aripiprazole: prescribing information – dosing, contraindications, interactions, side effects

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).

ABILIFY solution for injection is indicated for the rapid control of agitation and disturbed behaviours in adult patients with schizophrenia or with manic episodes in Bipolar I Disorder, when oral therapy is not appropriate.

Treatment with ABILIFY solution for injection should be discontinued as soon as clinically appropriate and the use of oral aripiprazole should be initiated.

Posology

Adults

Schizophrenia: the recommended starting dose for ABILIFY is 10 mg/day or 15 mg/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. 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 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 population

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 interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

ABILIFY is for oral use.

Orodispersible tablets or oral solution may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see section 5.2).

Posology

Adults

Schizophrenia: the recommended starting dose for ABILIFY is 10 mg/day or 15 mg/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. 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 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 interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

ABILIFY is for oral use.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

Orodispersible tablets or oral solution may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see section 5.2).

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 interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

ABILIFY is for oral use.

Orodispersible tablets or oral solution may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see section 5.2).

Posology

The recommended initial dose for ABILIFY solution for injection is 9.75 mg (1.3 mL), administered as a single intramuscular injection. The effective dose range of ABILIFY solution for injection is 5.25 mg to 15 mg as a single injection. A lower dose of 5.25 mg (0.7 mL) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5).

A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.

The maximum daily dose of aripiprazole is 30 mg (including all formulations of ABILIFY).

If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.

Special populations

Paediatric population
The safety and efficacy of ABILIFY solution for injection in children and adolescents aged 0 to 17 years have not been established. No data are available.

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 interactions
When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).
When concomitant administration of strong CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

ABILIFY solution for injection is for intramuscular use.

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

ABILIFY solution for injection should not be administered intravenously or subcutaneously.

It is ready to use and intended for short-term use only (see section 5.1).

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

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)

Common
Uncommon
Not known
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)
Gambling disorder
Impulse-control disorder
Binge eating
Compulsive shopping
Poriomania
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)

Common
Uncommon
Not known
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 system and breast disorders

Priapism
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.

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

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)
Gambling disorder
Impulse-control disorder
Binge eating
Compulsive shopping
Poriomania
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

Common
Uncommon
Not known

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 system and breast disorders

Priapism
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.

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

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)
Gambling disorder
Impulse-control disorder

Common
Uncommon
Not known

Binge eating
Compulsive shopping
Poriomania
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)

Common
Uncommon
Not known

Reproductive system and breast disorders

Priapism
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.

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

Summary of the safety profile

The most commonly reported adverse reactions in placebo-controlled trials were nausea, dizziness and somnolence each occurring in more than 3 % of patients treated with aripiprazole solution for injection.

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)
Gambling disorder
Impulse-control disorder
Binge eating
Compulsive shopping
Poriomania
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

Common
Uncommon
Not known

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
Mouth dry
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 system and breast disorders

Priapism
General disorders and administration site conditions
Fatigue

Temperature regulation disorder
(e.g. hypothermia, pyrexia)
Chest pain
Peripheral oedema
Investigations

Diastolic blood pressure increased
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

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.

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

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 (see section 4.8).

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.

Gambling disorder 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 medicinal product 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).

Lactose

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

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).

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 (see section 4.8).

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.

Gambling disorder 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 medicinal product 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).

Aspartame

ABILIFY orodispersible tablets contain aspartame. Aspartame is a source of phenylalanine. It may be harmful for people with phenylketonuria (PKU), a rare genetic disorder in which phenylalanine builds up because the body cannot remove it properly.

Lactose

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

Sodium

ABILIFY orodispersible tablets contain sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, 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).

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 (see section 4.8).

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.

Gambling disorder 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 medicinal product 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).

The efficacy of ABILIFY solution for injection in patients with agitation and disturbed behaviours has not been established related to conditions other than schizophrenia and manic episodes in Bipolar I Disorder.

Simultaneous administration of injectable antipsychotics and parenteral benzodiazepine may be associated with excessive sedation and cardiorespiratory depression. If parenteral benzodiazepine therapy is deemed necessary in addition to aripiprazole solution for injection, patients should be monitored for excessive sedation and for orthostatic hypotension (see section 4.5).

Patients receiving ABILIFY solution for injection should be observed for orthostatic hypotension.
Blood pressure, pulse, respiratory rate and level of consciousness should be monitored regularly.

The safety and efficacy of ABILIFY solution for injection has not been evaluated in patients with

alcohol or medicinal product intoxication (either with prescribed or illicit medicinal products).

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 (see section 4.8).

QT prolongation

In clinical trials of treatment with oral 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 (see section 4.8).

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 oral 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.

Gambling disorder 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 medicinal product 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).

Sodium

ABILIFY solution for injection 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 α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.

Given the primary central nervous system (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 interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as selective serotonin reuptake inhibitor/selective serotonin noradrenaline reuptake inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

No interaction studies have been performed with ABILIFY solution for injection. The information below is obtained from studies with oral aripiprazole.

Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.

Given the primary central nervous system (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 ABILIFY solution for injection

The administration of lorazepam solution for injection had no effect on the pharmacokinetics of ABILIFY solution for injection when administered concomitantly. However, in a single-dose, intramuscular study of aripiprazole (dose 15 mg) in healthy subjects, administered simultaneously with intramuscular lorazepam (dose 2 mg), the intensity of sedation was greater with the combination as compared to that observed with aripiprazole alone.

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 of oral aripiprazole 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 of oral aripiprazole 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

The administration of ABILIFY solution for injection had no effect on the pharmacokinetics of lorazepam solution for injection when administered concomitantly. However, in a single-dose, intramuscular study of aripiprazole (dose 15 mg) in healthy subjects, administered simultaneously with intramuscular lorazepam (dose 2 mg), the orthostatic hypotension observed was greater with the combination as compared to that observed with lorazepam alone.

In clinical studies, oral doses of 10 mg/day to 30 mg/day 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 interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there was no clinically important change in valproate, lithium or lamotrigine concentrations.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as selective serotonin reuptake inhibitor/selective serotonin noradrenaline reuptake inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

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).

