ABILIFY 7.5mg / ml injectible solution medication leaflet

ABILIFY 7.5 mg/mL solution for injection

Each mL contains 7.5 mg of aripiprazole. Each vial contains 9.75 mg aripiprazole.

For the full list of excipients, see section 6.1.

Solution for injection

Clear, colourless, aqueous solution.

ABILIFY solution for injection is indicated for the rapid control of agitation and disturbed behavioursin adult patients with schizophrenia or with manic episodes in Bipolar I Disorder, when oral therapy isnot appropriate.

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

The recommended initial dose for ABILIFY solution for injection is 9.75 mg (1.3 mL), administeredas a single intramuscular injection. The effective dose range of ABILIFY solution for injection is5.25 mg to 15 mg as a single injection. A lower dose of 5.25 mg (0.7 mL) may be given, on the basisof individual clinical status, which should also include consideration of medicinal products alreadyadministered either for maintenance or acute treatment (see section 4.5).

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

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

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

The safety and efficacy of ABILIFY solution for injection in children and adolescents aged 0 to17 years have not been established. No data are available.

No dosage adjustment is required for patients with mild to moderate hepatic impairment. In patientswith severe hepatic impairment, the data available are insufficient to establish recommendations. Inthese patients dosing should be managed cautiously. However, the maximum daily dose of 30 mgshould be used with caution 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 ABILIFY in the treatment of schizophrenia or manic episodes in Bipolar I

Disorder in patients aged 65 years and older has not been established. Owing to the greater sensitivityof 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,the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn fromthe combination therapy, aripiprazole dose should then be increased (see section 4.5).

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

ABILIFY solution for injection is for intramuscular use.

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

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

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

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

The efficacy of ABILIFY solution for injection in patients with agitation and disturbed behaviours hasnot been established related to conditions other than schizophrenia and manic episodes in Bipolar I

Disorder.

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

Patients receiving ABILIFY solution for injection should be observed for orthostatic hypotension.

Blood pressure, pulse, respiratory rate and level of consciousness should be monitored regularly.

The safety and efficacy of ABILIFY solution for injection has not been evaluated in patients withalcohol or medicinal product intoxication (either with prescribed or illicit medicinal products).

During antipsychotic treatment, improvement in the patient’s clinical condition may take several daysto 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 insome cases has been reported early after initiation or switch of antipsychotic treatment, includingtreatment with aripiprazole (see section 4.8). Close supervision of high-risk patients shouldaccompany antipsychotic treatment.

Aripiprazole should be used with caution in patients with known cardiovascular disease (history ofmyocardial 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, includingaccelerated or malignant. Cases of venous thromboembolism (VTE) have been reported withantipsychotic medicinal products. Since patients treated with antipsychotics often present withacquired risk factors for VTE, all possible risk factors for VTE should be identified before and duringtreatment with aripiprazole and preventive measures undertaken (see section 4.8).

In clinical trials of treatment with oral aripiprazole, the incidence of QT prolongation was comparableto placebo. Aripiprazole should be used with caution in patients with a family history of QTprolongation (see section 4.8).

In clinical trials of one year or less duration, there were uncommon reports of treatment emergentdyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in apatient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). Thesesymptoms 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 andsymptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinicalmonitoring should be considered.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rarecases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS arehyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregularpulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs mayinclude 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, orpresents with unexplained high fever without additional clinical manifestations of NMS, allantipsychotics, 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 disorderor have conditions associated with seizures (see section 4.8).

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials (n = 938; mean age: 82.4 years; range: 56 to 99 years) of aripiprazolein elderly patients with psychosis associated with Alzheimer’s disease, patients treated witharipiprazole 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 deathswere 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).

In the same trials, cerebrovascular adverse reactions (e.g. stroke, transient ischaemic attack), includingfatalities, were reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, 1.3 % ofaripiprazole-treated patients reported cerebrovascular adverse reactions compared with 0.6 % ofplacebo-treated patients in these trials. This difference was not statistically significant. However, inone of these trials, a fixed-dose trial, there was a significant dose response relationship forcerebrovascular adverse reactions in patients treated with aripiprazole (see section 4.8).

