Reagila^® (Capsules) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter, Plc. (Hungary)

Or

Gedeon Richter-Rus, JSC (Russia)

Packaging and Quality Control Release

GEDEON RICHTER, Plc. (Hungary)

Or

GEDEON RICHTER-RUS, JSC (Russia)

Contact Information

GEDEON RICHTER, Plc. (Hungary)

ATC Code

N05AX15 (Cariprazine)

Active Substance

Cariprazine (Rec.INN registered by WHO)

Dosage Forms

	Reagila®	Capsules 1.5 mg: 7 or 28 pcs.
		Capsules 3 mg: 7 or 28 pcs.
		Capsules 4.5 mg: 28 pcs.
		Capsules 6 mg: 28 pcs.

Dosage Form, Packaging, and Composition

Capsules hard gelatin, size No. 4; capsule cap – white opaque, capsule body – white opaque; the capsule body is printed with “GR 1.5” in black.

Excipients: pregelatinized corn starch, magnesium stearate;
hard gelatin capsule, size No. 4: cap gelatin, titanium dioxide (E171); body gelatin, titanium dioxide (E171).

Composition of black printing ink iron oxide black (E172), shellac, ethanol, water, propylene glycol, isopropanol, butanol, ammonia solution, potassium hydroxide.

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Capsules hard gelatin, size No. 4; capsule cap – blue-green opaque, capsule body – white opaque; the capsule body is printed with “GR 3” in black.

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

Composition of black printing ink iron oxide black (E172), shellac, ethanol, water, propylene glycol, isopropanol, butanol, ammonia solution, potassium hydroxide.

7 pcs. – blisters (1) – cardboard packs.
7 pcs. – blisters (4) – cardboard packs.

Capsules hard gelatin, size No. 4; capsule cap – blue-green opaque, capsule body – blue-green opaque; the capsule body is printed with “GR 4.5” in white.

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

Composition of white printing ink pharmaceutical glaze [shellac solution in ethanol], titanium dioxide (E171), isopropanol, ammonia solution, butanol, propylene glycol, simethicone.

7 pcs. – blisters (4) – cardboard packs.

Capsules hard gelatin, size No. 3; capsule cap – purple opaque, capsule body – white opaque; the capsule body is printed with “GR 6” in black.

Excipients: pregelatinized corn starch, magnesium stearate;
hard gelatin capsule, size No. 3: cap gelatin, titanium dioxide (E171), brilliant blue (E133), allura red (E129); body gelatin, titanium dioxide (E171).

Composition of black printing ink iron oxide black (E172), shellac, ethanol, water, propylene glycol, isopropanol, butanol, ammonia solution, potassium hydroxide.

7 pcs. – blisters (4) – cardboard packs.

Clinical-Pharmacological Group

Antipsychotic drug (neuroleptic)

Pharmacotherapeutic Group

Psycholeptics; other antipsychotic drugs

Pharmacological Action

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 towards 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 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 α₁-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 functional activity profile in vitro as the parent drug substance.

Pharmacodynamic effects

Preclinical in vivo studies have shown that Cariprazine at pharmacologically effective doses binds to D₃ receptors to the same extent as 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 when taken 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 from 12-hour Holter ECG monitoring were obtained from 129 patients before drug administration and at steady state. No QT interval prolongation was observed with cariprazine at doses exceeding therapeutic doses (9 mg/day or 18 mg/day). No patients receiving Cariprazine in the study had a QTc interval prolongation of ≥60 ms from baseline or a QTc interval >500 ms during the study.

Clinical efficacy

Schizophrenia

Short-term efficacy

The efficacy 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 the change from baseline in the total Positive and Negative Syndrome Scale (PANSS) score at 6 weeks, and the secondary endpoint was the change from baseline in the Clinical Global Impression-Severity (CGI-S) score at 6 weeks. In an international placebo-controlled study using fixed doses of cariprazine 1.5 mg, 3 mg, and 4.5 mg and risperidone 4 mg for analysis sensitivity, statistically significant improvement in the primary and secondary endpoints was demonstrated for all doses of cariprazine and the active control compared to placebo. In another international placebo-controlled study using fixed doses of cariprazine 3 mg and 6 mg and aripiprazole 10 mg for analysis sensitivity, both doses of cariprazine and the active control led to statistically significant improvement in both the primary and secondary endpoints compared to placebo. In a third international placebo-controlled study using fixed/flexible doses of cariprazine 3-6 mg and 6-9 mg, both cariprazine dose groups led to statistically significant improvement in both the primary and secondary endpoints compared to placebo.

The results of the change in the primary endpoint are summarized below in Table 1. The results of the change in the secondary endpoint (CGI) and additional endpoints confirmed the data obtained for the primary endpoint.

Table 1. Change from Baseline in Total PANSS Score at 6 Weeks in Schizophrenia Exacerbation Studies – ITT Population

SD: standard deviation; SE: standard error; LS: least squares; CI: confidence interval.

*Doses that are statistically significantly superior to placebo.

^a Difference (minus placebo effect) in LS mean change from baseline.

A study in subgroups of patients identified by age, sex, and race did not reveal significant differences in response to treatment with the drug.

Pharmacokinetics

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

Absorption

The absolute bioavailability of cariprazine is unknown. When taken orally, Cariprazine is well absorbed. With repeated administration of the drug, C_max in plasma for cariprazine and the main active metabolites is observed approximately after 3-8 hours.

A single dose of cariprazine 1.5 mg taken with a high-fat meal (900-1000 calories) did not have a significant effect on the C_max or AUC values of cariprazine (AUC_0-∞ increased by 12%, C_max decreased by <5% after a meal compared to fasting). The effect of food on the exposure of DCAR and DDCAR was also minimal.

