ABILIFY MAINTENA 960mg prolonged-release suspension for injection in pre-filled syringe medication leaflet

Abilify Maintena 720 mg prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 960 mg prolonged-release suspension for injection in pre-filled syringe

Abilify Maintena 720 mg prolonged-release suspension for injection in pre-filled syringe

Each pre-filled syringe contains 720 mg aripiprazole per 2.4 mL (300 mg/mL).

Abilify Maintena 960 mg prolonged-release suspension for injection in pre-filled syringe

Each pre-filled syringe contains 960 mg aripiprazole per 3.2 mL (300 mg/mL).

For the full list of excipients, see section 6.1.

Prolonged-release suspension for injection in pre-filled syringe

The suspension is white to off-white. The suspension is pH neutral (approximately 7.0).

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

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

Titration of the dose for Abilify Maintena is not required.

Starting regimen

The recommended starting dosing regimen when transitioning from Abilify Maintena 400 mg oncemonthly is Abilify Maintena 960 mg no sooner than 26 days after previous injection of Abilify

Maintena 400 mg. Abilify Maintena 960 mg should then be dosed once every 2 months (every56 days).

Initiation may also be started by following one of two additional regimens:

* One injection start: On the day of initiation following oral therapy, one injection of Abilify

Maintena 960 mg should be administered and treatment with 10 mg to 20 mg oral aripiprazoleper day for 14 consecutive days should be continued to maintain therapeutic aripiprazoleconcentrations during initiation of therapy.

* Two injection start: On the day of initiation following oral therapy, one injection of Abilify

Maintena 960 mg and one injection of Abilify Maintena 400 mg should be administered at twodifferent injection sites (see method of administration), along with one 20 mg dose of oralaripiprazole.

Dosing interval and dosing adjustments

After the injection start, the recommended maintenance dose is one injection of Abilify Maintena960 mg every second month. Inject Abilify Maintena 960 mg once every two months as a singleinjection 56 days after the previous injection. Patients may be given the injection up to 2 weeks beforeor 2 weeks after the scheduled 2-month dose.

If there are adverse reactions with the Abilify Maintena 960 mg dose, reduction to Abilify Maintena720 mg once every two months should be considered.

If more than 8 weeks and less than 14 weeks have elapsed since the last injection, the next dose of

Abilify Maintena 960 mg/720 mg should be administered as soon as possible. The once every twomonths schedule should then be resumed. If more than 14 weeks have elapsed since the last injection,the next dose of Abilify Maintena 960 mg/720 mg should be administered with concomitant oralaripiprazole for 14 days or with 2 separate injections (one each of Abilify Maintena 960 mg and

Abilify Maintena 400 mg or one each Abilify Maintena 720 mg and Abilify Maintena 300 mg)administered together with one 20 mg oral aripiprazole dose. The once every two months scheduleshould then be resumed.

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

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

No dose adjustment is required for patients with mild or moderate hepatic impairment. In patients withsevere hepatic impairment, the data available are insufficient to establish recommendations. In thesepatients dosing should be managed cautiously. Oral formulation should be preferred (see section 5.2).

Known CYP2D6 poor metabolisers

In patients who are known to be CYP2D6 poor metabolisers:

* Patients transitioning from Abilify Maintena 300 mg once monthly: The starting dose should beone injection of Abilify Maintena 720 mg g, no sooner than 26 days after previous injection of

Abilify Maintena 300 mg.

* One injection start (following transition from oral therapy): The starting dose should be oneinjection of Abilify Maintena 720 mg and treatment should be continued with the prescribeddose of oral aripiprazole per day for 14 consecutive days.

* Two injection start (following transition from oral therapy): The starting dose should be 2separate injections; one Abilify Maintena 720 mg and one Abilify Maintena 300 mg injection,together with a single dose of 20 mg oral aripiprazole (see method of administration).

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

Maintenance dose adjustments due to interactions with CYP2D6 and/or CYP3A4 inhibitors and/or

Maintenance dose adjustments should be made in patients taking concomitant strong CYP3A4inhibitors or strong CYP2D6 inhibitors for more than 14 days. If the CYP3A4 inhibitor or CYP2D6inhibitor is withdrawn, the dose may need to be increased to the previous dose (see section 4.5). Incase of adverse reactions despite dose adjustments of Abilify Maintena 960 mg, the necessity ofconcomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

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

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

Table 1: Maintenance dose adjustments of Abilify Maintena in patients who are takingconcomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4inducers for more than 14 days

Adjusted 2-monthly dose

Patients taking Abilify Maintena 960 mg*

Strong CYP2D6 or strong CYP3A4 inhibitors 720 mg

Strong CYP2D6 and strong CYP3A4 inhibitors Avoid use

CYP3A4 inducers Avoid use

*Avoid use in patients who already take 720 mg, e.g. due to adverse rections to the higher dose.

