Rxulti

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 



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 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 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 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
RXULTI 0.25 mg film-coated tablets 
Each film-coated tablet contains 0.25 mg brexpiprazole. 
Excipient with known effect 
Each film-coated tablet contains 48.2 mg lactose (as monohydrate). 
 
RXULTI 0.5 mg film-coated tablets 
Each film-coated tablet contains 0.5 mg brexpiprazole. 
Excipient with known effect 
Each film-coated tablet contains 47.9 mg lactose (as monohydrate). 
 
RXULTI 1 mg film-coated tablets 
Each film-coated tablet contains 1 mg brexpiprazole. 
Excipient with known effect 
Each film-coated tablet contains 47.4 mg lactose (as monohydrate). 
 
RXULTI 2 mg film-coated tablets 
Each film-coated tablet contains 2 mg brexpiprazole. 
Excipient with known effect 
Each film-coated tablet contains 46.4 mg lactose (as monohydrate). 
 
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). 
 
RXULTI 4 mg film-coated tablets 
Each film-coated tablet contains 4 mg brexpiprazole. 
Excipient with known effect 
Each film-coated tablet contains 44.4 mg lactose (as monohydrate). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet 
 



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RXULTI 0.25 mg film-coated tablets 
Light brown, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 0.25 
on 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 0.5 
on one side. 
 
RXULTI 1 mg film-coated tablets 
Light yellow, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 1 
on 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 on 
one side. 
 
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. 
 
RXULTI 4 mg film-coated tablets 
White, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 4 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 cross-titration 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 cross-titration 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. 



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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 
 
Factors Adjusted dose 
CYP2D6 poor metabolisers 
Known CYP2D6 poor metabolisers Administer half of the recommended dose 
Known CYP2D6 poor metabolisers taking 
strong/moderate CYP3A4 inhibitors 

Administer a quarter of the recommended dose 

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 
strong/moderate CYP3A4 inhibitors 

Administer a quarter of the recommended dose 

 
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. 
 



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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). 
 



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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. 
 



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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 



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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 



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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. 
 
SOC Very common Common Uncommon Not known 
Immune system 
disorders 

 Rash Angioedema 
Urticaria 

 



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SOC Very common Common Uncommon Not known 
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 
Sedation 

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 
increased1 

Blood creatine 
phosphokinase 
increased 

Blood pressure 
increased 
Blood triglycerides 
increased 
Hepatic enzymes 
increased 

 

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

 
Description of selected adverse reactions 
 
Extrapyramidal Symptoms (EPS) 



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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 × 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. 



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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 national reporting system 
listed in Appendix V. 
 
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 α1B/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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


13 

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 pre-specified 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. 
 



14 

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

Trial Treatment group n Primary efficacy measure: PANSS 

 
Mean baseline 

score (SD) 
 

LS mean change 
from baseline 

(SE) 

LS mean 
differencea, b 
(95 % CI) 

p-value 

1 Brexpiprazole (2 mg/day)* 180 
95.85 

(13.75) 
−20.73 
(1.55) 

−8.72 
(−13.1, −4.37) < 0.0001 

 Brexpiprazole (4 mg/day)* 178 
94.70 

(12.06) 
−19.65 
(1.54) 

−7.64 
(−12.0, −3.30) 0.0006 

 Placebo 178 95.69 (11.46) 
−12.01 
(1.60) -- -- 

2 Brexpiprazole (2 mg/day) 179 
96.30 

(12.91) 
−16.61 
(1.49) 

−3.08 
(−7.23, 1.07) 0.1448 

 Brexpiprazole (4 mg/day)* 181 
94.99 

(12.38) 
−20.00 
(1.48) 

−6.47 
(−10.6, −2.35) 0.0022 

 Placebo 180 94.63 (12.84) 
−13.53 
(1.52) -- -- 

3 Brexpiprazole (2 mg/day)* 113 
96.55 

(19.20) 
−14.95 
(2.00) 

−7.32 
(−13.04, −1.59) 0.0124 

 Brexpiprazole (4 mg/day) 109 
96.39 

(15.73) 
−11.49 
(2.10) 

−3.86 
(−9.71, 2.00) 0.1959 

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

4 
Brexpiprazole 

(2 mg/day to 4 mg/day
) 

150 
97.82 

(10.25) 
−19.99 
(1.51) −4.1 (−8.2, 0.1) 0.0560 

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

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 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 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). 
 