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

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma ordeath, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Riskfactors that may predispose patients to severe complications include obesity and family history ofdiabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence ratesof hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratoryvalues compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions inpatients treated with aripiprazole and with other atypical antipsychotics are not available to allowdirect comparisons. Patients treated with any antipsychotics, including aripiprazole, should beobserved for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia andweakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should bemonitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (seesection 4.8).

Weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, useof antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severecomplications. Weight gain has been reported post-marketing among patients prescribed oralaripiprazole. 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 induceclinically relevant weight gain in adults (see section 5.1). In clinical trials of adolescent patients withbipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks oftreatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gainis clinically significant, dose reduction should be considered (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 theseurges while taking aripiprazole. Other urges, reported, include: increased sexual urges, compulsiveshopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is importantfor prescribers to ask patients or their caregivers specifically about the development of new orincreased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or otherurges while being treated with aripiprazole. It should be noted that impulse-control symptoms can beassociated with the underlying disorder; however, in some cases, urges were reported to have stoppedwhen the dose was reduced or the medication was discontinued. Impulse control disorders may resultin harm to the patient and others if not recognised. Consider dose reduction or stopping the medicationif a patient develops such urges while taking aripiprazole (see section 4.8).

ABILIFY solution for injection contains sodium. This medicinal product contains less than 1 mmolsodium (23 mg) per dosage unit, that is to say essentially ‘sodium-free’.

Patients with attention deficit hyperactivity disorder (ADHD) comorbidity

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

Falls

Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which maylead to falls. Caution should be taken when treating patients at higher risk, and a lower starting doseshould be considered (e.g., elderly or debilitated patients; see section 4.2).

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

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

Given the primary CNS effects of aripiprazole, caution should be used when aripiprazole isadministered in combination with alcohol or other CNS medicinal products with overlapping adversereactions such as sedation (see section 4.8).

If aripiprazole is administered concomitantly with medicinal products known to cause QTprolongation or electrolyte imbalance, caution should be used.

Potential for other medicinal products to affect ABILIFY solution for injection

The administration of lorazepam solution for injection had no effect on the pharmacokinetics of

ABILIFY solution for injection when administered concomitantly. However, in a single-dose,intramuscular study of aripiprazole (dose 15 mg) in healthy subjects, administered simultaneouslywith intramuscular lorazepam (dose 2 mg), the intensity of sedation was greater with the combinationas compared to that observed with aripiprazole alone.

A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but thiseffect is deemed not clinically relevant. Aripiprazole is metabolised by multiple pathways involvingthe CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is requiredfor smokers.

Quinidine and other CYP2D6 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine)increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Aripiprazole doseshould be reduced to approximately one-half of its prescribed dose when concomitant administrationof aripiprazole with quinidine occurs. Other strong inhibitors of CYP2D6, such as fluoxetine andparoxetine, may be expected to have similar effects and similar dose reductions should therefore beapplied.

Ketoconazole and other CYP3A4 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole)increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitantuse of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazolecompared to that in CYP2D6 extensive metabolizers. When considering concomitant administration ofketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweighthe potential risks to the patient. When concomitant administration of ketoconazole with aripiprazoleoccurs, aripiprazole dose should be reduced to approximately one-half of its prescribed dose. Otherstrong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected tohave similar effects and similar dose reductions should therefore be applied (see section 4.2). Upondiscontinuation of the CYP2D6 or CYP3A4 inhibitor, the dosage of aripiprazole should be increasedto the level prior to the initiation of the concomitant therapy. When weak inhibitors of CYP3A4 (e.g.diltiazem) or CYP2D6 (e.g. escitalopram) are used concomitantly with aripiprazole, modest increasesin plasma aripiprazole concentrations may be expected.

