Mintegra

APPROVED

by the Order of the Ministry of Health of Ukraine

23.04.2020 No. 945

Marketing Authorization

No. UA/18061/01/01

UA/18061/01/02

UA/18061/01/03

PACKAGE LEAFLET

for medical use of a medicinal product

Mintegra

Qualitative and quantitative composition:

active substance: aripiprazole;

1 oral dispersible tablet contains aripiprazole 10 mg or 15 mg or 30 mg;

list of excipients:

10 mg tablets: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silica, magnesium stearate (E 470b), iron oxide red (E 172), aspartame (E 951), vanillin flavoring;

15 mg tablets: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silica, magnesium stearate (E 470b), iron oxide yellow (E 172), aspartame (E 951), vanillin flavoring;

30 mg tablets: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silica, magnesium stearate (E 470b), iron oxide red (E 172), aspartame (E 951), vanillin flavoring.

Pharmaceutical form. Oral dispersible tablet.

Main physical and chemical properties:

10 mg tablets – pink tablets, round with a flat surface, embossed "10" on one side and smooth on the other;

15 mg tablets - yellow tablets, round with a flat surface, embossed "15" on one side and smooth on the other;

30 mg tablets – pink tablets, round with a flat surface, embossed "30" on one side and smooth on the other;

Pharmacotherapeutic group. Psycholeptics. Antipsychotics. Other antipsychotics. Aripiprazole. ATC code N05A X12.

Pharmacological properties.

Pharmacodynamic properties.

Mechanism of action.

The therapeutic effect of aripiprazole in the treatment of schizophrenia and bipolar disorder I type is due to a combination of partial agonism for D₂-dopamine and HT_1А-serotonin receptors, as well as antagonism for 5-HT_2А-serotonin receptors. Aripiprazole showed antagonistic properties in animal models of dopaminergic hyperactivity and agonistic properties in animal models of dopaminergic hypoactivity. Aripiprazole has a high in vitro binding affinity with D₂- і D₃-dopamine receptors, 5-HT_1А- і 5-HT_2А-serotonin receptors, as well as a moderate affinity with D₄-dopamine receptors, 5-HT_2С- і 5-HT₇-serotonin, α-1-adrenergic and histamine Н₁-receptors. Aripiprazole also has a moderate affinity to serotonin reuptake sites and has no apparent affinity for muscarinic receptors. Interactions with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.

Aripiprazole at doses of 0.5 to 30 mg once daily in healthy volunteers for 2 weeks showed a dose-dependent decrease in the binding of ¹¹С-racloprid, a ligand of D₂-D₃- receptors, to the caudate nucleus and membrane, according to positron emission tomography.

Clinical efficacy and safety.

Adults.

Schizophrenia.

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

Body weight gain.

It has been established that aripiprazole does not cause a clinically significant weight gain.

Lipid indicators.

Aripiprazole does not cause clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL) and low-density lipoprotein (LDL).

Prolactin.

The prevalence of hyperprolactinaemia or an increase in serum prolactin in patients treated with aripiprazole (0.3%) was similar to placebo (0.2%).

Episodes of manic nature in bipolar disorder type I.

Aripiprazole has shown better efficacy than placebo in reducing manic symptoms for more than 3 weeks

Pharmacokinetic properties.

Absorption.

Aripiprazole is rapidly absorbed after oral administration, reaching the maximum concentration (C_max) in blood plasma after 3-5 hours. Aripiprazole undergoes minimal presystemic metabolism. The absolute bioavailability when taken orally is 87%. Fatty food does not affect the pharmacokinetic properties of aripiprazole.

Distribution:

Aripiprazole is intensively distributed in body tissues. The volume of distribution is 4.9 l/kg, indicating a large extravascular distribution. At therapeutic concentrations, more than 99% of aripiprazole and dehydroaripiprazole are bound to serum proteins, mainly albumin.

