Reagila, 3 mg capsules 28 pcs

Pharmacotherapeutic group: Antipsychotic agent (neuroleptic)

Pharmacological properties

Pharmacodynamics

The mechanism of action

The mechanism of action of cariprazine is not fully known. However, the therapeutic effect of cariprazine is thought to be provided by a combination of partial agonism toward D3-, D2-dopamine receptors (Ki values of 0.085-0.3 nmol/L vs. 0.49-0.71 nmol/L and 5-HT1A-serotonin receptors (Ki values of 1.4-2.6 nmol/L) and antagonism to 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-NT2C-serotonin and alpha1-adrenoceptors (Ki values of 134 nmol/L and 155 nmol/L, respectively). Cariprazine has no significant affinity for muscarinic cholinergic receptors (Ki50>1000 nmol/L). The two main active metabolites, desmethylcariprazine and didesmethylcariprazine, have a similar receptor binding profile and in vitro functional activity profile to cariprazine as the parent drug.

Pharmacodynamic Effects

In vivo preclinical studies have shown that cariprazine binds to D3 receptors at pharmacologically effective doses to the same extent as it does to D2 receptors. In patients with schizophrenia, we observed dose-dependent binding of cariprazine to D3 and D2-dopamine receptors in the brain (predominantly in D3-receptor-dominated areas) over a therapeutic dose range of 15 days.

The effect of cariprazine on the QT interval has been studied in patients with schizophrenia or schizoaffective disorder. 12-hour Holter ECG monitoring data were obtained in 129 patients before the drug was prescribed and after reaching equilibrium. No QT interval prolongation was observed when cariprazine was used in doses exceeding the therapeutic ones (9 mg/day or 18 mg/day). No QTc interval prolongation of ≥60 ms from baseline or QTc >500 ms during the study were reported in patients receiving cariprazine as part of the study.

Clinical efficacy

Efficacy with short-term use

The efficacy of cariprazine in acute schizophrenia was studied in three 6-week, multicenter, international, randomized, double-blind, placebo-controlled studies involving 1,754 patients aged 18 to 60 years. The primary endpoint in all studies of acute schizophrenia was change in baseline overall score on the Positive and Negative Syndrome Scale (PANSS) after 6 weeks, the secondary endpoint was change in baseline score on the General Clinical Impression of Severity (CGI-S) scale after 6 weeks. In an international placebo-controlled study using fixed-dose cariprazine 1.5 mg, 3.0 mg, and 4.5 mg and risperidone 4.0 mg, a statistically significant improvement in primary and secondary endpoints was demonstrated for all doses of cariprazine and active controls compared with placebo. In another international placebo-controlled study using fixed doses of 3.0 mg and 6.0 mg cariprazine and 10 mg aripiprazole for sensitivity analysis, both doses of cariprazine and the active control resulted in statistically significant improvements in both the primary and secondary endpoints compared with placebo. In a third international placebo-controlled, fixed/variable-dose study of 3.0-6.0 mg and 6.0-9.0 mg cariprazine, both groups of cariprazine doses resulted in statistically significant improvements in both the primary and secondary endpoints compared with placebo.

Pharmacokinetics

Cariprazine has two pharmacologically active metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (DDCAR), which have similar activity to cariprazine. Total exposure (sum of cariprazine and metabolites of DCAR and DDCAR) reaches 50% of the equilibrium exposure after approximately 1 week of daily administration, and 90% of the equilibrium exposure is reached after 3 weeks. In equilibrium, the exposure to didesmethylcariprazine is approximately 2-3 times greater than the exposure to cariprazine, and the exposure to desmethylcariprazine is approximately 30% of the exposure to cariprazine.

absorption

The absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed when taken orally. When the drug is taken repeatedly, the maximum concentration (C_max) in blood plasma of cariprazine and the main active metabolites is observed after about 3-8 hours.

