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ARIPIPRAZOLE 1 MG/ML ORAL SOLUTION

Active substance(s): ARIPIPRAZOLE

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SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
Aripiprazole 1 mg/ml oral solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 1 mg of aripiprazole.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Oral solution.
A clear, colourless liquid.

4.1

Therapeutic indications
Aripiprazole is indicated for the treatment of schizophrenia in adults and in
adolescents aged 15 years and older.
Aripiprazole 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).
Aripiprazole 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).

4.2

Posology and method of administration
Posology
Adults

Schizophrenia: the recommended starting dose for Aripiprazole is 10 or 15 mg/day
(i.e. 10 or 15 ml solution/day) with a maintenance dose of 15 mg/day administered on
a once-a-day schedule without regard to meals. Aripiprazole is effective in a dose
range of 10 to 30 mg/day (i.e. 10 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
Aripiprazole 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 (i.e. 30 ml solution/day).
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.
Aripiprazole oral solution may be used as an alternative to aripiprazole tablets for
patients who have difficulty swallowing aripiprazole tablets (see section 5.2).
Special population
Paediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose for
Aripiprazole is 10 mg/day administered on a once-a-day schedule without regard to
meals. Treatment should be initiated at 2 mg (using Aripiprazole 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). Aripiprazole is effective in a dose range of 10 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.
Aripiprazole 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 Aripiprazole is 10 mg/day administered on a once-a-day
schedule without regard to meals. Treatment should be initiated at 2 mg (using
Aripiprazole 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
undesirable effects 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, aripiprazole 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 aripiprazole 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 aripiprazole 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.
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 effectiveness of aripiprazole in the treatment of schizophrenia and 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 potent 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 potent 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
Aripiprazole oral solution is for oral use.
A 30 ml graduated measuring cup and a graduated 5 ml oral syringe are included in
the carton.

4.3

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

4.4

Special warnings and precautions for use
During antipsychotic treatment, improvement in the patient's clinical condition may
take several days to some weeks. Patients should be closely monitored throughout
this period.
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 therapy.
Results of an epidemiological study suggested that there was no increased risk of
suicidality with aripiprazole compared to other antipsychotics among adult patients
with schizophrenia or bipolar disorder. There are insufficient paediatric data to
evaluate this risk in younger patients (below 18 years of age), but there is evidence
that the risk of suicide persists beyond the first 4 weeks of treatment for atypical
antipsychotics, including aripiprazole.
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. As with other antipsychotics, 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 antipsychotic medicinal
products. 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 antipsychotic active
substances, including aripiprazole, must be discontinued.
Seizure
In clinical trials, uncommon cases of seizure were reported during treatment with
aripiprazole. Therefore, aripiprazole should be used with caution in patients who have
a history of seizure disorder or have conditions associated with seizures (see section
4.8).
Elderly patients with dementia-related psychosis
Increased mortality
In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56to
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 fixeddose 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 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
antipsychotic medicinal products, 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 antipsychotic medicinal products are not

available to allow direct comparisons. Patients treated with any antipsychotic
medicinal products, 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
As with other medicinal products, 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 comorbidities, use of antipsychotics known to cause weight gain, poorly managed lifestyle, and might lead to severe complications. Weight gain has been reported postmarketing 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 antipsychotic
medicinal product use, including aripiprazole. Aripiprazole and other antipsychotic
active substances should be used cautiously in patients at risk for aspiration
pneumonia.
Pathological gambling
Post-marketing reports of pathological gambling have been reported among patients
prescribed aripiprazole, regardless of whether these patients had a prior history of
gambling. Patients with a prior history of pathological gambling may be at increased
risk and should be monitored carefully (see section 4.8).
Patients with 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 coadministered.