Biotransformation

Aripiprazole is extensively metabolized in the liver, mainly by dehydrogenation, hydroxylation and N-dealkylation. According to in vitro studies, dehydrogenation and hydroxylation of aripiprazole occurs under the action of isoenzymes CYP3A4 and CYP2D6, and N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the main substance of the medicinal product that is in the systemic circulation. In the equilibrium state of dehydroaripiprazole, its active metabolite, is approximately 40%of the concentration-to-time ratio (AUC) of aripiprazole in blood plasma.

Excretion.

The mean half-life of aripiprazole is approximately 75 hours with high CYP2D6 metabolic activity and approximately 146 hours with low CYP2D6 metabolic activity. The total clearance of aripiprazole is 0,7 ml/min/kg, it is mainly represented by hepatic clearance.

After a single oral administration of ¹⁴C-labeled aripiprazole, approximately 27% was excreted in the urine and approximately 60% in the feces. Less than 1% of unchanged aripiprazole was excreted in the urine, approximately 18% of unchanged aripiprazole was excreted in the feces.

Pharmacokinetic properties in special group of patients

Elderly patients.

There are no differences between the pharmacokinetic properties of aripiprazole in healthy elderly volunteers and younger patients. There are also no visible differences in pharmacokinetics among different age groups of patients with schizophrenia.

Gender.

There are no differences between the pharmacokinetic properties of aripiprazole in healthy men and women. There was also no effect of gender on the pharmacokinetic properties of aripiprazole in patients with schizophrenia.

Smoking.

A population pharmacokinetic properties assessment did not find a clinically significant effect of smoking on the pharmacokinetic properties of aripiprazole.

Race.

A population pharmacokinetic properties evaluations did not reveal clinically significant race-related differences in the pharmacokinetic properties of aripiprazole.

Impaired renal function.

The pharmacokinetic properties of aripiprazole and dehydroaripiprazole were found to be the same both in patients with severe renal disease and in young healthy volunteers.

Impaired liver function.

In studies involving patients with liver cirrhosis of varying degrees (Child-Pugh classes A, B and C) after a single dose of aripiprazole did not show a significant effect of hepatic impairment on the pharmacokinetic properties of aripiprazole and dehydroaripiprazole. Due to the lack of data, it is not possible to draw definitive conclusions about metabolic activity in patients with decompensated liver cirrhosis (Child-Pugh class C).

Clinical particulars.

Therapeutic indications.

Treatment of schizophrenia in adults.

Treatment of moderate to severe manic episodes in type I of bipolar disorder, as well as to prevent 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 antagonism of α₁-adrenergic receptors, aripiprazole may potentiate the effect of some antihypertensive medicinal products.

As aripiprazole affects the central nervous system (CNS), caution should be exercised when co-administering alcohol or CNS medicinal products due to possible cross-reactions such as sedation (see section "Undesirable effects").

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

Potential effects of other medicinal products on the action of aripiprazole.

No clinically significant effect of the histamine Н₂-receptor blocker famotidine, which inhibits gastric hydrochloric acid secretion, on aripiprazole was observed, despite a decrease in the absorption rate of aripiprazole.

Aripiprazole is metabolized in several ways by the enzymes CYP2D6 and CYP3A4, but not by the enzymes CYP1A, therefore, smokers do not need to adjust the dose.

Quinidine and other CYP2D6 inhibitors.

In studies with healthy volunteers, potent inhibitors of the isoenzyme CYP2D6 (quinidine) increased the AUC of aripiprazole by 107%, while C_max remained unchanged. The AUC and C_max of dehydroaripiprazole, the active metabolite, decreased by 32% and 47%, respectively. Therefore, the dose of aripiprazole should be reduced by approximately 2 times when administered with quinidine. Other potent CYP2D6 inhibitors, such as fluoxetine and paroxetine, are likely to have similar effects, so a similar dose reduction is required.

Ketoconazole and other CYP3A4 inhibitors.

In studies in healthy volunteers, the potent CYP3A4 inhibitor (ketoconazole) increased the AUC and C_max of aripiprazole by 63% and 37%, respectively. The AUC and C_max of dehydroaripiprazole increased by 77% and 43%, respectively. In patients with reduced CYP2D6 metabolism, concomitant administration of potent CYP3A4 inhibitors may result in higher plasma concentrations of aripiprazole compared to those in patients with active CYP2D6 metabolism.