The safety and efficacy of Abilify Maintena 960 mg/720 mg in children and adolescents aged 0 to17 years have not been established. No data are available.

Abilify Maintena 960 mg and 720 mg is only intended for gluteal intramuscular injection and must notbe administered intravenously or subcutaneously. It must only be administered by a healthcareprofessional.

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

If initiating with any of the options that require two injections (one Abilify Maintena 960 mg or720 mg and one Abilify Maintena 400 mg or 300 mg ), inject into two different sites. DO NOT injectboth injections concomitantly into the same gluteal muscle.

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

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 daysto some weeks. Patients should be closely monitored throughout this period.

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

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

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has beenreported 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),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.

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 (see section 4.8).

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 of oral aripiprazole in elderly patients with psychosis associated with

Alzheimer's disease (n = 938; mean age: 82.4 years; range: 56 to 99 years), patients treated witharipiprazole were at an increased risk of death compared to placebo. The rate of death in oralaripiprazole-treated patients was 3.5 % compared to 1.7 % in placebo. 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 with oral aripiprazole, cerebrovascular adverse reactions (e.g., stroke, transientischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78 to88 years). Overall, 1.3 % of oral aripiprazole-treated patients reported cerebrovascular adversereactions compared with 0.6 % of placebo-treated patients in these trials. This difference was notstatistically significant. However, in one of these trials, a fixed-dose trial, there was a significant dose-response relationship for cerebrovascular adverse reactions in patients treated with aripiprazole (seesection 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 aripiprazole. No specific studies have been conductedwith Abilify Maintena in patients with hyperglycaemia or diabetes mellitus. Risk factors that maypredispose patients to severe complications include obesity and family history of diabetes. Patientstreated with aripiprazole should be observed for signs and symptoms of hyperglycaemia (such aspolydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factorsfor diabetes mellitus should be monitored 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 patients due to use of antipsychotics known to causeweight gain, co-morbidities, poorly managed lifestyle and might lead to severe complications. Weightgain has been reported post-marketing among patients prescribed oral aripiprazole. When seen, it isusually in those with significant risk factors such as history of diabetes, thyroid disorder, or pituitaryadenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain(see section 4.8).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with the use of aripiprazole.

Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Gambling disorder and other impulse control disorders

Patients can experience increased urges, particularly for gambling, and the inability to control 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 medicinal product was discontinued. Impulse control disorders mayresult in harm to the patient and others if not recognised. A dose reduction or stopping of themedicinal product should be considered if a patient develops such urges (see section 4.8).

Falls

Aripiprazole may cause somnolence, postural hypotension, motor and sensory instability, which 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).

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

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

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

Given the primary central nervous system (CNS) effects of aripiprazole, caution should be used whenaripiprazole is administered in combination with alcohol or other CNS medicinal products withoverlapping adverse reactions 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 aripiprazole

Quinidine and other strong CYP2D6 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP2D6 (quinidine)increased aripiprazole AUC by 107 %, while Cmax was unchanged. The AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32 % and 47 %, respectively. Other strong inhibitorsof CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similardose reduction should, therefore, be applied (see section 4.2).

Ketoconazole and other strong CYP3A4 inhibitors

In a clinical trial of oral aripiprazole in healthy subjects, a strong inhibitor of CYP3A4 (ketoconazole)increased aripiprazole AUC and Cmax by 63 % and 37 %, respectively. The AUC and Cmax of dehydro-aripiprazole increased by 77 % and 43 %, respectively. In CYP2D6 poor metabolisers, concomitantuse of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazolecompared to that in CYP2D6 extensive metabolisers (see section 4.2). When considering concomitantadministration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefitsshould outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such asitraconazole and HIV protease inhibitors may be expected to have similar effects and similar dosereductions should, therefore, be applied (see section 4.2). Upon discontinuation of the CYP2D6 or

CYP3A4 inhibitor, the dose of aripiprazole should be increased to the dose prior to the initiation of theconcomitant therapy. When weak inhibitors of CYP3A4 (e.g., diltiazem) or CYP2D6 (e.g.,escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazoleconcentrations 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 oralaripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric meansof Cmax and AUC after carbamazepine co-administration were 69 % and 71 % lower, respectively, thanthose following treatment with oral aripiprazole alone. Concomitant administration of Abilify

Maintena 960 mg/720 mg and other inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin,phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similareffects. The concomitant use of CYP3A4 inducers with Abilify Maintena 960 mg/720 mg should beavoided because the blood levels of aripiprazole are decreased and may be below the effective levels.

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs andsymptoms for this condition can occur especially in cases of concomitant use with other serotonergicmedicinal products, such as Selective Serotonin Reuptake Inhibitor/Serotonin Noradrenaline Reuptake

Inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazoleconcentrations (see section 4.8).

