Otsuka and Bristol-Myers Squibb

The following has been added to section 5.1  

In a 52-week, placebo-controlled trial, in patients with a current manic or mixed episode of Bipolar I Disorder who achieved sustained remission (Y-MRS and MADRS total scores ≤ 12) on aripiprazole (10 mg/day to 30 mg/day) adjunctive to lithium or valproate for 12 consecutive weeks, adjunctive aripiprazole demonstrated superiority over placebo with a 46% decreased risk (hazard ratio of 0.54) in preventing bipolar recurrence and a 65% decreased risk (hazard ratio of 0.35) in preventing recurrence into mania over adjunctive placebo but failed to demonstrate superiority over placebo in preventing recurrence into depression. Adjunctive aripiprazole demonstrated superiority over placebo on the secondary outcome measure, CGI-BP Severity of Illness score (mania).

In this trial, patients were assigned by investigators with either open-label lithium or valproate monotherapy to determine partial non-response. Patients were stabilised for at least 12 consecutive weeks with the combination of aripiprazole and the same mood stabilizer.

Stabilized patients were then randomised to continue the same mood stabilizer with double-blind aripiprazole or placebo. Four mood stabilizer subgroups were assessed in the randomised phase: aripiprazole + lithium; aripiprazole + valproate; placebo + lithium; placebo + valproate.

The Kaplan-Meier rates for recurrence to any mood episode for the adjunctive treatment arm were 16% in aripiprazole + lithium and 18% in aripiprazole + valproate compared to 45% in placebo + lithium and 19% in placebo + valproate.

In the pooled adolescent schizophrenia population (13-17 years) with exposure up to 2 years, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 29.5% and 48.3%, respectively.

4.2     Posology and method of administration

Posology

The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.

The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole).

If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.

ABILIFY solution for injection is for intramuscular use.

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

Paedriatic populationChildren and adolescents: there is no experience in children and adolescents under 18 years of age.

Patients with hepatic impairment: no dosage adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the data available are insufficient to establish recommendations. In these patients dosing should be managed cautiously. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section 5.2).

Patients with renal impairment: no dosage adjustment is required in patients with renal impairment.

Elderly: the effectiveness of ABILIFY solution for injection in patients who are 65 years of age or older has not been established. Owing to the greater sensitivity of this population, a lower starting dose should be considered when clinical factors warrant (see section 4.4).

Gender: no dosage adjustment is required for female patients as compared to male patients (see section 5.2).

Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5).

Dose adjustments due to interactions:

When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).

When concomitant administration of potent CYP3A4 inducers with aripiprazole occurs, the aripiprazole dose should be increased. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose should then be reduced to the recommended dose (see section 4.5).

Method of administration

ABILIFY solution for injection is for intramuscular use.

Cases of venous thromboembolism (VTE) have been reported with antipsychotic drugs. 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 and preventive measures undertaken.

The most commonly reported adverse reactions in placebo-controlled trials are nausea, dizziness and somnolence each occurring in more than 3% of patients treated with aripiprazole solution for injection..

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

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains 7.5 mg of aripiprazole.

A Each vial contains 9.75 mg aripiprazole.

4.2     Posology and method of administration

For intramuscular use.

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

The recommended initial dose for aripiprazole solution for injection is 9.75 mg (1.3 ml), administered as a single intramuscular injection. The effective dose range of aripiprazole solution for injection is 5.25‑15 mg as a single injection. A lower dose of 5.25 mg (0.7 ml) may be given, on the basis of individual clinical status, which should also include consideration of medicinal products already administered either for maintenance or acute treatment (see section 4.5). A second injection may be administered 2 hours after the first injection, on the basis of individual clinical status and no more than three injections should be given in any 24-hour period.

The maximum daily dose of aripiprazole is 30 mg (including all formulations of aripiprazole).

If continued treatment is indicated with oral aripiprazole, see the Summary of Product Characteristics for ABILIFY tablets, ABILIFY orodispersible tablets, or ABILIFY oral solution.

ABILIFY solution for injection is for intramuscular use.

To enhance absorption and minimise variability, injection into the deltoid or deep within the gluteus maximus muscle, avoiding adipose regions, is recommended.

ABILIFY solution for injection should not be administered intravenously or subcutaneously. ABILIFY solution for injection is ready to use and intended for short-term use only (see section 5.1).

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Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers (see section 4.5).

Dose adjustments due to interactions:

When concomitant administration of potent CYP3A4 or CYP2D6 inhibitors with aripiprazole occurs, the aripiprazole dose should be reduced. When the CYP3A4 or CYP2D6 inhibitor is withdrawn from the combination therapy, aripiprazole dose should then be increased (see section 4.5).

4.4     Special warnings and precautions for use

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Cardiovascular disorders: Aripiprazole should be used with caution in patients with known cardiovascular disease (history of myocardial infarction or ischaemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant.

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Tardive Dyskinesiadyskinesia: 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, dose reduction or discontinuation should be considered. These symptoms can temporally deteriorate or can even arise after discontinuation of treatment.

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Cerebrovascular adverse eventsreactions: in the same trials, cerebrovascular adverse eventsreactions (e.g. stroke, transient ischaemic attack), including fatalities, were reported in patients (mean age: 84 years; range: 78‑88 years). Overall, 1.3% of aripiprazole-treated patients reported cerebrovascular adverse eventsreactions 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 eventsreactions in patients treated with aripiprazole.

ABILIFY is not approved indicated for the treatment of dementia-related psychosis.

Hyperglycaemia and Diabetes diabetes Mellitusmellitus: hyperglycaemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ABILIFY. 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 eventsreactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse eventsreactions in patients treated with ABILIFY and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ABILIFY, 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.

Hypersensitivity: as with other medicinal products hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8).

Weight gain: weight gain is commonly seen in schizophrenic and bipolar mania patients due to co-morbidities, use of antipsychotics known to cause weight gain, poorly managed life-style, and might lead to severe complications. Weight gain has been reported post-marketing among patients prescribed ABILIFY. 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 5.1).

Dysphagia: oesophageal dysmotility and aspiration have been associated with antipsychotic drug usetreatment, including ABILIFY. Aripiprazole and other antipsychotic drugs should be used cautiously in patients at risk for aspiration pneumonia.

Hypersensitivity: as with other medications hypersensitivity reactions, characterised by allergic symptoms, may occur with aripiprazole (see section 4.8).

4.5     Interaction with other medicinal products and other forms of interaction

Due to its α1‑adrenergic receptor antagonism, aripiprazole has the potential to enhance the effect of certain antihypertensive agents.

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

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

4.8     Undesirable effects

The following undesirable effects adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):

The frequency listed below is defined using the following convention: common (³ 1/100,  to < 1/10) and uncommon (³ 1/1,000,  to < 1/100).

The following undesirable effects adverse reactionsoccurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):

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Other findings:

Undesirable effectsAdverse reactions known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse eventsreactions and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).

Post-Marketing:

The following adverse eventsreactions have been reported during post-marketing surveillance. The frequency of these eventsreactions is considered not known (cannot be estimated from the available data).

5.1     Pharmacodynamic properties

Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12

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6.3     Shelf life

18 months

After opening: uUse product immediately after opening and discard any unused amount.

6.6     Special precautions for disposal and other handling

Any unused product or waste material should be disposed of in accordance with local requirements.

9.       DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 4 June 2004

Date of latest renewal: 21 April 2009

10.     DATE OF REVISION OF THE TEXT

August 2008 04/2009

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/

4.4       Special warnings and precautions for use

Addition of: 'Results of an epidemiological study found that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with bipolar disorder.'

10.       DATE OF REVISION OF THE TEXT

Changed from March 2008 to August 2008

4.1     Therapeutic indications

ABILIFY solution for injection is indicated for the rapid control of agitation and disturbed behaviours in patients with schizophrenia or in patients with manic episodes in Bipolar I Disorder, when oral therapy is not appropriate.

Treatment with aripiprazole solution for injection should be discontinued as soon as clinically appropriate and the use of oral aripiprazole should be initiated.

4.4     Special warnings and precautions for use

The efficacy of aripiprazole solution for injection in patients with agitation and disturbed behaviours has not been established related to conditions other than schizophrenia and manic episodes in Bipolar I Disorder.

4.8     Undesirable effects

The following undesirable effects occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with aripiprazole solution for injection (see section 5.1):

The frequency listed below is defined using the following convention: common (³ 1/100, < 1/10) and uncommon (³ 1/1,000, < 1/100).

The following undesirable effects occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*) in clinical trials with oral formulations of aripiprazole (see section 5.1):

Extrapyramidal symptoms (EPS): Schizophrenia - in a long term 52-week controlled trial, aripiprazole-treated patients had an overall-lower incidence (25.8%) of EPS including parkinsonism, akathisia, dystonia and dyskinesia compared with those treated with haloperidol (57.3%). In a long term 26-week placebo-controlled trial, the incidence of EPS was 19% for aripiprazole-treated patients and 13.1% for placebo-treated patients. In another long-term 26-week controlled trial, the incidence of EPS was 14.8% for aripiprazole-treated patients and 15.1% for olanzapine-treated patients. Manic episodes in Bipolar I Disorder - in a 12-week controlled trial, the incidence of EPS was 23.5% for aripiprazole-treated patients and 53.3% for haloperidol-treated patients. In another 12-week trial, the incidence of EPS was 26.6% for patients treated with aripiprazole and 17.6% for those treated with lithium. In the long term 26-week maintenance phase of a placebo-controlled trial, the incidence of EPS was 18.2% for aripiprazole-treated patients and 15.7% for placebo-treated patients.

In placebo-controlled trials, the incidence of akathisia in bipolar patients was 12.1% with aripiprazole and 3.2% with placebo. In schizophrenia patients the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo.

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory parameters revealed no medically important differences. Elevations of CPK (Creatine Phosphokinase), generally transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as compared to 2.0% of patients who received placebo.

Other findings:

Undesirable effects known to be associated with antipsychotic therapy and also reported during treatment with aripiprazole include neuroleptic malignant syndrome, tardive dyskinesia, seizure, cerebrovascular adverse events and increased mortality in elderly demented patients, hyperglycaemia and diabetes mellitus (see section 4.4).

Post-Marketing:

The following adverse events have been reported during post-marketing surveillance. The frequency of these events is considered not known (cannot be estimated from the available data).