RXULTI 3 MG FILM-COATED TABLETS - summary of medicine characteristics

This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

1 NAME OF THE MEDICINAL PRODUCT

RXULTI 3 mg film-coated tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

RXULTI 3 mg film-coated tablets

Each film-coated tablet contains 3 mg brexpiprazole.

Excipient with known effect

Each film-coated tablet contains 45.4 mg lactose (as monohydrate).

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Film-coated tablet

RXULTI 3 mg film-coated tablets

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

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

RXULTI is indicated for the treatment of schizophrenia in adult patients.

4.2 Posology and method of administration

Posology

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

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

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

The maximum recommended daily dose is 4 mg.

Switching from other antipsychotics to brexpiprazole

When switching from other antipsychotics to brexpiprazole gradual crosstitration should be considered, with gradual discontinuation of the previous treatment while brexpiprazole treatment is initiated.

Switching to other antipsychotics from brexpiprazole

When switching to other antipsychotics from brexpiprazole, no gradual crosstitration is needed, the new antipsychotic should be initiated in its lowest dose while brexpiprazole is discontinued. It should be considered that plasma concentration of brexpiprazole will decline gradually and will be completely washed out in 1 to 2 weeks.

Special populations

Elderly

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

Renal impairment

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

Hepatic impairment

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 CYP2D6 poor metaboliser status. Further dosing modifications to a quarter of the recommended dose is required 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/inducers or strong CYP2D6 inhibitors. If the CYP3A4 inhibitor/inducers or CYP2D6 inhibitor is withdrawn, the dose may need to be returned to the original dose (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 be reassessed.

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

Patients taking strong CYP3A4 inducers

If brexpiprazole is used concomitantly with strong CYP3A4 inducers (e.g. rifampicin), in a patient stabilised on brexpiprazole it is necessary to titrate the daily dose of brexpiprazole stepwise up to double the recommended dose over the course of 1 to 2 weeks. Thereafter, if according to clinical response, further dose adjustments are required, the dose may be increased up to a maximum of three times the recommended daily dose. Daily dose must not exceed 12 mg when brexpiprazole is used concomitantly with strong CYP3A4 inducers.

Twice daily divided dosing of brexpiprazole is preferable 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 reach maximal effect after introduction. Conversely, on discontinuation, CYP3A4 induction may take at least 2 weeks to decline.

Paediatric population

The safety and efficacy of brexpiprazole in children and adolescents aged less than 18 years have not been established. No data are available.

Method of administration

Oral use

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

4.3 Contraindications

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

4.4 Special warnings and precautions for use

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

Suicidal ideation and behaviour

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

Cardiovascular disorders

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

Brexpiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension (including accelerated or malignant).

QT prolongation

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 when brexpiprazole is prescribed in patients with known cardiovascular disease, family history of QT prolongation, electrolyte imbalance or in concomitant use with other medicinal products thought to prolong the QT interval (see sections 4.8 and 5.1).

Venous thromboembolism

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

Orthostatic hypotension and syncope

Adverse reactions related to orthostatic hypotension can include dizziness, light-headedness and tachycardia. Generally, these risks are greatest at the beginning of treatment with antipsychotics and during dose escalation. Patients at increased risk of these adverse reactions (e.g. elderly) or at increased 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 of cerebrovascular disease, as well as patients who are antipsychotic-naive. In such patients, a lower starting 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 been reported in association with antipsychotic treatment, including brexpiprazole (see section 4.8). 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 increased 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 brexpiprazole must be discontinued immediately.

Extrapyramidal symptoms (EPS)

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.

Tardive dyskinesia

A syndrome of potentially irreversible, involuntary, dyskinetic movements may develop in patients treated with antipsychotics. 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.

Cerebrovascular adverse reactions

In placebo-controlled trials with some antipsychotics 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 subjects.

Elderly patients with dementia-related psychosis

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

Hyperglycaemia and diabetes mellitus

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

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

Weight gain and dyslipidaemia

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

Seizures

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

Body temperature regulation

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 experiencing conditions 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, or being subject to dehydration.

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic use. Brexpiprazole should 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 with brexpiprazole. Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking brexpiprazole. Other urges, reported, include: compulsive sexual behaviours, 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 be monitored carefully. Because patients may not recognise 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; however, in some cases, urges were reported to have stopped when the dose was reduced or the medication was discontinued. Compulsive behaviours may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medication if a patient develops such urges while taking brexpiprazole (see section 4.8).

