Arylental

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARILENTAL (ARILENTAL)

Composition:

Active substance: aripiprazole;

1 tablet contains 10 mg or 15 mg of aripiprazole;

Excipients: microcrystalline cellulose (type 101); lactose monohydrate; maize starch; hydroxypropylcellulose; microcrystalline cellulose (type 102); magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Arilental, tablets, 10 mg, pack of 7 in a blister, 1 blister or 4 blisters per pack: white, capsule-shaped, biconvex tablets, engraved with "10" on one side and "ZL" on the other;

Arilental, tablets, 15 mg, pack of 7 in a blister, 1 blister or 4 blisters per pack: white, round, biconvex tablets, engraved with "15" on one side and "ZL" on the other.

Pharmacotherapeutic group. Antipsychotic agents. Other neuroleptics. Aripiprazole. ATC code N05AX12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action.

It is believed that the efficacy of aripiprazole in schizophrenia and bipolar I disorder is mediated through a combination of its activity as a partial agonist at dopamine D2 and serotonin 5HT1 receptors and as an antagonist at serotonin 5HT2 receptors. Aripiprazole exhibits antagonist properties in animals with dopaminergic hyperactivity and agonist properties in animals with dopaminergic hypoactivity. Aripiprazole shows high binding affinity in vitro for dopamine D2 and D3 receptors, serotonin 5HT1a and 5HT2 receptors, and moderate affinity for dopamine D4, serotonin 5HT2c and 5HT7, alpha-1 adrenergic, and histamine H1 receptors. Aripiprazole also shows moderate binding affinity for serotonin reuptake inhibition and no significant affinity for muscarinic receptors. Interaction with other receptors, apart from dopamine and serotonin subtypes, may explain some of the other clinical effects of aripiprazole.

Aripiprazole, administered once daily at doses ranging from 0.5 to 30 mg for 2 weeks to healthy subjects, dose-dependently reduced the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate nucleus and putamen as measured by positron emission tomography.

Clinical efficacy and safety

Schizophrenia

Aripiprazole is effective in maintaining clinical improvement during continuation of therapy in adult patients who showed an initial response to treatment.

Weight gain

Aripiprazole has been shown not to cause clinically significant weight gain.

Lipid parameters

Aripiprazole does not cause clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL), or low-density lipoprotein (LDL) levels.

Prolactin

Prolactin levels were evaluated in all trials across all aripiprazole doses (n = 28,242). The incidence of hyperprolactinemia or increased serum prolactin levels in patients receiving aripiprazole (0.3%) was similar to that in the placebo group (0.2%). In patients receiving aripiprazole, the median time to onset was 42 days, and the median duration was 34 days.

The incidence of hypoprolactinemia or decreased serum prolactin levels in patients receiving aripiprazole was 0.4%, compared to 0.02% in patients receiving placebo. In patients receiving aripiprazole, the median time to onset was 30 days, and the median duration was 194 days.

Manic episodes in bipolar I disorder

Aripiprazole demonstrated superior efficacy compared to placebo in reducing manic symptoms over 3 weeks.

Paediatric patients

Schizophrenia in adolescents

In adolescents aged 13–17 years with schizophrenia and positive or negative symptoms, aripiprazole treatment was associated with statistically significant greater improvement in psychotic symptoms compared to placebo.

Manic episodes in bipolar disorder in children and adolescents

The most commonly reported treatment-emergent adverse reactions among patients receiving 30 mg tablets were: extrapyramidal disorder (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain over 30 weeks of treatment was 2.9 kg compared to 0.98 kg in placebo-treated patients.

Irritability associated with autistic disorder in paediatric patients (see section "Dosage and administration")

Clinical studies have demonstrated that aripiprazole is statistically significantly more effective than placebo.

Tics associated with Tourette’s disorder in paediatric patients (see section "Dosage and administration")

The clinical significance of the efficacy results of aripiprazole treatment in children with Tourette’s syndrome has not been established due to the magnitude of the treatment effect in comparison with the substantial placebo effect and unclear effects on psychosocial functioning. There are no long-term data on the efficacy and safety of aripiprazole in this disorder, which has a fluctuating course.

Pharmacokinetics.

