ARIPIPRAZOL SANDOZ 15mg tablets medication leaflet

Aripiprazole Sandoz 5 mg tablets

Aripiprazole Sandoz 10 mg tablets

Aripiprazole Sandoz 15 mg tablets

Aripiprazole Sandoz 20 mg tablets

Aripiprazole Sandoz 30 mg tablets

Aripiprazole Sandoz 5 mg tablets

Each tablet contains 5 mg of aripiprazole.

Excipient with known effect67.47 mg lactose (as monohydrate) per tablet.

Aripiprazole Sandoz 10 mg tablets

Each tablet contains 10 mg of aripiprazole.

Excipient with known effect62.67 mg lactose (as monohydrate) per tablet.

Aripiprazole Sandoz 15 mg tablets

Each tablet contains 15 mg of aripiprazole.

Excipient with known effect92.86 mg lactose (as monohydrate) per tablet.

Aripiprazole Sandoz 20 mg tablets

Each tablet contains 20 mg of aripiprazole.

Excipient with known effect125.72 mg lactose (as monohydrate) per tablet.

Aripiprazole Sandoz 30 mg tablets

Each tablet contains 30 mg of aripiprazole.

Excipient with known effect186.68 mg lactose (as monohydrate) per tablet.

For the full list of excipients, see section 6.1.

Tablet

Aripiprazole Sandoz 5 mg tablets

Blue coloured, mottled, round shaped tablet, with an approximate diameter of 6.0 mm, debossed with “SZ”on one side and “444” on the other side.

Aripiprazole Sandoz 10 mg tablets

Pink coloured, mottled, round shaped tablet, with an approximate diameter of 6.0 mm, debossed with “SZ”on one side and “446” on the other side.

Aripiprazole Sandoz 15 mg tablets

Yellow coloured, mottled, round shaped tablet, with an approximate diameter of 7.0 mm, debossed with“SZ” on one side and “447” on the other side.

Aripiprazole Sandoz 20 mg tablets

White coloured, round shaped tablet, with an approximate diameter of 7.8 mm, debossed with “SZ” on oneside and “448” on the other side.

Aripiprazole Sandoz 30 mg tablets

Pink coloured, mottled, round shaped tablet, with an approximate diameter of 9.0 mm, debossed with “SZ”on one side and “449” on the other side.

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

Aripiprazole Sandoz 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 manicepisodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).

Aripiprazole Sandoz 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).

Schizophrenia: the recommended starting dose for Aripiprazole Sandoz is 10 or 15 mg/day with amaintenance dose of 15 mg/day administered on a once-a-day schedule without regard to meals.

Aripiprazole Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher thana daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higherdose. The maximum daily dose should not exceed 30 mg.

Manic episodes in Bipolar I Disorder: the recommended starting dose for Aripiprazole Sandoz is 15 mgadministered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (seesection 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed30 mg.

Recurrence prevention of manic episodes in Bipolar I Disorder: for preventing recurrence of manic episodesin patients who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy atthe same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis ofclinical status.

Schizophrenia in adolescents aged 15 years and older: the recommended dose for Aripiprazole Sandoz is10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days, titrated to 5 mg for 2additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increasesshould be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section5.1). Aripiprazole Sandoz is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higherthan a daily dose of 10 mg has not been demonstrated although individual patients may benefit from a higherdose.

Aripiprazole Sandoz is not recommended for use in patients with schizophrenia below 15 years of age due toinsufficient 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 Sandoz is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatmentshould be initiated at 2 mg (using an appropriate aripiprazole containing medicinal product) for 2 days,titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. The treatment durationshould be the minimum necessary for symptom control and must not exceed 12 weeks. Enhanced efficacy atdoses higher than a daily dose of 10 mg has not been demonstrated, and a daily dose of 30 mg is associatedwith a substantially higher incidence of significant adverse reactions including EPS related events,somnolence, fatigue and weight gain (see section 4.8). Doses higher than 10 mg/day should therefore only beused in exceptional cases and with close clinical monitoring (see sections 4.4, pct. 4.8 and 5.1). Younger patientsare at increased risk of experiencing adverse events associated with aripiprazole. Therefore, Aripiprazole

Sandoz 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 Sandoz in children andadolescents aged below 18 years have not yet been established. Currently available data are described insection 5.1 but no recommendation on a posology can be made.

Tics associated with Tourette’s disorder: the safety and efficacy of Aripiprazole Sandoz in children andadolescents 6 to 18 years of age have not yet been established. Currently available data are described insection 5.1 but no recommendation on a posology can be made.

No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients withsevere hepatic impairment, the data available are insufficient to establish recommendations. In these patientsdosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used withcaution in patients with severe hepatic impairment (see section 5.2).

No dosage adjustment is required in patients with renal impairment.

The safety and efficacy of Aripiprazole Sandoz in the treatment of schizophrenia or manic episodes in

Bipolar I Disorder in patients aged 65 years and older has not been established. Owing to the greatersensitivity of this population, a lower starting dose should be considered when clinical factors warrant (seesection 4.4).

No dosage adjustment is required for female patients as compared to male patients (see section 5.2).

According to the metabolic pathway of aripiprazole no dosage adjustment is required for smokers (seesection 4.5).

Dose adjustments due to interactions

When concomitant administration of strong CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, thearipiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from thecombination therapy, aripiprazole dose should then be increased (see section 4.5).

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

Aripiprazole Sandoz is for oral use.

Orodispersible tablets or oral solution may be used as an alternative to Aripiprazole Sandoz tablets forpatients who have difficulty swallowing Aripiprazole Sandoz tablets (see section 5.2).

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

During antipsychotic treatment, improvement in the patient's clinical condition may take several days tosome 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 caseshas been reported early after initiation or switch of antipsychotic treatment, including treatment witharipiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotictreatment.

Aripiprazole should be used with caution in patients with known cardiovascular disease (history ofmyocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovasculardisease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, andtreatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Sincepatients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factorsfor VTE should be identified before and during treatment with aripiprazole and preventive measuresundertaken.

In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. Aripiprazoleshould be used with caution in patients with a family history of QT prolongation (see section 4.8).

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesiaduring treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient onaripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms cantemporally 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 symptomsof other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should beconsidered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of

NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia,muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or bloodpressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs may include elevated creatinephosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatinephosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If apatient develops signs and symptoms indicative of NMS, or presents with unexplained high fever withoutadditional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued.

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 conditionsassociated 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 elderlypatients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were atincreased 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 deathsappeared to be either cardiovascular (e.g. heart failure, sudden death) or infectious (e.g. pneumonia) in nature(see section 4.8).

In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), includingfatalities, 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 patientsin these trials. This difference was not statistically significant. However, in one of these trials, a fixed-dosetrial, there was a significant dose response relationship for cerebrovascular adverse reactions in patientstreated with aripiprazole (see section 4.8).

Aripiprazole is not indicated for the treatment of patients with dementia-related psychosis.

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death,has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors thatmay predispose patients to severe complications include obesity and family history of diabetes. In clinicaltrials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-relatedadverse 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 andwith other atypical antipsychotics are not available to allow direct comparisons. Patients treated with anyantipsychotic, including aripiprazole, should be observed for signs and symptoms of hyperglycaemia (suchas polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors fordiabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section4.8).

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use ofantipsychotics known to cause weight gain, poorly managed life-style, and might lead to severecomplications. Weight gain has been reported post-marketing among patients prescribed aripiprazole. Whenseen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder orpituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gainin adults (see section 5.1). In clinical trials of adolescent patients with bipolar mania, aripiprazole has beenshown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored inadolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should beconsidered (see section 4.8).

Dysphagia

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

Pathological gambling and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control these urgeswhile taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsive shopping, bingeor compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to askpatients or their caregivers specifically about the development of new or increased gambling urges, sexualurges, compulsive shopping, binge or compulsive eating, or other urges while being treated witharipiprazole. It should be noted that impulse-control symptoms can be associated with the underlyingdisorder; however, in some cases, urges were reported to have stopped when the dose was reduced or themedication was discontinued. Impulse control disorders may result in harm to the patient and others if notrecognised. Consider dose reduction or stopping the medication if a patient develops such urges while takingaripiprazole (see section 4.8).