Cariprazine can be taken regardless of meals.

Distribution

Based on population pharmacokinetic analysis, the apparent V_d of cariprazine was 916 L, DCAR – 475 L, DDCAR – 1568 L, indicating wide distribution of cariprazine and its main active metabolites. Cariprazine (CAR) and its main active metabolites are highly bound to plasma proteins (96-97% for CAR, 94-97% for DCAR, 92-97% for DDCAR).

Metabolism

The metabolism of cariprazine occurs through 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, desdichlorophenylpiperazinecariprazine 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 DCAR and HCAR metabolites. DCAR is further transformed by the CYP3A4 isoenzyme and, to a lesser extent, by 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 transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), and breast cancer resistance protein (BCRP). This means that interaction of cariprazine with inhibitors of Pgp, OATP1B1, OATP1B3, and BCRP is unlikely.

Excretion

Cariprazine and its main active metabolites are excreted primarily via hepatic metabolism. 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 unchanged form, 1.2% of the cariprazine dose is excreted by the kidneys, 3.7% – through the intestine. The mean terminal T_1/2 (from 1 to 3 days for cariprazine and desmethylcariprazine and from 13 to 19 days for didesmethylcariprazine) did not determine the time to reach steady state or the decrease in plasma concentration after discontinuation of treatment. When treating patients with cariprazine, the effective T_1/2 is more important than the terminal T_1/2. The effective T_1/2 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. The total plasma concentration of cariprazine decreases by 50% approximately after 1 week and by more than 90% approximately after 3 weeks.

Linearity

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

Pharmacokinetics in special patient groups

Renal impairment. A population pharmacokinetic modeling was performed using data from patients who participated in the cariprazine clinical development program and had varying renal function, including normal renal function (CrCl ≥90 ml/min), as well as mild (CrCl from 60 to 89 ml/min) and moderate (CrCl from 30 to 59 ml/min) renal impairment. No significant association was found between the plasma clearance of cariprazine and CrCl. The use of cariprazine in patients with severe renal impairment (CrCl <30 ml/min) has not been studied (see section "Dosage Regimen").

Hepatic impairment. A two-part study (single dose of cariprazine 1 mg [part A] and daily administration of cariprazine 0.5 mg for 14 days [part B]) was conducted in patients with varying degrees of hepatic impairment (Child-Pugh classes A and B). Compared to healthy subjects, patients with mild and moderate hepatic impairment showed an increase in exposure (C_max and AUC) of cariprazine by approximately 25%. Also, approximately 45% lower exposure of the main active metabolites, desmethylcariprazine and didesmethylcariprazine, was found when cariprazine was administered at a dose of 1 mg or 0.5 mg/day for 14 days.

With repeated administration of cariprazine, the total exposure of active substances (CAR+DCAR+DDCAR) (AUC and C_max) in patients with mild and moderate hepatic impairment decreased by 21-22% and 13-15%, respectively. However, compared to healthy subjects, when considering unbound concentrations in patients with mild and moderate hepatic impairment, 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 Regimen”).

Age, sex and race. In a population pharmacokinetic analysis, no clinically significant differences in pharmacokinetic parameters (AUC and C_max of the sum of cariprazine and its main active metabolites) depending on age, sex, and race were identified. This analysis included 2844 patients of various races, including 536 patients aged 50 to 65 years. Of the 2844 patients, 933 were women. Data on the use of cariprazine in patients over 65 years of age are insufficient.

Smoking.Cariprazine is not a substrate of the CYP1A2 isoenzyme, so no effect of smoking on the pharmacokinetics of cariprazine is expected.

Ability of cariprazine to affect other drugs

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

Indications

For the treatment of adult patients

• Schizophrenia;
• Manic or mixed episodes in bipolar I disorder;
• Depressive episodes in bipolar I disorder (bipolar depression);
• Major depressive disorder (MDD) as an adjunct to antidepressant therapy.

ICD codes

Dosage Regimen

Schizophrenia

The recommended initial dose of cariprazine is 1.5 mg. Subsequently, 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 treating physician based on clinical assessment. Due to the long T_1/2 of cariprazine and its active metabolites, dose changes have a small effect on the plasma concentration of the drug for several weeks. It is necessary to monitor for adverse reactions and patient response to therapy for several weeks after initiation of cariprazine and after each dose change (see section “Pharmacokinetics”).

Manic or mixed episodes in bipolar I disorder

The recommended dose range is from 3 mg to 6 mg once daily. The initial dose of cariprazine is 1.5 mg and may be increased to 3 mg on the second day. Depending on the clinical response and tolerability, further dose increases may be made in increments of 1.5 mg or 3 mg. The maximum recommended dose is 6 mg/day. In short-term controlled studies, doses above 6 mg/day did not provide an increase in efficacy sufficient to outweigh the dose-dependent adverse reactions.

Depressive episodes in bipolar I disorder (bipolar depression)

The initial dose of cariprazine is 1.5 mg once daily. Depending on the clinical response and tolerability, the dose may be increased to 3 mg once daily on the fifteenth day. The maximum recommended dose is 3 mg once daily.

Major depressive disorder (MDD) (as an adjunct to antidepressant therapy)

The initial dose of cariprazine is 1.5 mg once daily. Depending on the clinical response and tolerability, the dose may be increased to 3 mg once daily on the fifteenth day. In clinical studies, dose increases at intervals of less than 14 days led to an increased frequency of adverse reactions. The maximum recommended dose is 3 mg once daily.