Plasma exposure to aripiprazole after a single dose of Abilify Maintena is expected to remain for up to34 weeks (see section 5.2). This should be taken into account when initiating treatment in women ofchildbearing potential, considering a possible future pregnancy or breast-feeding. Abilify Maintenashould only be used in women planning to become pregnant if clearly necessary.

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.

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

New-born infants exposed to antipsychotics (including aripiprazole) during the third trimester 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, new-borninfants should be monitored carefully (see section 4.8).

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

Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fedinfant are likely if Abilify Maintena is administered to breast-feeding women. Since a single dose of

Abilify Maintena is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fedinfants may be at risk even from Abilify Maintena administration long before breast-feeding. Patientscurrently under treatment or who have been treated in the past 34 weeks with Abilify Maintena shouldnot breast feed.

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

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

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

Maintena 960 mg/720 mg clinical trials were similar to the ADRs observed in the Abilify Maintena400 mg/300 mg clinical trials.

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

The incidences of the ADRs associated with Abilify Maintena 400 mg/300 mg and 960 mg/720 mg aretabulated below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use.

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

The ADRs listed under the frequency “not known” were reported during post-marketing use.

System organ class Common Uncommon Not known

Blood and Neutropenia Leukopenialymphatic system Anaemiadisorders Thrombocytopenia

Neutrophil countdecreased

White blood cell countdecreased

Immune system Hypersensitivity Allergic reaction (e.g.disorders anaphylactic reaction,angioedema includingswollen tongue, tongueoedema, face oedema,pruritus, or urticaria)

Endocrine Blood prolactin Diabetic hyperosmolardisorders decreased coma

Hyperprolactinaemia Diabetic ketoacidosis

System organ class Common Uncommon Not known

Metabolism and Weight increaseda Hyperglycaemia Anorexianutrition disorders Diabetes mellitus Hypercholesterolaemia Decreased appetiteb

Weight decreased Hyperinsulinaemia Hyponatraemia

Hyperlipidaemia

Hypertriglyceridaemia

Appetite disorder

Psychiatric Agitation Suicidal ideation Completed suicidedisorders Anxiety Psychotic disorder Suicide attempt

Restlessness Hallucination Gambling disorder

Insomnia Delusion Impulse-control

Hypersexuality disorder

Panic reaction Binge eating

Depression Compulsive shopping

Affect lability Poriomania

Apathy Nervousness

Dysphoria Aggression

Sleep disorder

Bruxism

Libido decreased

Mood altered

Nervous system Extrapyramidal Dystonia Neuroleptic malignantdisorders disorder Tardive dyskinesia syndrome

Akathisia Parkinsonism Generalised tonic-

Tremor Movement disorder clonic seizure

Dyskinesia Psychomotor Serotonin syndrome

Sedation hyperactivity Speech disorder

Somnolence Restless legs syndrome

Dizziness Cogwheel rigidity

Headache Hypertonia

Bradykinesia

Drooling

Dysgeusia

Parosmia

Eye disorders Oculogyric crisis

Vision blurred

Eye pain

Diplopia

Photophobia

Cardiac disorders Ventricular Sudden deathextrasystoles Cardiac arrest

Bradycardia Torsades de pointes

Tachycardia Ventricular arrhythmia

Electrocardiogram T QT prolongedwave amplitudedecreased

Electrocardiogramabnormal

Electrocardiogram Twave inversion

Vascular disorders Hypertension Syncope

Orthostatic Venous embolismhypotension (including pulmonary

Blood pressure embolism and deepincreased vein thrombosis)

System organ class Common Uncommon Not known

Respiratory, Cough Oropharyngeal spasmthoracic and Hiccups Laryngospasmmediastinal Aspiration pneumoniadisorders

Gastrointestinal Dry mouth Gastrooesophageal Pancreatitisdisorders reflux disease Dysphagia

Dyspepsia

Nausea

Abdominal pain upper

Abdominal discomfort

Frequent bowelmovements

Salivary hypersecretion

Hepatobiliary Liver function test Hepatic failuredisorders abnormal Jaundice

Hepatic enzyme Hepatitisincreased Alkaline phosphatase

Alanine increasedaminotransferaseincreased

Gamma-glutamyltransferaseincreased

Blood bilirubinincreased

Aspartateaminotransferaseincreased

Skin and Alopecia Rashsubcutaneous tissue Acne Photosensitivitydisorders Rosacea reaction

Eczema Hyperhidrosis

Skin induration Drug reaction witheosinophilia andsystemic symptoms(DRESS)

Musculoskeletal Musculoskeletal Muscle rigidity Rhabdomyolysisand connective stiffness Muscle spasmstissue disorders Muscle twitching

