Reagila 1.5mg 28 capsules

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Composition Each 1.5 mg capsule contains: Active substance: Cariprazine 1.5 mg (in the form of 1.635 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: titanium dioxide E 171, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Each 3 mg capsule contains: Active substance: Cariprazine 3 mg (in the form of 3.270 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Each 4.5 mg capsule contains: Active substance: Cariprazine 4.5 mg (in the form of 4.905 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin; body: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin). Composition of black printing ink: Pharmaceutical glaze [shellac solution in ethanol], titanium dioxide E 171, isopropanol, aqueous ammonia, butanol, propylene glycol, simethicone. Each 6 mg capsule contains: Active substance: Cariprazine 6 mg (in the form of 6.540 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #3 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Description 1.5 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque white, capsule body - opaque white. The capsule body is printed with "GR 1.5" in black. 3 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque blue-green, capsule body - opaque white. The capsule body is printed with "Gღ 3" in black. 4.5 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque blue-green, capsule body - opaque green. The capsule body is printed with "Gღ 4.5" in white. 6 mg capsules: Hard gelatin capsules, size #3. Capsule cap - opaque lilac, capsule body - opaque white. The capsule body is printed with "Gღ 6" in black. Pharmacotherapeutic group: Psycholeptics. Other antipsychotics. Pharmacological properties Pharmacodynamics Mechanism of action The mechanism of action of cariprazine is not fully understood. However, it is hypothesized that the therapeutic effect of cariprazine is provided by partial agonism at D3, D2-dopamine receptors (Ki values of 0.085–0.3 nmol/L compared to 0.49–0.71 nmol/L, respectively) and 5-HT1A-serotonin receptors (Ki value of 1.4–2.6 nmol/L), and antagonism at 5-HT2B and 5-HT2A-serotonin receptors and H1-histamine receptors (Ki values of 0.58–1.1 nmol/L, 18.8 nmol/L, and 23.3 nmol/L, respectively). Cariprazine has low affinity for 5-HT2A-serotonin receptors and alpha1-adrenergic receptors (Ki values of 134 nmol/L and 155 nmol/L, respectively). Cariprazine has no significant affinity for muscarinic cholinergic receptors (IC50 > 1000 nmol/L). The two main active metabolites, desmethylcariprazine and dide smethylcariprazine, have a similar receptor binding profile and in vitro functional activity profile to the parent compound. Pharmacodynamic effects Preclinical in vivo studies have shown that cariprazine binds to D3 receptors to the same extent as D2 receptors at pharmacologically effective doses. In patients with schizophrenia, cariprazine showed dose-dependent binding to brain D3 and D2-dopamine receptors (primarily in regions with D3 receptor predominance) within the therapeutic dose range over 15 days. The effect of cariprazine on the QT interval was studied in patients with schizophrenia or schizoaffective disorder. ECG Holter monitoring data were collected for 12 hours in 129 patients before and at steady state. No QT interval prolongation was observed with cariprazine at doses exceeding the therapeutic range (9 mg/day or 18 mg/day). In patients receiving cariprazine within the study frameworks, neither QT interval prolongation by ≥60 ms from baseline nor QTc prolongation >500 ms was recorded. Clinical efficacy Efficacy in short-term use The efficacy of cariprazine in acute schizophrenia was studied in three 6-week multicenter international, randomized, double-blind, placebo-controlled trials involving 1754 patients aged 18 to 60 years. In all acute schizophrenia trials, the primary endpoint was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score after 6 weeks of treatment, and the secondary endpoint was the change from baseline in the Clinical Global Impression-Severity scale (CGI-S) after 6 weeks of treatment. In an international placebo-controlled trial using fixed doses of 1.5 mg, 3.0 mg, and 4.5 mg cariprazine and 4.0 mg risperidone, for analysis sensitivity, statistically significant improvements in primary and secondary endpoints were demonstrated for all doses of cariprazine and the active control compared to placebo. In another international placebo-controlled trial using fixed doses of 3.0 mg and 6.0 mg cariprazine and 10 mg aripiprazole, both doses of cariprazine and the active control resulted in statistically significant improvements in primary and secondary endpoints compared to placebo. In an international placebo-controlled trial using fixed/variable doses of 3.0–6.0 mg and 6.0–9.0 mg cariprazine, both dose groups of cariprazine showed statistically significant improvements in the primary and secondary endpoints compared to placebo. The results of the change in the primary endpoint are summarized in Table 1 below. The results of the changes in the secondary endpoint (CGI) and additional endpoints confirmed the data obtained for the primary endpoint. CI - Confidence Interval; ITT - Intent-to-Treat; LS - Least Squares; PANSS - Positive and Negative Syndrome Scale; SD - Standard Deviation; SE - Standard Error. Efficacy in long-term use The maintenance of the antipsychotic effect of cariprazine was studied in a long-term clinical trial with randomized discontinuation of the drug. A total of 751 patients with exacerbation symptoms of schizophrenia received cariprazine at doses of 3-9 mg/day for 20 weeks. Of these, 337 patients received cariprazine at doses of 3 to 6 mg/day. After stabilization of their condition, patients were randomized to receive fixed doses of cariprazine 3 mg or 6 mg (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary endpoint of the study was the time to relapse. By the end of the study, schizophrenia symptoms recurred in 49.0% of patients receiving placebo and 21.6% of patients receiving cariprazine. Thus, the time to relapse (92 days compared to 326 days, based on the 25th percentile) was significantly longer in the cariprazine group than in the placebo group (p=0.009). Efficacy in patients with schizophrenia with predominant negative symptoms The efficacy of cariprazine in the treatment of schizophrenia with predominant negative symptoms was studied in a 26-week multicenter double-blind clinical trial with active control. Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was evaluated compared to risperidone (dose range 3-6 g, target dose 4 mg) in patients with persistent negative symptoms of schizophrenia (n=461). 86% of patients were younger than 55 years, and 54% of them were male. Predominant persistent negative symptoms were defined as symptoms lasting at least 6 months with a high level of negative symptoms and a low level of positive symptoms [(PANSS negative symptom factor score ≥24, score ≥4 on at least 2 or 3 PANSS items (N1: blunted affect; N4: apathy; N6: alogia) and PANSS positive symptom factor score ≤19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptoms and clinically significant parkinsonism (EPs), were excluded from the study. In both the cariprazine and risperidone groups, a statistically significant improvement in the primary endpoint of efficacy from baseline was observed - the PANSS negative symptom factor score (PANSS-FSNS) (p <0.001). However, starting from week 14, statistically significant differences (p=0.002) favoring cariprazine over risperidone were observed (Table 2). In both the cariprazine and risperidone groups, a statistically significant improvement in the secondary endpoint of efficacy from baseline was observed - the Personal and Social Functioning Scale (PSF) (p <0.001). However, starting from week 10, statistically significant differences (p <0.001) favoring cariprazine over risperidone were observed (Table 2). Differences in scores on the Clinical Global Impression-Severity (p=0.005) and Improvement (p <0.001) scales, as well as the level of improvement on the PANSS-FSNS scale (improvement on PANSS-FSNS ≥30% at week 26; p=0.003), confirmed the results of the primary and secondary efficacy endpoints. Pharmacokinetics Cariprazine has two pharmacologically active metabolites, desmethylcariprazine (DCAR) and dide smethylcariprazine (DDCAR), which have similar activity to cariprazine. Total exposure (sum of cariprazine and DCAR and DDCAR metabolites) reaches 50% of steady-state exposure after approximately 1 week of daily use, and 90% of steady-state exposure is achieved after 3 weeks. At steady state, dide smethylcariprazine exposure is approximately 2-3 times higher than cariprazine exposure, and desmethylcariprazine exposure is approximately 30% of cariprazine exposure. Absorption The absolute bioavailability of cariprazine is unknown; cariprazine is well absorbed orally. With multiple dosing, the maximum concentration (Cmax) of cariprazine and its main active metabolites is observed approximately 3-8 hours after administration. A single oral dose of 1.5 mg cariprazine with a high-fat meal (900-1000 calories) did not significantly affect cariprazine Cmax or AUC (Area Under the "Concentration-Time" Curve) values (AUC0-∞ increased by 12%, Cmax decreased by <5% after food intake compared to fasting). The effect of food on DCAR and DDCAR exposure was also minimal. Cariprazine can be taken regardless of food intake. Distribution Based on population pharmacokinetic analysis, the apparent volume of distribution of cariprazine (V/F) was 916 L, DCAR - 475 L, DDCAR - 1568 L, indicating wide distribution of cariprazine and its main active metabolites. Cariprazine (CAR) and its main active metabolites are highly bound to plasma proteins (96–97% for CAR, 94–97% for DCAR, 92–97% for DDCAR). Metabolism Cariprazine metabolism occurs via demethylation (DCAR and DDCAR), hydroxylation (hydroxycariprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxyde smethylcariprazine, HDCAR, and hydroxyde dide smethylcariprazine, HDDCAR). Subsequently, HCAR, HDCAR, and HDDCAR metabolites are transformed