RXULTI 1mg tablets medication leaflet

RXULTI 0.25 mg film-coated tablets

RXULTI 0.5 mg film-coated tablets

RXULTI 1 mg film-coated tablets

RXULTI 2 mg film-coated tablets

RXULTI 3 mg film-coated tablets

RXULTI 4 mg film-coated tablets

RXULTI 0.25 mg film-coated tablets

Each film-coated tablet contains 0.25 mg brexpiprazole.

Each film-coated tablet contains approximately 45.8 mg lactose (as monohydrate).

RXULTI 0.5 mg film-coated tablets

Each film-coated tablet contains 0.5 mg brexpiprazole.

Each film-coated tablet contains approximately 45.5 mg lactose (as monohydrate).

RXULTI 1 mg film-coated tablets

Each film-coated tablet contains 1 mg brexpiprazole.

Each film-coated tablet contains approximately 45 mg lactose (as monohydrate).

RXULTI 2 mg film-coated tablets

Each film-coated tablet contains 2 mg brexpiprazole.

Each film-coated tablet contains approximately 44.1 mg lactose (as monohydrate).

RXULTI 3 mg film-coated tablets

Each film-coated tablet contains 3 mg brexpiprazole.

Each film-coated tablet contains approximately 43.1 mg lactose (as monohydrate).

RXULTI 4 mg film-coated tablets

Each film-coated tablet contains 4 mg brexpiprazole.

Each film-coated tablet contains approximately 42.2 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

Film-coated tablet

RXULTI 0.25 mg film-coated tablets

Light brown, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 0.25on one side.

RXULTI 0.5 mg film-coated tablets

Light orange, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 0.5on one side.

RXULTI 1 mg film-coated tablets

Light yellow, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 1on one side.

RXULTI 2 mg film-coated tablets

Light green, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 2 onone side.

RXULTI 3 mg film-coated tablets

Light purple, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 3 onone side.

RXULTI 4 mg film-coated tablets

White, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 4 one side.

RXULTI is indicated for the treatment of schizophrenia in adults and adolescents aged 13 years andolder.

Adult population

The recommended starting dose for brexpiprazole is 1 mg once daily on days 1 to 4.

Based on the patient’s clinical response and tolerability, the brexpiprazole dose can be titrated to 2 mgonce daily on day 5 through day 7 and then to 4 mg on day 8.

The recommended target dose range is 2 mg to 4 mg once daily. The maximum recommended dailydose is 4 mg.

The recommended starting dose for brexpiprazole is 0.5 mg once daily on days 1 to 4.

The brexpiprazole dose should be titrated to 1 mg once daily on day 5 through day 7 and then to 2 mgon day 8. Weekly dose increases can be made in 1 mg increments based on clinical response andtolerability.

The recommended target dose range is 2 mg to 4 mg once daily. The maximum recommended dailydose is 4 mg.

Switching from other antipsychotics to brexpiprazole

When switching from other antipsychotics to brexpiprazole, gradual cross-titration should beconsidered, with gradual discontinuation of the previous treatment while brexpiprazole treatment isinitiated.

Switching to other antipsychotics from brexpiprazole

When switching to other antipsychotics from brexpiprazole, no gradual cross-titration is needed. Thenew antipsychotic should be initiated in its lowest dose while brexpiprazole is discontinued. It shouldbe considered that plasma concentration of brexpiprazole will decline gradually and will becompletely washed out in 1 to 2 weeks.

The safety and efficacy of brexpiprazole in the treatment of schizophrenia in patients aged 65 yearsand older have not been established (see sections 4.4 and 5.2). It is not possible to advise on aminimum effective/safe dose in this population.

The maximum recommended dose in patients with moderate to severe impaired renal function isreduced to 3 mg once daily (see section 5.2).

The maximum recommended dose in patients with moderate to severe hepatic impairment(Child-Pugh score ≥ 7) is reduced to 3 mg once daily (see section 5.2).

CYP2D6 poor metabolisers

Dosing modifications to half the recommended doses is required for patients with known CYP2D6poor metaboliser status. Further dosing modifications to a quarter of the recommended dose isrequired for known CYP2D6 poor metabolisers while taking strong or moderate CYP3A4 inhibitors(see sections 4.5 and 5.2).

Dose adjustments due to interactions

Dose adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors/inducersor strong CYP2D6 inhibitors. If the CYP3A4 inhibitor/inducers or CYP2D6 inhibitor is withdrawn,the brexpiprazole dose may need to be returned to the dose used before the initiation of theconcomitant therapy (see section 4.5). In case of adverse reactions despite dose adjustments of

RXULTI, the necessity of concomitant use of RXULTI and CYP2D6 or CYP3A4 inhibitor should bereassessed.

Table 1: Dose adjustments of RXULTI in patients who are CYP2D6 poor metabolisers andfor concomitant use with CYP inhibitors

Factors Adjusted dose

CYP2D6 poor metabolisers

Known CYP2D6 poor metabolisers Administer half of the recommended dose

Known CYP2D6 poor metabolisers taking Administer a quarter of the recommended dosestrong/moderate CYP3A4 inhibitors

Patients taking CYP2D6 inhibitors and/or CYP3A4 inhibitors

Strong CYP2D6 inhibitors Administer half of the recommended dose

Strong CYP3A4 inhibitors Administer half of the recommended dose

Strong/moderate CYP2D6 inhibitors with Administer a quarter of the recommended dosestrong/moderate CYP3A4 inhibitors

Patients taking strong CYP3A4 inducers

If brexpiprazole is used concomitantly with strong CYP3A4 inducers (e.g., rifampicin), in a patientstabilised on brexpiprazole it is necessary to titrate the daily dose of brexpiprazole stepwise up todouble the recommended dose over the course of 1 to 2 weeks. Thereafter, if according to the clinicalresponse, further dose adjustments are required, the dose may be increased up to a maximum of threetimes the recommended daily dose. Daily dose must not exceed 12 mg when brexpiprazole is usedconcomitantly with strong CYP3A4 inducers. Twice daily divided dosing of brexpiprazole ispreferable, as once daily dosing results in high peak to trough fluctuation (see section 4.5).

CYP3A4 inducers exert their effect in a time-dependent manner and may take at least 2 weeks to reachmaximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take atleast 2 weeks to decline.