Patients with attention deficit hyperactivity disorder (ADHD) comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data areavailable on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken whenthese medicinal products are co-administered.

Falls

Aripiprazol may cause somnolence, postural hypotension, motor and sensory instability, which may lead tofalls. Caution should be taken when treating patients at higher risk, and a lower starting dose should beconsidered (e.g elderly or debilitated patients) (see section 4.2).

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

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

Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole is administered incombination with alcohol or other CNS medicinal products with overlapping adverse reactions such assedation (see section 4.8).

If aripiprazole is administered concomitantly with medicinal products known to cause QT prolongation orelectrolyte 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 isdeemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and

CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

Quinidine and other CYP2D6 inhibitors

In a clinical trial in healthy subjects, a strong inhibitor of CYP2D6 (quinidine) increased aripiprazole AUCby 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 ofits prescribed dose when concomitant administration of aripiprazole with quinidine occurs. Other stronginhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similardose reductions should therefore be applied.

Ketoconazole and other CYP3A4 inhibitors

In a clinical trial in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole) increased aripiprazole

AUC and Cmax by 63% and 37%, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77%and 43%, respectively. In CYP2D6 poor metabolisers, concomitant use of strong inhibitors of CYP3A4 mayresult in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers.

When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors witharipiprazole, potential benefits should outweigh the potential risks to the patient. When concomitantadministration of ketoconazole with aripiprazole occurs, aripiprazole dose should be reduced toapproximately one-half of its prescribed dose. Other strong inhibitors of CYP3A4, such as itraconazole and

HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should thereforebe applied (see section 4.2). Upon discontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage ofaripiprazole should be increased to the level prior to the initiation of the concomitant therapy. When weakinhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly witharipiprazole, modest increases in plasma aripiprazole concentrations may be expected.

Carbamazepine and other CYP3A4 inducers

Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazoleto patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC foraripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) wasadministered alone. Similarly, for dehydro-aripiprazole the geometric means of Cmax and AUC aftercarbamazepine co-administration were 69% and 71% lower, respectively, than those following treatmentwith aripiprazole alone. Aripiprazole dose should be doubled when concomitant administration ofaripiprazole occurs with carbamazepine. Concomitant administration of aripiprazole and other inducers of

CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St.

John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied.

Upon discontinuation of strong CYP3A4 inducers, the dosage of aripiprazole should be reduced to therecommended dose.

Valproate and lithium

When either valproate or lithium was administered concomitantly with aripiprazole, there was no clinicallysignificant change in aripiprazole concentrations and therefore no dose adjustment is necessary when eithervalproate or lithium is administered with aripiprazole.

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 ofsubstrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19(omeprazole), and CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did notshow potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to causeclinically important medicinal product interactions mediated by these enzymes.

When aripiprazole was administered concomitantly with either valproate, lithium or lamotrigine, there wasno clinically important change in valproate, lithium or lamotrigine concentrations.

Serotonin syndrome

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

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalieshave been reported; however, causal relationship with aripiprazole could not be established. Animal studiescould not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify theirphysician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due toinsufficient safety information in humans and concerns raised by animal reproductive studies, this medicinalproduct should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to thefoetus.

Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancyare at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary inseverity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,somnolence, respiratory distress, or feeding disorder. Consequently, newborn infants should be monitoredcarefully (see section 4.8).

Aripiprazole/metabolites are excreted in human milk. A decision must be made whether to discontinuebreast-feeding or to discontinue/abstain from aripiprazole therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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

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

The most commonly reported adverse reactions in placebo-controlled trials were akathisia and nausea eachoccurring in more than 3% of patients treated with oral aripiprazole.

The incidences of the Adverse Drug Reactions (ADRs) associated with aripiprazole therapy are tabulatedbelow. The table is based on adverse events reported during clinical trials and/or post-marketing use.

