]-labeled brexpiprazole, approximately 24.6% and 46% of the administered radioactivity was recovered in the urine and feces, respectively. Less than 1% of unchanged brexpiprazole was recovered in the urine and approximately 14% of the oral dose was recovered unchanged in the feces. The apparent oral clearance of brexpiprazole tablets after once-daily administration is 19.8 (± 11.4) mL/h/kg. Following multiple once-daily administration of brexpiprazole, the terminal half-lives of brexpiprazole and its major metabolite DM-3411 are 91.4 hours and 85.7 hours, respectively.

Linearity/nonlinearity

The pharmacokinetics of brexpiprazole are dose-proportional and time-invariant after single (0.2-8 mg) and multiple (0.5-4 mg) once daily administration.

Pharmacokinetics in special patient populations

Bull

Following a single dose of brexpiprazole (2 mg), elderly patients (aged 65 years and older) had similar systemic exposure to brexpiprazole (Cmax and AUC) compared to adult patients (aged 18-45 years; see sections 4.2 and 4.4).

Sex

In a population pharmacokinetic analysis, gender was found to be a statistically significant covariate. The exposure (AUC) of brexpiprazole was estimated to be 25% higher in women than in men (see section 4.8).

Paca

Although no specific pharmacokinetic studies have been performed, population pharmacokinetic analysis did not reveal evidence of clinically significant race-related differences in the pharmacokinetics of brexpiprazole.

CYP2D6 genotype

Population pharmacokinetic analysis demonstrated that brexpiprazole exposure was 47% higher in CYP2D6 poor metabolisers compared to extensive metabolisers (see section 4.2).

Smoking

In vitro studies using human liver enzymes have shown that brexpiprazole is not a substrate for CYP1A2, therefore smoking does not affect the pharmacokinetics of brexpiprazole.

Kidney dysfunction

In patients (n = 10) with severe renal impairment (creatinine clearance <30 mL/min), the AUC of brexpiprazole when administered orally (single dose of 3 mg) was increased by 68%, while Cmax was unchanged, compared to healthy volunteers. For patients with moderate or severe renal impairment (creatinine clearance 60 mL/min), the maximum recommended dose is reduced to 3 mg once daily (see section 4.2).

Liver dysfunction

In patients (n = 22) with varying degrees of hepatic impairment (Child-Pugh classes A, B and C), the AUC of oral brexpiprazole (single dose of 2 mg) increased by 24% in mild hepatic impairment, by 60% in moderate hepatic impairment, and was unchanged in severe hepatic impairment compared to matched healthy volunteers. For patients with moderate or severe hepatic impairment (Child-Pugh classes B and C), the maximum recommended dose is reduced to 3 mg once daily (see section 4.2).

Children

The safety and efficacy of brexeniprazole in children and adolescents under 18 years of age have not been established (see section 4.2).

Preclinical safety data

were mainly related to the increased pharmacological activity of brexpprazole. Based on AUC0-24h at the maximum recommended human dose (MRHD) of 4 mg/day, safety margins.

The effects observed in repeated dose toxicity studies in rats and monkeys were not obtainable in female and male rats and monkeys.

Cardiovascular toxicity

After oral administration, brexpiprazole reduced blood pressure and prolonged the OT interval in a safety pharmacology study in conscious male dogs, in repeated dose toxicity studies in male and female monkeys, and in a juvenile toxicity study in male and female dogs. The blood pressure-lowering effect of brexpiprazole is associated with the expected blockade of α-adrenoceptors in peripheral blood vessels.

Brexpiprazole did not demonstrate any genotoxic potential in in vitro and in vivo studies using clinically relevant exposures. Oral administration of brexpiprazole did not increase the incidence of tumors in a 2-year carcinogenicity study in male and female rats and male mice at exposures 4.4 and 3.1 times the MRDL, respectively. In female mice, an increased incidence of adenocarcinoma and adenosquamous carcinoma of the mammary gland and adenomas of the distal pituitary gland were observed at exposures similar to or even lower than clinically relevant exposures: these prolactin-mediated endocrine tumors have also been observed in rodents given other antipsychotics. The clinical relevance of these findings has not been established.

Reproductive toxicity

After oral administration, brexpiprazole did not affect the fertility of male rats, but prolonged diestrus and reduced fertility in female rats at exposure levels similar to or even lower than those achieved clinically at the MRDL. A significant increase in preimplantation losses was observed at exposures 4.1 times the clinical MRDL. In embryo-fetal developmental toxicity studies, brexpiprazole was not teratogenic in rats when administered orally at exposure levels (based on data in non-pregnant rats) achieved clinically at the MRDL. In rabbits, vertebral malformations were observed in 3 fetuses from 2 litters at maternally toxic oral doses of brexpiprazole with exposures approximately 16.5 times the clinical MRDL.

Growth retardation, mental retardation, and reduced viability of offspring were observed at maternally toxic doses of brexpiprazole in oral pre-/postnatal developmental toxicity studies in rats.