Absorption

Aripiprazole is well absorbed, and peak plasma concentrations occur within 3–5 hours after dosing. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability of the tablet formulation is 87%. A high-fat meal does not affect the pharmacokinetic properties of aripiprazole.

Distribution

Aripiprazole is widely distributed in body tissues. The volume of distribution is 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, more than 99% of aripiprazole and dehydro-aripiprazole are bound to serum proteins, primarily to albumin.

Biotransformation

Aripiprazole is extensively metabolized in the liver, primarily via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. According to in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug substance in systemic circulation. At steady state, dehydro-aripiprazole, an active metabolite, accounts for approximately 40% of the AUC of aripiprazole in plasma.

Elimination

The mean elimination half-life of aripiprazole is approximately 75 hours in CYP2D6 extensive metabolizers and approximately 146 hours in CYP2D6 poor metabolizers.

The total clearance of aripiprazole is 0.7 mL/min/kg. Aripiprazole is primarily eliminated via the liver.

After a single oral dose of aripiprazole, approximately 27% is excreted in urine and approximately 60% in feces. Less than 1% of aripiprazole is excreted unchanged in urine, and approximately 18% of the administered dose is excreted unchanged in feces.

Children

The pharmacokinetic properties of aripiprazole and hydro-aripiprazole in patients aged 10 to 17 years were similar to those in adults when body weight was taken into account.

Elderly patients

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy elderly patients and children, and there is no notable effect of age on pharmacokinetics in patients with schizophrenia.

Gender

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy male and female subjects, and there is no notable effect of gender on pharmacokinetics in patients with schizophrenia.

Smoking

Assessment of patient groups revealed no evidence of clinically significant effects of smoking on the pharmacokinetic properties of aripiprazole.

Race

Assessment of patient groups revealed no evidence of clinically significant effects of race on the pharmacokinetic properties of aripiprazole.

Renal impairment

The pharmacokinetic characteristics of aripiprazole and hydro-aripiprazole were found to be similar in patients with acute renal disease compared to young healthy individuals.

Hepatic impairment

A clinical study in patients with various 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 hydro-aripiprazole; however, the study included only 3 patients with Child-Pugh class C cirrhosis, which is insufficient for definitive conclusions.

Clinical characteristics.

Indications.

Treatment of schizophrenia in adults.

Treatment of moderate to severe manic episodes in bipolar I disorder, as well as prophylaxis of new manic episodes in adults who have previously experienced manic episodes and responded to aripiprazole treatment.

Contraindications.

Hypersensitivity to aripiprazole or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Due to α1-adrenergic receptor antagonism, aripiprazole may enhance the effect of certain antihypertensive agents.

Because of the primary effect of aripiprazole on the central nervous system (CNS), caution should be exercised when administering aripiprazole concomitantly with other CNS-active medicinal products, due to the potential for additive adverse reactions such as sedation.

Alcohol consumption should also be avoided during aripiprazole therapy. Aripiprazole should be used with caution in combination with other medicinal products that prolong the QT interval or affect electrolyte balance.

Potential effect of other medicinal products on aripiprazole.

The hydrochloric acid secretion inhibitor and H2-histamine receptor antagonist famotidine reduces the rate of aripiprazole absorption, but this effect is not considered clinically significant.

Aripiprazole is metabolized via multiple pathways involving CYP2D6 and CYP3A4 enzymes, but not CYP1A enzymes. Therefore, dose adjustment is not required in smokers.

Quinidine and other CYP2D6 inhibitors.

The dose of aripiprazole should be reduced by approximately half when administered concomitantly with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have a similar effect; therefore, dose reduction should be comparable when these agents are used.

In individuals with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to patients with normal CYP2D6 metabolism. When concomitant use of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefits should outweigh the possible risks to the patient. When aripiprazole is used concomitantly with ketoconazole, the dose of aripiprazole should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may theoretically have similar effects; therefore, dose reduction should be analogous.

After discontinuation of a CYP2D6 or CYP3A4 inhibitor, the dose of aripiprazole should be increased to the level used prior to initiation of concomitant therapy.

A slight increase in aripiprazole concentrations may occur with concomitant use of weak CYP3A4 inhibitors (e.g., diltiazem or escitalopram) or weak CYP2D6 inhibitors.

Carbamazepine and other CYP3A4 inducers.

