Other antipsychotics - ATC code: N05AX12

Aripiprazole

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

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.

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. 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.

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.

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

Gender: no dosage adjustment is required for female patients as compared to male patients.

Smoking status: according to the metabolic pathway of ABILIFY no dosage adjustment is required for smokers.

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.

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.

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.

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.

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.

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.

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.

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. 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.

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.

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.

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.

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 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.

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).

Otsuka and Bristol-Myers Squibb

(POM)

12 April 2012