Abizol

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

Composition:

Active substance: aripiprazole;

1 ml of solution contains 1 mg of aripiprazole;

Excipients: glycerin, disodium edetate, malic acid, sodium hydroxide, propylene glycol, methylparahydroxybenzoate (E 218), propylparahydroxybenzoate (E 216), sucrose, fructose, orange juice flavoring, purified water.

Pharmaceutical form. Oral solution.

Main physicochemical properties: clear, colorless to pale yellow solution with an orange aroma.

Pharmacotherapeutic group.

Psycholeptics. Antipsychotic agents. Other antipsychotics. ATC code N05A X12.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action. The therapeutic effect of aripiprazole in the treatment of schizophrenia and type I bipolar disorder is attributable to a combination of partial agonism at dopamine D2 and serotonin 5-HT1A receptors, and antagonism at serotonin 5-HT2A receptors. Aripiprazole has been shown to exhibit antagonistic properties in animal models of dopaminergic hyperactivity and agonistic properties in animal models of dopaminergic hypoactivity. Aripiprazole has high in vitro binding affinity for dopamine D2 and D3 receptors, serotonin 5-HT1A and 5-HT2A receptors, and moderate affinity for dopamine D4 receptors, serotonin 5-HT2C and 5-HT7 receptors, α1-adrenergic receptors, and histamine H1 receptors. Aripiprazole also has moderate affinity for serotonin receptors and lacks significant affinity for muscarinic receptors. Interaction with other receptors, apart from dopamine and serotonin subtypes, may explain some of the other clinical effects of aripiprazole.

Aripiprazole, administered to healthy volunteers 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 cause clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) or low-density lipoprotein (LDL) levels.

Prolactin

Prolactin levels were evaluated in all trials across all doses of aripiprazole (n = 28,242). 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 treated with aripiprazole was 0.4%, compared to 0.02% in placebo-treated patients. 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 and positive or negative symptoms, treatment with aripiprazole was associated with statistically significant greater improvement in psychotic symptoms compared to placebo.

Manic episodes in bipolar disorder in children and adolescents

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

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

Clinical trials have demonstrated that aripiprazole is statistically 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 treatment in children with Tourette's disorder has not been established due to the magnitude of the treatment effect compared to a 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, with peak plasma concentration (Cmax) reached within 3–5 hours after administration. Aripiprazole undergoes minimal presystemic metabolism. The absolute oral bioavailability of the drug is 87%. Administration with a high-fat meal does not affect the pharmacokinetics 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 doses, aripiprazole and dehydroaripiprazole are more than 99% bound to plasma proteins, primarily albumin.

Biological transformation. Aripiprazole is extensively metabolized in the liver, primarily via dehydrogenation, hydroxylation, and N-dealkylation. According to in vitro studies, CYP3A4 and CYP2D6 enzymes are responsible for dehydrogenation and hydroxylation of aripiprazole, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the primary active substance present in systemic circulation. At steady state, dehydroaripiprazole—the active metabolite—accounts for approximately 40% of the area under the plasma concentration-time curve (AUC) of aripiprazole.

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, primarily due to hepatic clearance. After a single oral dose of

14C-labeled aripiprazole, approximately 27% was excreted in urine and approximately 60% in feces. Less than 1% of unchanged aripiprazole was excreted in urine, and approximately 18% of unchanged aripiprazole was excreted in feces.

Oral solution

Aripiprazole is well absorbed following oral administration as a solution. At equivalent doses, Cmax of aripiprazole from the solution was slightly higher, but AUC was equivalent to that of tablets. In a relative bioavailability study comparing the pharmacokinetics of 30 mg aripiprazole oral solution with 30 mg aripiprazole tablets in healthy volunteers, the geometric mean ratio of Cmax (solution to tablets) was 122% (n = 30). The pharmacokinetics of a single dose of aripiprazole were linear and dose-proportional.

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.