A single administration of cariprazine at a dose of 1.5 mg along with a fatty meal (900-1000 calories) had no significant effect on the C_max values or AUC (area under the concentration-time curve) of cariprazine (AUC_0-∞ increased by 12%, C_max decreased by <5% after a meal compared with an empty stomach meal). 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 was 475 L, and DDCAR was 1,568 L, indicating a wide distribution of cariprazine and its major active metabolites. Cariprazine (CAR) and its major 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 (hydroxycariprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxydemethylcariprazine, HDCAR, and hydroxydidemethylcariprazine, HDDCAR). HCAR, HDCAR, and HDDCAR metabolites are subsequently transformed into their respective sulfate and glucuronide conjugates. Another metabolite, desdichlorophenylpiperazincariprasic acid (DDCPPCAR), is formed by dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by the CYP3A4 isoenzyme and, to a lesser extent, by CYP2D6 to the metabolites DCAR and HCAR. DCAR is further transformed by the CYP3A4 isoenzyme and, to a lesser extent, by CYP2D6 to DDCAR and HDCAR. DDCAR is further metabolized by the CYP3A4 isoenzyme to HDDCAR.

Cariprazine and its major active metabolites are not substrates of P-glycoprotein (P-gp), transport polypeptides of organic anions 1B1 and 1B3 (OATP1B1 and OATP1B3) and breast cancer resistance protein (BCRP). This means that interaction of cariprazine with P-gp, OATP1B1, OATP1B3 and BCRP inhibitors is unlikely.

Elimation

Cariprazine and its major active metabolites are eliminated primarily 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 as cariprazine and its metabolites.

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

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

Linearity

. With repeated administration, the plasma exposure of cariprazine and its two major active metabolites, desmethylcariprazine and didesmethylcariprazine, increases in proportion to the therapeutic dose of 1.5 to 6 mg.

Special patient groups

• Kidney function impairment

. Population pharmacokinetic modeling was performed using data from patients with schizophrenia enrolled in the cariprazine clinical trial program who had renal function differences, including normal renal function (creatinine clearance (CK) ≥90 mL/min) and mild (CK 60 to 89 mL/min) and moderate (CK 30 to 59 mL/min) renal impairment. There was no significant association between plasma clearance of cariprazine and creatinine clearance.

The use of cariprazine in patients with severe renal impairment (CK < 30 ml/min) has not been studied (see section “Dosage and administration”).

• Liver function impairment

. A 2-part study (a single dose of 1 mg of cariprazine [part A] and a daily dose of 0.5 mg of cariprazine for 14 days [part B]) involving patients with various liver dysfunctions (Child-Pugh grades A and B) was conducted. Compared with healthy individuals, patients with mild to moderate hepatic dysfunction showed an increase in exposure (C_max and AUC) to cariprazine of approximately 25%. There was also approximately 45% lower exposure to the major active metabolites, desmethylcariprasine and didesmethylcariprasine, when cariprazine was used at a dose of 1 mg or 0.5 mg daily for 14 days.

The total active substance exposure (CAR+DCAR+DDCAR) (AUC and Cmax) in patients with mild to moderate hepatic impairment (HI) was reduced by 21-22% and 13-15%, respectively, when cariprazine was administered repeatedly. At the same time, in comparison with healthy persons, when unbound concentrations in patients with mild and moderate PN are considered, 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 administration”).

• Age, sex and race

. In a population-based pharmacokinetic analysis, no clinically significant differences in pharmacokinetic parameters (AUC and Cmax of the sum of cariprazine and its major active metabolites) were found according to age, sex, and race. A total of 2,844 patients of different races were included in this analysis, 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 no effect of smoking on the pharmacokinetics of cariprazine is expected.

The ability of cariprazine to affect other drugs

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

Indications

Treatment of schizophrenia in adult patients.

Pharmacological effect

Pharmacotherapeutic group: antipsychotic (neuroleptic)

Pharmacological properties

Pharmacodynamics

Mechanism of action

The mechanism of action of cariprazine is not completely known. However, it is believed that the therapeutic effect of cariprazine is due to a combination of partial agonism at D3-, D2-dopamine receptors (Ki value 0.085-0.3 nmol/L compared with 0.49-0.71 nmol/L, respectively) and 5-HT1A-serotonin receptors (Ki value 1.4-2.6 nmol/L) and antagonism towards 5-HT2B- and 5-HT2A-serotonin receptors and H1-histamine receptors (Ki values ​​0.58-1.1 nmol/l, 18.8 nmol/l and 23.3 nmol/l, respectively). Cariprazine has low affinity for 5-HT2C-serotonin and alpha1-adrenergic receptors (Ki values ​​134 nmol/l and 155 nmol/l, respectively). Cariprazine does not have significant affinity for muscarinic cholinergic receptors (IC50>1000 nmol/l). The two main active metabolites, desmethylcariprazine and didesmethylcariprazine, have a similar receptor binding profile and in vitro functional activity profile to cariprazine as the parent drug.

