Reagila, 6 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

Cariprasine has two pharmacologically active metabolites, desmethylcariprasine (DCAR) and didesmethylcariprasine (DDCAR), which have similar activity to cariprasine. Total exposure (sum of cariprazine and DCAR and DDCAR metabolites) 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 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 between the ages of 50 and 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

Active ingredient

Composition

Capsules 6 mg:

Active ingredient:cariprazine hydrochloride 6.54 mg (equivalent to cariprazine 6 mg).

Excipients:Corn starch pregelatinized, magnesium stearate, hard gelatin capsule, size #3 (cap: gelatin, E171 titanium dioxide, E133 diamond blue dye, E129 charming red dye; body: gelatin, E171 titanium dioxide).

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

How to take, the dosage

Dosage method

The drug Reagil® is taken orally once daily at the same time, regardless of meals.

Doses

The recommended starting dose of cariprazine is 1.5 mg once daily. Thereafter, the dose is 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 on the basis of clinical evaluation. Because of the long elimination half-life of cariprazine and its active metabolites, dose changes have little effect on plasma concentrations for several weeks. Adverse reactions and patient response to therapy should be monitored for several weeks after starting cariprazine and after each dose change (see section “Pharmacokinetics”).

Transition from other antipsychotic medications to cariprazine

When switching from treatment with other antipsychotic medications to treatment with cariprazine, gradual cross-titration with gradual dose reduction of the previous medication while starting cariprazine should be considered.

Transition from cariprazine to other antipsychotics

When switching from treatment with cariprazine to treatment with other antipsychotics, gradual cross-titration is not required; the new antipsychotic medication should be started at the lowest dose after cariprazine withdrawal. Note that plasma concentrations of cariprazine and its active metabolites will decrease by 50% after approximately 1 week (see section “Pharmacokinetics”).

Special patient groups

Elderly age

. There is insufficient data on the use of cariprazine in patients 65 years of age or older to detect differences in response to treatment compared with younger patients (see Pharmacokinetics section). Dose selection in elderly patients should be done with more caution.

Renal dysfunction

In patients with mild to moderate renal dysfunction (creatinine clearance (CK) ≥30 ml/min and <89 ml/min) no adjustment of the drug dose is required. Safety and efficacy of cariprazine in patients with severe renal impairment (CKR <30 ml/min) has not been evaluated (see section “Pharmacokinetics”). The use of cariprazine is not recommended in patients with severe renal dysfunction.

Hepatic dysfunction

In patients with mild to moderate hepatic dysfunction (Child-Pugh score 5-9) no adjustment of the drug dose is required. Safety and efficacy of cariprazine in patients with severe hepatic impairment (10-15 Child-Pugh scores) has not been evaluated (see section “Pharmacokinetics”). The use of cariprazine in patients with severe hepatic impairment is not recommended.

Application in children

The safety and effectiveness of cariprazine in children and adolescents under the age of 18 years has not been established. No data are available.

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.

Inhibitors of CYP3A4 isoenzyme

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

In view of the long half-life of the active metabolites of cariprazine, a further increase in total plasma exposure to cariprazine can be expected with longer concomitant use. Thus, concomitant use of cariprazine with potent and moderate CYP3A4 isoenzyme inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, diltiazem, erythromycin, fluconazole, verapamil) is contraindicated (see See section “Contraindications”). Grapefruit juice should be avoided.

Inductors of CYP3A4 isoenzyme

. Concomitant use of cariprazine with potent and moderate CYP3A4 isoenzyme inducers may result in a marked decrease in the total plasma exposure of cariprazine, hence, Concomitant administration of cariprazine with potent and moderate inducers of CYP3A4 isoenzyme (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, Hypericum perforatum, bozentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see Contraindications).

CYP2D6 isoenzyme inhibitors

The CYP2D6 isoenzyme-mediated metabolic pathway plays a minor role in the biotransformation of cariprazine; metabolism is primarily performed by the CYP3A4 isoenzyme (see Pharmacokinetics section. section Pharmacokinetics). Therefore, it is unlikely that CYP2D6 isoenzyme inhibitors will have a clinically significant effect on the biotransformation of cariprazine.

The ability of cariprazine to affect other drugs

The ability of cariprazine to affect other drugs

Special Instructions

Suicidal thoughts and behavior

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

Akathisia, restlessness

Akathisia and restlessness are common adverse reactions with antipsychotic medications. Akathisia is a movement disorder characterized by feelings of inner restlessness and a need to be in constant motion, as well as actions such as swinging the body while standing or sitting, raising the legs to imitate walking in place, and crossing-crossing the legs while sitting. Because cariprazine may 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 closely monitor patients in the first phase of treatment. Prophylaxis includes gradually increasing the dose; therapeutic measures include a small reduction in the dose of cariprazine or the use of drugs to suppress EPS. The dose of the drug may be adjusted depending on the patient’s individual response to treatment and tolerability (see side effects section).

Late dyskinesia

. Late dyskinesia — 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 appear in a patient taking cariprazine, consideration should be given to withdrawing the drug.

Parkinson’s disease

When used in patients with Parkinson’s disease, antipsychotic medications may cause exacerbations of the background disease and lead to increased Parkinson’s disease symptoms. Therefore, when prescribing cariprazine to Parkinson’s patients, the physician must carefully weigh the benefits against the risks.

Eye symptoms/cataract

Preclinical studies of cariprazine have found lens clouding/cataract in dogs (see side effects section). However, a causal relationship between lens/cataract changes in human studies and cariprazine intake has not been established. Nevertheless, patients who develop symptoms potentially associated with cataracts should be referred for an ophthalmologic evaluation and then evaluated for continuation of therapy.

Malignant Neuroleptic Syndrome (MNS)

. The development of a life-threatening symptom complex, malignant neuroleptic syndrome, has been noted with the use of antipsychotics. Clinical manifestations of MNS 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 heart rhythm disorders). Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient presents with signs and symptoms of MNS or high fever of unclear etiology without additional clinical manifestations of MNS, cariprazine should be stopped immediately.

Convulsions and seizures

Cariprazine should be used with caution in patients with a history of seizures or with conditions associated with decreased seizure threshold.

Risk of acute cerebral haemorrhage disorder (AMI)

. An approximately 3-fold increased risk of cerebrovascular adverse reactions has been reported in randomized placebo-controlled clinical trials in patients with dementia with some atypical antipsychotics. The mechanism of increased risk has not been established. An increased risk cannot be ruled out with other antipsychotic drugs or in other patient groups.

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

Cardiovascular disorders

Cariprazine may cause orthostatic hypotension as well as arterial hypertension (see See 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.

In patients taking antipsychotic drugs, QT interval prolongation may occur.

In a clinical study investigating QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section “Pharmacodynamics”). Only a few cases of QT interval prolongation when taking cariprazine have been reported in clinical trials that did not meet the criteria for seriousness (see section “Adverse effects”). Thus, 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 drugs that may cause QT interval prolongation (see section “Pharmacodynamics”).

Cases of venous thromboembolism have been reported with antipsychotic drugs. Because patients taking antipsychotic drugs often have acquired VTE risk factors, all possible VTE risk factors should be identified before and during treatment with cariprazine and preventive measures should be taken.

Hyperglycemia and diabetes mellitus

. Patients with diabetes mellitus or who have risk factors for diabetes mellitus (e.g., obesity, family history of diabetes) require careful monitoring of serum glucose when initiating treatment with atypical antipsychotics. Adverse events associated with changes in glucose concentration have been reported in clinical trials of cariprazine (see section “Pharmacodynamics”).

Women of childbearing age

Women of childbearing age should use highly effective contraception while taking cariprazine and for at least 10 weeks after its termination (see “Interactions with cariprazine” sections.

Women of childbearing age should use highly effective contraception while taking cariprazine for at least 10 weeks after taking it (see “Interaction with other medicines” and “Use during pregnancy and breastfeeding”). Women who use hormonal means of systemic action should additionally use a second, barrier method of contraception.

Body weight changes

A significant increase in body weight has been observed while taking cariprazine. Patients should monitor their body weight regularly (see side effects).

Associates

The drug Reagil®, capsules, 3 mg, 4.5 mg, and 6 mg contain the dye red charm (E129), which may cause allergic reactions.