Pharmacokinetics in special patient populations

Elderly patients. No differences in the pharmacokinetic properties of aripiprazole were observed between elderly and young healthy volunteers, 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. Evaluation of patient groups revealed no evidence of clinically significant effects of smoking on the pharmacokinetics of aripiprazole.

Race. Evaluation of patient groups revealed no evidence of clinically significant effects of race on the pharmacokinetics 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 clinical study in patients with varying degrees of liver cirrhosis (Child-Pugh classes A, B, and C) showed no significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and hydroaripiprazole; however, only three patients with Child-Pugh class C cirrhosis were included, which is insufficient for definitive conclusions.

Clinical characteristics.

Indications.

The medicinal product is indicated for the treatment of schizophrenia in adults and adolescents aged 15 years and older.

The medicinal product 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 responded to aripiprazole treatment.

The medicinal product is indicated in children aged 13 years and older for the treatment of moderate to severe manic episodes of bipolar I disorder for a treatment duration of up to 12 weeks.

Contraindications.

Hypersensitivity to aripiprazole or to any of the excipients.

Interaction with other medicinal products and other forms of interaction.

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

Given the primary effect of aripiprazole on the central nervous system (CNS), caution should be exercised when administering aripiprazole concomitantly with alcohol or other CNS-active medicinal products due to possible additive adverse reactions, such as sedation (see section "Adverse reactions").

Aripiprazole should be used with caution in combination with other medicinal products that prolong the QT interval or disturb electrolyte balance.

Potential effect of other medicinal products on aripiprazole

The acid secretion inhibitor, H2-histamine receptor antagonist famotidine, reduces the absorption rate 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

In clinical studies, the potent CYP2D6 inhibitor quinidine was reported to increase aripiprazole AUC by 107% in healthy volunteers, while Cmax remained unchanged. AUC and Cmax of dehydro-aripiprazole, the active metabolite, decreased by 32% and 47%, respectively.

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

Studies have shown that potent CYP3A4 inhibitors (ketoconazole) increase aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax of dehydro-aripiprazole increased by 77% and 43%, respectively. Concomitant use of potent CYP3A4 inhibitors may lead to increased plasma concentrations of aripiprazole. When co-administering ketoconazole or other potent CYP3A4 inhibitors, the potential benefits and possible risks for the patient should be carefully considered. When co-administered with 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; therefore, dose reduction is also required (see section "Dosage and administration"). After discontinuation of CYP2D6 or CYP3A4 inhibitors, the aripiprazole dose should be increased to the original 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

Following co-administration with carbamazepine, a potent CYP3A4 inducer, Cmax and AUC of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole (30 mg). Similarly, Cmax and AUC of dehydro-aripiprazole when co-administered with carbamazepine were 69% and 71% lower, respectively, than during aripiprazole monotherapy.

The dose of aripiprazole should be doubled when co-administered 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 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 were co-administered with aripiprazole; therefore, dose adjustment is not required.

Potential effect of aripiprazole on other medicinal products

In clinical studies, aripiprazole at doses of 10–30 mg daily did not cause clinically relevant drug interactions mediated by CYP2D6 (dextromethorphan/3-methoxymorphinan ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Additionally, aripiprazole and dehydro-aripiprazole have not been shown to affect CYP1A2-mediated metabolism in vitro. Therefore, it is unlikely that aripiprazole exerts a clinically significant effect on substances metabolized by this enzyme.

No clinically significant changes in valproate, lithium, or lamotrigine concentrations 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 (see section "Adverse reactions").

Special precautions for use.

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

Suicidal tendencies. Suicidal behaviour is characteristic of patients with psychotic disorders and mood disturbances, and has been observed in some cases shortly after initiation of antipsychotic medicinal products, including aripiprazole (see section "Adverse reactions"). 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 cardiovascular diseases (including history of myocardial infarction or ischemic heart disease, or with heart failure and conduction disorders), cerebrovascular diseases, and conditions leading to arterial hypotension (dehydration, hypovolemia, and use of antihypertensive agents) or to hypertension, including exacerbation or malignant hypertension. Cases of venous thromboembolism have been reported during treatment with antipsychotics. Prior to and during antipsychotic therapy, possible risk factors for venous thromboembolism should be identified and appropriate preventive measures taken.