If co-administration of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is required, the potential benefits should outweigh the potential risks to the patient. If aripiprazole and ketoconazole are co-administered, the dose of aripiprazole should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may theoretically have the same effects, so doses should be reduced accordingly (see section «Posology and method of administration»).

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

There may be a slight increase in plasma aripiprazole concentrations when co-administered with weak inhibitors of CYP3A4 (e.g. diltiazem) or CYP2D6 (escitalopram).

Carbamazepine and other CYP3A4 inhibitors.

With the combined use of carbamazepine, a potent inducer of CYP3A4, the administration of aripiprazole in patients with schizophrenia and schizoaffective disorder, the geometric C_max and AUC of aripiprazole were 68% and 73% lower, compared with the corresponding indicators for aripiprazole monotherapy at a dose of 30 mg. Geometric mean C_max and AUC of dehydroaripiprazole when used in combination with carbamazepine were reduced by 69% and 71% compared with the corresponding indicators of aripiprazole monotherapy.

The dose of aripiprazole should be doubled when co-administered with carbamazepine. Co-administration of aripiprazole and other potent inducers of CYP3A4 (such as rifampicin, rifabutin, phenytoin, phenobarbital, primidone, efavirenz, nevirapine and St. John's Wort) has theoretically had a similar effect, so an appropriate dose increase is required. After discontinuation of potent CYP3A4 inducers, the dose of aripiprazole should be reduced to the recommended dose.

Valproate and lithium.

No clinically relevant changes in aripiprazole concentrations were observed when valproate or lithium were co-administered with aripiprazole, therefore no dose adjustment is required.

Potential effects of aripiprazole on the action of other medicinal products.

In clinical studies, aripiprazole 10–30 mg daily did not induce clinically important medicinal interactions mediated by CYP2D6 (dextromethorphan/3-methoxymorphine), CYP2C9 (warfarin), CYP2C19 (omeprazole), and CYP3A4 (dextromethorphan). In addition, 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 relevant changes in valproate, lithium or lamotrigine concentrations were observed when aripiprazole was co-administered with valproate, lithium or lamotrigine.

Serotonin syndrome.

Cases of serotonin syndrome have been reported in patients taking aripiprazole, especially when co-administered with other serotonergic medicinal products such as selective serotonin reuptake inhibitor (SSRI)/serotonin reuptake inhibitor and noradrenaline (SNRI)., or with medicinal products, which increase the concentration of aripiprazole (see section "Undesirable effects").

Special warnings and precautions for use.

With antipsychotic treatment, it may take several days to several weeks to improve the patient's clinical condition. During this period, the patient's condition should be closely monitored.

Suicide.

Suicidal behavior is common in patients with psychotic disorders and mood disorders and in some cases has been observed shortly after initiation of antipsychotic treatment, including aripiprazole (see section “Undesirable effects”). Antipsychotic treatment should be accompanied by close supervision of high-risk patients.

Cardiovascular disorders.

Aripiprazole should be used with caution in patients with a history of cardiovascular disease (myocardial infarction or coronary heart disease, heart failure or conduction disturbances), cerebrovascular disorders, conditions that predispose patients to hypotension (dehydration, hypovolemia, antihypertensives), hypertension, including progressive or malignant hypertension.

Cases of venous thromboembolism (VTE) have been reported during treatment with antipsychotic. As acquired risk factors for VTE are often observed in patients taking antipsychotics, all possible risk factors for VTE should be identified before and during aripiprazole treatment and all preventive measures taken.

QT interval prolongation.

The frequency of QT prolongation with aripiprazole treatment was comparable to that with placebo. However, caution should be exercised when administering aripiprazole to patients with a family history of QT prolongation (see section "Undesirable reactions").

Tardive dyskinesia

Symptoms of tardive dyskinesia have been reported rarely in patients receiving aripiprazole for up to 1 year. If symptoms of tardive dyskinesia occur in a patient taking aripiprazole, dose reduction or discontinuation should be considered (see section "Undesirable reactions"). These symptoms may worsen temporarily or even occur after stopping treatment.

Neuroleptic malignant syndrome (NMS).

NMS is a complex of symptoms associated with the use of antipsychotic that can potentially be fatal. In clinical trials with aripiprazole, cases of NMS were rare. Clinical manifestations of NMS are hyperpyrexia (very high body temperature), muscle rigidity, altered mental status and signs of autonomic nervous system disorders (irregular pulse or blood pressure, tachycardia, increased sweating and cardiac arrhythmia). Additional symptoms may include elevated creatine kinase levels, myoglobinuria (rhabdomyolysis) and acute renal failure. However, cases of elevated creatine kinase and rhabdomyolysis, not necessarily associated with NMS, have been isolated. If in the patient symptoms of NMS or unexplained very high body temperature without additional clinical manifestations of NMS develop, all neuroleptic active substances, including aripiprazole, should be discontinued.

Epileptic seizures.

Uncommon seizures have been reported with aripiprazole. Therefore, aripiprazole should be used with caution in patients with an epilepsy in the anamnesis or conditions associated with seizures.

Elderly patients with psychosis on the background of dementia.

Increased mortality: when using aripiprazole in elderly patients with psychosis on the background of Alzheimer's disease, the risk of death is increased. Although the causes of death were different, most of them were cardiovascular (e. g., heart failure, sudden death) or infectious (e. g., pneumonia) in nature (see section "Undesirable reactions").

Cerebrovascular undesirable effects: cerebrovascular adverse reactions (e. g., stroke, transient ischemic attack), including death, had in elderly patients (mean age 84 years; range 78–88 years). There was also a strong relationship between doses of medicinal product and the occurrence of cerebrovascular undesirable effects in patients taking aripiprazole.

Aripiprazole is not indicated for the treatment of patients with psychosis on the background of dementia.

Hyperglycemia and diabetes.

Hyperglycaemia, in some cases extremely severe and associated with ketoacidosis or hyperosmolar coma, including fatalities, has been reported in patients receiving atypical antipsychotics, including aripiprazole. Family anamnesis of obesity and diabetes are risk factors for severe complications. Aripiprazole studies did not show significant differences in the incidence of hyperglycaemic undesirable effects (including diabetes mellitus) or abnormal glucose levels compared with placebo. Based on the available data, it is not possible to make an accurate comparative assessment of the incidence of hyperglycemic undesirable effects in patients receiving aripiprazole and other atypical antipsychotics. Patients taking any antipsychotics, including aripiprazole, should be closely monitored for symptoms of hyperglycaemia (such as polydipsia, polyuria, polyphagia, and weakness), and patients with diabetes mellitus or risk factors for diabetes should be monitored regularly for elevated levels of glucose.

Hypersensitivity.

Hypersensitivity reactions characterized by allergic symptoms may occur with taking aripiprazole (see section "Undesirable reactions").

Body weight gain.

Patients with schizophrenia and bipolar mania often experience weight gain due to comorbidities, the use of antipsychotics that cause weight gain, and unhealthy lifestyles; this phenomenon can lead to serious complications. Post-marketing studies have shown the effect of aripiprazole on patient`s weight gain. During treatment with aripiprazole, cases of weight gain were usually observed in patients with significant risk factors, such as a history of diabetes mellitus, thyroid disorders, pituitary adenoma.

Dysphagia.

Neuroleptics, including aripiprazole, can cause disturbances in esophageal motility and gastric aspiration. Aripiprazole should be used with caution in patients at increased risk of aspiration pneumonia.

Pathological predisposition to gambling and other disorders of impulse control.

Patients may experience an increase in cases of pathological predisposition, especially to gambling, and an inability to control these attacks while taking aripiprazole. Hypersexuality, an irresistible urge to shopping, overeating or an uncontrolled urge to eat, 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 the symptoms of pulse control may be related to the underlying disorder, but it has sometimes been reported that cessation of motivation when reducing the dose of the medicinal product or when stopping treatment. Impulse control disorders can harm the patient and other people if they are not identified. If a patient develops such predispositions while taking aripiprazole, a reduction in dose or discontinuation should be considered.

Patients with concomitant attention deficit hyperactivity disorder (ADHD).

Despite the high incidence of comorbidities of bipolar disorder, I type and ADHD, data on the safety of concomitant use of aripiprazole and stimulants are very limited, so extreme caution should be exercised when prescribing these medicinal products concomitantly.

Fall.

Aripiprazole may cause drowsiness, postural hypotension, motor and sensory instability, which may lead to falls. Therefore, caution should be exercised when treating patients at higher risk (elderly or debilitated patients), or consider using a lower starting dose (see section "Posology and method of administration").

Important information of list of excipients.

Mintegra tablets contain lactose, therefore patients with rare hereditary problems of galactose intolerance, the lactase deficiency or glucose-galactose malabsorption should not take this medication.

Tablets Mintegra contain 9,0 or 13,5, or 27,0 mg/dose of sodium, respectively. Caution should be exercised when using the medicinal product in patients on a sodium-controlled diet.

This medication contains aspartame, which is a derivative of phenylalanine, which is dangerous for patients with phenylketonuria.

Fertility, pregnancy and lactation.

Pregnancy.

Adequate controlled studies of aripiprazole in pregnant women have not been performed. Congenital anomalies have been reported, but no causal relationship has been established with aripiprazole. Known animal studies do not rule out the possibility of undesirable effects on fetal development. Patients should inform their physician if they become pregnant or intend to become pregnant during treatment of aripiprazole. Due to insufficient information on the safety of aripiprazole during pregnancy, it should only be used when the expected benefit to the pregnant woman outweighs the potential risk to the fetus.

In neonates whose mothers have been taking antipsychotics (including aripiprazole) during the third trimester of pregnancy, undesirable effects, including extrapyramidal symptoms and/or withdrawal syndrome, may occur, which may vary in severity and duration. Cases of agitation, hypertension, hypotension, tremor, drowsiness, respiratory distress or feeding disorders are known. Therefore, the condition of such newborns should be closely monitored.

Lactation.

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

Fertility.

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

Effects on ability to drive and use machines.

Aripiprazole has minor or moderate influence on the ability to drive and use machines due to potential effects on the nervous system and visual organs and the manifestation of undesirable effects such as sedation, drowsiness, fainting, blurred vision, diplopia (see section “Undesirable effects”).

Posology and method of administration.

The medicinal product is intended for oral use. The tablet should be placed on the tongue, where it disperses rapidly in saliva. The tablet can be taken with or without liquid. It is difficult to remove the tablet from the oral cavity intact. As the tablet is fragile, it should be taken immediately after opening the blister. Alternatively, the tablet can be dispersed in water and the resulting suspension drunk. Oral dispersible tablets can be used as an alternative dosage form for patients who have difficulty swallowing.

Adults.

Schizophrenia: the recommended initial dose is 10 or 15 mg once a day, the maintenance dose is 15 mg once a day, regardless of food intake.

Aripiprazole is effective in a dose range of 10 to 30 mg per day. No increase in efficacy with a daily dose greater than 15 mg has been demonstrated, although an increased dose may be beneficial in some patients.

The maximum daily dose should not exceed 30 mg.

Manic episodes in bipolar disorder type I: the recommended initial dose is 15 mg once daily regardless of food intake (as monotherapy or as part of combination therapy). For some patients, increasing the dose may be effective. The maximum daily dose should not exceed 30 mg.

Prevention of recurrence of new manic episodes in bipolar disorder type I: to prevent recurrence of manic episodes in patients receiving aripiprazole as monotherapy or in combination therapy, the medicinal product should be continued at the same dose. Given the clinical condition of the patient, it is possible to adjust the daily dose, in particular its reduction.

Special categories of patients.

Patients with hepatic impairment. No dose adjustment is required in patients with mild to moderate hepatic impairment. There are insufficient data to provide recommendations for patients with severe hepatic impairment. The dose for these patients should be carefully selected. 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. No dose adjustment is required in patients with impaired renal function.

Elderly patients. The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in bipolar disorder type I in patients over 65 years of age have not been established. Given the higher sensitivity of this group of patients, lower starting doses should be considered unless prevented by other clinical factors (see section “Special warnings and precautions for use”).