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to< 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and notknown (cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they arederived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as 'notknown'

Common Uncommon Not known

Blood and Leukopenialymphatic system Neutropeniadisorders Thrombocytopenia

Immune system Allergic reaction (e.g. anaphylacticdisorders reaction, angioedema includingswollen tongue, tongue oedema,face oedema, pruritus allergic, orurticaria)

Endocrine Hyperprolactinaemia Diabetic hyperosmolar comadisorders Blood prolactin Diabetic ketoacidosisdecreased

Metabolism and Diabetes mellitus Hyperglycaemia Hyponatremianutrition disorders Anorexia

Psychiatric Insomnia Depression, Suicide attempt, suicidal ideationdisorders Anxiety Hypersexuality and completed suicide (see

Restlessness section 4.4)

Pathological gambling

Impulse-control disorders

Binge eating

Compulsive shopping

Poriomania

Aggression

Agitation

Nervousness

Nervous system Akathisia Tardive dyskinesia Neuroleptic Malignant Syndromedisorders Extrapyramidal Dystonia (NMS)disorder Restless legs Grand mal convulsion

Tremor syndrome Serotonin syndrome

Headache Speech disorder

Sedation

Somnolence

Dizziness

Common Uncommon Not known

Eye disorders Vision blurred Diplopia Oculogyric crisis

Photophobia

Cardiac disorders Tachycardia Sudden death unexplained

Torsades de pointes

Ventricular arrhythmias

Cardiac arrest

Bradycardia

Vascular disorders Orthostatic Venous thromboembolismhypotension (including pulmonary embolismand deep vein thrombosis)

Respiratory, Hiccups Aspiration pneumoniathoracic and Laryngospasmmediastinal Oropharyngeal spasmdisorders

Gastrointestinal Constipation Pancreatitisdisorders Dyspepsia Dysphagia

Nausea Diarrhoea

Salivary Abdominal discomforthypersecretion Stomach discomfort

Hepatobiliary Hepatic failuredisorders Hepatitis

Jaundice

Skin and Rashsubcutaneous tissue Photosensitivity reactiondisorders Alopecia

Hyperhidrosis

Drug Reaction with Eosinophiliaand Systemic Symptoms (DRESS)

Musculoskeletal Rhabdomyolysisand connective Myalgiatissue disorders Stiffness

Renal and urinary Urinary incontinencedisorders Urinary retention

Pregnancy, Drug withdrawal syndromepuerperium and neonatal (see section 4.6)perinatal conditions

Reproductive Priapismsystem and breastdisorders

General disorders Fatigue Temperature regulation disorderand administration (e.g. hypothermia, pyrexia)site conditions Chest pain

Peripheral oedema

Investigations Weight decreased

Alanine Aminotransferaseincreased

Aspartate Aminotransferaseincreased

Gamma-glutamyltransferaseincreased

Common Uncommon Not known

Alkaline phosphatase increased

QT prolonged

Blood glucose increased

Glycosylated haemoglobinincreased

Blood glucose fluctuation

Creatine phosphokinase increased

Schizophrenia: in a long term 52-week controlled trial, aripiprazole-treated patients had an overall-lowerincidence (25.8%) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia compared with thosetreated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was19% for aripiprazole-treated patients and 13.1% for placebo-treated patients. In another long-term 26-weekcontrolled 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% foraripiprazole-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, theincidence 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 and3.2% 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 insusceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neckmuscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/orprotrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and withgreater 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 serumprolactin as compared to baseline was observed with aripiprazole (section 5.1).

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentiallyclinically significant changes in routine laboratory and lipid parameters (see section 5.1) revealed nomedically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient andasymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients whoreceived placebo.

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 adverse reactions were similar to those in adults except for the following reactionsthat 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 profilein a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlledtrial.

The safety profile of a long-term, double-blind placebo controlled trial was also similar except for thefollowing reactions that were reported more frequently than paediatric patients taking placebo: weightdecreased, 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 oflow 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 72months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 25.6% and45.0%, respectively.

In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated witharipiprazole, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 37.0 %and 59.4 %, respectively.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older

The frequency and type of adverse reactions in adolescents with Bipolar I Disorder were similar to those inadults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0%), extrapyramidaldisorder (18.4%), akathisia (16.0%), and fatigue (11.8%); and commonly (≥ 1/100, < 1/10) abdominal painupper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.