Influence on ability to control vehicles and machinery

Synopsis

Contraindications

With caution

The drug Reagil® should be used with caution: In patients at high risk of suicide, with akathisia, insensitivity, increased risk of tardive dyskinesia, Parkinson’s disease, history of neuroleptic malignant syndrome, 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 susceptibility to arterial hypotension (e.g., dehydration, hypovolemia, treatment with hypotensive drugs), history of cardiovascular disease, risk of venous thromboembolic complications (see section “Special indications”). Women of childbearing age should use highly effective contraception while taking cariprazine and for at least 10 weeks after withdrawal.

If you have any of these conditions, always consult your doctor before taking the drug.

Side effects

Safety Profile Summary

The most common adverse drug reactions (ADRs) with cariprazine at doses of 1.5 to 6 mg were akathisia (19%) and parkinsonism (17.5%). Most 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 categorized by organ system class and preferred use term.

The adverse reactions are presented according to frequency of occurrence: Very common, 1/10 appointments (≥10%); common, 1/100 appointments (≥1% and < 10%); infrequent, 1/1000 appointments (≥0.1% and < 1%); rare, 1/10000 appointments (≥0.01% and < 0.1%); very rare, 1/10000 appointments (< 0.01%); frequency unknown-not enough data to estimate frequency of VRA. In each frequency group, adverse reactions are presented in descending order of severity.

Blood and lymphatic system disorders

Infrequent:anemia, eosinophilia.

Rarely: neutropenia.

immune system disorders

Rarely:hypersensitivity.

Endocrine system disorders

Infrequent: reduction of thyrotropic hormone concentration in the blood.

Rarely:hypothyroidism.

Disorders of metabolism and nutrition

Frequently:increased body weight, decreased appetite, increased appetite, dyslipidemia.

Infrequent: disorder of serum sodium, increased serum glucose concentration, diabetes mellitus.

Mental disorders

Frequently: sleep disorders1, anxiety.

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

Nervous system disorders

very often: akathisia2, parkinsonism3.

Frequently:drowsiness, dizziness, dystonia4, other extrapyramidal disorders and movement disorders5.

Infrequent:lethargy, dysesthesia, dyskinesia6, tardive dyskinesia.

Rarely:convulsive seizures/convulsions, amnesia, aphasia.

Frequency unknown: malignant neuroleptic syndrome.

Visual disturbances

Frequently: blurred vision.

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

Rarely: photophobia, cataracts.

Hearing and labyrinth disorders

Infrequent: vertigo.

Cardiac disorders

Often: tachyarrhythmia.

Infrequent:cardiac conduction disorders, bradyarrhythmia, QT interval prolongation on ECG, T wave disturbance on ECG.

vascular disorders

often:increased blood pressure.

Infrequent: decreased blood pressure.

Disorders of the respiratory system, thoracic and mediastinal organs

Infrequent:hiccups.

Gastrointestinal tract disorders

Frequently: nausea, constipation, vomiting.

Infrequent:gastroesophageal reflux disease.

Rarely:dysphagia.

Liver and biliary tract disorders

often:increased activity of “liver” enzymes.

Infrequent:increased blood bilirubin.

Frequency is unknown: toxic hepatitis

Skin and subcutaneous tissue disorders

Infrequent: itching, rash.

Musculoskeletal and connective tissue disorders

Frequently:increased serum creatine phosphokinase activity.

Rarely:rhabdomyolysis.

Recreational and urinary tract disorders

Infrequent:dysuria, pollakiuria.

Influence on the course of bpregnancyand, postpartum and perinatal conditions

Frequency unknown: discontinuation syndrome in newborns (see. Use in pregnancy and during breastfeeding)

General disorders and disorders at the site of administration

Frequently:fatigue.

Infrequent:thirst.

1Sleep disorders: insomnia, unusual/nightmare dreams, circadian sleep disturbance, dyssomnia, hypersomnia, sleep disturbance, intrasomnia disorder, nightmare dreams, sleep disturbance, somnambulism, early waking.

2Akathisia: akathisia, psychomotor hyperactivity, restlessness.

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

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

5Other extrapyramidal disorders and movement disorders: balance disorders, bruxism, salivation, dysarthria, unsteady gait, glabellar reflex disorders, decreased reflexes, movement disorders, restless legs syndrome, salivation, tongue movement disorders.