Muscle tightness

Myalgia

Pain in extremity

Arthralgia

Back pain

Joint range of motiondecreased

Nuchal rigidity

Trismus

Renal and urinary Nephrolithiasis Urinary retentiondisorders Glycosuria Urinary incontinence

System organ class Common Uncommon Not known

Pregnancy, Drug withdrawalpuerperium and syndrome neonatalperinatal conditions

Reproductive Erectile dysfunction Galactorrhoea Priapismsystem and breast Gynaecomastiadisorders Breast tenderness

Vulvovaginal dryness

General disorders Injection site paina Pyrexia Temperature regulationand administration Injection site induration Asthenia disordersite conditions Fatigue Gait disturbance (e.g. hypothermia,

Chest discomfort pyrexia)

Injection site reaction Chest pain

Injection site erythema Peripheral oedema

Injection sitediscomfort

Injection site pruritus

Thirst

Sluggishness

Investigations Blood creatine Blood glucose Blood glucosephosphokinase increased fluctuationincreased Blood glucosedecreased

Glycosylatedhaemoglobin increased

Waist circumferenceincreased

Blood cholesteroldecreased

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

The percentage of patients in an open-label study reporting any injection site-related adverse reaction(all reported as injection site pain) was 18.2 % for patients treated with Abilify Maintena 960 mg and9.0 % for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of thereported injection site pain occurred with the first injection of Abilify Maintena 960 mg patients (21 of24 patients) or Abilify Maintena 400 mg (7 of 12 patients), resolved within 5 days, and were reportedwith decreasing frequency and severity upon subsequent injections. The overall mean site visualanalog scale scores (0 = no pain to 100 = unbearably painful) for patient reported rating of pain weresimilar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the Abilify

Maintena 960 mg group compared to 1.3 post-dose for the Abilify Maintena 400 mg group.

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

Extrapyramidal Symptoms (EPS)

In trials in stable patients with schizophrenia, Abilify Maintena 400 mg/300 mg was associated with ahigher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia wasthe most frequently observed symptom (8.2 %) and typically started around Day 10 after firstinjection, and lasted a median of 56 days. Subjects with akathisia typically received anti-cholinergicmedicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substancessuch as propranolol and benzodiazepines (clonazepam and diazepam) were administered to controlakathisia. Parkinsonism events followed in frequency of 6.9 % for Abilify Maintena 400 mg/300 mg,4.2 % for oral aripiprazole 10 mg to 30 mg tablets and 3.0 % for placebo, respectively.

Data from an open-label study of patients treated with Abilify Maintena 960 mg, showed minimalchange from baseline in EPS scores, as assessed by the Simpson-Angus Rating scale (SAS), the

Abnormal Involuntary Movement Scale (AIMS) and the Barnes Akathisia Rating Scale (BARS). Theincidence of reported EPS-related events for patients treated with Abilify Maintena 960 mg was18.2 % compared to the incidence of patients treated with Abilify Maintena 400 mg, which was13.4 %.

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.

Weight

During the double-blind, active-controlled phase of the 38-week long-term trial (see section 5.1), theincidence of weight gain of ≥ 7 % from baseline to last visit was 9.5 % for Abilify Maintena400 mg/300 mg and 11.7 % for the oral aripiprazole tablets 10 mg to 30 mg. The incidence of weightloss of ≥ 7 % from baseline to last visit was 10.2 % for Abilify Maintena 400 mg/300 mg and 4.5 %for oral aripiprazole tablets 10 mg to 30 mg. During the double-blind, placebo-controlled phase of the52-week long-term trial (see section 5.1), the incidence of weight gain of ≥ 7 % from baseline to lastvisit was 6.4 % for Abilify Maintena 400 mg/300 mg and 5.2 % for placebo. The incidence of weightloss of ≥ 7 % from baseline to last visit was 6.4 % for Abilify Maintena 400 mg/300 mg and 6.7 % forplacebo. During double-blind treatment, mean change in body weight from baseline to last visit was−0.2 kg for Abilify Maintena 400 mg/300 mg and −0.4 kg for placebo (p = 0.812).

In an open-label, multiple-dose, randomised study in adult patients with schizophrenia (and bipolar Idisorder) in which two months presentation Abilify Maintena 960 mg was evaluated against monthly

Abilify Maintena 400 mg, the overall incidence of weight gain ≥ 7 % from baseline was comparablebetween Abilify Maintena 960 mg (40.6 %) and Abilify Maintena 400 mg (42.9 %). The mean changein body weight from baseline to last visit was 3.6 kg for Abilify Maintena 960 mg and 3.0 kg for

Abilify Maintena 400 mg.

