Zilaxera

INSTRUCTION for medical use of the medicinal product Zylaxera® (Zylaxera®)

Composition:

Active substance: aripiprazole;

1 tablet contains aripiprazole 5 mg or 10 mg, or 15 mg, or 30 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, corn starch, magnesium stearate, iron oxide red (E 172) — for 10 mg and 30 mg tablets, iron oxide yellow (E 172) — for 15 mg tablets, indigocarmine (E 132) — for 5 mg tablets.

Medicinal form. Tablets.

Main physicochemical properties:

• 5 mg tablets: round, beveled-edge tablets, blue in color with possible light or dark specks;
• 10 mg tablets: rectangular, light pink colored tablets with possible light or dark specks, engraved with "A10" on one side;
• 15 mg tablets: round, slightly biconvex tablets, light yellow to brownish-yellow in color with possible light or dark specks, beveled edges, engraved with "A15" on one side;
• 30 mg tablets: round, biconvex light pink colored tablets with possible dark or light specks, beveled edges, engraved with "A30" on one side.

Pharmacotherapeutic group. Antipsychotic agents. Other antipsychotics. Aripiprazole.

ATC code N05AX12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

It is hypothesized that the efficacy of aripiprazole in schizophrenia and type I bipolar 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 and no significant affinity for muscarinic receptors. Interactions with other receptors, apart from dopamine and serotonin subtypes, may explain some of the other clinical effects of aripiprazole.

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

It has been established that aripiprazole does not 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 of all aripiprazole doses (n = 28242). 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 mean time to onset was 42 days, and the mean 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 mean time to onset was 30 days, and the mean duration was 194 days.

Manic episodes in type I bipolar disorder

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

Pediatric patients

Schizophrenia in adolescents

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

Manic episodes in bipolar disorder in children and adolescents

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

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

Clinical studies demonstrated that aripiprazole was statistically more effective than placebo.

Tourette's disorder-related tics in pediatric patients (see section "Dosage and administration")

The clinical significance of aripiprazole treatment efficacy in children with Tourette's disorder has not been established due to the magnitude of treatment effect compared to 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 fluctuating disorder.

Pharmacokinetics.

Absorption

Aripiprazole is well absorbed, and peak plasma concentrations are reached 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 dehydroaripiprazole are protein-bound in plasma, primarily to albumin.

Biotransformation

Aripiprazole is actively metabolized by the liver, primarily via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro data indicate that CYP3A4 and CYP2D6 enzymes are responsible for the dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by the CYP3A4 enzyme. Aripiprazole is the predominant drug substance in the systemic circulation. At steady state, dehydroaripiprazole, 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 individuals with normal CYP2D6 metabolism and approximately 146 hours in poor CYP2D6 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 hydroaripiprazole 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 subjects and younger subjects, 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 hydroaripiprazole were 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 show a significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and hydroaripiprazole; however, the study included only 3 patients with Child-Pugh class C cirrhosis, which is insufficient to draw definitive conclusions.

Clinical characteristics.

Indications.

The medicinal product Zylaxera® is indicated for the treatment of schizophrenia in adults.

The medicinal product Zylaxera® is indicated for the treatment of moderate to severe manic episodes in bipolar I disorder, as well as for the prevention of new manic episodes in adults who have previously experienced manic episodes and who have responded to treatment with aripiprazole.

Contraindications.

Hypersensitivity to aripiprazole or to any of the excipients.

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 possibility of 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 disrupt electrolyte balance.

Potential effect of other medicinal products on aripiprazole.

The H2-histamine receptor antagonist famotidine, an inhibitor of gastric acid secretion, 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.

Ketoconazole and other CYP3A4 inhibitors.

In individuals with reduced CYP2D6 metabolism, concomitant administration of potent CYP3A4 inhibitors may lead to higher plasma concentrations of aripiprazole compared to those 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 minor increase in aripiprazole concentrations may occur with concomitant use of weak CYP3A4 inhibitors (e.g., diltiazem or escitalopram) or CYP2D6 inhibitors.

Carbamazepine and other CYP3A4 inducers.

When carbamazepine, a potent CYP3A4 inducer, was co-administered with oral aripiprazole in patients with schizophrenia and schizoaffective disorder, geometric mean Cmax and AUC of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean Cmax and AUC of dehydroaripiprazole were reduced by 69% and 71%, respectively, during co-administration 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 theoretically expected to have a similar effect; therefore, appropriate dose escalation of aripiprazole is required. After discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended level.

Valproate and lithium.

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

Serotonin syndrome.

Cases of serotonin syndrome have been reported in patients receiving aripiprazole, particularly when used concomitantly with other serotonergic agents, such as selective serotonin reuptake inhibitors / serotonin-norepinephrine reuptake inhibitors, 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-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan).

No clinically significant changes in concentrations of valproate, lithium, or lamotrigine were observed when administered concomitantly with aripiprazole.