Carbamazepine and other CYP3A4 inducers

Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oralaripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmaxand 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 thosefollowing treatment with aripiprazole alone. Aripiprazole dose should be doubled when concomitantadministration of aripiprazole occurs with carbamazepine. Concomitant administration of aripiprazoleand 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 doseincreases should therefore be applied. Upon discontinuation of strong CYP3A4 inducers, the dosage ofaripiprazole should be reduced to the recommended dose.

Valproate and lithium

When either valproate or lithium was administered concomitantly with aripiprazole, there was noclinically significant change in aripiprazole concentrations and therefore no dose adjustment isnecessary when either valproate or lithium is administered with aripiprazole.

Potential for aripiprazole to affect other medicinal products

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

In clinical studies, oral doses of 10 mg/day to 30 mg/day of aripiprazole had no significant effect onthe 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-mediatedmetabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal productinteractions mediated by these enzymes.

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

Serotonin syndrome

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

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenitalanomalies have been reported; however, causal relationship with aripiprazole could not be established.

Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must beadvised to notify their physician if they become pregnant or intend to become pregnant duringtreatment with aripiprazole. Due to insufficient safety information in humans and concerns raised byanimal reproductive studies, this medicinal product should not be used in pregnancy unless theexpected benefit clearly justifies the potential risk to the foetus.

Newborn infants exposed to antipsychotics (including aripiprazole) during the third trimester ofpregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms thatmay vary in severity and duration following delivery. There have been reports of agitation, hypertonia,hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborninfants should be monitored carefully (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 ofbreast-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 nausea, dizziness andsomnolence each occurring in more than 3 % of patients treated with aripiprazole solution forinjection.

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

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

The frequency of adverse reactions reported during post-marketing use cannot be determined as theyare derived from spontaneous reports. Consequently, the frequency of these adverse events is qualifiedas “not known”.

Common Uncommon Not known

Blood and Leukopenialymphatic system Neutropeniadisorders Thrombocytopenia

Immune system Allergic reaction (e.g.disorders anaphylactic reaction,angioedema including swollentongue, tongue oedema, faceoedema, 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 disorder

Binge eating

Compulsive shopping

Poriomania

Aggression

Agitation

Nervousness

Nervous system Akathisia Tardive dyskinesia Neuroleptic Malignant Syndromedisorders Extrapyramidal Dystonia Grand mal convulsiondisorder Restless legs Serotonin syndrome

Tremor syndrome Speech disorder

Sedation

Somnolence

Dizziness

Eye disorders Vision blurred Diplopia Oculogyric crisis

Photophobia

Cardiac disorders Tachycardia Sudden death unexplained

Torsades de pointes

Ventricular arrhythmia

Cardiac arrest

Bradycardia

Common Uncommon Not known

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

Respiratory, Hiccups Aspiration pneumoniathoracic and Laryngospasmmediastinal Oropharyngeal spasmdisorders

Gastrointestinal Constipation Mouth dry 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 Diastolic blood Weight decreasedpressure increased Weight gain

Alanine Aminotransferaseincreased

Aspartate Aminotransferaseincreased

Gamma-glutamyltransferaseincreased

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-lower incidence (25.8 %) of EPS including Parkinsonism, akathisia, dystonia and dyskinesia comparedwith those treated with haloperidol (57.3 %). In a long-term 26-week placebo-controlled trial, theincidence of EPS was 19 % for aripiprazole-treated patients and 13.1 % for placebo-treated patients. Inanother long-term 26-week controlled trial, the incidence of EPS was 14.8 % for aripiprazole-treatedpatients 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 treatedwith lithium. In the long-term 26-week maintenance phase of a placebo-controlled trial, the incidenceof 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 aripiprazoleand 3.2 % with placebo. In schizophrenia patients the incidence of akathisia was 6.2 % witharipiprazole 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 ofthe neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficultybreathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occurmore frequently and with greater severity with high potency and at higher doses of first generationantipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and youngerage 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 % ofpatients who received placebo.

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping and binge or compulsive eating canoccur in patients treated with aripiprazole (see section 4.4).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

No cases of overdose associated with adverse reactions were reported in clinical studies with

ABILIFY solution for injection. Care must be taken to avoid inadvertent injection of this medicinalproduct into a blood vessel. Following any confirmed or suspected accidental overdose/inadvertentintravenous administration, close observation of the patient is needed and if any potentially medicallyserious sign or symptom develops, monitoring, which should include continuous electrocardiographicmonitoring, is required. The medical supervision and monitoring should continue until the patientrecovers.

Signs and symptoms

In clinical trials and post-marketing experience, accidental or intentional acute overdose ofaripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg withno 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 receivedwith no fatalities. The potentially medically serious signs and symptoms reported includedsomnolence, transient loss of consciousness and extrapyramidal symptoms.

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway,oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinalproduct involvement should be considered. Therefore cardiovascular monitoring should be startedimmediately and should include continuous electrocardiographic monitoring to detect possiblearrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medicalsupervision and monitoring should continue until the patient recovers.

Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole Cmax byabout 41 % and AUC by about 51 %, suggesting that charcoal may be effective in the treatment ofoverdose.

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

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

It has been proposed that aripiprazole’s efficacy in schizophrenia and Bipolar I Disorder is mediatedthrough a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors andantagonism of serotonin 5-HT2A receptors. Aripiprazole exhibited antagonist properties in animalmodels of dopaminergic hyperactivity and agonist properties in animal models of dopaminergichypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin5-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 affinityfor the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction withreceptors other than dopamine and serotonin subtypes may explain some of the other clinical effects ofaripiprazole.

Aripiprazole doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects for2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptorligand, to the caudate and putamen detected by positron emission tomography.

Agitation in schizophrenia and Bipolar I Disorder with ABILIFY solution for injection

In two short-term (24-hour) placebo-controlled trials involving 554 schizophrenic adult patientspresenting with agitation and disturbed behaviours, ABILIFYsolution for injection was associatedwith statistically significant greater improvements in agitation/behavioural symptoms compared toplacebo and was similar to haloperidol.

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

Schizophrenia with oral aripiprazole

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic adultpatients, presenting with positive or negative symptoms, oral aripiprazole was associated withstatistically significantly greater 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 proportionof responder patients maintaining response to medicinal product at 52-weeks was similar in bothgroups (oral aripiprazole 77 % and haloperidol 73 %). The overall completion rate was significantlyhigher for patients on oral aripiprazole (43 %) than for oral haloperidol (30 %). Actual scores in ratingscales used as secondary endpoints, including PANSS and the Montgomery-Åsberg Depression Rating

Scale (MADRS) showed a significant improvement over haloperidol.

In a 26-week, placebo-controlled trial in adult stabilised patients with chronic schizophrenia, oralaripiprazole had significantly greater reduction in relapse rate, 34 % in oral aripiprazole group and57 % in placebo.

In clinical trials oral aripiprazole has not been shown to induce clinically relevant weight gain. In a26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included314 adult patients and where the primary endpoint was weight gain, significantly less patients had atleast 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 oral aripiprazole (n = 18, or 13 % of evaluable patients), compared to oral olanzapine(n = 45, or 33 % of evaluable patients).

Lipid parameters

In a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazolehas not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides,

High Density Lipoprotein (HDL) and Low Density Lipoprotein (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 %) wassimilar to that of placebo (0.2 %). For patients receiving aripiprazole, the median time to onset was42 days and median duration was 34 days.

The incidence of hypoprolactinaemia or decreased serum prolactin in patients treated with aripiprazolewas 0.4 %, compared with 0.02 % for patients treated with placebo. For patients receivingaripiprazole, the median time to onset was 30 days and median duration was 194 days.

Manic episodes in Bipolar I Disorder with oral aripiprazole

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 inreduction of manic symptoms over 3 weeks. These trials included patients with or without psychoticfeatures and with or without a rapid-cycling course.

In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic ormixed 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 mixedepisode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superiorefficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol atweek 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomaticremission 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 orvalproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole asadjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium orvalproate monotherapy.

In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients whoachieved remission on aripiprazole during a stabilization phase prior to randomisation, aripiprazoledemonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventingrecurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence intodepression.

In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I

Disorder who achieved sustained remission (Young Mania Rating Scale [YMRS] and MADRS withtotal scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for12 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 todemonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazoledemonstrated superiority over placebo on the secondary outcome measure in Clinical Global

Impression - Bipolar version (CGI-BP) Severity of Illness (SOI; mania) scores. In this trial, patientswere assigned by investigators with either open-label lithium or valproate monotherapy to determinepartial non-response. Patients were stabilised for at least 12 consecutive weeks with the combinationof aripiprazole and the same mood stabilizer. Stabilized patients were then randomised to continue thesame mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups wereassessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium;placebo + valproate. The Kaplan-Meier rates for recurrence to any mood episode for the adjunctivetreatment arm were 16 % in aripiprazole + lithium and 18 % in aripiprazole + valproate compared to45 % in placebo + lithium and 19 % in placebo + valproate.

The European Medicines Agency has deferred the obligation to submit the results of studies with

ABILIFY in one or more subsets of the paediatric population in the treatment of schizophrenia and inthe treatment of bipolar affective disorder (see section 4.2 for information on paediatric use).

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

Based on results from trials with oral administration of aripiprazole, aripiprazole is widely distributedthroughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensiveextravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole aregreater 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 systemiccirculation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40 % ofaripiprazole AUC in plasma.

The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisersof 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 % ofunchanged aripiprazole was excreted in the urine and approximately 18 % was recovered unchangedin the faeces.

There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and youngeradult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis inschizophrenic patients.

There are no differences in the pharmacokinetics of aripiprazole between healthy male and femalesubjects nor is there any detectable effect of gender in a population pharmacokinetic analysis inschizophrenic patients.

Smoking

Population pharmacokinetic evaluation of oral aripiprazole has revealed no evidence of clinicallyrelevant effects from smoking 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 similarin patients 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) did not reveal a significant effect of hepatic impairment on the pharmacokinetics ofaripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C livercirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

Administration of ABILIFY solution for injection was well tolerated and produced no direct targetorgan toxicity in rats or monkeys after repeated dosing at systemic exposures (AUC) that were 15 and5 times, respectively, human exposure at the maximum recommended human dose of 30 mgintramuscular. In intravenous reproductive toxicity studies, no new safety concerns were observed atmaternal exposures up to 15 (rat) and 29 (rabbit) times human exposure at 30 mg.

Non-clinical data reveal no special hazard for humans based on conventional oral aripiprazole studiesof safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity toreproduction and development.

Toxicologically significant effects were observed only at doses or exposures that were sufficiently inexcess of the maximum human dose or exposure, indicating that these effects were limited or of norelevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigmentaccumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 mg/kg/day to 60 mg/kg/day(3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increasedadrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). Thehighest nontumorigenic exposure in female rats was 7 times the human exposure at the recommendeddose.

An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates ofhydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 mg/kg/dayto 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinicaldose or 16 to 81 times the maximum recommended human dose based on mg/m2). However, theconcentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest doseproposed, 30 mg per day, were no more than 6 % of the bile concentrations found in the monkeys inthe 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 tothat observed in adult animals, and there was no evidence of neurotoxicity or adverse reactions ondevelopment.

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. Developmentaltoxicity, including dose-dependent delayed foetal ossification and possible teratogenic effects, wereobserved in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at dosesresulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommendedclinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.

Sulfobutylether β-cyclodextrin (SBECD)

Tartaric acid

Sodium hydroxide

Water for injections

Not applicable.

18 months

After opening: use product immediately.

Keep the vial in the outer carton in order to protect from light.

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

Each carton contains one single-use type I glass vial with a rubber butyl stopper and a 'tear-off'aluminium seal.

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

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 2921101 CT, Amsterdam

Netherlands

EU/1/04/276/036

Date of first authorisation: 04 June 2004

Date of latest renewal: 04 June 2009

{MM/YYYY}

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

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