Prolactin

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

Gambling disorder and other impulse control disorders

Gambling disorder, hypersexuality, compulsive shopping and binge or compulsive eating can occur inpatients 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 witharipiprazole. While experience with aripiprazole overdose is limited, among the few cases of overdose(accidental or intentional) reported in clinical trials and post marketing experience with oralaripiprazole, the highest estimated ingestion was a total of 1260 mg with no fatalities.

The potential for dose dumping has been evaluated by simulation of aripiprazole plasmaconcentrations after an Abilify Maintena 960 mg dose is entirely absorbed in the systemic circulation.

Based on the results of the simulation, if dose dumping would occur, aripiprazole concentrations mayreach up to 13.5 times the concentrations that are achieved by a therapeutic dose of Abilify Maintena960 mg without dose dumping. Furthermore, aripiprazole concentrations following dose dumpingwould decline within 5 days to concentrations normally observed following the administration of

Abilify Maintena 960 mg.

Signs and symptoms

Care must be taken to avoid inadvertent injection of this medicinal product into a blood vessel.

Following any confirmed or suspected accidental overdose/inadvertent intravenous administrationwith aripiprazole, close observation of the patient is needed. The potentially medically significantsigns and symptoms observed in overdose included lethargy, increased blood pressure, somnolence,tachycardia, nausea, vomiting and diarrhoea.

There is no specific antidote to aripiprazole. Management of overdose should concentrate onsupportive care, including close medical supervision and monitoring. Ensure an adequate airway,oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomaticmeasures. Treatment should consist of general measures employed in the management of overdosewith any medicinal product. Consider the possibility of multiple medicinal product overdose.

Consider the long-acting nature of the medicinal product and the long elimination half-life ofaripiprazole when assessing treatment needs and recovery.

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

It has been proposed that aripiprazole’s efficacy in schizophrenia is mediated through a combinationof partial agonism at dopamine D2 and serotonin 5-HT1A receptors and antagonism at serotonin 5-HT2Areceptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergichyperactivity and agonist properties of dopaminergic hypoactivity. Aripiprazole exhibits high bindingaffinity in vitro for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors and has 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 noappreciable affinity for cholinergic muscarinic receptors. Interaction with receptors other thandopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole oral doses ranging from 0.5 mg to 30 mg administered once a day to healthy subjects 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.

Maintenance treatment of schizophrenia in adults

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

The similarity of aripiprazole plasma concentrations of Abilify Maintena 960 mg to Abilify Maintena400 mg is presented in table 1.

Table 2: Geometric mean ratio and confidence interval (CI) following the fourthadministration of Abilify Maintena 960 mg or the seventh and eighth Abilify

Maintena 400 mg in the open-label study

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

AUC a c0-56 1.006 0.851 - 1.190

C b56/C28 1.011d 0.893 - 1.145

C bmax 1.071c 0.903 - 1.270a AUC0-56 following the fourth administration of Abilify Maintena 960 mg or the sum of AUC0-28 followingthe seventh and eighth administration of Abilify Maintena 400 mg.b Aripiprazole plasma concentrations following the fourth administration of Abilify Maintena 960 mg (C56)or the eighth administration of Abilify Maintena 400 mg (C28).c Abilify Maintena 960 mg (n = 34), Abilify Maintena 400 mg (n = 32)d Abilify Maintena 960 mg (n = 96), Abilify Maintena 400 mg (n = 82).

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

Efficacy of Abilify Maintena 400 mg/300 mg

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

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

Conversion phase, oral stabilisation phase, and double-blind, active-controlled phase.

Six-hundred and sixty-two patients eligible for the 38-week double-blind, active-controlled phase wererandomly assigned in a 2:2:1 ratio to double-blind treatment to one of 3 treatment groups: 1) Abilify

Maintena 2) the stabilisation dose of oral aripiprazole 10 mg to 30 mg, or 3) aripiprazole long-actinginjectable 50 mg/25 mg. The aripiprazole long-acting injectable 50 mg/25 mg dose was included as alow dose aripiprazole to test assay sensitivity for the non-inferiority design.

The results of analysis of the primary efficacy endpoint, the estimated proportion of patientsexperiencing impending relapse by end of week 26 of the double-blind, active-controlled phase,showed that Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10 mg to30 mg.

The estimated relapse rate by end of week 26 was 7.12 % for Abilify Maintena 400 mg/300 mg, and7.76 % for oral aripiprazole tablets 10 mg to 30 mg, a difference of −0.64 %.

The 95 % CI (−5.26, 3.99) for the difference in the estimated proportion of patients experiencingimpending relapse by end of week 26 excluded the predefined non-inferiority margin, 11.5 %.

Therefore, Abilify Maintena 400 mg/300 mg is non-inferior to aripiprazole oral tablets 10 mg to30 mg.

