Leaflet ABILIFY MAINTENA 400mg powder and solvent for prolonged-release suspension for injection
Product code: W65091001 Quantity: 1
Indicated for: schizophrenia; bipolar disorder
Route of administration: injectable
Substance: aripiprazole (antipsychotic)
ATC: N05AX12 (Nervous system | Antipsychotics | Other antipsychotics)
This medicine may affect your ability to drive or use machines.
This medicine may cause dizziness or vertigo.
This medicine may increase blood sugar.
This medicine may increase the risk of heart rhythm disturbances.
This medicine may increase the risk of seizures.
This medicine may cause drowsiness or reduced alertness.
Aripiprazole is an atypical antipsychotic used in the treatment of schizophrenia, bipolar disorder, and, in some cases, treatment-resistant major depression. It acts as a partial agonist of dopamine D2 and serotonin 5-HT1A receptors, as well as an antagonist of 5-HT2A receptors, helping to balance neurotransmitters in the brain.
Aripiprazole is available in tablet form, oral solutions, and long-acting injectable formulations. It is commonly used to reduce psychotic symptoms such as hallucinations and delusions and to stabilize mood in affective disorders.
Common side effects include nausea, dizziness, insomnia, and weight gain. In rare cases, severe adverse reactions such as neuroleptic malignant syndrome or tardive dyskinesia may occur.
Aripiprazole is an essential medication for managing psychiatric disorders, helping to improve patients' quality of life by reducing symptoms and preventing relapses.
General data about ABILIFY MAINTENA 400mg
- Substance: aripiprazole
- Date of latest medicines list: 01-06-2026
- Product code: W65091001
- Concentration: 400mg
- Pharmaceutical form: powder and solvent for prolonged-release suspension for injection
- Quantity: 1
- Product type: Original
- Price: 1001.87 RON
- Prescription status: P-RF - Medicines dispensed with a medical prescription that is retained by the pharmacy and cannot be renewed.
Pharmaceutical forms available for aripiprazole
Concentrations available for aripiprazole
- 10mg
- 15mg
- 1mg/ml
- 20mg
- 300mg
- 30mg
- 400mg
- 5mg
- 7.5mg/ml
- 960mg
Leaflet ABILIFY MAINTENA 400mg
Contents of the package leaflet for the medicine ABILIFY MAINTENA 400mg powder and solvent for prolonged-release suspension for injection
1. NAME OF THE MEDICINAL PRODUCT
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection
Each vial contains 300 mg aripiprazole.
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection
Each vial contains 400 mg aripiprazole.
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Each pre-filled syringe contains 300 mg aripiprazole.
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Each pre-filled syringe contains 400 mg aripiprazole.
After reconstitution each mL of suspension contains 200 mg aripiprazole.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Powder and solvent for prolonged-release suspension for injection
Powder: white to off-white
Solvent: clear solution
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilisedwith oral aripiprazole.
4.2 Posology and method of administration
For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior toinitiating treatment with Abilify Maintena.
Titration of the dose for Abilify Maintena is not required.
The starting dose can be administered by following one of two regimens:
* One injection start: On the day of initiation, one injection of Abilify Maintena 400 mg should beadministered and treatment with 10 mg to 20 mg oral aripiprazole per day for 14 consecutivedays should be continued to maintain therapeutic aripiprazole concentrations during initiation oftherapy.
* Two injection start: On the day of initiation, two separate injections of Abilify Maintena 400 mgshould be administered at two different injection sites (see method of administration), alongwith one 20 mg dose of oral aripiprazole.
After the injection start, the recommended maintenance dose of Abilify Maintena is 400 mg. Abilify
Maintena 400 mg should be administered once monthly as a single injection (no sooner than 26 daysafter the previous injection). If there are adverse reactions with the 400 mg dose, reduction of the doseto 300 mg once monthly should be considered.
Missed dosesMissed doses
Timing of missed dose Action
If 2nd or 3rd dose is missed and timesince last injection is:> 4 weeks and < 5 weeks The injection should be administered as soon as possibleand then the monthly injection schedule should beresumed.
