Frenorma

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FRENORMA (FRENORMA)

Composition:

Active substance: aripiprazole;

1 tablet contains aripiprazole 10 mg or 15 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hydroxypropylcellulose, maize starch, magnesium stearate, iron oxide red (E 172) – for 10 mg tablets, iron oxide yellow (E 172) – for 15 mg tablets.

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: pink, rectangular tablets with engraving «CL 74» on one side and smooth on the other side;

15 mg tablets: yellow, round tablets with engraving «CL 75» on one side and smooth on the other side.

Pharmacotherapeutic group. Antipsychotic agents. Other neuroleptics. Aripiprazole.

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 demonstrates moderate binding affinity for serotonin reuptake and lacks 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.

Administration of aripiprazole to healthy volunteers at doses ranging from 0.5 to 30 mg once daily for 2 weeks resulted in a dose-dependent reduction in 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

Adults

Schizophrenia

Aripiprazole is effective in maintaining clinical improvement during continued treatment in adult patients who have shown an initial response to therapy.

In a 26-week placebo-controlled study in patients with stabilized chronic schizophrenia, aripiprazole significantly reduced the rate of relapse: 34% in the aripiprazole group versus 57% in the placebo group.

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

The incidence of hyperprolactinemia or increased serum prolactin levels in patients treated with 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 bipolar I disorder

Aripiprazole demonstrated superior efficacy compared to placebo in reducing manic symptoms over a 3-week period.

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. In a subgroup analysis of adolescents aged 15 to 17 years, who constituted 74% of the total enrolled patients, efficacy was maintained throughout a 26-week open-label extension study.

Manic episodes in bipolar disorder in children and adolescents

Aripiprazole was studied in a 30-week placebo-controlled trial involving 296 children and adolescents (aged 10 to 17 years) who met DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for bipolar I disorder with or without manic or psychotic features and had a baseline YMRS score ≥ 20. Among patients included in the primary efficacy analysis, 139 had a current comorbid diagnosis of ADHD (attention-deficit/hyperactivity disorder).

Aripiprazole was superior to placebo in change from baseline at Week 4 and Week 12 in total YMRS score. In a retrospective analysis, improvement compared to placebo was more pronounced in patients with comorbid ADHD than in those without, in whom no difference from placebo was observed. Prevention of relapse has not been established.

The most commonly reported treatment-emergent adverse events 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")

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

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

The clinical significance of efficacy results with aripiprazole in children with Tourette’s syndrome has not been established due to the magnitude of treatment effect relative to a substantial placebo effect and unclear effects on psychosocial functioning. Long-term data on the efficacy and safety of aripiprazole in this fluctuating disorder are not available.

Pharmacokinetics.

Absorption

Aripiprazole is well absorbed, with peak plasma concentrations occurring 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 throughout 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 extensively metabolized in the liver, primarily via three biotransformation pathways: dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies indicate that CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, and CYP3A4 catalyzes N-dealkylation. Aripiprazole is the predominant drug moiety 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 CYP2D6 extensive metabolizers and approximately 146 hours in CYP2D6 poor metabolizers.

Total clearance of aripiprazole is 0.7 mL/min/kg and occurs primarily in the liver.

Following administration of 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% is excreted unchanged in feces.

Children

The pharmacokinetic properties of aripiprazole and hydroaripiprazole in patients aged 10 to 17 years were similar to those observed in adults after correction for differences in body weight.

Elderly patients

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy elderly volunteers and children. There was no notable effect of patient age on the pharmacokinetic analysis in patients with schizophrenia.

Gender

No differences in the pharmacokinetic properties of aripiprazole were observed between healthy male and female subjects. There was no notable effect of gender on the pharmacokinetic analysis 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 volunteers.

Hepatic impairment

A single-dose clinical study in patients with varying degrees of liver cirrhosis (Child-Pugh classes A, B, and C) did not reveal a significant effect of hepatic impairment on the pharmacokinetic properties of aripiprazole and hydroaripiprazole; however, the study included only 3 patients with Child-Pugh class C cirrhosis, which is insufficient to draw conclusions about their metabolic capacity.

Clinical characteristics.

Indications.

Treatment of schizophrenia in adults and adolescents aged 15 years and older.

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

Treatment of moderate to severe manic episodes in bipolar I disorder in adolescents aged 13 years and older, for up to 12 weeks.

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 prescribing aripiprazole concomitantly with other CNS-active medicinal products, due to possible additive adverse reactions such as sedation.

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

Potential effect of other medicinal products on aripiprazole

The gastric acid secretion inhibitor, H2-histamine receptor antagonist famotidine, reduces the rate of absorption of aripiprazole, 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 co-administered 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 patients with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may lead to 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 co-administered 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 reductions should be made accordingly.

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

A slight increase in aripiprazole concentration may occur when co-administered with weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram).