When carbamazepine, a potent CYP3A4 inducer, was coadministered with oral aripiprazole in patients with schizophrenia and schizoaffective disorder, geometric Cmax and AUC values of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. The geometric mean Cmax and AUC of dehydro-aripiprazole were reduced by 69% and 71%, respectively, during coadministration with carbamazepine compared to aripiprazole monotherapy.

The dose of aripiprazole should be doubled when administered concomitantly with carbamazepine. Other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) are expected to have a similar effect; therefore, appropriate dose escalation of aripiprazole is required. After discontinuation of potent CYP3A4 inducers, the aripiprazole dose should be reduced to the recommended level.

Valproate and lithium.

No clinically significant changes in aripiprazole concentrations were observed when valproate or lithium were coadministered with aripiprazole; therefore, dose adjustment is not required.

Serotonin syndrome.

Cases of serotonin syndrome have been reported in patients treated with aripiprazole, particularly when used concomitantly with other serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs), or with agents that increase aripiprazole concentrations.

Potential effect of aripiprazole on other medicinal products.

It is unlikely that aripiprazole causes clinically significant drug interactions mediated by CYP2D6 (dextromethorphan/3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan).

No clinically significant changes in valproate, lithium, or lamotrigine concentrations were observed when aripiprazole was coadministered with valproates, lithium, or lamotrigine.

Special precautions for use.

Improvement in the patient's clinical condition during treatment with antipsychotics may take from several days to several weeks. During this period, careful monitoring of patients is required.

Suicidal tendency: suicidal behavior is characteristic of patients with psychotic disorders and affective disorders, and in some cases has been observed shortly after initiation of antipsychotic therapy or switching from one antipsychotic to another, including treatment with aripiprazole. Antipsychotic treatment should be accompanied by close monitoring of patients belonging to high-risk groups.

Cardiovascular disorders: aripiprazole should be used with caution in patients with a history of cardiovascular diseases (myocardial infarction or ischemic heart disease, heart failure or conduction disorders), cerebrovascular disorders, conditions predisposing patients to hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or hypertension, including progressive and malignant hypertension.

Venous thromboembolism (VTE) has been reported during antipsychotic therapy.

Since acquired risk factors for VTE are frequently observed in patients taking antipsychotics, all possible risk factors for VTE should be identified before and during aripiprazole treatment, and all preventive measures should be taken.

QT interval prolongation: aripiprazole should be used with caution in patients with a family history of QT interval prolongation.

Tardive dyskinesia: if symptoms of tardive dyskinesia occur in a patient receiving aripiprazole, consideration should be given to reducing the dose or discontinuing treatment. These symptoms may temporarily worsen or even emerge after discontinuation of therapy.

Other extrapyramidal symptoms: akathisia and parkinsonism have been observed during aripiprazole use in children. If signs of other extrapyramidal symptoms occur, dose reduction should be considered and careful clinical monitoring of the patient should be maintained.

Neuroleptic Malignant Syndrome (NMS): NMS is a syndrome complex associated with the use of antipsychotic drugs, which may be fatal.

Clinical manifestations of NMS include hyperpyrexia (extremely high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (unstable pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional signs may include elevated creatine kinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. However, isolated cases of elevated creatine kinase levels and rhabdomyolysis not associated with NMS have also been reported. If a patient develops symptoms of NMS or extremely high body temperature of unknown origin without additional clinical signs of NMS, all antipsychotic medications, including aripiprazole, must be discontinued.

Seizures: rare cases of seizures have been reported during aripiprazole treatment. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures.

Elderly patients with psychosis associated with dementia.

Increased mortality: when aripiprazole is used in elderly patients with psychosis due to Alzheimer's disease, the risk of death is increased. Although the causes of death varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin.

Adverse cerebrovascular reactions: in elderly patients with psychosis due to Alzheimer's disease, adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatal outcomes, have been observed.

A strong association between drug dosage and the occurrence of cerebrovascular adverse events has been noted in patients receiving aripiprazole.

Aripiprazole is not indicated for the treatment of psychosis associated with dementia.

Hypoglycemia and diabetes mellitus: hyperglycemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatal outcomes, has been reported in patients treated with atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and a family history of diabetes. There is no precise comparative assessment of the risks of adverse reactions related to hyperglycemia in patients using aripiprazole versus other atypical antipsychotics. Careful monitoring of patients taking any antipsychotics, including aripiprazole, is necessary to detect symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes or risk factors for developing diabetes should be regularly monitored for increased glucose levels.

Hypersensitivity: hypersensitivity reactions may occur during use of aripiprazole.

Weight gain: weight gain is frequently observed in patients with schizophrenia and bipolar mania due to comorbid conditions, use of antipsychotics known to cause weight gain, and unhealthy lifestyle—this phenomenon may lead to serious complications. During aripiprazole treatment, weight gain has generally been observed in patients with significant risk factors, such as diabetes, thyroid disorders, or pituitary adenoma in medical history.

Aripiprazole does not cause clinically significant weight gain in adults.

Dysphagia: antipsychotics, including aripiprazole, may cause esophageal motility disorders and gastric content aspiration. Aripiprazole and other antipsychotics should be used with caution in patients at increased risk of aspiration pneumonia.

Pathological gambling and other impulse control disorders: patients may experience increased urges to gamble and inability to control these urges during aripiprazole treatment. Increased sexual desire, compulsive shopping, binge eating or drinking, and other impulsive and compulsive behaviors have also been reported. During treatment with aripiprazole, it is important for physicians to inquire about the development of new or worsening urges—such as gambling, sexual desire, compulsive shopping, binge drinking, or overeating. Symptoms of impulse control disorders may be related to the underlying disorder; however, in some cases, these disturbances resolved upon dose reduction or discontinuation of the drug. Impulse control disorders may harm patients and others if not recognized. Consideration should be given to reducing the dose or discontinuing the drug if such disorders occur during aripiprazole treatment (see "Adverse reactions").

Falls: aripiprazole may cause somnolence, postural hypotension, and motor or sensory instability, which may lead to falls. Caution is advised when treating patients at increased risk (e.g., elderly or frail patients); a lower initial dose should be considered (see "Dosage and administration").

Lactose: the medicinal product Arilental contains lactose. Patients with rare hereditary problems such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Patients with comorbid ADHD (attention deficit hyperactivity disorder): despite the high prevalence of comorbid bipolar I disorder and ADHD, safety data on the concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when prescribing these agents together.

Use during pregnancy or breastfeeding

Pregnancy

Adequate and well-controlled studies in pregnant women have not been conducted.

Congenital anomalies have been reported, but a causal relationship with aripiprazole use has not been established. Available animal data do not allow exclusion of a potential negative impact on fetal development. Patients should inform their physician if they become pregnant or intend to become pregnant during aripiprazole treatment. Due to insufficient information on the safety of aripiprazole use during pregnancy, the drug should be prescribed only if the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

In newborns whose mothers took antipsychotics (including aripiprazole) during the third trimester of pregnancy, adverse reactions may occur, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, careful monitoring of such newborns is required.

Period of breastfeeding

Aripiprazole passes into breast milk. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from aripiprazole therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

According to reproductive toxicity studies, aripiprazole does not affect fertility.

Ability to influence reaction speed when driving or operating machinery

Aripiprazole has a negligible or moderate effect on the ability to drive or operate machinery due to its potential effects on the nervous system and visual organs and the occurrence of adverse reactions such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").

Method of Administration and Dosage.

The drug should be taken orally.

Schizophrenia

Aripiprazole is recommended to be administered at an initial dose of 10 or 15 mg once daily, regardless of food intake. The maintenance dose is 15 mg daily. Efficacy has been demonstrated within a daily dose range of 10 to 30 mg. Increased efficacy with daily doses exceeding 15 mg has not been demonstrated, although some patients may benefit from higher doses.

The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder: the recommended initial dose of Aripiprazole is 15 mg. This dose should be taken once daily, regardless of food intake, either as monotherapy or as part of combination therapy. Dose escalation may be effective for some patients. The maximum daily dose should not exceed 30 mg.

Prevention of relapse of new manic episodes in bipolar I disorder: to prevent relapse of manic episodes in patients previously treated with aripiprazole as monotherapy or in combination therapy, treatment should be continued at the same dose. Dose adjustment, including dose reduction, may be considered based on the patient's clinical condition.