Gender. No dose adjustment is required depending on the patient's gender (see section “Pharmacological Properties”).

Smoking. Due to the metabolic pathway of aripiprazole, smokers do not require dose adjustment (see section “Interaction with other medicinal products and other forms of interaction”).

Dose adjustment due to interactions. The dose of aripiprazole should be reduced when co-administering potent CYP3A4 or CYP2D6 inhibitors with aripiprazole. If a CYP3A4 or CYP2D6 inhibitor is removed from the combination regimen, the dose of aripiprazole should be increased (see section “Interaction with other medicinal products and other forms of interaction”).

The dose of aripiprazole should be increased when co-administering potent CYP3A4 inducers with aripiprazole. If the CYP3A4 inducer is removed from the combination regimen, the aripiprazole dose should be reduced to the recommended dose (see section “Interaction with other medicinal products and other forms of interaction”).

Children.

The medicinal product is not used in children, as it is impossible to provide an initial dose according to the treatment regimen.

Overdose.

Reports of accidental or intentional overdose of aripiprazole in a single dose of up to 1260 mg, have been, which was not fatal. Medically important symptoms included lethargy, high blood pressure, drowsiness, tachycardia, nausea, vomiting, and diarrhea. In addition, cases of aripiprazole overdose in children (up to 195 mg) have been reported that have not been fatal. Potentially dangerous symptoms of overdose include drowsiness, short-term loss of consciousness, and extrapyramidal disorders.

Treatment: overdose requires maintenance therapy, adequate airway patency, oxygenation, mechanical ventilation and symptomatic treatment. Cardiac monitoring with ECG recording for arrhythmias should be started immediately. After a confirmed or suspected overdose of aripiprazole, close medical supervision is required until all symptoms have resolved.

Activated charcoal (50 g) administered 1 hour after taking aripiprazole reduces the AUC and blood C_max of aripiprazole by 51% and 41%, respectively, so its use is recommended in case of overdose.

Although there are no reliable data on the use of hemodialysis in aripiprazole overdose, the beneficial effect of this method is unlikely because aripiprazole is not excreted unchanged by the kidneys and is highly bound to plasma proteins.

Undesirable effects.

The most common undesirable effects were akathisia and nausea, each of which occurred in more than 3% of patients taking aripiprazole orally.

Adverse events have been ranked under headings of frequency using the following convention: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1 000 – < 1/100), rare (≥ 1/10000 – < 1/1,000), very rare (< 1/10 000), frequency unknown (cannot be calculated according to available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The frequency of adverse reactions during post-marketing use cannot be determined because information on undesirable effects is obtained from spontaneous reports. Therefore, the frequency of these adverse reactions is classified as "unknown".

Eye disorders: common - blurred vision; uncommon - diplopia; frequency unknown - ocular crisis.

Respiratory, thoracic and mediastinal disorders: uncommon - hiccups; frequency unknown - aspiration pneumonia, laryngospasm, oropharyngeal spasm.

Gastrointestinal disorders: common - constipation, dyspepsia, nausea, increased salivation, vomiting; frequency unknown - pancreatitis, dysphagia, diarrhea, abdominal discomfort, stomach discomfort.

Hepatobiliary disorders: frequency unknown - hepatic failure, hepatitis, jaundice, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased gamma-glutamyltransferase (GGT), increased alkaline phosphatase.

Renal and urinary disorders: frequency unknown - urinary incontinence, urinary retention.

Endocrine disorders: uncommon - hyperprolactinemia; frequency unknown - diabetic hyperosmolar coma, diabetic ketoacidosis.

Metabolism and nutrition disorders: common - diabetes mellitus; uncommon - hyperglycemia; frequency unknown - hyponatremia, anorexia, weight loss or gain.

Nervous system disorders: Common - akathisia, extrapyramidal disorders, tremor, headache, sedation, drowsiness, dizziness; uncommon - dystonia, tardive dyskinesia; frequency unknown - MNS, convulsions grand mal, serotonin syndrome, speech disorders.

