Mintegra
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product MINTegra (Mintegra)
Composition:
active substance: aripiprazole;
one orodispersible tablet contains aripiprazole 10 mg or 15 mg or 30 mg;
excipients:
tablets of 10 mg: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate (E 470b), iron oxide red (E 172), aspartame (E 951), vanillin flavoring;
tablets of 15 mg: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate (E 470b), iron oxide yellow (E 172), aspartame (E 951), vanillin flavoring;
tablets of 30 mg: lactose monohydrate, microcrystalline cellulose (E 460), sodium croscarmellose, colloidal anhydrous silicon dioxide, magnesium stearate (E 470b), iron oxide red (E 172), aspartame (E 951), vanillin flavoring.
Pharmaceutical form. Orodispersible tablets.
Main physicochemical properties:
tablets 10 mg – pink-colored, round-shaped, flat-surfaced tablets, embossed with "10" on one side and smooth on the other;
tablets 15 mg – yellow-colored, round-shaped, flat-surfaced tablets, embossed with "15" on one side and smooth on the other;
tablets 30 mg – pink-colored, round-shaped, flat-surfaced tablets, embossed with "30" on one side and smooth on the other.
Pharmacotherapeutic group. Psycholeptics. Antipsychotics. Other antipsychotics. Aripiprazole. ATC code N05AX12.
Pharmacological Properties
Pharmacodynamics
Mechanism of action
The therapeutic effect of aripiprazole in the treatment of schizophrenia and bipolar I disorder is mediated by a combination of partial agonism at D2-dopaminergic and 5-HT1A-serotonergic receptors, and antagonism at 5-HT2A-serotonergic receptors. Aripiprazole demonstrated antagonistic properties in animal models of dopaminergic hyperactivity and agonistic properties in animal models of dopaminergic hypoactivity. Aripiprazole has high binding affinity in vitro for D2- and D3-dopaminergic receptors, 5-HT1A- and 5-HT2A-serotonergic receptors, and moderate affinity for D4-dopaminergic receptors, 5-HT2C- and 5-HT7-serotonergic, α1-adrenergic, and histamine H1 receptors. Aripiprazole also has moderate affinity for serotonin reuptake sites and lacks significant affinity for muscarinic receptors. Interactions with receptors other than dopamine and serotonin subtypes may explain some of the other clinical effects of aripiprazole.
Aripiprazole administered at doses of 0.5 to 30 mg once daily for 2 weeks in healthy volunteers demonstrated dose-dependent reduction in binding of 11C-raclopride, a ligand for D2- and D3-receptors in the dorsolateral striatum, as assessed by positron emission tomography.
Clinical efficacy and safety
Adults
Schizophrenia
In three short-term (4 to 6 weeks) placebo-controlled trials involving 1228 adult patients with schizophrenia with positive and negative symptoms, aripiprazole demonstrated statistically significant improvement in psychiatric symptoms compared to placebo.
Aripiprazole is effective in maintaining clinical improvement during continued treatment in adult patients who initially responded to therapy. In a controlled trial using haloperidol as the active control, the proportion of patients who responded and continued to respond at week 52 was similar in both groups (77% in the aripiprazole group and 73% in the haloperidol group). The overall study completion rate was significantly higher in patients receiving aripiprazole (43%) compared to those receiving haloperidol (30%). Actual scores on rating scales, including the PANSS (Positive and Negative Syndrome Scale) and the Montgomery–Åsberg Depression Rating Scale, used as secondary endpoints, demonstrated significant improvement compared to haloperidol.
In a 26-week placebo-controlled trial in patients with stabilized chronic schizophrenia, aripiprazole significantly reduced relapse rates: 34% in the aripiprazole group versus 57% in the placebo group.
Body weight gain
Clinically significant weight gain associated with aripiprazole was not observed in clinical trials. In a 26-week controlled (active control: olanzapine), double-blind, multinational schizophrenia trial involving 314 patients, with weight gain as the primary endpoint, significantly fewer patients gained ≥7% of their baseline body weight (i.e., ≥5.6 kg with a mean baseline body weight of 80.5 kg) with aripiprazole (N = 18 or 13% of evaluable patients) compared to olanzapine (N = 45 or 33% of evaluable patients).
Lipid parameters
In a pooled analysis of lipid parameters from placebo-controlled clinical trials in adult patients, no clinically significant changes in total cholesterol, triglycerides, high-density lipoprotein (HDL), or low-density lipoprotein (LDL) concentrations induced by aripiprazole were observed.
Prolactin
Serum prolactin levels were assessed in all trials across all aripiprazole doses (n = 28242). The incidence of hyperprolactinemia or elevated serum prolactin levels in patients receiving aripiprazole (0.3%) was similar to that in the placebo group (0.2%). In patients receiving aripiprazole, the mean time to onset of such changes was 42 days, and the mean duration was 34 days.
The incidence of hypoprolactinemia or decreased serum prolactin levels in patients receiving aripiprazole was 0.4%, compared to 0.02% in the placebo group. In patients receiving aripiprazole, the mean time to onset of such changes was 30 days, and the mean duration was 194 days.
Manic episodes in bipolar I disorder
In two 3-week, dose-titration, placebo-controlled monotherapy trials involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole demonstrated greater efficacy compared to placebo. Efficacy was defined as reduction in severity of manic symptoms over 3 weeks of treatment. These trials included patients regardless of the presence of psychotic symptoms or rapid cycling.