The safety and efficacy of brexpiprazole in children and adolescents aged less than 13 years have notbeen established. No data are available.

Oral use.

The film-coated tablets can be taken with or without food.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

During antipsychotic treatment, improvement in the patient’s clinical condition may take several daysto some weeks. Patients should be closely monitored throughout this period.

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and insome cases has been reported early after initiation or switch of antipsychotic treatment, includingtreatment with brexpiprazole (see section 4.8). Close supervision of high-risk patients shouldaccompany antipsychotic treatment.

Brexpiprazole has not been evaluated in patients with a history of myocardial infarction/ischaemicheart disease or clinically significant cardiovascular disease since such patients were excluded fromclinical trials.

Brexpiprazole should be used with caution in patients with known cardiovascular disease (history ofmyocardial 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 (includingaccelerated or malignant).

QT prolongation can develop in patients treated with antipsychotics. In clinical trials, only a few, non-serious QT prolongations have been reported with brexpiprazole. Caution should be exercised whenbrexpiprazole is prescribed to patients with known cardiovascular disease, family history of QTprolongation, electrolyte imbalance or in case of concomitant use with other medicinal productsthought to prolong the QT interval (see sections 4.8 and 5.1).

Cases of venous thromboembolism (VTE) have been reported with antipsychotics. Since patientstreated with antipsychotics often present with acquired risk factors for VTE, all possible risk factorsfor VTE should be identified before and during treatment with brexpiprazole, and preventive measuresshould be undertaken.

Orthostatic hypotension and syncope

Adverse reactions related to orthostatic hypotension can include dizziness, light-headedness andtachycardia. Generally, these risks are greatest at the beginning of treatment with antipsychotics andduring dose escalation. Patients at increased risk of these adverse reactions (e.g., elderly) or atincreased risk of developing complications from hypotension include those with dehydration,hypovolemia, treatment with antihypertensive medicinal products, history of cardiovascular disease(e.g., heart failure, myocardial infarction, ischemia, or conduction abnormalities), history ofcerebrovascular disease, as well as patients who are antipsychotic-naïve. In such patients, a lowerstarting dose and slower titration should be considered, and orthostatic vital signs should be monitored(see section 4.2).

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has beenreported in association with antipsychotic treatment, including brexpiprazole (see section 4.8). Clinicalmanifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence ofautonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiacdysrhythmia). Additional signs may include increased creatine phosphokinase, myoglobinuria(rhabdomyolysis), and acute renal failure. If a patient develops signs and symptoms indicative of NMSor presents with unexplained high fever without additional clinical manifestations of NMS,brexpiprazole must be discontinued immediately.

Extrapyramidal symptoms (including acute dystonia) are known class effects for antipsychotics.

Brexpiprazole should be used with caution in patients with a known history of EPS.

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patientstreated with antipsychotics. Although the prevalence of the syndrome appears to be highest among theelderly, especially elderly women, it is impossible to rely upon prevalence estimates to predict, at theinception of antipsychotic treatment, which patients are likely to develop the syndrome. If signs andsymptoms of tardive dyskinesia appear in a patient on brexpiprazole, dose reduction or discontinuationshould be considered. These symptoms can temporally deteriorate or can even arise afterdiscontinuation of treatment.

In placebo-controlled trials with some antipsychotics in elderly patients with dementia, there was ahigher incidence of cerebrovascular adverse reactions (cerebrovascular accidents and transientischemic attacks), including fatalities, compared to placebo-treated subjects.

Elderly patients with dementia-related psychosis

Brexpiprazole has not been studied in elderly patients with dementia and is not recommended for thetreatment of elderly patients with dementia due to increased risk of overall mortality.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma ordeath, has been reported in patients treated with atypical antipsychotics. Risk factors that maypredispose patients to severe complications include obesity and family history of diabetes.

Patients treated with any antipsychotics, including brexpiprazole, should be observed for signs andsymptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness). Fasting plasmaglucose should be assessed before or soon after the initiation of the antipsychotic treatment. Duringlong term treatment the plasma glucose levels should be monitored regularly for worsening of glucosecontrol.

Weight gain and dyslipidaemia

Antipsychotics including brexpiprazole have been associated with metabolic changes, includingweight gain and dyslipidaemia. An increased frequency of weight gain has been observed withincreased duration of brexpiprazole treatment (see section 4.8). At the beginning of treatment, the lipidprofile should be assessed. Clinical monitoring of weight and lipid profile is recommended at baselineand during treatment.

As with other antipsychotics, brexpiprazole should be used with caution in patients who have a historyof seizure disorder or other conditions that potentially lower the seizure threshold. Seizures have beenreported during use of brexpiprazole (see section 4.8).

Disruption of the body’s ability to reduce core body temperature has been attributed to antipsychotics.

Appropriate care is advised when prescribing brexpiprazole for patients who will be experiencingconditions that may contribute to an elevation in core body temperature, e.g., exercising strenuously,exposure to extreme heat, receiving concomitant medicinal products with anticholinergic activity, orbeing subject to dehydration.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic use. Brexpiprazoleshould be used cautiously in patients at risk for aspiration pneumonia.

Impulse-control disorders

Impulse-control disorders including gambling disorder have been reported in patients treated withbrexpiprazole. Patients can experience increased urges, particularly for gambling, and the inability tocontrol these urges while taking brexpiprazole. Other reported urges include compulsive sexualbehaviours, compulsive shopping, binge eating, and other impulsive and compulsive behaviours.

Patients with a prior history of impulse-control disorders may be at increased risk and should bemonitored carefully. Because patients may not recognise these behaviours as abnormal, it is importantfor prescribers to ask patients or their caregivers specifically about the development of new orincreased impulse-control disorders or other compulsive behaviours while being treated withbrexpiprazole. It should be noted that impulse-control symptoms can be associated with the underlyingdisorder; however, in some cases, urges were reported to have stopped when the dose was reduced, orthe medicinal product was discontinued. Compulsive behaviours may result in harm to the patient andothers if not recognised. Consider dose reduction or stopping the medicinal product if a patientdevelops such urges while taking brexpiprazole (see section 4.8).

Leukopenia, neutropenia and agranulocytosis

Leukopenia, neutropenia and agranulocytosis (including fatal cases) have been reported duringtreatment with antipsychotics. Possible risk factors for leukopenia/neutropenia include pre-existinglow white blood cell count (WBC) and history of drug-induced leukopenia/neutropenia. Patients witha pre-existing low WBC or a history of drug-induced leukopenia/neutropenia should have theircomplete blood count (CBC) monitored frequently during the first few months of therapy andbrexpiprazole should be discontinued at the first sign of decline in WBC, in the absence of othercausative factors. Patients with neutropenia should be carefully monitored for fever or other symptomsor signs of infection and treated promptly if such symptoms or signs occur. Patients with severeneutropenia (absolute neutrophil count < 1 000/mm3) should discontinue brexpiprazole and have their

WBC followed until recovery.

Prolactin

Brexpiprazole can elevate prolactin levels. Elevations associated with brexpiprazole treatment aregenerally mild and may decline during administration, however, in some infrequent cases the effectmay persist during administration (see section 4.8).

RXULTI film-coated tablets contain lactose. Patients with rare hereditary problems of galactoseintolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicinalproduct.

Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6.

Potential for other medicinal products to affect brexpiprazole

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 % and did notchange the Cmax. Based on results of interaction studies, dose adjustment of brexpiprazole to half thedose is recommended when administered concomitantly with strong CYP3A4 inhibitors (itraconazole,ketoconazole, ritonavir, and clarithromycin).

Co-administration of rifampicin (600 mg twice daily for 12 days), a potent CYP3A4 inducer, with asingle 4 mg oral dose of brexpiprazole resulted in an approximate 31 % and 73 % decrease inbrexpiprazole Cmax and AUC, respectively. If brexpiprazole is used concomitantly with strong

CYP3A4 inducers (e.g., carbamazepine, phenobarbital, rifampicin, St. John’s Wort), the total dailydose requirement of brexpiprazole is increased by approximately a factor of three times therecommended daily dose. Once daily dosing of brexpiprazole in case of co-administration with

CYP3A4 inducers results in high peak to trough fluctuation (see section 4.2).

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 % and did not change the

Cmax. Based on results of interaction studies, dose adjustment of brexpiprazole to half the dose isrecommended when administered concomitantly with strong CYP2D6 inhibitors (quinidine,paroxetine, and fluoxetine).

Based on estimations from the population pharmacokinetic analysis, CYP2D6 extensive metabolisersreceiving both CYP3A4 and CYP2D6 inhibitors or CYP2D6 poor metabolisers receiving strong

CYP3A4 inhibitors are expected to have approximately 4-fold to 5-fold increase in brexpiprazoleconcentrations and dose adjustment to a quarter of the dose is recommended for these subjects (seesection 4.2).

Potential for brexpiprazole to affect other medicinal products

Based on results of in vitro studies, brexpiprazole is unlikely to cause clinically importantpharmacokinetic interactions with medicinal products metabolised by cytochrome P450 enzymes.

Brexpiprazole does not affect absorption of medicinal products that are substrates of Breast Cancer

Resistance Protein transporter (BCRP) and P-glycoprotein (P-gp) transporter.

If brexpiprazole is administered concomitantly with medicinal products known to cause QTprolongation (e.g. moxifloxacin) or electrolyte imbalance (e.g. diuretics such as furosemide,bendroflumethiazide), caution should be used.

If brexpiprazole is administered concomitantly with medicinal products known to increase creatinephosphokinase (CPK), e.g. statins like simvastatin, the possible additive effect with CPK increaseinduced by brexpiprazole should be considered.

No information on pharmacodynamic interactions of brexpiprazole is available at present. Cautionshould be exercised when prescribing other medicinal products concomitantly. Given the primary

Central Nervous System (CNS) effects of brexpiprazole, caution should be used when brexpiprazole istaken in combination with alcohol or other CNS medicinal products with overlapping adversereactions such as opiates like codeine or morphine (see section 4.8).

There are no or limited amount of data from the use of brexpiprazole in pregnant women. Studies inanimals have shown reproductive toxicity (see section 5.3). Brexpiprazole is not recommended duringpregnancy and in women of childbearing potential not using contraception.

Neonates exposed to antipsychotics, including brexpiprazole, during the third trimester of pregnancyare at risk of adverse reactions, including extrapyramidal and/or withdrawal symptoms that may varyin severity and duration following delivery. There have been reports of agitation, hypertonia,hypotonia, tremor, somnolence, respiratory distress and feeding disorder. Consequently, new-bornsshould be monitored carefully.

It is unknown whether brexpiprazole/metabolites are excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown excretion of brexpiprazole/ metabolites inmilk of rats (see section 5.3). A risk to the new-borns/infants cannot be excluded. A decision must bemade whether to discontinue breast-feeding or to discontinue/abstain from brexpiprazole therapytaking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

The effect of brexpiprazole on human fertility has not been evaluated. Studies in animals have showndecreased female fertility (see section 5.3).

Brexpiprazole has minor to moderate influence on the ability to drive and use machines due topotential nervous system effects, such as sedation and dizziness that are common adverse drugreactions (see section 4.8).

The most frequently observed adverse drug reactions (ADRs) in adults were akathisia (5.6 %) andweight gain (3.9 %) and in adolescents they were nausea (6.4%), somnolence (4.5%) and akathisia(3.6%).

The incidences of the ADRs associated with brexpiprazole therapy are tabulated below. The table isbased on adverse reactions reported in short-term placebo-controlled phase 2 and 3 adult clinical trialswith relevant therapeutic doses (2 mg to 4 mg) and short-term placebo-controlled phase 3 paediatricclinical trials with relevant therapeutic doses (1 mg to 4 mg).

All ADRs are listed by system organ class (SOC) 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 frequencygrouping, adverse reactions are presented in order of decreasing seriousness.

SOC Very common Common Uncommon Not known

Immune system Rash Angioedemadisorders Urticaria

Swelling face

Metabolism and Weightnutrition disorders increase

Psychiatric disorders Suicide attempt Gambling

Suicidal ideation disorder

Impulsivebehaviour

Binge eating

Compulsiveshopping

Compulsive sexualbehaviour

Nervous system Akathisia Parkinsonism Seizuresdisorders Dizziness Neuroleptic

Tremor malignant

Somnolence1 syndrome (NMS)

Cardiac disorders Electrocardiogram

QT prolonged

Vascular disorders Venousthromboembolism(includingpulmonaryembolism and deepvein thrombosis)

Orthostatichypotension

Respiratory, thoracic Coughand mediastinaldisorders

Gastrointestinal Diarrhoea Dental cariesdisorders Nausea Flatulence

Abdominalpain upper

Musculoskeletal and Back pain Myalgia Rhabdomyolysisconnective tissue Pain indisorders extremity

Pregnancy, Drug withdrawalpuerperium and syndromeperinatal conditions neonatal (seesection 4.6)

SOC Very common Common Uncommon Not known

Investigations Blood Blood creatine Blood pressureprolactin phosphokinase increasedincreased2 increased Blood triglyceridesincreased

Hepatic enzymesincreased1 Includes also sedation and hypersomnia2The categorisation of blood prolactin increased is based on Potentially Clinically Relevant (PCR) criteriaof > 1 × upper limit of normal (ULN).

Extrapyramidal Symptoms (EPS)

Akathisia was the most frequently reported EPS related ADR in the brexpiprazole2 mg/day to 4 mg/day group (5.6 %) compared to 4.5 % in placebo, followed by tremor (2.7 %)compared to 1.2 % in placebo. The incidences of other EPS-related ADRs reported in short-term,controlled trials are dyskinesia (0.4 %), extrapyramidal disorder (1.8 %) and Parkinsonism (0.4 %).

See section 4.4.

Akathisia

From fixed-dose trials there appears to be a dose-response relationship for akathisia in patients treatedwith brexpiprazole, with an increasing frequency with higher doses. The incidence of akathisia in thebrexpiprazole 1 mg/day, 2 mg/day, and 4 mg/day groups was 3.0 %, pct. 4.6 %, and 6.5 %, respectively,compared with 5.2 % of subjects in the placebo group.

The incidence of akathisia in the short-term, controlled trials (5.4 %) was similar to the incidence inthe long-term, open-label trials (5.7 %).

Suicidal behaviour

In short-term, controlled trials, Treatment Emergent Adverse Events (TEAEs) related to suicidalbehaviour were reported for 8 subjects (0.5 %, 2 serious events, 1 leading to discontinuation) in thebrexpiprazole treatment group and 3 subjects (0.4 %, none-serious) in the placebo group. In long-term,open-label trials, TEAEs related to suicidal behaviour were reported for 23 subjects (1.6 %). Overall,in the brexpiprazole clinical development program for schizophrenia, one death due to suicideoccurred but was not considered drug related by the investigator. Spontaneous cases reportingcompleted suicide and suicide attempt have been reported in the post-marketing setting. Seesection 4.4.

In the short-term controlled trials with brexpiprazole, 3 TEAEs related to QT prolongation werereported in the 2 mg to 4 mg group (0.3 %), compared with 3 TEAEs (0.5 %) reported in subjectsreceiving placebo. The incidence of TEAEs in long-term trials was similar to that of the short-termtrials.

The effects of brexpiprazole at therapeutic (4 mg) and supra-therapeutic (12 mg) doses on QT intervalwere evaluated in subjects with schizophrenia or schizoaffective disorder in a randomised,double-blind, placebo- and positive-controlled (moxifloxacin), parallel-arm trial. Subgroup analysesfrom this trial suggested that the QTc prolongation was larger in female subjects than in males (seesections 4.4, 4.5 and 5.1).

In short-term, controlled trials, the percentage of subjects with clinically significant weight gain(increase of ≥ 7 % from baseline in body weight) was 9.1 % in the brexpiprazole2 mg/day to 4 mg/day group, compared with 3.8 % in the placebo group.

In the long-term, open-label trial, the percentage of subjects with clinically significant weight gain(increase of ≥ 7 % in body weight) at any visit was 20.7 % and 0.4 % of the subjects discontinued dueto weight gain. In subjects who had a weight gain ≥ 7 % from baseline, weight increased over time,with mean weight gain up to 10.2 kg at week 52. The mean change in body weight overall for thebrexpiprazole group in the long term, open label trial was 2.1 kg at week 52. See section 4.4.

Prolactin

The incidence of blood prolactin increased was 0.9 % in the 2 mg to 4 mg brexpiprazole groupcompared to 0.5 % in the placebo group in short-term, controlled trials. Higher frequencies ofprolactin increased (1.5 % versus 0.60 %) were observed in females compared to males in short-termtrials. In addition, the frequencies of prolactin elevations > 1 × ULN in the 2 mg to 4 mg brexpiprazolegroup was 13.7 % in females versus 6.4 % in the placebo group and 11.1 % in males versus 10.3 % inthe placebo group. See section 4.4.

A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has beenreported in association with brexpiprazole (see section 4.4).

Nausea

For nausea, the incidence in the 2 mg to 4 mg brexpiprazole group was 2.3 % overall in short-termcontrolled trials, compared to 2.0 % in the placebo group. For vomiting, these incidences were 1.0 %in the brexpiprazole-treated group compared to 1.2 % in the placebo group.

In terms of gender differences, there were higher observed frequencies of nausea (4.8 % versus 2.8 %)and vomiting (4.6 % versus 1.4 %) in females compared to males among brexpiprazole-treatedsubjects in short-term trials. Concerning subjects receiving placebo, the frequency for nausea was2.8 % for males versus 3.2 % for females, whereas the frequency for vomiting was 3.0 % for malesversus 2.6 % for females (see section 5.2).

Adolescents aged 13 years and older with schizophrenia

Frequency, type and severity of adverse reactions in adolescents are expected to be similar as in adults.

Extrapyramidal Symptoms (EPS)

In short-term trials, akathisia was the most frequently reported EPS related ADR in the brexpiprazole1 mg/day to 4 mg/day group (3.6 %) compared to 2.9 % in placebo. The incidences of other

EPS-related ADRs reported in short-term, controlled trials in paediatric patients were muscle rigidity(0.9 %), hypokinesia (0.9 %) and tremor (0.9 %).