15 

Table 3: Key secondary efficacy results for 6-week trials in schizophrenia 
 
Trial Treatment group n Key secondary efficacy measure: CGI-S 

 Mean baseline 
score (SD) 

 

LS mean 
change from 
baseline (SE) 

LS mean 
differencea 
(95 % CI) 

p-value 

1 Brexpiprazole (2 mg/day)* 181 
4.90 

(0.64) 
−1.15 
(0.08) 

−0.33 
(−0.56, −0.10) 0.0056 

 Brexpiprazole (4 mg/day)* 178 
4.81 

(0.64) 
−1.20 
(0.08) 

−0.38 
(−0.61, −0.15) 0.0012 

 Placebo 181  
4.84 

(0.66) 
−0.82 
(0.09) -- -- 

2 Brexpiprazole (2 mg/day) 180 
4.96 

(0.65) 
−0.99 
(0.09) 

−0.19 
(−0.42, 0.05) 0.1269 

 Brexpiprazole (4 mg/day)* 183 
4.85 

(0.64) 
−1.19 
(0.08) 

−0.38 
(−0.62, −0.15) 0.0015 

 Placebo 181 4.87 (0.61) 
−0.81 
(0.09) -- -- 

3 Brexpiprazole (2 mg/day)* 113 
4.80 

(0.78) 
−0.84 
(0.11) 

−0.35 
(−0.67, −0.03) 0.0308 

 Brexpiprazole (4 mg/day) 109 
4.71 

(0.75) 
−0.64 
(0.12) 

−0.16 
(−0.48, 0.17) 0.3461 

 Placebo 113 4.73 (0.71) 
−0.48 
(0.12) -- -- 

4 Brexpiprazole* (2 mg/day to 4 mg/day)b 150 
4.96 

(0.59) 
−1.21 
(0.08) 

−0.27 
(−0.49, −0.06) 0.0142 

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

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. 
 



16 

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 α1-acid glycoprotein, and its protein binding is 
not affected by renal or hepatic impairment. Based on results of in vitro studies brexpiprazole protein 
binding is not affected by warfarin, diazepam, and digitoxin. 
 
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. 
 



17 

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 α1-adrenoceptors in peripheral blood 
vessels. 
 



18 

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 
 
RXULTI 0.25 mg film-coated tablets 
Iron oxide E 172 (yellow, red, black) 
 



19 

RXULTI 0.5 mg film-coated tablets 
Iron oxide E 172 (yellow, red) 
 
RXULTI 1 mg film-coated tablets 
Iron oxide E 172 (yellow) 
 
RXULTI 2 mg film-coated tablets 
Iron oxide E 172 (yellow, black) 
 
RXULTI 3 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. 
 
RXULTI 1 mg film-coated tablets 
10 or 28 film-coated tablets in Aluminium/PVC blisters. 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
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. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
RXULTI 0.25 mg film-coated tablets 
EU/1/18/1294/001 (28 film-coated tablets) 
 
RXULTI 0.5 mg film-coated tablets 
EU/1/18/1294/002 (28 film-coated tablets) 
 



20 

RXULTI 1 mg film-coated tablets 
EU/1/18/1294/003 (10 film-coated tablets) 
EU/1/18/1294/004 (28 film-coated tablets) 
 
RXULTI 2 mg film-coated tablets 
EU/1/18/1294/005 (28 film-coated tablets) 
 
