Bristol-Myers Squibb Pharmaceutical Limited

ABILIFY 5 mg tablets

ABILIFY 10 mg tablets

ABILIFY 15 mg tablets

ABILIFY 30 mg tablets

ABILIFY 10 mg orodispersible tablets

ABILIFY 15 mg orodispersible tablets

ABILIFY 1 mg/ml oral solution

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: 186.54 mg lactose

Orodispersible tablets

Each orodispersible tablet contains 10 mg of aripiprazole and excipient: 2 mg aspartame (E951)

Each orodispersible tablet contains 15 mg of aripiprazole and excipient: 3 mg aspartame (E951)

Oral solution

Each ml contains 1 mg of aripiprazole.

Excipients:

200 mg fructose per ml

400 mg sucrose per ml

1.8 mg methyl parahydroxybenzoate (E218) per ml

0.2 mg propyl parahydroxybenzoate (E216) per ml

For a full list of excipients, see section 6.1.

Tablets

5 mg: Rectangular and blue, engraved with "A-007" and "5" on one side.

10 mg: Rectangular and pink, engraved with "A-008" and "10" on one side.

15 mg: Round and yellow, engraved with "A-009" and "15" on one side.

30 mg: Round and pink, engraved with "A-011" and "30" on one side.

Orodispersible tablets

10 mg: Round and pink, marked with "A" over "640" on one side and "10" on the other.

15 mg: Round and yellow, marked with "A" over "641" on one side and "15" on the other.

Oral solution

Clear, colourless to light yellow liquid.

ABILIFY is indicated for the treatment of schizophrenia in adults and in adolescents 15 years and older.

ABILIFY is indicated for the treatment of moderate to severe manic episodes in Bipolar I Disorder and for the prevention of a new manic episode in patients who experienced predominantly manic episodes and whose manic episodes responded to aripiprazole treatment (see section 5.1).

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.

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.

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).

Hypersensitivity to the active substance or to any of the excipients.

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.

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic therapy, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy. Results of an epidemiological study suggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among patients with schizophrenia or bipolar disorder.

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 medicinal products) or hypertension, including accelerated or malignant.

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.

Conduction abnormalities: In clinical trials of aripiprazole, the incidence of QT prolongation was comparable to placebo. As with other antipsychotics, aripiprazole should be used with caution in patients with a family history of QT prolongation.

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, dose reduction or discontinuation should be considered. These symptoms can temporarily 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 ABILIFY, must be discontinued.

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.

Elderly patients with dementia-related psychosis:

Increased mortality: in three placebo-controlled trials (n= 938; mean age: 82.4 years; range: 56-99 years) of aripiprazole in elderly patients with psychosis associated with Alzheimer's disease, patients treated with aripiprazole were at increased risk of death compared to placebo. The rate of death in 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.

Cerebrovascular adverse reactions: in the same trials, 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 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.

ABILIFY is not indicated for the treatment of 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 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 reactions (including diabetes) or in abnormal glycaemia laboratory values compared to placebo. Precise risk estimates for hyperglycaemia-related adverse reactions 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 treatment, including ABILIFY. Aripiprazole and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.

Intolerance:

Tablets: 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.

Orodispersible tablets: ABILIFY orodispersible tablets contain aspartame, a source of phenylalanine which may be harmful for people with phenylketonuria.

Oral solution

The oral solution contains fructose. Patients with rare hereditary problems of fructose intolerance should not take the oral solution.

The oral solution contains methyl parahydroxybenzoate and propyl parahydroxybenzoate which may cause allergic reactions (possibly delayed).

The oral solution contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take the oral solution.

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 adverse reactions such as sedation (see section 4.8).

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

Potential for other medicinal products to affect ABILIFY:

A gastric acid blocker, the H2 antagonist famotidine, reduces aripiprazole rate of absorption but this effect is deemed not clinically relevant.

Aripiprazole is metabolised by multiple pathways involving the CYP2D6 and CYP3A4 enzymes but not CYP1A enzymes. Thus, no dosage adjustment is required for smokers.