Pharmacodynamic effects

Preclinical in vivo studies have shown that cariprazine, at pharmacologically effective doses, binds to D3 receptors to the same extent as 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 has been studied in patients with schizophrenia or schizoaffective disorder. Holter ECG monitoring data were obtained for 12 hours in 129 patients before the drug was prescribed and upon reaching a steady state. Prolongation of the QT interval was not observed when cariprazine was used in doses exceeding therapeutic doses (9 mg/day or 18 mg/day). In patients receiving cariprazine in the study, there was no QTc prolongation ≥60 ms from baseline or QTc prolongation >500 ms during the study.

Clinical effectiveness

Effective for short-term use

The effectiveness of cariprazine in acute schizophrenia was studied in three 6-week multicenter, international, randomized, double-blind, placebo-controlled studies involving 1754 patients aged 18 to 60 years. The primary endpoint in all acute schizophrenia studies was change in baseline Positive and Negative Syndrome Scale (PANSS) global score at 6 weeks, and the secondary endpoint was change in baseline Clinical Global Impression of Illness Severity (CGI-S) score at 6 weeks. 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 assay sensitivity demonstrated statistically significant improvements in the primary and secondary endpoints for all doses of cariprazine and active control compared with 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 testing, both doses of cariprazine and the active control resulted in statistically significant improvement in both the primary and secondary endpoints compared with placebo. In a third international placebo-controlled study using fixed/variable doses of cariprazine 3.0–6.0 mg and 6.0–9.0 mg, both cariprazine dose groups resulted in statistically significant improvements in both the primary and secondary endpoints compared with placebo.

Pharmacokinetics

Cariprazine has two pharmacologically active metabolites, desmethylcariprazine (DCAR) and didesmethylcariprazine (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, didesmethylcariprazine exposure is approximately 2-3 times that of cariprazine, and desmethylcariprazine exposure is approximately 30% of cariprazine exposure.

Suction

The absolute bioavailability of cariprazine is unknown. When taken orally, cariprazine is well absorbed. With repeated administration 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 taken with a fatty meal (900-1000 calories) had no significant effect on cariprazine Cmax or AUC (AUC0-∞increased by 12%, Cmax decreased by <5% after meals compared to fasting). 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) was 916 L for cariprazine, 475 L for DCAR, and 1568 L for DDCAR, indicating a broad distribution of cariprazine and its major 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% DDCAR).

Metabolism

Cariprazine is metabolized by demethylation (DCAR and DDCAR), hydroxylation (hydroxycariprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxydesmethylcariprazine, HDCAR, and hydroxydidesmethylcariprazine, HDDCAR). The metabolites HCAR, HDCAR and HDDCAR are subsequently transformed into the corresponding sulfate and glucuronide conjugates. Another metabolite, desdichlorophenylpiperazine cariprazine acid (DDCPPCAR), is formed by dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by CYP3A4 and, to a lesser extent, by CYP2D6 to DCAR and HCAR metabolites. DCAR is further transformed by CYP3A4 and, to a lesser extent, CYP2D6 into DDCAR and HDCAR. DDCAR is further metabolized by the CYP3A4 isoenzyme to HDDCAR.

Cariprazine and its major 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 cariprazine is unlikely to interact with inhibitors of P-gp, OATP1B1, OATP1B3 and BCRP.

Removal

Cariprazine and its main active metabolites are eliminated primarily through 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.