RXULTI 3 mg film-coated tablets 
EU/1/18/1294/006 (28 film-coated tablets) 
 
RXULTI 4 mg film-coated tablets 
EU/1/18/1294/007 (28 film-coated tablets) 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 26 July 2018 
 
 
10. DATE OF REVISION OF THE TEXT 
 
{MM/YYYY} 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


21 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 



22 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer(s) responsible for batch release 
 
Elaiapharm 
2881 Route des Crêtes 
Z.I. les Bouillides 
Sophia Antipolis 
06560 Valbonne 
France 
 
H. Lundbeck A/S 
Ottiliavej 9 
DK 2500 Valby 
Denmark 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic safety update reports (PSURs) 
 
The requirements for submission of PSURs for this medicinal product are set out in the list of Union 
reference dates (EURD list) provided for under Article 107c (7) of Directive 2001/83/EC and any 
subsequent updates published on the European medicines web-portal. 
 
The marketing authorisation holder (MAH) shall submit the first PSUR for this product within 
6 months following authorisation. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk management plan (RMP) 
 
The marketing authorisation holder (MAH) shall perform the required pharmacovigilance activities 
and interventions detailed in the agreed RMP presented in Module 1.8.2 of the marketing authorisation 
and any agreed subsequent updates of the RMP. 
 
An updated RMP should be submitted: 
 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to a significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



23 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 



24 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



25 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 0.25 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 0.25 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



26 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 0.25 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



27 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 0.25 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



28 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 0.5 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 0.5 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



29 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 0.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



30 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 0.5 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



31 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 1 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 1 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
10 film-coated tablets 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



32 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/003 
EU/1/18/1294/004 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



33 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 1 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



34 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 2 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 2 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



35 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/005 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 2 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



36 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 2 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



37 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 3 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 3 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 



38 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/006 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 3 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



39 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 3 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 



40 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 4 mg film-coated tablets 
brexpiprazole 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 4 mg brexpiprazole. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains lactose. 
See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Film-coated tablet 
 
28 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



41 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/18/1294/007 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription. 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
RXULTI 4 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC 
SN 
NN 



42 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
RXULTI 4 mg film-coated tablets 
brexpiprazole 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Otsuka 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 



43 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



44 

Package leaflet: Information for the user 
 

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 

 
brexpiprazole 

 
 This medicine is subject to additional monitoring. This will allow quick identification of new 

safety information. You can help by reporting any side effects you may get. See the end of section 4 
for how to report side effects. 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What RXULTI is and what it is used for 
2. What you need to know before you take RXULTI 
3. How to take RXULTI 
4. Possible side effects 
5. How to store RXULTI 
6. Contents of the pack and other information 
 
 
1. What RXULTI is and what it is used for 
 
RXULTI contains the active substance brexpiprazole, which belongs to a group of medicines called 
antipsychotics. 
 
It is used to treat schizophrenia in adult patients - a disease with symptoms such as hearing, seeing or 
sensing things - which are not there, suspiciousness, incoherent speech and behaviour and emotional 
flatness. People with this condition may also feel depressed, guilty, anxious or tense. 
 
RXULTI can help to keep the symptoms under control and to prevent relapse as you continue 
treatment. 
 
 
2. What you need to know before you take RXULTI 
 
Do not take RXULTI 
• if you are allergic to brexpiprazole or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
Tell your doctor immediately if you 
• experience a combination of fever, sweating, faster breathing, muscle stiffness and drowsiness 

or sleepiness (may be signs of neuroleptic malignant syndrome). 



45 

• are having any thoughts or feelings about hurting yourself or to commit suicide. Suicidal 
thoughts and behaviours are more likely at the beginning of the treatment. 

• or your family/carer notices that you are developing urges or cravings to behave in ways that are 
unusual for you and you cannot resist the impulse, drive or temptation to carry out certain 
activities that could harm yourself or others. These are called impulse-control disorders and can 
include behaviours such as addictive gambling, excessive eating or spending, an abnormally 
high sex drive or preoccupation with an increase in sexual thoughts or feelings. Your doctor 
may need to adjust or stop your dose. 

• have any difficulty in swallowing. 
• have or had a low number of white blood cells in your blood and get a fever or any other sign of 

infection. This may for example be the case if other medicines lowered your white blood cells in 
the past. Your doctor will regularly measure the white blood cells in your blood to minimise the 
risk for diseases called leukopenia, neutropenia and agranulocytosis. It is important that you get 
your blood checked regularly as this may be fatal. Your doctor will stop the treatment 
immediately if the white blood cells in your blood are too low. 

 
Talk to your doctor or pharmacist before taking RXULTI, or during treatment if you have 
• or had heart problems or a history of stroke, especially if you know that you have other risks 

factors for stroke. 
• dementia (loss of memory and other mental abilities) especially if you are elderly. 
• irregular heart beat or if someone else in your family has a history of irregular heart beat 

(including so called QT prolongation seen with ECG monitoring). Please inform your doctor if 
you take any other medicines that are known to prolong the QT interval. 

• an electrolyte imbalance (problems with the amount of salts in your blood). 
• or had low or high blood pressure. 
• a history of blood clots, or if someone else in your family has a history of blood clots, as 

medicines for schizophrenia have been associated with formation of blood clots. 
• or had dizziness on standing up due to a drop in your blood pressure, which may cause fainting. 
• or had problems with your movements called extrapyramidal symptoms (EPS) in the past. 

These may include jerky movements, spasms, restlessness or slow movements. 
• ever experienced or start to experience restlessness and inability to sit still. These symptoms 

may occur early during treatment. Tell your doctor if this happens. 
• diabetes or risk factors for diabetes (e.g. obesity, or someone else in your family has diabetes). 

Your doctor will need to check your blood sugar regularly since it may be increased by this 
medicine. Signs of high blood sugar level are excessive thirst, passing of large amounts of urine, 
increase in appetite and feeling weak. 

• a history of seizures (fits) or epilepsy. 
• ever inhaled food, stomach acid, or saliva into your lungs causing a disease called aspiration 

pneumonia. 
• increased levels of the hormone prolactin, or have a tumour in your pituitary gland. 
 
Weight gain 
This medicine may cause significant weight gain which may affect your health. Your doctor will 
therefore check your weight and your fats in the blood regularly. 
 
Body temperature 
While taking RXULTI you should avoid getting over-heated or dehydrated. Do not over-exercise and 
drink plenty of water. 
 
Children and adolescents 
This medicine must not be taken by children and adolescents under 18 years of age. The safety and 
effectiveness in these patients were not evaluated. 
 
Other medicines and RXULTI 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 



46 

RXULTI may increase the effect of medicines used to lower the blood pressure. Be sure to tell your 
doctor if you take a medicine to keep your blood pressure under control. 
 
Receiving RXULTI with some medicines may mean the doctor will need to change your dose of 
RXULTI or the other medicines. It is especially important to mention the following medicines to your 
doctor: 
• medicines to correct heart rhythm (such as quinidine), 
• antidepressants or herbal remedies used to treat depression and anxiety (such as fluoxetine, 

paroxetine, St. John's Wort), 
• antifungal medicines (such as ketoconazole, itraconazole), 
• certain medicines to treat HIV infection (such as efavirenz, nevirapine, and protease inhibitors 

e.g. indinavir, ritonavir), 
• anticonvulsants used to treat epilepsy, 
• antibiotics to treat bacterial infections (such as clarithromycin), 
• certain antibiotics used to treat tuberculosis (such as rifampicin), 
• medicines known to prolong your QT interval (an important measurement of your heart function 

in an electrocardiogram [ECG]), 
• medicines changing the salt concentrations in your body (causing a so-called electrolyte 

imbalance), 
• medicines increasing an enzyme called creatine phosphokinase (CPK), 
• medicines having an effect on the central nervous system. 
 
RXULTI with food and alcohol 
RXULTI can be taken with or without food. Alcohol should be avoided as it can influence how this 
medicine works. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
It is not recommended to take RXULTI during your pregnancy. If you are of childbearing age, you 
should use effective contraception while taking RXULTI. Babies of mothers who take this medicine 
during the last three months of their pregnancy may show the following symptoms: shaking, muscle 
stiffness and/or muscle weakness, sleepiness, restlessness, breathing problems and difficulty in 
feeding. If your baby has any of these symptoms you should contact your doctor. 
 
Talk to your doctor about the best way to feed your baby if you are taking RXULTI. Your doctor will 
consider the benefit of the therapy for you and the benefit of breast-feeding for your baby. 
 
Driving and using machines 
There is a chance that the medicine could affect your ability to drive and use machines. Please check 
that you are not feeling dizzy or sleepy before you start driving or handling machines. Do not drive or 
use any tools or machines until you know that this medicine does not affect you in a negative way. 
 
RXULTI contains lactose 
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor 
before taking this medicine. 
 
 
3. How to take RXULTI 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Your medicine will usually be given to you in increasing doses as follows: 
• for the first 4 days take one 1 mg film-coated tablet per day, 
• from day 5 to day 7 take two 1 mg film-coated tablet per day, 



47 

• from day 8 onwards take one film-coated tablet of the strength prescribed by your doctor each 
day. 

 
However, your doctor may prescribe a lower or higher dose to a maximum of 4 mg once a day. 
 
It does not matter whether you take your medicine with or without food. 
 
If you were taking other medicine to treat schizophrenia before starting RXULTI, your doctor will 
decide whether to stop the other medicine gradually or immediately and how to adjust the dose of 
RXULTI. Your doctor will also inform you how to act if you switch from RXULTI to other medicine. 
 
Patients with kidney problems 
If you have kidney problems, your doctor may adjust your dose of this medicine. 
 
Patients with liver problems 
If you have liver problems, your doctor may adjust your dose of this medicine. 
 
If you take more RXULTI than you should 
If you have taken more RXULTI than your prescribed dose, contact your doctor or your local hospital 
immediately. Remember to take the medicine pack with you so that it is clear what you have taken. 
 
If you forget to take RXULTI 
If you forget to take a dose, take it as soon as you remember it. However, if it is almost time for your 
next dose, skip the missed dose and continue as usual. Do not take a double dose to make up for a 
forgotten dose. If you miss two or more doses, contact your doctor. 
 
If you stop taking RXULTI 
If you stop taking this medicine you will lose the effects of the medicine. Even if you feel better, do 
not alter or stop your daily dose of RXULTI unless told to do so by your doctor as your symptoms 
may return. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
During treatment you may experience these serious side effects that require urgent medical attention. 
Tell your doctor immediately if you have: 
• thoughts or feelings about hurting yourself or to commit suicide or a suicide attempt 

(uncommon side effect - may affect up to 1 in 100 people). 
• combination of fever, sweating, muscle stiffness, and drowsiness or sleepiness. These can be the 

signs of the so-called neuroleptic malignant syndrome (it is not known how many people are 
affected). 

• irregularities in heart rhythm that may be due to abnormal nerve impulses in the heart, abnormal 
readings during heart examination (ECG), QT prolongation - it is not known how many people 
are affected. 

• symptoms related to blood clots in the veins especially in the legs (symptoms include swelling, 
pain and redness in the leg), which may travel through blood vessels to the lungs causing chest 
pain and difficulty in breathing (uncommon side effect - may affect up to 1 in 100 people). 

 
Other side effects 
 
Very common side effects (may affect more than 1 in 10 people): 
• during blood tests your doctor may find higher amounts of prolactin in your blood. 
 



48 

Common side effects (may affect up to 1 in 10 people): 
• rash, 
• weight gain, 
• akathisia (an uncomfortable feeling of inner restlessness and a compelling need to move 

constantly), 
• dizziness, 
• shaking, 
• feeling sleepy, 
• diarrhoea, 
• nausea, 
• pain in the upper abdomen, 
• back pain, 
• pain in arms or legs or both, 
• during blood tests your doctor may find higher amounts of creatine kinase (also called creatine 

phosphokinase) in your blood (enzyme important for muscle function). 
 
Uncommon side effects (may affect up to 1 in 100 people): 
• allergic reaction (e.g. swelling in the mouth, tongue, face and throat, itching, hives), 
• parkinsonism - medical condition with many various symptoms which include decreased or 

slow movements, slowness of thought, jerks when bending the limbs (cogwheel rigidity), 
shuffling steps, shaking, little or no facial expression, muscle stiffness, drooling, 

• dizziness on standing up due to a drop in your blood pressure, which may cause fainting, 
• cough, 
• tooth decay or cavities (dental caries), 
• flatulence, 
• muscle pain, 
• higher blood pressure, 
• during blood tests your doctor may find higher amounts of triglycerides in your blood, 
• during blood tests your doctor may find increases in liver enzymes. 
 
Other side effects (it is not known how many people are affected): 
• seizure, 
• muscle weakness, tenderness or pain and particularly, if at the same time, you feel unwell, have 

a high temperature or have dark urine. They may be caused by an abnormal muscle breakdown 
which can be life threatening and lead to kidney problems (a condition called rhabdomyolysis), 

• withdrawal symptoms in new-born babies if the mother has taken this medicine during 
pregnancy. 

• Inability to resist the impulse, drive or temptation to perform an action that could be harmful to 
you or others, which may include: 
- strong impulse to gamble excessively despite serious personal or family consequences 
- altered or increased sexual interest and behaviour of significant concern to you or to 

others, for example, an increased sexual drive 
- uncontrollable excessive shopping 
- binge eating (eating large amounts of food in a short time period) or compulsive eating 

(eating more food than normal and more than is needed to satisfy your hunger) 
Tell your doctor if you experience any of these behaviours; he/she will discuss ways of 
managing or reducing the symptoms. 

 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects, you can help provide more information on the safety 
of this medicine. 
 
 
5. How to store RXULTI 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


49 

Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister and on the outer carton 
after EXP. The expiry date refers to the last day of that month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What RXULTI film-coated tablets contain 
• The active substance is brexpiprazole. 

Each film-coated tablet contains 0.25 mg brexpiprazole. 
Each film-coated tablet contains 0.5 mg brexpiprazole. 
Each film-coated tablet contains 1 mg brexpiprazole. 
Each film-coated tablet contains 2 mg brexpiprazole. 
Each film-coated tablet contains 3 mg brexpiprazole. 
Each film-coated tablet contains 4 mg brexpiprazole. 

 
• The other ingredients are: 

 
Tablet core: 
Lactose monohydrate, maize starch, microcrystalline cellulose, low-substituted 
hydroxypropylcellulose, hydroxypropylcellulose, magnesium stearate, purified water. 
 
Tablet coat: 
Hypromellose, talc, titanium dioxide. 
 
RXULTI 0.25 mg film-coated tablets 
Iron oxide E 172 (yellow, red, black) 
 
RXULTI 0.5 mg film-coated tablets 
Iron oxide E 172 (yellow, red) 
 
RXULTI 1 mg film-coated tablets 
Iron oxide E 172 (yellow) 
 
RXULTI 2 mg film-coated tablets 
Iron oxide E 172 (yellow, black) 
 
RXULTI 3 mg film-coated tablets 
Iron oxide E 172 (red, black) 

 
What RXULTI film-coated tablets look like and contents of the pack 
 
RXULTI 0.25 mg film-coated tablets 
Light brown, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 0.25 
on 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 0.5 
on one side. 
 
RXULTI 1 mg film-coated tablets 



50 

Light yellow, round, 6 mm in diameter, shallow convex and bevel-edged, debossed with BRX and 1 
on 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 on 
one side. 
 
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. 
 
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 film-coated tablets are supplied in Aluminium/PVC blisters containing 10 or 28 film-coated 
tablets. 
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
 
Otsuka Pharmaceutical Netherlands B.V. 
Herikerbergweg 292 
1101 CT, Amsterdam 
Netherlands 
 
Manufacturer 
 
Elaiapharm 
2881 Route des Crêtes, Z.I. Les Bouillides-Sophia Antipolis, 
06560 Valbonne 
France 
 
H. Lundbeck A/S 
Ottiliavej 9 
2500 Valby 
Denmark 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Lundbeck S.A./N.V. 
Tél/Tel: +32 2 535 79 79 
Tél/Tel: +32 2 340 2828 
 

Lietuva 
H. Lundbeck A/S 
Tel: +45 36301311 

България 
Lundbeck Export A/S Representative Office 
Tel: +359 2 962 4696 
 

Luxembourg/Luxemburg 
Lundbeck S.A. 
Tél: +32 2 535 79 79 
Tél: +32 2 340 2828 
 

Česká republika 
Lundbeck Česká republika s.r.o. 
Tel: +420 225 275 600 
 

Magyarország 
Lundbeck Hungaria Kft. 
Tel: +36 1 4369980 
 



51 

Danmark 
Otsuka Pharma Scandinavia AB 
Tel: +46 8 54528660 
 

Malta 
H. Lundbeck A/S 
Tel: +45 36301311 

Deutschland 
Otsuka Pharma GmbH 
Tel: +49 69 1700860 
 

Nederland 
Lundbeck B.V. 
Tel: +31 20 697 1901 
 

Eesti 
H. Lundbeck A/S 
Tel: +45 36301311 
 

Norge 
Otsuka Pharma Scandinavia AB 
Tel: +46 8 54528660 

Ελλάδα 
Lundbeck Hellas S.A. 
Τηλ: +30 210 610 5036 
 

Österreich 
Lundbeck Austria GmbH 
Tel: +43 1 266 91 08 
Tel: +43 1 331 070 
 

España 
Otsuka Pharmaceutical S.A. 
Tel: +34 93 208 10 20 
 

Polska 
Lundbeck Poland Sp. z o. o. 
Tel.: +48 22 626 93 00 

France 
Otsuka Pharmaceutical France SAS 
Tél: +33 (0)1 47 08 00 00 
 

Portugal 
Lundbeck Portugal Lda 
Tel: +351 21 00 45 900 
 

Hrvatska 
Lundbeck Croatia d.o.o. 
Tel.: +385 1 644 82 63 
Tel.: +385 1 3649 210 
 

România 
Lundbeck Romania SRL  
Tel: +40 21319 88 26 
 

Ireland 
Lundbeck (Ireland) Limited 
Tel: +353 1 468 9800 
 

Slovenija 
Lundbeck Pharma d.o.o. 
Tel.: +386 2 229 4500 

Ísland 
Vistor hf. 
Sími: +354 535 7000 

Slovenská republika 
Lundbeck Slovensko s.r.o. 
Tel: +421 2 5341 42 18 
 

Italia 
Otsuka Pharmaceutical Italy S.r.l. 
Tel: +39 02 00 63 27 10 
 

Suomi/Finland 
Otsuka Pharma Scandinavia AB 
Tel: +46 8 54528660 

Κύπρος 
Lundbeck Hellas A.E 
Τηλ.: +357 22490305 

Sverige 
Otsuka Pharma Scandinavia AB 
Tel: +46 8 54528660 
 

Latvija 
H. Lundbeck A/S 
Tel: +45 36301311 

United Kingdom 
Otsuka Pharmaceuticals (UK) Ltd. 
Tel: +44 203 747 5300 
 

 
This leaflet was last revised in MM/YYYY. 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET