Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
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 days to some weeks. Patients should be closely monitored throughout this period.
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.
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 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 to 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).
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 should be undertaken.
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).
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 (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 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.
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.
Brexpiprazole has not been studied in elderly patients with dementia and is not recommended for the treatment of elderly patients with dementia due to increased risk of overall mortality.
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.
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.
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).
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.
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 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 reported urges 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 medicinal product was discontinued. Compulsive behaviours may result in harm to the patient and others if not recognised. Consider dose reduction or stopping the medicinal product if a patient develops such urges while taking brexpiprazole (see section 4.8).
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.
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).
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.
Brexpiprazole is predominantly metabolised by CYP3A4 and CYP2D6.
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).
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., carbamazepine, phenobarbital, rifampicin, St. John’s Wort), the total daily dose requirement of brexpiprazole is increased by approximately a factor of three times the recommended 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 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).
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 (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 creatine phosphokinase (CPK), e.g. statins like simvastatin, the possible additive effect with CPK increase induced by brexpiprazole should be considered.
No information on pharmacodynamic interactions of brexpiprazole is available at present. Caution should be exercised when prescribing other medicinal products concomitantly. 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 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 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.
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.
The effect of brexpiprazole on human fertility has not been evaluated. Studies in animals have shown decreased female fertility (see section 5.3).
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).
The most frequently observed adverse drug reactions (ADRs) in adults were akathisia (5.6%) and weight 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 is based on adverse reactions reported in short-term placebo-controlled phase 2 and 3 adult clinical trials with relevant therapeutic doses (2 mg to 4 mg) and short-term placebo-controlled phase 3 paediatric clinical 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 frequency grouping, adverse reactions are presented in order of decreasing seriousness.
| SOC | Very common | Common | Uncommon | Not known |
|---|---|---|---|---|
| Immune system disorders | Rash | Angioedema Urticaria Swelling face | ||
| Metabolism and nutrition disorders | Weight increase | |||
| Psychiatric disorders | Suicide attempt Suicidal ideation | Gambling disorder Impulsive behaviour Binge eating Compulsive shopping Compulsive sexual behaviour | ||
| Nervous system disorders | Akathisia Dizziness Tremor Somnolence1 | Parkinsonism | Seizures Neuroleptic malignant syndrome (NMS) | |
| Cardiac disorders | Electrocardiogram QT prolonged | |||
| Vascular disorders | Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Orthostatic hypotension | |||
| Respiratory, thoracic and mediastinal disorders | Cough | |||
| Gastrointestinal disorders | Diarrhoea Nausea Abdominal pain upper | Dental caries Flatulence | ||
| Musculoskeletal and connective tissue disorders | Back pain Pain in extremity | Myalgia | Rhabdomyolysis | |
| Pregnancy, puerperium and perinatal conditions | Drug withdrawal syndrome neonatal (see section 4.6) | |||
| Investigations | Blood prolactin increased2 | Blood creatine phosphokinase increased | Blood pressure increased Blood triglycerides increased Hepatic enzymes increased |
1 Includes also sedation and hypersomnia
2 The categorisation of blood prolactin increased is based on Potentially Clinically Relevant (PCR) criteria of >1 × upper limit of normal (ULN).
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%). See section 4.4.
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%).
In short-term, controlled trials, Treatment Emergent Adverse Events (TEAEs) related to suicidal behaviour were reported for 8 subjects (0.5%, 2 serious events, 1 leading to discontinuation) in the brexpiprazole 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 suicide occurred but was not considered drug related by the investigator. Spontaneous cases reporting completed suicide and suicide attempt have been reported in the post-marketing setting. See section 4.4.
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 in subjects receiving 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 sections 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 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. See section 4.4.
The incidence of blood prolactin increased was 0.9% in the 2 mg to 4 mg brexpiprazole group compared to 0.5% in the placebo group 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 × ULN in the 2 mg to 4 mg brexpiprazole group was 13.7% in females versus 6.4% in the placebo group and 11.1% in males versus 10.3% in the placebo group. See section 4.4.
A potentially fatal symptom complex referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with brexpiprazole (see section 4.4).
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 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-treated subjects in short-term trials. Concerning subjects receiving placebo, the frequency for nausea was 2.8% for males versus 3.2% for females, whereas the frequency for vomiting was 3.0% for males versus 2.6% for females (see section 5.2).
Frequency, type and severity of adverse reactions in adolescents are expected to be similar as in adults.
In short-term trials, akathisia was the most frequently reported EPS related ADR in the brexpiprazole 1 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%).
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.
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. The safety profile observed in the adolescent population is considered to be similar to that observed in the adult 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, compared with 4.9% in placebo group The mean increase in weight from baseline to last visit was 0.8 kg in 13 brexpiprazole and 0.0 kg in placebo-treated subjects. To adjust for normal growth, z-scores were derived (measured in standard deviations [SD]), which normalize for natural growth of children and adolescents 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 baseline to last visit was observed in brexpiprazole and placebo-treated groups. 4.5% of subjects in brexpiprazole and 3.9% subjects in placebo had an increase in age-and-gender-adjusted body weight z-score of at least 0.5 SD from baseline. TEAEs of weight gain was reported in 1.7% of all patients in the 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 treated group. Mean change in z-score from baseline to last visit was 0.10 SD for body weight, while 20% of patients had an increase in age-and gender-adjusted body weight z-score of at least 0.5 SD from baseline. TEAEs related to weight increased were observed in 11.5% of subjects, while other TEAEs related to weight increase, such as increased BMI and waist circumference, were each reported in one subject.
In the short-term trial, no treatment emergent adverse events associated with elevated prolactin were reported. The frequencies of prolactin elevations >1 × ULN in the 2 mg to 4 mg brexpiprazole group was 26.8% in females versus 6.3% in the placebo group and 24.5% in males versus 6% in the placebo group. In the long-term trials, 1.7% of the subjects reported TEAEs of blood prolactin increased 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 safety profile observed in the adolescent population is considered to be similar to that observed in the adult population (see section 4.4).
TEAEs of Nausea have been reported in the adolescent schizophrenia trials. The safety profile observed in the adolescent population is considered to be similar to that observed in the adult population.
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. 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 national reporting system listed in Appendix V.
Not applicable.
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