Leukopenia, neutropenia and agranulocytosis

Leukopenia, neutropenia and agranulocytosis (including fatal cases) have been reported during treatment with antipsychotics. Possible risk factors for leukopenia/ne­utropenia include pre-existing low white blood cell count (WBC) and history of drug-induced leukopenia/ne­utropenia. Patients with a pre-existing low WBC or a history of drug-induced leukopenia/ne­utropenia should have their complete blood count (CBC) monitored frequently during the first few months of therapy and brexpiprazole should be discontinued at the first sign of decline in WBC, in the absence of other causative factors. Patients with neutropenia should be carefully monitored for fever or other symptoms or signs of infection and treated promptly if such symptoms or signs occur. Patients with severe neutropenia (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 are generally mild and may decline during administration, however, in some infrequent cases the effect may persist during administration (see section 4.8).

Lactose

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

4.5 Interaction with other medicinal products and other forms of interaction

Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6.

Potential for other medicinal products to affect brexpiprazole

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 % and no change in Cmax. Based on results of interaction studies, dose adjustment of brexpiprazole to half the dose is recommended when administered concomitantly with strong CYP3A4 inhibitors (itraconazole, ketoconazole, ritonavir, and clarithromycin).

CYP3A4 inducers

Co-administration of rifampicin (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, respectively. If brexpiprazole is used concomitantly with strong CYP3A4 inducers (e.g. rifampicin), the total daily dose requirement of brexpiprazole is increased by approximately a factor of three times the recommended daily dose (see section 4.2). Once daily dosing while CYP3A4 inducers are administered results in high peak to trough fluctuation, hence twice daily divided dosing is preferable.

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 % and no change in Cmax. Based on results of interaction studies, dose adjustment of brexpiprazole to half the dose is recommended when administered concomitantly with strong CYP2D6 inhibitors (quinidine, paroxetine, and fluoxetine).

Based on estimations from the population pharmacokinetic analysis, CYP2D6 extensive metabolisers receiving 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 brexpiprazole concentrations and dose adjustment to a quarter of the dose is recommended for these subjects (see section 4.2).

Potential for brexpiprazole to affect other medicinal products

Based on results of in vitro studies, brexpiprazole is unlikely to cause clinically important pharmacokinetic 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 QT prolongation or electrolyte imbalance, caution should be used.

If brexpiprazole is administered concomitantly with medicinal products known to increase creatine phosphokinase (CPK) the possible additive effect with CPK increase induced by brexpiprazole should be considered.

Pharmacodynamic interactions

No information on pharmacodynamic interactions of brexpiprazole is available at present. Caution should be exercised when prescribing with other medicinal products. Given the primary Central Nervous System (CNS) effects of brexpiprazole, caution should be used when brexpiprazole is taken in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8).

4.6 Fertility, pregnancy and lactation

Pregnancy

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

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

Breast-feeding

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

Fertility

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

4.7 Effects on ability to drive and use machines

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

4.8 Undesirable effects

Summary of the safety profile

The most frequently observed adverse drug reactions (ADRs) were akathisia (5.6 %) and weight gain (3.9 %).

Tabulated list of adverse reactions

The incidences of the ADRs associated with brexpiprazole therapy are tabulated below. The table is based on adverse reactions reported in short-term placebo-controlled phase 2 and 3 clinical trials with relevant therapeutic doses (2 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The categorisation of blood prolactin increased is based on Potentially Clinically Relevant (PCR) criteria of > 1 x upper limit of normal (ULN).

Description of selected adverse reactions

Extrapyramidal Symptoms (EPS)

Akathisia was the most frequently reported EPS related ADR in the brexpiprazole 2 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 %).

Akathisia

From fixed-dose trials there appears to be a dose-response relationship for akathisia in patients treated with brexpiprazole, with an increasing frequency with higher doses. The incidence of akathisia in the brexpiprazole 1 mg/day, 2 mg/day, and 4 mg/day groups was 3.0 %, 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 in the long-term, open-label trials (5.7 %).

Suicidality

In short-term, controlled trials, Treatment Emergent Adverse Events (TEAEs) related to suicidality were reported for 8 subjects (0.5 %, 2 serious events, 1 leading to discontinuation) in the all brexpiprazole treatment group and 3 subjects (0.4 %, none serious) in the placebo group. In long-term, open-label trials, TEAEs related to suicidality were reported for 23 subjects (1.6 %).

Overall in the brexpiprazole clinical development program for schizophrenia, one death due to suicide, considered not drug related by the investigator, occurred. Spontaneous cases reporting completed suicide and suicide attempt have been reported in the post-marketing setting.

QT prolongation

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

The effects of brexpiprazole at therapeutic (4 mg) and supra-therapeutic

(12 mg) doses on QT interval were evaluated in subjects with schizophrenia or schizoaffective disorder in a randomised, double-blind, placebo- and positive-controlled (moxifloxacin), parallel-arm trial. Subgroup analyses from this trial suggested that the QTc prolongation was larger in female subjects than in males (see section 5.1).