Unchanged, 1.2% of the cariprazine dose 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 didesmethylcariprazine) did not predict the time to steady state or the decrease in plasma concentrations after discontinuation of treatment. When treating patients with cariprazine, 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 didesmethylcariprazine, or approximately 1 week for total cariprazine. The total plasma concentration of cariprazine gradually decreases after discontinuation or interruption of the drug. Total cariprazine plasma concentrations decrease by 50% after approximately 1 week and by more than 90% after approximately 3 weeks.

Linearity

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

Special patient groups

Renal dysfunction

Population pharmacokinetic modeling was performed using data obtained from patients with schizophrenia participating in the cariprazine clinical trial program with differences in renal function, including normal renal function (creatinine clearance (CR) ≥90 mL/min), as well as mild (CR 60 to 89 mL/min) and moderate (CR 30 to 59 mL/min) renal impairment. There was no significant relationship between plasma cariprazine clearance and creatinine clearance.

The use of cariprazine in patients with severe renal impairment (creatinine clearance <30 ml/min) has not been studied (see section "Dosage and Administration").

Liver dysfunction

A 2-part study (cariprazine 1 mg once [Part A] and cariprazine 0.5 mg daily for 14 days [Part B]) was conducted in patients with various hepatic impairments (Child-Pugh A and B). Compared with healthy controls, patients with mild to moderate hepatic impairment showed an approximately 25% increase in cariprazine exposure (Cmax and AUC). There was also an approximately 45% lower exposure to the major active metabolites, desmethylcariprazine and didesmethylcariprazine, when cariprazine was administered at a dose of 1 mg or 0.5 mg per day for 14 days.

With repeated dosing of cariprazine, the total exposure of active substances (CAR+DCAR+DDCAR) (AUC and Cmax) in patients with mild and moderate liver failure (LI) decreased by 21-22% and 13-15%, respectively. Moreover, 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 Administration”).

Age, gender and race

In a population pharmacokinetic analysis, clinically significant differences in pharmacokinetic parameters (AUC and Cmax of the sum of cariprazine and its main active metabolites) depending on age, gender and race were not identified. This analysis included 2844 patients of different races, of which 536 patients were aged 50 to 65 years. Of the 2844 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 smoking is not expected to influence the pharmacokinetics of cariprazine.

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 major active metabolites are not inhibitors of the transporters OATP1B1, OATP1B3, BCRP, 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, while cariprazine inhibits P-gp in the intestine (see section “Interactions with other drugs”).

Special instructions

Suicidal thoughts and behavior

Suicidality (suicidal thoughts, suicide attempts and completed suicide) is possible in the context 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 drugs.

Akathisia, restlessness

Akathisia and restlessness are common adverse reactions with antipsychotic medications. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a need to be in constant motion, as well as activities such as rocking the body while standing or sitting, lifting the legs to simulate walking in place, and crossing and uncrossing the legs while sitting. Because cariprazine can cause akathisia and restlessness, it should be used with caution in patients who have a history of or are predisposed to akathisia. Akathisia develops at the beginning of treatment. Therefore, it is important to closely monitor patients during the first phase of treatment. Prevention includes gradually increasing the dose; Treatment measures include a slight reduction in the dose of cariprazine or the use of drugs to relieve EPS. The dose of the drug can be adjusted depending on the patient’s individual response to treatment and tolerability (see section “Side effects”).

Tardive dyskinesia

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

Parkinson’s disease

When used in patients with Parkinson’s disease, antipsychotic drugs can cause exacerbations of the underlying disease and lead to increased symptoms of Parkinson’s disease. Therefore, when prescribing cariprazine to patients with Parkinson’s disease, the physician must 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 has not been established. However, patients who develop symptoms potentially related to cataracts should be referred for an ophthalmologic examination and then assessed for continued 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, disturbance of consciousness and disorders of the autonomic nervous system (pulse irregularity, instability of blood pressure, tachycardia, increased sweating and cardiac arrhythmias). Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient experiences signs and symptoms of NMS or high fever of unknown 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 diseases accompanied by a decrease in the seizure threshold.

Risk of acute cerebrovascular accident (ACVA)

An approximately 3-fold increase in the risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in patients with dementia when using some atypical antipsychotic drugs. The mechanism for increasing the risk has not been established. 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 section “Side effects”). Cariprazine should be used with caution in patients with cardiovascular disease predisposed to changes in blood pressure. It is necessary to control blood pressure.

