Use as an adjunctive therapy to antidepressants for the treatment of major depressive disorder (MDD)

Treatment of schizophrenia

For oral use once daily with or without food
Major Depressive Disorder
The recommended starting dose for brexpiprazole 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. The maximum recommended dose is 3mg/day. Periodically reassess to determine the continued need and appropriate dose for treatment.

Schizophrenia
The recommended starting dose for brexpiprazole 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.

Dosing Modifications for CYP2D6 Poor Metabolizers and for Concomitant Use with CYP Inhibitors/Inducers

* REXULTI may be administered without dosage adjustment in patients with MDD when administered with strong CYP2D6
inhibitors (e.g., paroxetine, fluoxetine).
** If the co-administered CYP3A4 inducer is discontinued, reduce the dosage to the original level over 1 to 2 weeks.

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), largely in patients taking atypical antipsychotic drugs, 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.

Brexpiprazole is not approved for the treatment of dementia-related psychosis.

Cerebrovascular Adverse Reactions
In placebo-controlled trials with some antipsychotic drugs in elderly patients with dementia, there was a higher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transient ischemic attacks), including fatalities, compared to placebo-treated patients.

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.

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 age 24 years and younger was greater in antidepressant-treated patients than in placebo-treated patients.

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.

Neuroleptic Malignant Syndrome (NMS)
A potential fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with administration of antipsychotic drugs including brexpiprazole. 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 brexpiprazole 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
A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotic drugs. Although the prevalence of the syndrome appears to be highest among the elderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at the inception of antipsychotic treatment, which patients are likely to develop the syndrome.

If signs and symptoms of tardive dyskinesia appear in a patient on brexpiprazole, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

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: (1) who suffer from a chronic illness that is known to respond to antipsychotic drugs; and (2) 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 Parameters
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. Assess fasting plasma glucose before or soon after initiation of antipsychotic medication, and monitor periodically during long-term treatment. Patients treated with any antipsychotic agents should be observed for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus (e.g. obesity, family history of diabetes) should be monitored regularly for worsening of glucose control.

Major Depressive Disorder
In the 6-week, placebo-controlled, fixed-dose clinical trials 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 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo.

In the long-term, open-label depression studies, 5% of patients with normal baseline fasting glucose experienced a shift to high while taking 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
In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with schizophrenia, the proportions of patients with shifts in fasting glucose from normal (<100 mg/dL) to high (≥126 mg/dL) or borderline (≥100 and <126 mg/dL) to high were similar in patients treated with REXULTI and placebo.

In the long-term, open-label schizophrenia studies, 8% of patients with normal baseline fasting glucose experienced a shift from normal to high while taking 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.

Weight Gain and Dyslipidemia:
Antipsychotic drugs have been associated with metabolic changes, including weight gain and dyslipidemia. Before or soon after initiation of antipsychotic medication, obtain a fasting lipid profile at baseline and monitor periodically during treatment. Clinical monitoring of weight is recommended.

Major Depressive Disorder
In the 6-week, placebo-controlled, fixed-dose clinical trials in patients with MDD, changes in fasting total cholesterol, LDL cholesterol, and HDL cholesterol were similar in REXULTI- and placebo-treated patients.

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 the short-term, placebo-controlled clinical studies of REXULTI+ADT in patients with MDD, 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 the short-term, placebo-controlled clinical studies of REXULTI in patients with schizophrenia, 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 premarketing clinical trials.

Fall 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
As with other antipsychotic drugs, Brexpiprazole should be used cautiously in patients with a history of seizures or with conditions that potentially lower the seizure threshold. Conditions that lower the seizure threshold may be more prevalent in patients 65 years or older.

Body Temperature Regulation
Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotic agents. Appropriate care is advised when prescribing brexpiprazole for patients who will be experiencing conditions that may contribute to an elevation in core body temperature e.g., exercising strenuously, exposure to extreme heat, receiving concomitant medication with anticholinergic activity, or being subject to dehydration.

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.