Switching from other antipsychotic drugs to Cariprazine

When switching from treatment with other antipsychotic drugs to treatment with cariprazine, consideration should be given to gradual cross-titration, with a gradual reduction in the dose of the previous drug while simultaneously initiating cariprazine.

Switching from cariprazine to other antipsychotic drugs

When switching from treatment with cariprazine to treatment with other antipsychotic drugs, gradual cross-titration is not required; the new antipsychotic drug should be initiated at the minimum dose after discontinuation of cariprazine. It should be taken into account that the plasma concentration of cariprazine and its active metabolites will decrease by 50% in approximately 1 week (see section “Pharmacokinetics”).

Missed dose

If a patient forgets to take the drug, it should be taken as soon as the patient remembers. Do not take the missed tablet if it is almost time for the next dose; continue with the regular dosing schedule.

Do not take a double dose to make up for a missed dose. The patient should consult a physician if 2 or more doses of the drug have been missed.

Special patient groups

Elderly patients

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

Patients with renal impairment

In patients with mild and moderate renal impairment (CrCl ≥30 ml/min and <89 ml/min), no dose adjustment of the drug is required. The safety and efficacy of cariprazine in patients with severe renal impairment (CrCl <30 ml/min) have not been evaluated (see section “Pharmacokinetics”). The use of cariprazine is not recommended in patients with severe renal impairment.

Patients with hepatic impairment

In patients with mild and moderate hepatic impairment (Child-Pugh score 5-9), no dose adjustment of the drug is required. 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.

Children

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

Method of administration

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

Alcohol consumption should be avoided while taking cariprazine (see section “Drug Interactions”).

Adverse Reactions

Summary of the safety profile

The most common adverse drug reactions (ADRs) with the use of cariprazine across all three indications were related to extrapyramidal symptoms.

Summary of adverse reactions

The adverse reactions listed below are distributed by system organ class and preferred term.

Adverse reactions are presented according to their frequency of occurrence: very common – more than 1/10 of administrations (≥10%); common – 1/10 to 1/100 administrations (≥1% and <10%); uncommon – 1/100 to 1/1000 administrations (≥0.1% and <1%); rare – 1/1000 to 1/10000 administrations (≥0.01% and <0.1%); very rare – <1/10000 administrations (<0.01%); frequency unknown – insufficient data to estimate the frequency of ADR. Within each frequency group, adverse reactions are presented in order of decreasing severity.

Schizophrenia

The safety profile of cariprazine based on several short-term and long-term clinical studies was evaluated in approximately 2000 patients with schizophrenia who took Cariprazine in the therapeutic dose range from 1.5 mg to 6 mg.

Blood and lymphatic system disorders uncommon – anemia, eosinophilia; rare – neutropenia.

Immune system disorders rare – hypersensitivity.

Endocrine system disorders uncommon – decreased blood thyroid-stimulating hormone concentration; rare – hypothyroidism.

Metabolism and nutrition disorders common – dyslipidemia, increased weight, decreased appetite, increased appetite; uncommon – diabetes mellitus, abnormal serum sodium content, increased blood glucose concentration.

Psychiatric disorders common – sleep disorders¹, anxiety; uncommon – suicidal behavior, delirium, depression.

Nervous system disorders very common – akathisia², parkinsonism³; common – lethargy, dizziness, dystonia⁴, other extrapyramidal disorders and movement disorders⁵; uncommon – tardive dyskinesia, dyskinesia⁶, dysesthesia, lethargy; rare – seizures/convulsions, amnesia, aphasia; frequency unknown – neuroleptic malignant syndrome.

Eye disorders common – blurred vision; uncommon – increased intraocular pressure, accommodation disorder, decreased visual acuity, eye irritation; rare – cataract, photophobia.

Ear and labyrinth disorders uncommon – vertigo.

Cardiac disorders common – tachyarrhythmia; uncommon – cardiac conduction disorders, bradyarrhythmia, QT interval prolongation on ECG, T-wave abnormality on ECG.

Vascular disorders common – increased blood pressure; uncommon – decreased blood pressure.

Respiratory, thoracic and mediastinal disorders uncommon – hiccups.

Gastrointestinal disorders common – vomiting, nausea, constipation; uncommon – gastroesophageal reflux disease; rare – dysphagia.

Hepatobiliary disorders common – increased hepatic enzyme activity; uncommon – increased blood bilirubin; frequency unknown – toxic hepatitis.

Skin and subcutaneous tissue disorders uncommon – pruritus, rash.

Musculoskeletal and connective tissue disorders common – increased serum creatine phosphokinase activity; rare – rhabdomyolysis.

Renal and urinary disorders uncommon – dysuria, pollakiuria.

Reproductive system and breast disorders: uncommon – decreased libido, increased libido, erectile dysfunction.

Pregnancy, puerperium and perinatal conditions frequency unknown – neonatal withdrawal syndrome (see section “Pregnancy and lactation”).

General disorders and administration site conditions common – fatigue; uncommon – thirst.

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

²Akathisia: akathisia, psychomotor hyperactivity, restlessness.

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

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

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

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

Manic or mixed episodes in bipolar I disorder

The safety profile of cariprazine based on one long-term and several short-term clinical studies was evaluated in approximately 500 patients with manic or mixed episodes in bipolar I disorder who took Cariprazine in the therapeutic dose range from 3 mg to 6 mg.

Metabolism disorders common – increased weight¹, decreased appetite.

Psychiatric disorders common – sleep disorders², anxiety; uncommon – confusion.

Nervous system disorders very common – akathisia³, parkinsonism⁴; common – headache⁵, dystonia⁶, lethargy⁷, dizziness, other extrapyramidal disorders and movement disorders⁸; uncommon – lethargy, dysgeusia, convulsions.