Weight gain

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 brexpiprazole 2 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 due to 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 the brexpiprazole group in the long term, open label trial was 2.1 kg at week 52.

Prolactin

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

Neuroleptic malignant syndrome

A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported 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-term controlled trials, compared to 2.0 % in placebo; for vomiting, these incidences were 1.0 % in the brexpiprazole-treated group compared to 1.2 % in 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-treated subjects in short-term trials, in subjects receiving placebo: the frequency for nausea was 2.8 % for males versus 3.2 % for females and for vomiting the frequency was 3.0 % for males versus 2.6 % for females (see section 5.2).

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Gastric lavage and treatment with an emetic may be useful immediately after overdose. An electrocardiogram 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 an adequate airway, oxygenation and ventilation, and management of symptoms. Close medical supervision and monitoring should continue until the patient recovers.

Oral activated charcoal and sorbitol (50 g/240 mL), administered one hour after ingesting 2 mg oral dose of 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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code N05AX16

Mechanism of action

Brexpiprazole is an atypical antipsychotic agent. The pharmacology of brexpiprazole is believed to be mediated by a 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 nM to 0.5 nM). Brexpiprazole also shows antagonist activity at noradrenergic a1B/2C receptors with affinity in the same sub-nanomolar Ki range (Ki: 0.2 nM to 0.6 nM).

Pharmacodynamic effects

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

Effects on QT

The effects of brexpiprazole on the QT interval were evaluated in patients with schizophrenia or schizoaffective disorder. In the overall analysis brexpiprazole did not prolong the QTc interval to clinically relevant extent following therapeutic and supra-therapeutic doses (4 mg/day; n = 62 or 12 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 in female subjects than in males. In the brexpiprazole 4 mg/day group, the maximum placebo-adjusted mean change from baseline in the QTcI interval was 5.2 ms (90 % CI: 1.5, 8.9) in males (n = 48) and 15.0 ms (90 % CI: 7.7., 22.3) in females (n = 14) at 6 hours post-dosing. In the brexpiprazole 12 mg/day group, the maximum placebo-adjusted mean change from baseline in the QTcI interval was 2.9 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 enrolled in the study does not allow to draw definitive conclusions.

Clinical efficacy and safety

The efficacy and safety of brexpiprazole in the treatment of adults with schizophrenia was studied in two 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, one multi-national, placebo-controlled, 52-week maintenance trial (trial 5). The trials included 2,690 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 treatment arms.

Short-term trials

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

Trial 4 assessed the efficacy, safety, and tolerability of brexpiprazole in a flexible dose range of 2 mg/day to 4 mg/day and 400 mg to 800 mg quetiapine extended release (XR) for assay sensitivity. In the short-term trials, the primary efficacy endpoint was defined as the mean change from baseline to week 6 in Positive and Negative Syndrome Scale (PANSS) total scores, a multi-item inventory composed 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 was also assessed in trials 3 and 5 as secondary endpoint.

The effects of brexpiprazole were also evaluated across a number of prespecified secondary endpoints; the specific aspects of symptoms of schizophrenia (PANSS Positive Subscale score, PANSS Negative Subscale score, PANSS Excited Component [PEC] score, PANSS Marder factors positive, negative, disorganised thoughts, uncontrolled hostility/exci­tement and anxiety/depres­sion), and analyses of response (defined as 30 % improvement in PANSS total score compared to baseline or a 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 in trial 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 numerically greater improvements on PANSS total score than the subjects in the placebo group, although, the difference at week 6 did not reach statistical significance for the primary efficacy analysis (p = 0.0560; see table 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

SD          Standard deviation

SE          Standard error

LS Mean Least-squares mean.

CI          Confidence interval

*             T­reatment statistically significantly superior to placebo

a            Dif­ference (brexpiprazole minus placebo) in least-squares mean change from

baseline, at week 6

b            The LS Mean, 95 % CI, and p-values for individual trials were derived from an

MMRM (Mixed effect Model Repeat Measurement) analysis as follows: fixed effects of site, treatment, visit, and treatment-by-visit interaction, with baseline and baseline-by-visit interaction as covariates. Unstructured variancecovariance 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 the primary endpoint.