Impulse-Control Disorders/Compulsive Behaviours
Post-marketing reports of impulse-control disorders including gambling have been reported very rarely in patients treated with brexpiprazole and other antipsychotics with partial agonist activity at dopamine receptors. Patients with a prior history of impulse-control disorders may be at increased risk and should be monitored carefully. 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 increased impulse-control disorders or other compulsive behaviours while being treated with brexpiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder. 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.

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 dose is reduced. In patients 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 dose is reduced. In patients 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.

Paediatric Use
Safety and effectiveness in patients under the age of 18 years has not yet been systemically evaluated.

Geriatric Use
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 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 pharmacokineticspharmacokinetics (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.

Other Special Populations
No dosage adjustment for brexpiprazole is required on the basis of a patient’s sex, race, or smoking status

Brexpiprazole is predominantly metabolized by CYP3A4 and CYP2D6. Based on results of drug interaction trials, dosing should be adjusted to half the recommended dose for patients administered with strong CYP2D6 or CYP3A4 inhibitors. Based on estimations from the population PK analysis, CYP2D6 EMs receiving both CYP3A4 and CYP2D6 inhibitors or CYP2D6 PMs receiving strong CYP3A4 inhibitors are expected to have approximately 4-5 fold increase in brexpiprazole concentrations; subsequently brexpiprazole dose should be accompanied with reduction of its dose to ¼ of the recommended dosage in these situations [see 4.2 Dosing Precautions].

If brexpiprazole is used concomitantly with a strong CYP3A4 inducer (i.e. rifampicin), it is necessary to increase the dose by two fold and further adjust it based on clinical response [see4.2 Dosing Precautions].

Medicinal Products
Quinidine and Other Strong CYP2D6 Inhibitors:
Co-administration of a 2 mg single oral dose of brexpiprazole with quinidine (324 mg/day for 7 days), a potent inhibitor of CYP2D6, increased the AUC of brexpiprazole by 94%.

Ketoconazole and Other Strong CYP3A4 Inhibitors:
Co-administration of ketoconazole (200 mg twice daily for 7 days), a potent inhibitor of CYP3A4, with a 2 mg single oral dose of brexpiprazole increased the AUC of brexpiprazole by 97%.

Ticlopidine and Other CYP2B6 Inhibitors:
Co-administration of a 2 mg single oral dose of brexpiprazole with ticlopidine (250 mg twice daily for 7 days), a potent inhibitor of CYP2B6, had no effect on brexpiprazole.

Rifampicin and Other CYP3A4 Inducers:
Co-administration of rifampin (600 mg twice daily for 12 days), a potent CYP3A4 inducer, with a single 4 mg oral dose of brexpiprazole resulted in an approximate 31% and 73% decrease in brexpiprazole Cmax and AUC.

Gastric Acid pH Modifiers:
Co-administration of omeprazole (40 mg once daily, 5 days), a widely used proton pump inhibitor (PPI), with a single oral dose of brexpiprazole (4 mg) resulted in no effect on absorption of brexpiprazole. Other gastric acid pH modifiers (PPIs, H2 receptor antagonists, etc.) are also not expected to affect the absorption of brexpiprazole.

Potential for brexpiprazole to Affect Other Drugs:
Based on results of in vitro studies, brexpiprazole is unlikely to cause clinically important pharmacokinetic interactions with drugs metabolized by cytochrome P450 enzymes. Clinical studies show that oral brexpiprazole (2 mg/day, 11 days) had no effect on the metabolism of dextromethorphan (a CYP2D6 substrate), lovastatin (a CYP3A4 substrate) or bupropion (a CYP2B6 substrate). Brexpiprazole does not affect absorption of drugs that are substrates of BCRP transporter (rosuvastatin) and PgP transporter (fexofenadine).

Food
Intake of food has no effect on the pharmacokinetics of brexpiprazole.

Safe use of brexpiprazole during pregnancy or lactation has not been established; therefore, use of brexpiprazole in pregnancy, in nursing mothers, or in women of childbearing potential requires that the benefits of treatment be weighed against the possible risks to mother and child.

