Bristol-Myers Squibb Pharmaceutical Limited

4.6     Fertility, pregnancy and lactation

 
The following text has been added :

Neonates exposed to antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.

4.8     Undesirable effects

the following has been added :

Under section 4.2 the sentence highlighted in red has been added

4.2     Posology and method of administration

Posology

Adults:

Schizophrenia:The recommended starting dose for ABILIFY is 10 or 15 mg/day (i.e. 10 or 15 ml solution/day) with a maintenance dose of 15 mg/day administered on a once‑a‑day schedule without regard to meals. For the oral solution, a calibrated measuring cup is included in the carton.

ABILIFY is effective in a dose range of 10 to 30 mg/day (i.e. 10 to 30 ml solution/day). Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Manic episodes:The recommended starting dose for ABILIFY is 15 mg (i.e. 15 ml solution/day) administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg (i.e. 30 ml solution/day).

Recurrence prevention of manic episodes in Bipolar I Disorder: For preventing recurrence of manic episodes in patients who have been receiving aripiprazole as monotherapy or combination therapy, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.

Under section  5.1     Pharmacodynamic properties  the following has been added:

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.

4.2     Posology and method of administration- the following text in red has been added

Paediatric population:

Schizophrenia in adolescents 15 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1).

ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated in adolescents although individual patients may benefit from a higher dose.

ABILIFY is not recommended for use in patients below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1).

Irritability associated with autistic disorder: the safety and efficacy of ABILIFY in children and adolescents below 18 years of age have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made.

4.8       Undesirable effects- the following text in red has been added

Paediatric population:

In a short-term, placebo-controlled clinical trial involving 302 adolescents (13-17 years) with schizophrenia, the frequency and type of undesirable effects were similar to those in adults except for the following events that were reported more frequently in adolescents receiving aripiprazole than in adults receiving aripiprazole (and more frequently than placebo): somnolence/sedation and extrapyramidal disorder were reported very commonly (≥ 1/10), and dry mouth, increased appetite and orthostatic hypotension were reported commonly (≥ 1/100 < 1/10).

The safety profile in a 26-week open-label extension trial was similar to that observed in the short-term, placebo-controlled trial.

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.

5.1     Pharmacodynamic properties- the following text in red has been added

Paediatric population:

Schizophrenia in adolescents:

 in a 6-week placebo-controlled trial involving 302 schizophrenic adolescent patients (13-17 years), presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

In a sub-analysis of the adolescent patients between the ages of 15 to 17 years, representing 74% of the total enrolled population, maintenance of effect was observed over the 26-week open-label extension trial.

Irritability associated with autistic disorder in paediatric patients (see section 4.2): aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible-dose (2-15 mg/day) and one fixed-dose (5, 10, or 15 mg/day)] and in one 52-week open-label trial. Dosing in these trials was initiated at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day in weekly increments to the target dose. Over 75% of patients were less than 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the Aberrant Behaviour Checklist Irritability subscale. However, the clinical relevance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of the long-term safety study was limited to 52 weeks. In the pooled trials, the incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) in aripiprazole-treated patients was 27/46 (58.7%) and 258/298 (86.6%), respectively. In the placebo-controlled trials, the mean weight gain was 0.4 kg for placebo and 1.6 kg for aripiprazole.

4.2     Posology and method of administration

Posology

Adults:

Schizophrenia:The recommended starting dose for ABILIFY is 10 or 15 mg/day (i.e. 10 or 15 ml solution/day) with a maintenance dose of 15 mg/day administered on a once‑a‑day schedule without regard to meals. For the oral solution, a calibrated measuring cup is included in the carton.

ABILIFY is effective in a dose range of 10 to 30 mg/day (i.e. 10 to 30 ml solution/day). Enhanced efficacy at doses higher than a daily dose of 15 mg has not been demonstrated although individual patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg.