In one 3-week, fixed-dose, placebo-controlled monotherapy trial involving patients with manic or mixed episodes of bipolar I disorder, aripiprazole did not demonstrate greater efficacy compared to placebo.
In two 12-week monotherapy trials (one placebo-controlled and one active-controlled) involving patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, aripiprazole demonstrated greater efficacy at week 3 and sustained efficacy comparable to lithium or haloperidol at week 12. The number of patients with mania achieving symptom remission with aripiprazole was comparable to those receiving lithium or haloperidol at week 12.
In a 6-week placebo-controlled trial involving patients with manic or mixed episodes of bipolar I disorder, with or without psychotic features, 2-week monotherapy with lithium or valproate at therapeutic doses was partially ineffective. However, adding aripiprazole as adjunctive therapy resulted in effective reduction of manic symptoms compared to monotherapy with lithium or valproate.
In a 26-week placebo-controlled trial with a 74-week extension, patients with bipolar disorder who achieved remission during the aripiprazole stabilization phase were enrolled. In this trial, aripiprazole was more effective than placebo in preventing relapses of bipolar disorder (mostly mania), but did not differ from placebo in preventing depressive relapses.
In a 52-week placebo-controlled trial in patients with manic or mixed episodes of bipolar I disorder who were in prolonged remission (total score on the Young Mania Rating Scale (Y-MRS) and Montgomery–Åsberg Depression Rating Scale (MADRS) ≤ threshold), adding aripiprazole (10 mg/day or 30 mg/day) to lithium or valproate over 12 weeks resulted in a 46% reduction in the risk of bipolar episode relapse (relative risk (RR)) and a 65% reduction in the risk of manic episode relapse (RR = 0.35) compared to adding aripiprazole to placebo. However, this combination did not surpass placebo in preventing depressive relapse. Adding aripiprazole was superior to placebo on the secondary endpoint—the Clinical Global Impressions-Bipolar (CGI-BP) severity score.
During this open-label trial, patients were stratified into groups receiving monotherapy with lithium or valproate to identify partial non-responders. Patients were stabilized for at least 12 weeks by adding aripiprazole to the same mood stabilizers. Stabilized patients were then randomized to continue the same mood stabilizers with either aripiprazole or placebo in a double-blind manner. Four subgroups participated in the randomized phase: aripiprazole + lithium, aripiprazole + valproate, placebo + lithium, placebo + valproate.
The rate of relapse of any mood change, determined by Kaplan–Meier method, was 16% in the aripiprazole + lithium group and 18% in the aripiprazole + valproate group, compared to 45% in the placebo + lithium group and 19% in the placebo + valproate group.
Children
Schizophrenia in adolescents
In a 6-week, placebo-controlled trial involving 302 adolescent patients (aged 13 to 17 years) with schizophrenia and positive or negative symptoms, aripiprazole was associated with statistically significant improvement in psychotic symptoms compared to placebo. In a subgroup analysis of adolescents aged 15 to 17 years, who constituted 74% of the total enrolled population, sustained efficacy was observed during a 26-week open-label extension trial.
In a 60–89-week, randomized, double-blind, placebo-controlled trial in adolescents (n = 146; aged 13 to 17 years) with schizophrenia, a statistically significant difference in the rate of relapse of psychotic symptoms was observed between the aripiprazole group (19.39%) and the placebo group (37.50%). The point estimate of RR was 0.461 (95% confidence interval (CI) 0.242 to 0.879) in the full population. In subgroup analysis, the point estimate of hazard ratio (HR) was 0.495 for patients aged 13 to 14 years compared to 0.454 for patients aged 15 to 17 years. However, the HR estimate for the younger group (aged 13 to 14 years) was imprecise, reflecting the smaller number of subjects in this group (aripiprazole: n = 29; placebo: n = 12), and the CI (0.151 to 1.628) did not allow conclusions about treatment effect. In contrast, the 95% CI for HR in the older subgroup (aripiprazole: n = 69; placebo: n = 36) was 0.242 to 0.879, allowing conclusions about treatment effect in older patients.
Manic episodes in bipolar I disorder in children and adolescents
Aripiprazole was studied in a 30-week, placebo-controlled trial involving 296 children and adolescents (aged 10 to 17 years) meeting DSM-IV (Diagnostic and Statistical Manual of Mental Disorders) criteria for bipolar I disorder with manic or mixed episodes, with or without psychotic features, and with a baseline YMRS score ≥20. Among patients included in the primary efficacy analysis, 139 had a comorbid diagnosis of attention-deficit/hyperactivity disorder (ADHD).
Aripiprazole was superior to placebo in the total Y-MRS score compared to baseline at week 4 and week 12. In a retrospective analysis, improvement compared to placebo was more pronounced in patients with comorbid ADHD than in the non-ADHD group, where no difference from placebo was observed. Relapse prevention has not been established.
The most common adverse reactions occurring in patients receiving 30 mg aripiprazole were extrapyramidal disorders (28.3%), somnolence (27.3%), headache (23.2%), and nausea (14.1%). Mean weight gain over the 30-week treatment period was 2.9 kg compared to 0.98 kg in patients receiving placebo.