In a clinical trial in healthy subjects, a potent inhibitor of CYP2D6 (quinidine) increased aripiprazole AUC by 107%, while C_max was unchanged. The AUC and C_max of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%. ABILIFY dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of ABILIFY with quinidine occurs. Other potent inhibitors of CYP2D6, such as fluoxetine and paroxetine, may be expected to have similar effects and similar dose reductions should therefore be applied.

In a clinical trial in healthy subjects, a potent inhibitor of CYP3A4 (ketoconazole) increased aripiprazole AUC and C_max by 63% and 37%, respectively. The AUC and C_max of dehydro-aripiprazole increased by 77% and 43%, respectively. In CYP2D6 poor metabolisers, concomitant use of potent inhibitors of CYP3A4 may result in higher plasma concentrations of aripiprazole compared to that in CYP2D6 extensive metabolizers. When considering concomitant administration of ketoconazole or other potent CYP3A4 inhibitors with ABILIFY, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconozole with ABILIFY occurs, ABILIFY dose should be reduced to approximately one-half of its prescribed dose. Other potent inhibitors of CYP3A4, such as itraconazole and HIV protease inhibitors, may be expected to have similar effects and similar dose reductions should therefore be applied.

Upon discontinuation of the CYP2D6 or 3A4 inhibitor, the dosage of ABILIFY should be increased to the level prior to the initiation of the concomitant therapy.

When weak inhibitors of CYP3A4 (e.g., diltiazem or escitalopram) or CYP2D6 are used concomitantly with ABILIFY, modest increases in aripiprazole concentrations might be expected.

Following concomitant administration of carbamazepine, a potent inducer of CYP3A4, the geometric means of C_max and AUC for aripiprazole were 68% and 73% lower, respectively, compared to when aripiprazole (30 mg) was administered alone. Similarly, for dehydro-aripiprazole the geometric means of C_max and AUC after carbamazepine co-administration were 69% and 71% lower, respectively, than those following treatment with aripiprazole alone.

ABILIFY dose should be doubled when concomitant administration of ABILIFY occurs with carbamazepine. Other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) may be expected to have similar effects and similar dose increases should therefore be applied. Upon discontinuation of potent CYP3A4 inducers, the dosage of ABILIFY should be reduced to the recommended dose.

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

Potential for ABILIFY to affect other medicinal products:

In clinical studies, 10-30 mg/day doses of aripiprazole had no significant effect on the metabolism of substrates of CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), 2C9 (warfarin), 2C19 (omeprazole), and 3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole did not show potential for altering CYP1A2-mediated metabolism in vitro. Thus, aripiprazole is unlikely to cause clinically important medicinal product interactions mediated by these enzymes.

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

There are no adequate and well-controlled trials of aripiprazole in pregnant women. Congenital anomalies have been reported; however, causal relationship with aripiprazole could not be established. Animal studies could not exclude potential developmental toxicity (see section 5.3). Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during treatment with aripiprazole. Due to insufficient safety information in humans and concerns raised by animal reproductive studies, this medicinal product should not be used in pregnancy unless the expected benefit clearly justifies the potential risk to the foetus.

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.

Aripiprazole was excreted in the milk of treated rats during lactation. It is not known whether aripiprazole is excreted in human milk. Patients should be advised not to breast feed if they are taking aripiprazole.

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).

The most commonly reported adverse reactions in placebo-controlled trials are akathisia and nausea, each occurring in more than 3% of patients treated with oral aripiprazole.

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

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.

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.

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.

Other findings:

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

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.

Post-Marketing:

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

In clinical trials and post-marketing experience, accidental or intentional acute overdose of aripiprazole alone was identified in adult patients with reported estimated doses up to 1,260 mg with no fatalities. The potentially medically important signs and symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting and diarrhoea. In addition, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received with no fatalities. The potentially medically serious signs and symptoms reported included somnolence, transient loss of consciousness and extrapyramidal symptoms.