Eye disorders common – blurred vision; uncommon – dry eye syndrome, photophobia.

Ear and labyrinth disorders uncommon – vertigo, tinnitus.

Cardiac disorders common – tachycardia⁹; uncommon – first-degree AV block.

Vascular disorders common – increased blood pressure¹⁰, decreased blood pressure¹¹; uncommon – flushing.

Respiratory, thoracic and mediastinal disorders uncommon – hiccups.

Gastrointestinal disorders common – nausea, constipation, vomiting, dyspepsia, dry mouth; uncommon – abdominal distension, dysphagia.

Hepatobiliary disorders uncommon – increased hepatic enzyme activity¹², abnormal liver function tests.

Musculoskeletal and connective tissue disorders common – musculoskeletal pain¹³; uncommon – increased serum creatine phosphokinase activity.

Renal and urinary disorders uncommon – pollakiuria.

Reproductive system and breast disorders uncommon – decreased libido.

General disorders and administration site conditions common – fatigue¹⁴.

¹Increased weight: increased weight, increased waist circumference

²Sleep disorders: insomnia, nightmares, early awakening.

³Akathisia: akathisia, restlessness, psychomotor hyperactivity.

⁴Parkinsonism: bradykinesia, extrapyramidal disorders, gait disturbance, joint stiffness, muscle rigidity, musculoskeletal stiffness, parkinsonism, tremor.

⁵ Headache: headache, tension headache.

⁶Dystonia: blepharospasm, dystonia, muscle spasm, muscle tightness, oromandibular dystonia.

⁷ Lethargy: hypersomnia, lethargy, somnolence.

⁸ Other extrapyramidal disorders and movement disorders: balance disorder, drooling, dysarthria, muscle twitching, restless legs syndrome, hypersalivation.

⁹ Tachycardia: increased heart rate, increased orthostatic heart rate response, postural orthostatic tachycardia syndrome, tachycardia, sinus tachycardia.

10 Increased blood pressure: increased blood pressure, increased diastolic blood pressure, hypertension.

¹¹Decreased blood pressure: orthostatic hypotension, hypotension.

¹²Increased hepatic enzyme activity: increased ALT, increased AST, abnormal hepatic enzyme activity.

¹³Musculoskeletal pain: arthralgia, musculoskeletal pain, myalgia, neck pain, pain, pain in extremity, jaw pain.

¹⁴Fatigue: asthenia, fatigue, lethargy.

Patients with bipolar depression

The safety profile of cariprazine based on studies was evaluated in approximately 1000 patients with bipolar depression who took Cariprazine in the therapeutic dose range from 1.5 mg to 3 mg.

Metabolism disorders common – increased appetite, increased weight; uncommon – hyperinsulinemia¹, hypercholesterolemia².

Psychiatric disorders common – sleep disorders³, anxiety⁴; uncommon – suicidal thoughts.

Nervous system disorders very common – akathisia⁵; common – lethargy⁶, dizziness⁷, parkinsonism⁸, other extrapyramidal disorders and movement disorders⁹; uncommon – dystonia¹⁰, dyskinesia, decreased mental activity.

Eye disorders uncommon – blurred vision, photophobia.

Ear and labyrinth disorders uncommon – vertigo.

Cardiac disorders uncommon – T-wave abnormality on ECG¹¹.

Gastrointestinal disorders common – nausea, vomiting; uncommon – abdominal pain¹², gastroesophageal reflux disease.

Hepatobiliary disorders uncommon – increased hepatic enzyme activity¹³.

Skin and subcutaneous tissue disorders uncommon – pruritus.

Musculoskeletal and connective tissue disorders common – musculoskeletal pain¹⁴; uncommon – muscle weakness.

Reproductive system and breast disorders uncommon – erectile dysfunction, orgasm disorder.

General disorders and administration site conditions common – fatigue¹⁵; uncommon – thirst, increased energy.

¹Hyperinsulinemia: increased blood glucose, increased blood insulin, increased glycated hemoglobin, hyperinsulinemia.

²Hypercholesterolemia: increased blood cholesterol, hypercholesterolemia.

³Sleep disorders: unusual dreams, sleep initiation disorder, insomnia, insomnia related to another mental disorder, intrasomnic disorder, nightmares, poor sleep quality, sleep disorder, early awakening.

⁴Anxiety: anxiety, feeling of worry, irritability, panic attacks, tension.

⁵Akathisia: agitation, akathisia, restlessness.

⁶Lethargy: hypersomnia, lethargy, somnolence.

⁷Dizziness: dizziness, postural dizziness.

⁸Parkinsonism: akinesia, extrapyramidal disorders, gait disturbance, joint stiffness, muscle rigidity, tremor.

⁹Other extrapyramidal disorders and movement disorders: bruxism, hypersalivation, drooling, restless legs syndrome.

¹⁰Dystonia: blepharospasm, dystonia, muscle tightness, muscle spasm.

¹¹T-wave abnormality on ECG: T-wave abnormality on ECG, ST segment depression on ECG, decreased T-wave amplitude on ECG.

¹²Abdominal pain: abdominal discomfort, abdominal distension, abdominal pain, upper abdominal pain

¹³Increased hepatic enzyme activity: increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyltransferase, increased hepatic enzymes.

¹⁴Musculoskeletal pain: arthralgia, back pain, myalgia, pain, pain in extremity.

¹⁵Fatigue: asthenia, fatigue, muscle fatigue, slowness.

