Source: European Medicines Agency (EU) Revision Year: 2025 Publisher: Otsuka Pharmaceutical Netherlands B.V., Herikerbergweg 292, 1101 CT, Amsterdam, Netherlands
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.
Abilify Maintena 400 mg/300 mg should not be used to manage acutely agitated or severely psychotic states when immediate symptom control is warranted.
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.
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).
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).
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.
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).
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).
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).
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, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with aripiprazole. 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 reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8).
Weight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to cause weight gain, co-morbidities, poorly managed life-style 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).
Oesophageal dysmotility and aspiration have been associated with the use of aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.
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).
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).
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 obtained from studies with oral aripiprazole. The 2-month dosing interval and long half-life of aripiprazole after dosing 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 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.
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).
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.
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 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 similar effects. The concomitant use of CYP3A4 inducers with Abilify Maintena 960 mg/720 mg should be avoided because the blood levels of aripiprazole are decreased and may be below the effective levels.
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).
Plasma exposure to aripiprazole after a single dose of Abilify Maintena 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. Abilify Maintena should 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. 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 9 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 Abilify Maintena. 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 Abilify Maintena before and during pregnancy may lead to adverse reactions in the 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-fed infant 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-fed infants may be at risk even from Abilify Maintena administration long before breast-feeding. Patients currently under treatment or who have been treated in the past 34 weeks with Abilify Maintena should not 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 potential nervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (see section 4.8).
The safety profile of Abilify Maintena 960 mg and Abilify Maintena 720 mg for the treatment of schizophrenia in adults is based on adequate and well-controlled studies of Abilify Maintena 400 mg and 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 Maintena 400 mg/300 mg clinical trials.
The most frequently observed ADRs reported in ≥5% of patients in two double-blind, long-term trial of 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 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.
The incidences of the ADRs associated with Abilify Maintena 400 mg/300 mg and 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 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 and 9.0% for patients treated with Abilify Maintena 400 mg. In both treatment groups, the majority of the reported injection site pain occurred with the first injection of Abilify Maintena 960 mg patients (21 of 24 patients) or Abilify Maintena 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 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 and typically started around day 16 after first injection, and lasted a median of 18 days.
In trials in stable patients with schizophrenia, Abilify Maintena 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 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 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 Abilify Maintena 960 mg was 18.2% compared to the incidence of patients treated with Abilify Maintena 400 mg, which was 13.4%.
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.
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 Abilify Maintena 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 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 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 Abilify Maintena 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 Abilify Maintena 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 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 I disorder) 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 comparable between Abilify Maintena 960 mg (40.6%) and Abilify Maintena 400 mg (42.9%). The mean change in 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.
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, hypersexuality, compulsive shopping and binge or compulsive eating can occur in patients treated with aripiprazole (see section 4.4).
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 the national reporting system listed in Appendix V.
This medicinal product must not be mixed with other medicinal products.
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