4.5

Interaction with other medicinal products and other forms of interaction
Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to
enhance the effect of certain antihypertensive agents.
Given the primary CNS effects of aripiprazole, caution should be used when
aripiprazole is taken 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 potent 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 potent 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 potent 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 potent 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
potent CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the
potential risks to the patient. When concomitant administration of ketoconozole with
aripiprazole occurs, aripiprazole dose should be reduced to approximately one-half of
its prescribed dose. Other potent 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.
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 escitalopram) or CYP2D6 are
used concomitantly with aripiprazole, modest increases in aripiprazole concentrations
might be expected.
Carbamazepine and other CYP3A4 inducers
Following concomitant administration of carbamazepine, a potent inducer of
CYP3A4, 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. Other potent 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 potent CYP3A4 inducers, the
dosage of aripiprazole should be reduced to the recommended dose.
Valproate and lithium
When either valproate or lithium were administered concomitantly with aripiprazole,
there was no clinically significant change in aripiprazole 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 SSRI/SNRI, or
with medicinal products that are known to increase aripiprazole concentrations (see
section 4.8).
Potential for aripiprazole to affect other medicinal products
In clinical studies, 10 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 dehydroaripiprazole 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.

4.6

Pregnancy and lactation
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 should 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.
Breast-feeding
Aripiprazole is excreted in human milk. Patients should be advised not to breast-feed
if they are taking aripiprazole.

4.7

Effects on ability to drive and use machines
As with other antipsychotics, patients should be cautioned about operating hazardous
machines, including motor vehicles, until they are reasonably certain that aripiprazole
does not affect them adversely. Some paediatric patients with Bipolar I Disorder have
an increased incidence of somnolence and fatigue (see section 4.8).

4.8

Undesirable effects
Summary of the safety profile
The most commonly reported adverse reactions in placebo-controlled trials are
akathisia and nausea each occurring in more than 3 % of patients treated with oral
aripiprazole.
Tabulated list of adverse reactions
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

Leukopenia
Neutropenia
Thrombocytopenia
Allergic reaction (e.g.
anaphylactic
reaction, angioedema
including swollen
tongue, tongue oedema,
face oedema, pruritus or
urticaria)

Blood and lymphatic
system disorders
Immune system
disorders

Hyperprolactinaemia Diabetic hyperosmolar
coma
Diabetic ketoacidosis

Endocrine disorders

Metabolism and
nutrition disorders

Not known

Diabetes mellitus

Hyperglycaemia

Hyponatremia
Anorexia
Weight decreased
Weight gain

Common

Uncommon

Not known

Psychiatric
disorders

Insomnia
Anxiety
Restlessness

Depression,
Hypersexuality

Suicide attempt, suicidal
ideation and completed
suicide (see section 4.4)
Pathological gambling
Aggression
Agitation
Nervousness

Nervous system
disorders

Tardive dyskinesia
Akathisia
Dystonia
Extrapyramidal
disorder
Tremor
Headache
Sedation Somnolence
Dizziness

Eye disorders
Cardiac disorders

Vision blurred

Diplopia
Tachycardia

Vascular disorders

Orthostatic
hypotension

Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders

Hiccups

Constipation
Dyspepsia
Nausea
Salivary
hypersecretion
Vomiting

Neuroleptic Malignant
Syndrome (NMS)
Grand mal convulsion
Serotonin syndrome
Speech disorder

Sudden unexplained
death
Torsades de pointes
QT prolongation
Ventricular arrhythmias
Cardiac arrest
Bradycardia
Venous
thromboembolism
(including pulmonary
embolism and deep vein
thrombosis)
Aspiration pneumonia
Laryngospasm
Oropharyngeal spasm
Pancreatitis
Dysphagia
Diarrhoea
Abdominal discomfort
Stomach discomfort

Common

Uncommon

Hepatobiliary
disorders

Skin and
subcutaneous tissue
disorders

Not known
Hepatic failure
Hepatitis
Jaundice
Increased Alanine
Aminotransferase (ALT)
Increased Aspartate
Aminotransferase (AST)
Increased Gamma
Glutamyl Transferase
(GGT)
Increased alkaline
phosphatase
Rash
Photosensitivity reaction
Alopecia
Hyperhidrosis

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 Fatigue
and administration
site conditions

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

Investigations

Blood glucose increased
Glycosylated
haemoglobin increased
Blood glucose
fluctuation
Increased creatine
phosphokinase

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 longterm 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazoletreated 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 undesirable effects 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 to < 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 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 (13-17 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 undesirable effects 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 to < 1/10) abdominal pain upper, heart rate
increased, weight increased, increased appetite, muscle twitching, and dyskinesia.
The following undesirable effects 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9

Overdose
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.