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

Tardive dyskinesia. In clinical studies of aripiprazole lasting up to one year, tardive dyskinesia symptoms were infrequently reported. If symptoms of tardive dyskinesia occur during treatment with Abizol, the dose should be reduced or the drug discontinued (see section "Adverse reactions"). After discontinuation of therapy, these symptoms may temporarily worsen or even appear following cessation of treatment.

Other extrapyramidal symptoms. In clinical trials of aripiprazole in children, akathisia and parkinsonism were observed. If manifestations or symptoms of other extrapyramidal disorders occur in patients receiving aripiprazole, the dose should be reduced and the patient's clinical condition carefully monitored.

Malignant neuroleptic syndrome (MNS). MNS is a potentially fatal syndrome associated with antipsychotic medicinal products. In clinical studies, isolated cases of MNS have been reported during treatment with aripiprazole. Clinical manifestations of MNS include hyperpyrexia (very high body temperature), muscle rigidity, altered mental status, and signs of autonomic nervous system instability (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 MNS, have also been observed. If a patient develops symptoms of MNS or unexplained very high body temperature without additional clinical signs of MNS, all antipsychotic medicinal products, including aripiprazole, should be discontinued.

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

Elderly patients with psychosis associated with dementia

Increased 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. The mortality rate was 3.5% with aripiprazole versus 1.7% with placebo, although causes of death varied: cardiovascular diseases (e.g., heart failure, sudden death), infections (e.g., pneumonia) (see section "Adverse reactions").

Cerebrovascular adverse reactions. In some clinical trials, cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal cases (mean age − 84 years, range 78 to 88 years), were reported. Overall, cerebrovascular adverse reactions were reported in 1.3% of patients receiving aripiprazole compared to 0.6% of patients receiving placebo.

This difference was not statistically significant. Furthermore, in one of these studies using a fixed dose, 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, 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 family history of diabetes. In clinical trials, aripiprazole did not show significant differences in the incidence of hyperglycemia-related disorders (including diabetes) or abnormal glycemic laboratory parameters compared to placebo. There is no precise comparative assessment of the risks of hyperglycemia-related adverse reactions in patients treated with aripiprazole versus other atypical antipsychotics. Careful monitoring of patients receiving any antipsychotics, including aripiprazole, is necessary, with attention to symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). Patients with diabetes mellitus or risk factors for developing diabetes should be regularly monitored for increased glucose levels (see section "Adverse reactions").

Hypersensitivity. As with other medicinal products, hypersensitivity reactions may occur during aripiprazole use, manifesting as allergic symptoms (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 antipsychotics, and lifestyle factors, which may lead to serious complications.

In the post-marketing period, weight gain has been observed in patients receiving aripiprazole. These patients have significant risk factors, such as history of diabetes mellitus, thyroid disorders, or pituitary adenoma. In clinical trials of aripiprazole in adults, no clinically significant weight gain was observed (see section "Pharmacological properties"). In clinical trials of aripiprazole in adolescents with bipolar disorder manic episodes, weight gain associated with aripiprazole use was recorded after 4 weeks of treatment. Body weight should be monitored in adolescents with bipolar disorder manic episodes. In case of significant weight gain, the possibility of dose reduction should be considered (see section "Adverse reactions").

Dysphagia. Antipsychotics, including aripiprazole, may cause esophageal motility disorders and aspiration; therefore, aripiprazole 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 during aripiprazole treatment. Hypersexuality, compulsive shopping, binge eating or uncontrolled eating, and other impulse and compulsive behaviour disorders have also been reported. It is important that physicians inform patients about the development of new or aforementioned disorders during aripiprazole treatment. It should be noted that impulse control symptoms 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 dose reduction or discontinuation of therapy (see section "Adverse reactions").