Adjunctive therapy for major depressive disorder

The safety profile of cariprazine was evaluated based on one long-term and several short-term clinical studies in approximately 1800 patients with MDD who took Cariprazine in the therapeutic dose range from 1.5 mg to 3 mg.

Metabolism and nutrition disorders: common – increased weight, increased appetite; uncommon – dyslipidemia¹, hyperinsulinemia², decreased appetite.

Psychiatric disorders: common – cognitive disorder³, insomnia⁴, anxiety⁵; uncommon – sleep disorders⁶.

Nervous system disorders very common – akathisia⁷; common – lethargy⁸, parkinsonism⁹, dizziness, dystonia¹⁰, headache¹¹; uncommon – dyskinesia, other extrapyramidal disorders¹², paresthesia.

Eye disorders common – blurred vision; uncommon – photophobia, dry eye syndrome.

Ear and labyrinth disorders uncommon – tinnitus, vertigo.

Cardiac disorders uncommon – tachycardia¹³, QT interval prolongation on ECG, palpitations.

Vascular disorders uncommon – orthostatic hypotension¹⁴, flushing.

Respiratory, thoracic and mediastinal disorders uncommon – hiccups.

Gastrointestinal disorders common – constipation, nausea, dry mouth; uncommon – vomiting, gastroesophageal reflux disease, gastritis, dysphagia, dyspepsia, abdominal distension.

Skin and subcutaneous tissue disorders common – hyperhidrosis; uncommon – rash.

Musculoskeletal and connective tissue disorders: uncommon – increased serum creatine phosphokinase activity, muscle weakness, musculoskeletal pain¹⁵.

Renal and urinary disorders uncommon – dysuria, pollakiuria.

Reproductive system and breast disorders: uncommon – decreased libido, erectile dysfunction, ejaculation disorder.

General disorders and administration site conditions common – fatigue¹⁶; uncommon – edema, increased energy, thirst.

¹ Dyslipidemia: increased blood cholesterol, increased blood triglycerides, dyslipidemia.

² Hyperinsulinemia: increased blood insulin, hyperinsulinemia.

³ Cognitive disorders: attention disturbance, memory impairment, thinking abnormal.

⁴ Insomnia: sleep initiation disorder, insomnia, intrasomnic disorder, early awakening.

⁵ Anxiety: anxiety, feeling of worry, irritability, panic attacks, tension.

⁶Sleep disorders: unusual dreams, nightmares, poor sleep quality, sleep disturbance.

⁷Akathisia: agitation, akathisia, restlessness.

⁸Lethargy: hypersomnia, lethargy, somnolence, stupor.

⁹Parkinsonism: extrapyramidal disorders, hypertonia, muscle rigidity, musculoskeletal stiffness, myoclonus, nuchal rigidity, parkinsonism, resting tremor, tremor.

¹⁰Dystonia: blepharospasm, dystonia, muscle spasm, muscle tightness, oromandibular dystonia.

¹¹Headache: headache, head discomfort, migraine, tension headache.

¹²Other extrapyramidal disorders: balance disorder, muscle twitching, restless legs syndrome.

¹³Tachycardia: increased heart rate, tachycardia.

¹⁴Orthostatic hypotension: postural dizziness, orthostatic hypotension.

¹⁵Musculoskeletal pain: myalgia, musculoskeletal pain, pain in extremity, jaw pain.

¹⁶Fatigue: asthenia, fatigue.

Description of selected adverse reactions

Lens opacity/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 examinations, and patients with existing cataracts were excluded from the studies. In the cariprazine clinical development program for the treatment of schizophrenia, several cases of cataracts were reported, characterized by slight lens opacities without visual impairment (13/3192; 0.4%). Some of these patients had aggravating factors. The most frequently reported ocular adverse event was blurred vision (placebo: 1/683; 0.1%, Cariprazine: 22/2048; 1.1%).

In short-term studies of bipolar mania and depression, the most frequent ocular adverse event was also blurred vision (placebo: 5/433; 1.2%, Cariprazine: 10/255; 3.9% and placebo: 2/545; 0.4%, Cariprazine 11/1014; 1.1%, respectively). In the pooled mania studies, the most frequent ocular adverse event was also blurred vision (17/485; 3.5%). In the bipolar mania and bipolar depression studies, no development of cataracts as an adverse event was reported within the therapeutic dose range.

In MDD studies in patients receiving Cariprazine as adjunctive therapy, the most frequent ocular adverse event was also blurred vision (placebo + antidepressant therapy (ADT): 12/1108; 1.1%; Cariprazine 1.5-3 mg + ADT: 71/1822; 3.9%). In MDD studies, no development of cataracts as an adverse event was reported when taken within the therapeutic dose range.

Extrapyramidal symptoms (EPS)

In short-term studies, EPS developed 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 noted in 1.8%; 0.2%; 3.6%; and 0.7% of patients receiving Cariprazine, placebo, risperidone, and aripiprazole, respectively.

In the placebo-controlled phase of the long-term maintenance 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 in 2.0% of patients taking placebo. Parkinsonism was noted in 7.8% and 1.0% of patients in the cariprazine and placebo groups, respectively.

In the negative symptoms study, EPS were identified 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 taking risperidone. Parkinsonism was noted in 5.2% and 7.4% of patients in the cariprazine and risperidone groups, respectively. In most cases, EPS were mild or moderate in severity and were resolved with conventional EPS medications. The rate of treatment discontinuation due to EPS-related ADRs was low.