> 5 weeks Concomitant oral aripiprazole should be restarted for14 days with next administered injection or two separateinjections given at one time, along with a single dose of20 mg oral aripiprazole. Monthly injection scheduleshould then resume.
If 4th or subsequent doses are missed(i.e., after attainment of steady state)and time since last injection is:> 4 weeks and < 6 weeks The injection should be administered as soon as possibleand then the monthly injection schedule should beresumed.
> 6 weeks Concomitant oral aripiprazole should be restarted for14 days with next administered injection or two separateinjections given at one time, along with a single dose of20 mg oral aripiprazole. Monthly injection scheduleshould then resume.
Special populationsElderly
The safety and efficacy of Abilify Maintena 400 mg/300 mg in the treatment of schizophrenia inpatients 65 years of age or older has not been established (see section 4.4).
Renal impairmentNo dose adjustment is required for patients with renal impairment (see section 5.2).
Hepatic impairmentNo 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:
* One injection start: The starting dose should be Abilify Maintena 300 mg and treatment shouldbe continued with the prescribed dose of oral aripiprazole per day for 14 consecutive days. Themaintenance dose should be Abilify Maintena 300 mg once monthly.
* Two injection start: The starting dose should be 2 separate injections of Abilify Maintena300 mg (see method of administration) along with one single dose of the previous prescribeddose of oral aripiprazole. The maintenance dose should be Abilify Maintena 300 mg oncemonthly.
In patients who are known to be CYP2D6 poor metabolisers and concomitantly use a strong CYP3A4inhibitor:
* One injection start: The starting dose should be reduced to 200 mg (see section 4.5) andtreatment should be continued with the prescribed dose of oral aripiprazole per day for14 consecutive days.
* Two injection start is not to be used in patients who are known to be CYP2D6 poor metabolisersand concomitantly use a strong CYP3A4 inhibitor.
After the injection start, see table below for the recommended maintenance dose of Abilify Maintena.
Abilify Maintena 400 mg and 300 mg should be administered once monthly as a single injection (nosooner than 26 days after the previous injection).
Maintenance dose adjustments due to interactions with CYP2D6 and/or CYP3A4 inhibitors and/or
CYP3A4 inducersMaintenance 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, the necessity of concomitantuse of CYP2D6 or CYP3A4 inhibitor should be reassessed.
Concomitant use of CYP3A4 inducers with Abilify Maintena 400 mg or 300 mg should be avoided formore than 14 days because the blood levels of aripiprazole are decreased and may be below theeffective levels (see section 4.5).
Maintenance dose adjustments of Abilify Maintena in patients who are taking concomitantstrong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than14 days
Adjusted monthly dose
Patients taking Abilify Maintena 400 mg
Strong CYP2D6 or strong CYP3A4 inhibitors 300 mg
Strong CYP2D6 and strong CYP3A4 inhibitors 200 mg*
CYP3A4 inducers Avoid use
Patients taking Abilify Maintena 300 mg
Strong CYP2D6 or strong CYP3A4 inhibitors 200 mg*
Strong CYP2D6 and strong CYP3A4 inhibitors 160 mg*
CYP3A4 inducers Avoid use
* 200 mg and 160 mg can be achieved via adjustment of the injection volume only by using Abilify Maintenapowder and solvent for prolonged-release suspension for injection.
Paediatric populationThe safety and efficacy of Abilify Maintena 400 mg/300 mg in children and adolescents aged 0 to17 years have not been established. No data are available.
Method of administrationAbilify Maintena 400 mg and 300 mg is only intended for intramuscular use and must not beadministered intravenously or subcutaneously. It should only be administered by a healthcareprofessional.
The suspension must be injected slowly as a single injection (doses must not be divided) into thegluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel.
If initiating with the two injection start, inject into two different sites in two different muscles. DO
NOT inject both injections concomitantly into the same deltoid or gluteal muscle. For known CYP2D6poor metabolisers administer in either two separate deltoid muscles or one deltoid and one glutealmuscle. DO NOT inject into two gluteal muscles.
Full instructions for use and handling of Abilify Maintena 400 mg and 300 mg are provided in thepackage leaflet (information intended for healthcare professionals).
For instructions on reconstitution of the medicinal product before administration, see section 6.6.
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 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 400 mg/300 mg should not be used to manage acutely agitated or severely psychoticstates when immediate 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.
Cardiovascular disordersAripiprazole 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).
QT prolongationIn 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).
Tardive dyskinesiaIn 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.
Neuroleptic malignant syndrome (NMS)NMS is a potentially fatal symptom complex associated with antipsychotics. In clinical trials, rarecases of NMS were reported during treatment with aripiprazole. Clinical manifestations of NMS arehyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregularpulse or blood pressure, tachycardia, diaphoresis and cardiac dysrhythmia). Additional signs mayinclude elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and acute renal failure.
However, elevated creatine phosphokinase and rhabdomyolysis, not necessarily in association with
NMS, have also been reported. If a patient develops signs and symptoms indicative of NMS, orpresents with unexplained high fever without additional clinical manifestations of NMS, allantipsychotics, including aripiprazole, must be discontinued (see section 4.8).
SeizureIn 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).
Cerebrovascular adverse reactionsIn 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 and diabetes mellitusHyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma ordeath, has been reported in patients treated with aripiprazole. Risk factors that may predispose patientsto severe complications include obesity and family history of diabetes. Patients treated witharipiprazole 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 fordiabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).
HypersensitivityHypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (seesection 4.8).
Weight gainWeight gain is commonly seen in schizophrenic patients due to use of antipsychotics known to causeweight gain, co-morbidities, poorly managed life-style 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).
SodiumThis 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 Abilify Maintena. The information below is obtainedfrom studies with oral aripiprazole.
Due to its α1-adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect ofcertain antihypertensive medicinal products.
Given the primary 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 400 mg/300 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 400 mg/300 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 Inhibitors/Serotonin Noradrenaline
Reuptake Inhibitors (SSRI/SNRI), or with medicinal products that are known to increase aripiprazoleconcentrations (see section 4.8).
4.6 Fertility, pregnancy and lactation
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.
PregnancyThere 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.
Breast-feedingAripiprazole/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.
FertilityAripiprazole 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 potentialnervous system and visual effects, such as sedation, somnolence, syncope, vision blurred, diplopia (seesection 4.8).
4.8 Undesirable effects
The most frequently observed adverse drug reactions (ADRs) reported in ≥ 5 % of patients in twodouble-blind, long-term trials of Abilify Maintena 400 mg/300 mg were weight increased (9.0 %),akathisia (7.9 %), insomnia (5.8 %) and injection site pain (5.1 %).
Tabulated list of adverse reactionsThe incidences of the ADRs associated with aripiprazole therapy are tabulated below. The table isbased 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.
Common Uncommon Not known
Blood and Neutropenia Leukopenialymphatic Anaemiasystem Thrombocytopeniadisorders Neutrophil countdecreased
White blood cell countdecreased
Immune Hypersensitivity Allergic reaction (e.g.system anaphylactic reaction,disorders angioedema includingswollen tongue, tongueoedema, face oedema,pruritus, or urticaria)
Endocrine Blood prolactin Diabetic hyperosmolardisorders decreased coma
Hyperprolactinaemia Diabetic ketoacidosis
Metabolism Weight increased Hyperglycaemia Anorexiaand nutrition Diabetes mellitus Hypercholesterolaemia Hyponatraemiadisorders Weight decreased Hyperinsulinaemia
Hyperlipidaemia
Hypertriglyceridaemia
Appetite disorder
Psychiatric Agitation Suicidal ideation Completed suicidedisorders Anxiety Psychotic disorder Suicide attempt
Restlessness Hallucination Gambling disorder
Insomnia Delusion Impulse-control disorder
Hypersexuality Binge eating
Panic reaction Compulsive shopping
Depression Poriomania
Affect lability Nervousness
Apathy Aggression
Dysphoria
Sleep disorder
Bruxism
Libido decreased
Mood altered
Nervous Extrapyramidal disorder Dystonia Neuroleptic malignantsystem Akathisia Tardive dyskinesia syndromedisorders Tremor Parkinsonism Generalized tonic-clonic
Dyskinesia Movement disorder seizure
Sedation Psychomotor Serotonin syndrome
Somnolence hyperactivity Speech disorder
Dizziness Restless legs syndrome
Headache Cogwheel rigidity
Hypertonia
Bradykinesia
Drooling
Dysgeusia
Parosmia
Eye disorders Oculogyric crisis
Vision blurred
Eye pain
Diplopia
Photophobia
Common Uncommon Not known
Cardiac Ventricular extrasystoles Sudden unexplaineddisorders Bradycardia death
Tachycardia Cardiac arrest
Electrocardiogram T Torsades de pointeswave amplitude Ventricular arrhythmiadecreased QT prolongation
Electrocardiogramabnormal
Electrocardiogram Twave inversion
Vascular Hypertension Syncopedisorders Orthostatic hypotension Venous
Blood pressure increased thromboembolism(including pulmonaryembolism and deep veinthrombosis)
Respiratory, Cough Oropharyngeal spasmthoracic and Hiccups Laryngospasmmediastinal Aspiration pneumoniadisorders
Gastrointestin Dry mouth Gastrooesophageal reflux Pancreatitisal disorders disease Dysphagia
Dyspepsia
VomitingDiarrhoea
Nausea
Abdominal pain upper
Abdominal discomfort
ConstipationFrequent bowelmovements
Salivary hypersecretion
Hepatobiliary Liver function test Hepatic failuredisorders abnormal Hepatic Jaundiceenzyme increased Hepatitis
Alanine aminotransferase Alkaline phosphataseincreased increased
Gamma-glutamyltransferase increased
Blood bilirubin increased
Aspartateaminotransferaseincreased
Skin and Alopecia Rashsubcutaneous Acne Photosensitivity reactiontissue Rosacea Hyperhidrosisdisorders Eczema Drug Reaction with
Skin induration Eosinophilia and
Systemic Symptoms(DRESS)
Common Uncommon Not known
Musculoskelet Musculoskeletal stiffness Muscle rigidity Rhabdomyolysisal and Muscle spasmsconnective Muscle twitchingtissue Muscle tightnessdisorders Myalgia
Pain in extremity
Arthralgia
Back pain
Joint range of motiondecreased
Nuchal rigidity
Trismus
Renal and Nephrolithiasis Urinary retentionurinary Glycosuria Urinary incontinencedisorders
Pregnancy, Drug withdrawalpuerperium syndrome neonatal (seeand perinatal section 4.6)conditions
Reproductive Erectile dysfunction Galactorrhoea Priapismsystem and Gynaecomastiabreast Breast tendernessdisorders Vulvovaginal dryness
General Injection site pain Pyrexia Temperature regulationdisorders and Injection site induration Asthenia disorder (e.g.administration Fatigue Gait disturbance hypothermia, pyrexia)site conditions Chest discomfort Chest pain
Injection site reaction Peripheral oedema
Injection site erythema
Injection site swellingInjection site discomfort
Injection site pruritus
Thirst
Sluggishness
Investigations Blood creatine Blood glucose increased Blood glucose fluctuationphosphokinase increased Blood glucose decreased
Glycosylatedhaemoglobin increased
Waist circumferenceincreased
Blood cholesteroldecreased
Blood triglyceridesdecreased
Description of selected adverse reactionsInjection site reactions
During the double-blind, controlled phases of the two long-term trials, injection site reactions wereobserved; those seen were generally mild to moderate in severity, and resolved over time. Injectionsite pain (incidence 5.1 %), had a median onset on day 2 after the injection and a median duration of4 days.
In an open-label study comparing bioavailability of Abilify Maintena 400 mg/300 mg administered inthe deltoid or gluteal muscle, injection site related reactions were slightly more frequent in the deltoidmuscle. The majority were mild and improved on subsequent injections. When compared to studieswhere Abilify Maintena 400 mg/300 mg was injected in the gluteal muscle, repeated occurrence ofinjection site pain was more frequent in the deltoid muscle.
NeutropeniaNeutropenia 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 first injection,and lasted a median of 56 days. Subjects with akathisia typically received anti-cholinergic medicinesas treatment, primarily benzatropine mesilate and trihexyphenidyl. Less often substances such aspropranolol 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, 4.15 % fororal aripiprazole 10 mg to 30 mg tablets and 3.0 % for placebo, respectively.
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).
Prolactin
In clinical trials for the approved indications and post-marketing, both increase and decrease in serumprolactin as compared to baseline was observed with aripiprazole (section 5.1).
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 of suspected adverse reactionsReporting 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.
4.9 Overdose
No cases of overdose associated with adverse reactions were reported in clinical studies witharipiprazole. Care must be taken to avoid inadvertent injection of this medicinal product into a bloodvessel. Following any confirmed or suspected accidental overdose/inadvertent intravenousadministration, close observation of the patient is needed and if any potentially medically serious signor symptom develops, monitoring, which should include continuous electrocardiographic monitoring,is required. The medical supervision and monitoring should continue until the patient recovers.
A simulation of dose dumping showed that the predicted median aripiprazole concentration reaches apeak of 4 500 ng/mL or approximately 9-times the upper therapeutic range. In case of dose dumping,aripiprazole concentrations are predicted to descend rapidly to the upper limit of the therapeuticwindow after approximately 3 days. By the 7th day, the median aripiprazole concentrations furtherdecline to concentrations following an IM depot dose with no dose dumping. While overdose is lesslikely with parenteral than oral medicinal products, reference information for oral aripiprazoleoverdose is presented below.
Signs and symptoms
In clinical trials and post-marketing experience, accidental or intentional acute overdose ofaripiprazole alone was identified in adult patients with reported estimated doses up to 1 260 mg (41-times highest recommended daily aripiprazole dose) with no fatalities. The potentially medicallyimportant signs and symptoms observed included lethargy, increased blood pressure, somnolence,tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose witharipiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentiallymedically serious signs and symptoms reported included somnolence, transient loss of consciousnessand extrapyramidal symptoms.
Management of overdoseManagement of overdose should concentrate on supportive therapy, maintaining an adequate airway,oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinalproduct involvement should be considered. Therefore, cardiovascular monitoring should be startedimmediately and should include continuous electrocardiographic monitoring to detect possiblearrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medicalsupervision and monitoring should continue until the patient recovers.
HaemodialysisAlthough there is no information on the effect of haemodialysis in treating an overdose witharipiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole ishighly bound to plasma proteins.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Psycholeptics, other antipsychotics, ATC code: N05AX12
Mechanism of actionIt 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.
Clinical efficacy and safetyMaintenance treatment of schizophrenia in adults
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 400 mg/300 mg 2) the stabilisation dose of oral aripiprazole 10 mg to 30 mg, or 3)aripiprazole long-acting injectable 50 mg/25 mg. The aripiprazole long-acting injectable 50 mg/25 mgdose was included as a low 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
NOTE: ARIP IMD 400/300 mg = Abilify Maintena 400 mg/300 mg;ARIP 10 mg to 30 mg = oral aripiprazole;
ARIP IMD 50/25 mg = Aripiprazole long-acting injectable
Further, the non-inferiority of Abilify Maintena 400 mg/300 mg compared to oral aripiprazole 10 mgto 30 mg is supported by the results of the analysis of the positive and negative syndrome scale score(PANSS).
Table 1 PANSS total score - change from baseline to week 38-LOCF: randomised efficacysamplea, b
PANSS total score - change from baseline to week 38-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.
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, Abilify Maintena 400 mg/300 mg stabilisation, anddouble-blind placebo-controlled. Patients fulfilling the oral stabilisation requirement in the oralstabilisation phase were assigned to receive, in a single-blind fashion, Abilify Maintena400 mg/300 mg and began an Abilify Maintena 400 mg/300 mg stabilisation phase for a minimum of12 weeks and a maximum of 36 weeks. Patients eligible for the double-blind, placebo-controlled phasewere randomly assigned in a 2:1 ratio to double-blind treatment with Abilify Maintena 400 mg/300 mgor 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 Maintena 400 mg/300 mg (−0.38 ng/mL) compared witha mean increase in placebo (1.67 ng/mL). The incidences of Abilify Maintena 400 mg/300 mg patientswith 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) showed superiority 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 showedan improvement (decrease) from baseline over time.
Table 2 PANSS total score - change from baseline to week 10: randomised efficacy sample
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 %).
Paediatric populationThe 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).
5.2 Pharmacokinetic properties
Aripiprazole absorption into the systemic circulation is slow and prolonged following Abilify
Maintena 400 mg/300 mg administration due to low solubility of aripiprazole particles.The averageabsorption half-life of Abilify Maintena 400 mg/300 mg is 28 days. Absorption of aripiprazole fromthe IM depot formulation was complete relative to the IM standard (immediate-release) formulation.
The dose adjusted Cmax values for the depot formulation were approximately 5 % of Cmax from IMstandard formulation.Following a single dose administration of Abilify Maintena 400 mg/300 mg inthe deltoid and gluteal muscle, the extent of absorption (AUC) was similar for both injection sites, butthe rate of absorption (Cmax) was higher following administration to the deltoid muscle. Followingmultiple intramuscular doses, the plasma concentrations of aripiprazole gradually rise to amaximum plasma concentration at a median tmax of 7 days for the gluteal muscle and 4 days for thedeltoid muscle. Steady state concentrations for the typical subject were attained by the fourth dose forboth sites of administration. Less than dose-proportional increases in aripiprazole and dehydro-aripiprazole concentrations and AUC parameters are observed after monthly Abilify Maintenainjections of 300 mg to 400 mg.
DistributionBased on results from trials with oral administration of aripiprazole, aripiprazole is widely distributedthroughout the body with an apparent volume of distribution of 4.9 L/kg, indicating extensiveextravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole aregreater than 99 % bound to serum proteins, binding primarily to albumin.
BiotransformationAripiprazole 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. After multiple dose administration of Abilify Maintena 400 mg/300 mg, dehydro-aripiprazole, the active metabolite, represents about 29.1 % to 32.5 % of aripiprazole AUC in plasma.
EliminationAfter administration of multiple dose of Abilify Maintena 400 mg/300 mg, the mean aripiprazoleterminal elimination half-life is respectively 46.5 and 29.9 days presumably due to absorption rate-limited kinetics. Following a single oral dose of [14C]-labelled aripiprazole, approximately 27 % of theadministered radioactivity was recovered in the urine and approximately 60 % in the faeces. Less than1 % of unchanged aripiprazole was excreted in the urine and approximately 18 % was recoveredunchanged in the faeces.
Pharmacokinetics in special patient groupsCYP2D6 poor metabolisers
Based on population pharmacokinetic evaluation of Abilify Maintena 400 mg/300 mg, the total bodyclearance of aripiprazole was 3.71 L/h in normal metabolisers of CYP2D6 and approximately 1.88 L/h(approximately 50 % lower) in poor metabolisers of CYP2D6 (for dose recommendation, seesection 4.2).
ElderlyAfter 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 Abilify Maintena 400 mg/300 mg inschizophrenia patients.
GenderAfter 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 Abilify Maintena 400 mg/300 mg inclinical trials in patients with schizophrenia.
Smoking
Population pharmacokinetic evaluation of oral aripiprazole has revealed no evidence of clinicallyrelevant effects from smoking on the pharmacokinetics of aripiprazole.
RacePopulation pharmacokinetic evaluation showed no evidence of race-related differences on thepharmacokinetics of aripiprazole.
Renal impairmentIn 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.
Hepatic impairmentA 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.
5.3 Preclinical safety data
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. 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.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Carmellose sodium
Mannitol (E421)
Sodium dihydrogen phosphate monohydrate (E339)
Sodium hydroxide (E524)
SolventWater for injections
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
Abilify Maintena 400 mg/300 mg powder and solvent for prolonged-release suspension for injection
The suspension should be injected immediately after reconstitution but can be stored below 25 °C forup to 4 hours in the vial.
Abilify Maintena 400 mg/300 mg powder and solvent for prolonged-release suspension for injectionin pre-filled syringe
The suspension should be injected immediately after reconstitution but can be stored below 25 °C forup to 2 hours in the syringe.
After reconstitutionAbilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection
Chemical and physical in-use stability has been demonstrated for 4 hours at 25 °C. From amicrobiological point of view, unless the method of opening/ reconstitution precludes the risk ofmicrobial contamination, the product should be used immediately. If not used immediately, in-usestorage times and conditions are the responsibility of user. Do not store the reconstituted suspension inthe syringe.
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
If the injection is not performed immediately after reconstitution, the syringe can be kept below 25 °Cfor up to 2 hours.
6.4 Special precautions for storage
Do not freeze.
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Keep the syringe in the outer carton in order to protect from light.
For storage conditions after reconstitution of the medicinal product, see section 6.3.
6.5 Nature and contents of container
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection
Vial
Type-I glass vial stoppered with a laminated rubber stopper and sealed with a flip-off aluminium cap.
Solvent2 mL Type-I glass vial stoppered with a laminated rubber stopper and sealed with a flip-off aluminiumcap.
Single pack
Each single pack containing one vial of powder, 2 mL vial of solvent, one 3 mL luer lock syringe withpre-attached 38 mm (1.5 inch) 21 gauge, hypodermic safety needle with needle protection device, one3 mL disposable syringe with luer lock tip, one vial adapter and three hypodermic safety needles: one25 mm (1 inch) 23 gauge, one 38 mm (1.5 inch) 22 gauge and one 51 mm (2 inch) 21 gauge.
Multipack
Bundle pack of 3 single packs.
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Clear glass pre-filled syringe (type-I glass) with grey chlorobutyl stoppers (front-, middle- and endstopper), polypropylene front assembly, polypropylene finger grip, plunger rod, and silicone over-cap.
The front chamber between front stopper and middle stopper contains the powder and the rearchamber between middle stopper and end stopper the solvent.
Single pack
Each single pack containing one pre-filled syringe, and three hypodermic safety needles: one 25 mm(1 inch) 23 gauge, one 38 mm (1.5 inch) 22 gauge and one 51 mm (2 inch) 21 gauge.
Multipack
Bundle pack of 3 single packs.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection
Shake the vial vigorously for at least 30 seconds until the suspension appears uniform.
If the injection is not performed immediately after reconstitution shake it vigorously for at least60 seconds to re-suspend prior to injection.
Abilify Maintena 300 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection in pre-filled syringe
Vertically shake the syringe vigorously for 20 seconds until medicine is uniformly milky-white anduse immediately. If the injection is not performed immediately after reconstitution, the syringe can bekept below 25 °C for up to 2 hours. Shake the syringe vigorously for at least 20 seconds to re-suspendprior to injection if the syringe has been left for more than 15 minutes.
Gluteal muscle administration
The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermicsafety needle; for obese patients (Body mass index > 28 kg/m2), a 51 mm (2 inch), 21 gaugehypodermic safety needle should be used. Gluteal injections should be alternated between the twogluteal muscles.
Deltoid muscle administration
The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safetyneedle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used.
Deltoid injections should be alternated between the two deltoid muscles.
The powder and solvent vials and the pre-filled syringe are for single-use only.
Discard vial, adapter, syringe, needles, unused suspension and water for injections appropriately.
Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.
Full instructions for use and handling of Abilify Maintena 400 mg/300 mg are provided in the packageleaflet (information intended for healthcare professionals).
10. DATE OF REVISION OF THE TEXT
MM/YYYY
Detailed information on this medicinal product is available on the website of the European Medicines
Agency http://www.ema.europa.eu.