Neonates exposed to antipsychotic drugs during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity; while in some cases symptoms have been selflimited, in other cases neonates have required intensive care unit support and prolonged hospitalization.

The effect of brexpiprazole on labor and delivery in humans is unknown. Parturition in rats was not affected by brexpiprazole.

Brexpiprazole was excreted in milk of rats during lactation. It is not known whether brexpiprazole or its metabolites are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug considering the risk of drug discontinuation to the mother.

REXULTI, like other antipsychotics, has the potential to impair judgment, thinking, or motor skills. In 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.

In 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 placebotreated patients.

Patients should be cautioned about operating hazardous machinery, including motor vehicles, until they are reasonably certain that REXULTI therapy does not affect them adversely.

MDD:
Summary of the safety profile
The most frequently observed adverse drug reactions (ADRs) reported in double-blind placebo controlled phase 2/3 clinical trials within the recommended doses (1-3 mg/day) were akathisia (9%), and weight gain (8%). Adverse reactions were usually mild or moderate and did not generally lead to cessation of therapy.

Tabulated list of adverse reactions
The incidences of the ADRs associated with brexpiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials.

All ADRs are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data).

Additional adverse drug reactions were reported: dyspepsia , agitation, and hypersensitivity.

Description of selected adverse reactions
EPS related events:
In short-term placebo controlled trials, the incidence of EPS-related events, excluding akathisia events, was 7.7% for brexpiprazole-treated subjects versus 4.6% for placebo-treated subjects.

The incidence of akathisia for brexpiprazole-treated subjects was 9.2% versus 2.8% for placebo-treated subjects. New occurrences of akathisia were reported in all treatment arms more often within the first weeks following treatment initiation and they were mild to moderate in severity.

Weight Gain
The percentage of subjects in short-term placebo-controlled trials who had a potentially clinically relevant increase in body weight (7%) was 4.7 % for brexpiprazole compared with 1.5 % in the placebo group. The mean body weight increase in the short-term trials at last visit was 1.5 kg for brexpiprazole compared with 0.3 kg in the placebo group.

In the long-term, open-label schizophrenia studies, the mean change in body weight from baseline to last visit was 2.7 kg at last observation.

Schizophrenia
Summary of the safety profile
The most frequently observed adverse drug reactions (ADRs) reported in double-blind placebo controlled phase 2/ 3 clinical trials within the recommended doses (2-4 mg/day) were akathisia (6%), and weight gain (5%). Adverse reactions were usually mild or moderate and did not generally lead to cessation of therapy.

Tabulated list of adverse reactions
The incidences of the ADRs associated with brexpiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials.

All ADRs are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Additional adverse drug reactions were reported: constipation, dyspepsia, fatigue, increased appetite, somnolence, agitation, anxiety, insomnia, hypersensitivity and blood prolactin increased .

Description of selected adverse reactions
Akathisia and EPS related ADRs
In short-term placebo controlled trials, the incidence of EPS-related events, excluding akathisia events, was 7.1% for brexpiprazole-treated subjects versus 5.6 % for placebo-treated subjects. The incidence of akathisia events for brexpiprazole treated subjects was 5.8% versus 4.0% for placebo-treated subjects.

New occurrences of akathisia were reported in all treatment arms more often within the first weeks following treatment initiation and they were mild to moderate in severity.

Weight Gain
The percentage of subjects in short-term placebo-controlled trials who had a potentially clinically relevant increase in body weight (7%) was 10.3 % for brexpiprazole compared with 4.4 % in the placebo group. The mean body weight increase in the short-term trials at last visit was 1.2 kg for brexpiprazole compared with 0.2 kg in the placebo group. (In the long-term, open-label schizophrenia studies, the mean change in body weight from baseline to last visit was 1.1 kg at last observation.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

To report any side effect(s):

• Saudi Arabia:
  • The National Pharmacovigilance Centre (NPC)
    • Fax: +966-11-205-7662
    • SFDA Call Center: 19999
    • E-mail: npc.drug@sfda.gov.sa
    • Website: https://ade.sfda.gov.sa 
• Other GCC States:
  Please contact the relevant competent authority.

No specific information is available on the treatment of overdose with brexpiprazole. 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 haemodialysis in treating an overdose with brexpiprazole, haemodialysis is unlikely to be useful in overdose management since brexpiprazole is highly bound to plasma proteins.

Brexpiprazole has high affinity (Ki<5 nM) for multiple monoaminergic receptors including serotonin 5-HT1A, 5-HT2A, 5-HT2B, 5-HT7, dopamine D2, D3, and noradrenergic α1A, α1B, α1D, and α2C 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 exhibits a moderate affinity for histamine H1 receptor (19 nM) and a very weak affinity for muscarinic M1 receptor (67% inhibition at 10 μM). Dose-response occupancy and brain/plasma exposure relationship were determined in vivo or ex vivo for D2/D3, 5-HT2A, 5-HT1A, 5-HT6, and 5-HT7 receptors as well as for the 5-HT transporter in preclinical studies. These results are consistent with the relative in vitro binding affinities and indicate that brexpiprazole has potent activity at several targets in the central nervous system (CNS) at relevant plasma exposures.

Despite a low intrinsic activity at the D2 receptor and potent antipsychotic effect, brexpiprazole showed low liability for catalepsy (animal model for extrapyramidal side effect) and for inducing tardive dyskinesia (indicative of post-synaptic D2 receptors increased sensitivity). The potencies of these effects were similar or lower to other antipsychotic agents. Brexpiprazole showed very low tendency to induce ptosis(animal model for sedation) and its relatively low binding affinity to H1 receptor compared to that for D2 receptor would further suggest a low potential for H1-related sedative effect.

Brexpiprazole does not prolong QTcI or QTcF at the clinical (4 mg) or at a supra-therapeutic (12 mg) dose range, and no correlation has been observed between brexpiprazole concentrations and QTcI or QTcF prolongation. No apparent dose dependent categorical changes in QTc and brexpiprazole dose was observed.

Mechanism of Action
Brexpiprazole binds with high affinity to multiple serotonin, dopamine and noradrenergic receptors. While the precise mechanism of action of brexpiprazole in treating psychiatric conditions is unknown, the pharmacology of brexpiprazole is believed to be mediated by a combination of high binding affinity and functional activities at multiple monoaminergic receptors. It has modulatory activity at the serotonin and dopamine systems that combines partial agonist activity at serotonergic 5-HT1A and at dopaminergic D2 receptors with antagonist activity at serotonergic 5-HT2A receptors, with similar high affinities at all of these receptors (Ki: 0.1-0.5 nM). Brexpiprazole also shows antagonist activity at noradrenergic α1B/2C with affinity in the same sub-nanomolar Ki range (Ki: 0.2-0.6 nM). The 5 HT1A/D2 receptor partial agonist activity in combination with 5¬HT2A and α1B/2C receptors antagonism of brexpiprazole may contribute with antipsychotic efficacy.

Clinical efficacy
Major Depressive Disorder
The efficacy of brexpiprazole in the adjunctive treatment of major depressive disorder (MDD) was demonstrated in two 6-week, placebo-controlled, fixed-dose trials 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 (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 two 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. Results from the primary and key secondary efficacy parameters for both fixed dose trials are shown below.

An examination of population subgroups did not reveal evidence of differential response based on age, gender, race or choice of prospective antidepressant.

Summary of Efficacy Results for Pivotal Studies in Adjunctive Treatment of MDD

SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=unadjusted confidence interval
* Dose statistically significantly superior to placebo
^a Difference (drug minus placebo) in least-squares mean change from baseline

Schizophrenia
The efficacy of brexpiprazole in adults with schizophrenia was demonstrated in two 6-week, placebocontrolled, fixed-dose clinical trials in patients who met DSM-IV-TR criteria for schizophrenia.

The primary efficacy endpoint of both 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).