ECG changes

QT interval prolongation may occur in patients taking antipsychotic drugs.

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

Venous thromboembolism (VTE)

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

Hyperglycemia and diabetes mellitus

In patients with diabetes mellitus or who have risk factors for developing diabetes mellitus (eg, obesity, family history of diabetes), serum glucose levels should be carefully monitored when initiating treatment with atypical antipsychotics. In clinical studies of cariprazine, adverse events associated with changes in glucose concentrations were reported (see section “Pharmacodynamics”).

Women of childbearing age

Women of childbearing potential should use highly effective contraception while taking cariprazine and for at least 10 weeks after stopping it (see sections “Interactions with other drugs” and “Use during pregnancy and breastfeeding”). Women using systemic hormonal agents should additionally use a second, barrier method of contraception.

Change in body weight

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

Excipients

Reagila®, capsules, 3 mg, 4.5 mg and 6 mg contain charming red dye (E129), which can cause allergic reactions.

Impact on the ability to drive vehicles and machinery

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

Active ingredient

Cariprazine

Composition

Capsules 3 mg

Active ingredient: cariprazine hydrochloride 3.27 mg (equivalent to cariprazine 3 mg).

Excipients: pregelatinized corn starch, magnesium stearate, hard gelatin capsule, size No. 4 (lid: gelatin, titanium dioxide E171, yellow iron oxide dye E172, brilliant blue dye E133, charming red dye E129; body: gelatin, titanium dioxide E171).

Composition of black ink for printing: iron dye black oxide E172, shellac, ethanol, water, propylene glycol, isopropanol, butanol, aqueous ammonia, potassium hydroxide.

Pregnancy

Your doctor should advise women of childbearing 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 stopping taking Reagila®. It is currently unknown whether cariprazine has the ability to reduce the effectiveness of systemic hormonal contraceptives, therefore patients taking systemic hormonal contraceptives should additionally use a barrier method of contraception (see section “Interactions with other drugs”).

Pregnancy

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

Preclinical animal studies have demonstrated 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 cariprazine, contraception should be continued for at least 10 weeks due to the slow elimination of active metabolites.

Infants exposed to antipsychotic drugs (including cariprazine) during the third trimester of pregnancy are at risk for postpartum adverse reactions, including extrapyramidal effects and/or withdrawal symptoms, which may vary in severity and duration. These newborns presented with agitation, hypertonicity, hypotonicity, tremor, somnolence, respiratory distress, and feeding disturbances. The severity of these complications varied. In some cases, symptoms resolved spontaneously, while in other cases, treatment in an intensive care unit and prolonged hospitalization were required. Therefore, such newborns need careful monitoring.

Breastfeeding period

It is unknown whether cariprazine and its main active metabolites are excreted in breast milk. Cariprazine and its metabolites are excreted into the milk of rats during lactation. A risk to newborns/infants cannot be excluded. Women taking Reagila® should avoid breastfeeding.

Fertility

The effect of cariprazine on human fertility has not been studied. In preclinical studies, female rats showed decreased fertility and fertility.

Contraindications

Hypersensitivity to the active substance or any auxiliary component of the drug (see section “Composition”).
Concomitant use of strong or moderate inhibitors of the CYP3A4 isoenzyme (see section “Interaction with other drugs”).
Concomitant use of strong or moderate inducers of the CYP3A4 isoenzyme (see section “Interaction with other drugs”).
Elderly people with dementia. Cariprazine has not been studied in elderly patients with dementia. Cariprazine is contraindicated in these patients due to the increased risk of all-cause mortality.

With caution

Reagila® should be used with caution: in patients with a high risk of suicide, with akathisia, restlessness, an increased risk of tardive dyskinesia, Parkinson’s disease, a history of neuroleptic malignant syndrome, a history of seizures or conditions that lower the seizure threshold, cataracts, in patients with risk factors for stroke, diabetes mellitus, risk factors for hyperglycemia, risk of obesity; a tendency to arterial hypotension (for example, with dehydration, hypovolemia, during treatment with antihypertensive drugs), a history of cardiovascular diseases, the risk of venous thromboembolic complications (see section “Special instructions”). Women of childbearing potential should use highly effective contraception while taking cariprazine and for at least 10 weeks after stopping it.