The estimated proportion of patients experiencing impending relapse by end of week 26 for Abilify

Maintena 400 mg/300 mg was 7.12 %, which was statistically significantly lower than in aripiprazolelong-acting injectable 50 mg/25 mg (21.80 %; p = 0.0006). Thus, superiority of Abilify Maintena400 mg/300 mg over the aripiprazole long-acting injectable 50 mg/25 mg was established, and thevalidity of the trial design was confirmed.

The Kaplan-Meier curves of the time from randomisation to impending relapse during the 38-week,double-blind, active-controlled phase for Abilify Maintena 400 mg/300 mg, oral aripiprazole 10 mg to30 mg, and aripiprazole long-acting injectable 50 mg/25 mg are shown in figure 1.

Figure 1: Kaplan-Meier product limit plot for time to exacerbation of psychoticsymptoms/impending relapse

ARIP IMD 400/ 300 mg

ARIP 10-30 mg

ARIP IMD 50/25 mg1 .00.8.60.4

Log-Rank Test0.2

ARIP IMD 400/300 mg vs. ARIP 10-30 mg: p value 0.9920

ARIP IMD 400/300 mg vs. ARIP IMD 50/25 mg: p value < 0.00010.0

Numbers of Subjects at Risk

IMD 400/ 300 mg

ARIP 10-30 mg

IMD 50/25 mg

Days from Randomization

NOTE: ARIP IMD 400/300 mg = Abilify Maintena; ARIP 10 mg to 30 mg = oral aripiprazole; ARIP IMD50/25 mg = Aripiprazole long-acting injectable

Further, the non-inferiority of Abilify Maintena compared to oral aripiprazole 10 mg to 30 mg issupported by the results of the analysis of the positive and negative syndrome scale score (PANSS).

Table 3: PANSS total score - change from baseline to week 38-Last Observation Carried

Forward (LOCF): randomised efficacy samplea, b

Abilify Maintena Oral aripiprazole Aripiprazolelong-acting injectable400 mg/300 mg 10-30 mg/day 50 mg/25 mg(n = 263) (n = 266) (n = 131)

Mean baseline (SD) 57.9 (12.94) 56.6 (12.65) 56.1 (12.59)

Mean change (SD) −1.8 (10.49) 0.7 (11.60) 3.2 (14.45)

P-value NA 0.0272 0.0002a Negative change in score indicates improvement.b Only patients having both baseline and at least one post baseline were included. P-values were derived fromcomparison for change from baseline within analysis of covariance model with treatment as term andbaseline as covariate.

Proportion of subjects free of impending relapse

The second trial was a 52-week, randomised, withdrawal, double-blind, trial conducted in US adultpatients with a current diagnosis of schizophrenia. This trial consisted of a screening phase and4 treatment phases: Conversion, oral stabilisation, IM stabilisation, and double-blind placebo-controlled. Patients fulfilling the oral stabilisation requirement in the oral stabilisation phase wereassigned to receive, in a single-blind fashion, Abilify Maintena 400 mg/300 mg and began an IMphase for a minimum of 12 weeks and a maximum of 36 weeks. Patients eligible for the double-blind,placebo-controlled phase were randomly assigned in a 2:1 ratio to double-blind treatment with Abilify

Maintena 400 mg/300 mg or placebo, respectively.

The final efficacy analysis included 403 randomised patients and 80 exacerbations of psychoticsymptoms/impending relapse events. In the placebo group 39.6 % of the patients had progressed toimpending relapse, whilst in the Abilify Maintena 400 mg/300 mg group impending relapse occurredin 10 % of the patients; thus, patients in the placebo group had a 5.03-fold greater risk of experiencingimpending relapse.

Prolactin

In the double-blind, active-controlled phase of the 38-week trial, from baseline to last visit there was amean decrease in prolactin levels in Abilify Maintena 400 mg/300 mg (−0.33 ng/mL) compared with amean increase in oral aripiprazole tablets 10 mg to 30 mg (0.79 ng/mL; p < 0.01). The incidence of

Abilify Maintena 400 mg/300 mg patients with prolactin levels > 1 time the upper limit of normalrange (ULN) at any assessment was 5.4 % compared with 3.5 % of the patients on oral aripiprazoletablets 10 mg to 30 mg.

Male patients generally had a higher incidence than female patients in each treatment group.

In the double-blind placebo-controlled phase of the 52-week trial, from baseline to last visit there wasa mean decrease in prolactin levels in Abilify Mainten 400 mg/300 mg a (−0.38 ng/mL) comparedwith a mean increase in placebo (1.67 ng/mL). The incidences of Abilify Maintena 400 mg/300 mgpatients with prolactin levels > 1 time the ULN was 1.9 % compared to 7.1 % for placebo patients.

Acute treatment of schizophrenia in adults

The efficacy of Abilify Maintena 400 mg/300 mg in acutely relapsed adult patients with schizophreniawas established in a short-term (12-week), randomised, double-blind, placebo-controlled trial(n = 339). The primary endpoint (change in PANSS total score from baseline to week 10) showedsuperiority of Abilify Maintena 400 mg/300 mg (n = 167) over placebo (n = 172). Similar to the

PANSS total score, both the PANSS positive and negative subscale scores also showed animprovement (decrease) from baseline over time.

Table 4: PANSS total score - change from baseline to week 10: randomised efficacy sample a

Abilify Maintena Placebo400 mg/300 mg

Mean baseline (SD) 102.4 (11.4) 103.4 (11.1)n = 162 n = 167

LS mean change (SE) −26.8 (1.6) −11.7 (1.6)n = 99 n = 81

P-value < 0.0001

Treatment differenceb (95 % CI) −15.1 (−19.4, −10.8)a Data were analysed using a mixed model repeated measures (MMRM) approach. The analysis included onlysubjects who were randomly assigned to treatment, given at least one injection, had baseline and at least onepost-baseline efficacy assessment.

b Difference (Abilify Maintena minus placebo) in least squares mean change from baseline.

Abilify Maintena 400 mg/300 mg also showed statistically significant improvement in symptomsrepresented by Clinical Global Impressions Severity, CGI-S (CGI-S) score change from baseline toweek 10.

Personal and social functioning were evaluated using the Personal and Social Performance (PSP)scale. The PSP is a validated clinician-rated scale that measures personal and social functioning in fourdomains: socially useful activities (e.g., work and study), personal and social relationships, self-care,and disturbing and aggressive behaviours. There was a statistically significant treatment difference infavour of Abilify Maintena 400 mg/300 mg compared to placebo at week 10 (+7.1, p < 0.0001, 95 %

CI: 4.1, 10.1 using an ANCOVA model (LOCF)).

The safety profile was consistent with that known to Abilify Maintena 400 mg/300 mg. Nevertheless,there were differences from what has been observed with maintenance use in the treatment ofschizophrenia. In a short-term (12-week), randomised, double-blind, placebo-controlled trial with

Abilify Maintena 400 mg/300 mg treated subjects the symptoms which had at least twice the incidenceof placebo were increased weight and akathisia. The incidence of weight gain of ≥ 7 % from baselineto last visit (Week 12) was 21.5 % for Abilify Maintena 400 mg/300 mg compared with the placebogroup 8.5 %. Akathisia was the most frequently observed EPS symptom (Abilify Maintena400 mg/300 mg 11.4 % and placebo group 3.5 %).

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

Abilify Maintena in all subsets of the paediatric population in schizophrenia (see section 4.2 forinformation on paediatric use).

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

Abilify Maintena 960 mg/720 mg delivers aripiprazole over a 2-month period, compared to Abilify

Maintena 400 mg/300 mg. Abilify Maintena doses of 960 mg and 720 mg, administered in the glutealmuscle, result in aripiprazole total exposure ranges that are encompassed within the exposure rangecorresponding to 300 mg and 400 mg doses of Abilify Maintena (dosed once a month), respectively.

Additionally, mean observed maximum plasma concentrations (Cmax) and plasma concentrations ofaripiprazole at the end of the dosing interval were similar for Abilify Maintena 960 mg/720 mg ascompared to corresponding doses of Abilify Maintena 400 mg/300 mg (see section 5.1).

The mean aripiprazole plasma concentration compared to the time profiles following the fourthadministration of Abilify Maintena 960 mg (n = 102) or the seventh and eighth administration of

Abilify Maintena 400 mg (n = 93) in the gluteal muscle of patients with schizophrenia (and bipolar Idisorder) are shown in figure 2.

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

Absorption/Distribution

Aripiprazole absorption into the systemic circulation is slow and prolonged following gluteal injectiondue to low solubility of aripiprazole particles. The release profile of aripiprazole from Abilify

Maintena 960 mg/720 mg results in sustained plasma concentrations over 2 months following glutealinjection(s). The release of the active substance after a single 780 mg dose of 2-monthly aripiprazoleready-to-use long-acting-injectable starts Day 1 and lasts for as long as 34 weeks.

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. Following administration of multiple doses of Abilify Maintena 960 mg/720 mg, dehydro-aripiprazole, the active metabolite, represents approximately 30 % of aripiprazole AUC in plasma.

Following a single oral dose of [14C]-labelled aripiprazole, approximately 25 % and 55 % of theadministered radioactivity was recovered in the urine faeces, respectively. Less than 1 % of unchangedaripiprazole was excreted in the urine and approximately 18 % was recovered unchanged in the faeces.

No specific studies have been performed with Abilify Maintena in special patient groups.

CYP2D6 poor metabolisers

Based on population pharmacokinetic analysis, the plasma concentrations of aripiprazole is around 2-fold higher in poor metabolisers of CYP2D6 compared with normal CYP2D6 metabolisers. (seesection 4.2).

After oral administration of aripiprazole, there are no differences in the pharmacokinetics ofaripiprazole between healthy elderly and younger adult subjects. Similarly, there was no detectableeffect of age in a population pharmacokinetic analysis of aripiprazole in schizophrenia patients.

After oral administration of aripiprazole, there are no differences in the pharmacokinetics ofaripiprazole between healthy male and female subjects. Similarly, there was no clinically relevanteffect of gender in a population pharmacokinetic analysis of aripiprazole in clinical trials in patientswith schizophrenia.

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.

In a single-dose study with oral administration of aripiprazole, the pharmacokinetic characteristics ofaripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal diseasecompared to that in young healthy subjects.

A single-dose study with oral administration of aripiprazole to subjects with varying degrees of livercirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment onthe pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patientswith Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

The toxicological profile for aripiprazole administered to experimental animals by intramuscularinjection is generally similar to that seen following oral administration at comparable plasma levels.

With intramuscular injection, however an inflammatory response was seen at the injection site, andconsisted of granulomatous inflammation, foci (deposited active substance), cellular infiltrates,oedema (swelling) and, in monkeys, fibrosis. These effects gradually resolved with discontinuation ofdosing.

Non-clinical safety data for orally administered aripiprazole reveal no special hazard for humans basedon conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenicpotential, toxicity to reproduction and development.

Oral aripiprazole

For oral aripiprazole, toxicologically significant effects were observed only at doses or exposures thatwere sufficiently in excess of the maximum human dose or exposure, indicating that these effects werelimited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity inrats after 104 weeks of oral administration at approximately 3- to 10-times the mean steady-state AUCat the maximum recommended human dose and increased adrenocortical carcinomas and combinedadrenocortical adenomas/carcinomas in female rats at approximately 10-times the mean steady-state

AUC at the maximum recommended human dose. The highest non-tumorigenic exposure in femalerats was approximately 7-times the human exposure at the recommended dose.

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 or approximately 16- to 81-times the maximum recommended human dose based onmg/m2.

However, the concentrations of the sulphate conjugates of hydroxy-aripiprazole in human bile at thehighest dose proposed, 30 mg per day, were no more than 6 % of the bile concentrations found in themonkeys in the 39-week study and are well below (6 %) their limits of in vitro solubility.

In repeated dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparableto that observed in adult animals, and there was no evidence of neurotoxicity or adverse events ondevelopment.

Based on results of a full range of standard genotoxicity tests, aripiprazole was considered non-genotoxic in humans. Aripiprazole did not impair fertility in reproductive toxicity studies.

Developmental toxicity, including dose-dependent delayed foetal ossification and possible teratogeniceffects, were observed in rats at doses resulting in sub-therapeutic exposures (based on AUC) and inrabbits at doses resulting in exposures approximately 3- and 11-times the mean steady-state AUC atthe maximum recommended clinical dose. Maternal toxicity occurred at doses similar to thoseeliciting developmental toxicity.

Carmellose sodium

Macrogol

Povidone (E1201)

Sodium chloride

Sodium dihydrogen phosphate monohydrate (E339)

Sodium hydroxide (for pH adjustment) (E524)

Water for injections

This medicinal product must not be mixed with other medicinal products.

3 years

Do not freeze.

Pre-filled syringe (cyclic-olefin-copolymer) with bromobutyl plunger stopper and bromobutyl tip-capand polypropylene plunger rod and finger grip.

Abilify Maintena 960 mg prolonged-release suspension for injection in pre-filled syringe

Each 960 mg pack contains one pre-filled syringe, and two sterile safety needles: one 38 mm(1.5 inch) 22 gauge and one 51 mm (2 inch) 21 gauge.

Abilify Maintena 720 mg prolonged-release suspension for injection in pre-filled syringe

Each 720 mg pack contains one pre-filled syringe, and two sterile safety needles: one 38 mm(1.5 inch) 22 gauge and one 51 mm (2 inch) 21 gauge.

Tap the syringe on your hand at least 10 times. After tapping, shake the syringe vigorously for at least10 seconds.

Gluteal muscle administration

The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge sterile safetyneedle; for obese patients (Body mass index > 28 kg/m2), a 51 mm (2 inch), 21 gauge sterile safetyneedle should be used.

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

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

Otsuka Pharmaceutical Netherlands B.V.

Herikerbergweg 2921101 CT, Amsterdam

Netherlands

Abilify Maintena 720 mg prolonged-release suspension for injection in pre-filled syringe

EU/1/13/882/009

Abilify Maintena 960 mg prolonged-release suspension for injection in pre-filled syringe

EU/1/13/882/010

Date of first authorisation: 25 March 2024

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

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