Following oral administration to pregnant rats, brexpiprazole was shown to be transferred to the fetus and into milk at concentrations that were generally comparable to levels in maternal blood.

Indication

Treatment of schizophrenia in adult patients.

Contraindication

Hypersensitivity to the active substance or to any of the excipients. Hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption. KPAIN TOBAPHO

Children under 18 years of age.

Interaction with other medicinal products and other types of interactions

Brexpiprazole is primarily metabolized by CYP3A4 and CYP2D6.

Potential effects of other medicinal products on the action of brexpiprazole

SURZA4 inhibitors

Concomitant use of ketoconazole (200 mg twice daily for 7 days), a potent

CYP3A4 inhibitor, with a single oral dose of 2 mg brexpiprazole resulted in a 97% increase in brexpiprazole AUC, but no change in Cmax. Based on the results of interaction studies, it is recommended to adjust the brexpiprazole dosage to half the dose when co-administered with potent CYP3A4 inhibitors (itraconazole, ketoconazole, ritonavir, and

clarithromycin).

Inductors SҮRZA4

Co-administration of rifampicin (600 mg twice daily for 12 days), a potent CYP3A4 inducer, with a single oral dose of 4 mg brexpiprazole resulted in a 31% and 73% decrease in brexpiprazole Cmax and AUC, respectively. If brexpiprazole is co-administered with a potent CYP3A4 inducer (e.g. rifampicin), the total daily dose of brexpiprazole should be increased approximately three-fold compared to the recommended daily dose (see section 4.2). Once-daily dosing with concomitant CYP3A4 inducers results in high fluctuations in peak to trough concentrations, and a split daily dose is preferred.

CYP2D6 inhibitors

When a single oral dose of 2 mg brexpiprazole was co-administered with quinidine (324 mg/day for 7 days), a potent CYP2D6 inhibitor, the AUC of brexpiprazole increased by 94%, but Cmax was unchanged. Based on the results of interaction studies, it is recommended that the dosage of brexpiprazole be adjusted to half the dose when co-administered with a potent CYP2D6 inhibitor (quinidine, paroxetine, and fluoxetine).

Based on population pharmacokinetic analysis, an approximately 4- to 5-fold increase in brexpiprazole concentrations is expected in CYP2D6 extensive metabolisers receiving CYP3A4 and CYP2D6 inhibitors or in CYP2D6 poor metabolisers receiving a potent CYP3A4 inhibitor, and a four-fold dose reduction is recommended in these patients (see section 4.2).

Potential effects of brexpiprazole on the effects of other medicinal products

In vitro studies suggest that clinically significant pharmacokinetic interactions of brexpiprazole with drugs metabolized by cytochrome P450 enzymes are unlikely. Brexpiprazole does not affect the absorption of drugs that are substrates of the transporters BCRP (breast cancer resistance protein) and P-gp (P-glycoprotein). Caution should be exercised when brexpiprazole is administered concomitantly with other drugs that prolong the QT interval or disrupt electrolyte balance. When brexpiprazole is administered concomitantly with drugs that increase creatine phosphokinase (CPK) levels, the potential additive effect of brexpiprazole on CPK levels should be considered.

There are currently no data on pharmacodynamic interactions of brexpiprazole. Caution should be exercised when prescribing with other medicinal products. Given the primary effect of brexpiprazole on the central nervous system (CNS), caution should be exercised when co-administering alcohol or other medicinal products that affect the CNS due to the potential for cross-reactions, such as sedation (see section 4.8).

Application features

During treatment with antipsychotics, clinical improvement may take several days to several weeks to occur. Patients should be closely monitored during this period.

Suicidal thinking and behavior

The emergence of suicidal behaviour is characteristic of psychotic illnesses in mood disorders and in some cases has been observed shortly after initiation or switch to antipsychotic treatment, including brexpiprazole (see section 4.8). Antipsychotic treatment should be accompanied by close monitoring in high-risk patients.

Cardiovascular disorders

Brexpiprazole has not been studied in patients with a history of myocardial infarction, ischemic heart disease, or clinically significant cardiovascular disease, as such

patients were not included in clinical trials. Brexpiprazole should be used with caution in patients with established cardiovascular disease.

disease (history of myocardial infarction or ischemic heart disease, heart failure or conduction disorders), cerebrovascular disease, as well as conditions that contribute to arterial hypotension (dehydration, hypovolemia and treatment with antihypertensive drugs) or arterial hypertension (including late-stage or malignant arterial hypertension).

QT prolongation

QT prolongation may occur in patients treated with antipsychotics. Only a few non-serious cases of QT prolongation have been reported in clinical trials with brexpiprazole. Caution should be exercised when prescribing brexpiprazole to patients with established cardiovascular disease, a family history of QT prolongation, electrolyte imbalance, or concomitant use with medicinal products known to prolong the QT interval (see sections 5.1 and 4.8).

Venous thromboembolism

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. Since patients treated with antipsychotic drugs often have risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with brexpiprazole and preventive measures should be taken.

Orthostatic hypotension and syncope

Adverse reactions associated with orthostatic hypotension may include dizziness, syncope and tachycardia. These risks are generally higher at the beginning of treatment with antipsychotics and during dose increases. Patients at increased risk of these adverse reactions (e.g. elderly patients) or at increased risk of developing complications of hypotension include those with dehydration, hypovolemia, treatment with antihypertensive drugs, history of cardiovascular disease (e.g. heart failure, myocardial infarction, ischemia or conduction disorders), history of cerebrovascular disease, and patients who have not previously received antipsychotics. In such patients, a lower starting dose with slower titration should be used and orthostatic vital signs should be monitored (see section 4.2).

Neuroleptic malignant syndrome (NMS)

A potentially fatal symptom complex called neuroleptic malignant syndrome (NMS) has been reported in association with antipsychotic treatment, including brexpiprazole (see section 4.8). Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, altered mental status, and signs of autonomic instability (irregular pulse or unstable blood pressure, tachycardia, sweating, and cardiac arrhythmia). Additional features may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms suggestive of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, brexpiprazole should be discontinued immediately.

Extrapyramidal symptoms

Extrapyramidal symptoms (including acute dystonia) are a known class effect of -antipsychotics. Brexpiprazole should be used with caution in patients with a history of -extrapyramidal symptoms.

Patients receiving antipsychotics may develop a syndrome of potentially irreversible involuntary dyskinetic movements. Although the syndrome is more common in elderly patients, especially elderly women, prevalence estimates cannot be relied upon to predict which patients may develop this syndrome at the start of antipsychotic treatment. If signs and symptoms of tardive dyskinesia develop in a patient receiving brexpiprazole, dose reduction or discontinuation of brexpiprazole should be considered. Temporary exacerbation or even recurrence of these symptoms may occur after discontinuation of treatment.

Cerebrovascular adverse reactions

In placebo-controlled trials, some antipsychotics have been associated with a higher incidence of cerebrovascular adverse reactions (strokes and transient ischemic attacks), including fatal events, in elderly patients with dementia compared to patients treated with placebo.

Elderly patients with dementia-related psychosis

Brexpiprazole has not been studied in elderly patients with dementia and is not recommended for use in elderly patients with dementia due to an increased risk of all-cause mortality.

Hyperglycemia and diabetes mellitus

Hyperglycemia, in some cases extremely severe and associated with ketoacidosis, hyperosmolar coma, or fatal outcome, has been reported in patients treated with atypical antipsychotics. Risk factors that may predispose a patient to severe complications include obesity and a family history of diabetes.

Patients treated with antipsychotics, including brexpiprazole, should be observed for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Fasting plasma glucose levels should be determined before or shortly after initiating antipsychotic treatment. During long-term treatment, plasma glucose levels should be determined regularly to detect worsening of glycemic control.

Weight gain and dyslipidemia

Antipsychotics, including brexpiprazole, have been associated with metabolic changes, including weight gain and dyslipidemia. An increased incidence of weight gain has been observed with increasing duration of treatment with brexpiprazole (see section 4.8). Lipid profiles should be assessed at the start of treatment. Clinical monitoring of weight and lipid profiles is recommended at baseline and during treatment.

Convulsions

As with other antipsychotics, brexpiprazole should be used with caution in patients with a history of seizure disorders or other conditions that potentially lower the seizure threshold. Seizures have been reported with brexpiprazole (see section 4.8).

Body temperature regulation

Antipsychotic medications have been associated with impaired ability to lower body temperature. Brexpiprazole should be used with caution in patients with conditions that predispose to increased body temperature, such as strenuous exercise, exposure to extreme heat, concomitant use of medications with anticholinergic activity, or dehydration.

Dysphagia

Esophageal motility disorders and aspiration have been associated with the use of antipsychotics. Brexpiprazole should be used with caution in patients at risk of aspiration pneumonia.

Impulse control disorder

Impulse control disorders, including pathological gambling, have been reported in patients treated with brexpiprazole. Patients may experience an increase in pathological gambling, particularly gambling, which they are unable to control while taking brexpiprazole. Other reported cases of pathological gambling include compulsive sexual behaviour, compulsive shopping, uncontrollable eating and other impulsive and compulsive behaviours. Patients with a history of impulsive disorders may be at increased risk and should be monitored closely. Since patients may not recognise such behaviour as pathological, it is important for physicians to specifically ask patients or their carers about the development of new or increased impulse control disorders or other forms of compulsive behaviour during treatment with brexpiprazole. It should be noted that symptoms of impulse control disorders may be related to the underlying disease, but in some cases the pathological tendency has been reported to disappear when the dose of the drug is reduced or when treatment is discontinued. Compulsive behavior can harm the patient and others if it is