Zinole is indicated for the treatment of schizophrenia in adults and in adolescents aged 15
years and older.
Zinole 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).
Zinole is indicated for the treatment up to 12 weeks of moderate to severe manic episodes in
Bipolar I Disorder in adolescents aged 13 years and older (see section 5.1).

Posology
Adults
Schizophrenia: the recommended starting dose for Zinole is 10 or 15 mg/day with a
maintenance dose of 15 mg/day administered on a once-a-day schedule without regard to
meals. Zinole is effective in a dose range of 10 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 Zinole 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.
Special populations
Paediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose for Zinole 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). Zinole 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 Zinole 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
Zinole is for oral 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: 56-99 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: 78-88 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 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
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 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).
Lactose
Zinole tablets contain lactose. Patients with rare hereditary problems of galactose intolerance,
the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal
product.
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 co-administered.

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, 10-30 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.

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).

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 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, or urticaria)
Endocrine disorders Hyperprolactinaemia Diabetic hyperosmolar
coma Diabetic
ketoacidosis
Hyperglycaemia
Metabolism and nutrition
disorders
Diabetes mellitus Hyperglycaemia Hyponatremia Anorexia
Weight decreased
Weight gain
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 Akathisia
Extrapyramidal
disorder Tremor
Headache Sedation
Somnolence
Dizziness
Tardive dyskinesia
Dystonia
Neuroleptic Malignant
Syndrome (NMS)
Grand mal convulsion
Serotonin syndrome
Speech disorder
Eye disorders Vision blurred Diplopia
Cardiac disorders Tachycardia Sudden unexplained death
Torsades de pointes
QT prolongation
Ventricular arrhythmias
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
Increased Alanine
Aminotransferase (ALT)
Increased Aspartate
Aminotransferase (AST)
Increased Gamma
Glutamyl Transferase
(GGT)
Increased alkaline
phosphatase
Skin and subcutaneous
tissue disorders
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 and
administration site
conditions
Fatigue 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 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 (13-17 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,
< 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 (13-17 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- 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, < 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 (10-17 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:
To report any side effect(s):
− The National Pharmacovigilance and Drug Safety Centre (NPC)
Fax: +966-11-205-7662
Call NPC at +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.
Toll free phone: 8002490000
E-mail: npc.drug@sfda.gov.sa
Website: www.sfda.gov.sa/npc

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.

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 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 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
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, multi-national 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 stabilization phase prior to randomization,
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 stabilizer.
Stabilized patients were then randomised to continue the same mood stabilizer with
double-blind aripiprazole or placebo. Four mood stabilizer 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: Mean improvement from baseline YMRS score by psychiatric comorbidity
Psychiatric
comorbidities Week 4 Week 12
ADHD
Week 4 Week 12
Zinole 10 mg
(n = 48)
14.9 15.1
Zinole 10 mg
(n = 44)
15.2 15.6
Zinole 30 mg
(n = 51)
16.7 16.9
Zinole 30 mg
(n = 48)
15.9 16.7
Placebo
(n = 52)a
7.0 8.2
Placebo
(n = 47)b
6.3 7.0
No psychiatric
comorbidities Week 4 Week 12
No ADHD
Week 4 Week 12
Zinole 10 mg
(n = 27)
12.8 15.9 Zinole 10 mg
(n = 37)
12.7 15.7
Zinole 30 mg
(n = 25)
Zinole 30 mg
15.3 14.7 (n = 30) 14.6 13.4
Placebo
(n = 18)
9.4 9.7
Placebo
(n = 25)
9.9 10.0
a n = 51 at Week 4
b n = 46 at Week 4
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, placebo-controlled
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 - 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 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 - 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).

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.
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.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to
reproduction and development.
Toxicologically significant effects were observed only at doses or exposures that were
sufficiently in excess of the maximum human dose or exposure, indicating that these effects
were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical
toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104
weeks at 20 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.

Zinole 10 mg tablets
Lactose monohydrate
Maize starch pregelatinized
Povidone
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate
Red iron oxide

Not applicable.

Do not store above 30°C

Zinole 10 mg tablets: Aluminium /Aluminium foil blisters in cartons of 30 tablets.

No special requirements for disposal.