Rxulti · 4.1 Therapeutic indications · 1

HOS-097191 · has-adverse-reaction-information · PDF-Seite 9

Summary of the safety profile 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%). 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 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. 9 SOC Very common Common Uncommon Not known Immune system Rash Angioedema disorders Urticaria Swelling face Metabolism and Weight nutrition disorders increase Psychiatric disorders Suicide attempt Gambling Suicidal ideation disorder Impulsive behaviour Binge eating Compulsive shopping Compulsive sexual behaviour Nervous system Akathisia Parkinsonism Seizures disorders Dizziness Neuroleptic Tremor malignant Somnolence1 syndro

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HOS-097187 · has-contraindication-information · PDF-Seite 5

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

HOS-097186 · has-indication-information · PDF-Seite 3

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

HOS-097189 · has-interaction-information · PDF-Seite 8

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 did not change the 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., 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). 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 did not change the 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) tr

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HOS-097190 · has-pregnancy-information · PDF-Seite 9

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).

HOS-097188 · has-warning-information · PDF-Seite 5

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 to patients with known cardiovascular disease, family history of QT prolongation, electrolyte imbalance or in case of 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 should be undertaken. 5 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 dehydratio

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