Special patient groups

Patients with hepatic impairment. Dose adjustment is not required in patients with mild or moderate hepatic impairment. Insufficient data are available to provide recommendations for patients with severe hepatic impairment. Dosing in these patients should be carefully individualized. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section "Pharmacokinetics").

Patients with renal impairment. Dose adjustment is not required in patients with renal impairment.

Elderly patients. The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in bipolar I disorder in patients aged 65 years and older have not been established. Given the increased sensitivity of this patient population, consideration should be given to using lower initial doses, if permitted by other clinical factors (see section "Special precautions for use").

Gender. Dose adjustment based on patient gender is not required (see section "Pharmacokinetics").

Smoking. Due to the metabolic pathway of aripiprazole, dose adjustment is not required for smokers (see section "Interaction with other medicinal products and other forms of interaction").

Dose adjustment due to drug interactions. When strong CYP3A4 or CYP2D6 inhibitors are co-administered with aripiprazole, the dose of aripiprazole should be reduced. If a CYP3A4 or CYP2D6 inhibitor is discontinued from the treatment regimen, the aripiprazole dose should be increased (see section "Interaction with other medicinal products and other forms of interaction").

When strong CYP3A4 inducers are co-administered with aripiprazole, the dose of aripiprazole should be increased. If a CYP3A4 inducer is discontinued from the treatment regimen, the aripiprazole dose should be reduced to the recommended level (see section "Interaction with other medicinal products and other forms of interaction").

Children. Not to be used in children.

Overdose.

Symptoms

Cases of intentional or accidental acute aripiprazole overdose up to 1260 mg have been reported in adult patients, without fatal outcome. Potentially clinically significant observed symptoms included lethargy, elevated blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea.

Additionally, reports of accidental overdose with aripiprazole alone (up to 195 mg) in children have been received, which were non-fatal. Potentially clinically significant observed symptoms included somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Treatment

Supportive therapy is required in cases of overdose, including maintenance of airway patency, oxygenation, mechanical ventilation if necessary, and symptomatic monitoring. The possibility of overdose with multiple medicinal products should be considered. Immediate cardiovascular monitoring with ECG recording should be initiated to detect arrhythmias. After confirmed or suspected aripiprazole overdose, careful medical observation and monitoring of the patient are required until the patient's condition normalizes.

Activated charcoal (50 g) administered one hour after aripiprazole intake reduced the Cmax of aripiprazole by approximately 41% and the AUC by approximately 51%, suggesting potential effectiveness of activated charcoal in overdose management.

Hemodialysis

Although there are no reliable data on the use of hemodialysis in aripiprazole overdose, a beneficial effect of this method is unlikely because aripiprazole is not excreted unchanged by the kidneys and is highly protein-bound.

Adverse reactions

The most commonly observed adverse reactions were akathisia and nausea. Each of these symptoms occurred in more than 3% of patients treated with oral aripiprazole.

All adverse reactions are listed by system organ class and frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

The frequency of adverse reactions identified during the post-marketing period cannot be estimated because they are derived from spontaneous reports. Therefore, the frequency of these adverse reactions is classified as not known.

