During antipsychotic treatment, improvement in the patient's clinical condition may take several days to some weeks. Patients should be closely monitored throughout this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and mood disorders and in some cases has been reported early after initiation or switch of antipsychotic treatment, including treatment with aripiprazole (see section 4.8). Close supervision of high-risk patients should accompany antipsychotic therapy.

Results of an epidemiological study suggested that there was no increased risk of suicidality with aripiprazole compared to other antipsychotics among adult patients with schizophrenia or bipolar disorder. There are insufficient paediatric data to evaluate this risk in younger patients (below 18 years of age), but there is evidence that the risk of suicide persists beyond the first 4 weeks of treatment for atypical antipsychotics, including aripiprazole.

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, 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 ARIPEX and preventive measures undertaken.

QT prolongation

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 (see section 4.8).

Tardive dyskinesia:

In clinical trials of one year or less duration, there were uncommon reports of treatment emergent dyskinesia during treatment with aripiprazole. If signs and symptoms of tardive dyskinesia appear in a patient on ARIPEX, dose reduction or discontinuation should be considered. These symptoms can temporarily deteriorate or can even arise after discontinuation of treatment.

Other extrapyramidal symptoms

In paediatric clinical trials of aripiprazole akathisia and parkinsonism were observed. If signs and symptoms of other EPS appear in a patient taking aripiprazole, dose reduction and close clinical monitoring should be considered.

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 ARIPEX, 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 (see section 4.8).

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 (see section 4.8).

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 (see section 4.8).

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

Hyperglycemia and diabetes mellitus:

Hyperglycemia, in some cases extreme and associated with ketoacidosis or hyperosmolar coma or death, has been reported in patients treated with atypical antipsychotic agents, including ARIPEX. 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 hyperglycemia-related adverse reactions (including diabetes) or in abnormal glycemia laboratory values compared to placebo. Precise risk estimates for hyperglycemia-related adverse reactions in patients treated with ARIPEX and with other atypical antipsychotic agents are not available to allow direct comparisons. Patients treated with any antipsychotic agents, including ARIPEX, should be observed for signs and symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia and weakness) and patients with diabetes mellitus or with risk factors for diabetes mellitus should be monitored regularly for worsening of glucose control (see section 4.8).

Hypersensitivity:

As with other medicinal products, hypersensitivity reactions, characterized 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 ARIPEX. 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). In clinical trials of adolescent patients with bipolar mania, aripiprazole has been shown to be associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section 4.8).

Dysphagia:

Esophageal dysmotility and aspiration have been associated with antipsychotic treatment, including ARIPEX. Aripiprazole and other antipsychotic active substances should be used cautiously in patients at risk for aspiration pneumonia.

Pathological gambling

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

Intolerance:

Tablets: ARIPEX tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the lapp lactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Patients with ADHD comorbidity

Despite the high comorbidity frequency of Bipolar I Disorder and ADHD, very limited safety data are available on concomitant use of aripiprazole and stimulants; therefore, extreme caution should be taken when these medicinal products are co-administered.

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 ARIPEX:

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

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

Quinidine and other CYP2D6 inhibitors

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%. ARIPEX dose should be reduced to approximately one-half of its prescribed dose when concomitant administration of ARIPEX 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.

Ketoconazole and other CYP3A4 inhibitors

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 metabolizes, 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 ARIPEX, potential benefits should outweigh the potential risks to the patient. When concomitant administration of ketoconozole with ARIPEX occurs, ARIPEX 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 ARIPEX 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 ARIPEX, modest increases in aripiprazole concentrations might be expected.

Carbamazepine and other CYP3A4 inducers

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.

ARIPEX dose should be doubled when concomitant administration of ARIPEX 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 ARIPEX should be reduced to the recommended dose.

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

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking aripiprazole, and possible signs and symptoms for this condition can occur especially in cases of concomitant use with other serotonergic medicinal products, such as SSRI/SNRI, or with medicinal products that are known to increase aripiprazole concentrations (see section 4.8).

Potential for ARIPEX 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.

Pregnancy

Pregnancy category C

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 fetus.

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.

Breast-feeding

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).

Summary of the safety profile

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.

Tabulated list of adverse reactions

All ADRs are listed by system organ class and frequency; very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

The frequency of adverse reactions reported during post-marketing use cannot be determined as they are derived from spontaneous reports. Consequently, the frequency of these adverse events is qualified as "not known"

Description of selected adverse reactions

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.

Akathisia

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 medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.

Prolactin

In clinical trials for the approved indications and post-marketing, both increase and decrease in serum prolactin as compared to baseline was observed with aripiprazole (section 5.1).

Laboratory parameters

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.

Paediatric population

Schizophrenia in adolescents aged 15 years and older

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 reactions 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.

The safety profile of a long-term, double-blind placebo controlled trial was also similar except for the following reactions that were reported more frequently than paediatric patients taking placebo: weight decreased, blood insulin increased, arrhythmia, and leukopenia were reported commonly (≥ 1/100, < 1/10).

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. In the adolescent (13-17 years) schizophrenia population with aripiprazole exposure of 5 to 30 mg up to 72 months, incidence of low serum prolactin levels in females (<3 ng/ml) and males (< 2 ng/ml) was 25.6 % and 45.0 %, respectively.

In two long term trials with adolescent (13-17 years) schizophrenia and bipolar patients treated with aripiprazole, incidence of low serum prolactin levels in females (<3 ng/ml) and males (<2 ng/ml) was 37.0 % and 59.4 %, respectively.

Manic episodes in Bipolar I Disorder in adolescents aged 13 years and older

The frequency and type of undesirable effects in adolescents with Bipolar I Disorder were similar to those in adults except for the following reactions: very commonly (≥ 1/10) somnolence (23.0 %), extrapyramidal disorder (18.4 %), akathisia (16.0 %), and fatigue (11.8 %); and commonly (≥ 1/100, < 1/10) abdominal pain upper, heart rate increased, weight increased, increased appetite, muscle twitching, and dyskinesia.

The following undesirable effects had a possible dose response relationship; extrapyramidal disorder (incidences were 10 mg, 9.1 %, 30 mg, 28.8 %, placebo, 1.7 %,); and akathisia (incidences were 10 mg, 12.1 %, 30 mg, 20.3 %, placebo, 1.7 %).

Mean changes in body weight in adolescents with Bipolar I Disorder at 12 and 30 weeks for aripiprazole were 2.4 kg and 5.8 kg, and for placebo 0.2 kg and 2.3 kg, respectively.

In the paediatric population somnolence and fatigue were observed more frequently in patients with bipolar disorder compared to patients with schizophrenia.

In the paediatric bipolar population (10-17 years) with exposure up to 30 weeks, incidence of low serum prolactin levels in females (< 3 ng/ml) and males (< 2 ng/ml) was 28.0 % and 53.3 %, respectively.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via:

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.

Biotransformation:

Aripiprazole is extensively metabolized 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 feces. Less than 1% of unchanged aripiprazole was excreted in the urine and approximately 18% was recovered unchanged in the feces.

Pharmacokinetics in special patient groups

Pediatric population:

The pharmacokinetics of aripiprazole and dehydro-aripiprazole in pediatric 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

Population pharmacokinetic evaluation has revealed no evidence of clinically significant effects from smoking on the pharmacokinetics of aripiprazole.

Race

Population pharmacokinetic evaluation showed no evidence of race-related differences on the pharmacokinetics of aripiprazole.

Renal impairment:

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 impairment:

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:

Magnesium Stearate

Avicel PH 102

Croscarmellose Sodium Type A

Red Iron Oxide

Yellow Iron Oxide

Spectracol Brilliant Blue LK815030

Lactose Fast Flow

Not Applicable

Store below 30°C

Tablets

Reel AL/OPA/PVC Blister and Aluminum Foil

Each pack contains 30 tablets

No Special Disposal