Psychiatric disorders common - insomnia, anxiety, worry; uncommon - depression, hypersexuality; frequency unknown - suicide attempts, suicidal thoughts and suicide, pathological gambling, impulse control disorders, compulsive overeating, irresistible urge to shop, dromomania, aggression, agitation, nervousness.

Cardiac disorders uncommon - tachycardia; frequency unknown - sudden death of unknown etiology, torsades de pointes, QT prolongation, ventricular arrhythmia, cardiac arrest, bradycardia.

Vascular disorders uncommon - orthostatic hypotension; frequency unknown - venous thromboembolism (including pulmonary embolism and deep vein thrombosis), hypertension, fainting.

Blood and lymphatic system disorders: frequency unknown - leukopenia, neutropenia, thrombocytopenia.

Immune system disorders: Frequency unknown - allergic reactions (e. g. anaphylactic reaction, angioedema, including swelling of the tongue, swelling of the face, itching or hives).

Skin and subcutaneous tissue disorders: frequency unknown - rash, photosensitivity reaction, alopecia, sweating.

Musculoskeletal and connective tissue disorders: Frequency unknown - rhabdomyolysis, myalgia, stiffness.

Pregnancy, postpartum period and perinatal status: Frequency unknown - withdrawal syndrome of medicinal products in newborns.

Reproductive system and breast disorders: Frequency unknown - priapism.

General disorders: common - fatigue; frequency unknown - thermoregulatory disorders (hypothermia, pyrexia), chest pain, peripheral edema.

Investigations: frequency unknown - increase in blood glucose concentration, increase in glycosylated hemoglobin, fluctuations in blood glucose concentration, increase in creatine phosphokinase.

Description of selected adverse reactions.

Extrapyramidal disorders included parkinsonism, akathisia, dystonia, dyskinesia.

Dystonia.

This class of medicinal products is characterized by symptoms of dystonia, prolonged pathological muscle contraction, which may occur in patients during the first days of treatment. Symptoms of dystonia include spasm of the neck muscles, which sometimes progresses to a narrowed throat, difficulty swallowing, breathing, and/or protrusion of the tongue. As these symptoms may occur at low doses, they occur more frequently and more severely with high-dose first-generation neuroleptics. An increased risk of acute dystonia is observed in men and younger patients.

Prolactin.

In clinical trials for approved indications, there were cases of both an increase and a decrease in serum prolactin compared to baseline.

Investigations:

No clinically significant differences were found between normal laboratory parameters and lipid parameters in the groups of patients receiving aripiprazole and placebo. Elevations in creatine phosphokinase, usually temporary and asymptomatic, were observed in 3.5% of patients receiving aripiprazole and 2.0% of patients receiving placebo.

Pathological predisposition to gambling and other disorders of impulse control.

Pathological gambling, hypersexuality, an irresistible urge to shop, overeating, or an uncontrolled craving for food may occur in patients taking aripiprazole.

Other data.

Undesirable effects detected with aripiprazole treatment include NMS, tardive dyskinesia, convulsions, cerebrovascular undesirable effects, and increased mortality in elderly patients with dementia, hyperglycemia, and diabetes mellitus (see section “Special warnings and precautions for use”).

Reported suspected adverse reactions.

Reporting suspected adverse reactions after registration of a medicinal product is an important procedure. This allows for continued monitoring of the benefit/risk ratio for the respective drug. Healthcare providers should be informed of any suspected adverse reactions through the national alert system.

Shelf life.3 years.

Special precautions for storage.

Store in the original package at a temperature below 25°C. Keep out of the reach of children.

Nature and contents of container.

10 tablets in a blister, 3 blisters in a carton pack.

Category of release.Prescription only medicine.

Marketing authorisation holder.

PrJSC “Pharmaceutical firm “Darnitsa”.

The marketing authorisation holder's location and address of the place of business.

13, Boryspilska Street, Kyiv, 02093, Ukraine.

Manufacturer.

Rontis Hellas Medical and Pharmaceutical Products S.A.

The manufacturer's location and address of the place of business.

P.O. Box 3012 Larisa Industrial Area, Larisa, 41004, Greece.

Date of last revision. 23.04.2020.