The following adverse reactions had a possible dose response relationship; extrapyramidal disorder(incidences were 10 mg, 9.1%, 30 mg, 28.8%, placebo, 1.7%,); and akathisia (incidences were 10 mg,12.1%, 30 mg, 20.3%, placebo, 1.7%).

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazolewere 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 bipolardisorder compared to patients with schizophrenia.

In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serumprolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 28.0% and 53.3%, respectively.

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating can occur inpatients treated with aripiprazole (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allowscontinued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are askedto report any suspected adverse reactions via the national reporting system listed in Appendix V.

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alonewas identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. Thepotentially medically important signs and symptoms observed included lethargy, increased blood pressure,somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose witharipiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medicallyserious signs and symptoms reported included somnolence, transient loss of consciousness andextrapyramidal symptoms.

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway,oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal productinvolvement should be considered. Therefore cardiovascular monitoring should be started immediately andshould include continuous electrocardiographic monitoring to detect possible arrhythmias. Following anyconfirmed or suspected overdose with aripiprazole, close medical supervision and monitoring shouldcontinue until the patient recovers.

Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax by about41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose.

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 plasmaproteins.

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

It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediated througha combination of partial agonism at dopamine D2 and serotonin 5-HT1a receptors and antagonism ofserotonin 5-HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergichyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibitedhigh binding affinity in vitro for dopamine D2 and D3, serotonin 5-HT1a and 5-HT2a receptors and moderateaffinity 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 appreciableaffinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes mayexplain 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 weeksproduced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, to the caudateand putamen detected by positron emission tomography.

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 significantlygreater improvements in psychotic symptoms compared to placebo.

Aripiprazole is effective in maintaining the clinical improvement during continuation therapy in adultpatients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion ofresponder 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 onaripiprazole (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 improvementover haloperidol.

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

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 patientsand where the primary end-point was weight gain, significantly less patients had at least 7% weight gain overbaseline (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 notbeen shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and

LDL.

Prolactin

Prolactin levels were evaluated in all trials of all doses of aripiprazole (n=28,242). The incidence ofhyperprolactinaemia or increased serum prolactin in patients treated with aripiprazole (0.3%) was similar tothat of placebo (0.2%). For patients receiving aripiprazole, the median time to onset was 42 days and medianduration was 34 days.

The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazole was0.4%, compared with 0.02% for patients treated with placebo. For patients receiving aripiprazole, the mediantime 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 ormixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction ofmanic symptoms over 3 weeks. These trials included patients with or without psychotic features and with orwithout a rapid-cycling course.

In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixedepisode 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 episodeof Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy toplacebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazolealso demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium orhaloperidol 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 monotherapyfor 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superiorefficacy 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 achievedremission on aripiprazole during a stabilization phase prior to randomisation, aripiprazole demonstratedsuperiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania butfailed 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, adjunctivearipiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) inpreventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence intomania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrenceinto depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcomemeasure, CGI-BP Severity of Illness score (mania). In this trial, patients were assigned by investigators witheither open-label lithium or valproate monotherapy to determine partial non-response. Patients werestabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same moodstabilizer. Stabilized patients were then randomised to continue the same mood stabilizer with double-blindaripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole+ lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate. The Kaplan-Meier rates forrecurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate.

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 significantlygreater improvements in psychotic symptoms compared to placebo. In a sub-analysis of the adolescentpatients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenanceof 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; ages13-17 years) with schizophrenia, there was a statistically significant difference in the rate of relapse ofpsychotic symptoms between the aripiprazole (19.39%) and placebo (37.50%) groups. The point estimate ofthe hazard ratio (HR) was 0.461 (95% confidence interval, 0.242-0.879) in the full population. In subgroupanalyses the point estimate of the HR was 0.495 for subjects 13 to 14 years of age compared to 0.454 forsubjects 15 to 17 years of age. However, the estimation of the HR for the younger (13-14 years) group wasnot 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 bedrawn on the presence of a treatment effect. In contrast the 95% confidence interval for the HR in the oldersubgroup (aripiprazole, n = 69; placebo, n = 36) was 0.242 to 0.879 and hence a treatment effect could beconcluded 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 withoutpsychotic features and had a Y-MRS score ≥ 20 at baseline. Among the patients included in the primaryefficacy 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 totalscore. In a post-hoc analysis, the improvement over placebo was more pronounced in the patients withassociated co-morbidity of ADHD compared to the group without ADHD, where there was no differencefrom placebo. Recurrence prevention was not established.