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

Description of individual adverse reactions

Crystalline lens opacity/cataracts

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

Extrapyramidal symptoms (EPS)

In short-term studies, the development of EPS was reported 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 occurred in 1.8%; 0.2%; 3.6% and 0.7% of patients receiving cariprazine, placebo, risperidone and aripiprazole, respectively.

In a placebo-controlled phase of a long-term study, preservation 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 receiving cariprazine and in 2.0% of patients receiving placebo. Parkinsonism was reported in 7.8% and 1.0% of patients in the cariprazine and placebo groups, respectively.

In a study of negative symptomatology, EPS were found 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 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, EPS were of mild to moderate severity and were resolved with the usual EPS medications. The frequency of treatment withdrawal due to EPS-related NERs was low.

Venous thromboembolism (VTE)

Venous thromboembolism, including pulmonary artery thromboembolism and deep vein thrombosis, has been reported with an unspecified frequency when using antipsychotic drugs.

Elevated activity of “hepatic” enzymes

Hepatic transaminases (ALT, AST) are often observed to increase when using antipsychotic drugs. In clinical trials of cariprazine, the incidence of increased ALT, AST activity was 2.2% in patients taking cariprazine, 1.6% in patients receiving risperidone, and 0.4% in patients taking placebo. No liver damage was observed with cariprazine.

Changes in body weight

In short-term studies, a slightly more pronounced 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 study of maintenance of therapeutic effect there were no clinically significant differences in the change of 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 (that is, an increase of at least 7%) during the 20 weeks of cariprazine administration, whereas in the double-blind phase, a potentially clinically significant increase in body weight was observed in 9.8% of patients who continued cariprazine, compared with 7.1% of patients randomized to the placebo group after 20 weeks of open-label cariprazine. In the negative symptomology 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 placebo-controlled clinical study of QT interval prolongation, no QT interval prolongation was observed with cariprazine (see section “Pharmacokinetics”). Only a few cases of QT interval prolongation with cariprazine have been reported in other clinical trials that did not meet the criteria for severity. During the long-term open-label treatment period, 3 patients (0.4%) reported Basett-adjusted QT interval duration (QTcB) >500 ms. One of these patients also had Friedericia-corrected QT interval duration (QTcF) >500 ms. Lengthening of the baseline 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 effect maintenance study, lengthening of the baseline QTcB interval by more than 60 ms was observed in 12 patients (1.6%), and QTcF – in 4 patients (0.5%). In a double-blind treatment period, lengthening of the baseline QTcB interval by 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 HRs, as well as reactions not listed in these instructions, should be reported to the physician.

Overdose

One case of an unintentional single drug overdose (48 mg/day) is known. This patient experienced orthostatic hypotension and sedation. The patient made a full recovery the same day.

Treatment of overdose

The treatment of overdose includes maintenance of adequate airway patency, oxygenation and ventilation, and symptomatic therapy. Cardiovascular function monitoring should be initiated immediately, including continuous monitoring of the electrocardiogram to detect possible cardiac rhythm abnormalities. If severe extrapyramidal symptoms develop, anticholinergic drugs should be prescribed. Because of the high degree of cariprazine binding 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.

Pregnancy use

Physicians should advise women of childbearing age to avoid pregnancy while taking Reagil®. Patients with preserved fertility should use a highly effective contraceptive method during treatment and for at least 10 weeks after discontinuation of Reagil®. It is currently unknown whether cariprazine has the ability to reduce the effectiveness of systemic hormonal contraceptives, so patients taking systemic hormonal contraceptives should use an additional barrier method of contraception (see section “Interactions with other medications”).

Pregnancy

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

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

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

Newborns exposed to antipsychotic drugs (including cariprazine) during the third trimester of pregnancy are at risk of developing adverse reactions after delivery, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration. Agitation, hypertonicity, hypotonicity, tremor, somnolence, respiratory disturbances, and feeding disorders have been reported in these newborns. The severity of these complications varied. In some cases the symptoms stopped on their own, while in other cases they required intensive care unit treatment and prolonged hospitalization. Therefore, these newborns need careful monitoring.

Breastfeeding period

It is not known whether cariprazine and its major active metabolites penetrate into breast milk. Cariprazine and its metabolites penetrate into rat milk during lactation. Risks to newborns/infants cannot be ruled out. Women taking Reagil® should stop breastfeeding.

Fertility

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