into corresponding conjugates with sulfate and glucuronide. Another metabolite, deschlorophenylpiperazinecariprazine acid (DDCPPCAR), is formed by dealkylation and subsequent oxidation of cariprazine. Cariprazine is metabolized by the CYP3A4 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme to DCAR and HCAR metabolites. DCAR is further transformed by the CYP3A4 isoenzyme and, to a lesser extent, by CYP2D6 to DDCAR and HDCAR metabolites. DDCAR is further metabolized by the CYP3A4 isoenzyme to HDDCAR. Cariprazine and its main active metabolites are not substrates of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), and breast cancer resistance protein (BCRP). This means that interactions of cariprazine with P-gp, OATP1B1, OATP1B3, and BCRP inhibitors are unlikely. Excretion Cariprazine and its main active metabolites are primarily excreted through hepatic metabolism. In patients with schizophrenia, after administration of cariprazine 12.5 mg/day, 20.8% of the dose was excreted by the kidneys in the form of cariprazine and its metabolites. Unchanged cariprazine is excreted by the kidneys at 1.2% and by the intestines at 3.7%. The mean terminal elimination half-life (1 to 3 days for cariprazine and desmethylcariprazine, and 13 to 19 days for dide smethylcariprazine) did not determine the time to reach steady state or the decrease in concentration in blood plasma after discontinuation of treatment. During cariprazine treatment, the effective half-life is more important than the terminal half-life. The effective half-life is approximately 2 days for cariprazine and desmethylcariprazine, 8 days for dide smethylcariprazine, or approximately 1 week for total cariprazine. The total concentration of cariprazine in blood plasma gradually decreases after discontinuation or interruption of administration. The total cariprazine concentration in blood plasma decreases by approximately 50% after 1 week and by more than 90% after approximately 3 weeks after completion of administration. Linearity With multiple dosing, the exposure of cariprazine and its two main active metabolites, desmethylcariprazine and dide smethylcariprazine, in blood plasma increases proportionally to the therapeutic dose from 1.5 to 6 mg. Pharmacokinetics in specific patient populations Renal impairment Population pharmacokinetic modeling was performed using data from patients with schizophrenia participating in the cariprazine clinical trial program who had varying degrees of renal function, including normal renal function (creatinine clearance (CrCl) ≥90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant correlation was found between cariprazine plasma clearance and creatinine clearance. The use of cariprazine in patients with severe renal impairment (CrCl <30 mL/min) has not been studied (see section "Dosage and Administration"). Hepatic impairment A study consisting of two parts (single dose of cariprazine 1 mg [Part A] and daily dose of cariprazine 0.5 mg for 14 days [Part B]) was conducted involving patients with various degrees of hepatic impairment (Child-Pugh classes A and B). Compared to healthy subjects, patients with mild and moderate hepatic impairment showed an approximately 25% increase in cariprazine exposure (Cmax and AUC). A 45% lower exposure of the main active metabolites, desmethylcariprazine and dide smethylcariprazine, was also observed with cariprazine at doses of 1 mg or 0.5 mg per day for 14 days. With multiple dosing of cariprazine, the total exposure of active substances (CAR+DCAR+DDCAR) (AUC and Cmax) in patients with mild and moderate hepatic insufficiency decreased by 21-22% and 13-15%, respectively. Compared to healthy subjects, considering the sum of bound and unbound substances. In addition, in patients with mild and moderate hepatic insufficiency, the unbound fraction of substances decreased by 12-13% and increased by 20-25%, respectively. The use of cariprazine in patients with severe hepatic impairment (Child-Pugh class C) has not been studied (see section "Dosage and Administration"). Age, sex, and race In the population pharmacokinetic analysis, no clinically significant differences in pharmacokinetic parameters (sum of AUC and Cmax of cariprazine and its main active metabolites) were observed based on age, sex, and race. The analysis included 2844 patients of various races, of whom 536 were aged 50 to 65 years. Of the 2844 patients, 933 were female (see section "Dosage and Administration"). Data on the use of cariprazine in patients over 65 years of age are insufficient. Smoking Cariprazine is not a substrate of the CYP1A2 isoenzyme; therefore, the effect of smoking on cariprazine pharmacokinetics is not expected. Cariprazine's ability to affect other drugs Cariprazine and its main active metabolites did not induce CYP1A2, CYP2B6, and CYP3A4 isoenzymes, nor did they inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isoenzymes in vitro. Cariprazine and its main active metabolites are not inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR metabolites are not inhibitors of the P-gp transporter, while cariprazine inhibits P-gp in the intestine (see section "Drug Interactions"). Indications for use Treatment of schizophrenia in adult patients. Contraindications - Hypersensitivity to the active substance or any of the excipients (see section "Composition"). - Concomitant use of strong or moderate inhibitors of the CYP3A4 isoenzyme (see section "Drug Interactions"). - Concomitant use of strong or moderate inducers of the CYP3A4 isoenzyme (see section "Drug Interactions"). Use during pregnancy and lactation Women of reproductive potential/contraception Physicians should advise women of reproductive potential to avoid pregnancy while taking Reagila®. Patients with preserved reproductive function should use highly effective methods of contraception during treatment and for at least 10 weeks after discontinuation of Reagila®. It is currently unknown whether cariprazine can reduce the effectiveness of systemic hormonal contraceptives; therefore, patients taking systemic hormonal contraceptives should also use a barrier method of contraception (see section "Drug Interactions"). Pregnancy There is no or insufficient data on the use of cariprazine in pregnant women. Preclinical studies in animals have shown reproductive toxicity, including developmental malformations in rats. The use of Reagila® is not recommended during pregnancy and in women of reproductive potential who are not using contraception. After discontinuation of cariprazine, contraception should be continued for at least 10 weeks due to the slow elimination of active metabolites. Neonates exposed to antipsychotic drugs (including cariprazine) during the third trimester of pregnancy are at risk of developing adverse reactions after birth, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration. These neonates have shown agitation, hypertonia, tremor, somnolence, respiratory distress syndrome, and feeding disorders. The severity of these complications varied. In some cases, symptoms resolved spontaneously, while in others, treatment in an intensive care unit and continued hospitalization were required. Therefore, such neonates require appropriate monitoring. Breastfeeding It is unknown whether cariprazine and its main active metabolites are excreted in breast milk. Cariprazine and its metabolites are excreted in rat milk. A risk to newborns/infants cannot be excluded during lactation. Women taking Reagila® should refrain from breastfeeding. Fertility The effect of cariprazine on human fertility has not been studied. In preclinical studies, decreased fertility and conception ability were observed in female rats. Dosage and administration Method of administration Reagila® is taken orally once daily at the same time, regardless of food intake. Dosage The recommended starting dose of cariprazine is 1.5 mg once daily. Subsequently, if necessary, the dose can be gradually increased by 1.5 mg/day up to a maximum dose of 6 mg/day. The minimum effective dose should be determined by the treating physician based on clinical assessment. Due to the long half-life of cariprazine and its active metabolites, dose changes have a small effect on drug concentration in blood plasma for several weeks. It is necessary to monitor for adverse reactions and patient response to therapy for several weeks after starting cariprazine and after each dose change (see section "Pharmacokinetics"). Switching from other antipsychotic drugs to cariprazine When switching from treatment with other antipsychotic drugs to cariprazine, gradual cross-titration should be considered, with gradual reduction of the dose of the previous drug concurrently with the initiation of cariprazine. Switching from cariprazine to other antipsychotic drugs When switching from cariprazine treatment to other antipsychotic drugs, gradual cross-titration is not necessary; the new antipsychotic drug should be started at the minimum dose with simultaneous discontinuation of cariprazine. It should be considered that the concentration of cariprazine and its active metabolites in blood plasma will decrease by 50% after approximately 1 week (see section "Pharmacokinetics"). Special patient populations Elderly patients Data on the use of cariprazine in patients aged 65 and older are insufficient to identify differences in treatment response compared to younger patients (see section "Pharmacokinetics"). Dose selection in elderly patients should be done with particular caution. Patients with renal impairment In patients with mild and moderate renal impairment (creatinine clearance (CrCl) ≥30 mL/min and <89 mL/min), dose adjustment is not required. The safety and efficacy of cariprazine in patients with severe renal impairment (CrCl <30 mL/min) have not been evaluated (see section "Pharmacokinetics"). The use of cariprazine is not recommended in patients with severe renal impairment. Patients with hepatic impairment In patients with mild and moderate hepatic impairment (5-9 Child-Pugh points), dose adjustment is not required. The safety and efficacy of cariprazine in patients with severe hepatic impairment (10-15 Child-Pugh points) have not been evaluated (see section "Pharmacokinetics"). The use of cariprazine is not recommended in patients with severe hepatic impairment. Pediatric population The efficacy and safety of cariprazine in children and adolescents under 18 years of age have not been established. No data are available. Adverse reactions Summary of safety profile The most frequent adverse drug reactions with cariprazine at doses of 1.5-6 mg were akathisia (19%) and parkinsonism (17.5%). Most adverse reactions were mild to moderate in severity. List of adverse reactions The adverse reactions listed below, based on pooled data from cariprazine studies in schizophrenia, are categorized by organ system class and preferred term. Adverse reactions are presented according to frequency of occurrence: very common - 1/10 prescriptions (≥10%); common - 1/100 prescriptions (≥1% and <10%); uncommon - 1/1000 prescriptions (≥0.1% and <1%); rare - 1/10,000 prescriptions (≥0.01% and <0.1%); very rare - less than 1/10,000 prescriptions (<0.01%); frequency unknown - insufficient data to assess the frequency of adverse drug reactions. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Blood and lymphatic system disorders Uncommon: anemia, eosinophilia. Rare: neutropenia. Immune system disorders Rare: hypersensitivity. Endocrine system disorders Uncommon: decreased serum thyroid-stimulating hormone concentration. Rare: hypothyroidism. Metabolism and nutrition disorders Common: weight gain, decreased appetite, increased appetite, dyslipidemia. Uncommon: disturbance of serum sodium concentration, increased serum glucose concentration, diabetes mellitus. Psychiatric disorders Common: sleep disorder1, anxiety. Uncommon: suicidal behavior, delirium, depression, decreased libido. Increased libido, erectile dysfunction. Nervous system disorders Very common: akathisia2, parkinsonism3. Common: somnolence, dizziness, dystonia4, other extrapyramidal and movement disorders5. Uncommon: lethargy, dysesthesia, dyskinesia6, tardive dyskinesia. Rare: seizures/convulsions, amnesia, aphasia. Frequency unknown: neuroleptic malignant syndrome. Eye disorders Common: blurred vision. Uncommon: eye irritation, increased intraocular pressure, accommodation disorders, decreased visual acuity. Rare: photophobia, cataracts. Ear and labyrinth disorders Uncommon: vertigo. Cardiac disorders Common: tachycardia. Uncommon: cardiac conduction disorders, bradycardia, QT interval prolongation on ECG. T wave abnormality on ECG. Vascular disorders Common: increased blood pressure. Uncommon: decreased blood pressure. Respiratory, thoracic and mediastinal disorders Uncommon: hiccups. Gastrointestinal disorders Common: nausea, constipation, vomiting. Uncommon: gastroesophageal reflux disease. Rare: dysphagia. Hepato-biliary disorders Common: increased activity of "liver" enzymes. Uncommon: increased serum bilirubin concentration. Frequency unknown: toxic hepatitis. Skin and subcutaneous tissue disorders Uncommon: itching, rash. Musculoskeletal and connective tissue disorders Common: increased serum creatine phosphokinase activity. Rare: rhabdomyolysis. Renal and urinary disorders Uncommon: dysuria, pollakiuria. Pregnancy, childbirth and postpartum conditions Frequency unknown: neonatal withdrawal syndrome (see section "Use during pregnancy and lactation"). General disorders and administration site conditions Common: fatigue. Uncommon: thirst. 1Sleep disorder: insomnia, unusual/nightmare dreams, sleep circadian rhythm disorder, dyssomnia, hypersomnia, difficulty falling asleep, intrasomnic disorder. Nightmare dreams, sleep disturbance, somnambulism, early awakening. 2Akathisia: akathisia, psychomotor hyperactivity, restlessness. 3Parkinsonism: akinetic-rigid syndrome, bradykinesia, bradyphrenia, cogwheel rigidity, extrapyramidal disorders, gait disturbance, hypokinesia, joint stiffness, tremor, mask-like face, muscle rigidity, musculoskeletal stiffness, neck muscle rigidity, parkinsonism. 4Dystonia: blepharospasm, dystonia, muscle tension, oromandibular dystonia, torticollis, trismus. 5Other extrapyramidal and movement disorders: balance disorder, bruxism, sialorrhea, dysarthria, shuffling gait, glabellar reflex disorder, decreased tendon reflexes, movement disorders, restless legs syndrome, increased salivation, tongue movement disorder. 6Dyskinesia: choreoathetosis, dyskinesia, facial grimacing, oculogyric crisis, tongue protrusion. Description of individual adverse reactions Cataract/lens opacity Cataract development was observed in preclinical studies of cariprazine. Therefore, in clinical studies, cataract development was adequately checked by ophthalmic examination with a slit lamp, and patients with cataracts were excluded from the study. During the clinical development program of cariprazine for the treatment of schizophrenia, several cases of cataracts were recorded, characterized by mild lens opacity without visual impairment (13/3192; 0.4%). Some of these patients had confounding factors. The most common adverse event reported in the visual system was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%). Extrapyramidal symptoms In short-term studies, the development of extrapyramidal symptoms was observed in 27%, 11.5%, 30.7%, and 15.1% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Akathisia was reported in 13.6%, 5.1%, 9.3%, and 9.9% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Parkinsonism was observed in 13.6%, 5.7%, 22.1%, and 5.3% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Dystonia was observed in 1.8%, 0.2%, 3.6%, and 0.7% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. In the placebo-controlled phase of the long-term maintenance efficacy study, extrapyramidal symptoms were observed in 13.7% of patients in the cariprazine group compared to 3.0% in the placebo group. Akathisia was reported in 3.9% of patients receiving cariprazine and 2% of patients receiving placebo. Parkinsonism was observed in 7.8% and 1.0% of patients in the cariprazine and placebo groups, respectively. In the negative symptoms study, extrapyramidal symptoms were observed in 14.3% of patients in the cariprazine group and 11.7% of patients in the risperidone group. Akathisia was observed in 10.0% of patients receiving cariprazine and 5.2% of patients receiving risperidone. Parkinsonism was observed in 5.2% and 7.4% of patients in the cariprazine and risperidone groups, respectively. In most cases, extrapyramidal symptoms were mild to moderate in severity and were resolved with conventional medications for treating extrapyramidal symptoms. The incidence of treatment discontinuation due to adverse drug reactions related to extrapyramidal symptoms was low. Venous thromboembolism Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported with the use of antipsychotic drugs with unknown frequency. Increase in liver transaminase activity An increase in liver transaminase activity (alanine aminotransferase, aspartate aminotransferase) is common with the use of antipsychotic drugs. In clinical trials of cariprazine, the incidence of increased alanine aminotransferase and aspartate aminotransferase activity was 2.2% in patients receiving cariprazine, 1.6% in patients receiving risperidone, and 0.4% in patients receiving placebo. No liver damage was observed with the use of cariprazine. Body weight changes In short-term studies, a slightly greater increase in body weight was observed in the cariprazine group compared to the placebo group: 1 kg and 0.3 kg, respectively. In the long-term maintenance efficacy study, no clinically significant changes in baseline body weight were observed by the end of the treatment period (1.1 kg in the cariprazine group and 0.9 kg in the placebo group). During the 20-week open-label phase of cariprazine treatment, potentially clinically significant weight gain (i.e., an increase of at least 7%) developed in 9.0% of patients, while in the double-blind phase, potentially clinically significant weight gain was observed in 9.8% of patients continuing cariprazine compared to 7.1% of patients randomized to placebo after 20 weeks of open-label cariprazine. In the negative symptoms study, the mean change in body weight was -0.3 kg with cariprazine and +0.6 kg with risperidone, and potentially clinically significant weight gain was observed in 6% of patients in the cariprazine group and 7.4% in the risperidone group. QT interval prolongation In a clinical study evaluating QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section "Pharmacokinetics"). In other clinical studies, a few cases of QT interval prolongation were recorded with cariprazine, which did not meet the criteria for severity. During the long-term open-label treatment period, QT interval prolongation with Bazett's correction (QTcB) >500 ms was recorded in 3 patients (0.4%). One of these patients had QT interval prolongation with Fridericia's correction (QTcF) >500 ms. Baseline QT interval prolongation by >60 ms was observed in 7 patients (1%), and QTcF in 2 patients (0.3%). During the open-label phase of the long-term maintenance efficacy study, baseline QT interval prolongation by >60 ms was observed in 12 patients (1.6%), and QTcF in 4 patients (0.5%). During the double-blind period of treatment, baseline QT interval prolongation by >60 ms was observed in 3 patients receiving cariprazine (3.1%) and 2 patients receiving placebo (2%). Reporting of suspected adverse reactions It is important to report suspected adverse reactions after the drug is registered. This allows for continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions using the national reporting system. Overdose One case of accidental single overdose of the drug (48 mg/day) is known. This patient experienced orthostatic hypotension and sedation. The patient's condition fully recovered on the same day. Treatment of overdose Treatment of overdose includes maintaining adequate airway patency, oxygenation, and ventilation, as well as symptomatic therapy. Continuous monitoring of cardiovascular system function, including continuous ECG monitoring, should be initiated immediately to detect possible cardiac rhythm disturbances. In case of severe extrapyramidal symptoms, anticholinergic drugs should be administered. Due to the high binding of cariprazine to plasma proteins, hemodialysis is likely to be ineffective. The patient should be under appropriate medical supervision until full recovery. There is no specific antidote for cariprazine. Drug interactions Cariprazine's ability to affect other drugs The metabolism of cariprazine and its main active metabolites, desmethylcariprazine and dide smethylcariprazine, is primarily mediated by the CYP3A4 isoenzyme and to a lesser extent by the CYP2D6 isoenzyme. CYP3A4 isoenzyme inhibitors Ketoconazole, a strong inhibitor of the CYP3A4 isoenzyme, caused a twofold increase in total cariprazine exposure (sum of cariprazine and its active metabolites) in blood plasma when co-administered with cariprazine for a short period (4 days), regardless of whether only unbound substances or the sum of unbound and bound components were considered. Due to the long half-life of the active metabolites of cariprazine, further increases in total cariprazine exposure in blood plasma may be expected with longer concomitant use. Therefore, concomitant use of cariprazine with strong and moderate inhibitors of the CYP3A4 isoenzyme (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see section "Contraindications"). Grapefruit juice should be avoided. CYP3A4 isoenzyme inducers Concomitant use of cariprazine with strong and moderate inducers of the CYP3A4 isoenzyme may cause a marked decrease in total cariprazine exposure in blood plasma; therefore, concomitant use of cariprazine with strong and moderate inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section "Contraindications"). CYP2D6 isoenzyme inhibitors The metabolic pathway mediated by the CYP2D6 isoenzyme plays a secondary role in the biotransformation of cariprazine; metabolism is primarily mediated by the CYP3A4 isoenzyme (see section "Pharmacokinetics"). Therefore, it is unlikely that CYP2D6 isoenzyme inhibitors will have a clinically significant effect on cariprazine biotransformation. Cariprazine's ability to affect other drugs Substrates of P-glycoprotein (P-gp) Cariprazine theoretically inhibits P-gp in vitro at maximum concentration in the intestine. The clinical significance of this effect is not fully established; however, the use of P-gp substrates with a narrow therapeutic range, such as dabigatran and digoxin, may require additional monitoring and dose adjustment. Hormonal contraceptives It is currently unknown whether cariprazine can reduce the effectiveness of systemic hormonal contraceptives; therefore, women taking systemic hormonal contraceptives should also use a barrier method of contraception. Pharmacodynamic interactions Given the primary effect of the drug on the central nervous system, Reagila® should be used with caution with other centrally acting drugs and alcohol. Precautions Suicidal thoughts and behavior Suicidality (suicidal thoughts, suicide attempts, and completed suicide) may occur in the context of psychosis and is usually observed at the beginning of treatment or after switching from therapy with other antipsychotic drugs. Patients at high risk of suicide should be under appropriate observation during treatment with antipsychotic drugs. Akathisia, restlessness Akathisia and restlessness are common adverse reactions with the use of antipsychotic drugs. Akathisia is a movement disorder characterized by a feeling of inner restlessness and the need to be constantly in motion, as well as actions such as rocking back and forth while standing or sitting, lifting the legs to simulate walking in place, and crossing and uncrossing the legs while sitting. Since cariprazine can cause akathisia and restlessness, it should be used with caution in patients who have already experienced symptoms of akathisia or have a predisposition to it. Akathisia develops at the beginning of treatment. Therefore, it is important to adequately monitor patients during the initial phase of treatment. Prevention includes gradual dose increase; therapeutic measures include a slight reduction in cariprazine dose or the use of drugs to manage extrapyramidal symptoms. The dose of the drug may be adjusted based on the patient's individual response and tolerance to treatment (see section "Adverse Reactions"). Tardive dyskinesia Tardive dyskinesia is a syndrome that includes potentially irreversible, rhythmic involuntary movements, primarily of the tongue and/or face, which may occur in patients taking antipsychotic drugs. If symptoms and signs of tardive dyskinesia are observed in a patient taking cariprazine, the advisability of discontinuing the drug should be considered. Parkinson's disease When used in patients with Parkinson's disease, antipsychotic drugs may exacerbate the underlying condition and lead to an increase in Parkinson's disease symptoms. That is, when prescribing cariprazine to patients with Parkinson's disease, the physician should adequately assess the benefits and risks. Ocular symptoms/cataracts Lens opacity/cataracts were observed in preclinical studies of cariprazine in dogs (see section "Adverse Reactions"). However, a causal relationship between lens changes/cataracts and cariprazine intake in humans has not been established. Nevertheless, patients who develop symptoms potentially related to cataracts should be referred for an ophthalmological examination and then the possibility of continuing therapy should be assessed. Neuroleptic Malignant Syndrome The development of a life-threatening symptom complex - neuroleptic malignant syndrome - has been reported with the use of antipsychotics. Clinical manifestations of neuroleptic malignant syndrome include hyperthermia, muscle rigidity, increased serum creatine phosphokinase activity, impaired consciousness, and autonomic nervous system disturbances (irregular pulse, unstable blood pressure, increased sweating, and cardiac rhythm disturbances). Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops neuroleptic malignant syndrome or unexplained high fever without additional clinical manifestations of neuroleptic malignant syndrome, cariprazine should be discontinued immediately. Seizures and convulsive episodes Cariprazine should be used with caution in patients with a history of seizures or with conditions that lower the threshold for convulsive readiness. Elderly patients with dementia The use of cariprazine in patients with dementia has not been studied. The drug is not recommended for elderly patients with dementia due to an increased risk of overall mortality. Risk of acute cerebrovascular events A approximately 3-fold increase in the risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in patients with dementia using some atypical antipsychotic drugs. The mechanism of increased risk has not been established. An increased risk cannot be ruled out with the use of other antipsychotic drugs or in other patient groups. Cardiac and vascular disorders - Blood pressure disorders Cariprazine can cause orthostatic hypotension, as well as arterial hypertension (see section "Adverse Reactions"). Cariprazine should be used with caution in patients with cardiovascular diseases who are prone to blood pressure changes. Blood pressure should be monitored. - ECG changes In patients taking antipsychotic drugs, QT interval prolongation may occur. In clinical studies aimed at studying QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section "Pharmacodynamics"). In clinical studies, a few cases of QT interval prolongation were recorded with cariprazine, which did not meet the criteria for severity (see section "Adverse Reactions"). Therefore, cariprazine should be used with caution in patients with cardiovascular diseases and in patients with a family history of QT interval prolongation, as well as in patients taking medications that can cause QT interval prolongation (see section "Pharmacokinetics"). - Venous thromboembolism Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have acquired risk factors for venous thromboembolism, all possible risk factors for venous thromboembolism should be identified before and during treatment with cariprazine, and preventive measures should be taken. Hyperglycemia and diabetes mellitus In patients with diabetes mellitus or patients with risk factors for developing diabetes mellitus (e.g., obesity, family history of diabetes), adequate monitoring of serum glucose levels is required at the beginning of treatment with atypical antipsychotics. Adverse events related to changes in glucose concentration were recorded in clinical trials of cariprazine (see section "Pharmacodynamics"). Women of reproductive potential Women of reproductive potential should use highly effective methods of contraception while taking cariprazine and for at least 10 weeks after discontinuation (see sections "Drug Interactions" and "Use during pregnancy and lactation"). Women using systemic hormonal contraceptives should also use a second, barrier method of contraception. Body weight changes Significant weight gain has been observed with cariprazine. Patients should regularly monitor their body weight (see section "Adverse Reactions"). Excipients Reagila® capsules, 3 mg, 4.5 mg, and 6 mg contain the dye brilliant red (E 129), which may cause allergic reactions. Ability to drive and operate machinery Cariprazine has a weak or moderate effect on the ability to drive vehicles and operate machinery. Patients should exercise caution when operating potentially hazardous machinery, including vehicles, until they are sure that Reagila® does not negatively affect their abilities. Packaging 7 capsules in a PVC/PE/PVDC and aluminum foil blister. 1 or 4 (for 1.5 mg and 3 mg dosages) or 4 (for 4.5 mg or 6 mg dosages) blisters with patient information leaflet in a cardboard box. Storage conditions The medicinal product does not require special storage temperature conditions. Store in the original packaging, protected from light. Keep out of reach of children. Shelf life 5 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions By prescription.

Active

cariprazine

What is it?

Composition Each 1.5 mg capsule contains: Active substance: Cariprazine 1.5 mg (in the form of 1.635 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: titanium dioxide E 171, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Each 3 mg capsule contains: Active substance: Cariprazine 3 mg (in the form of 3.270 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Each 4.5 mg capsule contains: Active substance: Cariprazine 4.5 mg (in the form of 4.905 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #4 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin; body: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, yellow iron oxide E 172, gelatin). Composition of black printing ink: Pharmaceutical glaze [shellac solution in ethanol], titanium dioxide E 171, isopropanol, aqueous ammonia, butanol, propylene glycol, simethicone. Each 6 mg capsule contains: Active substance: Cariprazine 6 mg (in the form of 6.540 mg cariprazine hydrochloride). Excipients: Pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size #3 (cap: brilliant red E 129, brilliant blue E 133, titanium dioxide E 171, gelatin; body: titanium dioxide E 171, gelatin). Composition of black printing ink: Black iron oxide E 172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide. Description 1.5 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque white, capsule body - opaque white. The capsule body is printed with "GR 1.5" in black. 3 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque blue-green, capsule body - opaque white. The capsule body is printed with "Gღ 3" in black. 4.5 mg capsules: Hard gelatin capsules, size #4. Capsule cap - opaque blue-green, capsule body - opaque green. The capsule body is printed with "Gღ 4.5" in white. 6 mg capsules: Hard gelatin capsules, size #3. Capsule cap - opaque lilac, capsule body - opaque white. The capsule body is printed with "Gღ 6" in black. Pharmacotherapeutic group: Psycholeptics. Other antipsychotics. Pharmacological properties Pharmacodynamics Mechanism of action The mechanism of action of cariprazine is not fully understood. However, it is hypothesized that the therapeutic effect of cariprazine is provided by partial agonism at D3, D2-dopamine receptors (Ki values of 0.085–0.3 nmol/L compared to 0.49–0.71 nmol/L, respectively) and 5-HT1A-serotonin receptors (Ki value of 1.4–2.6 nmol/L), and antagonism at 5-HT2B and 5-HT2A-serotonin receptors and H1-histamine receptors (Ki values of 0.58–1.1 nmol/L, 18.8 nmol/L, and 23.3 nmol/L, respectively). Cariprazine has low affinity for 5-HT2A-serotonin receptors and alpha1-adrenergic receptors (Ki values of 134 nmol/L and 155 nmol/L, respectively). Cariprazine has no significant affinity for muscarinic cholinergic receptors (IC50 > 1000 nmol/L). The two main active metabolites, desmethylcariprazine and dide smethylcariprazine, have a similar receptor binding profile and in vitro functional activity profile to the parent compound. Pharmacodynamic effects Preclinical in vivo studies have shown that cariprazine binds to D3 receptors to the same extent as D2 receptors at pharmacologically effective doses. In patients with schizophrenia, cariprazine showed dose-dependent binding to brain D3 and D2-dopamine receptors (primarily in regions with D3 receptor predominance) within the therapeutic dose range over 15 days. The effect of cariprazine on the QT interval was studied in patients with schizophrenia or schizoaffective disorder. ECG Holter monitoring data were collected for 12 hours in 129 patients before and at steady state. No QT interval prolongation was observed with cariprazine at doses exceeding the therapeutic range (9 mg/day or 18 mg/day). In patients receiving cariprazine within the study frameworks, neither QT interval prolongation by ≥60 ms from baseline nor QTc prolongation >500 ms was recorded. Clinical efficacy Efficacy in short-term use The efficacy of cariprazine in acute schizophrenia was studied in three 6-week multicenter international, randomized, double-blind, placebo-controlled trials involving 1754 patients aged 18 to 60 years. In all acute schizophrenia trials, the primary endpoint was the change from baseline in the Positive and Negative Syndrome Scale (PANSS) total score after 6 weeks of treatment, and the secondary endpoint was the change from baseline in the Clinical Global Impression-Severity scale (CGI-S) after 6 weeks of treatment. In an international placebo-controlled trial using fixed doses of 1.5 mg, 3.0 mg, and 4.5 mg cariprazine and 4.0 mg risperidone, for analysis sensitivity, statistically significant improvements in primary and secondary endpoints were demonstrated for all doses of cariprazine and the active control compared to placebo. In another international placebo-controlled trial using fixed doses of 3.0 mg and 6.0 mg cariprazine and 10 mg aripiprazole, both doses of cariprazine and the active control resulted in statistically significant improvements in primary and secondary endpoints compared to placebo. In an international placebo-controlled trial using fixed/variable doses of 3.0–6.0 mg and 6.0–9.0 mg cariprazine, both dose groups of cariprazine showed statistically significant improvements in the primary and secondary endpoints compared to placebo. The results of the change in the primary endpoint are summarized in Table 1 below. The results of the changes in the secondary endpoint (CGI) and additional endpoints confirmed the data obtained for the primary endpoint. CI - Confidence Interval; ITT - Intent-to-Treat; LS - Least Squares; PANSS - Positive and Negative Syndrome Scale; SD - Standard Deviation; SE - Standard Error. Efficacy in long-term use The maintenance of the antipsychotic effect of cariprazine was studied in a long-term clinical trial with randomized discontinuation of the drug. A total of 751 patients with exacerbation symptoms of schizophrenia received cariprazine at doses of 3-9 mg/day for 20 weeks. Of these, 337 patients received cariprazine at doses of 3 to 6 mg/day. After stabilization of their condition, patients were randomized to receive fixed doses of cariprazine 3 mg or 6 mg (n=51) or placebo (n=51) in a double-blind manner for up to 72 weeks. The primary endpoint of the study was the time to relapse. By the end of the study, schizophrenia symptoms recurred in 49.0% of patients receiving placebo and 21.6% of patients receiving cariprazine. Thus, the time to relapse (92 days compared to 326 days, based on the 25th percentile) was significantly longer in the cariprazine group than in the placebo group (p=0.009). Efficacy in patients with schizophrenia with predominant negative symptoms The efficacy of cariprazine in the treatment of schizophrenia with predominant negative symptoms was studied in a 26-week multicenter double-blind clinical trial with active control. Cariprazine (dose range 3-6 mg, target dose 4.5 mg) was evaluated compared to risperidone (dose range 3-6 g, target dose 4 mg) in patients with persistent negative symptoms of schizophrenia (n=461). 86% of patients were younger than 55 years, and 54% of them were male. Predominant persistent negative symptoms were defined as symptoms lasting at least 6 months with a high level of negative symptoms and a low level of positive symptoms [(PANSS negative symptom factor score ≥24, score ≥4 on at least 2 or 3 PANSS items (N1: blunted affect; N4: apathy; N6: alogia) and PANSS positive symptom factor score ≤19]. Patients with secondary negative symptoms, such as moderate to severe depressive symptoms and clinically significant parkinsonism (EPs), were excluded from the study. In both the cariprazine and risperidone groups, a statistically significant improvement in the primary endpoint of efficacy from baseline was observed - the PANSS negative symptom factor score (PANSS-FSNS) (p <0.001). However, starting from week 14, statistically significant differences (p=0.002) favoring cariprazine over risperidone were observed (Table 2). In both the cariprazine and risperidone groups, a statistically significant improvement in the secondary endpoint of efficacy from baseline was observed - the Personal and Social Functioning Scale (PSF) (p <0.001). However, starting from week 10, statistically significant differences (p <0.001) favoring cariprazine over risperidone were observed (Table 2). Differences in scores on the Clinical Global Impression-Severity (p=0.005) and Improvement (p <0.001) scales, as well as the level of improvement on the PANSS-FSNS scale (improvement on PANSS-FSNS ≥30% at week 26; p=0.003), confirmed the results of the primary and secondary efficacy endpoints. Pharmacokinetics Cariprazine has two pharmacologically active metabolites, desmethylcariprazine (DCAR) and dide smethylcariprazine (DDCAR), which have similar activity to cariprazine. Total exposure (sum of cariprazine and DCAR and DDCAR metabolites) reaches 50% of steady-state exposure after approximately 1 week of daily use, and 90% of steady-state exposure is achieved after 3 weeks. At steady state, dide smethylcariprazine exposure is approximately 2-3 times higher than cariprazine exposure, and desmethylcariprazine exposure is approximately 30% of cariprazine exposure. Absorption The absolute bioavailability of cariprazine is unknown; cariprazine is well absorbed orally. With multiple dosing, the maximum concentration (Cmax) of cariprazine and its main active metabolites is observed approximately 3-8 hours after administration. A single oral dose of 1.5 mg cariprazine with a high-fat meal (900-1000 calories) did not significantly affect cariprazine Cmax or AUC (Area Under the "Concentration-Time" Curve) values (AUC0-∞ increased by 12%, Cmax decreased by <5% after food intake compared to fasting). The effect of food on DCAR and DDCAR exposure was also minimal. Cariprazine can be taken regardless of food intake. Distribution Based on population pharmacokinetic analysis, the apparent volume of distribution of cariprazine (V/F) was 916 L, DCAR - 475 L, DDCAR - 1568 L, indicating wide distribution of cariprazine and its main active metabolites. Cariprazine (CAR) and its main active metabolites are highly bound to plasma proteins (96–97% for CAR, 94–97% for DCAR, 92–97% for DDCAR). Metabolism Cariprazine metabolism occurs via demethylation (DCAR and DDCAR), hydroxylation (hydroxycariprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxyde smethylcariprazine, HDCAR, and hydroxyde dide smethylcariprazine, HDDCAR). Subsequently, HCAR, HDCAR, and HDDCAR metabolites are transformed into corresponding conjugates with sulfate and glucuronide. Another metabolite, deschlorophenylpiperazinecariprazine acid (DDCPPCAR), is formed by dealkylation and subsequent oxidation of cariprazine. Cariprazine is metabolized by the CYP3A4 isoenzyme and, to a lesser extent, by the CYP2D6 isoenzyme to DCAR and HCAR metabolites. DCAR is further transformed by the CYP3A4 isoenzyme and, to a lesser extent, by CYP2D6 to DDCAR and HDCAR metabolites. DDCAR is further metabolized by the CYP3A4 isoenzyme to HDDCAR. Cariprazine and its main active metabolites are not substrates of P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), and breast cancer resistance protein (BCRP). This means that interactions of cariprazine with P-gp, OATP1B1, OATP1B3, and BCRP inhibitors are unlikely. Excretion Cariprazine and its main active metabolites are primarily excreted through hepatic metabolism. In patients with schizophrenia, after administration of cariprazine 12.5 mg/day, 20.8% of the dose was excreted by the kidneys in the form of cariprazine and its metabolites. Unchanged cariprazine is excreted by the kidneys at 1.2% and by the intestines at 3.7%. The mean terminal elimination half-life (1 to 3 days for cariprazine and desmethylcariprazine, and 13 to 19 days for dide smethylcariprazine) did not determine the time to reach steady state or the decrease in concentration in blood plasma after discontinuation of treatment. During cariprazine treatment, the effective half-life is more important than the terminal half-life. The effective half-life is approximately 2 days for cariprazine and desmethylcariprazine, 8 days for dide smethylcariprazine, or approximately 1 week for total cariprazine. The total concentration of cariprazine in blood plasma gradually decreases after discontinuation or interruption of administration. The total cariprazine concentration in blood plasma decreases by approximately 50% after 1 week and by more than 90% after approximately 3 weeks after completion of administration. Linearity With multiple dosing, the exposure of cariprazine and its two main active metabolites, desmethylcariprazine and dide smethylcariprazine, in blood plasma increases proportionally to the therapeutic dose from 1.5 to 6 mg. Pharmacokinetics in specific patient populations Renal impairment Population pharmacokinetic modeling was performed using data from patients with schizophrenia participating in the cariprazine clinical trial program who had varying degrees of renal function, including normal renal function (creatinine clearance (CrCl) ≥90 mL/min), as well as mild (CrCl 60 to 89 mL/min) and moderate (CrCl 30 to 59 mL/min) renal impairment. No significant correlation was found between cariprazine plasma clearance and creatinine clearance. The use of cariprazine in patients with severe renal impairment (CrCl <30 mL/min) has not been studied (see section "Dosage and Administration"). Hepatic impairment A study consisting of two parts (single dose of cariprazine 1 mg [Part A] and daily dose of cariprazine 0.5 mg for 14 days [Part B]) was conducted involving patients with various degrees of hepatic impairment (Child-Pugh classes A and B). Compared to healthy subjects, patients with mild and moderate hepatic impairment showed an approximately 25% increase in cariprazine exposure (Cmax and AUC). A 45% lower exposure of the main active metabolites, desmethylcariprazine and dide smethylcariprazine, was also observed with cariprazine at doses of 1 mg or 0.5 mg per day for 14 days. With multiple dosing of cariprazine, the total exposure of active substances (CAR+DCAR+DDCAR) (AUC and Cmax) in patients with mild and moderate hepatic insufficiency decreased by 21-22% and 13-15%, respectively. Compared to healthy subjects, considering the sum of bound and unbound substances. In addition, in patients with mild and moderate hepatic insufficiency, the unbound fraction of substances decreased by 12-13% and increased by 20-25%, respectively. The use of cariprazine in patients with severe hepatic impairment (Child-Pugh class C) has not been studied (see section "Dosage and Administration"). Age, sex, and race In the population pharmacokinetic analysis, no clinically significant differences in pharmacokinetic parameters (sum of AUC and Cmax of cariprazine and its main active metabolites) were observed based on age, sex, and race. The analysis included 2844 patients of various races, of whom 536 were aged 50 to 65 years. Of the 2844 patients, 933 were female (see section "Dosage and Administration"). Data on the use of cariprazine in patients over 65 years of age are insufficient. Smoking Cariprazine is not a substrate of the CYP1A2 isoenzyme; therefore, the effect of smoking on cariprazine pharmacokinetics is not expected. Cariprazine's ability to affect other drugs Cariprazine and its main active metabolites did not induce CYP1A2, CYP2B6, and CYP3A4 isoenzymes, nor did they inhibit CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isoenzymes in vitro. Cariprazine and its main active metabolites are not inhibitors of transporters OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR metabolites are not inhibitors of the P-gp transporter, while cariprazine inhibits P-gp in the intestine (see section "Drug Interactions"). Indications for use Treatment of schizophrenia in adult patients. Contraindications - Hypersensitivity to the active substance or any of the excipients (see section "Composition"). - Concomitant use of strong or moderate inhibitors of the CYP3A4 isoenzyme (see section "Drug Interactions"). - Concomitant use of strong or moderate inducers of the CYP3A4 isoenzyme (see section "Drug Interactions"). Use during pregnancy and lactation Women of reproductive potential/contraception Physicians should advise women of reproductive potential to avoid pregnancy while taking Reagila®. Patients with preserved reproductive function should use highly effective methods of contraception during treatment and for at least 10 weeks after discontinuation of Reagila®. It is currently unknown whether cariprazine can reduce the effectiveness of systemic hormonal contraceptives; therefore, patients taking systemic hormonal contraceptives should also use a barrier method of contraception (see section "Drug Interactions"). Pregnancy There is no or insufficient data on the use of cariprazine in pregnant women. Preclinical studies in animals have shown reproductive toxicity, including developmental malformations in rats. The use of Reagila® is not recommended during pregnancy and in women of reproductive potential who are not using contraception. After discontinuation of cariprazine, contraception should be continued for at least 10 weeks due to the slow elimination of active metabolites. Neonates exposed to antipsychotic drugs (including cariprazine) during the third trimester of pregnancy are at risk of developing adverse reactions after birth, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration. These neonates have shown agitation, hypertonia, tremor, somnolence, respiratory distress syndrome, and feeding disorders. The severity of these complications varied. In some cases, symptoms resolved spontaneously, while in others, treatment in an intensive care unit and continued hospitalization were required. Therefore, such neonates require appropriate monitoring. Breastfeeding It is unknown whether cariprazine and its main active metabolites are excreted in breast milk. Cariprazine and its metabolites are excreted in rat milk. A risk to newborns/infants cannot be excluded during lactation. Women taking Reagila® should refrain from breastfeeding. Fertility The effect of cariprazine on human fertility has not been studied. In preclinical studies, decreased fertility and conception ability were observed in female rats. Dosage and administration Method of administration Reagila® is taken orally once daily at the same time, regardless of food intake. Dosage The recommended starting dose of cariprazine is 1.5 mg once daily. Subsequently, if necessary, the dose can be gradually increased by 1.5 mg/day up to a maximum dose of 6 mg/day. The minimum effective dose should be determined by the treating physician based on clinical assessment. Due to the long half-life of cariprazine and its active metabolites, dose changes have a small effect on drug concentration in blood plasma for several weeks. It is necessary to monitor for adverse reactions and patient response to therapy for several weeks after starting cariprazine and after each dose change (see section "Pharmacokinetics"). Switching from other antipsychotic drugs to cariprazine When switching from treatment with other antipsychotic drugs to cariprazine, gradual cross-titration should be considered, with gradual reduction of the dose of the previous drug concurrently with the initiation of cariprazine. Switching from cariprazine to other antipsychotic drugs When switching from cariprazine treatment to other antipsychotic drugs, gradual cross-titration is not necessary; the new antipsychotic drug should be started at the minimum dose with simultaneous discontinuation of cariprazine. It should be considered that the concentration of cariprazine and its active metabolites in blood plasma will decrease by 50% after approximately 1 week (see section "Pharmacokinetics"). Special patient populations Elderly patients Data on the use of cariprazine in patients aged 65 and older are insufficient to identify differences in treatment response compared to younger patients (see section "Pharmacokinetics"). Dose selection in elderly patients should be done with particular caution. Patients with renal impairment In patients with mild and moderate renal impairment (creatinine clearance (CrCl) ≥30 mL/min and <89 mL/min), dose adjustment is not required. The safety and efficacy of cariprazine in patients with severe renal impairment (CrCl <30 mL/min) have not been evaluated (see section "Pharmacokinetics"). The use of cariprazine is not recommended in patients with severe renal impairment. Patients with hepatic impairment In patients with mild and moderate hepatic impairment (5-9 Child-Pugh points), dose adjustment is not required. The safety and efficacy of cariprazine in patients with severe hepatic impairment (10-15 Child-Pugh points) have not been evaluated (see section "Pharmacokinetics"). The use of cariprazine is not recommended in patients with severe hepatic impairment. Pediatric population The efficacy and safety of cariprazine in children and adolescents under 18 years of age have not been established. No data are available. Adverse reactions Summary of safety profile The most frequent adverse drug reactions with cariprazine at doses of 1.5-6 mg were akathisia (19%) and parkinsonism (17.5%). Most adverse reactions were mild to moderate in severity. List of adverse reactions The adverse reactions listed below, based on pooled data from cariprazine studies in schizophrenia, are categorized by organ system class and preferred term. Adverse reactions are presented according to frequency of occurrence: very common - 1/10 prescriptions (≥10%); common - 1/100 prescriptions (≥1% and <10%); uncommon - 1/1000 prescriptions (≥0.1% and <1%); rare - 1/10,000 prescriptions (≥0.01% and <0.1%); very rare - less than 1/10,000 prescriptions (<0.01%); frequency unknown - insufficient data to assess the frequency of adverse drug reactions. Within each frequency group, adverse reactions are presented in order of decreasing seriousness. Blood and lymphatic system disorders Uncommon: anemia, eosinophilia. Rare: neutropenia. Immune system disorders Rare: hypersensitivity. Endocrine system disorders Uncommon: decreased serum thyroid-stimulating hormone concentration. Rare: hypothyroidism. Metabolism and nutrition disorders Common: weight gain, decreased appetite, increased appetite, dyslipidemia. Uncommon: disturbance of serum sodium concentration, increased serum glucose concentration, diabetes mellitus. Psychiatric disorders Common: sleep disorder1, anxiety. Uncommon: suicidal behavior, delirium, depression, decreased libido. Increased libido, erectile dysfunction. Nervous system disorders Very common: akathisia2, parkinsonism3. Common: somnolence, dizziness, dystonia4, other extrapyramidal and movement disorders5. Uncommon: lethargy, dysesthesia, dyskinesia6, tardive dyskinesia. Rare: seizures/convulsions, amnesia, aphasia. Frequency unknown: neuroleptic malignant syndrome. Eye disorders Common: blurred vision. Uncommon: eye irritation, increased intraocular pressure, accommodation disorders, decreased visual acuity. Rare: photophobia, cataracts. Ear and labyrinth disorders Uncommon: vertigo. Cardiac disorders Common: tachycardia. Uncommon: cardiac conduction disorders, bradycardia, QT interval prolongation on ECG. T wave abnormality on ECG. Vascular disorders Common: increased blood pressure. Uncommon: decreased blood pressure. Respiratory, thoracic and mediastinal disorders Uncommon: hiccups. Gastrointestinal disorders Common: nausea, constipation, vomiting. Uncommon: gastroesophageal reflux disease. Rare: dysphagia. Hepato-biliary disorders Common: increased activity of "liver" enzymes. Uncommon: increased serum bilirubin concentration. Frequency unknown: toxic hepatitis. Skin and subcutaneous tissue disorders Uncommon: itching, rash. Musculoskeletal and connective tissue disorders Common: increased serum creatine phosphokinase activity. Rare: rhabdomyolysis. Renal and urinary disorders Uncommon: dysuria, pollakiuria. Pregnancy, childbirth and postpartum conditions Frequency unknown: neonatal withdrawal syndrome (see section "Use during pregnancy and lactation"). General disorders and administration site conditions Common: fatigue. Uncommon: thirst. 1Sleep disorder: insomnia, unusual/nightmare dreams, sleep circadian rhythm disorder, dyssomnia, hypersomnia, difficulty falling asleep, intrasomnic disorder. Nightmare dreams, sleep disturbance, somnambulism, early awakening. 2Akathisia: akathisia, psychomotor hyperactivity, restlessness. 3Parkinsonism: akinetic-rigid syndrome, bradykinesia, bradyphrenia, cogwheel rigidity, extrapyramidal disorders, gait disturbance, hypokinesia, joint stiffness, tremor, mask-like face, muscle rigidity, musculoskeletal stiffness, neck muscle rigidity, parkinsonism. 4Dystonia: blepharospasm, dystonia, muscle tension, oromandibular dystonia, torticollis, trismus. 5Other extrapyramidal and movement disorders: balance disorder, bruxism, sialorrhea, dysarthria, shuffling gait, glabellar reflex disorder, decreased tendon reflexes, movement disorders, restless legs syndrome, increased salivation, tongue movement disorder. 6Dyskinesia: choreoathetosis, dyskinesia, facial grimacing, oculogyric crisis, tongue protrusion. Description of individual adverse reactions Cataract/lens opacity Cataract development was observed in preclinical studies of cariprazine. Therefore, in clinical studies, cataract development was adequately checked by ophthalmic examination with a slit lamp, and patients with cataracts were excluded from the study. During the clinical development program of cariprazine for the treatment of schizophrenia, several cases of cataracts were recorded, characterized by mild lens opacity without visual impairment (13/3192; 0.4%). Some of these patients had confounding factors. The most common adverse event reported in the visual system was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%). Extrapyramidal symptoms In short-term studies, the development of extrapyramidal symptoms was observed in 27%, 11.5%, 30.7%, and 15.1% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Akathisia was reported in 13.6%, 5.1%, 9.3%, and 9.9% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Parkinsonism was observed in 13.6%, 5.7%, 22.1%, and 5.3% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. Dystonia was observed in 1.8%, 0.2%, 3.6%, and 0.7% of patients receiving cariprazine, placebo, risperidone, and aripiprazole, respectively. In the placebo-controlled phase of the long-term maintenance efficacy study, extrapyramidal symptoms were observed in 13.7% of patients in the cariprazine group compared to 3.0% in the placebo group. Akathisia was reported in 3.9% of patients receiving cariprazine and 2% of patients receiving placebo. Parkinsonism was observed in 7.8% and 1.0% of patients in the cariprazine and placebo groups, respectively. In the negative symptoms study, extrapyramidal symptoms were observed in 14.3% of patients in the cariprazine group and 11.7% of patients in the risperidone group. Akathisia was observed in 10.0% of patients receiving cariprazine and 5.2% of patients receiving risperidone. Parkinsonism was observed in 5.2% and 7.4% of patients in the cariprazine and risperidone groups, respectively. In most cases, extrapyramidal symptoms were mild to moderate in severity and were resolved with conventional medications for treating extrapyramidal symptoms. The incidence of treatment discontinuation due to adverse drug reactions related to extrapyramidal symptoms was low. Venous thromboembolism Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported with the use of antipsychotic drugs with unknown frequency. Increase in liver transaminase activity An increase in liver transaminase activity (alanine aminotransferase, aspartate aminotransferase) is common with the use of antipsychotic drugs. In clinical trials of cariprazine, the incidence of increased alanine aminotransferase and aspartate aminotransferase activity was 2.2% in patients receiving cariprazine, 1.6% in patients receiving risperidone, and 0.4% in patients receiving placebo. No liver damage was observed with the use of cariprazine. Body weight changes In short-term studies, a slightly greater increase in body weight was observed in the cariprazine group compared to the placebo group: 1 kg and 0.3 kg, respectively. In the long-term maintenance efficacy study, no clinically significant changes in baseline body weight were observed by the end of the treatment period (1.1 kg in the cariprazine group and 0.9 kg in the placebo group). During the 20-week open-label phase of cariprazine treatment, potentially clinically significant weight gain (i.e., an increase of at least 7%) developed in 9.0% of patients, while in the double-blind phase, potentially clinically significant weight gain was observed in 9.8% of patients continuing cariprazine compared to 7.1% of patients randomized to placebo after 20 weeks of open-label cariprazine. In the negative symptoms study, the mean change in body weight was -0.3 kg with cariprazine and +0.6 kg with risperidone, and potentially clinically significant weight gain was observed in 6% of patients in the cariprazine group and 7.4% in the risperidone group. QT interval prolongation In a clinical study evaluating QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section "Pharmacokinetics"). In other clinical studies, a few cases of QT interval prolongation were recorded with cariprazine, which did not meet the criteria for severity. During the long-term open-label treatment period, QT interval prolongation with Bazett's correction (QTcB) >500 ms was recorded in 3 patients (0.4%). One of these patients had QT interval prolongation with Fridericia's correction (QTcF) >500 ms. Baseline QT interval prolongation by >60 ms was observed in 7 patients (1%), and QTcF in 2 patients (0.3%). During the open-label phase of the long-term maintenance efficacy study, baseline QT interval prolongation by >60 ms was observed in 12 patients (1.6%), and QTcF in 4 patients (0.5%). During the double-blind period of treatment, baseline QT interval prolongation by >60 ms was observed in 3 patients receiving cariprazine (3.1%) and 2 patients receiving placebo (2%). Reporting of suspected adverse reactions It is important to report suspected adverse reactions after the drug is registered. This allows for continuous monitoring of the benefit-risk balance of the drug. Healthcare professionals are asked to report any suspected adverse reactions using the national reporting system. Overdose One case of accidental single overdose of the drug (48 mg/day) is known. This patient experienced orthostatic hypotension and sedation. The patient's condition fully recovered on the same day. Treatment of overdose Treatment of overdose includes maintaining adequate airway patency, oxygenation, and ventilation, as well as symptomatic therapy. Continuous monitoring of cardiovascular system function, including continuous ECG monitoring, should be initiated immediately to detect possible cardiac rhythm disturbances. In case of severe extrapyramidal symptoms, anticholinergic drugs should be administered. Due to the high binding of cariprazine to plasma proteins, hemodialysis is likely to be ineffective. The patient should be under appropriate medical supervision until full recovery. There is no specific antidote for cariprazine. Drug interactions Cariprazine's ability to affect other drugs The metabolism of cariprazine and its main active metabolites, desmethylcariprazine and dide smethylcariprazine, is primarily mediated by the CYP3A4 isoenzyme and to a lesser extent by the CYP2D6 isoenzyme. CYP3A4 isoenzyme inhibitors Ketoconazole, a strong inhibitor of the CYP3A4 isoenzyme, caused a twofold increase in total cariprazine exposure (sum of cariprazine and its active metabolites) in blood plasma when co-administered with cariprazine for a short period (4 days), regardless of whether only unbound substances or the sum of unbound and bound components were considered. Due to the long half-life of the active metabolites of cariprazine, further increases in total cariprazine exposure in blood plasma may be expected with longer concomitant use. Therefore, concomitant use of cariprazine with strong and moderate inhibitors of the CYP3A4 isoenzyme (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see section "Contraindications"). Grapefruit juice should be avoided. CYP3A4 isoenzyme inducers Concomitant use of cariprazine with strong and moderate inducers of the CYP3A4 isoenzyme may cause a marked decrease in total cariprazine exposure in blood plasma; therefore, concomitant use of cariprazine with strong and moderate inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section "Contraindications"). CYP2D6 isoenzyme inhibitors The metabolic pathway mediated by the CYP2D6 isoenzyme plays a secondary role in the biotransformation of cariprazine; metabolism is primarily mediated by the CYP3A4 isoenzyme (see section "Pharmacokinetics"). Therefore, it is unlikely that CYP2D6 isoenzyme inhibitors will have a clinically significant effect on cariprazine biotransformation. Cariprazine's ability to affect other drugs Substrates of P-glycoprotein (P-gp) Cariprazine theoretically inhibits P-gp in vitro at maximum concentration in the intestine. The clinical significance of this effect is not fully established; however, the use of P-gp substrates with a narrow therapeutic range, such as dabigatran and digoxin, may require additional monitoring and dose adjustment. Hormonal contraceptives It is currently unknown whether cariprazine can reduce the effectiveness of systemic hormonal contraceptives; therefore, women taking systemic hormonal contraceptives should also use a barrier method of contraception. Pharmacodynamic interactions Given the primary effect of the drug on the central nervous system, Reagila® should be used with caution with other centrally acting drugs and alcohol. Precautions Suicidal thoughts and behavior Suicidality (suicidal thoughts, suicide attempts, and completed suicide) may occur in the context of psychosis and is usually observed at the beginning of treatment or after switching from therapy with other antipsychotic drugs. Patients at high risk of suicide should be under appropriate observation during treatment with antipsychotic drugs. Akathisia, restlessness Akathisia and restlessness are common adverse reactions with the use of antipsychotic drugs. Akathisia is a movement disorder characterized by a feeling of inner restlessness and the need to be constantly in motion, as well as actions such as rocking back and forth while standing or sitting, lifting the legs to simulate walking in place, and crossing and uncrossing the legs while sitting. Since cariprazine can cause akathisia and restlessness, it should be used with caution in patients who have already experienced symptoms of akathisia or have a predisposition to it. Akathisia develops at the beginning of treatment. Therefore, it is important to adequately monitor patients during the initial phase of treatment. Prevention includes gradual dose increase; therapeutic measures include a slight reduction in cariprazine dose or the use of drugs to manage extrapyramidal symptoms. The dose of the drug may be adjusted based on the patient's individual response and tolerance to treatment (see section "Adverse Reactions"). Tardive dyskinesia Tardive dyskinesia is a syndrome that includes potentially irreversible, rhythmic involuntary movements, primarily of the tongue and/or face, which may occur in patients taking antipsychotic drugs. If symptoms and signs of tardive dyskinesia are observed in a patient taking cariprazine, the advisability of discontinuing the drug should be considered. Parkinson's disease When used in patients with Parkinson's disease, antipsychotic drugs may exacerbate the underlying condition and lead to an increase in Parkinson's disease symptoms. That is, when prescribing cariprazine to patients with Parkinson's disease, the physician should adequately assess the benefits and risks. Ocular symptoms/cataracts Lens opacity/cataracts were observed in preclinical studies of cariprazine in dogs (see section "Adverse Reactions"). However, a causal relationship between lens changes/cataracts and cariprazine intake in humans has not been established. Nevertheless, patients who develop symptoms potentially related to cataracts should be referred for an ophthalmological examination and then the possibility of continuing therapy should be assessed. Neuroleptic Malignant Syndrome The development of a life-threatening symptom complex - neuroleptic malignant syndrome - has been reported with the use of antipsychotics. Clinical manifestations of neuroleptic malignant syndrome include hyperthermia, muscle rigidity, increased serum creatine phosphokinase activity, impaired consciousness, and autonomic nervous system disturbances (irregular pulse, unstable blood pressure, increased sweating, and cardiac rhythm disturbances). Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops neuroleptic malignant syndrome or unexplained high fever without additional clinical manifestations of neuroleptic malignant syndrome, cariprazine should be discontinued immediately. Seizures and convulsive episodes Cariprazine should be used with caution in patients with a history of seizures or with conditions that lower the threshold for convulsive readiness. Elderly patients with dementia The use of cariprazine in patients with dementia has not been studied. The drug is not recommended for elderly patients with dementia due to an increased risk of overall mortality. Risk of acute cerebrovascular events A approximately 3-fold increase in the risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in patients with dementia using some atypical antipsychotic drugs. The mechanism of increased risk has not been established. An increased risk cannot be ruled out with the use of other antipsychotic drugs or in other patient groups. Cardiac and vascular disorders - Blood pressure disorders Cariprazine can cause orthostatic hypotension, as well as arterial hypertension (see section "Adverse Reactions"). Cariprazine should be used with caution in patients with cardiovascular diseases who are prone to blood pressure changes. Blood pressure should be monitored. - ECG changes In patients taking antipsychotic drugs, QT interval prolongation may occur. In clinical studies aimed at studying QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section "Pharmacodynamics"). In clinical studies, a few cases of QT interval prolongation were recorded with cariprazine, which did not meet the criteria for severity (see section "Adverse Reactions"). Therefore, cariprazine should be used with caution in patients with cardiovascular diseases and in patients with a family history of QT interval prolongation, as well as in patients taking medications that can cause QT interval prolongation (see section "Pharmacokinetics"). - Venous thromboembolism Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have acquired risk factors for venous thromboembolism, all possible risk factors for venous thromboembolism should be identified before and during treatment with cariprazine, and preventive measures should be taken. Hyperglycemia and diabetes mellitus In patients with diabetes mellitus or patients with risk factors for developing diabetes mellitus (e.g., obesity, family history of diabetes), adequate monitoring of serum glucose levels is required at the beginning of treatment with atypical antipsychotics. Adverse events related to changes in glucose concentration were recorded in clinical trials of cariprazine (see section "Pharmacodynamics"). Women of reproductive potential Women of reproductive potential should use highly effective methods of contraception while taking cariprazine and for at least 10 weeks after discontinuation (see sections "Drug Interactions" and "Use during pregnancy and lactation"). Women using systemic hormonal contraceptives should also use a second, barrier method of contraception. Body weight changes Significant weight gain has been observed with cariprazine. Patients should regularly monitor their body weight (see section "Adverse Reactions"). Excipients Reagila® capsules, 3 mg, 4.5 mg, and 6 mg contain the dye brilliant red (E 129), which may cause allergic reactions. Ability to drive and operate machinery Cariprazine has a weak or moderate effect on the ability to drive vehicles and operate machinery. Patients should exercise caution when operating potentially hazardous machinery, including vehicles, until they are sure that Reagila® does not negatively affect their abilities. Packaging 7 capsules in a PVC/PE/PVDC and aluminum foil blister. 1 or 4 (for 1.5 mg and 3 mg dosages) or 4 (for 4.5 mg or 6 mg dosages) blisters with patient information leaflet in a cardboard box. Storage conditions The medicinal product does not require special storage temperature conditions. Store in the original packaging, protected from light. Keep out of reach of children. Shelf life 5 years. Do not use after the expiry date indicated on the packaging. Dispensing conditions By prescription.