Patients with comorbid ADHD (attention deficit hyperactivity disorder) Despite the high prevalence of comorbid conditions such as bipolar I disorder and ADHD, safety data on concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when co-prescribing these medicinal products.

Falls. Aripiprazole may cause somnolence, orthostatic hypotension, and motor or sensory instability, which may lead to falls. Caution should be exercised when treating patients at increased risk, and treatment should be initiated with lower starting doses (e.g., in elderly or debilitated patients; see section "Dosage and administration").

Fructose and sucrose

The oral solution contains fructose and sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this medicinal product.

Parahydroxybenzoates

The oral solution contains methyl parahydroxybenzoate and propyl parahydroxybenzoate. May cause allergic reactions (possibly delayed).

Sodium

The oral solution contains sodium. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy

Adequate controlled studies of aripiprazole in pregnant women have not been conducted. Congenital anomalies have been reported, but a causal relationship with aripiprazole use has not been established. Available animal study data do not allow exclusion of potential embryofetotoxicity. Patients should inform their physician if they become pregnant or intend to become pregnant during aripiprazole treatment. Due to insufficient information on the safety of aripiprazole use during pregnancy, it should be prescribed only if the expected benefit to the mother outweighs the potential risk to the fetus.

In newborns whose mothers received antipsychotics (including aripiprazole) during the third trimester of pregnancy, adverse reactions including extrapyramidal symptoms and/or withdrawal syndrome may occur, varying in severity and duration. Cases of agitation, increased or decreased muscle tone, tremor, somnolence, respiratory distress, or feeding difficulties have been reported. Therefore, careful monitoring of such newborns is required.

Breastfeeding period

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

Fertility

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

Ability to affect reaction speed when driving or operating machinery.

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

Dosage and Administration

Dosage

Adults

Schizophrenia. The recommended initial dose is 10 mg daily or 15 mg daily (i.e., 10 mL or 15 mL of oral solution daily), with a maintenance dose of 15 mg daily. Administered once daily, independent of food intake. Abilify is effective within a dosage range of 10 mg to 30 mg daily (i.e., 10 mL to 30 mL of oral solution daily). Increased efficacy with doses exceeding 15 mg daily has not been demonstrated, although some patients may benefit from higher doses. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder. The recommended initial dose of Abilify is 15 mg (i.e., 15 mL of oral solution daily), administered once daily, independent of food intake. The drug may be used as monotherapy or as part of combination therapy (see section "Pharmacological Properties"). Dose increases may be effective for some patients. The maximum daily dose should not exceed 30 mg.

Prevention of new manic episodes in bipolar I disorder. To prevent relapse of manic episodes, patients previously treated with aripiprazole as monotherapy or in combination therapy should continue the same dose. Dose adjustments, including dose reductions, may be considered based on the patient's clinical condition.

Special patient groups

Patients with hepatic impairment

Dose adjustment is not required in patients with mild to moderate hepatic impairment. Insufficient data are available to provide recommendations for patients with severe hepatic impairment. Doses should be titrated cautiously in these patients. The maximum daily dose of 30 mg should be used with caution in patients with severe hepatic impairment (see section "Pharmacological Properties").

Patients with renal impairment

Dose adjustment is not required in patients with renal impairment.

Elderly patients

The efficacy and safety of aripiprazole in the treatment of schizophrenia and bipolar I disorder in patients aged 65 years and older have not been established. Given the increased sensitivity of this patient group, lower initial doses should be considered if clinical factors permit (see section "Special Warnings and Precautions for Use").

Gender

No dose adjustment is required for female patients compared to male patients (see section "Pharmacological Properties").

Smoking

Due to the metabolic pathway of aripiprazole, no dose adjustment is required for smokers (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Dose adjustment due to interactions

When co-administered with strong inhibitors of CYP3A4 or CYP2D6, the dose of aripiprazole should be reduced. If a CYP3A4 or CYP2D6 inhibitor is discontinued from combination therapy, the dose of aripiprazole should be increased (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

When co-administered with strong inducers of CYP3A4, the dose of aripiprazole should be increased. If a CYP3A4 inducer is discontinued from 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").

Method of Administration

Abilify is intended for oral administration.

Orally disintegrating tablets or oral solution may be used as an alternative to Abilify tablets for patients who have difficulty swallowing tablets (see section "Pharmacological Properties").

Children.

Schizophrenia in adolescents aged 15 years and older. The recommended initial dose is 10 mg daily, administered once daily, independent of food intake. Treatment should be initiated at 2 mg (using Abilify 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. Subsequent dose increases, if needed, should be in 5 mg increments, not exceeding the maximum daily dose of 30 mg (see section "Pharmacological Properties"). Abilify is effective in the dose range of 10 mg to 30 mg daily. Increased efficacy with doses exceeding 10 mg daily has not been demonstrated, although some patients may benefit from higher doses.

Abilify is not recommended for patients with schizophrenia under 15 years of age due to insufficient data on safety and efficacy (see sections "Pharmacological Properties" and "Undesirable Effects").

Manic episodes in bipolar I disorder in adolescents aged 13 years and older. The recommended dose is 10 mg daily, administered once daily, independent of food intake. Treatment should be initiated at 2 mg (using Abilify 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 the minimum necessary to control symptoms and should not exceed 12 weeks. Increased efficacy with doses exceeding 10 mg daily has not been demonstrated, and a daily dose of 30 mg is associated with a significantly higher incidence of serious adverse reactions, including extrapyramidal symptoms, somnolence, fatigue, and weight gain (see section "Undesirable Effects"). Therefore, doses exceeding 10 mg daily should be used only in exceptional cases and under close clinical monitoring (see sections "Pharmacological Properties", "Special Warnings and Precautions for Use", and "Undesirable Effects"). Younger patients have an increased risk of adverse reactions associated with aripiprazole. Therefore, Abilify is not recommended for patients under 13 years of age (see sections "Pharmacological Properties" and "Undesirable Effects").

Agitation associated with autism. The safety and efficacy of aripiprazole in children and adolescents under 18 years of age have not been established. Insufficient data are available to provide dosage recommendations (see section "Pharmacological Properties").

Tourette's disorder. The safety and efficacy of aripiprazole in children and adolescents aged 6 to 18 years have not been established. Insufficient data are currently available to provide dosage recommendations (see section "Pharmacological Properties").

Overdose.

Signs and Symptoms

Cases of intentional or accidental acute overdose of aripiprazole in doses up to 1260 mg have been reported in adult patients, without fatal outcome. Clinically significant symptoms observed included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. Additionally, accidental overdose with aripiprazole alone (up to 195 mg) in children has been reported without fatal outcome. Clinically significant symptoms observed included somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Treatment

Management of overdose should include supportive care, ensuring airway patency, oxygenation, mechanical ventilation if necessary, and symptomatic control. The possibility of multiple drug overdose should be considered. Therefore, immediate cardiovascular monitoring, including continuous ECG monitoring to detect possible arrhythmias, is required. After confirmed or suspected aripiprazole overdose, careful medical supervision and monitoring are necessary until the patient recovers.

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

Hemodialysis

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

Summary of Safety Profile

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.

List of Adverse Reactions

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

All adverse reactions are classified by system organ class and frequency: 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 available data). Within each frequency category, 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.

