Arip mt

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Arip MT (ARIP MT)

Composition:

Active substance: aripiprazole;

1 tablet contains aripiprazole 10 mg or 15 mg;

Excipients: mannite (E 421), colloidal anhydrous silicon dioxide, magnesium stearate, crospovidone, hydroxypropylcellulose, microcrystalline cellulose, tartaric acid, vanillin, potassium acesulfame.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: round, white to almost white tablets with imprint «10» on one side and smooth on the other side;

15 mg tablets: round, white to almost white tablets with imprint «15» on one side and smooth on the other side.

Pharmacotherapeutic group. Antipsychotic agents (neuroleptics).

ATC code N05A X12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

It is hypothesized 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 and lacks significant affinity for muscarinic receptors. Interaction with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole administered to healthy subjects at doses of 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 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 have shown an initial response to treatment.

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

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

Prolactin. Prolactin levels were evaluated in trials across 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 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 a period of more than 3 weeks.

Pediatric patients

Schizophrenia in adolescents

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

Manic episodes in bipolar disorder in children and adolescents

The most commonly reported adverse effects during treatment 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 patients receiving placebo.

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

Based on study results, aripiprazole demonstrated statistically greater efficacy compared to placebo.

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

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

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 bound to serum proteins, primarily albumin.

Biotransformation

Aripiprazole is extensively metabolized in the liver, primarily via three metabolic pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro data indicate that CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant drug substance in 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 adjusted for body weight.

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 did not reveal any evidence of clinically significant effects of smoking on the pharmacokinetic properties of aripiprazole.

Race

Assessment of patient groups did not reveal any 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, only 3 patients with Child-Pugh class C cirrhosis were included in the study, which is insufficient to draw definitive conclusions.

Clinical characteristics.

Indications.

Adults.

Treatment of schizophrenia.

Treatment of moderate to severe manic episodes in bipolar I disorder.

Prevention of new manic episodes in patients who have already experienced such episodes and have been treated with aripiprazole.

Contraindications.

Hypersensitivity to aripiprazole or to any other component of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Aripiprazole may potentially enhance the effect of certain antihypertensive agents due to α1-adrenergic receptor blockade.

Given the primary effect of aripiprazole on the central nervous system, caution should be exercised when administering aripiprazole concomitantly with alcohol and other medicinal products affecting the central nervous system.

Caution is advised when using aripiprazole concomitantly with medicinal products that may prolong the QT interval or cause electrolyte imbalances.

Potential effect of other medicinal products on aripiprazole

No significant effect on aripiprazole pharmacokinetics was observed with famotidine, an H2 histamine receptor blocker that causes marked suppression of gastric hydrochloric acid secretion.

Aripiprazole is metabolized via multiple pathways, including CYP2D6 and CYP3A4 enzymes, but not by CYP1A enzymes. Therefore, dosage adjustment is not required for smokers.

Quinidine and other CYP2D6 inhibitors

Potent CYP2D6 inhibitors (quinidine) increase aripiprazole AUC by 107%, while maximum concentration (Cmax) remains unchanged.

AUC and Cmax of dehydroaripiprazole, the active metabolite, decrease by 32% and 47%, respectively. The dose of aripiprazole should be reduced by half when coadministered with quinidine. Other CYP2D6 inhibitors, such as fluoxetine and paroxetine, may have similar effects, and dose reduction may be necessary.

Ketoconazole and other CYP3A4 inhibitors

Studies have shown that potent CYP3A4 inhibitors (ketoconazole) increase aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax of dehydroaripiprazole increase by 77% and 43%, respectively. Concomitant use of potent CYP3A4 inhibitors may lead to increased blood concentrations of aripiprazole. When coadministering ketoconazole or other potent CYP3A4 inhibitors, the potential benefits and possible risks for the patient should be carefully weighed. When coadministering ketoconazole, the recommended dose of aripiprazole should be reduced by approximately half. Similar effects are expected with other potent CYP3A4 inhibitors such as itraconazole or HIV protease inhibitors, so dose reduction is also required. After discontinuation of CYP2D6 or CYP3A4 inhibitors, the aripiprazole dose should be increased to the initial level. With concomitant use of weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram), a moderate increase in aripiprazole concentration may be expected.