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 both trials, brexpiprazole 4 mg/day demonstrated efficacy over placebo in the PANSS total score and showed greater improvement in CGI-S score compared to placebo. In one trial, brexpiprazole 2 mg/day demonstrated efficacy over placebo in the PANSS total score and CGI-S score. Results from the primary and key secondary efficacy parameters for both fixed dose trials are shown below.

Examination of population subgroups based on age, gender and race did not show any statistical evidence of differential responsiveness

Summary of Efficacy Results for Pivotal Studies in Schizophrenia

SD=standard deviation; SE=standard error; LS Mean=least-squares mean; CI=unadjusted confidence interval
* Dose statistically significantly superior to placebo
^a Difference (drug minus placebo) in least-squares mean change from baseline

Maintenance:
The safety and efficacy of brexpiprazole 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. A pre-specified interim analysis demonstrated a statistically significantly longer time to impending relapse in patients randomized to the brexpiprazole 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 brexpiprazole group compared to placebo-treated patients. The key secondary endpoint, the proportion of patients who met the criteria for impending relapse, was lower in brexpiprazole-treated patients (13.5%) compared with placebo group (38.5%).

Absorption
Brexpiprazole is well absorbed after administration of the tablet, with peak plasma concentrations occurring within 4.0 hours after single dose administrations; the absolute oral bioavailability of the tablet formulation is 95.1%. Brexpiprazole steady-state concentrations are attained within 10-12 days of dosing. Brexpiprazole can be administered with or without food. Administration of a 4 mg brexpiprazole 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) increase in proportion to the dose administered. In vitro studies of brexpiprazole do 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±0.418l/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, and digitoxin.

Metabolism and Elimination
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. The in vitro inhibitory potential of brexpiprazole on MDR1 (P-gp), OAT1, OAT3, OCT2, multidrug and toxin extruders (MATE1), MATE2-K, OATP1B1, OATP1B3, and OCT1 has also been evaluated; brexpiprazole was only identified as a potential inhibitor of the BCRP efflux transporter but was not considered to be an inhibitor for the other tested transporters.

In vivo brexpiprazole is metabolized primarily by CYP3A4 and CYP2D6 enzymes. After single and multiple dose administrations, brexpiprazole and a major metabolite, DM 3411, are the predominant drug moieties in the systemic circulation. At steady-state, DM-3411 represents 23.1-47.7% of brexpiprazole exposure (AUC) in plasma. It should be noted that in vivo preclinical studies have shown that at clinically relevant plasma exposures of brexpiprazole, DM-3411 brain exposures were below the detection limit. Thus, DM-3411 is considered not to contribute to the therapeutic effects of brexpiprazole.

Based on the results of in vitro data, brexpiprazole showed little to no inhibition of CYP450 isozymes.

Following a single oral dose of [14 C]-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 excreted in the urine and approximately 14% of the oral dose was recovered unchanged in the feces. Apparent oral clearance of brexpiprazole oral tablet after once daily administration is 19.8 (±11.4) mL/h/kg. After multiple once daily administration of brexpiprazole, the terminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is 91.4 hours and 85.7 hours, respectively.

Special Populations
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 and 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 black people 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.

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, and mutagenesis
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.

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).

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.

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.

Cardiovascular Toxicity
Decreased blood pressure and prolonged QT interval and QTc were noted in the conscious dog in the safety pharmacology study of 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.

The active substance is brexpiprazole. Each tablet contains 0.25 mg/ 0.5 mg / 1 mg / 2 mg / 3 mg / 4mg of brexpiprazole respectively.

The other excipients are lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, magnesium stearate, hypromellose, talc, titanium dioxide, iron oxide red (0.25 mg, 0.5 mg, 3 mg), iron oxide yellow (0.25 mg, 0.5 mg, 1 mg, 2 mg), ferrosoferric oxide (0.25 mg, 2 mg, 3mg).

Not applicable

Do not store above 30°C

Brexpiprazole tablets are supplied in blisters packed in cartons containing 28 tablets.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.