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: 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 5HT1a receptors and antagonism of serotonin 5HT2a 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 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4,
serotonin 5HT2c and 5HT7, 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 to 30 mg administered once a day to healthy
subjects for 2 weeks produced a dose-dependent reduction in the binding of 11Craclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron
emission tomography.
Clinical efficacy and safety
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-Asberg Depression
Rating Scale 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: In clinical trials aripiprazole has not been shown to induce clinically
relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multinational study of schizophrenia which included 314 adult patients and where the
primary end-point was weight gain, significantly less patients had at least 7 % weight
gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5
kg) on aripiprazole (n = 18, or 13 % of evaluable patients), compared to olanzapine (n
= 45, or 33 % of evaluable patients).
Lipid parameters: In a pooled analysis on lipid parameters from placebo controlled
clinical trials in adults, aripiprazole has not been shown to induce clinically relevant
alterations in levels of total cholesterol, triglycerides, HDL and LDL.
-Total cholesterol: incidence of changes in levels from normal (< 5.18 mmol/l) to
high (≥ 6.22 mmol/l) was 2.5 % for aripiprazole and 2.8 % for placebo and mean
change from baseline was -0.15 mmol/l (95 % CI: -0.182, -0.115) for aripiprazole and
-0.11 mmol/l (95 % CI: -0.148, -0.066) for placebo.
-Fasting triglycerides: incidence of changes in levels from normal (< 1.69 mmol/l) to
high (≥ 2.26 mmol/l) was 7.4 % for aripiprazole and 7.0 % for placebo and mean
change from baseline was 0.11 mmol/l (95 % CI: -0.182, -0.046) for aripiprazole and
-0.07 mmol/l (95 % CI: -0.148, 0.007) for placebo.
-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (< 1.04
mmol/l) was 11.4 % for aripiprazole and 12.5 % for placebo and mean change from
baseline was -0.03 mmol/l (95 % CI: -0.046, -0.017) for aripiprazole and -0.04
mmol/l (95 % CI: -0.056, -0.022) for placebo.
-Fasting LDL: incidence of changes in levels from normal (< 2.59 mmol/l) to high (≥
4.14 mmol/l) was 0.6 % for aripiprazole and 0.7 % for placebo and mean change from
baseline was -0.09 mmol/l (95 % CI: -0.139, -0.047) for aripiprazole and -0.06
mmol/l (95 % CI: -0.116, -0.012) for placebo.
Prolactin: Prolactin levels were evaluated in all trials of all doses of aripiprazole (n =
28,242). The incidence of hyperprolactinaemia or increased serum prolactin in
patients treated with aripiprazole (0.3 %) was similar to that of placebo (0.2 %). For
patients receiving aripiprazole, the median time to onset was 42 days and median
duration was 34 days.

