4.1. Therapeutic indications

Aripiprazole Otsuka is indicated for maintenance treatment of schizophrenia in adult patients stabilised with aripiprazole.

4.2. Posology and method of administration

Posology

For patients who have never taken aripiprazole, tolerability with aripiprazole must be established prior to initiating treatment with Aripiprazole Otsuka.

Titration of the dose for Aripiprazole Otsuka is not required.

Starting regimen

The recommended starting dosing regimen when transitioning from Aripiprazole Otsuka 400 mg once monthly is Aripiprazole Otsuka 960 mg no sooner than 26 days after previous injection of Aripiprazole Otsuka 400 mg. Aripiprazole Otsuka 960 mg should then be dosed once every 2 months (every 56 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 Aripiprazole Otsuka 960 mg should be administered and treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutive days should be continued to maintain therapeutic aripiprazole concentrations during initiation of therapy.

• Two injection start: On the day of initiation following oral therapy, one injection of Aripiprazole Otsuka 960 mg and one injection of Aripiprazole Otsuka 400 mg should be administered at two different injection sites (see method of administration), along with one 20 mg dose of oral aripiprazole.

Dosing interval and dosing adjustments

After the injection start, the recommended maintenance dose is one injection of Aripiprazole Otsuka 960 mg every second month. Inject Aripiprazole Otsuka 960 mg once every two months as a single injection 56 days after the previous injection. Patients may be given the injection up to 2 weeks before or 2 weeks after the scheduled 2- month dose.

If there are adverse reactions with the Aripiprazole Otsuka 960 mg dose, reduction to Aripiprazole Otsuka 720 mg once every two months should be considered.

Missed doses

If more than 8 weeks and less than 14 weeks have elapsed since the last injection, the next dose of Aripiprazole Otsuka 960 mg/720 mg should be administered as soon as possible. The once every two months schedule should then be resumed. If more than 14 weeks have elapsed since the last injection, the next dose of Aripiprazole Otsuka 960 mg/720 mg should be administered with concomitant oral aripiprazole for 14 days or with 2 separate injections (one each of Aripiprazole Otsuka 960 mg and Aripiprazole Otsuka 400 mg or one each Aripiprazole Otsuka 720 mg and Aripiprazole Otsuka 300 mg) administered together with one 20 mg oral aripiprazole dose. The once every two months schedule should then be resumed.

Special populations

Elderly

The safety and efficacy of Aripiprazole Otsuka 960 mg/720 mg in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4). No recommendations on dosing can be made.

Renal impairment

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

Hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. 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 Aripiprazole Otsuka 300 mg once monthly: The starting dose should be one injection of Aripiprazole Otsuka 720 mg g, no sooner than 26 days after previous injection of Aripiprazole Otsuka 300 mg.

• One injection start (following transition from oral therapy): The starting dose should be one injection of Aripiprazole Otsuka 720 mg and treatment should be continued with the prescribed dose of oral aripiprazole per day for 14 consecutive days.

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

Thereafter, a maintenance dose of Aripiprazole Otsuka 720 mg should be administered once every two months as a single injection.

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

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

Concomitant use of CYP3A4 inducers with Aripiprazole Otsuka 960 mg/720 mg for more than 14 days should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Aripiprazole Otsuka 960 mg/720 mg should not be used in patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP2D6 and/or CYP3A4 inhibitor.

Table 1: Maintenance dose adjustments of Aripiprazole Otsuka in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

Adjusted 2-monthly dose

Patients taking Aripiprazole Otsuka 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.

Paediatric population

The safety and efficacy of Aripiprazole Otsuka 960 mg/720 mg in children and adolescents aged 0 to 17 years have not been established. No data are available.

Method of administration

Aripiprazole Otsuka 960 mg and 720 mg is only intended for gluteal intramuscular injection and must not be administered intravenously or subcutaneously. It must only be administered by a healthcare professional.

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

If initiating with any of the options that require two injections (one Aripiprazole Otsuka 960 mg or 720 mg and one Aripiprazole Otsuka 400 mg or 300 mg), inject into two different sites. DO NOT inject both injections concomitantly into the same gluteal muscle.

Full instructions for use and handling of Aripiprazole Otsuka 960 mg/720 mg are provided in the package leaflet (information intended for healthcare professionals).

4.3. Contraindications

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

4.4. Special warnings and precautions for use

During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

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

Aripiprazole Otsuka should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses, and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic treatment.

Cardiovascular disorders

Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicinal products) or hypertension, including accelerated or malignant. Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with aripiprazole and preventive measures undertaken (see section 4.8).

QT prolongation

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

Tardive dyskinesia

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on aripiprazole, dose reduction or discontinuation should be considered (see section 4.8). These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

Neuroleptic malignant syndrome (NMS)

NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rare cases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia).

Additional signs may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure. However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS or presents with unexplained high fever without additional clinical manifestations of NMS, all antipsychotics, including aripiprazole, must be discontinued (see section 4.8).

Seizure

In clinical trials, uncommon cases of seizure were reported during treatment with aripiprazole. Therefore, aripiprazole should be used with caution in patients who have a history of seizure disorder or have conditions associated with seizures (see section 4.8).

Elderly patients with dementia-related psychosis

Increased mortality

In three placebo-controlled trials 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 with aripiprazole were at an increased risk of death compared to placebo. The rate of death in oral aripiprazole- treated patients was 3.5 % compared to 1.7 % in placebo. Although the causes of deaths were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature (see section 4.8).

Cerebrovascular adverse reactions

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

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

Hyperglycaemia and diabetes mellitus

Hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with aripiprazole. No specific studies have been conducted with Aripiprazole Otsuka in patients with hyperglycaemia or diabetes mellitus. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. Patients treated with aripiprazole should be observed for signs and symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity

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

Weight gain

Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed lifestyle and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed oral aripiprazole. When seen, it is usually in those with significant risk factors such as history of diabetes, thyroid disorder, or pituitary adenoma. In clinical trials aripiprazole has not been shown to induce clinically relevant weight gain (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 these urges while taking aripiprazole. Other urges reported include increased sexual urges, compulsive shopping, binge or compulsive eating, and other impulsive and compulsive behaviours. It is important for prescribers to ask patients or their caregivers specifically about the development of new or increased gambling urges, sexual urges, compulsive shopping, binge or compulsive eating, or other urges while being treated with aripiprazole. It should be noted that impulse-control symptoms can be associated with the underlying disorder; however, in some cases, urges were reported to have stopped when the dose was reduced or the medicinal product was discontinued. Impulse control disorders may result in harm to the patient and others if not recognised. A dose reduction or stopping of the medicinal 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 may lead to falls. Caution should be taken when treating patients at higher risk, and a lower starting dose should be considered (e.g., elderly or debilitated patients; see section 4.2).

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Aripiprazole Otsuka. The information below is obtained from studies with oral aripiprazole. The 2- month dosing interval and long half-life of aripiprazole after dosing with Aripiprazole Otsuka 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 of certain antihypertensive medicinal products.

Given the primary central nervous system (CNS) effects of aripiprazole, caution should be used when aripiprazole is administered in combination with alcohol or other CNS medicinal products with overlapping adverse reactions such as sedation (see section 4.8).

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

Potential for other medicinal products to affect aripiprazole

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 inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose 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, concomitant use of strong inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolisers (see section 4.2). When considering concomitant administration of ketoconazole or other strong CYP3A4 inhibitors with aripiprazole, potential benefits should outweigh the potential risks to the patient. Other strong inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors may be expected to have similar effects and similar dose reductions should, therefore, be applied (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 the concomitant therapy. When weak inhibitors of CYP3A4 (e.g., diltiazem) or CYP2D6 (e.g., escitalopram) are used concomitantly with aripiprazole, modest increases in plasma aripiprazole concentrations may be expected.

Carbamazepine and other CYP3A4 inducers

Following concomitant administration of carbamazepine, a strong inducer of CYP3A4, and oral aripiprazole to patients with schizophrenia or schizoaffective disorder, the geometric means of Cmax and AUC for aripiprazole were 68 % and 73 % lower, respectively, compared to when oral aripiprazole (30 mg) was administered alone. Similarly, for dehydro- aripiprazole the geometric means of Cmax and AUC after carbamazepine co- administration were 69 % and 71 % lower, respectively, than those following treatment with oral aripiprazole alone. Concomitant administration of Aripiprazole Otsuka 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 similar effects. The concomitant use of CYP3A4 inducers with Aripiprazole Otsuka 960 mg/720 mg should be avoided 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 and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as Selective Serotonin Reuptake Inhibitor/Serotonin Noradrenaline Reuptake Inhibitor (SSRI/SNRI), or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Plasma exposure to aripiprazole after a single dose of Aripiprazole Otsuka is expected to remain for up to 34 weeks (see section 5.2). This should be taken into account when initiating treatment in women of childbearing potential, considering a possible future pregnancy or breast-feeding. Aripiprazole Otsuka should only be used in women planning to become pregnant if clearly necessary.

Pregnancy

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients must be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole.

Prescribers need to be aware of the long-acting properties of Aripiprazole Otsuka. Aripiprazole has been detected 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 of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, new-born infants should be monitored carefully (see section 4.8).

Maternal exposure to Aripiprazole Otsuka before and during pregnancy may lead to adverse reactions in the newborn child. Aripiprazole Otsuka should not be used during pregnancy unless clearly necessary.

Breast-feeding

Aripiprazole/metabolites are excreted in the breast milk to such an extent that effects on the breast-fed infant are likely if Aripiprazole Otsuka is administered to breast-feeding women. Since a single dose of Aripiprazole Otsuka is expected to remain for up to 34 weeks in plasma (see section 5.2), breast-fed infants may be at risk even from Aripiprazole Otsuka administration long before breast- feeding.

Patients currently under treatment or who have been treated in the past 34 weeks with Aripiprazole Otsuka should not breast feed.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The safety profile of Aripiprazole Otsuka 960 mg and Aripiprazole Otsuka 720 mg for the treatment of schizophrenia in adults is based on adequate and well- controlled studies of Aripiprazole Otsuka 400 mg and Aripiprazole Otsuka 300 mg. In general, the observed adverse drug reactions (ADRs) in Aripiprazole Otsuka 960 mg/720 mg clinical trials were similar to the ADRs observed in the Aripiprazole Otsuka 400 mg/300 mg clinical trials.

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

Tabulated list of adverse reactions

The incidences of the ADRs associated with Aripiprazole Otsuka 400 mg/300 mg and Aripiprazole Otsuka 960 mg/720 mg are tabulated 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 (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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

System organ class

Common

Uncommon

Not known

Blood and lymphatic system disorders

Neutropenia

Anaemia

Thrombocytopenia

Neutrophil count decreased

White blood cell count decreased

Leukopenia

Immune system disorders

Hypersensitivity

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

Endocrine disorders

Blood prolactin decreased

Hyperprolactinaemia

Diabetic hyperosmolar coma

Diabetic ketoacidosis

Metabolism and nutrition disorders

Weight increaseda

Diabetes mellitus

Weight decreased

Hyperglycaemia

Hypercholesterolaemia

Hyperinsulinaemia

Hyperlipidaemia

Hypertriglyceridaemia

Appetite disorder

Anorexia

Decreased appetiteb

Hyponatraemia

Psychiatric disorders

Agitation

Anxiety

Restlessness

Insomnia

Suicidal ideation

Psychotic disorder

Hallucination

Delusion

Hypersexuality

Panic reaction

Depression

Affect lability

Apathy

Dysphoria

Sleep disorder

Bruxism

Libido decreased

Mood altered

Completed suicide

Suicide attempt

Gambling disorder

Impulse-control disorder

Binge eating

Compulsive shopping

Poriomania

Nervousness

Aggression

Nervous system disorders

Extrapyramidal disorder

Akathisia

Tremor

Dyskinesia

Sedation

Somnolence

Dizziness

Headache

Dystonia

Tardive dyskinesia

Parkinsonism

Movement disorder

Psychomotor hyperactivity

Restless legs syndrome

Cogwheel rigidity

Hypertonia

Bradykinesia

Drooling

Dysgeusia

Parosmia

Neuroleptic malignant syndrome

Generalised tonic- clonic seizure

Serotonin syndrome

Speech disorder

Eye disorders

Oculogyric crisis

Vision blurred

Eye pain

Diplopia

Photophobia

Cardiac disorders

Ventricular extrasystoles

Bradycardia

Tachycardia

Electrocardiogram T wave amplitude decreased

Electrocardiogram abnormal

Electrocardiogram T wave inversion

Sudden death

Cardiac arrest

Torsades de pointes

Ventricular arrhythmia QT prolonged

Vascular disorders

Hypertension

Orthostatic hypotension

Blood pressure increased

Syncope

Venous embolism (including pulmonary embolism and deep vein thrombosis)

Respiratory, thoracic and mediastinal disorders

Cough

Hiccups

Oropharyngeal spasm

Laryngospasm

Aspiration pneumonia

Gastrointestinal disorders

Dry mouth

Gastrooesophageal reflux disease

Dyspepsia

Vomiting

Diarrhoea

Nausea

Abdominal pain upper

Abdominal discomfort

Constipation

Frequent bowel movements

Salivary hypersecretion

Pancreatitis

Dysphagia

Hepatobiliary disorders

Liver function test abnormal

Hepatic enzyme increased

Alanine aminotransferase increased

Gamma- glutamyltransferase increased

Blood bilirubin increased

Aspartate aminotransferase increased

Hepatic failure

Jaundice

Hepatitis

Alkaline phosphatase increased

Skin and subcutaneous tissue disorders

Alopecia

Acne

Rosacea

Eczema

Skin induration

Rash

Photosensitivity reaction

Hyperhidrosis

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Musculoskeletal and connective tissue disorders

Musculoskeletal stiffness

Muscle rigidity

Muscle spasms

Muscle twitching

Muscle tightness

Myalgia

Pain in extremity

Arthralgia

Back pain

Joint range of motion decreased

Nuchal rigidity

Trismus

Rhabdomyolysis

Renal and urinary disorders

Nephrolithiasis

Glycosuria

Urinary retention

Urinary incontinence

Pregnancy, puerperium and perinatal conditions

Drug withdrawal syndrome neonatal

Reproductive system and breast disorders

Erectile dysfunction

Galactorrhoea

Gynaecomastia

Breast tenderness

Vulvovaginal dryness

Priapism

General disorders and administration site conditions

Injection site paina

Injection site induration

Fatigue

Pyrexia

Asthenia

Gait disturbance

Chest discomfort

Injection site reaction

Injection site erythema

Injection site swelling

Injection site discomfort

Injection site pruritus

Thirst

Sluggishness

Temperature regulation disorder (e.g. hypothermia, pyrexia)

Chest pain

Peripheral oedema

Investigations

Blood creatine phosphokinase increased

Blood glucose increased

Blood glucose decreased

Glycosylated haemoglobin increased

Waist circumference increased

Blood cholesterol decreased

Blood triglycerides decreased

Blood glucose fluctuation

a: Reported as very common in Aripiprazole Otsuka 960 mg/720 mg clinical trials.

b: Reported only in Aripiprazole Otsuka 960 mg/720 mg clinical trial program

Description of selected adverse reactions

Injection site reactions

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 Aripiprazole Otsuka 960 mg and 9.0 % for patients treated with Aripiprazole Otsuka 400 mg. In both treatment groups, the majority of the reported injection site pain occurred with the first injection of Aripiprazole Otsuka 960 mg patients (21 of 24 patients) or Aripiprazole Otsuka 400 mg (7 of 12 patients), resolved within 5 days, and were reported with decreasing frequency and severity upon subsequent injections. The overall mean site visual analog scale scores (0 = no pain to 100 = unbearably painful) for patient reported rating of pain were similar in both treatment groups at the last injection: 0.8 pre-dose and 1.4 post-dose for the Aripiprazole Otsuka 960 mg group compared to 1.3 post-dose for the Aripiprazole Otsuka 400 mg group.

Neutropenia

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

Extrapyramidal Symptoms (EPS)

In trials in stable patients with schizophrenia, Aripiprazole Otsuka 400 mg/300 mg was associated with a higher frequency of EPS symptoms (18.4 %) than oral aripiprazole treatment (11.7 %). Akathisia was the most frequently observed symptom (8.2 %) and typically started around Day 10 after first injection, and lasted a median of 56 days.

Subjects with akathisia typically received anti-cholinergic medicines as treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such as propranolol and benzodiazepines (clonazepam and diazepam) were administered to control akathisia. Parkinsonism events followed in frequency of 6.9 % for Aripiprazole Otsuka 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 Aripiprazole Otsuka 960 mg, showed minimal change 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). The incidence of reported EPS-related events for patients treated with Aripiprazole Otsuka 960 mg was 18.2 % compared to the incidence of patients treated with Aripiprazole Otsuka 400 mg, which was 13.4 %.

Dystonia

Class effect: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include spasm of the neck muscles, sometimes progressing to tightness of the throat, swallowing difficulty, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity with high potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.

Weight

During the double-blind, active-controlled phase of the 38-week long-term trial (see section 5.1), the incidence of weight gain of ≥ 7 % from baseline to last visit was 9.5 % for Aripiprazole Otsuka 400 mg/300 mg and 11.7 % for the oral aripiprazole tablets 10 mg to 30 mg. The incidence of weight loss of ≥ 7 % from baseline to last visit was 10.2 % for Aripiprazole Otsuka 400 mg/300 mg and 4.5 % for oral aripiprazole tablets 10 mg to 30 mg. During the double-blind, placebo- controlled phase of the 52-week long-term trial (see section 5.1), the incidence of weight gain of ≥ 7 % from baseline to last visit was 6.4 % for Aripiprazole Otsuka 400 mg/300 mg and 5.2 % for placebo. The incidence of weight loss of ≥ 7 % from baseline to last visit was 6.4 % for Aripiprazole Otsuka 400 mg/300 mg and 6.7 % for placebo. During double-blind treatment, mean change in body weight from baseline to last visit was −0.2 kg for Aripiprazole Otsuka 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 I disorder) in which two months presentation

Aripiprazole Otsuka 960 mg was evaluated against monthly Aripiprazole Otsuka 400 mg, the overall incidence of weight gain ≥ 7 % from baseline was comparable between Aripiprazole Otsuka 960 mg (40.6 %) and Aripiprazole Otsuka 400 mg (42.9 %). The mean change in body weight from baseline to last visit was 3.6 kg for Aripiprazole Otsuka 960 mg and 3.0 kg for Aripiprazole Otsuka 400 mg.

Prolactin

In clinical trials for the approved indications and in post-marketing data both increase and decrease in serum 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 in patients treated with aripiprazole (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No cases of overdose associated with adverse reactions were reported in clinical studies with aripiprazole. 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 oral aripiprazole, 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 plasma concentrations after an Aripiprazole Otsuka 960 mg dose is entirely absorbed in the systemic circulation. Based on the results of the simulation, if dose dumping would occur, aripiprazole concentrations may reach up to 13.5 times the concentrations that are achieved by a therapeutic dose of Aripiprazole Otsuka 960 mg without dose dumping. Furthermore, aripiprazole concentrations following dose dumping would decline within 5 days to concentrations normally observed following the administration of Aripiprazole Otsuka 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 administration with aripiprazole, close observation of the patient is needed. The potentially medically significant signs and symptoms observed in overdose included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea.

Management of overdose

There is no specific antidote to aripiprazole. Management of overdose should concentrate on supportive care, including close medical supervision and monitoring. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Use supportive and symptomatic measures.

Treatment should consist of general measures employed in the management of overdose with 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 of aripiprazole when assessing treatment needs and recovery.