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

Side Effects

Security Profile Summary

The most common adverse drug reactions (ADRs) with cariprazine in doses of 1.5–6 mg were akathisia (19%) and parkinsonism (17.5%). Most adverse events were mild or moderate in severity.

List of adverse reactions

The adverse reactions listed below, based on pooled data from studies of cariprazine in schizophrenia, are categorized by organ system class and preferred use term.

Adverse reactions are presented according to the frequency of occurrence: very often – 1/10 prescriptions (≥10%); often – 1/100 prescriptions (≥1% and <10%); uncommon – 1/1000 prescriptions (≥0.1% and <1%); rarely – 1/10,000 prescriptions (≥0.01% and <0.1%); very rarely - 1/10,000 prescriptions (<0.01%); frequency unknown - insufficient data to estimate the frequency of ADRs. Within each frequency group, adverse reactions are presented in descending order of severity.

Blood and lymphatic system disorders

Uncommon: anemia, eosinophilia.

Rarely: neutropenia.

Immune system disorders

Rarely: hypersensitivity.

Endocrine system disorders

Uncommon: decreased concentration of thyroid-stimulating hormone in the blood.

Rarely: hypothyroidism.

Metabolic and nutritional disorders

Common: weight gain, decreased appetite, increased appetite, dyslipidemia.

Uncommon: disturbance of serum sodium levels, increased serum glucose concentrations, diabetes mellitus.

Mental disorders

Common: sleep disorders1, anxiety.

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

Nervous system disorders

Very common: akathisia2, parkinsonism3.

Common: lethargy, dizziness, dystonia4, other extrapyramidal disorders and movement disorders5.

Uncommon: lethargy, dysesthesia, dyskinesia6, tardive dyskinesia.

Rare: seizures/convulsions, amnesia, aphasia.

Frequency unknown: neuroleptic malignant syndrome.

Visual disorders

Common: blurred vision.

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

Rarely: photophobia, cataract.

Hearing and labyrinth disorders

Uncommon: vertigo.

Heart disorders

Common: tachyarrhythmia.

Uncommon: cardiac conduction disturbances, bradyarrhythmia, prolongation of the QT interval on the ECG, disturbance of the T wave on the 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.

Rarely: dysphagia.

Disorders of the liver and biliary tract

Often: increased activity of liver enzymes.

Uncommon: increased blood bilirubin levels.

Frequency unknown: toxic hepatitis

Skin and subcutaneous tissue disorders

Uncommon: itching, rash.

Musculoskeletal and connective tissue disorders

Often: increased serum creatine phosphokinase activity.

Rare: rhabdomyolysis.

Renal and urinary tract disorders

Uncommon: dysuria, pollakiuria.

Effect on pregnancy, postpartum and perinatal conditions

Not known: withdrawal syndrome in newborns (see section “Use during pregnancy and breastfeeding”)

General and administration site disorders

Common: fatigue.

Uncommon: thirst.

1Sleep disorders: insomnia, unusual/nightmare dreams, circadian sleep rhythm disorder, dyssomnia, hypersomnia, sleep disturbance, intrasomnic disorder, nightmares, sleep disturbance, somnambulism, early awakening.

2Akathisia: akathisia, psychomotor hyperactivity, restlessness.

3Parkinsonism: akinesia, bradykinesia, bradyphrenia, cogwheel rigidity, extrapyramidal disorders, gait disturbance, hypokinesia, joint stiffness, tremor, mask-like face, muscle rigidity, musculoskeletal stiffness, nuchal rigidity, parkinsonism.

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

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

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

Description of selected adverse reactions

Lens opacification/cataract

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

Extrapyramidal symptoms (EPS)

In short-term studies, EPS occurred 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 treatment maintenance study, EPS were observed in 13.7% of patients in the cariprazine group compared with 3.0% in the placebo group. Akathisia was reported in 3.9% of patients receiving cariprazine and 2.0% of patients receiving placebo. Parkinsonism was observed 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 receiving cariprazine and in 5.2% of patients receiving 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 or moderate in severity and were resolved with conventional medications for the treatment of EPS. The incidence of treatment discontinuation due to ADRs 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 during the use of antipsychotic drugs.