Akathisia

The incidence of akathisia in the brexpiprazole-treated paediatric subjects in a short-term, randomized,double-blind trial was 3.6 % versus 2.9 % for placebo-treated subjects.

The incidence of akathisia in the ongoing-long-term, open label trial was 5.1 %. See section 4.4.

Suicidal behaviour

In a short-term, controlled trial, a TEAE of suicidal behaviour was reported in 1 subject (0.9 %, non-serious event) in the brexpiprazole treatment group and none in the placebo group. In a long-term,open-label trial, TEAEs of suicidal behaviour were reported in 8 subjects (2.7 %). See section 4.4.

No TEAEs related to QT prolongation have been reported in the adolescent schizophrenia trials. Thesafety profile observed in the adolescent population is considered to be similar to that observed in theadult population (see section 4.4).

In a short-term, controlled trial the percentage of subjects with clinically significant weight gain (increase of ≥ 7 % from baseline in body weight) was 8.2 % in brexpiprazole treated group, comparedwith 4.9 % in placebo group The mean increase in weight from baseline to last visit was 0.8 kg inbrexpiprazole and 0.0 kg in placebo-treated subjects. To adjust for normal growth, z-scores werederived (measured in standard deviations [SD]), which normalize for natural growth of children andadolescents by comparisons to age- and gender- matched population standards. A z-score change<0.5 SD is considered not clinically significant. In this study, no change in mean z-score from baselineto last visit was observed in brexpiprazole and placebo-treated groups. 4.5 % of subjects inbrexpiprazole and 3.9 % subjects in placebo had an increase in age-and-gender-adjusted body weightz-score of at least 0.5 SD from baseline. TEAEs of weight gain was reported in 1.7% of all patients inthe brexpiprazole group compared to 3.4% in placebo group. See section 4.4.

In the long-term, open-label trial, the percentage of subjects with clinically significant weight gain(increase of ≥ 7 % from baseline in body weight) at any visit was 44.6% in brexpiprazole treatedgroup. Mean change in z-score from baseline to last visit was 0.10 SD for body weight, while 20% ofpatients had an increase in age-and gender-adjusted body weight z-score of at least 0.5 SD frombaseline. TEAEs related to weight increased were observed in 11.5 % of subjects, while other TEAEsrelated to weight increase, such as increased BMI and waist circumference, were each reported in onesubject.

Prolactin

In the short-term trial, no treatment emergent adverse events associated with elevated prolactin werereported. The frequencies of prolactin elevations > 1 × ULN in the 2 mg to 4 mg brexpiprazole groupwas 26.8 % in females versus 6.3 % in the placebo group and 24.5 % in males versus 6 % in theplacebo group. In the long-term trials, 1.7% of the subjects reported TEAEs of blood prolactinincreased and 0.7% subjects reported TEAEs of hyperprolactinaemia. See section 4.4.

No TEAEs related to NMS have been reported in the adolescent schizophrenia trials. The safetyprofile observed in the adolescent population is considered to be similar to that observed in the adultpopulation (see section 4.4).

Nausea

TEAEs of Nausea have been reported in the adolescent schizophrenia trials. The safety profileobserved in the adolescent population is considered to be similar to that observed in the adultpopulation.

Somnolence including sedation and hypersomnia

In short-term trials, the incidence of somnolence-related TEAEs (sedation, somnolence, hypersomnia)was 7.3% in the brexpiprazole 2-4 mg group compared to 6.7% in the placebo group. In a long-term,open-label trial, the incidence of somnolence-related TEAEs (sedation, somnolence, hypersomnia)was 11.9%. These TEAEs were mild to moderate in severity.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Gastric lavage and treatment with an emetic may be useful immediately after overdose. Anelectrocardiogram should be obtained in case of overdose and if QT interval prolongation is present,cardiac monitoring should be instituted.

Otherwise, management of overdose should concentrate on supportive therapy, maintaining anadequate airway, oxygenation and ventilation, and management of symptoms. Close medicalsupervision and monitoring should continue until the patient recovers.

Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting 2 mg oraldose of brexpiprazole, decreased brexpiprazole Cmax and AUC by approximately 5 % to 23 % and31 % to 39 % respectively. However, there is insufficient information available on the therapeuticpotential of activated charcoal in treating an overdose with brexpiprazole.

Although there is no information on the effect of haemodialysis in treating an overdose withbrexpiprazole, haemodialysis is unlikely to be useful in overdose management since brexpiprazole ishighly bound to plasma proteins.

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code N05AX16

Brexpiprazole is an atypical antipsychotic agent. The pharmacology of brexpiprazole is believed to bemediated by a modulatory activity at the serotonin and dopamine systems that combines partial agonistactivity at serotonergic 5-HT1A and at dopaminergic D2 receptors with antagonist activity atserotonergic 5-HT2A receptors, with similar high affinities at all of these receptors(Ki: 0.1 nM to 0.5 nM). Brexpiprazole also shows antagonist activity at noradrenergic α1B/2C receptorswith affinity in the same sub-nanomolar Ki range (Ki: 0.2 nM to 0.6 nM).

Influences of genetic variation on the pharmacodynamic responses to brexpiprazole have not beeninvestigated.

Effects on QT

The effects of brexpiprazole on the QT interval were evaluated in patients with schizophrenia orschizoaffective disorder. In the overall analysis, brexpiprazole did not prolong the QTc interval to aclinically relevant extent following therapeutic and supra-therapeutic doses (4 mg/day; n = 62 or12 mg/day; n = 53) and no correlation has been observed between brexpiprazole concentrations and

QTc prolongation.

Subgroup analyses from the thorough QTc trial suggested that the QTc prolongation was larger infemale subjects than in males. In the brexpiprazole 4 mg/day group, the maximum placebo-adjustedmean change from baseline in the QTcI interval was 5.2 ms (90 % CI: 1.5, 8.9) in males (n = 48) and15.0 ms (90 % CI: 7.7., 22.3) in females (n = 14) at 6 hours post-dosing. In the brexpiprazole12 mg/day group, the maximum placebo-adjusted mean change from baseline in the QTcI interval was2.9 ms (90 % CI: −1.2, 6.9) in males (n = 40) at 12 hours post-dosing and 10.4 ms (90 % CI: 2.7, 18.2)in females (n = 13) at 24 hours post-dosing. The smaller number of female than male subjects enrolledin the study does not allow to draw definitive conclusions.