The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated
with aripiprazole was 0.4 %, compared with 0.02 % for patients treated with placebo.
For patients receiving aripiprazole, the median time to onset was 30 days and median
duration was 194 days
Manic episodes in Bipolar I Disorder
In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving
patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole
demonstrated superior efficacy to placebo in reduction of manic symptoms over 3
weeks. These trials included patients with or without psychotic features and with or
without a rapid-cycling course.
In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients
with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to
demonstrate superior efficacy to placebo.
In two 12-week, placebo- and active-controlled monotherapy trials in patients with a
manic or mixed episode of Bipolar I Disorder, with or without psychotic features,
aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance
of effect comparable to lithium or haloperidol at week 12. Aripiprazole also
demonstrated a comparable proportion of patients in symptomatic remission from
mania as lithium or haloperidol at week 12.
In a 6-week, placebo-controlled trial involving patients with a manic or mixed
episode of Bipolar I Disorder, with or without psychotic features, who were partially
non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum
levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy
in reduction of manic symptoms than lithium or valproate monotherapy.
In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic
patients who achieved remission on aripiprazole during a stabilisation phase prior to
randomisation, aripiprazole demonstrated superiority over placebo in preventing
bipolar recurrence, primarily in preventing recurrence into mania but failed to
demonstrate superiority over placebo in preventing recurrence into depression.
In a 52-week, placebo-controlled trial, in patients with a current manic or mixed
episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and
MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to
lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated
superiority over placebo with a 46 % decreased risk (hazard ratio of 0.54) in
preventing bipolar recurrence and a 65 % decreased risk (hazard ratio of 0.35) in
preventing recurrence into mania over adjunctive placebo but failed to demonstrate
superiority over placebo in preventing recurrence into depression. Adjunctive
aripiprazole demonstrated superiority over placebo on the secondary outcome
measure, CGI-BP Severity of Illness score (mania).
In this trial, patients were assigned by investigators with either open-label lithium or
valproate monotherapy to determine partial non-response. Patients were stabilised for
at least 12 consecutive weeks with the combination of aripiprazole and the same
mood stabiliser.
Stabilised patients were then randomised to continue the same mood stabiliser with
double-blind aripiprazole or placebo. Four mood stabiliser subgroups were assessed

in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo +
lithium; placebo + valproate.
The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive
treatment arm were 16 % in aripiprazole + lithium and 18 % in aripiprazole +
valproate compared to 45 % in placebo + lithium and 19 % in placebo + valproate.
Paediatric population
Schizophrenia in adolescents
In a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients
(13-17 years), presenting with positive or negative symptoms, aripiprazole was
associated with statistically significantly greater improvements in psychotic
symptoms compared to placebo.
In a sub-analysis of the adolescent patients between the ages of 15 to 17 years,
representing 74 % of the total enrolled population, maintenance of effect was
observed over the 26-week open-label extension trial.
In a 60- to 89-week, randomised, double-blind, placebo-controlled trial in adolescent
subjects (n = 146; ages 13-17 years) with schizophrenia, there was a statistically
significant difference in the rate of relapse of psychotic symptoms between the
aripiprazole (19.39 %) and placebo (37.50 %) groups. The point estimate of the
hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full
population. In subgroup analyses the point estimate of the HR was 0.495 for subjects
13 to 14 years of age compared to 0.454 for subjects 15 to 17 years of age. However,
the estimation of the HR for the younger (13-14 years) group was not precise,
reflecting the smaller number of subjects in that group (aripiprazole, n = 29; placebo,
n = 12), and the confidence interval for this estimation (ranging from 0.151 to 1.628)
did not allow conclusions to be drawn on the presence of a treatment effect. In
contrast the 95 % confidence interval for the HR in the older subgroup (aripiprazole,
n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could be
concluded in the older patients.
Manic episodes in Bipolar I Disorder in children and adolescents
Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children
and adolescents (10-17 years), who met DSM-IV criteria for Bipolar I Disorder with
manic or mixed episodes with or without psychotic features and had a Y-MRS score
≥ 20 at baseline. Among the patients included in the primary efficacy analysis, 139
patients had a current co-morbid diagnosis of ADHD.
Aripiprazole was superior to placebo in change from baseline at week 4 and at week
12 on the Y-MRS total score. In a post-hoc analysis, the improvement over placebo
was more pronounced in the patients with associated co-morbidity of ADHD
compared to the group without ADHD, where there was no difference from placebo.
Recurrence prevention was not established.
Table 1:
comorbidity

Mean improvement from baseline YMRS score by psychiatric

Psychiatric
Week 4
comorbidities

Week 12

ADHD

Week 4

Week 12

Aripiprazole
10 mg
(n = 48)
Aripiprazole
30 mg
(n = 51)
Placebo
(n = 52)a

15.1

Aripiprazole
10 mg
(n = 44)

15.2

15.6

16.7

16.9

Aripiprazole
30 mg
(n = 48)

15.9

16.7

7.0

8.2

Placebo (n = 47)b

6.3

7.0

Week 12

No ADHD

Week 4

Week 12

15.9

Aripiprazole
10 mg
(n = 37)