In trial 1, statistically significant greater improvement on the CGI-S, the key secondary efficacy measure, at week 6 was also shown for the

2 mg/day and 4 mg/day compared to the placebo dose groups. Due to the testing hierarchy the greater improvement shown for both

2 mg/day and 4 mg/day on 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

SD          Standard deviation

SE          Standard error

LS Mean Least-squares mean

CI          Confidence interval

*             T­reatment statistically significantly superior to placebo

a            Dif­ference (brexpiprazole minus placebo) in least-squares mean change from

baseline, at week 6

b          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 assessing the delay in time to impending relapse of schizophrenia, patients with schizophrenia, who responded to treatment with brexpiprazole 1 mg/day to 4 mg/day, were stabilised over

12 weeks to 36 weeks, and then randomised in a double-blind manner to either continue treatment with the stabilisation dose of brexpiprazole (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 significantly longer 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 the stabilisation, brexpiprazole improved clinical symptomology (as assessed by PANSS, CGI-S and CGI-I, [Analysis of Covariance – ANCOVA Last Observation Carried Forward – LOCF]) and functioning (as assessed by Global Assessment of Functioning (GAF) [ANCOVA LOCF]). These improvements were maintained during the 52-week double-blind maintenance phase in patients on brexpiprazole whereas patients randomised to placebo showed deterioration in PANSS, CGI-S and CGI-I, and GAF scores [ANCOVA LOCF]). Brexpiprazole maintained symptom control and functioning compared to placebo.

Paediatric population

The European Medicines Agency has deferred the obligation to submit the results of efficacy and safety studies with brexpiprazole in the paediatric population from 13 years to less than 18 years of age (see section 4.2 for information on paediatric use).

5.2 Pharmacokinetic properties

Absorption

Brexpiprazole is 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 days to 12 days of dosing. 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. Based on in vivo studies, brexpiprazole is neither a substrate nor an inhibitor of efflux transporters, such as Multi Drug Resistance (MDR) 1 (P-gp) and BCRP.

Distribution

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 bound in plasma (greater than

99 %) to serum albumin and a1-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.

Biotransformation

Based on in vitro metabolism studies using recombinant human cytochrome P450, the metabolism of brexpiprazole was shown to be mainly mediated by CYP3A4 and CYP2D6 leading to formation of oxidative 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 in plasma with more than 10 % of plasma exposure.

At steady-state, DM-3411 represents 23.1 % to 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.

Elimination

Following a single oral dose of [14C]-labelled brexpiprazole, approximately 24.6 % and 46 % of the administered radioactivity was recovered in the urine and faeces, respectively. Less than 1 % of unchanged brexpiprazole was excreted in the urine and approximately 14 % of the oral dose was recovered unchanged in the faeces. Apparent oral clearance of brexpiprazole 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.

Linearity/non-linearity

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.

Pharmacokinetics in special populations

Age

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 adult subjects (18 years to 45 years old; see sections 4.2 and 4.4).

Gender

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).

Race

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

CYP2D6 genotype

Population pharmacokinetic evaluation shows that CYP2D6 poor metabolisers have 47 % higher exposure 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; smoking should, therefore, not have an effect on the pharmacokinetics of brexpiprazole.

Renal impairment

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 was not 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 (see section 4.2).

Hepatic impairment

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 in severe 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).

Paediatric population

The safety and efficacy of brexpiprazole in children and adolescents aged less than 18 years have not been established (see section 4.2).

5.3 Preclinical safety data

Effects observed in repeated-dose toxicity studies in rats and monkeys were mainly related to the exaggerated 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 and male rats and monkey.

Cardiovascular toxicity

Following oral administration, brexpiprazole decreased blood pressure and prolonged QT interval in safety pharmacology study in conscious male dog, in repeated-dose toxicity studies in male and female monkeys and in juvenile toxicity study in male and female dogs. The effect of brexpiprazole on blood pressure reduction is attributed to the expected blockade of a1-adrenoceptors in peripheral blood vessels.

Genotoxicity, carcinogenicity

Brexpiprazole did not show any genotoxic potential in both in vitro and in vivo studies using clinically relevant exposures. Brexpiprazole administered orally did not increase in the incidence of tumours in 2-year carcinogenicity study in both male and female rats and in male mice at exposures up to 4.4-fold and 3.1-fold the MRHD. In female mice, an increased incidence of mammary gland adenocarcinoma and adeno-squamous carcinoma, and pars distalis adenoma of the pituitary gland, was observed at similar or even lower clinically relevant exposures: these prolactin-mediated endocrine tumours were also observed in rodents with other antipsychotics and their clinical relevance is unknown.

Reproductive toxicity

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

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

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

Environmental risk assessment (ERA)

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

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Low-substituted hydroxypropyl­cellulose

Hydroxypropyl­cellulose

Magnesium stearate

Purified water

Tablet coat

Hypromellose

Talc

Titanium dioxide

RXULTI3 mg film-coated tablets

Iron oxide E 172 (red, black)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

RXULTI 0.25 mg, 0.5 mg, 2 mg, 3 mg and 4 mg film-coated tablets

28 film-coated tablets in Aluminium/PVC blisters.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

This medicinal product may pose a risk to the environment (see section 5.3). Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 292

1101 CT, Amsterdam

Netherlands