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 values of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean Cmax and AUC values of dehydro-aripiprazole were reduced by 69% and 71%, respectively, during co-administration with carbamazepine compared to aripiprazole monotherapy.

The dose of aripiprazole should be doubled when co-administered with carbamazepine. Other potent CYP3A4 inducers (rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) are theoretically expected to have a similar effect; therefore, a corresponding dose increase 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 concentration were observed when valproate or lithium was co-administered with aripiprazole; therefore, dose adjustment is not required.

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).

Aripiprazole in vitro showed no potential to alter CYP1A2-mediated metabolism. Therefore, it is unlikely that aripiprazole will cause clinically significant interactions with medicinal products metabolized by these enzymes.

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

Serotonin syndrome

Cases of serotonin syndrome have been reported in patients taking 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.

Special precautions for use.

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

Suicidal tendencies. Suicidal behavior is characteristic of patients with psychotic disorders and affective disorders and has been observed shortly after initiation of antipsychotic therapy or switching from one antipsychotic to another, including treatment with aripiprazole. Antipsychotic therapy 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 or 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. As with other antipsychotics, 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 transiently worsen or even emerge after discontinuation of therapy.

Other extrapyramidal symptoms. Akathisia and parkinsonism were observed in pediatric clinical trials of aripiprazole. 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 complex of symptoms associated with the use of antipsychotic drugs and may potentially be fatal.

Clinical manifestations of NMS include hyperpyrexia (very high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system dysfunction (irregular 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 necessarily associated with NMS, have also been reported. If a patient develops symptoms of NMS or unexplained very high body temperature without additional clinical signs of NMS, all antipsychotic medications, including aripiprazole, should be discontinued.

Seizures. Seizures have been reported infrequently during treatment with aripiprazole; therefore, the drug 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 fatal outcomes is increased. Although the causes of death varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin.

Cerebrovascular adverse reactions. Cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal cases, have been reported in patients (mean age: 84 years; range: 78 to 88 years). Overall, in these studies, 1.3% of patients receiving aripiprazole reported cerebrovascular adverse events compared to 0.6% of patients receiving placebo. This difference was not statistically significant. A marked dose-dependent relationship between aripiprazole dose and the occurrence of cerebrovascular adverse events was observed in patients receiving aripiprazole.

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 adverse reactions related to hyperglycemia in patients treated with aripiprazole versus other atypical antipsychotics. Close monitoring of patients taking any antipsychotics, including aripiprazole, is necessary, with attention to symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). The condition of patients with diabetes or risk factors for diabetes should be regularly monitored for increased glucose levels.

Hypersensitivity. As with other medications, 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 lack of a healthy lifestyle; this phenomenon may lead to serious complications. During treatment with aripiprazole, weight gain has generally been 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.

In clinical trials of adolescent patients with bipolar mania, aripiprazole was associated with weight gain after 4 weeks of treatment. Weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered (see section "Adverse reactions").

Dysphagia. Antipsychotics, including aripiprazole, may cause esophageal motility disorders and aspiration of gastric contents. 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 episodes of pathological gambling and inability to control these impulses while taking aripiprazole. Hypersexuality, compulsive shopping, binge eating or uncontrolled eating, and other disorders of impulsive and compulsive behavior have also been reported. It is important that physicians inform patients about the development of new or aforementioned disorders during treatment with aripiprazole. It should be noted that symptoms of impulse control disorders may be related to the underlying disorder; however, cessation of impulses has sometimes been reported upon dose reduction or discontinuation of treatment. Impulse control disorders may harm the patient and others if not recognized. If such tendencies develop during aripiprazole treatment, consideration should be given to reducing the dose or discontinuing treatment.

Lactose. The drug Frenorma contains lactose; therefore, it should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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

Falls. Aripiprazole may cause somnolence, orthostatic hypotension, and motor and sensory instability, which may lead to falls. Caution should be exercised when treating patients at higher risk, and consideration should be given to using lower initial doses (e.g., elderly or debilitated patients; see section "Dosage and administration").

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 could not be 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 treatment with aripiprazole. Due to insufficient safety data in humans and problems identified in reproductive animal studies, this drug should not be used during pregnancy unless the expected benefit clearly outweighs the potential risk to the fetus.

Newborns whose mothers took 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. Agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be closely monitored.

Breastfeeding period

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 mother.

Fertility

According to reproductive toxicity studies, aripiprazole did not impair fertility.

Ability to influence reaction speed when driving vehicles or operating machinery.

Aripiprazole has a minor or moderate effect on the ability to drive vehicles 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.

Adults

Schizophrenia. The recommended initial dose of Frenorma is 10 or 15 mg once daily, with a maintenance dose of 15 mg once daily. The medication should be taken independently of food intake.

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

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

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

Children

Schizophrenia in adolescents aged 15 years and older. The recommended dose of aripiprazole is 10 mg once daily, independent of food intake. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/mL) for 2 days, then titrated to 5 mg* over the next 2 days to reach the recommended daily dose of 10 mg. If necessary, further dose increases should be made in 5 mg* increments, without exceeding the maximum daily dose of 30 mg. Aripiprazole is effective within a dosage range of 10 to 30 mg daily. Improved efficacy at doses exceeding 10 mg daily has not been demonstrated, although higher doses may be beneficial for some individual patients. Aripiprazole is not recommended for patients with schizophrenia under 15 years of age due to insufficient safety and efficacy data.

Manic episodes in type I bipolar disorder in adolescents aged 13 years and older. The recommended dose of aripiprazole is 10 mg once daily, independent of food intake. Treatment should be initiated at 2 mg (using aripiprazole oral solution 1 mg/mL) for 2 days, then titrated to 5 mg* over the next 2 days to reach the recommended daily dose of 10 mg. The duration of treatment should be as short as clinically necessary and should not exceed 12 weeks. Improved efficacy at doses exceeding 10 mg daily has not been demonstrated, and a daily dose of 30 mg is associated with a significantly higher incidence of adverse reactions, including extrapyramidal symptoms, somnolence, fatigue, and weight gain (see section "Adverse reactions"). Therefore, doses exceeding 10 mg daily should only be used in exceptional cases and under close clinical monitoring. Younger patients have an increased risk of adverse reactions associated with aripiprazole. Thus, aripiprazole is not recommended for patients under 13 years of age.

Agitation associated with autism. The safety and efficacy of aripiprazole in children and adolescents under 18 years of age have not been established.

Tics associated with Tourette’s disorder. The safety and efficacy of aripiprazole in children and adolescents aged 6 to 18 years have not been established.

*- use aripiprazole formulations with appropriate dosage strengths.

Population-specific considerations

Hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. Insufficient data are available to make recommendations for patients with severe hepatic impairment. In such patients, dosing should be performed with caution. However, the maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section "Pharmacological properties").

Renal impairment

Dose adjustment is not required in patients with renal impairment.

Elderly patients

The efficacy of Frenorma in the treatment of schizophrenia and type I bipolar disorder in patients aged 65 years and older has not been established. Due to increased sensitivity in this patient group, consideration should be given to reducing the initial dose in the presence of clinical factors (see section "Special precautions").

Gender

Female patients do not require dose adjustment compared to male patients (see section "Pharmacological properties").

Smoking

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

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

Children.

The medicinal product Frenorma is indicated for the treatment of schizophrenia in adolescents aged 15 years and older, and for the treatment of moderate to severe manic episodes of type I bipolar disorder in adolescents aged 13 years and older for up to 12 weeks (see section "Method of administration and dosage"). Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL).

Overdose.

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

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

Management of overdose should include supportive care, ensuring airway patency, oxygenation, mechanical ventilation if necessary, and symptom control. The possibility of multiple drug overdose should be considered. Therefore, immediate cardiovascular monitoring is required, including continuous ECG monitoring to detect possible arrhythmias.

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

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

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

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.

Description of individual adverse reactions

Adults

Extrapyramidal symptoms (EPS)

Schizophrenia. In a 52-week controlled study, the incidence of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, was lower in patients receiving aripiprazole (25.8%) compared to those 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 phase of a 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 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: symptoms of dystonia, characterized by prolonged pathological contraction of muscle groups, may occur in susceptible patients during the first few days of treatment. Dystonic symptoms include neck muscle spasms, sometimes progressing to throat constriction, difficulty swallowing, breathing difficulties, and/or protrusion of the tongue. Although these symptoms may occur at low doses, they are more frequent and severe with higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger patients.

Prolactin

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

Laboratory parameters

Comparison of laboratory parameters in patients receiving aripiprazole and placebo revealed no potentially clinically significant differences. Elevations in creatine phosphokinase levels were generally transient and asymptomatic, observed in 3.5% of patients receiving aripiprazole and in 2.0% of patients in the placebo group.

Paediatric patients

Schizophrenia in adolescents aged 15 years and older

In a short-term placebo-controlled clinical trial 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, 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).

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

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

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 paediatric patients with bipolar disorder compared to those with 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

Pathological gambling, hypersexuality, compulsive shopping, binge eating, or loss of control over eating may occur in patients taking aripiprazole.

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 30 °C in the original packaging.

Keep out of the reach of children.

Packaging.

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

Prescription status. Prescription only.

Manufacturer. MACLEODS PHARMACEUTICALS LIMITED.

Manufacturer's address and location of operations.

Village Thedda, P.O. Lodhymaira, Tehsil Baddi, District Solan, Himachal Pradesh, 174101, India.