12.7

15.7

15.3

14.7

Aripiprazole
30 mg
(n = 30)

14.6

13.4

9.4

9.7

Placebo (n = 25)

9.9

10.0

14.9

No
psychiatric
Week 4
comorbidities
Aripiprazole
10 mg
(n = 27)
Aripiprazole
30 mg
(n = 25)
Placebo
(n = 18)
a

12.8

n = 51 at Week 4
n = 46 at Week 4

b

The most common treatment-emergent adverse events among patients receiving 30
mg were extrapyramidal disorder (28.3 %), somnolence (27.3 %), headache (23.2 %),
and nausea (14.1 %). Mean weight gain in the 30 weeks treatment-interval was 2.9 kg
as compared to 0.98 kg in patients treated with placebo.
Irritability associated with autistic disorder in paediatric patients (see section 4.2)
Aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebocontrolled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15
mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2
mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly
increments to the target dose. Over 75 % of patients were less than 13 years of age.
Aripiprazole demonstrated statistically superior efficacy compared to placebo on the
Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of
this finding has not been established. The safety profile included weight gain and
changes in prolactin levels. The duration of the long-term safety study was limited to
52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females
(< 3 ng/ml) and males (< 2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7 %)
and 258/298 (86.6 %), respectively. In the placebo-controlled trials, the mean weight
gain was 0.4 kg for placebo and 1.6 kg for aripiprazole.
Aripiprazole was also studied in a placebo-controlled, long-term maintenance trial.
After a 13-26 week stabilisation on aripiprazole (2-15 mg/day) patients with a stable
response were either maintained on aripiprazole or substituted to placebo for further
16 weeks. Kaplan-Meier relapse rates at week 16 were 35 % for aripiprazole and 52
% for placebo; the hazard ratio for relapse within 16 weeks (aripiprazole/placebo)

was 0.57 (non-statistically significant difference). The mean weight gain over the
stabilisation phase (up to 26 weeks) on aripiprazole was 3.2 kg, and a further mean
increase of 2.2 kg for aripiprazole as compared to 0.6 kg for placebo was observed in
the second phase (16 weeks) of the trial. Extrapyramidal symptoms were mainly
reported during the stabilisation phase in 17 % of patients, with tremor accounting for
6.5 %.
Tics associated with Tourette’s disorder in paediatric patients (see section 4.2)
The efficacy of aripiprazole was studied in paediatric subjects with Tourette’s
disorder (aripiprazole: n = 99, placebo: n = 44) in a randomised, double-blind,
placebo controlled, 8 week study using a fixed dose weight-based treatment group
design over the dose range of 5 mg/day to 20 mg/day and a starting dose of 2 mg.
Patients were 7 to 17 years of age and presented an average score of 30 on Total Tic
Score on the Yale Global Tic Severity Scale (TTS-YGTSS) at baseline. Aripiprazole
showed an improvement on TTS-YGTSS change from baseline to Week 8 of 13.35,
for the low dose group (5 mg or 10 mg) and 16.94 for the high dose group (10 mg or
20 mg) as compared with an improvement of 7.09 to in the placebo group.
The efficacy of aripiprazole in paediatric subjects with Tourette’s syndrome
(aripiprazole: n = 32, placebo: n = 29) was also evaluated over a flexible dose range
of 2 mg/day to 20 mg/day and a starting dose of 2 mg, in a 10 week, randomised,
double blind, placebo-controlled study conducted in South Korea. Patients were 6 to
18 years and presented an average score of 29 on TTS-YGTSS at baseline.
Aripiprazole group showed an improvement of 14.97 on TTS-YGTSS change from
baseline to Week 10 as compared with an improvement of 9.62 in the placebo group.
In both of these short term trials, the clinical relevance of the efficacy findings has not
been established, considering the magnitude of treatment effect compared to the large
placebo effect and the unclear effects regarding psycho-social functioning. No long
term data are available with regard to the efficacy and the safety of aripiprazole in
this fluctuating disorder.
The European Medicines Agency has deferred the obligation to submit the results of
studies with aripiprazole in one or more subsets of the paediatric population in the
treatment of schizophrenia and in the treatment of bipolar affective disorder (see
section 4.2 for information on paediatric use).