In the 3-week bipolar mania studies, the incidence of reported adverse drug reactions related to extrapyramidal symptoms, excluding akathisia and restlessness, was 27.5% in patients treated with cariprazine compared with 11.3% in patients receiving placebo. The incidence of akathisia and restlessness was 23.5% in patients treated with cariprazine compared with 5.5% in patients receiving placebo. The incidence of parkinsonism was 18.4% in patients treated with cariprazine compared with 8.6% in patients receiving placebo.

In controlled bipolar depression studies, the incidence of reported adverse drug reactions related to extrapyramidal symptoms was 16.3% in patients treated with cariprazine compared with 7.3% in patients receiving placebo. Akathisia was reported in 13.4% of patients treated with cariprazine and in 6.4% in the placebo group. Parkinsonism was observed in 3.1% and 1.7% of patients receiving Cariprazine and placebo, respectively.

In MDD studies in patients receiving Cariprazine as adjunctive therapy, the incidence of reported adverse drug reactions related to EPS, excluding akathisia and restlessness, was 7.3% in the group taking 1.5-3 mg cariprazine + ADT compared with 3.6% in the placebo + ADT group. The incidence of akathisia and restlessness was 18.5% in patients taking Cariprazine 1.5-3 mg + ADT and 4.1% in the placebo + ADT group. Parkinsonism was observed in 4.5% of patients in the group taking 1.5-3 mg cariprazine + ADT and 1.8% in the placebo + ADT group, respectively.

Venous thromboembolism (VTE)

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

Elevated liver enzymes

Elevated liver transaminases (ALT, AST) are frequently observed with the use of antipsychotic drugs. In clinical studies of cariprazine, the incidence of elevated ALT, AST was 2.2% in patients taking Cariprazine, 1.6% in patients receiving risperidone, and 0.4% in patients taking placebo. Liver damage was not observed with the use of cariprazine. In mania studies, the incidence of elevated liver enzymes was 1.7% in the cariprazine group and 1.2% in the placebo group. In bipolar depression studies, the incidence of elevated liver enzymes was 1.3% in the cariprazine group and 0.7% in the placebo group.

In MDD studies in patients receiving Cariprazine as adjunctive therapy, the incidence of elevated liver enzymes was 0.66% in the group taking 1.5-3 mg cariprazine + ADT and 1.35% in the placebo + ADT group.

Weight changes

In short-term schizophrenia therapy studies, a slightly more pronounced weight increase was observed in the cariprazine group compared to the placebo group: 1 kg and 0.3 kg, respectively. In the long-term maintenance study for schizophrenia therapy, no clinically significant differences in the change from baseline body weight were observed 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 over 20 weeks of cariprazine intake, a potentially clinically significant weight increase (defined as an increase of ≥7%) developed in 9.0% of patients, whereas in the double-blind phase, a potentially clinically significant weight increase was observed in 9.8% of patients who continued taking cariprazine, compared with 7.1% of patients randomized to the placebo group after 20 weeks of open-label cariprazine intake. In the negative symptoms study, the mean weight change was -0.3 kg with cariprazine and +0.6 kg with risperidone, and a potentially clinically significant weight increase was observed in 6% of patients in the cariprazine group and 7.4% in the risperidone group. In short-term mania studies, the mean weight change was similar in both groups: +0.2 kg in the placebo group and +0.5 kg in the cariprazine group. In the long-term mania study, the mean change from baseline in the endpoint (body weight) was approximately 1 kg. In the long-term mania study, a potentially clinically significant weight increase (≥7% increase from baseline) was observed in 9.3% of patients.

In bipolar depression studies, the mean change in body weight from baseline to the end of the treatment period was not clinically significant (-0.1 kg for placebo, 0.7 kg for cariprazine 1.5 mg, and 0.4 kg for cariprazine 3 mg).

In short-term MDD studies in patients receiving Cariprazine as adjunctive therapy, the mean change in body weight from baseline to the end of the double-blind treatment period was 0.84 kg and 0.22 kg in the cariprazine + ADT group and placebo + ADT group, respectively. In long-term MDD studies in patients receiving Cariprazine as adjunctive therapy, the mean change in body weight from baseline to the end of the open-label treatment period was 1.56 kg in the cariprazine + ADT group.

QT interval prolongation

In a clinical placebo-controlled QT study with cariprazine, no QT interval prolongation was observed. In other clinical studies, only a few cases of QT interval prolongation with cariprazine were reported, which did not meet the seriousness criteria. During the long-term open-label treatment period, 3 patients (0.4%) had a Bazett’s corrected QT interval (QT_cB) >500 ms. One of these patients also had a Fridericia’s corrected QT interval (QT_cF) >500 ms. A QTcB increase from baseline of 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 maintenance study, a QTcB increase from baseline of 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 QTcB increase from baseline of more than 60 ms was noted in 3 patients taking Cariprazine (3.1%) and in 2 patients receiving placebo (2%).

In short-term mania studies, one patient in the cariprazine group and two patients in the placebo group had a Bazett’s corrected QT interval (QT_cB) > 500 ms post-baseline. No patient had a Fridericia’s corrected QT interval (QT_cF) > 500 ms. In long-term mania studies, no patient taking Cariprazine had a QTcB or QTcF > 500 ms post-baseline. No serious adverse events related to ECG findings were observed.

In bipolar depression studies, several patients in both the modal daily dose cariprazine groups and the placebo group had an increase in QTcB and QTcF of > 60 ms from baseline at any time during the double-blind treatment period: overall for cariprazine 0.9% (10/1167) compared to placebo 0.4% (2/510) and overall for cariprazine 0.2% (2/1167) compared to placebo 0% (0/510), respectively.

In short-term MDD studies in patients receiving Cariprazine as adjunctive therapy, the increase in QTcB of >60 ms from baseline was 0.4% in the cariprazine + ADT group and 0.3% in the placebo + ADT group. The increase in QTcF of >60 ms from baseline was the same (0.1%) in both groups. In long-term MDD studies in patients receiving Cariprazine as adjunctive therapy, the increase in QTcB and QTcF of >60 ms from baseline was 0.6% in the cariprazine + ADT group.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the drug’s benefit-risk balance. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting systems of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of the drug;
• Concomitant use of potent inhibitors of the CYP3A4 isoenzyme (see section “Drug Interactions”);
• Concomitant use of potent or moderate inducers of the CYP3A4 isoenzyme (see section “Drug Interactions”);
• Elderly patients with dementia. The use of cariprazine in elderly patients with dementia has not been studied. Cariprazine is contraindicated in such patients due to an increased risk of overall mortality.

With caution

In patients at high risk of suicide, with akathisia, restlessness, increased risk of tardive dyskinesia, Parkinson’s disease, history of neuroleptic malignant syndrome, history of seizures or conditions that lower the seizure threshold, cataract, in patients with risk factors for stroke, diabetes mellitus, risk factors for hyperglycemia, risk of obesity; predisposition to arterial hypotension (e.g., dehydration, hypovolemia, treatment with antihypertensive drugs), history of cardiovascular diseases, risk of venous thromboembolic complications (see section “Special Precautions”). Women of childbearing potential should use highly effective contraceptive measures during cariprazine treatment and for at least 10 weeks after its discontinuation.

Use in Pregnancy and Lactation

Women of childbearing potential

The physician 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 Reagila^®.

Pregnancy

Data on the use of cariprazine in pregnant women are absent or limited.

In preclinical studies in animals, reproductive toxicity was identified, including malformations in rats.

The use of Reagila^® during pregnancy and in women of childbearing potential not using reliable contraceptive methods 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 adverse reactions after birth, including extrapyramidal disorders and/or withdrawal syndrome, which may vary in severity and duration. Agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, and feeding disorders have been observed in these newborns. The severity of these complications varied. In some cases, the symptoms resolved spontaneously, while in others, intensive care unit treatment and prolonged hospitalization were required. Therefore, such newborns require careful monitoring.

Breastfeeding period

It is unknown whether Cariprazine and its main active metabolites pass into breast milk. Cariprazine and its metabolites pass into the milk of rats during lactation. A risk to newborns/infants cannot be excluded. Women taking Reagila^® should refrain from breastfeeding.

Fertility

The effect of cariprazine on human fertility has not been studied. In preclinical studies, reduced fertility and conception ability were observed in female rats.

Use in Hepatic Impairment

In patients with mild and moderate hepatic impairment (5-9 points on the Child-Pugh scale), no dose adjustment of the drug is required.

The use of cariprazine in patients with severe hepatic impairment is not recommended.

Use in Renal Impairment

In patients with mild and moderate renal impairment (CrCl ≥30 ml/min and <89 ml/min), no dose adjustment of the drug is required.

The use of cariprazine is not recommended in patients with severe renal impairment.

Pediatric Use

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

Geriatric Use

The use of cariprazine in elderly patients with dementia has not been studied. Cariprazine is contraindicated in such patients due to an increased risk of overall mortality.

Special Precautions

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 the start of treatment or after switching from therapy with other antipsychotic drugs. During treatment with antipsychotic drugs, patients at high risk of suicide should be under close supervision.

Akathisia, restlessness

Akathisia and restlessness are common adverse reactions with the use of antipsychotic drugs. Akathisia is a movement disorder characterized by a feeling of inner restlessness and a need to be in constant motion, as well as actions such as rocking the body while standing or sitting, lifting the legs as if marching in place, and crossing and uncrossing the legs while sitting. Since Cariprazine may cause akathisia and restlessness, it should be used with caution in patients who have already experienced symptoms of akathisia or are predisposed to it. Akathisia develops at the beginning of treatment. Therefore, it is important to conduct careful monitoring of patients in the first phase of treatment. Prevention includes gradual dose escalation; therapeutic measures include a slight reduction in the dose of cariprazine or the use of medications to manage EPS. The drug dose may be adjusted depending on the individual patient’s response to treatment and tolerance (see section “Adverse Reactions”).

Tardive dyskinesia

Tardive dyskinesia is a syndrome involving potentially irreversible, rhythmic, involuntary movements, primarily of the tongue and/or face, which may occur in patients receiving antipsychotic drugs. If signs and symptoms of tardive dyskinesia appear in a patient taking Cariprazine, the advisability of discontinuing the drug should be considered.

Parkinson’s Disease

When used in patients with Parkinson’s disease, antipsychotic medications may cause exacerbation of the underlying disease and lead to an increase in the symptoms of Parkinson’s disease. Therefore, when prescribing Cariprazine to patients with Parkinson’s disease, the physician should carefully weigh the benefits and risks.

Ocular Symptoms/Cataract

Preclinical studies of cariprazine revealed lens opacity/cataract in dogs (see section “Adverse Reactions”). However, a causal relationship between lens changes/cataract in human studies and cariprazine intake has not been established. Nevertheless, patients who develop symptoms potentially associated with cataract should be referred for an ophthalmological examination and then the possibility of continuing therapy should be assessed.

Neuroleptic Malignant Syndrome (NMS)

A life-threatening symptom complex – Neuroleptic Malignant Syndrome – has been reported during treatment with antipsychotics. Clinical manifestations of NMS include hyperthermia, muscle rigidity, increased serum creatine phosphokinase activity, altered mental status, and autonomic nervous system disturbances (irregular pulse, blood pressure instability, tachycardia, increased sweating, and cardiac arrhythmias). Additional manifestations may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient shows signs and symptoms of NMS or high fever of unknown etiology without additional clinical manifestations of NMS, Cariprazine must be discontinued immediately.