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose 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 overdose 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 overdose

Management of overdose 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 overdose 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 overdose.

Haemodialysis

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

5.
PHARMACOLOGICAL PROPERTIES

No cases of overdose associated with adverse reactions were reported in clinical studies with ABILIFY solution for injection. Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel. Following any confirmed or suspected accidental overdose/inadvertent

intravenous administration, close observation of the patient is needed and if any potentially medically serious sign or symptom develops, monitoring, which should include continuous electrocardiographic monitoring, is required. The medical supervision and monitoring should continue until the patient recovers.

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose 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 overdose 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 overdose

Management of overdose 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 overdose 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 overdose.

Haemodialysis

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

5.
PHARMACOLOGICAL PROPERTIES

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. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Adults

Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adult patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantly higher for patients on aripiprazole (43 %) than for haloperidol (30 %). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Åsberg Depression Rating Scale (MADRS) showed a significant improvement over haloperidol.

In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34 % in aripiprazole group and 57 % in placebo.

Weight gain

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. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Agitation in schizophrenia and Bipolar I Disorder with ABILIFY solution for injection In two short-term (24-hour) placebo-controlled trials involving 554 schizophrenic adult patients presenting with agitation and disturbed behaviours, ABILIFYsolution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to haloperidol.

In one short-term (24-hour) placebo-controlled trial involving 291 patients with bipolar disorder presenting with agitation and disturbed behaviours, ABILIFY solution for injection was associated with statistically significant greater improvements in agitation/behavioural symptoms compared to placebo and was similar to the reference arm lorazepam. The observed mean improvement from baseline on the PANSS Excitement Component score at the primary 2-hour endpoint was 5.8 for placebo, 9.6 for lorazepam, and 8.7 for ABILIFY solution for injection. In subpopulation analyses on patients with mixed episodes or on patients with severe agitation, a similar pattern of efficacy to the overall population was observed but statistical significance could not be established due to a reduced sample size.

Schizophrenia with oral aripiprazole
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adult patients, presenting with positive or negative symptoms, oral aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

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.

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.

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

Absorption

Aripiprazole administered intramuscularly as a single-dose to healthy subjects is well absorbed and has an absolute bioavailability of 100 %. The aripiprazole AUC in the first 2 hours after an intramuscular injection was 90 % greater than the AUC after the same dose as a tablet; systemic exposure was generally similar between the 2 formulations. In 2 studies in healthy subjects the median times to the peak plasma concentrations were 1 and 3 hours after dosing.

Distribution

Based on results from trials with oral administration of aripiprazole, 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.

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with aripiprazole.

Posology

For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena.

Titration of the dose for Abilify Maintena is not required.

The starting dose can be administered by following one of two regimens:

• One injection start: On the day of initiation, one injection of Abilify Maintena 400 mg should be administered and treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days should be continued to maintain therapeutic aripiprazole concentrations during initiation of therapy.
• Two injection start: On the day of initiation, two separate injections of Abilify Maintena 400 mg should be administered at two different injection sites (see method of administration), along with one 20 mg dose of oral aripiprazole.

After the injection start, the recommended maintenance dose of Abilify Maintena is 400 mg. Abilify Maintena 400 mg should be administered once monthly as a single injection (no sooner than 26 days after the previous injection). If there are adverse reactions with the 400 mg dose, reduction of the dose to 300 mg once monthly should be considered.

Missed doses

Missed doses
Timing of missed dose
Action
If 2nd or 3rd dose is missed and time since last injection is:

> 4 weeks and < 5 weeks
The injection should be administered as soon as possible and then the monthly injection schedule should be resumed.
> 5 weeks
Concomitant oral aripiprazole should be restarted for
14 days with next administered injection or two separate injections given at one time, along with a single dose of 20 mg oral aripiprazole. Monthly injection schedule should then resume.
If 4th or subsequent doses are missed
(i.e., after attainment of steady state) and time since last injection is:

> 4 weeks and < 6 weeks
The injection should be administered as soon as possible and then the monthly injection schedule should be resumed.
> 6 weeks
Concomitant oral aripiprazole should be restarted for
14 days with next administered injection or two separate injections given at one time, along with a single dose of 20 mg oral aripiprazole. Monthly injection schedule should then resume.

Special populations

Elderly
The safety and efficacy of Abilify Maintena 400 mg/300 mg in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4).

Renal impairment
No dose adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild or 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. Oral formulation should be preferred (see section 5.2).

Known CYP2D6 poor metabolisers
In patients who are known to be CYP2D6 poor metabolisers:

• One injection start: The starting dose should be Abilify Maintena 300 mg and treatment should be continued with the prescribed dose of oral aripiprazole per day for 14 consecutive days. The maintenance dose should be Abilify Maintena 300 mg once monthly.
• Two injection start: The starting dose should be 2 separate injections of Abilify Maintena 300 mg (see method of administration) along with one single dose of the previous prescribed dose of oral aripiprazole. The maintenance dose should be Abilify Maintena 300 mg once monthly.

In patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP3A4 inhibitor:

• One injection start: The starting dose should be reduced to 200 mg (see section 4.5) and treatment should be continued with the prescribed dose of oral aripiprazole per day for 14 consecutive days.
• Two injection start is not to be used in patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP3A4 inhibitor.

After the injection start, see table below for the recommended maintenance dose of Abilify Maintena.
Abilify Maintena 400 mg and 300 mg should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).

Maintenance dose adjustments due to interactions with CYP2D6 and/or CYP3A4 inhibitors and/or CYP3A4 inducers Maintenance dose adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dose may need to be increased to the previous dose (see section 4.5). In case of adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Abilify Maintena 400 mg or 300 mg should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Maintenance dose adjustments of Abilify Maintena in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

Adjusted monthly dose
Patients taking Abilify Maintena 400 mg
Strong CYP2D6 or strong CYP3A4 inhibitors
300 mg
Strong CYP2D6 and strong CYP3A4 inhibitors
200 mg*
CYP3A4 inducers
Avoid use
Patients taking Abilify Maintena 300 mg
Strong CYP2D6 or strong CYP3A4 inhibitors
200 mg*
Strong CYP2D6 and strong CYP3A4 inhibitors
160 mg*
CYP3A4 inducers
Avoid use
* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Abilify Maintena powder and solvent for prolonged-release suspension for injection.

Paediatric population
The safety and efficacy of Abilify Maintena 400 mg/300 mg in children and adolescents aged 0 to 17 years have not been established. No data are available.

Method of administration

Abilify Maintena 400 mg and 300 mg is only intended for intramuscular use and must not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional.

The suspension must be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.

If initiating with the two injection start, inject into two different sites in two different muscles. DO NOT inject both injections concomitantly into the same deltoid or gluteal muscle. For known CYP2D6 poor metabolisers administer in either two separate deltoid muscles or one deltoid and one gluteal muscle. DO NOT inject into two gluteal muscles.

Full instructions for use and handling of Abilify Maintena 400 mg and 300 mg are provided in the package leaflet (information intended for healthcare professionals).

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Posology

For patients who have never taken aripiprazole, tolerability with aripiprazole must be established prior to initiating treatment with Abilify Maintena.

Titration of the dose for Abilify Maintena is not required.

Starting regimen

The recommended starting dosing regimen when transitioning from Abilify Maintena 400 mg once monthly is Abilify Maintena 960 mg no sooner than 26 days after previous injection of Abilify Maintena 400 mg. Abilify Maintena 960 mg should then be dosed once every 2 months (every 56 days).

Initiation may also be started by following one of two additional regimens:
- One injection start: On the day of initiation following oral therapy, one injection of Abilify Maintena 960 mg should be administered and treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days should be continued to maintain therapeutic aripiprazole concentrations during initiation of therapy.
- Two injection start: On the day of initiation following oral therapy, one injection of Abilify Maintena 960 mg and one injection of Abilify Maintena 400 mg should be administered at two

different injection sites (see method of administration), along with one 20 mg dose of oral aripiprazole.

Dosing interval and dosing adjustments

After the injection start, the recommended maintenance dose is one injection of Abilify Maintena 960 mg every second month. Inject Abilify Maintena 960 mg once every two months as a single injection 56 days after the previous injection. Patients may be given the injection up to 2 weeks before or 2 weeks after the scheduled 2-month dose.

If there are adverse reactions with the Abilify Maintena 960 mg dose, reduction to Abilify Maintena 720 mg once every two months should be considered.

Missed doses

If more than 8 weeks and less than 14 weeks have elapsed since the last injection, the next dose of Abilify Maintena 960 mg/720 mg should be administered as soon as possible. The once every two months schedule should then be resumed. If more than 14 weeks have elapsed since the last injection, the next dose of Abilify Maintena 960 mg/720 mg should be administered with concomitant oral aripiprazole for 14 days or with 2 separate injections (one each of Abilify Maintena 960 mg and Abilify Maintena 400 mg or one each Abilify Maintena 720 mg and Abilify Maintena 300 mg) administered together with one 20 mg oral aripiprazole dose. The once every two months schedule should then be resumed.

Special populations

Elderly
The safety and efficacy of Abilify Maintena 960 mg/720 mg in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4). No recommendations on dosing can be made.

Renal impairment
No dose adjustment is required for patients with renal impairment (see section 5.2).

Hepatic impairment
No dose adjustment is required for patients with mild or 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. Oral formulation should be preferred (see section 5.2).

Known CYP2D6 poor metabolisers
In patients who are known to be CYP2D6 poor metabolisers:
- Patients transitioning from Abilify Maintena 300 mg once monthly: The starting dose should be one injection of Abilify Maintena 720 mg g, no sooner than 26 days after previous injection of Abilify Maintena 300 mg.
- One injection start (following transition from oral therapy): The starting dose should be one injection of Abilify Maintena 720 mg and treatment should be continued with the prescribed dose of oral aripiprazole per day for 14 consecutive days.
- Two injection start (following transition from oral therapy): The starting dose should be 2 separate injections; one Abilify Maintena 720 mg and one Abilify Maintena 300 mg injection, together with a single dose of 20 mg oral aripiprazole (see method of administration).

Thereafter, a maintenance dose of Abilify Maintena 720 mg should be administered once every two months as a single injection.

Maintenance dose adjustments due to interactions with CYP2D6 and/or CYP3A4 inhibitors and/or CYP3A4 inducers Maintenance dose adjustments should be made in patients taking concomitant strong CYP3A4 inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6 inhibitor is withdrawn, the dose may need to be increased to the previous dose (see section 4.5). In case of adverse reactions despite dose adjustments of Abilify Maintena 960 mg, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Abilify Maintena 960 mg/720 mg for more than 14 days should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Abilify Maintena 960 mg/720 mg should not be used in patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP2D6 and/or CYP3A4 inhibitor.

Table 1:
Maintenance dose adjustments of Abilify Maintena in patients who are taking

concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4

inducers for more than 14 days

Adjusted 2-monthly dose
Patients taking Abilify Maintena 960 mg*
Strong CYP2D6 or strong CYP3A4 inhibitors
720 mg
Strong CYP2D6 and strong CYP3A4 inhibitors
Avoid use
CYP3A4 inducers
Avoid use
*Avoid use in patients who already take 720 mg, e.g. due to adverse rections to the higher dose.

Paediatric population
The safety and efficacy of Abilify Maintena 960 mg/720 mg in children and adolescents aged 0 to 17 years have not been established. No data are available.

Method of administration

Abilify Maintena 960 mg and 720 mg is only intended for gluteal intramuscular injection and must not be administered intravenously or subcutaneously. It must only be administered by a healthcare professional.

The suspension must be injected slowly as a single injection (doses must not be divided) into the gluteal muscle, alternating the injections between the right and left side. Care must be taken to avoid inadvertent injection into a blood vessel.

If initiating with any of the options that require two injections (one Abilify Maintena 960 mg or 720 mg and one Abilify Maintena 400 mg or 300 mg ), inject into two different sites. DO NOT inject both injections concomitantly into the same gluteal muscle.

Full instructions for use and handling of Abilify Maintena 960 mg/720 mg are provided in the package leaflet (information intended for healthcare professionals).

