Abilify Maintena 400 mg powder and solvent for prolonged-release suspension for injection

Each vial contains 400 mg aripiprazole.

After reconstitution each ml of suspension contains 200 mg aripiprazole.

For the full list of excipients, see section 6.1.

Powder and solvent for prolonged-release suspension for injection

Powder: white to off-white

Solvent: clear solution

 

Abilify Maintena is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole.

Posology

For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena.

The recommended starting and maintenance dose of Abilify Maintena is 400 mg.

Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection).

After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy.

If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered.

Missed doses

Missed doses
If 2nd or 3rd dose is missed and time since last injection is:	Action
> 4 weeks and < 5 weeks	The injection should be administered as soon as possible and then resume monthly injection schedule.
> 5 weeks	Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.
If 4th or subsequent doses are missed (i.e., after attainment of steady state) and time since last injection is:	Action
> 4 weeks and < 6 weeks	The injection should be administered as soon as possible and then resume monthly injection schedule.
> 6 weeks	Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.

Special populations

Elderly patients

The safety and efficacy of Abilify Maintena in the treatment of schizophrenia in patients 65 years of age or older has not been established (see section 4.4).

Renal impairment

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

Hepatic impairment

No dosage 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 requiring cautious dosing, oral formulation should be preferred (see section 5.2).

Known CYP2D6 poor metabolisers

In patients who are known to be CYP2D6 poor metabolisers, the starting and maintenance dose should be 300 mg. When used concomitantly with strong CYP3A4 inhibitors the dose should be reduced to 200 mg (see section 4.5).

Dose adjustments due to interactions

Dosage adjustments should be done 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 dosage may need to be increased to the previous dose (see section 4.5). In case of adverse reactions despite dose adjustments of Abilify Maintena, the necessity of concomitant use of CYP2D6 or CYP3A4 inhibitor should be reassessed.

Concomitant use of CYP3A4 inducers with Abilify Maintena should be avoided for more than 14 days because the blood levels of aripiprazole are decreased and may be below the effective levels (see section 4.5).

Dose adjustments of Abilify Maintena in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than 14 days

	Adjusted dose
Patients taking 400 mg of Abilify Maintena
Strong CYP2D6 or strong CYP3A4 inhibitors	300 mg
Strong CYP2D6 and strong CYP3A4 inhibitors	200 mg
CYP3A4 inducers	Avoid use
Patients taking 300 mg of Abilify Maintena
Strong CYP2D6 or strong CYP3A4 inhibitors	200 mg
Strong CYP2D6 and strong CYP3A4 inhibitors	160 mg
CYP3A4 inducers	Avoid use

Paediatric population

The safety and efficacy of Abilify Maintena in children and adolescents aged 0-17 years have not been established. No data are available.

Method of administration

Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional. The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial. The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel. Sites of injections should be rotated between the two gluteal or deltoid muscles.

The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle. For obese patients (Body mass index > 28 kg/m²), a 50 mm (2 inch), 21 gauge hypodermic safety needle should be used.

The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle. For obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle should be used (see section 6.6).

The powder and solvent vials are for single-use only.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

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.

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

Abilify Maintena 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 Abilify Maintena 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 Abilify Maintena, dose reduction or discontinuation of 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 antipsychotic medicinal products. 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 antipsychotic medicinal products, 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: 56-99 years), patients treated with aripiprazole are 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 the placebo group. 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: 78-88 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).

Abilify Maintena 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 atypical antipsychotic medicines, including aripiprazole. Risk factors that may predispose patients to severe complications include obesity and family history of diabetes. In clinical trials with aripiprazole, there were no significant differences in the incidence rates of hyperglycaemia-related adverse reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions in patients treated with aripiprazole and with other atypical antipsychotic medicines are not available to allow direct comparisons. Patients treated with any antipsychotic medicinal products, including 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.

Weight gain

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).

Dysphagia

Oesophageal dysmotility and aspiration have been associated with antipsychotic medicinal product use, including aripiprazole. Aripiprazole should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling

Post-marketing reports of pathological gambling have been reported among patients prescribed oral aripiprazole, regardless of whether these patients had a prior history of gambling. Patients with a prior history of pathological gambling may be at increased risk and should be monitored carefully (see section 4.8).