Management of overdose should concentrate on supportive therapy, maintaining an adequate airway, oxygenation and ventilation, and management of symptoms. The possibility of multiple medicinal product involvement should be considered. Therefore cardiovascular monitoring should be started immediately and should include continuous electrocardiographic monitoring to detect possible arrhythmias. Following any confirmed or suspected overdose with aripiprazole, close medical supervision and monitoring should continue until the patient recovers.

Activated charcoal (50 g), administered one hour after aripiprazole, decreased aripiprazole C_max by about 41% and AUC by about 51%, suggesting that charcoal may be effective in the treatment of overdose.

Although there is no information on the effect of haemodialysis in treating an overdose with aripiprazole, haemodialysis is unlikely to be useful in overdose management since aripiprazole is highly bound to plasma proteins.

Pharmacotherapeutic group: other antipsychotics, ATC code: N05AX12

It has been proposed that aripiprazole's efficacy in schizophrenia and Bipolar I Disorder is mediated through a combination of partial agonism at dopamine D2 and serotonin 5HT1a receptors and antagonism of serotonin 5HT2a receptors. Aripiprazole exhibited antagonist properties in animal models of dopaminergic hyperactivity and agonist properties in animal models of dopaminergic hypoactivity. Aripiprazole exhibited high binding affinity in vitro for dopamine D2 and D3, serotonin 5HT1a and 5HT2a receptors and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic and histamine H1 receptors. Aripiprazole also exhibited moderate binding affinity for the serotonin reuptake site and no appreciable affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole doses ranging from 0.5 to 30 mg administered once a day to healthy subjects for 2 weeks produced a dose-dependent reduction in the binding of ¹¹C-raclopride, a D2/D3 receptor ligand, to the caudate and putamen detected by positron emission tomography.

Further information on clinical trials:

Schizophrenia in adults:

In three short-term (4 to 6 weeks) placebo-controlled trials involving 1,228 schizophrenic patients, presenting with positive or negative symptoms, aripiprazole was associated with statistically significantly greater improvements in psychotic symptoms compared to placebo.

ABILIFY is effective in maintaining the clinical improvement during continuation therapy in patients who have shown an initial treatment response. In a haloperidol-controlled trial, the proportion of responder patients maintaining response to medicinal product at 52-weeks was similar in both groups (aripiprazole 77% and haloperidol 73%). The overall completion rate was significantly higher for patients on aripiprazole (43%) than for haloperidol (30%). Actual scores in rating scales used as secondary endpoints, including PANSS and the Montgomery-Asberg Depression Rating Scale showed a significant improvement over haloperidol.

In a 26-week, placebo-controlled trial in stabilised patients with chronic schizophrenia, aripiprazole had significantly greater reduction in relapse rate, 34% in aripiprazole group and 57% in placebo.

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.

Weight gain: in clinical trials aripiprazole has not been shown to induce clinically relevant weight gain. In a 26-week, olanzapine-controlled, double-blind, multi-national study of schizophrenia which included 314 patients and where the primary end-point was weight gain, significantly less patients had at least 7% weight gain over baseline (i.e. a gain of at least 5.6 kg for a mean baseline weight of ~80.5 kg) on aripiprazole (N= 18, or 13% of evaluable patients), compared to olanzapine (N= 45, or 33% of evaluable patients).

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.

Manic episodes in Bipolar I Disorder:

In two 3-week, flexible-dose, placebo-controlled monotherapy trials involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole demonstrated superior efficacy to placebo in reduction of manic symptoms over 3 weeks. These trials included patients with or without psychotic features and with or without a rapid-cycling course.

In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with a manic or mixed episode of Bipolar I Disorder, aripiprazole failed to demonstrate superior efficacy to placebo.

In two 12-week, placebo- and active-controlled monotherapy trials in patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, aripiprazole demonstrated superior efficacy to placebo at week 3 and a maintenance of effect comparable to lithium or haloperidol at week 12. Aripiprazole also demonstrated a comparable proportion of patients in symptomatic remission from mania as lithium or haloperidol at week 12.

In a 6-week, placebo-controlled trial involving patients with a manic or mixed episode of Bipolar I Disorder, with or without psychotic features, who were partially non-responsive to lithium or valproate monotherapy for 2 weeks at therapeutic serum levels, the addition of aripiprazole as adjunctive therapy resulted in superior efficacy in reduction of manic symptoms than lithium or valproate monotherapy.