Manic episodes:The recommended starting dose for ABILIFY is 15 mg (i.e. 15 ml solution/day) administered on a once-a-day schedule without regard to meals as monotherapy or combination therapy (see section 5.1). Some patients may benefit from a higher dose. The maximum daily dose should not exceed 30 mg (i.e. 30 ml solution/day).

Recurrence prevention of manic episodes in Bipolar I Disorder: For preventing recurrence of manic episodes in patients who have been receiving aripiprazole, continue therapy at the same dose. Adjustments of daily dosage, including dose reduction should be considered on the basis of clinical status.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

ABILIFY oral solution and orodispersible tablets may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see section 5.2).

Paediatric patientspopulation:

Schizophrenia in adolescents 15 years and older: the recommended dose for ABILIFY is 10 mg/day administered on a once-a-day schedule without regard to meals. Treatment should be initiated at 2 mg (using ABILIFY oral solution 1 mg/ml) for 2 days, titrated to 5 mg for 2 additional days to reach the recommended daily dose of 10 mg. When appropriate, subsequent dose increases should be administered in 5 mg increments without exceeding the maximum daily dose of 30 mg (see section 5.1).

ABILIFY is effective in a dose range of 10 to 30 mg/day. Enhanced efficacy at doses higher than a daily dose of 10 mg has not been demonstrated in adolescents although individual patients may benefit from a higher dose.

ABILIFY is not recommended for use in patients below 15 years of age due to insufficient data on safety and efficacy (see sections 4.8 and 5.1).

ABILIFY tablets, orodispersible tablets and oral solution are for oral use.

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 in the treatment of schizophrenia and Bipolar I Disorder in patients 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 tablets, orodispersible tablets and oral solution are for oral use.

The orodispersible tablet should be placed in the mouth on the tongue, where it will rapidly disperse in saliva. It can be taken with or without liquid. Removal of the intact orodispersible tablet from the mouth is difficult. Since the orodispersible tablet is fragile, it should be taken immediately on opening the blister. Alternatively, disperse the tablet in water and drink the resulting suspension.

ABILIFY oral solution and orodispersible tablets may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see section 5.2).

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 akithisia and nausea, each occurring in more than 3% of patients treated with oral aripiprazole.

4.5     Interaction with other medicinal products and other forms of interaction

Potential for ABILIFY to affect other medicinal products:

When aripiprazole was administered concomitantly with either valproate or , lithium or lamotrigine, there was no clinically important change in valproate or , lithium or lamotrigine concentrations.

4.8       Undesirable effects

The following adverse reactions occurred more often (≥ 1/100) than placebo, or were identified as possibly medically relevant adverse reactions (*):

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).

Comparisons between aripiprazole and placebo in the proportions of patients experiencing potentially clinically significant changes in routine laboratory and lipid parameters (see section 5.1) 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.

5.       PHARMACOLOGICAL PROPERTIES

5.1     Pharmacodynamic properties

Further information on clinical trials:

Lipid parameters: in a pooled analysis on lipid parameters from placebo controlled clinical trials in adults, aripiprazole has not been shown to induce clinically relevant alterations in levels of total cholesterol, triglycerides, HDL and LDL.

-Total cholesterol: incidence of changes in levels from normal (<5.18 mmol/l) to high (≥ 6.22 mmol/l) was 2.5% for aripiprazole and 2.8% for placebo and mean change from baseline was -0.15 mmol/l

(95% CI: -0.182, -0.115) for aripiprazole and -0.11 mmol/l (95% CI: -0.148, -0.066) for placebo.

-Fasting triglycerides: incidence of changes in levels from normal (<1.69 mmol/l) to high (≥ 2.26 mmol/l) was 7.4% for aripiprazole and 7.0% for placebo and mean change from baseline was -0.11 mmol/l (95% CI: -0.182, -0.046) for aripiprazole and -0.07 mmol/l (95% CI: -0.148, 0.007) for placebo.