Special precautions for use.

Improvement of 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 careful 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 patients taking antipsychotics often have acquired risk factors for VTE, 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 appear in a patient taking aripiprazole, consideration should be given to reducing the dose or discontinuing treatment. These symptoms may temporarily worsen or even emerge after discontinuation of treatment.

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 potentially fatal syndrome associated with the use of antipsychotic drugs.

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 very high body temperature of unknown origin without additional clinical features of NMS, all antipsychotic medications, including aripiprazole, should be discontinued immediately.

Seizures: rare cases of seizures have been observed 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 associated with Alzheimer's disease, the risk of death is increased. Although the causes of fatal outcomes 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 associated with Alzheimer's disease, adverse cerebrovascular events (e.g., stroke, transient ischemic attack), including fatal cases, have been observed.

A strong dose-dependent relationship between aripiprazole and the occurrence of cerebrovascular adverse events has been noted in patients receiving the drug.

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

Hyperglycemia 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 hyperglycemia-related adverse reactions 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). Patients with diabetes or risk factors for diabetes should be regularly monitored for elevated glucose levels.

Hypersensitivity: hypersensitivity reactions may occur during the use of aripiprazole.

Weight gain: weight gain is commonly 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. Cases of weight gain during aripiprazole treatment were generally observed in patients with significant risk factors, such as diabetes, thyroid disorders, or pituitary adenoma in their medical history.

Aripiprazole does not cause clinically significant weight gain in adults.

Dysphagia: antipsychotics, including aripiprazole, may impair esophageal motility and cause 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 an increased urge to gamble and an inability to control this urge during aripiprazole treatment. Increased sexual drive, 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 urges, compulsive shopping, binge drinking, or overeating (see "Adverse reactions"). Symptoms of impulse control disorders may be related to the underlying disorder; however, in some cases, these disturbances resolved with 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 medication if such disorders occur during aripiprazole treatment.

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

Lactose: Zilaxera® contains lactose. This medicinal product should not be administered to patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

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

There are no adequate and well-controlled studies of aripiprazole use in pregnant women. Congenital anomalies have been reported, but a causal relationship with aripiprazole has not been established. Animal studies have not ruled out a potential adverse effect on fetal development. Patients should be advised to inform their physician if they become pregnant or plan to become pregnant during aripiprazole treatment. Due to insufficient human safety data and problems identified in reproductive animal studies, this medication should not be used during pregnancy unless the expected benefit clearly outweighs the potential risk to the fetus.

Newborns whose mothers have taken antipsychotics (including aripiprazole) during the third trimester of pregnancy are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration after birth. Reports include agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding difficulties. Therefore, newborns should be closely monitored.

Aripiprazole and its metabolites are excreted in breast milk. The decision to discontinue breastfeeding or to discontinue/abstain from aripiprazole therapy should be made considering the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Reproductive toxicity studies indicate that aripiprazole does not impair fertility.

Effects on ability to drive and use machines

Aripiprazole has a negligible or moderate influence on the ability to drive and operate machinery, as it may cause nervous system-related side effects and visual effects such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").

Method of Administration and Dosage

Adults

Schizophrenia: The recommended initial dose of Zylaxer® is 10 or 15 mg once daily, with a maintenance dose of 15 mg once daily, administered independently of food intake.

Zylaxer® is effective within a dosage range of 10 to 30 mg daily. Superior efficacy of doses exceeding 15 mg daily has not been demonstrated, although higher doses may be beneficial for individual patients. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder: The recommended initial dose of Zylaxer® is 15 mg once daily, administered independently of food intake, either as monotherapy or in combination therapy (see section "Pharmacological properties"). Higher doses may be beneficial for certain patients. The maximum daily dose should not exceed 30 mg.

Prevention of new manic episodes in bipolar I disorder: To prevent recurrence of manic episodes in patients receiving aripiprazole as monotherapy or in combination therapy, treatment should be continued at the same dose. Dose adjustment, including dose reduction, should be considered based on clinical status.

Hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. There is insufficient data to provide recommendations for patients with severe hepatic impairment. In such patients, dosing should be performed with caution, particularly regarding the use of the maximum daily dose of 30 mg (see section "Pharmacological properties").

Renal impairment

Dose adjustment is not required in patients with renal impairment.

Geriatric patients

The efficacy and safety of Zylaxer® in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older have not been established. Due to the increased sensitivity of this patient group, a lower initial dose should be considered when clinical factors are present (see section "Special precautions").

Gender

Male and female patients do not require dose adjustment based on gender (see section "Pharmacological properties").

Smoking

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

Dose adjustment due to drug interactions

When co-administered with strong CYP3A4 or CYP2D6 inhibitors, the dose of aripiprazole should be reduced. After discontinuation of a CYP3A4 or CYP2D6 inhibitor as part of combination therapy, the aripiprazole dose should be increased (see section "Interaction with other medicinal products and other forms of interaction").

When co-administered with strong CYP3A4 inducers, the dose of aripiprazole should be increased. After discontinuation of a CYP3A4 inducer as part of combination therapy, the aripiprazole dose should be reduced to the recommended dose (see section "Interaction with other medicinal products and other forms of interaction").

Children

The safety and efficacy of aripiprazole in children have not been studied.

Overdose

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

Additionally, data on accidental aripiprazole overdose (up to 195 mg) in children without fatal outcomes have been reported. Potentially clinically significant observed symptoms included somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Management of overdose should include supportive care, maintenance of airway patency, oxygen therapy, mechanical ventilation if necessary, and symptomatic treatment. The possibility of overdose with multiple medicinal products should be considered. Therefore, immediate cardiovascular monitoring is required, including ECG monitoring to detect potential arrhythmias.

After confirmed or suspected aripiprazole overdose, close medical supervision and monitoring of the patient's condition are necessary until recovery.

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

Although information regarding the effect of hemodialysis in aripiprazole overdose is lacking, hemodialysis is unlikely to be beneficial in treating overdose due to the extensive plasma protein binding of aripiprazole.

Adverse Reactions

The most common adverse reactions were akathisia and nausea, occurring in more than 3% of patients treated with oral aripiprazole.

The table below lists adverse reactions observed during clinical trials and during post-marketing use of aripiprazole. The frequency of adverse reactions reported in the post-marketing period cannot be estimated from the available data.

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 controlled 12-week 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

Class effect: in susceptible patients, symptoms of dystonia, consisting of prolonged muscle contractions in muscle groups, may occur during the first few days of treatment. Dystonia symptoms include neck muscle spasms, which sometimes progress to throat tightness, difficulty swallowing, difficulty breathing, 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 increased in males and younger patients.

Prolactin

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

Laboratory parameters

Comparison of laboratory parameters (including lipid profile) in patients receiving aripiprazole and placebo did not reveal 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.

Paediatric patients

Schizophrenia in adolescents aged 15 years and older

In a short-term placebo-controlled clinical study involving 302 adolescents (aged 13 to 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults, except for the following reactions observed more frequently in adolescents than in adults receiving aripiprazole (more frequently than with placebo): somnolence/sedation and extrapyramidal disorders (very common), as well as dry mouth, increased appetite, and orthostatic hypotension (common).

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

The safety profile identified in a long-term double-blind placebo-controlled clinical study was also similar, except for the following adverse reactions that occurred commonly and more frequently in children and adolescents compared to the placebo group: weight decrease, increased blood insulin levels, arrhythmia, and leukopenia.

In the pooled group of adolescents with schizophrenia aged 13–17 years exposed to the drug for up to 2 years, the frequency of prolactin level decrease in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 29.5% and 48.3%, respectively.

In adolescents with schizophrenia aged 13–17 years receiving 5 to 30 mg aripiprazole for up to 72 months, the frequency of prolactin level decrease in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 25.6% and 45.0%, respectively.

In two clinical studies involving adolescents (aged 13–17 years) with schizophrenia and bipolar disorder receiving aripiprazole, the frequency of prolactin level decrease in girls (< 3 ng/mL) and boys (< 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 adverse reactions in adolescents with bipolar I disorder were similar to those in adults, except for the following adverse reactions: very common (≥ 1/10) — somnolence (23.0%), extrapyramidal disorders (18.4%), akathisia (16.0%), and fatigue (11.8%); common (≥ 1/100, < 1/10) — upper abdominal pain, palpitations, weight gain, increased appetite, muscle twitching, and dyskinesia.

Adverse reactions that may be dose-dependent: extrapyramidal disorders (incidence with aripiprazole 10 mg — 9.1%, 30 mg — 28.8%, placebo — 1.7%); akathisia (incidence with aripiprazole 10 mg — 12.1%, 30 mg — 20.3%, placebo — 1.7%).

Mean change in body weight in adolescents with bipolar I disorder at week 12 and week 30 of aripiprazole treatment was 2.4 kg and 5.8 kg, respectively, compared to 0.2 kg and 2.3 kg in the placebo group.

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

In paediatric patients aged 10–17 years exposed to the drug for up to 30 weeks, the frequency of prolactin level decrease in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 28.0% and 53.3%, respectively.

Pathological gambling and other impulse control disorders

Patients taking aripiprazole may experience pathological gambling, increased sexual drive (hypersexuality), compulsive shopping, and compulsive overeating.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

The medicinal product does not require special storage conditions.

Keep out of reach of children.

Packaging.

10 tablets in a blister, 3 or 6 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. KRKA, d.d., Novo mesto, Slovenia.

Manufacturer's address and place of business.

Šmarješka cesta 6, 8501 Novo mesto, Slovenia.