Seizures and Convulsions

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

Risk of Acute Cerebrovascular Accident

An approximately 3-fold increase in the risk of cerebrovascular adverse reactions was observed in randomized placebo-controlled clinical trials in patients with dementia using some atypical antipsychotic drugs. The mechanism of the increased risk has not been established. An increased risk cannot be excluded when using other antipsychotic drugs or in other patient groups.

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

Cardiovascular Disorders

Blood Pressure Changes. Cariprazine may cause orthostatic hypotension, as well as arterial hypertension (see section “Adverse Reactions”). Cariprazine should be used with caution in patients with cardiovascular diseases predisposed to blood pressure changes. Blood pressure should be monitored.

ECG Changes. Patients taking antipsychotic drugs may experience QT interval prolongation. In a clinical study designed to investigate QT interval prolongation, no QT interval prolongation was observed with cariprazine compared to placebo (see section “Pharmacological Properties”). In clinical studies, only a few cases of QT interval prolongation with cariprazine were reported, which did not meet the criteria for severity (see section “Adverse Reactions”). 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 medications that can cause QT interval prolongation (see section “Pharmacological Properties”).

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

Hyperglycemia and Diabetes Mellitus

In patients with diabetes mellitus or with risk factors for developing diabetes mellitus (e.g., obesity, family history of diabetes), serum glucose levels should be carefully monitored when starting treatment with atypical antipsychotics. Adverse events related to changes in glucose concentration were reported in clinical studies of cariprazine (see section “Pharmacological Properties”).

Weight Change

Significant weight gain has been observed with cariprazine intake. Patients should have their body weight monitored regularly (see section “Adverse Reactions”).

Concomitant Use with Moderate CYP3A4 Enzyme Inhibitors

Concomitant use of cariprazine with moderate CYP3A4 enzyme inhibitors may lead to an increase in the total exposure of cariprazine. Given the potential increase in exposure, monitoring of the patient’s individual response and therapy tolerance is recommended; if necessary, the dose of cariprazine should be (temporarily) reduced (see section “Drug Interactions”).

Excipients

The drug Reagila^®, capsules, 3 mg, 4.5 mg and 6 mg contain the dye Allura Red (E129), which may cause allergic reactions.

Effect on Ability to Drive and Use Machines

Cariprazine has a minor to moderate influence on the ability to drive and use machines. Patients should be cautious about operating potentially hazardous machinery, including vehicles, until they are fully confident that Reagila^® does not adversely affect their abilities.

Overdose

Symptoms one case of unintentional single overdose of the drug (48 mg/day) is known. This patient experienced orthostatic hypotension and a sedative effect. The patient’s condition fully recovered on the same day.

Treatment of overdose includes maintaining adequate airway patency, oxygenation and ventilation, as well as symptomatic therapy. Monitoring of cardiovascular functions, including continuous ECG monitoring to detect possible cardiac arrhythmias, should be initiated immediately. If severe extrapyramidal symptoms develop, anticholinergic drugs should be administered. Due to the high degree of plasma protein binding of cariprazine, hemodialysis is likely to be ineffective. The patient should be under close medical supervision until complete recovery. There is no specific antidote for cariprazine.

Drug Interactions

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 CYP3A4 isoenzyme inhibitor, when used short-term (4 days) concomitantly with cariprazine, caused a 2-fold increase in the total plasma exposure of cariprazine (the sum of cariprazine and its active metabolites), regardless of whether only unbound substances or the sum of unbound and bound components are considered.

Due to the long T_1/2 of cariprazine’s active metabolites, further increase in total plasma exposure of cariprazine can be expected with longer concomitant use. Therefore, concomitant use of cariprazine with potent 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 section “Contraindications”).

Concomitant use of erythromycin (500 mg twice daily), a moderate CYP3A4 isoenzyme inhibitor, for 3 weeks, caused an average 1.4 (1.03-2.32) fold increase in total plasma exposure of cariprazine. Given the potential increase in exposure with concomitant use of cariprazine with moderate CYP3A4 isoenzyme inhibitors (e.g., erythromycin, fluconazole, diltiazem, verapamil), monitoring of the patient’s individual response and therapy tolerance is recommended; if necessary, the dose of cariprazine should be (temporarily) reduced. Due to the long half-life of cariprazine and its active metabolites, the initiation or discontinuation of therapy with moderate CYP3A4 isoenzyme inhibitors or a change in the drug dose has little effect on the plasma concentration of the drug for several weeks. Adverse reactions and patient response to therapy should be monitored for several weeks after initiation or discontinuation of concomitant use or after each dose change of cariprazine.

Grapefruit juice should be avoided.

CYP3A4 Isoenzyme Inducers

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

CYP2D6 Isoenzyme Inhibitors

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

Ability of Cariprazine to Affect Other Drugs

P-glycoprotein (P-gp) Substrates

Cariprazine at the theoretical maximum intestinal concentration inhibits P-gp in vitro. The clinical significance of this effect is not fully established; nevertheless, 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

In a drug interaction study, the use of cariprazine at a dose of 6 mg/day for 28 days did not have a clinically significant effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Pharmacodynamic Interaction

Given the primary effect of cariprazine on the CNS, Reagila^® should be used with caution with other centrally acting drugs and alcohol.

Storage Conditions

The drug should be stored in the original packaging to protect from light, in a place inaccessible to children. No special temperature storage conditions are required.

Shelf Life

The shelf life is 5 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.