-HDL: incidence of changes in levels from normal (≥ 1.04 mmol/l) to low (<1.04 mmol/l) was 11.4% for aripiprazole and 12.5% for placebo and mean change from baseline was -0.03 mmol/l

(95% CI: -0.046, -0.017) for aripiprazole and -0.04 mmol/l (95% CI: -0.056, -0.022) for placebo.

-Fasting LDL: incidence of changes in levels from normal (<2.59 mmol/l) to high (≥ 4.14 mmol/l) was 0.6% for aripiprazole and 0.7% for placebo and mean change from baseline was -0.09 mmol/l

(95% CI: -0.139, -0.047) for aripiprazole and -0.06 mmol/l (95% CI: -0.116, -0.012) for placebo.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Tablets

Each tablet contains 5 mg of aripiprazole and excipient: 67 mg lactose

Each tablet contains 10 mg of aripiprazole and excipient: 62.18 mg lactose

Each tablet contains 15 mg of aripiprazole and excipient: 57 mg lactose

Each tablet contains 30 mg of aripiprazole and excipient: 187186.54 mg lactose

4.2       Posology and method of administration

Oral use.

Schizophrenia:

The recommended starting dose for ABILIFY is 10 or 15 mg/day with a maintenance dose of 15 mg/day administered on a once‑a‑day schedule without regard to meals. For the oral solution, a calibrated, propylene measuring cup is included in the carton.

.....

ABILIFY oral solution and orodispersible tablets may be used as an alternative to ABILIFY tablets for patients who have difficulty swallowing ABILIFY tablets (see also section 5.2).

ABILIFY tablets, orodispersible tablets and oral solution are for oral use.

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

Dosage 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 ischemic heart disease, heart failure, or conduction abnormalities), cerebrovascular disease, conditions which would predispose patients to hypotension (dehydration, hypovolaemia, and treatment with antihypertensive medicationsmedicinal products) or hypertension, including accelerated or malignant.

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Tardive dDyskinesia: 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 temporarily 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 dDiabetes 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 medications, hypersensitivity reactions characterised by allergic symptoms, may occur with aripiprazole (see section 4.8).

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

Intolerance:

Tablets: The ABILIFY tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take the oral tablets.

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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 effectsadverse reactions such as sedation (see section 4.8).

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

4.7       Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed. However, as with other antipsychotics, patients should be cautioned about operating hazardous machines, including motor vehicles, until they are reasonably certain that aripiprazole does not affect them adversely (see section 4.8).

4.8       Undesirable effects

The following undesirable effectsadverse reactions occurred more often ( > 1/100 ) than placebo, or were identified as possibly medically relevant adverse reactions (*):

The frequency listed below is defined using the following convention:

common (  > 1/100,  to < 1/10 ) and uncommon (  > 1/1,000,  to < 1/100 ).

...................................

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 also 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

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 last 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

moderate hepatic impairment. In patients with severe hepatic impairment, the data available

are insufficient to establish recommendations. In these patients dosing should be managed

Uncommon: tachycardia*

Common: extrapyramidal disorder, akathisia, tremor, dizziness, somnolence, sedation, headache

Common: blurred vision

Common: dyspepsia, vomiting, nausea, constipation, salivary hypersecretion

Uncommon: orthostatic hypotension*

Common: fatigue

Common: restlessness, insomnia anxiety

Uncommon: depression*

Extrapyramidal symptoms (EPS): Schizophrenia - in a long term 52-week controlled trial,

patients and 15.1% for olanzapine-treated patients. Manic episodes in Bipolar I Disorder - in

transient and asymptomatic, were observed in 3.5% of aripiprazole treated patients as

compared to 2.0% of patients who received placebo.

The following adverse events have also been reported during post-marketing surveillance.

Deleted: In placebo-controlled

Deleted: very rarely (

Deleted: (the calculation for

Deleted: Blood and the

Pharmacotherapeutic group: antipsychotics, ATC code: N05AX12

dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for

2 weeks produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3

6.6 Instructions for disposal and other handling

March 2008

Deleted: No special

Deleted: February

Hypersensitivity: