Arithero

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ARIRETO (ARITERO)

Composition:

Active substance: aripiprazole;

1 tablet contains 5 mg or 10 mg of aripiprazole;

Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, hydroxypropylcellulose, magnesium stearate, indigo carmine (E 132) – for 5 mg tablets; iron oxide red (E 172) – for 10 mg tablets.

Pharmaceutical form. Tablets.

Main physicochemical properties:

• 5 mg tablets: from light blue to blue in color, modified rectangular-shaped, biconvex tablets with beveled edges, marked with "I" on one side and "95" on the other;
• 10 mg tablets: from light pink to pink in color, modified rectangular-shaped, biconvex tablets with beveled edges, marked with "I" on one side and "96" on the other.

Pharmacotherapeutic group. Antipsychotic agents (neuroleptics). Aripiprazole.

ATC code N05AX12.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The therapeutic effect of aripiprazole in schizophrenia is mediated by a combination of partial agonist activity at dopamine D2 and serotonin 5HT1A receptors, and antagonist activity at serotonin 5-HT2A receptors. In animal experiments, aripiprazole demonstrated antagonism toward dopamine hyperactivity and agonism toward dopamine hypoactivity. Aripiprazole exhibits high binding affinity in vitro 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, alpha-1 adrenergic receptors, and H1 histamine receptors. Aripiprazole also shows moderate affinity for serotonin reuptake sites and lacks affinity for muscarinic receptors. Interactions with both dopamine and serotonin receptors may explain some of the clinical effects of aripiprazole.

Aripiprazole administered to healthy volunteers at doses of 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.

Pharmacokinetics.

Absorption

Aripiprazole is well absorbed, with peak plasma concentration (Cmax) occurring 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 is bound to plasma proteins, primarily albumin.

Biotransformation

Aripiprazole is extensively metabolized in the liver, primarily via three metabolic pathways: dehydrogenation, hydroxylation, and N-dealkylation. Based on in vitro studies, the enzymes CYP3A4 and CYP2D6 are responsible for dehydrogenation and hydroxylation of aripiprazole, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the predominant compound in systemic circulation. At steady state, dehydroaripiprazole, an 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 individuals with normal CYP2D6 metabolism and approximately 146 hours in individuals with poor CYP2D6 metabolism.

The total clearance of aripiprazole is 0.7 mL/min/kg and occurs primarily in the liver. After a single oral dose, approximately 27% is excreted in urine and approximately 60% in feces. Less than 1% of unchanged aripiprazole is excreted in urine, and approximately 18% of the administered dose is excreted unchanged in feces.

Elderly patients

No differences in the pharmacokinetic properties of aripiprazole have been observed between healthy elderly and younger patients, and there is no notable effect of patient age on the pharmacokinetic analysis in patients with schizophrenia.

Gender

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

Smoking

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

Race

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

Renal impairment

The pharmacokinetic characteristics of aripiprazole and hydroaripiprazole were similar in patients with acute renal disease compared to young healthy volunteers.

Hepatic impairment

A single-dose 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 pharmacokinetic properties of aripiprazole and hydroaripiprazole. However, the study included only three patients with Child-Pugh class C cirrhosis, which is insufficient to draw conclusions regarding their metabolic capacity.

Clinical characteristics.

Indications.

Treatment of schizophrenia in adults.

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.

Contraindications.

Hypersensitivity to aripiprazole or to any other component 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.

Since aripiprazole affects the central nervous system (CNS), caution should be exercised when co-administering alcohol or other CNS-acting agents 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 disrupt electrolyte balance.

Potential influence of other medicinal products on aripiprazole

The gastric 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 for smokers.

Quinidine and other CYP2D6 inhibitors

In studies in healthy volunteers, potent inhibitors of the CYP2D6 isoenzyme (quinidine) increased the area under the concentration-time curve (AUC) of aripiprazole by 107%, while maximum concentration (Cmax) remained unchanged. AUC and Cmax of dehydroaripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Therefore, 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, thus requiring a comparable dose reduction.

Ketoconazole and other CYP3A4 inhibitors

In studies in healthy volunteers, the potent CYP3A4 inhibitor ketoconazole increased AUC and Cmax of aripiprazole by 63% and 37%, respectively. AUC and Cmax of dehydroaripiprazole increased by 77% and 43%, respectively. In individuals with reduced CYP2D6 metabolism, concomitant use of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to patients with normal CYP2D6 activity. When co-administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the expected benefit should outweigh the potential risk 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, thus requiring appropriate dose reductions (see section "Dosage and administration").

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

A minor increase in plasma concentration of aripiprazole 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 co-administered with carbamazepine, a potent CYP3A4 inducer, geometric mean Cmax and AUC of oral aripiprazole in patients with schizophrenia and schizoaffective disorder were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean Cmax and AUC of dehydroaripiprazole decreased 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. Concomitant use of aripiprazole with other potent CYP3A4 inducers (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine, and St. John’s wort) is theoretically expected to have a similar effect, thus requiring appropriate dose increases. After discontinuation of potent CYP3A4 inducers, the aripiprazole dose should be reduced to the recommended level.

Valproate and lithium

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

Potential influence of aripiprazole on other medicinal products

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

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/selective serotonin-norepinephrine reuptake inhibitors (SSRIs/SNRIs), or with agents that increase aripiprazole concentrations (see section "Adverse reactions").

Special precautions for use.

Improvement in 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 mood disorders, and has been observed shortly after initiation of neuroleptic therapy or switching from one neuroleptic to another, including treatment with aripiprazole (see section "Adverse reactions"). Neuroleptic 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, or conditions predisposing patients to arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs) or arterial hypertension, including progressive or malignant hypertension. Cases of venous thromboembolism (VTE) have been observed during neuroleptic therapy. Since patients receiving neuroleptics often have acquired risk factors for VTE, all possible VTE risk factors should be identified and appropriate preventive measures implemented before and during aripiprazole treatment.

QT interval prolongation

In clinical trials of aripiprazole, QT interval prolongation has been observed compared to placebo. Caution should be exercised when administering aripiprazole to patients with a family history of QT interval prolongation (see section "Adverse reactions").

Tardive dyskinesia

In clinical trials, symptoms of tardive dyskinesia were rarely reported in patients treated with aripiprazole for up to one year. If symptoms of tardive dyskinesia occur in a patient receiving aripiprazole, dose reduction or discontinuation of treatment should be considered (see section "Adverse reactions"). These symptoms may transiently worsen or even emerge after discontinuation of treatment.

Other extrapyramidal symptoms

In clinical trials of aripiprazole in children, akathisia and parkinsonism were observed. If signs of other extrapyramidal symptoms occur, dose reduction should be considered and careful clinical monitoring of the patient should be maintained.

Neuroleptic Malignant Syndrome (NMS)

NMS is a potentially life-threatening condition associated with the use of neuroleptic drugs. Cases of NMS were rare in clinical trials of aripiprazole. 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 and rhabdomyolysis, not necessarily associated with NMS, have also been observed. If a patient develops symptoms of NMS or unexplained high fever without additional clinical features of NMS, all neuroleptic medications, including aripiprazole, should be discontinued immediately.

Seizures

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

Elderly patients with psychosis associated with dementia

Increased mortality

In clinical trials, use of aripiprazole in elderly patients with Alzheimer's disease (mean age 82 years) was associated with an increased risk of mortality compared to placebo. Mortality rates were 3.5% with aripiprazole versus 1.7% with placebo. Although causes of death varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin (see section "Adverse reactions").

Cerebrovascular adverse reactions

In some clinical trials in elderly patients (mean age 84 years; range 78–88 years), cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal events, were observed. Overall, cerebrovascular adverse reactions were reported in 1.3% of patients receiving aripiprazole compared to 0.6% of placebo recipients. This difference was not statistically significant. Furthermore, in one of these fixed-dose studies, a relationship between aripiprazole use and cerebrovascular adverse reactions was described (see section "Adverse reactions").

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

Hyperglycemia and diabetes mellitus

Hyperglycemia, sometimes 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. 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 hyperglycemia-related adverse reaction risks in patients treated with aripiprazole versus other atypical antipsychotics. Careful monitoring of patients receiving any antipsychotic, including aripiprazole, is required, with attention to symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, and weakness). The condition of patients with diabetes or risk factors for diabetes should be regularly monitored for increased glucose levels (see section "Adverse reactions").

Hypersensitivity

Hypersensitivity reactions, characterized by allergic symptoms, may occur during aripiprazole treatment (see section "Adverse reactions").

Weight gain

Weight gain is frequently observed in patients with schizophrenia and bipolar manic episodes due to comorbid conditions, use of antipsychotics known to cause weight gain, and lack of a healthy lifestyle, which may lead to serious complications. In post-marketing studies, weight gain was observed in patients treated with aripiprazole. These patients often have significant risk factors, such as a history of diabetes, thyroid disorders, or pituitary adenoma.

In clinical trials of aripiprazole in adults, no clinically significant weight gain was recorded. In clinical trials of aripiprazole in adolescents with bipolar manic episodes, weight gain associated with aripiprazole use was observed after 4 weeks of treatment. Body weight should be monitored in adolescents with bipolar mania. In case of significant weight gain, consideration should be given to reducing the dose (see section "Adverse reactions").

Dysphagia

Neuroleptics, including aripiprazole, may cause esophageal motility disorders and aspiration of gastric contents. Aripiprazole and other neuroleptics 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 urges, particularly gambling, and inability to control these impulses during aripiprazole treatment. Hypersexuality, compulsive shopping, binge eating or uncontrolled eating, and other impulsive and compulsive behaviors have also been reported. It is important that physicians inform patients about the development of new or aforementioned disorders during aripiprazole treatment. Although symptoms of impulse control disorders may be related to the underlying condition, there have been reports of resolution of impulses with dose reduction or discontinuation of treatment. Impulse control disorders can harm the patient and others if not recognized. If such urges develop during aripiprazole treatment, consideration should be given to dose reduction or discontinuation of therapy (see section "Adverse reactions").

Lactose

The medicinal product Aritro contains lactose. Patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Patients with comorbid ADHD (attention deficit hyperactivity disorder)

Despite the high comorbidity of bipolar I disorder and ADHD, safety data on the concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when prescribing these medicinal products together.

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").

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate and well-controlled studies on the use of aripiprazole in pregnant women. Congenital anomalies have been reported, but a causal relationship with aripiprazole could not be established. Animal studies did not exclude a potential adverse effect on fetal development. Patients should be advised to inform their physician if they become pregnant or intend to become pregnant during aripiprazole treatment. Due to insufficient safety data in humans and adverse findings in animal reproductive studies, this medicinal product should not be used during pregnancy unless the expected benefit to the mother clearly outweighs the potential risk to the fetus.

Newborns whose mothers received neuroleptics (including aripiprazole) during the third trimester of pregnancy are at risk of adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration after birth. Cases of agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be closely monitored (see section "Adverse reactions").

Period of breastfeeding

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

Fertility

Based on reproductive toxicity studies, aripiprazole does not affect 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

Aritero tablets are for oral use.

Adults

Schizophrenia. The recommended initial dose is 10 mg/day or 15 mg/day, with a maintenance dose of 15 mg/day. This dose should be taken once daily, regardless of food intake. The drug is effective within a dosage range of 10 to 30 mg/day. Increased efficacy with doses exceeding 15 mg/day has not been demonstrated, although higher doses may benefit some patients. The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar I disorder. The recommended initial dose is 15 mg. This dose should be taken once daily, regardless of food intake, either as monotherapy or as part of combination therapy (see section "Pharmacological Properties"). Higher doses may be beneficial 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 in patients receiving aripiprazole as monotherapy or in combination therapy, continue treatment at the same dose. Dose adjustment, including dose reduction, should be considered based on the patient's clinical status.

Special Patient Groups

Hepatic impairment

Dose adjustment is not required in patients with mild or moderate hepatic impairment. There is insufficient data available to make dosage recommendations for patients with severe hepatic impairment. Dosing in these patients should be done 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 safety and efficacy of Aritero in treating schizophrenia or manic episodes in bipolar I disorder in patients aged 65 years and older have not been established. Due to increased sensitivity in this patient group, a lower starting dose should be considered when clinical factors are present (see section "Special Warnings and Precautions for Use").

Gender

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

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. If a CYP3A4 or CYP2D6 inhibitor is discontinued from the treatment regimen, 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. If a CYP3A4 inducer is discontinued from the treatment regimen, 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 safety and efficacy of aripiprazole in children have not been established.

Overdose

Symptoms

Cases of intentional or accidental acute aripiprazole overdose, with doses up to 1260 mg, have been reported in adult patients 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 (in doses up to 195 mg) in children have been reported, with no fatal outcome. Potentially clinically significant observed symptoms included somnolence, transient loss of consciousness, and extrapyramidal symptoms.

Treatment

Management of overdose should include supportive care, ensuring airway patency, oxygen therapy, mechanical ventilation if necessary, and symptom control. The possibility of overdose with multiple medicinal products 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 the Cmax of aripiprazole by approximately 41% and the AUC by approximately 51%, suggesting potential effectiveness of activated charcoal in overdose management.

Hemodialysis

Although information on the effect of hemodialysis in treating 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 frequency of adverse reactions associated with aripiprazole therapy is listed below. The table is based on adverse reactions reported during clinical trials and/or post-marketing use.

All adverse reactions are listed by system organ class 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 the available data). Within each frequency grouping, adverse reactions are listed in order of decreasing severity.

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

System Organ Class	Common	Uncommon	Frequency not known
Blood and lymphatic system disorders			leukopenia, neutropenia, thrombocytopenia
Immune system disorders			allergic reactions (e.g., anaphylactic reactions; angioedema, including tongue swelling; facial swelling, pruritus or urticaria)
Endocrine disorders		hyperprolactinemia, decreased prolactin levels in blood	hyperosmolar non-ketotic coma, diabetic ketoacidosis
Metabolism and nutrition disorders	diabetes mellitus	hyperglycemia	hyponatremia, anorexia
Psychiatric disorders	insomnia, restlessness, agitation	depression, hypersexuality	suicide attempts, suicidal ideation and completed suicide (see section "Special precautions"), pathological gambling, impulse control disorders, binge eating, compulsive shopping, kleptomania, aggression, agitation, nervousness
Nervous system disorders	akathisia, extrapyramidal disorders, tremor, headache, sedation, somnolence, dizziness	tardive dyskinesia, dystonia, restless legs syndrome	neuroleptic malignant syndrome (NMS), grand mal seizure, serotonin syndrome, speech disorder
Eye disorders	blurred vision	diplopia, photophobia	acute angle-closure glaucoma
Cardiac disorders		tachycardia	sudden death, torsades de pointes, ventricular arrhythmia, cardiac arrest, bradycardia
Vascular disorders		orthostatic hypotension	venous thromboembolism (including pulmonary embolism and deep vein thrombosis), arterial hypertension, syncope
Respiratory, thoracic and mediastinal disorders		hiccups	aspiration pneumonia, laryngospasm, oropharyngeal spasm
Gastrointestinal disorders	constipation, dyspepsia, nausea, hypersalivation, vomiting		pancreatitis, dysphagia, diarrhea, gastrointestinal 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 "Pregnancy and breastfeeding")
Reproductive system and breast disorders			priapism
General disorders and administration site conditions	fatigue		disturbances in temperature regulation (e.g., hypothermia, pyrexia), chest pain, peripheral edema
Investigations			decreased body weight, increased body weight, increased levels of alanine aminotransferase (ALT), increased levels of aspartate aminotransferase (AST), increased levels of gamma-glutamyl transferase (GGT), increased alkaline phosphatase levels, prolonged QT interval, increased blood glucose levels, increased glycosylated hemoglobin levels, blood glucose fluctuations, increased creatine phosphokinase levels

Description of individual adverse reactions

Dystonia

Class effect of medicinal products. Symptoms of dystonia, involving prolonged pathological contraction of muscle groups, may occur in susceptible patients during the first few days of treatment. Dystonic symptoms include neck muscle spasms, which sometimes progress to throat constriction, difficulty swallowing, breathing difficulties, and/or tongue protrusion. 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 increased in males and younger patients.

Prolactin

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

Laboratory parameters

The proportion of patients with clinically significant changes in standard laboratory and lipid parameters was not substantially different between the aripiprazole and placebo groups. Transient and asymptomatic elevations were observed in 3.5% of patients receiving aripiprazole, compared to 2.0% in the placebo group.

Pathological gambling and other impulse control disorders

Pathological gambling, hypersexuality, compulsive shopping, binge eating, or uncontrolled eating urges may occur in patients taking aripiprazole.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach of children.

Packaging.

30 tablets in a container, 1 container in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Hetero Labs Limited.

Manufacturer's address and location of its operations.

Unit-V, Block V and V-A, TSIIC - Formulation SEZ, S. Nos 439, 440, 441 & 458, Polepally Village, Jadcherla Mandal, Telangana State, 509301, India.