The most common treatment-emergent adverse events among patients receiving 30 mg were extrapyramidaldisorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain in the 30weeks 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 inthese trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day inweekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazoledemonstrated 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 safetyprofile included weight gain and changes in prolactin levels. The duration of the long-term safety study waslimited 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 weekstabilisation on aripiprazole (2-15 mg/day) patients with a stable response were either maintained onaripiprazole 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) was0.57 (non-statistically significant difference). The mean weight gain over the stabilisation phase (up to 26weeks) on aripiprazole was 3.2 kg, and a further mean increase of 2.2 kg for aripiprazole as compared to0.6 kg for placebo was observed in the second phase (16 weeks) of the trial. Extrapyramidal symptoms weremainly 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 changefrom 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, ina 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 animprovement of 14.97 on TTS-YGTSS change from baseline to week 10 as compared with an improvementof 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 effectsregarding psycho-social functioning. No long term data are available with regard to the efficacy and thesafety of aripiprazole in this fluctuating disorder.

The European Medicines Agency has deferred the obligation to submit the results of studies with thereference medicinal product containing aripiprazole in one or more subsets of the paediatric population in thetreatment of schizophrenia and in the treatment of bipolar affective disorder (see section 4.2 for informationon paediatric use).

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 tabletformulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.

Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg,indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways:dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation iscatalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. Atsteady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC inplasma.

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 administeredradioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchangedaripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 10 to 17 years of agewere similar to those in adults after correcting for the differences in body weights.

There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adultsubjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenicpatients.

There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjectsnor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenicpatients.

Smoking

Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects fromsmoking on the pharmacokinetics of aripiprazole.

Population pharmacokinetic evaluation showed no evidence of race-related differences on thepharmacokinetics of aripiprazole.

The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar inpatients with severe renal disease compared to young healthy subjects.

A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) didnot 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 drawconclusions 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 excessof the maximum human dose or exposure, indicating that these effects were limited or of no relevance toclinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/orparenchymal 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 combinedadrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC atthe maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 timesthe human exposure at the recommended dose.

An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxymetabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times themaximum recommended human dose based on mg/m2). However, the concentrations of the sulphateconjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no morethan 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) theirlimits of in vitro solubility.

In repeat-dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to thatobserved 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 dosesresulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred atdoses similar to those eliciting developmental toxicity.

Aripiprazole Sandoz 5 mg tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Indigo Carmine (E 132) Aluminium lake

Aripiprazole Sandoz 10 mg tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Red iron oxide (E 172)

Aripiprazole Sandoz 15 mg tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Yellow iron oxide (E 172)

Aripiprazole Sandoz 20 mg tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Aripiprazole Sandoz 30 mg tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Red iron oxide (E 172)

Not applicable.

2 years

Aripiprazole Sandoz 5 mg, 10 mg, 15 mg, 30 mg tablets

After first opening of the bottle: 3 months

This medicinal product does not require any special storage conditions.

Aripiprazole Sandoz 5 mg, 10 mg, 15 mg, 30 mg tablets

For storage conditions after first opening of the bottle, see section 6.3.

Aluminium//Aluminium blister.

Aripiprazole Sandoz 5 mg, 10 mg, 15 mg, 30 mg tablets

High density polyethylene (HDPE) tablet container (bottle) containing a silica gel desiccant and a polyestercoil.

Aripiprazole Sandoz 5 mg, 10 mg, 15 mg, 30 mg tablets

Blister packs in cartons: 10, 14, 16, 28, 30, 35, 56, 70 tablets

Blister packs (unit dose) in cartons: 14 x 1, 28 x 1, 49 x 1, 56 x 1, 98 x 1 tablet

Bottle packs in cartons: 100 tablets

Aripiprazole Sandoz 20 mg tablets

Blister packs in cartons: 14, 28, 49, 56, 98 tablets

Not all pack sizes may be marketed.

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

Sandoz GmbH

Biochemiestrasse 106250 Kundl

Austria

Aripiprazole Sandoz 5 mg tablets

EU/1/15/1029/001 (10 tablets)

EU/1/15/1029/002 (14 tablets)

EU/1/15/1029/003 (16 tablets)

EU/1/15/1029/004 (28 tablets)

EU/1/15/1029/005 (30 tablets)

EU/1/15/1029/006 (35 tablets)

EU/1/15/1029/007 (56 tablets)

EU/1/15/1029/008 (70 tablets)

EU/1/15/1029/009 (14 x 1 tablets)

EU/1/15/1029/010 (28 x 1 tablets)

EU/1/15/1029/011 (49 x 1 tablets)

EU/1/15/1029/012 (56 x 1 tablets)

EU/1/15/1029/013 (98 x 1 tablets)

EU/1/15/1029/014 (100 tablets)

Aripiprazole Sandoz 10 mg tablets

EU/1/15/1029/015 (10 tablets)

EU/1/15/1029/016 (14 tablets)

EU/1/15/1029/017 (16 tablets)

EU/1/15/1029/018 (28 tablets)

EU/1/15/1029/019 (30 tablets)

EU/1/15/1029/020 (35 tablets)

EU/1/15/1029/021 (56 tablets)

EU/1/15/1029/022 (70 tablets)

EU/1/15/1029/023 (14 x 1 tablets)

EU/1/15/1029/024 (28 x 1 tablets)

EU/1/15/1029/025 (49 x 1 tablets)

EU/1/15/1029/026 (56 x 1 tablets)

EU/1/15/1029/027 (98 x 1 tablets)

EU/1/15/1029/028 (100 tablets)

Aripiprazole Sandoz 15 mg tablets

EU/1/15/1029/029 (10 tablets)

EU/1/15/1029/030 (14 tablets)

EU/1/15/1029/031 (16 tablets)

EU/1/15/1029/032 (28 tablets)

EU/1/15/1029/033 (30 tablets)

EU/1/15/1029/034 (35 tablets)

EU/1/15/1029/035 (56 tablets)

EU/1/15/1029/036 (70 tablets)

EU/1/15/1029/037 (14 x 1 tablets)

EU/1/15/1029/038 (28 x 1 tablets)

EU/1/15/1029/039 (49 x 1 tablets)

EU/1/15/1029/040 (56 x 1 tablets)

EU/1/15/1029/041 (98 x 1 tablets)

EU/1/15/1029/042 (100 tablets)

Aripiprazole Sandoz 20 mg tablets

EU/1/15/1029/043 (14 tablets)

EU/1/15/1029/044 (28 tablets)

EU/1/15/1029/045 (49 tablets)

EU/1/15/1029/046 (56 tablets)

EU/1/15/1029/047 (98 tablets)

Aripiprazole Sandoz 30 mg tablets

EU/1/15/1029/048 (10 tablets)

EU/1/15/1029/049 (14 tablets)

EU/1/15/1029/050 (16 tablets)

EU/1/15/1029/051 (28 tablets)

EU/1/15/1029/052 (30 tablets)

EU/1/15/1029/053 (35 tablets)

EU/1/15/1029/054 (56 tablets)

EU/1/15/1029/055 (70 tablets)

EU/1/15/1029/056 (14 x 1 tablets)

EU/1/15/1029/057 (28 x 1 tablets)

EU/1/15/1029/058 (49 x 1 tablets)

EU/1/15/1029/059 (56 x 1 tablets)

EU/1/15/1029/060 (98 x 1 tablets)

EU/1/15/1029/061 (100 tablets)

Date of first authorisation: 20 August 2015

Date of latest authorisation:

{MM/YYYY}

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.