In a 26-week, placebo-controlled trial, followed by a 74-week extension, in manic patients who achieved remission on aripiprazole during a stabilization phase prior to randomization, aripiprazole demonstrated superiority over placebo in preventing bipolar recurrence, primarily in preventing recurrence into mania but failed to demonstrate superiority over placebo in preventing recurrence into depression.

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.

Absorption:

Aripiprazole is well absorbed, with peak plasma concentrations occurring within 3-5 hours after dosing. Aripiprazole undergoes minimal pre-systemic metabolism. The absolute oral bioavailability of the tablet formulation is 87%. There is no effect of a high fat meal on the pharmacokinetics of aripiprazole.

Distribution:

Aripiprazole is widely distributed throughout the body with an apparent volume of distribution of 4.9 l/kg, indicating extensive extravascular distribution. At therapeutic concentrations, aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins, binding primarily to albumin.

Metabolism:

Aripiprazole is extensively metabolised by the liver primarily by three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalysed by CYP3A4. Aripiprazole is the predominant medicinal product moiety in systemic circulation. At steady state, dehydro-aripiprazole, the active metabolite, represents about 40% of aripiprazole AUC in plasma.

Elimination:

The mean elimination half-lives for aripiprazole are approximately 75 hours in extensive metabolisers of CYP2D6 and approximately 146 hours in poor metabolisers of CYP2D6.

The total body clearance of aripiprazole is 0.7 ml/min/kg, which is primarily hepatic.

Following a single oral dose of [¹⁴C]-labelled aripiprazole, approximately 27% of the administered radioactivity was recovered in the urine and approximately 60% in the faeces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the faeces.

Orodispersible tablets

Aripiprazole orodispersible tablet is bioequivalent to aripiprazole tablets, with a similar rate and extent of absorption. Aripiprazole orodispersible tablets may be used as an alternative to aripiprazole tablets.

Oral solution:

Aripiprazole is well absorbed when administered orally as the solution. At equivalent doses, the peak plasma concentrations of aripiprazole (C_max) from the solution were somewhat higher but the systemic exposure (AUC) was equivalent to tablets. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole as the oral solution to 30 mg aripiprazole tablets in healthy subjects, the solution to the tablet ratio of geometric mean Cmax values was 122% (N=30). The single-dose pharmacokinetics of aripiprazole were linear and dose-proportional.

Pharmacokinetics in special patient groups

Paediatric population:

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in paediatric patients 13 to 17 years of age were similar to those in adults after correcting for the differences in body weights.

Elderly:

There are no differences in the pharmacokinetics of aripiprazole between healthy elderly and younger adult subjects, nor is there any detectable effect of age in a population pharmacokinetic analysis in schizophrenic patients.

Gender:

There are no differences in the pharmacokinetics of aripiprazole between healthy male and female subjects nor is there any detectable effect of gender in a population pharmacokinetic analysis in schizophrenic patients.

Smoking and Race:

Population pharmacokinetic evaluation has revealed no evidence of clinically significant race-related differences or effects from smoking upon the pharmacokinetics of aripiprazole.

Renal Disease:

The pharmacokinetic characteristics of aripiprazole and dehydro-aripiprazole were found to be similar in patients with severe renal disease compared to young healthy subjects.

Hepatic Disease:

A single-dose study in subjects with varying degrees of liver cirrhosis (Child-Pugh Classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydro-aripiprazole, but the study included only 3 patients with Class C liver cirrhosis, which is insufficient to draw conclusions on their metabolic capacity.

Non-clinical safety data revealed no special hazard for humans based on conventional studies of safety pharmacology, repeat-dose toxicity, genotoxicity, carcinogenic potential, and toxicity to reproduction and development.