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

Summary of the safety profile

The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in two double-blind, long-term trials of Abilify Maintena 400 mg/300 mg were weight increased (9.0 %), akathisia (7.9 %), insomnia (5.8 %) and injection site pain (5.1 %).

Tabulated list of adverse reactions

The incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table is based on adverse reactions 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 ADRs listed under the frequency “not known” were reported during post-marketing use.

Common

Uncommon

Not known
Blood and lymphatic system disorders

Neutropenia
Anaemia
Thrombocytopenia
Neutrophil count decreased
White blood cell count decreased
Leukopenia
Immune system disorders

Hypersensitivity

Allergic reaction (e.g.
anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders

Blood prolactin decreased
Hyperprolactinaemia
Diabetic hyperosmolar coma
Diabetic ketoacidosis
Metabolism and nutrition disorders
Weight increased
Diabetes mellitus
Weight decreased

Hyperglycaemia
Hypercholesterolaemia
Hyperinsulinaemia
Hyperlipidaemia
Hypertriglyceridaemia
Appetite disorder
Anorexia
Hyponatraemia
Psychiatric disorders
Agitation
Anxiety
Restlessness
Insomnia
Suicidal ideation
Psychotic disorder
Hallucination
Delusion
Hypersexuality
Panic reaction
Depression
Affect lability
Apathy
Dysphoria
Sleep disorder
Bruxism
Libido decreased
Mood altered
Completed suicide
Suicide attempt
Gambling disorder
Impulse-control disorder
Binge eating
Compulsive shopping
Poriomania
Nervousness
Aggression

Nervous system disorders
Extrapyramidal disorder
Akathisia
Tremor
Dyskinesia
Sedation
Somnolence
Dizziness
Headache
Dystonia
Tardive dyskinesia
Parkinsonism
Movement disorder
Psychomotor hyperactivity
Restless legs syndrome
Cogwheel rigidity
Hypertonia
Bradykinesia
Drooling
Dysgeusia
Parosmia
Neuroleptic malignant syndrome
Generalized tonic-clonic seizure
Serotonin syndrome
Speech disorder

Eye disorders

Oculogyric crisis
Vision blurred
Eye pain
Diplopia
Photophobia

Common

Uncommon

Not known
Cardiac disorders

Ventricular extrasystoles
Bradycardia
Tachycardia
Electrocardiogram T wave amplitude decreased
Electrocardiogram abnormal
Electrocardiogram T wave inversion
Sudden unexplained death
Cardiac arrest
Torsades de pointes
Ventricular arrhythmia
QT prolongation

Vascular disorders

Hypertension
Orthostatic hypotension
Blood pressure increased

Syncope
Venous thromboembolism
(including pulmonary embolism and deep vein thrombosis)
Respiratory, thoracic and mediastinal disorders

Cough
Hiccups
Oropharyngeal spasm
Laryngospasm
Aspiration pneumonia
Gastrointestin al disorders
Dry mouth
Gastrooesophageal reflux disease
Dyspepsia
Vomiting
Diarrhoea
Nausea
Abdominal pain upper
Abdominal discomfort
Constipation
Frequent bowel movements
Salivary hypersecretion
Pancreatitis
Dysphagia
Hepatobiliary disorders

Liver function test abnormal Hepatic enzyme increased
Alanine aminotransferase increased
Gamma-glutamyl transferase increased
Blood bilirubin increased
Aspartate aminotransferase increased
Hepatic failure
Jaundice
Hepatitis
Alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Alopecia
Acne
Rosacea
Eczema
Skin induration
Rash
Photosensitivity reaction
Hyperhidrosis
Drug Reaction with
Eosinophilia and
Systemic Symptoms
(DRESS)

Common

Uncommon

Not known
Musculoskelet al and connective tissue disorders
Musculoskeletal stiffness
Muscle rigidity
Muscle spasms
Muscle twitching
Muscle tightness
Myalgia
Pain in extremity
Arthralgia
Back pain
Joint range of motion decreased
Nuchal rigidity
Trismus
Rhabdomyolysis
Renal and urinary disorders

Nephrolithiasis
Glycosuria
Urinary retention
Urinary incontinence
Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal (see section 4.6)
Reproductive system and breast disorders
Erectile dysfunction
Galactorrhoea
Gynaecomastia
Breast tenderness
Vulvovaginal dryness
Priapism
General disorders and administration site conditions

Injection site pain
Injection site induration
Fatigue
Pyrexia
Asthenia
Gait disturbance
Chest discomfort
Injection site reaction
Injection site erythema
Injection site swelling
Injection site discomfort
Injection site pruritus
Thirst
Sluggishness
Temperature regulation disorder (e.g.
hypothermia, pyrexia)
Chest pain
Peripheral oedema
Investigations

Blood creatine phosphokinase increased
Blood glucose increased
Blood glucose decreased
Glycosylated haemoglobin increased
Waist circumference increased
Blood cholesterol decreased
Blood triglycerides decreased
Blood glucose fluctuation

Description of selected adverse reactions

Injection site reactions
During the double-blind, controlled phases of the two long-term trials, injection site reactions were observed; those seen were generally mild to moderate in severity, and resolved over time. Injection site pain (incidence 5.1 %), had a median onset on day 2 after the injection and a median duration of 4 days.

In an open-label study comparing bioavailability of Abilify Maintena 400 mg/300 mg administered in the deltoid or gluteal muscle, injection site related reactions were slightly more frequent in the deltoid

muscle. The majority were mild and improved on subsequent injections. When compared to studies where Abilify Maintena 400 mg/300 mg was injected in the gluteal muscle, repeated occurrence of injection site pain was more frequent in the deltoid muscle.

Neutropenia
Neutropenia has been reported in the clinical program with Abilify Maintena 400 mg/300 mg and typically started around day 16 after first injection, and lasted a median of 18 days.

Extrapyramidal Symptoms (EPS)
In trials in stable patients with schizophrenia, Abilify Maintena 400 mg/300 mg was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was the most frequently observed symptom (8.2 %) and typically started around day 10 after first injection, and lasted a median of 56 days. Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia.
Parkinsonism events followed in frequency of 6.9 % for Abilify Maintena 400 mg/300 mg, 4.15 % for oral aripiprazole 10 mg to 30 mg tablets and 3.0 % for placebo, respectively.

