ABILIFY is indicated for the treatment of schizophrenia in adults and in adolescents aged 15 years and older. ABILIFY is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in adults who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1). ABILIFY is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1).

Posology Adults Schizophrenia: the recommended starting dose for ABILIFY is 10 mg/day or 15 mg/day (i.e. 10 mL or 15 mL solution/day) with a maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals. ABILIFY is effective in a dose range of 10 mg/day to 30 mg/day (i.e. 10 mL to 30 mL solution/day). Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Manic episodes in Bipolar I Disorder: the recommended starting dose for ABILIFY is 15 mg (i.e. 15 mL solution/day) administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg. Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodes in patients, who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status. Paediatric population Schizophrenia in adolescents aged 15 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/mL) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1). ABILIFY is effective in a dose range of 10 mg/day to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higher dose. ABILIFY is not recommended for use in patients with schizophrenia below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1). Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/mL) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment duration should be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associated with a substantially higher incidence of significant adverse reactions including EPS related events, somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only be used in exceptional cases and with close clinical monitoring (see sections 4.4, 4.8 and 5.1). Younger patients are at increased risk of experiencing adverse events associated with aripiprazole. Therefore, ABILIFY is not recommended for use in patients below 13 years of age (see sections 4.8 and 5.1). Irritability associated with autistic disorder: the safety and efficacy of ABILIFY in children and adolescents aged below 18 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Tics associated with Tourette’s disorder: the safety and efficacy of ABILIFY in children and adolescents 6 to 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Special populations Hepatic impairment No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2). Renal impairment No dosage adjustment is required in patients with renal impairment. Elderly The safety and efficacy of ABILIFY in the treatment of schizophrenia or manic episodes in Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4). Gender No dosage adjustment is required for female patients as compared to male patients (see section 5.2). Smoking status According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (see section 4.5). Dose adjustments due to

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

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period. Suicidality 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 aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic treatment. Cardiovascular disorders Aripiprazole 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. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. 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 aripiprazole and preventive measures undertaken. QT prolongation In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazole should be used with caution in patients with a family history of QT prolongation (see section 4.8). Tardive dyskinesia In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment. Other extrapyramidal symptoms In paediatric clinical trials of aripiprazole akathisia and Parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered. Neuroleptic Malignant Syndrome (NMS) NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. 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 elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued. Seizure In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8). Elderly patients with dementia-related psychosis Increased mortality In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 to 99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in aripiprazole-treated patients was 3.5 % compared to 1.7 % in the placebo group. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature (see section 4.8). Cerebrovascular adverse reactions In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, 1.3 % of aripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % of placebo-treated patients in these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8). Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis. 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, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotics are not available to allow direct comparisons. Patients treated with any antipsychotics, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8). Hypersensitivity Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8). Weight gain Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co- morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain in adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8). Dysphagia Oesophageal dysmotility and aspiration have been associated with the use of antipsychotics, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia. Pathological gambling and other impulse control disorders Patients can experience increased urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. 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. Impulse control disorders 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 aripiprazole (see section 4.8). Fructose The oral solution contains fructose. Fructose may damage teeth. Patients with hereditary fructose intolerance (HFI) should not take/be given this medicinal product. Sucrose The oral solution contains sucrose. -Sucrose may be harmful to the teeth. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase- isomaltase insufficiency should not take this medicinal product. Parahydroxybenzoate The oral solution contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. May cause allergic reactions (possibly delayed). Sodium The oral solution contains sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’. Patients with attention deficit hyperactivity disorder (ADHD) comorbidity Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered. Falls Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2).

Due to its a1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products. Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8). If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation or electrolyte imbalance, caution should be used. Potential for other medicinal products to affect aripiprazole A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers. Quinidine and other CYP2D6 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Aripiprazole dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied. Ketoconazole and other CYP3A4 inhibitors In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should therefore be applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increased to the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected. Carbamazepine and other CYP3A4 inducers Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, than those following treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to the recommended dose. Valproate and lithium When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinically significant change in aripiprazole concentrations and therefore no dose adjustment is necessary when either valproate or lithium is administered with aripiprazole. Potential for aripiprazole to affect other medicinal products In clinical studies, 10 mg/day to 30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3- methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product

Pregnancy There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus. Newborn infants exposed to antipsychotics (including aripiprazole) 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, or feeding disorder. Consequently, newborn infants should be monitored carefully (see section 4.8). Breast-feeding Aripiprazole/metabolites are excreted in human milk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Aripiprazole did not impair fertility based on data from reproductive toxicity studies.

Aripiprazole has minor to moderate influence on the ability to drive and use machines due to potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8).

Summary of the safety profile The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea each occurring in more than 3 % of patients treated with oral aripiprazole. Tabulated list of adverse reactions The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulated below. The table is based on adverse events reported during clinical trials and/or post-marketing use. All ADRs are listed by system organ class and frequency; very common (= 1/10), common (= 1/100 to < 1/10), uncommon (= 1/1,000 to < 1/100), rare (= 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known". Common Uncommon Not known Blood and lymphatic system disorders Leukopenia Neutropenia Thrombocytopenia Immune system disorders Allergic reaction (e.g. anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus allergic, or urticaria) Endocrine disorders Hyperprolactinaemia Blood prolactin decreased Diabetic hyperosmolar coma Diabetic ketoacidosis Metabolism and nutrition disorders Diabetes mellitus Hyperglycaemia Hyponatremia Anorexia Psychiatric disorders Insomnia Anxiety Restlessness Depression Hypersexuality Suicide attempt, suicidal ideation and completed suicide (see section 4.4) Pathological gambling Impulse-control disorder Binge eating Compulsive shopping Poriomania Common Uncommon Not known Aggression Agitation Nervousness Nervous system disorders Akathisia Extrapyramidal disorder Tremor Headache Sedation Somnolence Dizziness Tardive dyskinesia Dystonia Restless legs syndrome Neuroleptic Malignant Syndrome Grand mal convulsion Serotonin syndrome Speech disorder Eye disorders Vision blurred Diplopia Photophobia Oculogyric crisis Cardiac disorders Tachycardia Sudden death unexplained Torsades de pointes Ventricular arrhythmia Cardiac arrest Bradycardia Vascular disorders Orthostatic hypotension Venous thromboembolism (including pulmonary embolism and deep vein thrombosis) Hypertension Syncope Respiratory, thoracic and mediastinal disorders Hiccups Aspiration pneumonia Laryngospasm Oropharyngeal spasm Gastrointestinal disorders Constipation Dyspepsia Nausea Salivary hypersecretion Vomiting Pancreatitis Dysphagia Diarrhoea Abdominal discomfort Stomach discomfort Hepatobiliary disorders Hepatic failure Hepatitis Jaundice Skin and subcutaneous tissue disorders Rash Photosensitivity reaction Alopecia Hyperhidrosis Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Musculoskeletal and connective tissue disorders Rhabdomyolysis Myalgia Stiffness Renal and urinary disorders Urinary incontinence Urinary retention Pregnancy, puerperium and perinatal conditions Drug withdrawal syndrome neonatal (see section 4.6) Reproductive Priapism Common Uncommon Not known system and breast disorders General disorders and administration site conditions Fatigue Temperature regulation disorder (e.g. hypothermia, pyrexia) Chest pain Peripheral oedema Investigations Weight decreased Weight gain Alanine Aminotransferase increased Aspartate Aminotransferase increased Gamma-glutamyltransferase increased Alkaline phosphatase increased QT prolonged Blood glucose increased Glycosylated haemoglobin increased Blood glucose fluctuation Creatine phosphokinase increased Description of selected adverse reactions Adults Extrapyramidal symptoms (EPS) Schizophrenia: in a long-term 52-week controlled trial, aripiprazole-treated patients had an overall-lower incidence (25.8 %) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3 %). In a long-term 26-week placebo-controlled trial, the incidence of EPS was 19 % for aripiprazole-treated patients and 13.1 % for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazole-treated patients and 15.1 % for olanzapine- treated patients. Manic episodes in Bipolar I Disorder: in a 12-week controlled trial, the incidence of EPS was 23.5 % for aripiprazole-treated patients and 53.3 % for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6 % for patients treated with aripiprazole and 17.6 % for those treated with lithium. In the long-term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2 % for aripiprazole-treated patients and 15.7 % for placebo-treated patients. Akathisia In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1 % with aripiprazole and 3.2 % with placebo. In schizophrenia patients the incidence of akathisia was 6.2 % with aripiprazole and 3.0 % with placebo. Dystonia Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups. Prolactin In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1). Laboratory parameters Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5 % of aripiprazole treated patients as compared to 2.0 % of patients who received placebo. Paediatric population Schizophrenia in adolescents aged 15 years and older In a short-term placebo-controlled clinical trial involving 302 adolescents (13 to 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults except for the following reactions that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): Somnolence/sedation and extrapyramidal disorder were reported very commonly (= 1/10), and dry mouth, increased appetite, and orthostatic hypotension were reported commonly (= 1/100, < 1/10). The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial. The safety profile of a long-term, double-blind, placebo-controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (= 1/100, < 1/10). In the pooled adolescent schizophrenia population (13 to 17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 29.5 % and 48.3 %, respectively. In the adolescent (13 to 17 years) schizophrenia population with aripiprazole exposure of 5 mg to 30 mg up to 72 months, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 25.6 % and 45.0 %, respectively. In two long-term trials with adolescent (13 to 17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 37.0 % and 59.4 %, respectively. Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (= 1/10) somnolence (23.0 %), extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (= 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia. The following adverse reactions had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1 %; 30 mg, 28.8 %; placebo, 1.7 %); and akathisia (incidences were 10 mg, 12.1 %; 30 mg, 20.3 %; placebo, 1.7 %). Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively. In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia. In the paediatric bipolar population (10 to 17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/mL) and males (< 2 ng/mL) was 28.0 % and 53.3 %, respectively. Pathological gambling and other impulse control disorders Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4). Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Signs and symptoms In clinical trials and post-marketing experience, accidental or intentional acute of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms. Management of Management of should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected with aripiprazole, close medical supervision and monitoring should continue until the patient recovers. Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment of . Haemodialysis Although there is no information on the effect of haemodialysis in treating an with aripiprazole, haemodialysis is unlikely to be useful in management since aripiprazole is highly bound to plasma proteins.

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12 Mechanism of action It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and moderate affinity for dopamine D4, serotonin 5-HT2C and 5-HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors.

Absorption Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3 to 5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87 %. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole. Distribution Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99 % bound to serum proteins, binding primarily to albumin. Biotransformation Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40 % of aripiprazole AUC in plasma. Elimination The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6. The total body clearance of aripiprazole is 0.7 mL/min/kg, which is primarily hepatic. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27 % of the administered radioactivity was recovered in the urine and approximately 60 % in the faeces. Less than 1 % of unchanged aripiprazole was excreted in the urine and approximately 18 % was recovered unchanged in the faeces. Oral Solution Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the peak plasma concentrations of aripiprazole (Cmax) from the solution were somewhat higher but the systemic exposure (AUC) was equivalent to tablets. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to the tablet ratio of geometric mean Cmax values was 122 % (n = 30). The single-dose pharmacokinetics of aripiprazole was linear and dose-proportional. Paediatric population The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of age were similar to those in adults after correcting for the differences in body weights. Pharmacokinetics in special patient groups Elderly There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients. Gender There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients. Smoking Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole. Race Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole. Renal impairment The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects. Hepatic impairment A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development. Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose- dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 mg/kg/day to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose. An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 mg/kg/day to 125 mg/kg/day (1 to 3 times the mean steady- state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6 % of the bile concentrations found in the monkeys in the 39-week study and are well below (6 %) their limits of in vitro solubility. In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions on development. Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic. Aripiprazole did not impair fertility in reproductive toxicity studies. Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.

Disodium edetate Fructose Glycerin Lactic acid Methyl parahydroxybenzoate (E 218) Propylene glycol Propyl parahydroxybenzoate (E 216) Sodium hydroxide Sucrose Purified water Orange flavour

The oral solution should not be diluted with other liquids or mixed with any food prior to administration.

3 years After first opening: 6 months.

This medicinal product does not require any special storage conditions. For storage conditions after first opening of the medicinal product, see section 6.3.

PET-bottles with polypropylene child-resistant closure containing 50 mL, 150 mL or 480 mL per bottle. Each carton contains 1 bottle and both a calibrated polypropylene measuring cup with a graduation interval of 2.5 mL and a calibrated polypropylene low-density polyethylene dropping pipette with a graduation interval of 0.5 mL. Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

Feb. 16, 2026

spc-doc_PLGB 50697-0001.pdf

Bulk SPC upload Feb2026