Toxicologically significant effects were observed only at doses or exposures that were sufficiently in excess of the maximum human dose or exposure, indicating that these effects were limited or of no relevance to clinical use. These included: dose-dependent adrenocortical toxicity (lipofuscin pigment accumulation and/or parenchymal cell loss) in rats after 104 weeks at 20 to 60 mg/kg/day (3 to 10 times the mean steady-state AUC at the maximum recommended human dose) and increased adrenocortical carcinomas and combined adrenocortical adenomas/carcinomas in female rats at 60 mg/kg/day (10 times the mean steady-state AUC at the maximum recommended human dose). The highest nontumorigenic exposure in female rats was 7 times the human exposure at the recommended dose.

An additional finding was cholelithiasis as a consequence of precipitation of sulphate conjugates of hydroxy metabolites of aripiprazole in the bile of monkeys after repeated oral dosing at 25 to 125 mg/kg/day (1 to 3 times the mean steady-state AUC at the maximum recommended clinical dose or 16 to 81 times the maximum recommended human dose based on mg/m²). However, the concentrations of the sulphate conjugates of hydroxy aripiprazole in human bile at the highest dose proposed, 30 mg per day, were no more than 6% of the bile concentrations found in the monkeys in the 39-week study and are well below (6%) their limits of in vitro solubility.

In repeat dose studies in juvenile rats and dogs, the toxicity profile of aripiprazole was comparable to that observed in adult animals, and there was no evidence of neurotoxicity or adverse effects on development.

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 teratogenic effects, were observed in rats at doses resulting in subtherapeutic exposures (based on AUC) and in rabbits at doses resulting in exposures 3 and 11 times the mean steady-state AUC at the maximum recommended clinical dose. Maternal toxicity occurred at doses similar to those eliciting developmental toxicity.

Tablets

Lactose monohydrate

Maize starch

Microcrystalline cellulose

Hydroxypropyl cellulose

Magnesium stearate

Indigo carmine aluminium lake (E132) (5 mg tablets)

Red iron oxide (E172) (10 mg and 30 mg tablets)

Yellow iron oxide (E172) (15 mg tablets)

Orodispersible tablets

Calcium silicate

Croscarmellose sodium

Crospovidone

Silicon dioxide

Xylitol

Microcrystalline cellulose

Aspartame (E951)

Acesulfame potassium

Vanilla flavour (including vanillin and ethyl vanillin)

Tartaric acid

Magnesium stearate

Red iron oxide (E172) (10 mg orodispersible tablets)

Yellow iron oxide (E172) (15 mg orodispersible tablets)

Oral solution

Disodium edetate

Fructose

Glycerin

Lactic acid

Methyl parahydroxybenzoate (E218)

Propylene glycol

Propyl parahydroxybenzoate (E216)

Sodium hydroxide

Sucrose

Purified water

Natural orange cream with other natural flavours

Tablets and orodispersible tablets

Not applicable.

Oral solution

The oral solution should not be diluted with other liquids or mixed with any food prior to administration.

Tablets and orodispersible tablets

3 years

Oral solution

3 years

After first opening: 6 months.

Tablets and orodispersible tablets

Store in the original package in order to protect from moisture.

Oral solution

This medicinal product does not require any special storage conditions.

Tablets

Aluminium perforated unit dose blisters in cartons of 28 x 1 tablets.

Orodispersible tablets

Carton of 28 x 1 tablets in cold-formed aluminium perforated unit dose blisters.

Oral solution

PET-bottles with polypropylene child-resistant closure containing 150 ml per bottle.

Each carton contains one bottle and both a calibrated polypropylene measuring cup and a calibrated polypropylene low-density polyethylene dropper.

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

Otsuka Pharmaceutical Europe Ltd.

Hunton House Highbridge Business Park, Oxford Road

Uxbridge - Middlesex UB8 1HU - United Kingdom

Tablets

5 mg: EU/1/04/276/002

10 mg: EU/1/04/276/007

15 mg: EU/1/04/276/012

30 mg: EU/1/04/276/017

Orodispersible tablets

10 mg: EU/1/04/276/025

15 mg: EU/1/04/276/028

Oral solution

EU/1/04/276/034

Date of first authorisation: 4 June 2004

Date of latest renewal: 4 June 2009

September 2011

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