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.

Weight
During the double-blind, active-controlled phase of the 38-week long-term trial (see section 5.1), the incidence of weight gain of  7 % from baseline to last visit was 9.5 % for Abilify Maintena 400 mg/300 mg and 11.7 % for the oral aripiprazole tablets 10 mg to 30 mg. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena 400 mg/300 mg and 4.5 % for oral aripiprazole tablets 10 mg to 30 mg. During the double-blind, placebo-controlled phase of the 52-week long-term trial (see section 5.1), the incidence of weight gain of  7 % from baseline to last visit was 6.4 % for Abilify Maintena 400 mg/300 mg and 5.2 % for placebo. The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena 400 mg/300 mg and 6.7 % for placebo. During double-blind treatment, mean change in body weight from baseline to last visit was −0.2 kg for Abilify Maintena 400 mg/300 mg and −0.4 kg for placebo (p = 0.812).

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).

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

Summary of the safety profile

The safety profile of Abilify Maintena 960 mg and Abilify Maintena 720 mg for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena 400 mg and Abilify Maintena 300 mg. In general, the observed adverse drug reactions (ADRs) in Abilify Maintena 960 mg/720 mg clinical trials were similar to the ADRs observed in the Abilify Maintena 400 mg/300 mg clinical trials.

The most frequently observed ADRs reported in ≥ 5 % of patients in two double-blind, long-term trial of Abilify Maintena 400 mg/300 mg were weight increased (9.0%), akathisia (7.9%) and insomnia (5.8%). In the Abilify Maintena 960 mg/720 mg clinical trials, weight increased (22.7%), injection site pain (18.2%) akathisia (9.8 %), anxiety (8.3 %), headache (7.6 %), insomnia (7.6 %), and constipation (6.1 %) were the most frequently observed ADRs.

Tabulated list of adverse reactions

The incidences of the ADRs associated with Abilify Maintena 400 mg/300 mg and 960 mg/720 mg are tabulated below. The table is based on adverse reactions 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 ADRs listed under the frequency “not known” were reported during post-marketing use.

System organ class

Common
Uncommon
Not known
Blood and lymphatic system disorders

Neutropenia
Anaemia
Thrombocytopenia
Neutrophil count decreased
White blood cell count decreased
Leukopenia
Immune system disorders

Hypersensitivity
Allergic reaction (e.g.
anaphylactic reaction, angioedema including swollen tongue, tongue oedema, face oedema, pruritus, or urticaria) Endocrine disorders

Blood prolactin decreased
Hyperprolactinaemia
Diabetic hyperosmolar coma
Diabetic ketoacidosis

System organ class

Common
Uncommon
Not known
Metabolism and nutrition disorders
Weight increaseda
Diabetes mellitus
Weight decreased
Hyperglycaemia
Hypercholesterolaemia
Hyperinsulinaemia
Hyperlipidaemia
Hypertriglyceridaemia
Appetite disorder
Anorexia
Decreased appetiteb
Hyponatraemia
Psychiatric disorders
Agitation
Anxiety
Restlessness
Insomnia
Suicidal ideation
Psychotic disorder
Hallucination
Delusion
Hypersexuality
Panic reaction
Depression
Affect lability
Apathy
Dysphoria
Sleep disorder
Bruxism
Libido decreased
Mood altered
Completed suicide
Suicide attempt
Gambling disorder
Impulse-control disorder
Binge eating
Compulsive shopping
Poriomania
Nervousness
Aggression

Nervous system disorders
Extrapyramidal disorder
Akathisia
Tremor
Dyskinesia
Sedation
Somnolence
Dizziness
Headache
Dystonia
Tardive dyskinesia
Parkinsonism
Movement disorder
Psychomotor hyperactivity
Restless legs syndrome
Cogwheel rigidity
Hypertonia
Bradykinesia
Drooling
Dysgeusia
Parosmia
Neuroleptic malignant syndrome
Generalised tonic- clonic seizure
Serotonin syndrome
Speech disorder

Eye disorders

Oculogyric crisis
Vision blurred
Eye pain
Diplopia
Photophobia

Cardiac disorders

Ventricular extrasystoles
Bradycardia
Tachycardia
Electrocardiogram T wave amplitude decreased
Electrocardiogram abnormal
Electrocardiogram T wave inversion
Sudden death
Cardiac arrest
Torsades de pointes
Ventricular arrhythmia
QT prolonged
Vascular disorders

Hypertension
Orthostatic hypotension
Blood pressure increased
Syncope
Venous embolism
(including pulmonary embolism and deep vein thrombosis)

System organ class

Common
Uncommon
Not known
Respiratory, thoracic and mediastinal disorders

Cough
Hiccups
Oropharyngeal spasm
Laryngospasm
Aspiration pneumonia
Gastrointestinal disorders
Dry mouth
Gastrooesophageal reflux disease
Dyspepsia
Vomiting
Diarrhoea
Nausea
Abdominal pain upper
Abdominal discomfort
Constipation
Frequent bowel movements
Salivary hypersecretion
Pancreatitis
Dysphagia
Hepatobiliary disorders

Liver function test abnormal
Hepatic enzyme increased
Alanine aminotransferase increased
Gamma- glutamyltransferase increased
Blood bilirubin increased
Aspartate aminotransferase increased
Hepatic failure
Jaundice
Hepatitis
Alkaline phosphatase increased
Skin and subcutaneous tissue disorders

Alopecia
Acne
Rosacea
Eczema
Skin induration
Rash
Photosensitivity reaction
Hyperhidrosis
Drug reaction with eosinophilia and systemic symptoms
(DRESS)
Musculoskeletal and connective tissue disorders
Musculoskeletal stiffness
Muscle rigidity
Muscle spasms
Muscle twitching
Muscle tightness
Myalgia
Pain in extremity
Arthralgia
Back pain
Joint range of motion decreased
Nuchal rigidity
Trismus
Rhabdomyolysis
Renal and urinary disorders

Nephrolithiasis
Glycosuria
Urinary retention
Urinary incontinence

a: Reported as very common in Abilify Maintena 960 mg/720 mg clinical trials.
b: Reported only in Abilify Maintena 960 mg/720 mg clinical trial program

Description of selected adverse reactions

Injection site reactions
The percentage of patients in an open-label study reporting any injection site-related adverse reaction (all reported as injection site pain) was 18.2 % for patients treated with Abilify Maintena 960 mg and 9.0 % for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of the reported injection site pain occurred with the first injection of Abilify Maintena 960 mg patients (21 of 24 patients) or Abilify Maintena 400 mg (7 of 12 patients), resolved within 5 days, and were reported with decreasing frequency and severity upon subsequent injections. The overall mean site visual analog scale scores (0 = no pain to 100 = unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the Abilify Maintena 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group.

Neutropenia
Neutropenia has been reported in the clinical program with Abilify Maintena 400 mg/300 mg and typically started around day 16 after first injection, and lasted a median of 18 days.

Extrapyramidal Symptoms (EPS)
In trials in stable patients with schizophrenia, Abilify Maintena 400 mg/300 mg was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was System organ class

Common
Uncommon
Not known
Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal
Reproductive system and breast disorders
Erectile dysfunction
Galactorrhoea
Gynaecomastia
Breast tenderness
Vulvovaginal dryness
Priapism
General disorders and administration site conditions

Injection site paina
Injection site induration
Fatigue
Pyrexia
Asthenia
Gait disturbance
Chest discomfort
Injection site reaction
Injection site erythema
Injection site swelling
Injection site discomfort
Injection site pruritus
Thirst
Sluggishness
Temperature regulation disorder
(e.g. hypothermia, pyrexia)
Chest pain
Peripheral oedema
Investigations

Blood creatine phosphokinase increased

Blood glucose increased
Blood glucose decreased
Glycosylated haemoglobin increased
Waist circumference increased
Blood cholesterol decreased
Blood triglycerides decreased
Blood glucose fluctuation

the most frequently observed symptom (8.2 %) and typically started around Day 10 after first injection, and lasted a median of 56 days. Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia. Parkinsonism events followed in frequency of 6.9 % for Abilify Maintena 400 mg/300 mg, 4.2 % for oral aripiprazole 10 mg to 30 mg tablets and 3.0 % for placebo, respectively.

Data from an open-label study of patients treated with Abilify Maintena 960 mg, showed minimal change from baseline in EPS scores, as assessed by the Simpson-Angus Rating scale (SAS), the Abnormal Involuntary Movement Scale (AIMS) and the Barnes Akathisia Rating Scale (BARS). The incidence of reported EPS-related events for patients treated with Abilify Maintena 960 mg was 18.2 % compared to the incidence of patients treated with Abilify Maintena 400 mg, which was 13.4 %.

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.

Weight
During the double-blind, active-controlled phase of the 38-week long-term trial (see section 5.1), the incidence of weight gain of ≥ 7 % from baseline to last visit was 9.5 % for Abilify Maintena 400 mg/300 mg and 11.7 % for the oral aripiprazole tablets 10 mg to 30 mg. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena 400 mg/300 mg and 4.5 % for oral aripiprazole tablets 10 mg to 30 mg. During the double-blind, placebo-controlled phase of the 52-week long-term trial (see section 5.1), the incidence of weight gain of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena 400 mg/300 mg and 5.2 % for placebo. The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena 400 mg/300 mg and 6.7 % for placebo. During double-blind treatment, mean change in body weight from baseline to last visit was −0.2 kg for Abilify Maintena 400 mg/300 mg and −0.4 kg for placebo (p = 0.812).

In an open-label, multiple-dose, randomised study in adult patients with schizophrenia (and bipolar I disorder) in which two months presentation Abilify Maintena 960 mg was evaluated against monthly Abilify Maintena 400 mg, the overall incidence of weight gain ≥ 7 % from baseline was comparable between Abilify Maintena 960 mg (40.6 %) and Abilify Maintena 400 mg (42.9 %). The mean change in body weight from baseline to last visit was 3.6 kg for Abilify Maintena 960 mg and 3.0 kg for Abilify Maintena 400 mg.

Prolactin
In clinical trials for the approved indications and in post-marketing data both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Gambling disorder and other impulse control disorders
Gambling disorder, 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 national reporting system listed in Appendix V.

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.

Use in patients who are in an acutely agitated or severely psychotic state

Abilify Maintena 400 mg/300 mg should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, 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 (see section 4.8).

QT prolongation

In clinical trials of treatment with oral 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.

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 (see section 4.8).

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 of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56 to 99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. 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 with oral aripiprazole, 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 oral 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 aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. Patients treated with 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 patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral 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 (see section 4.8).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of aripiprazole.
Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Gambling disorder 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 medicinal product was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. A dose reduction or stopping of the medicinal product should be considered if a patient develops such urges (see section 4.8).

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).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

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.

Use in patients who are in an acutely agitated or severely psychotic state

Abilify Maintena should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, 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 (see section 4.8).

QT prolongation

In clinical trials of treatment with oral 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.

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 (see section 4.8).

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 of oral aripiprazole in elderly patients with psychosis associated with Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56 to 99 years), patients treated with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. 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 with oral aripiprazole, 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 oral 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 aripiprazole. No specific studies have been conducted with Abilify Maintena in patients with hyperglycaemia or diabetes mellitus. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. Patients treated with 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 patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed lifestyle and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral 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 (see section 4.8).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of aripiprazole.
Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Gambling disorder 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 medicinal product was discontinued. Impulse control disorders may

result in harm to the patient and others if not recognised. A dose reduction or stopping of the medicinal product should be considered if a patient develops such urges (see section 4.8).

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).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole.

Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.

Given the primary central nervous system (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

Quinidine and other strong CYP2D6 inhibitors
In a clinical trial of oral aripiprazole 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. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied (see section 4.2).