	Common	Uncommon	Frequency not known
Blood and lymphatic system disorders			leukopenia, neutropenia, thrombocytopenia
Immune system disorders			allergic reactions (e.g. anaphylactic reactions, angioneurotic edema, including tongue swelling, tongue edema, facial swelling, pruritus or urticaria)
Endocrine disorders		hyperprolactinemia, decreased blood prolactin levels	diabetic hyperosmolar coma, diabetic ketoacidosis
Metabolism and nutrition disorders	diabetes mellitus	hyperglycemia	hyponatremia, anorexia
Psychiatric disorders	insomnia, agitation, restlessness	depression, hypersexuality	suicide attempt, suicidal ideation and suicide (see section "Special warnings and precautions for use"), pathological gambling, impulse control disorders, compulsive overeating, compulsive shopping, pyromania, aggression, agitation, nervousness
Nervous system disorders	akathisia, extrapyramidal disorders, tremor, headache, sedation, somnolence, dizziness	late dyskinesia, dystonia, restless legs syndrome	malignant neuroleptic syndrome (MNS), grand mal seizure, serotonin syndrome, speech disorder
Eye disorders	blurred vision	diplopia, photophobia	acute glaucoma crisis
Cardiac disorders		tachycardia	sudden death, torsades de pointes ventricular tachycardia, ventricular arrhythmia, cardiac arrest, bradycardia
Vascular disorders		orthostatic hypotension	venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, syncope
Respiratory, thoracic and mediastinal disorders		hiccups	aspiration pneumonia, laryngospasm, oropharyngeal spasm
Gastrointestinal disorders	constipation, dyspepsia, nausea, vomiting, hypersalivation		pancreatitis, dysphagia, diarrhea, abdominal discomfort, stomach discomfort
Hepatobiliary disorders			hepatic failure, hepatitis, jaundice
Skin and subcutaneous tissue disorders			rash, photosensitivity reactions, alopecia, increased sweating, drug reaction with eosinophilia and systemic symptoms (DRESS)
Musculoskeletal and connective tissue disorders			rhabdomyolysis, myalgia, muscle rigidity
Renal and urinary disorders			urinary incontinence, urinary retention
Pregnancy, puerperium and perinatal conditions			drug withdrawal syndrome in newborns (see section "Use in pregnancy or breastfeeding")
Reproductive system and breast disorders			priapism
General disorders and administration site conditions	fatigue		temperature regulation disorders (e.g. hypothermia, hyperthermia), chest pain, peripheral edema
Investigations			weight increased, weight decreased, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyl transferase (GGT), increased alkaline phosphatase, QT interval prolongation, increased blood glucose, increased glycated hemoglobin, blood glucose fluctuations, increased creatine phosphokinase

Description of individual adverse reactions

Extrapyramidal symptoms (EPS)

Schizophrenia. In a 52-week controlled study in patients treated with aripiprazole, the incidence of EPS, including parkinsonism, akathisia, dystonia, and dyskinesia, was lower (25.7%) compared to patients treated with 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 treated with aripiprazole and 15.1% in patients treated with 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 treated with haloperidol. In another 12-week study, the incidence of EPS was 26.6% in patients treated with aripiprazole and 17.6% in patients treated with lithium. In the long-term 26-week placebo-controlled phase of a study, the incidence of EPS was 18.2% in patients treated with 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, i.e., prolonged abnormal contractions of muscle groups, may occur during the first few days of treatment. Symptoms of dystonia include neck muscle spasms, sometimes progressing 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 more pronounced at higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger patients.

Prolactin

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

Laboratory parameters

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

Paediatric population

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 treated with 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, 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.

In the pooled group of adolescents with schizophrenia aged 13–17 years exposed to the drug for up to 2 years, the incidence 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 who received 5 to 30 mg of aripiprazole for up to 72 months, the incidence 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 treated with aripiprazole, the incidence 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 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 incidence 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 sexual desire (hypersexuality), compulsive shopping, and compulsive overeating (see section "Special precautions").

Shelf life.

2 years.

Storage conditions.

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

Keep out of reach of children.

After first opening of the bottle, do not store for more than 6 months.

Packaging.

150 mL of solution in a bottle, one bottle with a measuring cup and dosing syringe in a cardboard package.

Prescription category. Prescription only.

Manufacturer.

Nobel Ilac Sanayi ve Ticaret A.S.

Manufacturer's address and place of business.

Sankaklar Quarter, Eskisehir Yolu Akcakoca Highway No: 299, 81100 Duzce, Turkey.