The efficacy and safety of brexpiprazole in the treatment of adults with schizophrenia was studied intwo multi-national and one regional (Japan), 6-week, randomised, double-blind, placebo-controlled,fixed-dose clinical trials (trials 1 to 3), a multi-national, 6-week, randomised, double-blind,placebo-controlled, active reference (quetiapine), flexible-dose clinical trial (trial 4), and, onemulti-national, placebo-controlled, 52-week maintenance trial (trial 5). The trials included2 690 patients with the age of 18 years to 65 years.

In trials 1, 2 and 3, brexpiprazole was titrated as described in section 4.2 with 1 mg for 4 days,followed by 2 mg on days 5 to 7. On day 8, the dose was increased to 4 mg for some of the treatmentarms.

Short-term trials

In the three fixed-dose, short-term trials (trials 1, 2 and 3), subjects were randomised to brexpiprazole2 mg once daily, 4 mg once daily or placebo.

Trial 4 assessed the efficacy, safety, and tolerability of brexpiprazole in a flexible dose range of2 mg/day to 4 mg/day and 400 mg to 800 mg quetiapine extended release (XR) for assay sensitivity. Inthe short-term trials, the primary efficacy endpoint was defined as the mean change from baseline toweek 6 in Positive and Negative Syndrome Scale (PANSS) total scores, a multi-item inventorycomposed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts,uncontrolled hostility/excitement, and anxiety/depression.

The key secondary endpoint in trials 1, 2 and 4 was the Clinical Global Impression of Severity(CGI-S) of schizophrenia, a 7-point clinician’s assessment of the severity of disease. The CGI-S wasalso assessed in trials 3 and 5 as secondary endpoint.

The effects of brexpiprazole were also evaluated across a number of pre-specified secondaryendpoints: the specific aspects of symptoms of schizophrenia (PANSS Positive Subscale score,

PANSS Negative Subscale score, PANSS Excited Component [PEC] score, PANSS Marder factorspositive, negative, disorganised thoughts, uncontrolled hostility/excitement and anxiety/depression),and analyses of response (defined as 30 % improvement in PANSS total score compared to baseline ora CGI-I score of 1 [very much improved] or 2 [much improved]).

Efficacy was demonstrated in trial 1 for both brexpiprazole 2 mg/day and 4 mg/day and replicated intrial 2 only for brexpiprazole 4 mg/day and in trial 3 only for brexpiprazole 2 mg/day.

In the flexible-dose trial 4, at week 6, subjects in the brexpiprazole treatment group had numericallygreater improvements on PANSS total score than the subjects in the placebo group, although, thedifference at week 6 did not reach statistical significance for the primary efficacy analysis (p = 0.0560;see table 2). In the same trial, the active reference, quetiapine XR added for assay sensitivity only,separated from placebo.

Table 2: Primary efficacy results for 6-week trials in schizophrenia

Trial Treatment group n Primary efficacy measure: PANSS

Mean baseline LS mean change LS mean p-valuescore (SD) from baseline differencea, b(SE) (95 % CI)1 Brexpiprazole(2 mg/day)* 180 95.85 −20.73 −8.72(13.75) (1.55) (−13.1, −4.37) < 0.0001

Brexpiprazole 94.70 −19.65 −7.64(4 mg/day)* 178 (12.06) (1.54) (−12.0, −3.30) 0.0006

Placebo 178 95.69 −12.01(11.46) (1.60) -- --2 Brexpiprazole 96.30 −16.61 −3.08(2 mg/day) 179 (12.91) (1.49) (−7.23, 1.07) 0.1448

Brexpiprazole 181 94.99 −20.00 −6.47(4 mg/day)* (12.38) (1.48) (−10.6, −2.35) 0.0022

Placebo 180 94.63 −13.53(12.84) (1.52) -- --3 Brexpiprazole 96.55 −14.95 −7.32(2 mg/day)* 113 (19.20) (2.00) (−13.04, −1.59) 0.0124

Brexpiprazole 109 96.39 −11.49 −3.86(4 mg/day) (15.73) (2.10) (−9.71, 2.00) 0.1959

Trial Treatment group n Primary efficacy measure: PANSS

Mean baseline LS mean change LS mean p-valuescore (SD) from baseline differencea, b(SE) (95 % CI)

Placebo 113 97.19 −7.63(19.27) (2.11) -- --

Brexpiprazole 97.82 −19.994 (2 mg/day to 4 mg/day 150 (10.25) (1.51) −4.1) (−8.2, 0.1) 0.0560

Placebo 159 98.38 −15.93(10.30) (1.49) -- --

SD Standard deviation

SE Standard error

LS Mean Least-squares mean.

CI Confidence interval

* Treatment statistically significantly superior to placeboa Difference (brexpiprazole minus placebo) in least-squares mean change from baseline, at week 6b The LS Mean, 95 % CI, and p-values for individual trials were derived from an MMRM (Mixedeffect Model Repeat Measurement) analysis as follows: fixed effects of site, treatment, visit, andtreatment-by-visit interaction, with baseline and baseline-by-visit interaction as covariates.

Unstructured variance-covariance matrix structure was used.

The primary statistical analysis was performed using an MMRM model with MAR (Missing At

Random) imputation. Results of a sensitivity analysis using placebo based multiple imputation (PMI)were consistent with the primary analysis.

Results for the (key) secondary outcome parameter and additional endpoints were supportive of theprimary endpoint.

In trial 1, statistically significant greater improvement on the CGI-S, the key secondary efficacymeasure, at week 6 was also shown for the 2 mg/day and 4 mg/day compared to the placebo dosegroups. Due to the testing hierarchy the greater improvement shown for both 2 mg/day and 4 mg/dayon the CGI-S can only be considered supportive for trials 2, 3 and 4 (see table 3).

Table 3: Key secondary efficacy results for 6-week trials in schizophrenia

Trial Treatment group n Key secondary efficacy measure: CGI-S

Mean baseline LS mean LS mean p-valuescore (SD) change from differenceabaseline (SE) (95 % CI)1 Brexpiprazole 4.90 −1.15 −0.33(2 mg/day)* 181 (0.64) (0.08) (−0.56, −0.10) 0.0056

Brexpiprazole 178 4.81 −1.20 −0.38(4 mg/day)* (0.64) (0.08) (−0.61, −0.15) 0.0012

Placebo 181 4.84 −0.82(0.66) (0.09) -- --2 Brexpiprazole 180 4.96 −0.99 −0.19(2 mg/day) (0.65) (0.09) (−0.42, 0.05) 0.1269

Brexpiprazole(4 mg/day)* 183 4.85 −1.19 −0.38(0.64) (0.08) (−0.62, −0.15) 0.0015

Placebo 181 4.87 −0.81(0.61) (0.09) -- --3 Brexpiprazole(2 mg/day)* 113 4.80 −0.84 −0.35(0.78) (0.11) (−0.67, −0.03) 0.0308

Brexpiprazole 4.71 −0.64 −0.16(4 mg/day) 109 (0.75) (0.12) (−0.48, 0.17) 0.3461

Trial Treatment group n Key secondary efficacy measure: CGI-S

Mean baseline LS mean LS mean p-valuescore (SD) change from differenceabaseline (SE) (95 % CI)

Placebo 113 4.73 −0.48(0.71) (0.12) -- --4 Brexpiprazole* 4.96 −1.21 −0.27(2 mg/day to 4 mg/day)b 150 (0.59) (0.08) (−0.49, −0.06) 0.0142

Placebo 159 4.94 −0.93(0.57) (0.08) -- --

SD Standard deviation

SE Standard error

LS Mean Least-squares mean

CI Confidence interval

* Treatment statistically significantly superior to placeboa Difference (brexpiprazole minus placebo) in least-squares mean change from baseline, at week 6b Mean dose 3.5 mg/day

Maintenance of efficacy trial

In trial 5, a long-term trial designed to assess the maintenance of effect of brexpiprazole by assessingthe delay in time to impending relapse of schizophrenia, patients with schizophrenia, who respondedto treatment with brexpiprazole 1 mg/day to 4 mg/day, were stabilised over 12 weeks to 36 weeks, andthen randomised in a double-blind manner to either continue treatment with the stabilisation dose ofbrexpiprazole (n = 96) or to receive placebo (n = 104) for 52 weeks or until relapse occurred.

In the primary analysis of time to impending relapse patients on brexpiprazole showed a significantlylonger time to relapse compared with patients on placebo (p < 0.0001). At week 52 brexpiprazole(13.5 %) reduced the risk of impending relapse by 71 % compared with placebo (38.5 %). During thestabilisation, brexpiprazole improved clinical symptomology (as assessed by PANSS, CGI-S and

CGI-I, [Analysis of Covariance - ANCOVA Last Observation Carried Forward - LOCF]) andfunctioning (as assessed by Global Assessment of Functioning (GAF) [ANCOVA LOCF]). Theseimprovements were maintained during the 52-week double-blind maintenance phase in patients onbrexpiprazole whereas patients randomised to placebo showed deterioration in PANSS, CGI-S and

CGI-I, and GAF scores [ANCOVA LOCF]). Brexpiprazole maintained symptom control andfunctioning compared to placebo.

The efficacy and safety of brexpiprazole in the treatment of paediatric patients with schizophrenia wasstudied in one 6-week, randomised, double-blind and placebo- controlled trial (trial 6) and an on-goinglong-term, 24-month open-label trial. The short-term trial included 110 patients randomized tobrexpiprazole, 101 patients to aripiprazole for assay sensitivity and 104 patients to placebo with amean age of 15 years.

In the short-term trial (trial 6), patients received either brexpiprazole 2 to 4 mg/day, aripiprazole 10 to20 mg/day or placebo.

The primary efficacy endpoint was defined as the mean change from baseline to week 6 in Positiveand Negative Syndrome Scale (PANSS) total scores.

Brexpiprazole 2 to 4 mg/day and aripiprazole showed statistically significant improvements comparedto placebo in the mean change from baseline in the PANSS Total Score.

Interim analyses from long-term trial with flexible doses of brexpiprazole 1 to 4 mg/day showedmaintained improvement in symptoms from baseline through month 24 in PANSS Total Score.

Table 4: Primary efficacy results for 6-week trial in schizophrenia in Paediatric Patients

Trial Treatment group n Primary efficacy measure: PANSS

Mean baseline LS mean LS mean p-valuescore (SD) change from differenceabaseline (SE) (95 % CI)6 Brexpiprazole (2 mg/day 110 101.06 -22.75 -5.33to 4 mg/day)* (14.87) (1.49) (-9.55, -1.10) 0.0136

Aripiprazole (10 mg/day 101 101.03 -23.95 -6.53 0.0032to 20 mg/day) (13.08) (1.57) (-10.8, -2.21)

Placebo 103b 102.17 -17.42(16.30) (1.58) -- --

SD Standard deviation

SE Standard error

LS Mean Least-squares mean

CI Confidence interval

* Treatment statistically significantly superior to placeboa Difference (brexpiprazole minus placebo) in least-squares mean change from baseline, at week 6b Efficacy sample includes treated subjects who have baseline and at least 1 post-baseline efficacyevaluation for the PANSS Total Score

Furthermore, a pharmacokinetic/pharmacodynamic analysis has been considered supportive for thecomparison of clinical efficacy data between adolescents and adults with schizophrenia.

Brexpiprazole is absorbed after administration of the tablet, with peak plasma concentrationsoccurring within 4.0 hours after single dose administrations; the absolute oral bioavailability of thetablet formulation is 95.1 %. Brexpiprazole steady-state concentrations are attained within10 days to 12 days of dosing. Administration of a 4 mg brexpiprazole tablet with a standard high fatmeal did not significantly affect the Cmax or AUC of brexpiprazole. After single and multiple oncedaily dose administration, brexpiprazole exposure (Cmax and AUC) increase in proportion to the doseadministered. Based on in vivo studies, brexpiprazole is neither a substrate nor an inhibitor of effluxtransporters, such as Multi Drug Resistance (MDR) 1 (P-gp) and BCRP.

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

Based on in-vitro metabolism studies using recombinant human cytochrome P450, the metabolism ofbrexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6 leading to formation ofoxidative metabolites. Based on in vitro data brexpiprazole showed little to no inhibition of other

CYP450 isozymes. In-vivo, the metabolism of brexpiprazole is mainly mediated by CYP3A4 and

CYP2D6 leading to formation of oxidative metabolites with only one metabolite, DM-3411, present inplasma with more than 10 % of plasma exposure.

At steady-state, DM-3411 represents 23.1 % to 47.7 % of brexpiprazole exposure (AUC) in plasma. Itshould be noted that in-vivo preclinical studies have shown that at clinically relevant plasma exposuresof brexpiprazole, DM-3411 brain exposures were below the detection limit. Thus, DM-3411 isconsidered not to contribute to the therapeutic effects of brexpiprazole.

Following a single oral dose of [14C]-labelled brexpiprazole, approximately 24.6 % and 46 % of theadministered radioactivity was recovered in the urine and faeces, respectively. Less than 1 % ofunchanged brexpiprazole was excreted in the urine and approximately 14 % of the oral dose wasrecovered unchanged in the faeces. Apparent oral clearance of brexpiprazole tablet after once dailyadministration is 19.8 (± 11.4) mL/h/kg. After multiple once daily administration of brexpiprazole, theterminal elimination half-life of brexpiprazole and its major metabolite, DM-3411, is 91.4 hours and85.7 hours, respectively.

The pharmacokinetic of brexpiprazole is dose proportional and time-invariant after single-dose(0.2 mg to 8 mg) and multiple-dose (0.5 mg to 4 mg) using once-daily administration.

After single dose administration of brexpiprazole (2 mg), elderly subjects (older than 65 years)exhibited similar brexpiprazole systemic exposure (Cmax and AUC) in comparison with the adultsubjects (18 years to 45 years old; see sections 4.2 and 4.4).

Population PK evaluation identified gender as statistically significant covariate. The exposure (AUC)of brexpiprazole in women was estimated to be 25 % higher than in men (see section 4.8).

Although no specific pharmacokinetic study was conducted, population pharmacokinetic evaluationrevealed no evidence of clinically significant race-related differences in the pharmacokinetics ofbrexpiprazole.

CYP2D6 genotype

Population pharmacokinetic evaluation shows that CYP2D6 poor metabolisers have 47 % higherexposure to brexpiprazole compared to extensive metabolisers (see section 4.2).

Smoking

Based on studies utilising human liver enzymes in vitro, brexpiprazole is not a substrate for CYP1A2.

Therefore, smoking should not have an effect on the pharmacokinetics of brexpiprazole.

In subjects (n = 10) with severe renal impairment (CLcr < 30 mL/min), AUC of oral brexpiprazole(3 mg single dose) compared to matched healthy subjects was increased by 68 % while its Cmax wasnot changed. For patients with moderate to severe renal impairment (creatinine clearance

CLcr < 60 mL/minute), the maximum recommended dose is reduced to 3 mg once daily (seesection 4.2).

In subjects (n = 22) 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 insevere hepatic impairment. For patients with moderate to severe hepatic impairment (Child-Pugh

Classes B and C), the maximum recommended dose is reduced to 3 mg once daily (see section 4.2).

A multiple dose PK study (0.5, 1, 2, 3 or 4 mg/day) has been conducted in 24 paediatric patients aged13 years to 17 years old. Population PK analysis indicated systemic exposure (Cmax and AUC) ofbrexpiprazole in paediatric patients (13 to 17 years of age) was comparable to that in adult patientsacross the dose range from 0.5 to 4 mg.

Effects observed in repeated-dose toxicity studies in rats and monkeys were mainly related to theexaggerated pharmacological activity of brexpiprazole. No safety margins based on AUC0-24 h at the

Maximum Recommended Human Dose (MRHD) of 4 mg/day could be derived in both female andmale rats and monkey.

Cardiovascular toxicity

Following oral administration, brexpiprazole decreased blood pressure and prolonged QT interval insafety pharmacology study in conscious male dog, in repeated-dose toxicity studies in male andfemale monkeys and in juvenile toxicity study in male and female dogs. The effect of brexpiprazole onblood pressure reduction is attributed to the expected blockade of α1-adrenoceptors in peripheral bloodvessels.

Genotoxicity, carcinogenicity

Brexpiprazole did not show any genotoxic potential in both in vitro and in vivo studies using clinicallyrelevant exposures. Brexpiprazole administered orally did not increase the incidence of tumours in a2-year carcinogenicity study in both male and female rats and in male mice at exposures up to 4.4-foldand 3.1-fold the MRHD. In female mice, an increased incidence of mammary gland adenocarcinomaand adeno-squamous carcinoma, and pars distalis adenoma of the pituitary gland, was observed atsimilar or even lower clinically relevant exposures: these prolactin-mediated endocrine tumours werealso observed in rodents with other antipsychotics and their clinical relevance is unknown.

Following oral administration, brexpiprazole did not affect male fertility in rats but prolonged diestrusand decreased fertility in female rats at similar or even lower exposure levels than those clinicallyachieved at MRHD. Significant increased pre-implantation losses were observed at 4.1-fold theclinical exposure at MRHD. In embryo-foetal developmental toxicity studies, brexpiprazole was notteratogen in orally treated rats up to exposure levels (based on data in non-pregnant rats) clinicallyachieved at MRHD. In rabbit, vertebral malformations were seen in 3 foetuses from 2 litters atmaternally toxic brexpiprazole oral doses corresponding to exposure approximately 16.5-fold theclinical exposure at MRHD.

Delayed growth, physical development and impaired viability of the offspring were observed atmaternally toxic brexpiprazole doses in a pre-/post-natal developmental toxicity study in orallyadministered rats.

Following oral administration in pregnant rats, foetus and milk transfer of brexpiprazole wasdemonstrated at concentrations that were generally comparable to levels seen in maternal blood.

Brexpiprazole is very persistent and very bio-accumulative but not toxic, to the environment: possibleenrichment of brexpiprazole in terrestrial food chains might pose a concern (see section 6.6).

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RXULTI 0.25 mg film-coated tablets

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3 years

This medicinal product does not require any special storage conditions.

RXULTI 0.25 mg and 0.5 mg film-coated tablets28 film-coated tablets in Aluminium/PVC blisters.

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