Ketoconazole and other strong CYP3A4 inhibitors
In a clinical trial of oral aripiprazole 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 metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. 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 dose of aripiprazole should be increased to the dose 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 oral 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 oral aripiprazole alone. Concomitant administration of Abilify Maintena 400 mg/300 mg 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. The concomitant use of CYP3A4 inducers with Abilify Maintena 400 mg/300 mg should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as Selective Serotonin Reuptake Inhibitors/Serotonin Noradrenaline Reuptake Inhibitors (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

No interaction studies have been performed with Abilify Maintena. The information below is obtained from studies with oral aripiprazole. The 2-month dosing interval and long half-life of aripiprazole after dosing with Abilify Maintena 960 mg or 720 mg should also be considered when assessing the drug- drug interaction potential.

Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive medicinal products.

Given the primary central nervous system (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

Quinidine and other strong CYP2D6 inhibitors
In a clinical trial of oral aripiprazole 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. Other strong inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reduction should, therefore, be applied (see section 4.2).

Ketoconazole and other strong CYP3A4 inhibitors
In a clinical trial of oral aripiprazole 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 metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. 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 dose of aripiprazole should be increased to the dose 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 oral 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 oral aripiprazole alone. Concomitant administration of Abilify Maintena 960 mg/720 mg 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. The concomitant use of CYP3A4 inducers with Abilify Maintena 960 mg/720 mg should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.

Serotonin syndrome
Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as Selective Serotonin Reuptake Inhibitor/Serotonin Noradrenaline Reuptake Inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

Women of childbearing potential

Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to remain for up to 34 weeks (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. Abilify Maintena should only be used in women planning to become pregnant if clearly necessary.

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..

Prescribers need to be aware of the long-acting properties of Abilify Maintena. Aripiprazole has been detected in plasma in adult patients up to 34 weeks after a single-dose administration of the prolonged- release suspension.

New-born 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, new-born infants should be monitored carefully (see section 4.8).

Maternal exposure to Abilify Maintena before and during pregnancy may lead to adverse reactions in the newborn child. Abilify Maintena should not be used during pregnancy unless clearly necessary.

Breast-feeding

Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if Abilify Maintena is administered to breast-feeding women. Since a single dose of Abilify Maintena is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fed infants may be at risk even from Abilify Maintena administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 34 weeks with Abilify Maintena should not breast feed.

Fertility

Aripiprazole did not impair fertility based on data from reproductive toxicity studies with aripiprazole.

Women of childbearing potential

Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to remain for up to 34 weeks (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. Abilify Maintena should only be used in women planning to become pregnant if clearly necessary.

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.

Prescribers need to be aware of the long-acting properties of Abilify Maintena. Aripiprazole has been detected in plasma in adult patients up to 34 weeks after a single-dose administration of the prolonged- release suspension.

New-born 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, new-born infants should be monitored carefully (see section 4.8).

Maternal exposure to Abilify Maintena before and during pregnancy may lead to adverse reactions in the newborn child. Abilify Maintena should not be used during pregnancy unless clearly necessary.

Breast-feeding

Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if Abilify Maintena is administered to breast-feeding women. Since a single dose of Abilify Maintena is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fed infants may be at risk even from Abilify Maintena administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 34 weeks with Abilify Maintena should not breast feed.

Fertility

Aripiprazole did not impair fertility based on data from reproductive toxicity studies with aripiprazole.

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).

No cases of overdose associated with adverse reactions were reported in clinical studies with aripiprazole. Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel. Following any confirmed or suspected accidental overdose/inadvertent intravenous administration, close observation of the patient is needed and if any potentially medically serious sign or symptom develops, monitoring, which should include continuous electrocardiographic monitoring, is required. The medical supervision and monitoring should continue until the patient recovers.

A simulation of dose dumping showed that the predicted median aripiprazole concentration reaches a peak of 4 500 ng/mL or approximately 9-times the upper therapeutic range. In case of dose dumping, aripiprazole concentrations are predicted to descend rapidly to the upper limit of the therapeutic window after approximately 3 days. By the 7th day, the median aripiprazole concentrations further decline to concentrations following an IM depot dose with no dose dumping. While overdose is less likely with parenteral than oral medicinal products, reference information for oral aripiprazole overdose is presented below.

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1 260 mg (41- times highest recommended daily aripiprazole dose) 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 overdose 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 overdose

Management of overdose 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 overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.

Haemodialysis

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

5.
PHARMACOLOGICAL PROPERTIES

No cases of overdose associated with adverse reactions were reported in clinical studies with aripiprazole. While experience with aripiprazole overdose is limited, among the few cases of overdose (accidental or intentional) reported in clinical trials and post marketing experience with oral aripiprazole, the highest estimated ingestion was a total of 1260 mg with no fatalities.

The potential for dose dumping has been evaluated by simulation of aripiprazole plasma concentrations after an Abilify Maintena 960 mg dose is entirely absorbed in the systemic circulation.
Based on the results of the simulation, if dose dumping would occur, aripiprazole concentrations may reach up to 13.5 times the concentrations that are achieved by a therapeutic dose of Abilify Maintena 960 mg without dose dumping. Furthermore, aripiprazole concentrations following dose dumping would decline within 5 days to concentrations normally observed following the administration of Abilify Maintena 960 mg.

Signs and symptoms

Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel.
Following any confirmed or suspected accidental overdose/inadvertent intravenous administration with aripiprazole, close observation of the patient is needed. The potentially medically significant signs and symptoms observed in overdose included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea.

Management of overdose

There is no specific antidote to aripiprazole. Management of overdose should concentrate on supportive care, including close medical supervision and monitoring. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures. Treatment should consist of general measures employed in the management of overdose with any medicinal product. Consider the possibility of multiple medicinal product overdose.
Consider the long-acting nature of the medicinal product and the long elimination half-life of aripiprazole when assessing treatment needs and recovery.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12

Mechanism of action

It has been proposed that aripiprazole’s efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and has 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 cholinergic muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole oral doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Maintenance treatment of schizophrenia in adults

Abilify Maintena 400 mg/300 mg
The efficacy of Abilify Maintena 400 mg/300 mg in the maintenance treatment of patients with schizophrenia was established in two randomised, double-blind, long-term trials.

The pivotal trial was a 38 week, randomised, double-blind, active-controlled trial designed to establish the efficacy, safety, and tolerability of this medicinal product administered as monthly injections compared to once daily oral aripiprazole tablets 10 mg to 30 mg as maintenance treatment in adult patients with schizophrenia. This trial consisted of a screening phase and 3 treatment phases:
Conversion phase, oral stabilisation phase, and double-blind, active-controlled phase.

Six-hundred and sixty two patients eligible for the 38-week double-blind, active-controlled phase were randomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) Abilify Maintena 400 mg/300 mg 2) the stabilisation dose of oral aripiprazole 10 mg to 30 mg, or 3) aripiprazole long-acting injectable 50 mg/25 mg. The aripiprazole long-acting injectable 50 mg/25 mg dose was included as a low dose aripiprazole to test assay sensitivity for the non-inferiority design.

The results of analysis of the primary efficacy endpoint, the estimated proportion of patients experiencing impending relapse by end of week 26 of the double-blind, active-controlled phase, showed that Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10 mg to 30 mg.
The estimated relapse rate by end of week 26 was 7.12 % for Abilify Maintena 400 mg/300 mg, and 7.76 % for oral aripiprazole tablets 10 mg to 30 mg, a difference of −0.64 %.

Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12

Mechanism of action

It has been proposed that aripiprazole’s efficacy in schizophrenia is mediated through a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and has 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 cholinergic muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole oral doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Clinical efficacy and safety

Maintenance treatment of schizophrenia in adults
The efficacy of Abilify Maintena 960 mg, administered once every two months, was established in part, on the basis of pharmacokinetic bridging through an open-label, multiple-dose, randomized, parallel-arm multi-centre study. The study demonstrated that Abilify Maintena 960 mg provides similar aripiprazole concentrations, and thus similar effectiveness, to Abilify Maintena 400 mg over the dosing interval (see section 5.2).

The similarity of aripiprazole plasma concentrations of Abilify Maintena 960 mg to Abilify Maintena 400 mg is presented in table 1.

Table 2:
Geometric mean ratio and confidence interval (CI) following the fourth administration of Abilify Maintena 960 mg or the seventh and eighth Abilify Maintena 400 mg in the open-label study

Parameter

Ratio
(Abilify Maintena 960 mg/Abilify Maintena 400 mg)
90 % CI

AUC0-56a
1.006c
0.851 - 1.190
C56/C28b
1.011d
0.893 - 1.145
Cmaxb
1.071c
0.903 - 1.270 a
AUC0-56 following the fourth administration of Abilify Maintena 960 mg or the sum of AUC0-28 following the seventh and eighth administration of Abilify Maintena 400 mg.
b
Aripiprazole plasma concentrations following the fourth administration of Abilify Maintena 960 mg (C56) or the eighth administration of Abilify Maintena 400 mg (C28).
c
Abilify Maintena 960 mg (n = 34), Abilify Maintena 400 mg (n = 32) d
Abilify Maintena 960 mg (n = 96), Abilify Maintena 400 mg (n = 82).

The effectiveness of Abilify Maintena 960 mg/720 mg in the treatment of schizophrenia is further supported by the established effectiveness of Abilify Maintena 400 mg/300 mg, as summarised below:

Efficacy of Abilify Maintena 400 mg/300 mg

Absorption

Aripiprazole absorption into the systemic circulation is slow and prolonged following Abilify Maintena 400 mg/300 mg administration due to low solubility of aripiprazole particles.The average absorption half-life of Abilify Maintena 400 mg/300 mg is 28 days. Absorption of aripiprazole from the IM depot formulation was complete relative to the IM standard (immediate-release) formulation.
The dose adjusted Cmax values for the depot formulation were approximately 5 % of Cmax from IM standard formulation.Following a single dose administration of Abilify Maintena 400 mg/300 mg in the deltoid and gluteal muscle, the extent of absorption (AUC) was similar for both injection sites, but the rate of absorption (Cmax) was higher following administration to the deltoid muscle. Following multiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to a maximum plasma concentration at a median tmax of 7 days for the gluteal muscle and 4 days for the deltoid muscle. Steady state concentrations for the typical subject were attained by the fourth dose for both sites of administration. Less than dose-proportional increases in aripiprazole and dehydro- aripiprazole concentrations and AUC parameters are observed after monthly Abilify Maintena injections of 300 mg to 400 mg.

Distribution

Based on results from trials with oral administration of aripiprazole, 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:

The pharmacokinetics of aripiprazole after administration of Abilify Maintena, presented below, are based on gluteal administration.

Abilify Maintena 960 mg/720 mg delivers aripiprazole over a 2-month period, compared to Abilify Maintena 400 mg/300 mg. Abilify Maintena doses of 960 mg and 720 mg, administered in the gluteal muscle, result in aripiprazole total exposure ranges that are encompassed within the exposure range corresponding to 300 mg and 400 mg doses of Abilify Maintena (dosed once a month), respectively.
Additionally, mean observed maximum plasma concentrations (Cmax) and plasma concentrations of aripiprazole at the end of the dosing interval were similar for Abilify Maintena 960 mg/720 mg as compared to corresponding doses of Abilify Maintena 400 mg/300 mg (see section 5.1).

The mean aripiprazole plasma concentration compared to the time profiles following the fourth administration of Abilify Maintena 960 mg (n = 102) or the seventh and eighth administration of Abilify Maintena 400 mg (n = 93) in the gluteal muscle of patients with schizophrenia (and bipolar I disorder) are shown in figure 2.

Figure 2:
Mean Aripiprazole plasma concentration vs. time profile following the fourth administration of Abilify Maintena 960 mg or the seventh and eighth administration of Abilify Maintena 400 mg

Absorption/Distribution

Aripiprazole absorption into the systemic circulation is slow and prolonged following gluteal injection due to low solubility of aripiprazole particles. The release profile of aripiprazole from Abilify Maintena 960 mg/720 mg results in sustained plasma concentrations over 2 months following gluteal injection(s). The release of the active substance after a single 780 mg dose of 2-monthly aripiprazole ready-to-use long-acting-injectable starts Day 1 and lasts for as long as 34 weeks.

Biotransformation

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: