Reagila capsules 4.5mg, 28pcs

Composition

4.5 mg capsules

Active ingredient: cariprazine hydrochloride 4,905 mg (equivalent to cariprazine 4,5 mg).

Auxiliary substances: pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size no. 4 (cap: gelatin, titanium dioxide E 171, dye iron oxide yellow E 172, dye brilliant blue E 133, dye enchanting red E 129; shell: gelatin, titanium dioxide E 171, dye iron oxide yellow E 172, dye brilliant blue E 133, dye enchanting red E 129).

White ink composition for printing: pharmaceutical glaze [shellac solution in ethanol], titanium dioxide E 171, isopropanol, water ammonia, butanol, propylene glycol, simethicone.

Pharmacological action

Pharmacotherapeutic group: antipsychotic agent (neuroleptic)

Pharmacological properties

Pharmacodynamics

Mechanism of action

The mechanism of action of cariprazine is not fully known. However, it is assumed that the therapeutic effect of cariprazine is provided by a combination of partial agonism against D3 -, D2-dopamine receptors (Ki value 0.085-0.3 nmol/l compared to 0.49-0.71 nmol/l, respectively) and 5-HT1A-serotonin receptors (Ki value 1.4-2.6 nmol/L) and antagonism against 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 a low affinity for 5-HT2C-serotonin and alpha-1-adrenergic receptors (Ki values of 134 nmol / l and 155 nmol/l, respectively). Cariprazine has no significant affinity for muscarinic cholinergic receptors (IR 50>1000 nmol / l). The two main active metabolites, desmethylcariprazine and didezmethylcariprazine, have a similar receptor binding profile and functional activity profile in vitro to cariprazine, just like the original drug substance.

Pharmacodynamic effects

Preclinical in vivo studies have shown that cariprazine binds to D3 receptors at pharmacologically effective doses to the same extent as it binds to D2 receptors. In patients with schizophrenia, dose-dependent binding of cariprazine to D3 and D2 dopamine receptors of the brain (mainly in areas with a predominance of D3 receptors) was observed in the therapeutic dose range for 15 days.

The effect of cariprazine on the QT interval was studied in patients with schizophrenia or schizoaffective disorder. Data were obtained from Holter ECG monitoring for 12 hours in 129 patients before the drug was prescribed and after reaching an equilibrium state. No prolongation of the QT interval was observed when cariprazine was administered at doses higher than therapeutic (9 mg/day or 18 mg/day). In patients treated with cariprazine in the study, there was no prolongation of the QTc interval by ≥60 ms from baseline, nor QTc prolongation >500 ms during the study.

Clinical efficacy

Effectiveness 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 1,754 patients aged 18 to 60 years. The primary endpoint in all acute schizophrenia studies was a change in the baseline overall score on the Positive and Negative Syndromes scale (PANSS) at 6 weeks, and the secondary endpoint was a change in the baseline score on the overall clinical impression of disease Severity scale (CGI-S) at 6 weeks. In an international placebo-controlled study using fixed doses of cariprazine 1.5 mg,3.0 mg, and 4.5 mg and risperidone 4.0 mg for sensitivity analysis, there was a statistically significant improvement in the primary and secondary endpoints for all cariprazine doses and active controls compared to placebo. In another international placebo-controlled study using fixed doses of cariprazine 3.0 mg and 6.0 mg and aripiprazole 10 mg for sensitivity analysis, both doses of cariprazine and the active control resulted in statistically significant improvements in both the primary and secondary endpoints compared to placebo. In the third international placebo-controlled study using fixed / variable doses of cariprazine 3.0-6.0 mg and 6.0-9.0 mg, both groups of cariprazine doses resulted in statistically significant improvements in both the primary and secondary endpoints compared to placebo.

Pharmacokinetics

Cariprazine has two pharmacologically active metabolites, desmethylcariprazine (DCAR) and didezmethylcariprazine (DDCAR), which have similar activity to cariprazine. Total exposure (the sum of cariprazine and the DCAR and DDCAR metabolites) reaches 50% of the steady-state exposure after approximately 1 week of daily use, and 90% of the steady-state exposure is reached after 3 weeks. At steady state, the exposure of didezmethylcariprazine is approximately 2-3 times that of cariprazine, and the exposure of desmethylcariprazine is approximately 30% of the exposure of cariprazine.

Suction

The absolute bioavailability of cariprazine is unknown. When taken orally, cariprazine is well absorbed. With repeated use of the drug, the maximum concentration (cmax) in the blood plasma of cariprazine and the main active metabolites is observed after approximately 3-8 hours.

A single 1.5 mg dose of cariprazine with a high-fat diet (900-1000 calories) did not significantly affect the_cmax or AUC values (area under the concentration-time curve). cariprazine (AUC_{0 –∞}increased by 12%, _cmax decreased by The effect of food on DCAR and DDCAR exposure was also minimal.

Cariprazine can be used regardless of food intake.

Distribution

Based on population pharmacokinetic analysis, the apparent volume of distribution (V/F) of cariprazine was 916 L, DCAR – 475 L, DDCAR – 1568 L, which indicates a 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 is metabolized by demethylation (DCAR and DDCAR), hydroxylation (hydroxycaryprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxydesmethylcariprazine, HDCAR, and hydroxydidezmethylcariprazine, HDDCAR). The metabolites HCAR, HDCAR, and HDDCAR are subsequently transformed into the corresponding conjugates with sulfate and glucuronide. Another metabolite, desdichlorophenylpiperazine cariprazinic acid (DDCPPCAR), is formed by dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by the isoenzyme CYP3A4 and, to a lesser extent, CYP2D6 to the metabolites DCAR and HCAR. DCAR is further transformed by the isoenzyme CYP3A4 and, to a lesser extent, CYP2D6 into DDCAR and HDCAR. 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 transport polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), and breast cancer resistance protein (BCRP). This means that the interaction of cariprazine with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP is unlikely.

Deduction

Cariprazine and its main active metabolites are mainly eliminated by hepatic metabolism. In patients with schizophrenia, after taking cariprazine at a dose of 12.5 mg/day,20.8% of the dose was excreted by the kidneys in the form of cariprazine and its metabolites.

In unchanged form,1.2% of the dose of cariprazine is excreted by the kidneys,3.7% – through the intestines.

The mean terminal half-life (1 to 3 days for cariprazine and desmethylcariprazine and 13 to 19 days for didezmethylcariprazine) did not determine the time to reach equilibrium or decrease in plasma concentrations after discontinuation of treatment. When treating patients with cariprazine, the effective half-life is more important than the final half-life. The effective elimination half-life is approximately 2 days for cariprazine and desmethylcariprazine,8 days for didezmethylcariprazine, or approximately 1 week for total cariprazine. The total plasma concentration of cariprazine gradually decreases after discontinuation or interruption of the drug. The concentration of total cariprazine in blood plasma decreases by 50% after approximately 1 week and by more than 90% after approximately 3 weeks after the end of use.

Linearity

With repeated use, the exposure of cariprazine and its two main active metabolites, desmethylcariprazine and didezmethylcariprazine, in blood plasma increases in proportion to the therapeutic dose from 1.5 to 6 mg.

Special patient groups

• Impaired renal function

A population-based pharmacokinetic simulation was performed using data obtained from patients with schizophrenia who participated in the cariprazine clinical trial program and had differences in renal function, including normal renal function (creatinine clearance ≥90 ml/min), as well as mild (creatinine clearance 60 to 89 ml/min) and moderate (creatinine clearance 30 to 59 ml/min) renal insufficiency. There was no significant association between plasma cariprazine clearance and creatinine clearance.

Use of cariprazine in patients with severe renal impairment (CC

• Impaired liver function

A 2-part study was conducted (a single dose of 1 mg cariprazine [Part A] and a daily dose of 0.5 mg cariprazine for 14 days [Part B]) in patients with various liver disorders (Child-Pugh classes A and B). Compared with healthy subjects, patients with mild to moderate hepatic impairment showed an increase in cariprazine exposure (_cmax and AUC) of approximately 25%. Approximately 45% lower exposure to the main active metabolites, desmethylcariprazine and didezmethylcariprazine, was also detected when cariprazine was administered at a dose of 1 mg or 0.5 mg per day for 14 days.

With repeated use of cariprazine, the total exposure of active substances (CAR+DCAR+DDCAR) (AUC and Cmax) in patients with mild and moderate hepatic insufficiency (PU) decreased by 21-22% and 13-15%, respectively. At the same time, compared with healthy individuals, if we take into account the concentrations of unbound substances in patients with mild and moderate PN, the total exposure 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 use”).

• Age, gender, and race

In a population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetic parameters (AUC and Cmax of the sum of cariprazine and its main active metabolites) were found depending on age, gender, and race. This analysis included 2,844 patients of various races, including 536 patients aged 50 to 65 years. Of the 2,844 patients,933 were women. There are insufficient data on the use of cariprazine in patients over 65 years of age.

• Smoking

Cariprazine is not a substrate of the CYP1A2 isoenzyme, so the effect of smoking on the pharmacokinetics of cariprazine is not expected.

The ability of cariprazine to affect other drugs

Cariprazine and its main active metabolites did not induce the isoenzymes CYP1A2, CYP2B6 and CYP3A4 and did not inhibit the isoenzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP219, CYP2D6, CYP2E1 and CYP3A4 in vitro. Cariprazine and its main active metabolites are not inhibitors of OATP1B1, OATP1B3, BCRP transporters, organic cation transporter protein 2 (OCT2), and organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. The DCAR and DDCAR metabolites are not inhibitors of the P-gp transporter, whereas cariprazine inhibits P-gp in the gut (see section “Interaction with other drugs”).

Indications

Treatment of schizophrenia in adult patients.

Use during pregnancy and lactation

The doctor should recommend that women of childbearing age 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 Reagil®. Currently, it is not known whether cariprazine has the ability to reduce the effectiveness of systemic hormonal contraceptives, so patients taking systemic hormonal contraceptives should additionally use a barrier method of contraception (see the section “Interactions with other medications”).

Pregnancy

There are no or insufficient data on the use of cariprazine in pregnant women.

Preclinical animal studies have revealed reproductive toxicity, including malformations in rats.

The use of Reagila® during pregnancy and in women of childbearing age who do not use reliable methods of contraception is not recommended. After stopping taking cariprazine, contraception should be continued for at least 10 weeks due to the slow elimination of active metabolites.

Newborns exposed to antipsychotic medications (including cariprazine) during the third trimester of pregnancy are at risk of developing adverse reactions after delivery, including extrapyramidal disorders and / or withdrawal symptoms, which may vary in severity and duration. These newborns showed agitation, hypertonicity, hypotonicity, tremor, drowsiness, respiratory disorders, and feeding disorders. The severity of these complications varied. In some cases, the symptoms stopped on their own, while in other cases, treatment in the intensive care unit and an extension of hospitalization were required. Therefore, such newborns need careful monitoring.

Breast-feeding period

It is not known whether cariprazine and its main active metabolites are excreted in breast milk. Cariprazine and its metabolites enter the milk of rats during lactation. The risk for newborns/children cannot be excluded. Women taking Reagila® should stop breastfeeding.

Fertility

The effect of cariprazine on human fertility has not been studied. In preclinical studies, female rats showed a decrease in fertility and the ability to conceive.

Contraindications

• Hypersensitivity to the Active ingredient or any auxiliary component of the drug (see the section “Composition”).
• Concomitant use of potent or moderate inhibitors of the CYP3A4 isoenzyme (see section “Interaction with other drugs”).
• Concomitant use of potent or moderate inducers of the CYP3A4 isoenzyme (see section “Interaction with other drugs”).
• Elderly people with dementia. The use of cariprazine in elderly patients with dementia has not been studied. Cariprazine is contraindicated in such patients due to the increased risk of overall mortality.

With caution

Reactila® should be used with caution: in patients with a high risk of suicide, akathisia, restlessness, increased risk of tardive dyskinesia, Parkinson’s disease, neuroleptic malignant syndrome in the anamnesis, seizures in the anamnesis or conditions that reduce the threshold of convulsive readiness, cataracts, in patients with risk factors for stroke, diabetes mellitus, risk factors for hyperglycemia, risk of obesity; a tendency to hypotension (for example, patients with dehydration, hypovolemia, or antihypertensive medications), a history of cardiovascular diseases, and the risk of venous thromboembolic complications (see the section “Special instructions”). Women of childbearing age should use highly effective contraceptive measures while taking cariprazine and at least 10 weeks after its withdrawal.

If you have any of these diseases, be sure to consult your doctor before taking the drug.

Side effects

Summary of the security profile

The most frequent adverse drug reactions (NLR) with cariprazine in doses of 1.5 – 6 mg were akathisia (19%) and Parkinsonism (17.5%). Most of the adverse events were mild to moderate in severity.

List of adverse reactions

The adverse reactions listed below, based on pooled data from studies of cariprazine in schizophrenia, are divided into classes of organ systems and terms of preferred use.

Adverse reactions are presented according to the frequency of occurrence: very common-1/10 prescriptions (≥10%); common-1/100 prescriptions (≥1% and <10%); infrequent – 1/1000 prescriptions (≥0.1% and <1%); rare – 1/10000 prescriptions (≥0.01% and <0.1%); very rare – 1/10000 prescriptions ( In each frequency group, adverse reactions are presented in descending order of severity.

Disorders of the blood and lymphatic system

Infrequently: anemia, eosinophilia.

Rarely: neutropenia.

Immune system disorders

Rarely: hypersensitivity.

Endocrine system disorders

Infrequently: a decrease in the concentration of thyroid-stimulating hormone in the blood.

Rarely: hypothyroidism.

Metabolic and nutritional

disorders are common: weight gain, decreased appetite, increased appetite, dyslipidemia.

Infrequently: violation of the sodium content in the blood serum, increased concentration of glucose in the blood serum, diabetes mellitus.

Mental disorders

Are Common: sleep disorders%^%1, anxiety.

Infrequently: suicidal behavior, delirium, depression, decreased libido, increased libido, erectile dysfunction.

Nervous system disorders

Very often: akathisia%^%2, parkinsonism%^%3.

Often: lethargy, dizziness, dystonia%^%4, other extrapyramidal disorders and motor disorders%^%5.

Infrequently: lethargy, dysesthesia, dyskinesia%^%6, tardive dyskinesia.

Rarely: convulsive seizures, amnesia, aphasia.

Frequency unknown: neuroleptic malignant syndrome.

Visual disturbances

are common: blurred vision.

Infrequently: eye irritation, increased intraocular pressure, impaired accommodation, decreased visual acuity.

Rarely: photophobia, cataracts.

Hearing disorders and labyrinth disorders

Infrequently: vertigo.

Disorders of the heart

Often: tachyarrhythmia.

Infrequently: cardiac conduction disorders, bradyarrhythmia, prolongation of the QT interval on the ECG, violation of the T wave on the ECG.

Vascular disorders

are Common: increased blood pressure.

Infrequently: reducing blood pressure.

Respiratory, thoracic and mediastinal disorders

Infrequently: hiccups.

Gastrointestinal disorders

are Common: nausea, constipation, vomiting.

Infrequently: gastroesophageal reflux disease.

Rarely: dysphagia.

Liver and biliary tract disorders

are common: increased activity of “liver” enzymes.

Infrequently: increased blood bilirubin content.

Frequency unknown: toxic hepatitis

Skin and subcutaneous tissue disorders

Infrequently: itching, rash.

Musculoskeletal and connective tissue

disorders are common: increased serum creatine phosphokinase activity.

Rarely: rhabdomyolysis.

Kidney and urinary tract disorders

Infrequently: dysuria, pollakiuria.

Effects on the courseofpregnancy, postpartum and perinatal conditions

Frequency unknown: withdrawal syndrome in newborns (see section “Use during pregnancy and lactation”)

General disorders and disorders at the injection site

Often: fatigue.

Infrequently: thirst.

1 Sleep disorders: insomnia, unusual/nightmarish dreams, sleep circadian rhythm disorder, dissomnia, hypersomnia, sleep disturbance, intrasomnia disorder, nightmares, sleep disturbance, somnambulism, early awakening.

2 Akathisia: akathisia, psychomotor hyperactivity, restlessness.

3 Parkinsonism: akinesia, bradykinesia, bradyphrenia, cogwheel rigidity, extrapyramidal disorders, gait disorders, hypokinesia, joint stiffness, tremor, masked face, muscle rigidity, musculoskeletal stiffness, occipital muscle rigidity, Parkinsonism.

4 Dystonia: blepharospasm, dystonia, muscle tension, oromandibular dystonia, torticollis, trismus.

5 Other extrapyramidal disorders and motor disorders: balance disorders, bruxism, drooling, dysarthria, unsteadiness of gait, glabellar reflex disorder, decreased reflexes, motor disorders, restless legs syndrome, drooling, tongue movement disorders.

6 Dyskinesia: choreoathetosis, dyskinesia, antics, oculohiric crisis, tongue protrusion.

Description of individual adverse reactions

Opacity of the lens/cataract

In preclinical studies of cariprazine, the development of cataracts was observed. Therefore, in clinical studies, cataract formation was carefully monitored by examining the eyes with a slit lamp, and patients with existing cataracts were excluded from the studies. During the cariprazine clinical development program for the treatment of schizophrenia, several cases of cataracts were reported, characterized by a slight clouding of the lens without visual impairment (13/3192; 0.4%). Some of these patients had aggravating factors. The most frequently reported visual organ adverse event was blurred vision (placebo: 1/683; 0.1%, cariprazine: 22/2048; 1.1%).

Extrapyramidal symptoms (EPS)

In short-term studies, EPS was reported in 27%,11.5%,30.7%, and 15.1% of patients treated with cariprazine, placebo, risperidone, and aripiprazole, respectively. Akathisia was reported in 13.6%,5.1%,9.3%, and 9.9% of patients treated with cariprazine, placebo, risperidone, and aripiprazole, respectively. Parkinsonism was observed in 13.6%,5.7%,22.1%, and 5.3% of patients treated with cariprazine, placebo, risperidone, and aripiprazole, respectively. Dystonia was reported in 1.8%,0.2%,3.6%, and 0.7% of patients treated with cariprazine, placebo, risperidone, and aripiprazole, respectively.

In the placebo-controlled phase of the long-term study, maintenance of the therapeutic effect of EPS was 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 treated with cariprazine and 2.0% of patients treated with placebo. Parkinsonism was reported in 7.8% and 1.0% of patients in the cariprazine and placebo groups, respectively.

In the study, negative symptoms of EPS were detected in 14.3% of patients in the cariprazine group and in 11.7% of patients in the risperidone group. Akathisia was observed in 10.0% of patients treated with cariprazine and 5.2% of patients treated with risperidone. Parkinsonism was observed in 5.2% and 7.4% of patients in the cariprazine and risperidone groups, respectively. Most cases of EPS were mild to moderate in severity and were eliminated by conventional medications for the treatment of EPS. The rate of discontinuation of treatment due to NLR associated with EPS was low.

Venous thromboembolism (VTE)

Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported with unknown frequency with antipsychotic medications.

Increased activity of “liver” enzymes

When using antipsychotic drugs, an increase in the activity of hepatic transaminases (ALT, AST) is often observed. In clinical trials of cariprazine, the frequency of increased ALT and AST activity was 2.2% in patients taking cariprazine,1.6% in patients receiving risperidone, and 0.4% in patients taking placebo. When using cariprazine, liver damage was not observed.

Changes in body weight

In short-term studies, the cariprazine group showed a slightly more pronounced increase in body weight compared to the placebo group: 1 kg and 0.3 kg, respectively. In a long-term study of the maintenance of the therapeutic effect, there were no clinically significant differences in changes in the initial body weight by the end of the treatment period (1.1 kg in the cariprazine group and 0.9 kg in the placebo group). In the open-label phase of the study,9.0% of patients developed a potentially clinically significant increase in body weight (i. e., an increase of at least 7%) during 20 weeks of cariprazine use, while in the double-blind phase, a potentially clinically significant increase in body weight was observed in 9.8% of patients who continued taking cariprazine, compared with 7.1% of patients randomized to placebo after 20 weeks of open-label cariprazine. In the negative symptoms study, the average 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.

Prolongation of the QT interval

In a placebo-controlled clinical trial of QT prolongation, no QT prolongation was observed with cariprazine (see section “Pharmacokinetics”). In other clinical studies, there were only a few cases of QT prolongation when taking cariprazine that did not meet the criteria for severity. During the long-term open treatment period,3 patients (0.4%) had a Basett-adjusted QT interval (QTcB) >500 ms. One of these patients also had a Friederite-adjusted QT interval (QTcF) of >500 ms. Prolongation of the initial QTcB interval by more than 60 ms was observed in 7 patients (1%), and QTcF – in 2 patients (0.3%). In the open – label phase of the long-term therapeutic maintenance study,12 patients (1.6%) and 4 patients (0.5%) experienced an extension of the initial QTcB interval by more than 60 ms, while QTcF was observed in 4 patients (0.5%). During the double-blind treatment period, an increase in the initial QTcB interval of more than 60 ms was observed in 3 patients taking cariprazine (3.1%) and 2 patients receiving placebo (2%).

The occurrence or deterioration of the listed NLR, as well as reactions not specified in these instructions, should be reported to the doctor.

Interaction

Ability of other drugs to affect cariprazine

The metabolism of cariprazine and its main active metabolites, desmethylcariprazine and didezmethylcariprazine, is mediated mainly by the CYP3A4 isoenzyme and to a lesser extent by the CYP2D6 isoenzyme.

Inhibitors of the CYP3A4 isoenzyme

Ketoconazole, a potent inhibitor of the CYP3A4 isoenzyme, caused a twofold increase in total plasma exposure to cariprazine (the sum of cariprazine and its active metabolites) when administered concomitantly with cariprazine for a short period of time (4 days), regardless of whether only unbound substances or the sum of unbound and bound components were taken into account.

Due to the long half-life of the active metabolites of cariprazine, a further increase in total plasma exposure to cariprazine can be expected with prolonged concomitant use. Thus, the concomitant use of cariprazine with potent and moderate inhibitors of the CYP3A4 isoenzyme (for example, boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see the section “Contraindications”). You should avoid consuming grapefruit juice.

Inducers of the CYP3A4 isoenzyme

Concomitant use of cariprazine with potent and moderate inducers of the CYP3A4 isoenzyme can lead to a marked decrease in the total exposure of cariprazine in blood plasma, therefore, concomitant use of cariprazine with potent and moderate inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see the section “Contraindications”).

Inhibitors of the CYP2D6 isoenzyme

The metabolic pathway mediated by the CYP2D6 isoenzyme plays a secondary role in the biotransformation of cariprazine; metabolism is mainly carried out by the CYP3A4 isoenzyme (see section “Pharmacokinetics”). Therefore, it is unlikely that inhibitors of the CYP2D6 isoenzyme will have a clinically significant effect on the biotransformation of cariprazine.

The ability of cariprazine to affect other drugs

P-Glycoprotein (P-gp)substrates

Cariprazine in the theoretical maximum concentration in the intestine inhibits P-gp in vitro. 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

Currently, it is not known whether cariprazine has the ability to reduce the effectiveness of systemic hormonal contraceptives, so women taking systemic hormonal contraceptives should additionally use a barrier method of contraception.

Pharmacodynamic interactions

Given the main effect of cariprazine on the central nervous system, Reagila® should be used with caution with other centrally acting drugs and alcohol.

How to take, course of use and dosage

Method of application

Reagila® is taken orally once a day at the same time, regardless of food intake.

Doses

The recommended starting dose of cariprazine is 1.5 mg once daily. In the future, the dose should be slowly increased in increments of 1.5 mg / day to a maximum dose of 6 mg / day.

The minimum effective dose is determined by the attending physician based on a clinical assessment. Due to the long half-life of cariprazine and its active metabolites, dose changes have little effect on the concentration of the drug in the blood plasma for several weeks. It is necessary to monitor the adverse reactions and response of patients to therapy for several weeks after starting cariprazine and after each dose change (see the section “Pharmacokinetics”).

Switching from other antipsychotic medications to cariprazine

When switching from treatment with other antipsychotic drugs to treatment with cariprazine, the possibility of gradual cross-titration with a gradual decrease in the dose of the previous drug should be considered while starting cariprazine.

Switching from cariprazine to other antipsychotic medications

When switching from treatment with cariprazine to treatment with other antipsychotic drugs, gradual cross-titration is not required, it is necessary to start taking a new antipsychotic drug at the minimum dose after stopping cariprazine. It should be noted that the concentration of cariprazine and its active metabolites in the blood plasma will decrease by 50% after approximately 1 week (see the section “Pharmacokinetics”).

Special patient groups

Advanced age

Data on the use of cariprazine in patients aged 65 years and older are insufficient to identify differences in response to treatment compared with younger patients (see section “Pharmacokinetics”). Dose selection in elderly patients should be carried out with greater caution.

Impaired renal function

In patients with mild to moderate renal impairment (creatinine clearance (CC) ≥30 ml / min and Safety and efficacy of cariprazine in patients with severe renal impairment (CC It was not evaluated (see section “Pharmacokinetics”). Cariprazine is not recommended in patients with severe renal impairment.

Impaired liver function

No dose adjustment is required in patients with mild to moderate hepatic impairment (Child-Pugh score 5-9). The safety and efficacy of cariprazine in patients with severe hepatic impairment (Child-Pugh score 10-15) have not been evaluated (see section “Pharmacokinetics”). The use of cariprazine in patients with severe hepatic impairment is not recommended.

Use in children

The safety and efficacy of cariprazine in children and adolescents under 18 years of age have not been established. No data available.

Overdose

There is one known case of unintentional single overdose of the drug (48 mg / day). Orthostatic hypotension and sedation were observed in this patient. On the same day, the patient’s condition fully recovered.

Overdose treatment

Treatment of overdose includes maintaining adequate airway patency, oxygenation and ventilation, as well as symptomatic therapy. Cardiovascular function monitoring should be initiated immediately, including continuous monitoring of an electrocardiogram to detect possible cardiac arrhythmias. If severe extrapyramidal symptoms develop, anticholinergic medications should be prescribed. Due to the high degree of binding of cariprazine to plasma proteins, hemodialysis is probably ineffective. The patient should be under close medical supervision until full recovery. There is no specific antidote for cariprazine.

Description

Solid gelatin capsules, size # 4. Capsule cap – blue-green opaque, capsule body-blue-green opaque. The capsule body is marked with the inscription “GR 4.5” in white. The contents of the capsules are white or yellowish-white powder.

Special instructions

Suicidal thoughts and behavior

Suicidality (suicidal thoughts, suicide attempts, and committed suicide) is possible against the background of psychosis and is usually observed immediately after starting treatment or after switching from therapy with other antipsychotic drugs. Patients at high risk of suicide should be closely monitored during treatment with antipsychotic medications.

Akathisia, restlessness

Akathisia and restlessness are common adverse reactions when taking antipsychotic medications. Akathisia is a movement disorder characterized by a feeling of internal restlessness and the need to be in constant motion, as well as actions such as swaying the body in a standing or sitting position, lifting the legs in imitation of walking in place, and crossing-crossing the legs in a sitting position. 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 carefully monitor patients during the first phase of treatment. Prevention includes a gradual increase in the dose; treatment measures include a small reduction in the dose of cariprazine or the use of drugs to stop EPS. The dose of the drug can be adjusted depending on the individual patient’s response to treatment and tolerability (see the section “Side effects”).

Tardive dyskinesia

Tardive dyskinesia is a syndrome involving potentially irreversible, rhythmic, involuntary movements, mainly of the tongue and / or face, that may occur in patients receiving antipsychotic medications. If signs and symptoms of tardive dyskinesia appear in a patient taking cariprazine, discontinuation of the drug should be considered.

Parkinson’s disease

When used in patients with Parkinson’s disease, antipsychotic medications can exacerbate the underlying disease and lead to increased symptoms of Parkinson’s disease. Therefore, when prescribing cariprazine to patients with Parkinson’s disease, the doctor should carefully weigh the benefits and risks.

Eye symptoms/Cataracts

Preclinical studies of cariprazine revealed lens opacities/cataracts in dogs (see section “Side effects”). However, a causal relationship between lens changes/cataracts in human studies and cariprazine intake has not been established. However, patients who develop symptoms potentially related to cataracts should be referred for an eye exam and then evaluated for continuing therapy.

Neuroleptic malignant syndrome (NMS)

When using antipsychotics, the development of a life – threatening symptom complex-neuroleptic malignant syndrome-was noted. Clinical manifestations of NMS include hyperthermia, muscle rigidity, increased serum creatine phosphokinase activity, impaired consciousness, and autonomic nervous system disorders (irregular pulse, unstable blood pressure, tachycardia, increased sweating, and cardiac arrhythmias). Additional symptoms may include myoglobinuria (rhabdomyolysis) and acute renal failure.If the patient shows signs and symptoms of NMS or high fever of unclear etiology without additional clinical manifestations of NMS, cariprazine should be discontinued immediately.

Convulsions and seizures

Cariprazine should be used with caution in patients with a history of seizures or with diseases associated with a decrease in the seizure readiness threshold.

Risk of acute cerebrovascular accident(ACI)

An approximately 3-fold increase in the risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in patients with dementia with the use of certain atypical antipsychotic drugs. There is no mechanism for increasing the risk. An increased risk cannot be excluded with the use of other antipsychotic drugs or in other patient groups.

Cariprazine should be used with caution in patients with risk factors for stroke.

Disorders of the heart and blood vessels

• Changes in blood pressure

Cariprazine can cause orthostatic hypotension, as well as arterial hypertension (see the section “Side effects”). Cariprazine should be used with caution in patients with cardiovascular diseases predisposed to changes in blood pressure. Blood pressure should be monitored.

• ECG changes

Patients taking antipsychotic medications may experience prolongation of the QT interval.

In a clinical study aimed at studying the prolongation of the QT interval, when using cariprazine compared with placebo, there was no prolongation of the QT interval (see the section “Pharmacodynamics”). In clinical studies, only a few cases of prolongation of the QT interval with cariprazine were reported that did not meet the criteria for severity (see the section “Side effects”). Therefore, cariprazine should be used with caution in patients with cardiovascular diseases and in patients with a family history of QT prolongation, as well as in patients taking medications that may cause QT prolongation (see section “Pharmacodynamics”).

• Venous thromboembolism (VTE)

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Since patients taking antipsychotic medications often have acquired VTE risk factors, it is necessary to identify all possible VTE risk factors before and during treatment with cariprazine and take preventive measures.

Hyperglycemia and diabetes mellitus

In patients with diabetes mellitus or with risk factors for developing diabetes mellitus (for example, obesity, a family history of diabetes), when starting treatment with atypical antipsychotics, it is necessary to carefully monitor the blood glucose level in the blood. Adverse events associated with changes in glucose concentrations have been reported in clinical studies of cariprazine (see section “Pharmacodynamics”).

Women of childbearing age

Women of childbearing age should use highly effective contraceptives while taking cariprazine and at least 10 weeks after the end of taking it (see the sections ” Interaction with other medications” and ”Use during pregnancy and lactation”). Women using systemic hormonal agents should additionally use a second, barrier method of contraception.

Change in body weight

When taking cariprazine, a significant increase in body weight was observed. Patients should regularly monitor their body weight (see section “Side effects”).

Auxiliary substances

Reagila ® capsules,3 mg,4.5 mg and 6 mg contain the dye red charming (E 129), which can cause allergic reactions.

Influence on the ability to drive vehicles and mechanisms

Cariprazine has a mild to moderate effect on the ability to drive vehicles and mechanisms. Patients should use caution when operating potentially dangerous machinery, including vehicles, until they are fully confident that Reagila® does not adversely affect their abilities.

Form of production

7 capsules of 1.5 mg,3 mg in a blister of PVC/PE/PVDC and aluminum foil. 1 or 4 blisters together with the instructions for use are placed in a cardboard box.

7 capsules of 4.5 mg,6 mg in a blister of PVC/PE/PVDC and aluminum foil. 4 blisters together with the instructions for use are placed in a cardboard box.

Storage conditions

Store the blister in its outer packaging to protect it from light. The medicinal product does not require special temperature storage conditions. Keep out of reach of children.

Shelf

life is 5 years. Do not use after the expiration date indicated on the package.

Active ingredient

Cariprazine

Conditions of release from pharmacies

By prescription

Dosage form

Capsules