5.2

Pharmacokinetic properties
Absorption
Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5
hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The
absolute oral bioavailability of the tablet formulation is 87 %. There is no effect of a
high fat meal on the pharmacokinetics of aripiprazole.
Distribution
Aripiprazole is widely distributed throughout the body with an apparent volume of
distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic
concentrations, aripiprazole and dehydro-aripiprazole are greater than 99 % bound to
serum proteins, binding primarily to albumin.
Biotransformation

Aripiprazole is extensively metabolised by the liver primarily by three
biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation.
Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for
dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed
by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic
circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents
about 40 % of aripiprazole AUC in plasma.
Elimination
The mean elimination half-lives for aripiprazole are approximately 75 hours in
extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers
of CYP2D6.
The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic.
Following a single oral dose of [14C]-labelled aripiprazole, approximately 27 % of the
administered radioactivity was recovered in the urine and approximately 60 % in the
faeces. Less than 1 % of unchanged aripiprazole was excreted in the urine and
approximately 18 % was recovered unchanged in the faeces.
Oral Solution
Aripiprazole is well absorbed when administered orally as the solution. At equivalent
doses, the peak plasma concentrations of aripiprazole (Cmax) from the solution were
somewhat higher but the systemic exposure (AUC) was equivalent to tablets. In a
relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole
as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to
the tablet ratio of geometric mean Cmax values was 122 % (n = 30). The single dose
pharmacokinetics of aripiprazole was linear and dose-proportional.
Pharmacokinetics in special patient groups
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.
Elderly
There are no differences in the pharmacokinetics of aripiprazole between healthy
elderly and younger adult subjects, nor is there any detectable effect of age in a
population pharmacokinetic analysis in schizophrenic patients.
Gender
There are no differences in the pharmacokinetics of aripiprazole between healthy
male and female subjects nor is there any detectable effect of gender in a population
pharmacokinetic analysis in schizophrenic patients.
Smoking
Population pharmacokinetic evaluation has revealed no evidence of clinically
significant effects from smoking on the pharmacokinetics of aripiprazole.
Race
Population pharmacokinetic evaluation showed no evidence of race-related
differences on the pharmacokinetics of aripiprazole.
Renal impairment

The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were
found to be similar in patients with severe renal disease compared to young healthy
subjects.
Hepatic impairment
A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh
Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the
pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included
only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions
on their metabolic capacity.

5.3

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

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Disodium edetate
Erythritol (E 968)
Hypromellose
Macrogol 4000
Phosphoric acid, concentrated (for pH adjustment)
Propylene glycol (E 1520)
Sodium benzoate (E 211)
Sucralose (E 955)
Water, purified
Grape flavour

6.2

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

6.3

Shelf life
2 years
After first opening: Use within 6 months

6.4

Special precautions for storage
Do not refrigerate or freeze.
Store in the original package in order to protect from light.

6.5

Nature and contents of container
Amber glass bottle with a PE/PP child-resistant screw cap closure containing 150 ml
of oral solution, placed in an outer cardboard carton. The cardboard carton also

contains a 5 ml graduated oral PP syringe (graduated at every 0.5 ml) and HDPE
plunger, and a PP 30 ml graduated measuring cup (graduated at every 5 ml).
Amber PET bottle with a PE/PP child-resistant screw cap closure containing 150 ml
of oral solution, placed in an outer cardboard carton. The cardboard carton also
contains a 5 ml graduated oral PP syringe (graduated at every 0.5 ml) and HDPE
plunger, and a PP 30 ml graduated measuring cup (graduated at every 5 ml).

6.6

Special precautions for disposal
No special requirements.

7

MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close,
Potters Bar,
Hertfordshire, EN6 1TL
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 04569/1667

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/07/2016

10

DATE OF REVISION OF THE TEXT
26/10/2017

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