Irritability associated with autistic disorder in children
The effect of aripiprazole was studied in patients aged 6 to 17 years in two 8-week, placebo-controlled trials [one flexible dose (2–15 mg/day) and one fixed-dose (5 mg/day, 10 mg/day, or 15 mg/day)] and one open-label 52-week trial. In these trials, dosing started at 2 mg/day, increased to 5 mg/day after one week, and increased by 5 mg/day weekly steps to the target dose. Over 75% of patients were under 13 years of age. Aripiprazole demonstrated statistically superior efficacy compared to placebo on the irritability subscale of the Aberrant Behavior Checklist. However, the clinical significance of this finding has not been established. The safety profile included weight gain and changes in prolactin levels. The duration of safety assessment was limited to 52 weeks. In pooled trials, the frequencies of low serum prolactin levels (<3 ng/mL in females and <2 ng/mL in males) in patients receiving aripiprazole were 27/46 (58.7%) and 258/298 (86.6%), respectively. In placebo-controlled trials, mean weight gain was 0.4 kg in the placebo group and 1.6 kg in the aripiprazole group.
Aripiprazole was also studied in a long-term, placebo-controlled trial. After 13–26 weeks of stabilization on aripiprazole (2–15 mg/day), patients with stable response continued aripiprazole or were switched to placebo for the next 16 weeks. The Kaplan–Meier relapse rate at week 16 was 35% in the aripiprazole group and 52% in the placebo group; the risk ratio for relapse over 16 weeks (aripiprazole/placebo) was 0.57 (statistically non-significant difference). Mean weight gain during the stabilization phase (up to 26 weeks) with aripiprazole was 3.2 kg, and further mean weight gain of 2.2 kg in the aripiprazole group compared to 0.6 kg in the placebo group was observed in the second phase (16 weeks) of the study. Extrapyramidal symptoms were mainly observed during the stabilization phase in 17% of patients, with tremor in 6.5%.
Tics associated with Tourette’s disorder in children
The efficacy of aripiprazole was studied in children with Tourette’s disorder (aripiprazole: n = 99, placebo: n = 44) in a randomized, double-blind, placebo-controlled, 8-week trial with fixed doses based on body weight, in the dose range of 5 to 20 mg/day, starting at 2 mg. Patients were aged 7 to 17 years and had a mean baseline score of 30 on the Yale Global Tic Severity Scale (YGTSS). With aripiprazole, improvement in YGTSS score from baseline to week 8 was 13.35 in the low-dose group (5 mg or 10 mg) and 16.94 in the high-dose group (10 mg or 20 mg), compared to 7.09 improvement in the placebo group.
The efficacy of aripiprazole in children with Tourette’s syndrome (aripiprazole: n = 32, placebo: n = 29) was also evaluated in a flexible dose range of 2 to 20 mg/day, starting at 2 mg, in a 10-week, randomized, double-blind, placebo-controlled trial conducted in South Korea. Patients were aged 6 to 18 years and had a mean baseline YGTSS score of 29. In the aripiprazole group, improvement in YGTSS score from baseline to week 10 was 14.97, compared to 9.62 in the placebo group.
In both of these short-term trials, the clinical significance of efficacy results was not established, considering the magnitude of treatment effect relative to a large placebo effect and unclear effects on psychosocial functioning. Long-term data on efficacy and safety of aripiprazole in this fluctuating disorder are lacking.
Pharmacokinetics
Absorption
Aripiprazole is rapidly absorbed after oral administration, reaching peak plasma concentration (Cmax) within 3–5 hours. Aripiprazole undergoes minimal presystemic metabolism. The absolute oral bioavailability is 87%. Administration with a high-fat meal does not affect the pharmacokinetics of aripiprazole.
Distribution
Aripiprazole is extensively distributed into body tissues. The volume of distribution is 4.9 L/kg, indicating extensive extravascular distribution. At therapeutic concentrations, more than 99% of aripiprazole and dehydroaripiprazole are bound to plasma proteins, primarily albumin.
Biotransformation
Aripiprazole is extensively metabolized in the liver, primarily via dehydrogenation, hydroxylation, and N-dealkylation. In vitro studies indicate that dehydrogenation and hydroxylation of aripiprazole are mediated by CYP3A4 and CYP2D6 isoenzymes, while N-dealkylation is catalyzed by CYP3A4. Aripiprazole is the main 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 patients with high CYP2D6 metabolic activity and approximately 146 hours in those with low CYP2D6 metabolic activity. 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. Total clearance of aripiprazole is 0.7 mL/min/kg, primarily due to hepatic elimination.
Children
The pharmacokinetics of aripiprazole and dehydroaripiprazole in patients aged 10 to 17 years were similar to those in adults after adjustment for differences in body weight.
Pharmacokinetics in special patient populations
Elderly patients
No differences in the pharmacokinetics of aripiprazole between elderly and younger healthy volunteers were observed, and no effect of age was noted in population pharmacokinetic analyses in patients with schizophrenia.
Sex
No differences in the pharmacokinetics of aripiprazole between healthy male and female volunteers were observed, and no effect of sex was detected in population pharmacokinetic analyses in patients with schizophrenia.
Smoking
Population pharmacokinetic assessment did not reveal a clinically significant effect of smoking on the pharmacokinetics of aripiprazole.
Race
No evidence of racial differences in the pharmacokinetics of aripiprazole has been identified.
Renal impairment
Pharmacokinetic characteristics of aripiprazole and dehydroaripiprazole were found to be similar in patients with severe renal disease and in young healthy volunteers.
Hepatic impairment
In a single-dose study in patients with varying degrees of liver cirrhosis (Child–Pugh classes A, B, and C), no significant effect of hepatic impairment on the pharmacokinetics of aripiprazole and dehydroaripiprazole was observed; however, only three patients with Child–Pugh class C cirrhosis were included, which is insufficient to draw conclusions about metabolic capacity.
Clinical Characteristics
Indications
Treatment of schizophrenia in adults and adolescents aged 15 years and older.
Treatment of moderate to severe manic episodes in bipolar I disorder, and prevention of recurrent manic episodes in adults who have previously experienced manic episodes and responded to aripiprazole treatment.
For treatment of moderate to severe manic episodes of bipolar I disorder in adolescents aged 13 years and older for up to 12 weeks.
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 at α1-adrenergic receptors, aripiprazole may enhance the effect of certain antihypertensive medicinal products.
Since aripiprazole affects the central nervous system (CNS), caution should be exercised when co-administering 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 disrupt electrolyte balance.
Potential influence of other medicinal products on aripiprazole
No clinically significant effect of the histamine H2-receptor blocker famotidine, which suppresses gastric hydrochloric acid secretion, on aripiprazole has been observed, despite a reduction in the rate of aripiprazole absorption.
Aripiprazole is metabolized through 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 studies in healthy volunteers, the potent CYP2D6 isoenzyme inhibitor (quinidine) increased aripiprazole AUC by 107%, while Cmax remained unchanged. AUC and Cmax of dehydro-aripiprazole, 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, and a comparable dose reduction is necessary.
Ketoconazole and other CYP3A4 inhibitors
In studies in healthy volunteers, the potent CYP3A4 inhibitor (ketoconazole) increased aripiprazole AUC and Cmax by 63% and 37%, respectively. AUC and Cmax of dehydro-aripiprazole 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 metabolism.
If concomitant use of ketoconazole or other potent CYP3A4 inhibitors with aripiprazole is necessary, the potential benefits should outweigh the possible risks to the patient. When aripiprazole is co-administered with ketoconazole, the dose of aripiprazole should be reduced by approximately half. Other potent CYP3A4 inhibitors, such as itraconazole and HIV protease inhibitors, may theoretically produce similar effects; therefore, dose adjustments should be made accordingly (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 the concomitant therapy.
A slight increase in plasma concentration of aripiprazole may occur when weak CYP3A4 inhibitors (e.g., diltiazem) or weak CYP2D6 inhibitors (e.g., escitalopram) are used concomitantly.
Carbamazepine and other CYP3A4 inducers
When carbamazepine, a potent CYP3A4 inducer, was co-administered with oral aripiprazole in patients with schizophrenia and schizoaffective disorder, geometric mean values of Cmax and AUC of aripiprazole were 68% and 73% lower, respectively, compared to monotherapy with aripiprazole 30 mg. Geometric mean values of Cmax and AUC of dehydro-aripiprazole were reduced by 69% and 71%, respectively, during co-administration with carbamazepine compared to aripiprazole monotherapy.
The dose of aripiprazole should be doubled when co-administered with carbamazepine. 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; therefore, appropriate dose increases are 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 influence 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-methoxymorphine ratio), CYP2C9 (warfarin), CYP2C19 (omeprazole), or CYP3A4 (dextromethorphan). Furthermore, aripiprazole and dehydro-aripiprazole 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 during concomitant administration with aripiprazole.
Serotonin syndrome
Cases of serotonin syndrome have been observed in patients taking aripiprazole, particularly when used concomitantly with other serotonergic medicinal products such as selective serotonin reuptake inhibitors (SSRIs)/serotonin-norepinephrine reuptake inhibitors (SNRIs), or with medicinal products that increase aripiprazole concentrations (see section "Adverse Reactions").
Special precautions for use
Improvement in the patient's clinical condition during antipsychotic treatment may take from several days to several weeks. During this period, careful monitoring of the patient's condition is required.
Suicide
Suicidal behavior is characteristic of patients with psychotic disorders and mood disorders, and has been observed shortly after initiation of antipsychotic treatment, including treatment with 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 a history of cardiovascular diseases (myocardial infarction or ischemic heart disease, heart failure, or conduction disorders), cerebrovascular disorders, conditions predisposing patients to arterial hypotension (dehydration, hypovolemia, use of antihypertensive drugs), arterial hypertension, including accelerated or malignant hypertension.
Cases of venous thromboembolism (VTE) have been observed during treatment with antipsychotic drugs. Since patients taking neuroleptics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during aripiprazole treatment, and all preventive measures should be taken.
QT interval prolongation
The frequency of QT interval prolongation during aripiprazole treatment was comparable to that with placebo. However, caution should be exercised when administering aripiprazole to patients with a family history of QT interval prolongation (see section "Adverse reactions").
Tardive dyskinesia
Tardive dyskinesia symptoms have rarely been reported in patients who have taken aripiprazole for up to 1 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
Akatisia and parkinsonism have been observed in pediatric clinical trials of aripiprazole. If signs and symptoms of other extrapyramidal symptoms appear in a patient taking aripiprazole, dose reduction and careful monitoring of the patient's condition are required.
Neuroleptic Malignant Syndrome (NMS)
NMS is a complex of symptoms associated with the use of antipsychotic drugs, which may potentially be fatal. Cases of NMS development 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, excessive sweating, and cardiac arrhythmia). Additional signs may include elevated creatine kinase levels, myoglobinuria (rhabdomyolysis), and acute renal failure. However, isolated cases of elevated creatine kinase levels and rhabdomyolysis, not necessarily associated with NMS, have also been observed. If a patient develops symptoms of NMS or unexplained very high body temperature without additional clinical manifestations of NMS, all neuroleptic active substances, including aripiprazole, should be discontinued.
Seizures
Seizures have been infrequently observed during aripiprazole treatment. Therefore, aripiprazole should be used with caution in patients with a history of epilepsy or conditions associated with seizures.
Elderly patients with psychosis associated with dementia
Increased mortality. When aripiprazole is used in elderly patients with psychosis associated with Alzheimer's disease, the risk of fatal outcome is increased. Although the causes of death were varied, most were of cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) origin (see section "Adverse reactions").
Cerebrovascular adverse reactions. Cerebrovascular adverse reactions (e.g., stroke, transient ischemic attack), including fatal cases, have been observed in elderly patients (mean age − 84 years; range 78−88 years). A clear dose-related relationship between aripiprazole and the occurrence of cerebrovascular adverse reactions has also been observed in patients receiving the drug.
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 occurred in patients taking atypical antipsychotics, including aripiprazole. Risk factors for severe complications include obesity and family history of diabetes. In aripiprazole studies, no significant differences were observed in the frequency of hyperglycemic adverse reactions (including diabetes mellitus) or pathological glucose levels compared to placebo. Based on available data, it is not possible to make a precise comparative assessment of the frequency of hyperglycemic adverse reactions in patients taking aripiprazole versus other atypical antipsychotics. Close monitoring of patients taking any neuroleptics, including aripiprazole, is required, with attention to symptoms of hyperglycemia (such as polydipsia, polyuria, polyphagia, and weakness). The condition of patients with diabetes or risk factors for developing diabetes should be regularly monitored for increased glucose levels.
Hypersensitivity
Hypersensitivity reactions characterized by allergic symptoms may occur during aripiprazole use (see section "Adverse reactions").
Weight gain
Weight gain is commonly observed in patients with schizophrenia and bipolar mania due to comorbid conditions, use of weight-gain-inducing neuroleptics, and unhealthy lifestyle; this phenomenon may lead to serious complications. Weight gain has been reported in patients taking aripiprazole during post-marketing studies.
Cases of weight gain during aripiprazole treatment typically occurred in patients with significant risk factors, such as a history of diabetes, thyroid disorders, or pituitary adenoma.
Clinical studies have not shown that aripiprazole causes clinically significant weight gain in adults. In clinical trials involving adolescent patients with bipolar mania, aripiprazole was associated with weight gain after 4 weeks of treatment. Therefore, weight gain should be monitored in adolescent patients with bipolar mania. If weight gain is clinically significant, dose reduction should be considered.
Dysphagia
Neuroleptics, including aripiprazole, may cause esophageal motility disorders and gastric content aspiration. 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 urges, particularly to gambling, and inability to control these urges while taking aripiprazole. Hypersexuality, compulsive shopping, binge eating or uncontrolled food intake, and other impulse and compulsive behavior disorders have also been reported. It is important for physicians to inform patients about the development of new or aforementioned disorders during aripiprazole treatment. Impulse control symptoms may be related to the underlying disorder; however, cessation of urges has sometimes been reported upon dose reduction or discontinuation of the drug. Impulse control disorders may harm the patient and others if not recognized. If such urges develop during aripiprazole treatment, consideration should be given to reducing the dose or discontinuing the drug.
Patients with comorbid attention deficit hyperactivity disorder (ADHD)
Despite the high comorbidity of bipolar I disorder and ADHD, data on the safety of concomitant use of aripiprazole and stimulants are very limited; therefore, extreme caution is required when co-prescribing these drugs.
Falls
Aripiprazole may cause somnolence, postural hypotension, and motor or sensory instability, which may lead to falls. Therefore, caution is required when treating patients at higher risk (elderly or debilitated patients), or consideration should be given to using a lower initial dose (see section "Dosage and administration").
Important information about excipients
Mintegra tablets contain lactose; therefore, patients with rare hereditary conditions such as galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.
Mintegra tablets contain 9.0, 13.5, or 27.0 mg/dose of sodium, respectively. Caution should be exercised when administering the drug to patients on a sodium-controlled diet.
This medicinal product contains aspartame, a phenylalanine derivative, which is dangerous for patients with phenylketonuria.
Use during pregnancy or breastfeeding
Pregnancy
Adequate controlled studies of aripiprazole in pregnant women have not been conducted. Congenital anomalies have been reported; however, a causal relationship with aripiprazole use has not been established. Available animal study data do not rule out the possibility of a negative effect on intrauterine development. Patients should inform their physician if pregnancy occurs or if they plan 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 pregnant woman outweighs the potential risk to the fetus.
Newborns whose mothers took neuroleptics (including aripiprazole) during the third trimester of pregnancy may experience adverse reactions, including extrapyramidal symptoms and/or withdrawal syndrome, which may vary in severity and duration. Cases of agitation, arterial hypertension, arterial hypotension, tremor, somnolence, respiratory distress syndrome, or feeding disorders have been reported. Therefore, careful monitoring of such newborns is required.
Period of breastfeeding
Aripiprazole is excreted in breast milk. A decision should be made regarding discontinuation of breastfeeding or discontinuation/abstention from aripiprazole therapy, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.
Fertility
According to reproductive toxicity studies, aripiprazole does not affect fertility.
Ability to influence reaction speed when driving or operating machinery
Aripiprazole has a minor or moderate effect on the ability to drive or operate machinery due to its potential impact on the nervous system and visual organs, and the occurrence of adverse reactions such as sedative effect, somnolence, syncope, blurred vision, and diplopia (see section "Adverse reactions").
Method of Administration and Dosage
The medicinal product is intended for oral administration. The tablet should be placed on the tongue, where it rapidly disperses in saliva. The tablet may be taken with or without liquid. It is difficult to remove the tablet from the oral cavity intact. Since the tablet is fragile, it should be taken immediately after opening the blister. Alternatively, the tablet may be dispersed in water and the resulting suspension swallowed. Orally disintegrating tablets may be used as an alternative dosage form for patients who have difficulty swallowing.
Adults
Schizophrenia. The recommended initial dose is 10 mg or 15 mg once daily; the maintenance dose is 15 mg once daily, regardless of food intake.
Aripiprazole is effective within a dosage range of 10 to 30 mg daily. No increase in efficacy has been observed with daily doses exceeding 15 mg, although higher doses may be beneficial for some patients.
The maximum daily dose should not exceed 30 mg.
Manic episodes in type I bipolar disorder. The recommended initial dose is 15 mg once daily, regardless of food intake (as monotherapy or in combination therapy). Dose escalation may be effective for some patients. The maximum daily dose should not exceed 30 mg.
Prevention of recurrence of new manic episodes in type I bipolar disorder. To prevent recurrence of manic episodes in patients previously treated with aripiprazole as monotherapy or in combination therapy, treatment with the medicinal product should be continued at the same dose. Dose adjustment, including dose reduction, may be considered based on the patient's clinical status.
Pediatric population
Schizophrenia in adolescents aged 15 years and older: the recommended dose of aripiprazole is 10 mg/day administered once daily regardless of food intake. Treatment should be initiated at 2 mg for 2 days, then adjusted to 5 mg for an additional 2 days to reach the recommended daily dose of 10 mg. If necessary, subsequent dose increases should be made in 5 mg increments, not exceeding the maximum daily dose of 30 mg.
Aripiprazole is not recommended for patients with schizophrenia under 15 years of age due to insufficient data on safety and efficacy.
Manic episodes in type I bipolar disorder in adolescents aged 13 years and older. The recommended dose of aripiprazole is 10 mg/day administered once daily regardless of food intake. Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL) for 2 days, then adjusted to 5 mg for an additional 2 days to achieve 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. No increase in efficacy has been observed with doses higher than 10 mg/day, and a daily dose of 30 mg is associated with a significantly higher incidence of adverse reactions, including extrapyramidal symptoms (EPS), somnolence, fatigue, and weight gain (see section "Adverse Reactions"). Therefore, doses above 10 mg/day should only be used in exceptional cases and under careful clinical monitoring (see sections "Pharmacodynamics", "Special Warnings and Precautions for Use", and "Adverse Reactions"). Younger patients have an increased risk of adverse reactions associated with aripiprazole. Therefore, the medicinal product Mintegrа is not recommended for patients under 13 years of age (see sections "Pharmacodynamics" and "Adverse Reactions").
Agitation associated with autism. The safety and efficacy of Mintegrа in children and adolescents under 18 years of age have not yet been established. Available data are described in the "Pharmacodynamics" section, but dosage recommendations cannot be provided.
Tics associated with Tourette’s disorder. The safety and efficacy of Mintegrа in children and adolescents aged 6 to 18 years have not yet been established. Available data are described in the "Pharmacodynamics" section, but dosage recommendations cannot be provided.
Special patient groups
Patients with hepatic impairment. Dose adjustment is not required in patients with mild or moderate hepatic impairment. There are insufficient data 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. The pharmacokinetic profiles of aripiprazole and dehydro-aripiprazole are similar in patients with severe renal impairment and in young healthy volunteers. Dose adjustment is not required in patients with renal impairment.
Elderly patients. The safety and efficacy of aripiprazole in the treatment of schizophrenia or manic episodes in type I bipolar disorder in patients aged 65 years and older have not been established. There are no differences in the pharmacokinetics of aripiprazole between elderly and younger healthy volunteers. No apparent differences in pharmacokinetics have been observed among different age groups of patients with schizophrenia. Due to the potentially higher sensitivity of this patient group, consideration should be given to initiating treatment with lower doses, unless contraindicated by other clinical factors (see section "Special Warnings and Precautions for Use").
Gender. There are no differences in the pharmacokinetics of aripiprazole between healthy men and women. No influence of gender on the pharmacokinetics of aripiprazole has been observed in patients with schizophrenia. Dose adjustment based on patient gender is not required (see section "Pharmacological Properties").
Smoking. Population pharmacokinetic assessment did not reveal a clinically significant effect of smoking on the pharmacokinetics of aripiprazole. Given the metabolic pathway of aripiprazole, dose adjustment is not required for smokers (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").
Dose adjustment due to interactions. When administered concomitantly 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 administered concomitantly 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").
Children
The medicinal product Mintegrа is indicated for the treatment of schizophrenia in adolescents aged 15 years and older, and for the treatment of moderate to severe manic episodes in type I bipolar disorder in adolescents aged 13 years and older for up to 12 weeks (see section "Method of Administration and Dosage"). Treatment should be initiated at a dose of 2 mg (using aripiprazole oral solution 1 mg/mL).
Overdose
Cases of accidental or intentional overdose of aripiprazole with single doses up to 1260 mg, not resulting in fatal outcome, have been reported. Medically significant symptoms included lethargy, increased blood pressure, somnolence, tachycardia, nausea, vomiting, and diarrhea. Cases of overdose in children (ingestion up to 195 mg) not leading to fatal outcome have also been described. Potentially dangerous symptoms of overdose include somnolence, transient loss of consciousness, and extrapyramidal disorders.
Treatment. Supportive therapy is required in cases of overdose, including maintenance of adequate airway patency, oxygenation, mechanical ventilation, and symptomatic treatment. The possibility of multiple medicinal product involvement in overdose should be considered. Immediate cardiac monitoring with ECG recording should be initiated to detect arrhythmias. After confirmed or suspected overdose of aripiprazole, careful medical observation is necessary until all symptoms have resolved.
Activated charcoal (50 g), administered 1 hour after aripiprazole intake, reduces AUC and Cmax of aripiprazole in blood by 51% and 41%, respectively; therefore, its use is recommended in cases of overdose.
Although there are no reliable data on the use of hemodialysis in aripiprazole overdose, a beneficial effect from this method is unlikely because aripiprazole is not excreted unchanged by the kidneys and is highly bound to plasma proteins.
Adverse Reactions
The most commonly observed adverse reactions were akathisia and nausea, each occurring in more than 3% of patients receiving oral aripiprazole.
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 available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
The frequency of adverse reactions during post-marketing use cannot be determined as information is derived from spontaneous reports. Therefore, the frequency of these adverse reactions is classified as "frequency not known".
Eye disorders: common – blurred vision; uncommon – diplopia, photophobia; frequency not known – oculogyric crisis.
Respiratory, thoracic and mediastinal disorders: uncommon – hiccup; frequency not known – aspiration pneumonia, laryngospasm, oropharyngeal spasm.
Gastrointestinal disorders: common – constipation, dyspepsia, nausea, increased salivation, vomiting; frequency not known – pancreatitis, dysphagia, diarrhea, abdominal discomfort, gastric discomfort.
Hepatobiliary disorders: frequency not known – hepatic failure, hepatitis, jaundice.
Renal and urinary disorders: frequency not known – urinary incontinence, urinary retention.
Endocrine disorders: uncommon – hyperprolactinaemia, decreased blood prolactin level; frequency not known – diabetic hyperosmolar coma, diabetic ketoacidosis.
Metabolism and nutrition disorders: common – diabetes mellitus; uncommon – hyperglycaemia; frequency not known – hyponatraemia, anorexia.
Nervous system disorders: common – akathisia, extrapyramidal disorder, tremor, headache, sedation, somnolence, dizziness; uncommon – dystonia, tardive dyskinesia, restless legs syndrome; frequency not known – CNS depression, grand mal convulsion, serotonin syndrome, speech disorder.
Psychiatric disorders: common – insomnia, anxiety, agitation; uncommon – depression, hypersexuality; frequency not known – suicide attempt, suicidal ideation and suicide, pathological gambling, impulse control disorders, compulsive eating, compulsive buying, kleptomania, aggression, agitation, restlessness.
Cardiac disorders: uncommon – tachycardia; frequency not known – sudden death of unknown aetiology, polymorphic ventricular tachycardia of torsades de pointes type, QT interval prolongation, ventricular arrhythmia, cardiac arrest, bradycardia.
Vascular disorders: uncommon – orthostatic hypotension; frequency not known – venous thromboembolism (including pulmonary embolism and deep vein thrombosis), arterial hypertension, syncope.
Blood and lymphatic system disorders: frequency not known – leukopenia, neutropenia, thrombocytopenia.
Immune system disorders: frequency not known – allergic reactions (e.g., anaphylactic reaction, angioedema, including tongue swelling, facial swelling, pruritus or urticaria).
Skin and subcutaneous tissue disorders: frequency not known – rash, photosensitivity reaction, alopecia, increased sweating, drug reaction with eosinophilia and systemic symptoms (DRESS).
Musculoskeletal and connective tissue disorders: frequency not known – rhabdomyolysis, myalgia, rigidity.
Pregnancy, puerperium and perinatal conditions: frequency not known – neonatal drug withdrawal syndrome.
Reproductive system disorders: frequency not known – priapism.
General disorders and administration site conditions: common – fatigue; frequency not known – thermoregulatory disorders (hypothermia, pyrexia), chest pain, peripheral oedema.