Increased activity of liver enzymes

When using antipsychotic drugs, an increase in the activity of liver transaminases (ALT, AST) is often observed. In clinical studies of cariprazine, the incidence of increased ALT and AST activity was 2.2% in patients taking cariprazine, 1.6% in patients taking risperidone, and 0.4% in patients taking placebo. No liver damage was observed with cariprazine.

Changes in body weight

In short-term studies, the cariprazine group experienced slightly greater weight gain compared to the placebo group: 1 kg and 0.3 kg, respectively. In the long-term maintenance study, there were no clinically significant differences in baseline body weight at 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, during 20 weeks of cariprazine, 9.0% of patients developed potentially clinically significant weight gain (i.e., an increase of at least 7%), while in the double-blind phase, potentially clinically significant weight gain was observed in 9.8% of patients who continued cariprazine, compared with 7.1% of patients randomized to placebo after 20 weeks of open-label cariprazine. In the negative symptom study, mean weight change 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 prolongation

In a clinical placebo-controlled study of QT prolongation with cariprazine, no prolongation of the QT interval was observed (see section “Pharmacokinetics”). Other clinical studies have reported only a few cases of QT prolongation with cariprazine that did not meet criteria for severity. During the long-term open-label treatment period, 3 patients (0.4%) had a Bazett-corrected QT interval (QTcB) >500 ms. One of these patients also had a QTcF interval >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 a long-term maintenance study, prolongation of the baseline QTcB interval by more than 60 ms was observed in 12 patients (1.6%) and QTcF in 4 patients (0.5%). During the double-blind treatment period, a prolongation of the baseline QTcB interval of more than 60 ms was observed in 3 patients receiving cariprazine (3.1%) and in 2 patients receiving placebo (2%).

The occurrence or worsening of the listed ADRs, as well as reactions not listed in these instructions, should be reported to your doctor.

Interaction

The ability of other drugs to affect cariprazine

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

CYP3A4 isoenzyme inhibitors

Ketoconazole, a potent inhibitor of CYP3A4, when coadministered short-term (4 days) with cariprazine, caused a two-fold increase in the total plasma exposure of cariprazine (the sum of cariprazine and its active metabolites), regardless of whether the unbound substances alone or the sum of the unbound and bound components were considered.

Due to the long half-life of the active metabolites of cariprazine, a further increase in the total plasma exposure of cariprazine can be expected with prolonged concomitant use. Thus, the simultaneous use of cariprazine with strong 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 section “Contraindications”). Grapefruit juice should be avoided.

Inducers of the CYP3A4 isoenzyme

Concomitant use of cariprazine with strong and moderate inducers of the CYP3A4 isoenzyme can lead to a marked decrease in the total exposure of cariprazine in the blood plasma, therefore, simultaneous use of cariprazine with strong 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 section “Contraindications”).

CYP2D6 isoenzyme inhibitors

The CYP2D6-mediated metabolic pathway plays a minor role in the biotransformation of cariprazine; metabolism is mainly carried out by the CYP3A4 isoenzyme (see section “Pharmacokinetics”). Therefore, it is unlikely that CYP2D6 inhibitors 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, at its theoretical maximum intestinal concentration, 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 index, such as dabigatran and digoxin, may require additional monitoring and dose adjustment.

Hormonal contraceptives

It is currently unknown whether cariprazine has the ability to reduce the effectiveness of systemic hormonal contraceptives, therefore 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.

Overdose

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

Treatment of overdose

Treatment of overdose includes maintaining an adequate airway, oxygenation and ventilation, as well as symptomatic therapy. Monitoring of cardiovascular functions should be started immediately, including continuous monitoring of the electrocardiogram to identify possible cardiac arrhythmias. If severe extrapyramidal symptoms develop, anticholinergic drugs 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 complete recovery. There is no specific antidote for cariprazine.

Storage conditions

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

Shelf life

5 years.
Do not use after the expiration date stated on the package.

Manufacturer

Gedeon Richter, Hungary