System organ class	Common (≥ 1/100 — < 1/10)	Uncommon (≥ 1/1000 — < 1/100)	Frequency not known (cannot be estimated from available data)
Blood and lymphatic system disorders			Leukopenia, neutropenia, thrombocytopenia
Immune system disorders			Allergic reactions (e.g. anaphylactic reactions; angioneurotic edema, including tongue edema; tongue swelling, facial swelling, pruritus or urticaria)
Endocrine system disorders		Hyperprolactinemia, decreased blood prolactin levels	Hyperosmolar hyperglycemic state, diabetic ketoacidosis
Metabolism and nutrition disorders	Diabetes mellitus	Hypoglycemia	Hyponatremia, anorexia, weight decreased, weight increased
Psychiatric disorders	Insomnia, restlessness, agitation	Depression, hypersexuality	Suicide attempt, suicidal thoughts, suicide (see section "Special warnings and precautions for use"), pathological gambling, impulse control disorders, compulsive overeating, kleptomania, pyromania, aggression, agitation, nervousness
Nervous system disorders	Akathisia, extrapyramidal disorders, tremor, headache, sedation, somnolence, dizziness	Tardive dyskinesia, dystonia, restless legs syndrome	Neuroleptic malignant syndrome (NMS), grand mal seizure, serotonin syndrome, speech disorder
Eye disorders	Blurred vision	Diplopia, photophobia	Acute angle-closure glaucoma
Cardiac disorders		Tachycardia	Sudden death, torsades de pointes, QT interval prolongation, ventricular arrhythmia, cardiac arrest, bradycardia
Vascular disorders		Orthostatic hypotension	Vein thrombosis and thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, syncope
Respiratory, thoracic and mediastinal disorders		Hiccups	Aspiration pneumonia, laryngospasm, oropharyngeal spasm
Gastrointestinal disorders	Constipation, dyspepsia, nausea, hypersalivation, vomiting		Pancreatitis, dysphagia, diarrhea, abdominal discomfort, stomach discomfort
Hepatobiliary disorders			Liver failure, hepatitis, jaundice, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyltransferase (GGT), increased alkaline phosphatase
Skin and subcutaneous tissue disorders			Rash, photosensitivity reactions, alopecia, increased sweating, drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)
Musculoskeletal and connective tissue disorders			Rhabdomyolysis, myalgia, muscle rigidity
Renal and urinary disorders			Urinary incontinence, urinary retention
Pregnancy, puerperium and perinatal conditions			Drug withdrawal syndrome in newborns (see section "Use during pregnancy or breastfeeding")
Reproductive system and breast disorders			Priapism
General disorders and administration site conditions	Fatigue		Thermoregulatory disorders (e.g. hypothermia, pyrexia), chest pain, peripheral edema
Investigations			Increased blood glucose, increased glycated hemoglobin, blood glucose fluctuations, increased creatine phosphokinase

Description of individual adverse reactions

Extrapyramidal symptoms (EPS)

Schizophrenia. In a 52-week controlled study in patients receiving aripiprazole, the incidence of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, was lower (25.7%) compared to patients receiving haloperidol (57.3%). In a long-term 26-week placebo-controlled study, the incidence of EPS was 19% among patients treated with aripiprazole and 13.1% among patients receiving placebo. In another 26-week controlled study, the incidence of EPS was 14.8% in patients receiving aripiprazole and 15.1% in patients receiving olanzapine.

Manic episodes in bipolar I disorder. In a 12-week controlled study, the incidence of EPS was 23.5% in patients treated with aripiprazole and 53.3% in patients receiving haloperidol. In another 12-week study, the incidence of EPS was 26.6% in patients receiving aripiprazole and 17.6% in patients receiving lithium. In the long-term 26-week placebo-controlled trial phase, the incidence of EPS was 18.2% in patients receiving aripiprazole and 15.7% in patients receiving placebo.

Akathisia

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

Dystonia

Drug class effect: in susceptible patients, symptoms of dystonia, characterized by prolonged abnormal contractions of muscle groups, may occur during the first few days of treatment. Symptoms of dystonia include neck muscle spasms, which may sometimes progress to throat tightness, difficulty swallowing, breathing difficulties, and/or protrusion of the tongue. Although these symptoms may occur at low doses, they are more frequent and severe at higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger patients.

Prolactin

In clinical trials conducted for approved indications and during the post-marketing period, both increases and decreases in serum prolactin levels have been observed compared to baseline levels.

Laboratory parameters

Comparison of laboratory parameters (including lipid profile) in patients receiving aripiprazole and placebo revealed no potentially clinically significant differences. Elevations in creatine phosphokinase (CPK) levels, mostly transient and asymptomatic, were observed in 3.5% of patients taking aripiprazole, compared to 2.0% in the placebo group.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions during the post-marketing surveillance period. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging. 7 tablets per blister, 1 blister or 4 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

Actavis Ltd./Actavis Ltd.

Manufacturer's address and location of operations.

BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta /
BLB015, BLB016, Bulebel Industrial Estate, Zejtun, ZTN3000, Malta.

Marketing Authorization Holder.

UAB “Farmlyga” / JSC "Farmliga".

Address of the Marketing Authorization Holder.

Antakalnio g. 48A-304, Vilnius, Republic of Lithuania /
Antakalnio g. 48A-304, Vilnius, Republic of Lithuania.

Date of last review.