Investigations: frequency not known – increased blood glucose concentration, increased glycated haemoglobin level, fluctuation in blood glucose concentration, increased creatine phosphokinase (CPK) level, increased alanine aminotransferase, increased aspartate aminotransferase, increased γ-glutamyltransferase, increased alkaline phosphatase, weight increase or decrease.
Other data
Adverse reactions identified during aripiprazole treatment include increased mortality in elderly patients with dementia, hyperglycaemia and diabetes mellitus (see section "Special warnings and precautions for use").
Description of selected adverse reactions
Extrapyramidal symptoms (EPS)
Schizophrenia. In a 52-week controlled study in patients receiving aripiprazole, the incidence of EPS, including parkinsonism, akathisia, dystonia and dyskinesia, was lower (25.7%) compared to patients receiving haloperidol (57.3%). In a long-term 26-week placebo-controlled study, the incidence of EPS was 19% among patients treated with aripiprazole and 13.1% among those receiving placebo. In another 26-week controlled study, the incidence of EPS was 14.8% in patients receiving aripiprazole and 15.1% in those receiving olanzapine.
Manic episodes in bipolar I disorder. In a 12-week controlled study, the incidence of EPS was 23.5% in patients treated with aripiprazole and 53.3% in those receiving haloperidol. In another 12-week study, the incidence of EPS was 26.6% in patients receiving aripiprazole and 17.6% in those receiving lithium. In the long-term 26-week placebo-controlled phase of a study, the incidence of EPS was 18.2% in patients receiving aripiprazole and 15.7% in those 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
A class effect: symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonia symptoms include neck muscle spasms, sometimes progressing to throat tightness, difficulty swallowing, difficulty breathing, and/or tongue protrusion. Although these symptoms may occur at low doses, they are more frequent and severe at higher doses of first-generation antipsychotics. The risk of acute dystonia is higher in males and younger patients.
Prolactin
In clinical trials for approved indications and during the post-marketing period, both increases and decreases in serum prolactin levels have been observed compared to baseline levels.
Laboratory parameters
Comparison of laboratory parameters (including lipid profile) in patients receiving aripiprazole and placebo revealed no potentially clinically significant differences. Increases in CPK levels were mostly transient and asymptomatic, observed in 3.5% of patients taking aripiprazole, compared to 2.0% in the placebo group.
Paediatric patients
Schizophrenia in adolescents aged 15 years and older
In a short-term placebo-controlled clinical trial involving 302 adolescents (aged 13 to 17 years) with schizophrenia, the frequency and type of adverse reactions were similar to those in adults, except for the following reactions, which were observed more frequently in adolescents than in adults receiving aripiprazole (more frequently than placebo): somnolence/sedation and extrapyramidal disorders (very common), as well as dry mouth, increased appetite, 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 level, arrhythmia, and leukopenia.
In the combined group of adolescents with schizophrenia aged 13–17 years exposed to the drug for up to 2 years, the frequency of decreased prolactin levels in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 29.5% and 48.3%, respectively.
In adolescents with schizophrenia aged 13–17 years receiving 5 to 30 mg of aripiprazole for up to 72 months, the frequency of decreased prolactin levels in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 25.6% and 45.0%, respectively.
In two clinical trials involving adolescents (aged 13–17 years) with schizophrenia and bipolar disorder receiving aripiprazole, the frequency of decreased prolactin levels in girls (< 3 ng/mL) and boys (< 2 ng/mL) was 37.0% and 59.4%, respectively.
Manic episodes in bipolar I disorder in adolescents aged 13 years and older
The frequency and type of adverse reactions in adolescents with bipolar I disorder were similar to those in adults, except for the following: very common (≥ 1/10) – somnolence (23.0%), extrapyramidal disorders (18.4%), akathisia (16.0%), and fatigue (11.8%); common (≥ 1/100, < 1/10) – upper abdominal pain, palpitations, weight gain, increased appetite, muscle twitching, and dyskinesia.
Adverse reactions possibly dose-dependent: extrapyramidal disorders (incidence with aripiprazole 10 mg – 9.1%, 30 mg – 28.8%, placebo – 1.7%); akathisia (incidence with aripiprazole 10 mg – 12.1%, 30 mg – 20.3%, placebo – 1.7%).
The mean change in body weight in adolescents with bipolar I disorder at week 12 and week 30 of aripiprazole treatment was 2.4 kg and 5.8 kg, respectively, compared to 0.2 kg and 2.3 kg in the placebo group.
Somnolence and fatigue were observed more frequently in paediatric patients with bipolar disorder compared to those with schizophrenia.
In paediatric patients aged 10–17 years exposed to the drug for up to 30 weeks, the frequency of 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 buying, and compulsive eating.
Reporting suspected adverse reactions
Reporting suspected adverse reactions after drug authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and/or lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.
Packaging
10 tablets in a blister; 3 blisters in a carton.
Prescription category. Prescription only.
Marketing authorization holder
JSC "Pharmaceutical company "Darnitsya".
Address of the marketing authorization holder and location of its operations
13 Borispilska Street, Kyiv, 02093, Ukraine.
Manufacturer
Rontis Hellas Medical and Pharmaceutical Products S.A.
Address of the manufacturer and location of its operations
P.O. Box 3012, Larissa Industrial Area, Larissa, 41004, Greece.