Carbamazepine and other CYP3A4 inducers

Administration of 30 mg aripiprazole with carbamazepine, a potent CYP3A4 inducer, resulted in a reduction of aripiprazole Cmax and AUC by 68% and 73%, respectively, and a reduction in Cmax and AUC of its active metabolite dehydroaripiprazole by 69% and 71%, respectively. The dose of aripiprazole should be doubled when coadministered with carbamazepine. A similar effect can be expected with other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, St. John’s wort). After discontinuation of potent CYP3A4 inducers, the aripiprazole dose should be reduced to the recommended dose.

Valproate and lithium

No clinically significant effect on aripiprazole concentration was observed when valproate or lithium were coadministered with aripiprazole; therefore, dose adjustment is not required.

Effect of aripiprazole on other medicinal products

At doses of 10–30 mg/day, aripiprazole has no effect on the metabolism of CYP2D6 substrates (dextromethorphan/3-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Furthermore, aripiprazole and its major metabolite dehydroaripiprazole do not affect CYP1A2 enzyme activity in vitro. The likelihood of clinically significant effects of aripiprazole on medicinal products metabolized by these enzymes is low. Thus, aripiprazole does not cause clinically significant interactions mediated by these enzymes. When aripiprazole is administered concomitantly with valproate, lithium, or lamotrigine, there are no clinically important changes in the concentrations of valproate, lithium, or lamotrigine.

Serotonin syndrome

Serotonin syndrome has been reported in patients taking aripiprazole, particularly when used concomitantly with serotonergic medicinal products such as serotonin reuptake inhibitors / serotonin-norepinephrine reuptake inhibitors, or medicinal products that increase aripiprazole concentrations (see section "Adverse reactions").

Special precautions for use.

Clinical improvement with antipsychotic agents may take from several days to several weeks. During this period, careful monitoring of patients is required.

Suicidal behaviour

Suicidal behaviour, typical of psychiatric disorders and mood disturbances, has been observed immediately after initiating or changing neuroleptics, including aripiprazole (see section "Adverse reactions"). Patients at high risk of suicide require close medical supervision when treated with neuroleptics.

Cardiovascular disorders

Aripiprazole should be used with caution in patients with cardiovascular diseases (including history of myocardial infarction or ischemic heart disease, heart failure, or conduction disorders), cerebrovascular disorders, or conditions leading to arterial hypotension (dehydration, hypovolemia, and treatment with antihypertensive agents), or arterial hypertension, including exacerbation or malignant hypertension. Cases of venous thromboembolism have been reported during treatment with neuroleptics. Before initiating and during treatment with neuroleptics, possible risk factors for venous thromboembolism should be identified and appropriate preventive measures taken.

Conduction disturbances

During clinical trials of aripiprazole, QT interval prolongation has been observed compared to placebo. Aripiprazole, like other neuroleptics, should be used with caution in patients with a history of QT interval prolongation (see section "Adverse reactions").

Tardive dyskinesia

The risk of developing tardive dyskinesia increases with the duration of neuroleptic therapy. Therefore, if symptoms of tardive dyskinesia appear during aripiprazole treatment, the dose should be reduced or treatment discontinued (see section "Adverse reactions"). After discontinuation of treatment, these symptoms may transiently worsen or even emerge.

Other extrapyramidal symptoms

Aripiprazole has been associated with akathisia and parkinsonism in children. If signs of other extrapyramidal symptoms occur, dose reduction should be considered, and careful clinical monitoring of the patient should be performed.

Malignant neuroleptic syndrome (MNS)

A life-threatening complex of symptoms known as malignant neuroleptic syndrome has been reported during treatment with neuroleptics, including aripiprazole. This syndrome is characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (irregular pulse and blood pressure, tachycardia, diaphoresis, and cardiac arrhythmias). Additionally, increased creatine phosphokinase activity, myoglobinuria (rhabdomyolysis), and acute renal failure may occur. If symptoms of MNS or unexplained fever develop, all neuroleptics, including aripiprazole, should be discontinued.

Seizures

Seizures were infrequently reported in clinical trials of aripiprazole. Therefore, aripiprazole should be used with caution in patients with a history of seizures or conditions associated with seizure occurrence (see section "Adverse reactions").

Geriatric patients with psychosis associated with dementia

Increased risk of mortality

In clinical trials of aripiprazole in elderly patients with Alzheimer's disease (mean age 82 years), an increased risk of mortality was observed compared to placebo. Mortality rates were 3.5% with aripiprazole versus 1.7% with placebo. Causes of death varied and included cardiovascular events (e.g., heart failure, sudden cardiac death) and infections (e.g., pneumonia) (see section "Adverse reactions").

Cerebrovascular adverse reactions

Cerebrovascular adverse events (e.g., stroke, transient ischemic attacks), including fatal cases (mean age 84 years, range 78 to 88 years), have been reported. Overall, cerebrovascular adverse events occurred in 1.3% of patients receiving aripiprazole compared to 0.6% of those receiving placebo. This difference was not statistically significant. Furthermore, in fixed-dose studies, a relationship between aripiprazole use and cerebrovascular adverse reactions was observed (see section "Adverse reactions").

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

Hyperglycemia and diabetes mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, which may lead to hyperosmolar coma or even death, has been reported in patients treated with atypical neuroleptics, including aripiprazole. Although the relationship between atypical neuroleptic use and hyperglycemic disorders remains unclear, patients with diagnosed diabetes should have regular blood glucose monitoring during treatment with atypical neuroleptics. Patients with risk factors for diabetes (e.g., obesity, family history of diabetes) should have blood glucose levels assessed at the beginning of treatment and periodically during therapy. All patients receiving atypical neuroleptics should be continuously monitored for symptoms of hyperglycemia (such as increased thirst, frequent urination, polyphagia, weakness). In patients with diabetes or risk factors for diabetes, regular glucose monitoring is recommended (see section "Adverse reactions").

Hypersensitivity

As with other medicinal products, hypersensitivity/allergic reactions are possible (see section "Adverse reactions").

Weight gain

Weight gain is frequently observed in patients with schizophrenia or bipolar disorder manic episodes due to comorbid conditions, use of other weight-gain-inducing neuroleptics, and lifestyle factors, which may lead to serious complications.

Weight gain has been observed in patients treated with aripiprazole. These patients often have significant risk factors such as history of diabetes, thyroid disorders, or pituitary adenoma. In clinical trials, aripiprazole did not cause clinically significant weight gain in adults (see section "Pharmacodynamics"). If significant weight gain occurs, dose reduction should be considered (see section "Adverse reactions").

Dysphagia

Neuroleptics, including aripiprazole, may impair esophageal motility and cause aspiration. Aripiprazole, like other neuroleptics, should be used with caution in patients at increased risk of aspiration pneumonia.

Pathological gambling and other impulse control disorders

Cases of pathological gambling and inability to control this urge have been reported in patients treated with aripiprazole. Hypersexuality, compulsive shopping, binge eating, or uncontrolled eating urges, and other impulse and compulsive behaviour disorders have also been reported. It is important that patients and caregivers inform the physician about the development of new or aforementioned disorders during aripiprazole treatment. Impulse control disorders may be related to the underlying condition; however, in some cases, pathological urges have resolved with dose reduction or discontinuation of treatment. Impulse control disorders may harm the patient and others if not recognized. If such disorders develop during aripiprazole treatment, dose reduction or discontinuation should be considered (see section "Adverse reactions").

Patients with comorbid attention deficit hyperactivity disorder (ADHD)

Despite the high prevalence of comorbid ADHD and bipolar disorders, safety data on the concomitant use of aripiprazole and stimulants are limited; therefore, caution is advised when using the medicinal product Arip MT.

Falls

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

Use during pregnancy or breastfeeding

Pregnancy

Adequate and well-controlled studies on the use of aripiprazole in pregnant women have not been conducted. Congenital anomalies have been reported, but a causal relationship has not been established. Animal studies do not exclude the possibility of embryofetotoxicity. Patients should consult their physician if pregnancy occurs or is planned during aripiprazole treatment. Due to insufficient safety data during pregnancy, the drug should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus. Use of neuroleptics, including aripiprazole, during the third trimester of pregnancy may lead to adverse reactions in newborns, including extrapyramidal and/or withdrawal symptoms of varying severity and duration. Reports include agitation, arterial hypertension or hypotension, tremor, somnolence, respiratory distress, or feeding difficulties. Therefore, newborns should be closely monitored.

Breastfeeding

Aripiprazole passes into breast milk. If aripiprazole use is necessary, breastfeeding should be discontinued.

Fertility

Reproductive toxicity studies indicate that aripiprazole does not impair fertility.

Ability to influence psychomotor performance when driving or operating machinery

Aripiprazole, like other neuroleptics, has a slight to moderate effect on the ability to drive or operate machinery: it may affect the nervous system and visual organs, causing adverse reactions such as sedation, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions"). During treatment, patients should refrain from driving or operating machinery until their individual response to the drug is known.

Dosage and Administration

The tablets are intended for oral administration to adults.

Schizophrenia. The recommended initial dose is 10 or 15 mg once daily, regardless of food intake. The maintenance dose is 15 mg daily. The effective dose range is 10 to 30 mg daily. Increased efficacy with doses higher than 15 mg has not been demonstrated, although some patients may require higher doses. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder. The recommended initial dose is 15 mg once daily, regardless of food intake, both as monotherapy and in combination therapy. Some patients may require higher doses. The maximum daily dose should not exceed 30 mg.

Prevention of recurrent manic episodes in bipolar I disorder. For prevention of manic episodes in patients previously treated with aripiprazole as monotherapy or in combination therapy, treatment should be continued at the same doses.

Adjustment or reduction of the daily dose should be determined by the physician based on the patient's clinical condition.

Patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. Insufficient data are available to provide recommendations for patients with severe hepatic impairment. In such patients, dose selection should be made with extreme caution. Particular caution is required when using the maximum daily dose of 30 mg (see section "Pharmacological properties").

Patients with renal impairment

Dose adjustment is not required.

Elderly patients

The efficacy of aripiprazole in treating schizophrenia and bipolar I disorder in patients aged 65 years and older has not been studied. Due to the increased sensitivity of this patient population, consideration should be given to using lower initial doses (see section "Special precautions for use").

Gender

Dose adjustment based on patient gender is not required (see section "Pharmacological properties").

Smoking

Due to the metabolic pathway of aripiprazole, dose adjustment for smokers is not necessary (see section "Special precautions for use").

Dose adjustment in drug interactions

When aripiprazole is co-administered with strong inhibitors of CYP3A4 or CYP2D6, the dose of aripiprazole should be reduced. When inhibitors of CYP3A4 or CYP2D6 are discontinued during combination therapy, the dose of aripiprazole should be increased (see section "Special precautions for use").

When aripiprazole is co-administered with a strong inducer of CYP3A4, the dose of aripiprazole should be increased. When an inducer of CYP3A4 is discontinued during combination therapy, the dose of aripiprazole should be reduced to the recommended dose (see section "Special precautions for use").

Children

The safety and efficacy of aripiprazole in children (under 18 years of age) have not been established.

Overdose.

Cases of accidental or intentional aripiprazole overdose with single doses up to 1260 mg, not resulting in fatal outcomes, have been reported. Potentially clinically significant symptoms included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. Additionally, cases of aripiprazole overdose in children (ingestion up to 195 mg) not leading to fatal outcomes have been described. Potentially dangerous symptoms of overdose include somnolence, transient loss of consciousness, and extrapyramidal disorders.

Treatment: supportive therapy is required in case of overdose, including ensuring adequate airway patency, oxygenation, effective lung ventilation, and symptomatic treatment. Concomitant drug reactions should be considered. Immediate cardiac monitoring with ECG should be initiated to detect arrhythmias. After confirmed or suspected aripiprazole overdose, close medical observation is necessary until all symptoms have resolved.

Activated charcoal (50 g), administered one hour after aripiprazole intake, reduces AUC and Cmax of aripiprazole in blood by 51% and 41%, respectively, supporting its use in overdose management.

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 bound to plasma proteins.

Adverse Reactions.

Summary of safety profile.

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

List of adverse reactions.

The table below lists adverse events observed during clinical trials and during post-marketing use of aripiprazole.

All adverse reactions are listed by system organ classes 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), frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.

The frequency of adverse reactions reported 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.

Description of individual adverse reactions

Extrapyramidal symptoms (EPS)

Schizophrenia: In a 52-week long-term controlled study in patients receiving aripiprazole, the overall incidence of EPS (25.8%), including parkinsonism, akathisia, dystonia, and dyskinesia, was lower than in patients receiving haloperidol (57.3%). In a 26-week long-term placebo-controlled study, the incidence of EPS was 19% in patients receiving aripiprazole and 13.1% in patients receiving placebo. In another 26-week long-term 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 receiving 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. During the long-term 26-week maintenance phase of a placebo-controlled study, 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 and 3.2% with placebo. In patients with schizophrenia, the incidence of akathisia was 6.2% with aripiprazole and 3.0% with placebo.

Dystonia

Symptoms of dystonia, characterized by prolonged pathological muscle contractions, are typical for this class of medicinal products and may occur in patients during the first days of treatment. Dystonia symptoms include neck muscle spasms, sometimes progressing to throat tightness, difficulty swallowing, breathing difficulties, and/or tongue protrusion. Since these symptoms may occur even with low doses, they are more frequent and more severe with high 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 compared to baseline levels have been observed.

Laboratory parameters

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

Pediatric 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 observed in adults, except for the following reactions, which were more frequently observed 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), were very commonly observed.

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, which were common and occurred more frequently in children and adolescents compared to the placebo group: weight decrease, increased blood insulin levels, arrhythmia, and leukopenia (common).

In the pooled group of adolescents with schizophrenia aged 13–17 years exposed to the drug for up to 2 years, the frequency of decreased prolactin levels 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 of aripiprazole for up to 72 months, the frequency of decreased prolactin levels 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 decreased prolactin levels 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 possibly 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%).

The 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 more frequently observed in pediatric patients with bipolar disorder compared to those with schizophrenia.

In pediatric patients aged 10–17 years exposed to the drug for up to 30 weeks, the frequency of decreased prolactin levels 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 libido (hypersexuality), compulsive shopping, and compulsive overeating.

Reporting suspected adverse reactions

Reporting of adverse reactions after drug authorization is highly important. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or 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.

Store at temperatures not exceeding 25 °C in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a strip, 3 strips in a cardboard pack.

10 tablets in a blister; 3 blisters in a cardboard pack.

Prescription category. Prescription only.

Manufacturer.

TORRENT PHARMACEUTICALS LTD.

Manufacturer's location and address of its business premises.

Indrad Plant, Vill. Indrad, Taluka Kadi, Dist. Mehsana, Gujarat 382721, India.