Reagila

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REAGILA (REAGILA®)

Composition:

Hard capsules of 1.5 mg

Active substance: cariprazine;

1 capsule contains cariprazine 1.5 mg (as cariprazine hydrochloride 1.635 mg).

Excipients: pregelatinized maize starch, magnesium stearate.

Hard capsule shell: titanium dioxide, E 171; gelatin; black printing ink: iron oxide black, E 172; shellac; ethanol; water; propylene glycol; isopropanol; butanol; aqueous ammonia; potassium hydroxide.

Hard capsules of 3 mg

Active substance: cariprazine;

1 capsule contains cariprazine 3 mg (as cariprazine hydrochloride 3.270 mg).

Excipients: pregelatinized maize starch, magnesium stearate.

Hard capsule shell: titanium dioxide, E 171; gelatin; Ponceau 4R (E 129); brilliant blue FCF (E 133); iron oxide yellow, E 172; black printing ink: iron oxide black, E 172; shellac; ethanol; water; propylene glycol; isopropanol; butanol; aqueous ammonia; potassium hydroxide.

Hard capsules of 4.5 mg

Active substance: cariprazine;

1 capsule contains cariprazine 4.5 mg (as cariprazine hydrochloride 4.905 mg).

Excipients: pregelatinized maize starch, magnesium stearate.

Hard capsule shell: titanium dioxide, E 171; gelatin; Ponceau 4R (E 129); brilliant blue FCF (E 133); iron oxide yellow, E 172; white printing ink: pharmaceutical glaze (shellac dissolved in ethanol); titanium dioxide, E 171; isopropanol; butanol; aqueous ammonia; propylene glycol; simethicone.

Hard capsules of 6 mg

Active substance: cariprazine;

1 capsule contains cariprazine 6 mg (as cariprazine hydrochloride 6.540 mg).

Excipients: pregelatinized maize starch, magnesium stearate.

Hard capsule shell: titanium dioxide, E 171; gelatin; Ponceau 4R (E 129); brilliant blue FCF (E 133); black printing ink: iron oxide black, E 172; shellac; ethanol; water; propylene glycol; isopropanol; butanol; aqueous ammonia; potassium hydroxide.

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

Capsules 1.5 mg. Hard gelatin capsules, size № 4. Capsule cap — opaque white, capsule body — opaque white. Marked on the body in black ink: «GR 1.5». Contents of capsules — white or yellowish-white powder.

Capsules 3 mg. Hard gelatin capsules, size № 4. Capsule cap — opaque green, capsule body — opaque white. Marked on the body in black ink: «GR 3». Contents of capsules — white or yellowish-white powder.

Capsules 4.5 mg. Hard gelatin capsules, size № 4. Capsule cap — opaque green, capsule body — opaque green. Marked on the body in white ink: «GR 4.5». Contents of capsules — white or yellowish-white powder.

Capsules 6 mg. Hard gelatin capsules, size № 3. Capsule cap — opaque violet, capsule body — opaque white. Marked on the body in black ink: «GR 6». Contents of capsules — white or yellowish-white powder.

Pharmacotherapeutic group. Psycholeptics, other antipsychotics.

ATC code N05AX15.

Pharmacological Properties

Pharmacodynamics.

Mechanism of action

The mechanism of action of cariprazine has not been fully elucidated. However, the therapeutic effect of cariprazine may be mediated through a combination of partial agonist activity at D3- and D2-dopamine receptors (Ki values ranging from 0.085–0.3 nM and 0.49–0.71 nM, respectively) and 5‑HT1A serotonin receptors (Ki values ranging from 1.4–2.6 nM), as well as antagonist activity at 5‑HT2B-, 5‑HT2A-serotonin and H1-histamine receptors (Ki values ranging from 0.58–1.1 nM, 18.8 nM, and 23.3 nM, respectively). Cariprazine has low affinity for 5‑HT2C-serotonin and α1-adrenergic receptors (Ki values of 134 nM and 155 nM, respectively). Cariprazine has no significant affinity for muscarinic cholinergic receptors (IC50 > 1000 nM). Two major active metabolites—desmethyl-cariprazine and didesmethyl-cariprazine—bind to receptors and exhibit a functional activity profile in vitro similar to that of the parent active substance.

Pharmacodynamic effects

Preclinical in vivo studies show that cariprazine binds to D3-receptors to a similar extent as to D2-receptors at pharmacologically effective doses. Dose-dependent binding to D3- and D2-dopamine receptors in the brain (with predominant binding in areas of elevated D3 synthesis) was observed in patients with schizophrenia who received therapeutic doses of cariprazine for 15 days.

The effect of cariprazine on the QT interval was evaluated in patients with schizophrenia or schizoaffective disorder. Results from 12-hour Holter ECG monitoring were collected from 129 patients at baseline and at steady state. With subtherapeutic doses (9 mg/day or 18 mg/day), no QT interval prolongation was observed. No patient treated with cariprazine experienced a QT interval increase ≥ 60 ms from baseline, and no patient had a QT interval > 500 ms during the study.

Clinical efficacy and safety

Efficacy in short-term treatment

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

Results for the primary efficacy endpoint are presented in Table 1 below. Results for the secondary efficacy endpoint (CGI) and additional endpoints supported the findings of the primary endpoint.

Table 1. Change from baseline to week 6 in total PANSS score in acute schizophrenia exacerbation studies — ITT population.

	Baseline Mean ± SD	Change LS Mean (SE)	Treatment difference vs placebo (95% CI)	P-value
Total PANSS score (MMRM)
Study RGH-MD-16 (n = 711)
Placebo	97.3 ± 9.22	13.29 (1.82)
Cariprazine 1.5 mg/day	97.1 ± 9.13	21.27 (1.77)	7.97 (–12.94, –3.01)	0.0017
Cariprazine 3 mg/day	97.2 ± 8.66	21.45 (1.74)	8.16 (–13.09, –3.22)	0.0013
Cariprazine 4.5 mg/day	96.7 ± 9.01	23.77 (1.74)	10.48 (–15.41, –5.55)	< 0.0001
Risperidone 4 mg/day	98.1 ± 9.50	29.27 (1.74)	15.98 (–20.91, –11.04)	< 0.0001*
Study RGH-MD-04 (n = 604)
Placebo	96.5 ± 9.1	14.3 (1.5)
Cariprazine 3 mg/day	96.1 ± 8.7	20.2 (1.5)	6.0 (–10.1, –1.9)	0.0044
Cariprazine 6 mg/day	95.7 ± 9.4	23.0 (1.5)	8.8 (–12.9, –4.7)	< 0.0001
Aripiprazole 10 mg/day	95.6 ± 9.0	21.2 (1.4)	7.0 (–11.0, –2.9)	0.0008*
Study RGH-MD-05 (n = 439)
Placebo	96.6 ± 9.3	16.0 (1.6)
Cariprazine 3–6 mg/day	96.3 ± 9.3	22.8 (1.6)	6.8 (–11.3, –2.4)	0.0029
Cariprazine 6–9 mg/day	96.3 ± 9.0	25.9 (1.7)	9.9 (–14.5, –5.3)	< 0.0001

CI – confidence interval; ITT – intent-to-treat analysis; LS mean – least squares mean; PANSS – Positive and Negative Syndrome Scale; SE – standard error; SD – standard deviation; MMRM – mixed-effects model for repeated measures.

* Compared with placebo.

Efficacy in long-term use

The efficacy of cariprazine for maintaining antipsychotic effect was evaluated in a long-term clinical trial with a randomized withdrawal phase. Overall, 751 patients with acute symptoms of schizophrenia received cariprazine at a dose of 3–9 mg/day for 20 weeks, of whom 337 received cariprazine within the dose range of 3–6 mg/day. Subsequently, stabilized patients were randomized in a double-blind manner to receive either fixed doses of cariprazine of 3–6 mg (n = 51) or placebo (n = 51) for up to 72 weeks. The primary outcome of the study was time to relapse. At the end of the study, 49.0% of patients receiving placebo versus 21.6% of patients receiving cariprazine experienced a relapse of schizophrenia symptoms. Thus, time to relapse (92 vs. 326 days based on the 25th percentile) was significantly longer in the cariprazine group than in the placebo group (p = 0.009).

Efficacy in predominantly negative symptoms of schizophrenia

The efficacy of cariprazine in the treatment of predominantly negative symptoms of schizophrenia was evaluated in a 26-week, multicenter, double-blind, active-controlled clinical trial. Cariprazine (dose range 3–4 mg, target dose 4.5 mg) was compared with risperidone (dose range 3–6 mg, target dose 4 mg) in patients with persistent predominantly negative symptoms of schizophrenia (n = 461). 86% of patients were under 55 years of age, and 54% were male.

Persistent predominantly negative symptoms were defined as symptoms lasting at least 6 months and characterized by high levels of negative symptoms and low levels of positive symptoms [(PANSS negative symptom score ≥ 24, score ≥ 4 on at least 2 of 3 PANSS items (N1: blunted affect, N4: lack of motivation, N6: poverty of speech) and PANSS positive symptom score ≤ 19]. Patients with secondary negative symptoms due to moderate to severe depressive symptoms or clinically significant parkinsonism (extrapyramidal symptoms [EPS]) were excluded.

Both cariprazine- and risperidone-treated patients demonstrated statistically significant improvement in the change from baseline to the primary efficacy endpoint—the PANSS negative symptom score (PANSS-FSNS) (p < 0.001). However, starting at week 14, a statistically significant difference in favor of cariprazine compared to risperidone was observed (p = 0.002) (Table 2). Both cariprazine- and risperidone-treated patients also demonstrated statistically significant improvement in the change from baseline to the secondary efficacy endpoint—the Personal and Social Performance (PSP) scale total score (p < 0.001). However, starting at week 10, a statistically significant difference in favor of cariprazine compared to risperidone was observed (p = 0.001) (Table 2).

Both differences in Clinical Global Impressions–Severity (CGI-S) (p = 0.005) and Clinical Global Impressions–Improvement (CGI-I) (p < 0.001) scores, as well as response rate based on PANSS-FSNS (improvement in PANSS-FSNS ≥ 30% at week 26; p = 0.003), supported the findings on primary and secondary efficacy endpoints.

Table 2. Summary of results from study RGH-188-005

Efficiency parameter	Cariprazine LS mean value	Risperidone LS mean value	Calculated measure of treatment difference	95% CI	p-value
PANSS-FSNS at baseline	27.8	27.5	-	-	-
PANSS-FSNS at week 26	18.5	19.6	-	-	-
PANSS-FSNS change from baseline to week 26	8.9	7.4	1.5	2.4; 0.5	0.002
Total PSP score at baseline	48.8	48.2	-	-	-
Total PSP score at week 26	64.0	59.7	-	-	-
Total PSP score change from baseline to week 26	14.3	9.7	4.6	2.7; 6.6	< 0.001
LS mean – least squares mean.

Pediatric population

The European Medicines Agency has waived the obligation to submit the results of a study on the use of cariprazine for the treatment of schizophrenia in various pediatric populations. For information on use of the medicinal product in children, see section "Children".

Pharmacokinetics

Cariprazine has two pharmacologically active metabolites with actions similar to cariprazine — desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR). Total exposure to cariprazine (sum of cariprazine + DCAR and DDCAR) reaches 50% of steady-state exposure approximately 1 week after administration of a daily dose, and 90% of steady-state exposure is achieved within 3 weeks. At steady state, DDCAR exposure is approximately two- to three-fold higher than cariprazine exposure, while DCAR exposure is approximately 30% of cariprazine exposure.

Absorption

The absolute bioavailability of cariprazine is unknown. Cariprazine is well absorbed after oral administration. Following multiple doses, maximum plasma concentrations of cariprazine and its major active metabolites are typically reached approximately 3–8 hours after administration.

Administration of a single 1.5 mg dose of cariprazine with a high-fat meal (900–1000 calories) did not significantly affect the Cmax or AUC of cariprazine (AUC0–∞ increased by 12%, Cmax decreased by 5% when administered with food compared to fasting). Food also had minimal effects on the metabolites DCAR and DDCAR.

Cariprazine may be administered independently of food intake.

Distribution

Based on population pharmacokinetic analysis, the apparent volume of distribution (Vd) was 916 L for cariprazine, 475 L for DCAR, and 1,568 L for DDCAR, indicating extensive distribution of cariprazine and its major active metabolites. Cariprazine and its major active metabolites are highly bound to plasma proteins (cariprazine — 96–97%, DCAR — 94–97%, DDCAR — 92–97%).

Biotransformation

Cariprazine metabolism involves demethylation (to DCAR and DDCAR), hydroxylation (hydroxy-cariprazine, HCAR), and a combination of demethylation and hydroxylation (hydroxy-desmethyl-cariprazine, HDCAR, and hydroxy-didesmethyl-cariprazine, HDDCAR). Subsequently, the metabolites HCAR, HDCAR, and HDDCAR are biotransformed into corresponding sulfate and glucuronide conjugates. An additional metabolite, deschlorophenyl-piperazine-cariprazine acid (DDCPPCAR), is formed via dealkylation and subsequent oxidation of cariprazine.

Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6 to DCAR and HCAR. DCAR is further metabolized by CYP3A4 and to a lesser extent by CYP2D6 to DDCAR and HDCAR. DDCAR is then metabolized by CYP3A4 to HDDCAR.

Cariprazine and its major active metabolites are not substrates for P-glycoprotein (P-gp), organic anion transporting polypeptides 1B1 and 1B3 (OATP1B1 and OATP1B3), or breast cancer resistance protein (BCRP). Therefore, interactions between cariprazine and inhibitors of P-gp, OATP1B1, OATP1B3, or BCRP are considered unlikely.

Elimination

Elimination of cariprazine and its major active metabolites occurs primarily via hepatic metabolism. After administration of 12.5 mg/day cariprazine in patients with schizophrenia, 20.8% of the dose was excreted in urine as cariprazine and its metabolites.

Unchanged cariprazine is excreted in 1.2% of the dose in urine and 3.7% of the dose in feces.

The terminal elimination half-life (1–3 days for cariprazine and DCAR and 13–19 days for DDCAR) does not predict the time required to reach steady state or the decline in plasma concentration after discontinuation of treatment. For patients taking cariprazine, the effective half-life is more relevant than the terminal half-life. The effective (functional) half-life is approximately 2 days for cariprazine and DCAR, 8 days for DDCAR, and approximately 1 week for total cariprazine. Plasma concentrations of total cariprazine will gradually decrease after discontinuation or interruption of treatment. Plasma concentrations of total cariprazine decrease by 50% approximately 1 week after discontinuation, and a reduction of more than 90% occurs approximately 3 weeks after discontinuation.

Linearity

After repeated administration, plasma concentrations of cariprazine and its two major active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), increase proportionally within the therapeutic dose range of 1.5 mg to 6 mg.

Special patient groups

Renal impairment

Population pharmacokinetic modeling was performed using data from patients enrolled in a clinical study of cariprazine treatment for schizophrenia with varying degrees of renal function, including normal renal function (creatinine clearance (CrCl) ≥ 90 mL/min) and mild (CrCl 60–89 mL/min) and moderate (CrCl 30–59 mL/min) renal impairment. No significant relationship was observed between plasma clearance of cariprazine and creatinine clearance.

The effect of cariprazine has not been studied in patients with severe renal impairment (CrCl < 30 mL/min) (see section "Dosage and administration").

Hepatic impairment

A two-part study (single 1 mg dose of cariprazine [Part A] and 0.5 mg daily dose of cariprazine for 14 days [Part B]) was conducted in patients with varying degrees of hepatic impairment (Child-Pugh classes A and B). After administration of a single 1 mg dose of cariprazine or 14 days of 0.5 mg daily dosing, patients with mild or moderate hepatic impairment had approximately 25% higher cariprazine concentrations (Cmax and AUC) and approximately 45% lower concentrations of the major active metabolites, desmethyl-cariprazine and didesmethyl-cariprazine, compared to patients with normal hepatic function.

After multiple dosing, the total active component (CAR + DCAR + DDCAR) exposure (AUC and Cmax) decreased by 21–22% and 13–15%, respectively, in patients with mild or moderate hepatic impairment (HI) compared to patients with normal hepatic function when both bound and unbound concentrations were considered. For the unbound total component, a decrease of 12–13% and an increase of 20–25% were calculated in patients with mild and moderate HI, respectively.

The effect of cariprazine has not been studied in patients with severe hepatic impairment (Child-Pugh class C) (see section "Dosage and administration").

Age, gender, and race

In population pharmacokinetic analyses, there were no clinically significant differences in pharmacokinetic parameters (AUC and Cmax of cariprazine and its major active metabolites) based on age, gender, or race. The analysis included data from 2,844 patients of various races, including 536 patients aged 50–65 years and 933 female patients (see section "Dosage and administration"). Data in elderly patients (over 65 years) are limited.

Smoking

Since cariprazine is not a substrate for CYP1A2, smoking is not expected to influence the pharmacokinetics of cariprazine.

Potential effect of cariprazine on other medicinal products

Cariprazine and its major active metabolites did not induce the enzymes CYP1A2, CYP2B6, or CYP3A4 and were not inhibitors of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4 in vitro. Cariprazine and its major active metabolites are not inhibitors of the transporter proteins OATP1B1, OATP1B3, BCRP, organic cation transporter 2 (OCT2), or organic anion transporters 1 and 3 (OAT1 and OAT3) in vitro. DCAR and DDCAR were not inhibitors of the P-gp transporter protein, although cariprazine was an inhibitor of intestinal P-gp (see section "Interaction with other medicinal products and other forms of interaction").

Preclinical safety data

Cariprazine caused bilateral cataracts and secondary retinal changes (retinal detachment and bone-like degeneration of the retina) in dogs. The total exposure (AUC) of cariprazine achieved at the maximum no-observed-adverse-effect level (NOAEL) for ocular toxicity was 4.2 times higher than the clinical AUC at the maximum recommended human dose (MRHD) of 6 mg/day. Increased incidence of retinal degeneration/atrophy was observed in albino rats in a 2-year study at clinically relevant drug exposures.

Phospholipidosis was observed in the lungs of rats, dogs, and mice (with or without inflammation) and in the adrenal cortex of dogs at clinically relevant drug exposures. Lung inflammation was observed in dogs receiving cariprazine for 1 year, with NOAEL and corresponding AUC values exceeding those at the MRHD by 2.7 times (males) and 1.7 times (females). At the end of a 2-month drug-free period, no inflammation was observed at exposures 4.2 times higher than clinical exposure at the MRHD; however, inflammation persisted at higher doses.

Adrenal cortical hypertrophy was observed in rats (females only) at concentrations 4.1 times higher than those at the MRHD and at clinically relevant total plasma concentrations of cariprazine in mice. Reversible hypertrophy/hyperplasia and vacuolization/vesiculation of the adrenal cortex were observed in dogs, with a NOAEL 4.2 times higher than that at the MRHD.

In female rats, reduced fertility and mating index were observed at clinically relevant exposures based on mg/m² body surface area. No effect on male fertility was observed at exposures 4.3 times higher than clinical exposure at the MRHD.

Administration of cariprazine to rats during organogenesis caused developmental abnormalities, reduced offspring survival, and developmental delay at exposures lower than human exposure at the MRHD of 6 mg/day. In rabbits, cariprazine showed maternal toxicity but no fetal risk at exposures 5.8 times higher than clinical exposure at the MRHD.

Clinically relevant exposures to cariprazine administered to pregnant female rats during organogenesis, throughout pregnancy, and during lactation reduced postnatal survival, birth weight, and weaning weight in first-generation offspring. Additionally, in the absence of maternal toxicity, pallor, reduced body temperature, and developmental delay (underdevelopment of renal papillae and reduced auditory reflex in males) were observed in fetuses. Fertility in first-generation offspring was unaffected, but second-generation rats showed similar clinical signs and reduced body weight.

Cariprazine and its metabolites penetrated into the milk of lactating rats.

Clinical characteristics.

Indications.

For the treatment of schizophrenia in adult patients.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Concomitant use of a strong CYP3A4 inhibitor (see section "Interaction with other medicinal products and other forms of interaction").

Concomitant use of a strong or moderate CYP3A4 inducer (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Potential effect of other drugs on cariprazine

Metabolism of cariprazine and its main active metabolites, desmethyl-cariprazine (DCAR) and didesmethyl-cariprazine (DDCAR), is primarily mediated by CYP3A4, with minimal involvement of CYP2D6.

Inhibitors of CYP3A4

Ketoconazole, a strong CYP3A4 inhibitor, increases plasma levels of total cariprazine (cariprazine and its active metabolites) by 2-fold during short-term (4 days) concomitant use, when considering either unbound or unbound + bound components.

Due to the long elimination half-life of the active components of cariprazine, a further increase in plasma levels of total cariprazine may be expected during longer-term combination therapy. Therefore, co-administration of cariprazine with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated (see section "Contraindications").

Erythromycin (500 mg twice daily), a moderate CYP3A4 inhibitor, caused on average a 1.4-fold (range 1.03–2.32-fold) increase in plasma exposure of total cariprazine after 3 weeks of concomitant administration. Therefore, during concomitant use of cariprazine with a moderate CYP3A4 inhibitor (e.g., erythromycin, fluconazole, diltiazem, verapamil), individual response and tolerability should be monitored and, if necessary, the dose of cariprazine should be (temporarily) reduced, considering the potential for increased exposure. Due to the long elimination half-life of cariprazine and its active metabolites, initiation, discontinuation, or dose adjustment of a moderate CYP3A4 inhibitor may not be fully reflected in plasma drug levels within the first few weeks. Patients should be monitored for adverse reactions and treatment response for several weeks after starting or stopping concomitant medications or after any dose change of cariprazine.

Grapefruit juice should be avoided.

Inducers of CYP3A4

Concomitant administration of cariprazine with strong or moderate CYP3A4 inducers may lead to a significant reduction in total cariprazine exposure; therefore, co-administration of cariprazine with strong or moderate CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort (Hypericum perforatum), bosentan, efavirenz, etravirine, modafinil, nafcillin) is contraindicated (see section "Contraindications").

Inhibitors of CYP2D6

CYP2D6-mediated pathways play a minor role in cariprazine metabolism; the primary pathway is via CYP3A4 (see section "Pharmacokinetics"). Therefore, inhibitors of CYP2D6 are unlikely to have a clinically significant effect on cariprazine metabolism.

Potential effect of cariprazine on other drugs

P-glycoprotein (P-gp) substrates

Cariprazine is an inhibitor of P-gp in vitro at its theoretically highest intestinal concentration. The clinical implications of this effect are not fully understood; however, enhanced monitoring and dose adjustment may be required when using P-gp substrates with a narrow therapeutic index, such as dabigatran and digoxin.

Hormonal contraceptives

In a drug interaction study, 28-day treatment with cariprazine at a dose of 6 mg daily had no clinically relevant effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel).

Pharmacodynamic interactions

Due to its primary effects on the central nervous system, the medicinal product Reagila should be used cautiously in combination with other centrally acting medicinal products and alcohol.

Special precautions for use.

Suicidal thoughts and behavior

The possibility of suicidality (suicidal thoughts, suicide attempts, and completed suicide) is inherent to psychiatric disorders and is generally observed shortly after initiation or change of antipsychotic therapy. Antipsychotic therapy should be accompanied by close monitoring of patients at high risk.

Akathisia, agitation

Akathisia and agitation are adverse effects of antipsychotics that occur frequently. Akathisia is a movement disorder characterized by a subjective feeling of inner restlessness and an irresistible urge to be in constant motion, along with behaviors such as rocking while standing or sitting, lifting the foot as if marching in place, and crossing and uncrossing legs while sitting. Since cariprazine may cause akathisia and agitation, it should be used with caution in patients who are prone to or already exhibit symptoms of akathisia. Akathisia typically develops early in treatment; therefore, careful monitoring during the initial phase of therapy is essential. Prevention includes gradual dose escalation; therapeutic interventions may include slight dose reduction of cariprazine or use of medications for extrapyramidal symptoms. The dose may be adjusted depending on individual response and tolerability (see section "Adverse reactions").

Tardive dyskinesia

Tardive dyskinesia is a syndrome characterized by rhythmic involuntary movements predominantly affecting the tongue and/or face and may develop in patients treated with antipsychotics. If symptoms of tardive dyskinesia appear in a patient receiving cariprazine, consideration should be given to discontinuing the drug.

Parkinson's disease

When antipsychotics are administered to patients with Parkinson's disease, worsening of the underlying condition and exacerbation of Parkinson's disease symptoms may occur. Therefore, when prescribing cariprazine to patients with Parkinson's disease, physicians must carefully weigh the benefit-risk ratio.

Ocular symptoms/ cataract

In preclinical studies of cariprazine in dogs, lens opacities/ cataracts were observed (see sections "Adverse reactions" and "Preclinical safety data"). A causal relationship between lens changes/ cataracts observed during human studies and cariprazine use has not been established. However, patients who may develop symptoms potentially related to cataracts should be advised to undergo ophthalmological examination, and the need for continued treatment should be reassessed.

Neuroleptic Malignant Syndrome (NMS)

A potentially fatal condition known as neuroleptic malignant syndrome (NMS) has been reported with antipsychotic therapy. Clinical manifestations of NMS include hyperpyrexia, muscle rigidity, elevated serum creatine phosphokinase levels, altered mental status, and signs of autonomic dysfunction (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac arrhythmia). Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. If a patient develops symptoms suggestive of NMS, or develops unexplained high fever without other clinical features of NMS, cariprazine should be discontinued immediately.

Seizures and convulsions

Cariprazine should be used cautiously in patients with a history of seizures or conditions that may potentially lower the seizure threshold.

Elderly patients with dementia

The efficacy and safety of cariprazine in elderly patients with dementia have not been established. Therefore, the drug is not recommended for use in such patients due to an increased risk of overall mortality.

Risk of cerebrovascular adverse events (CVAE)

In randomized, placebo-controlled clinical trials in patients with dementia treated with certain atypical antipsychotics, the risk of cerebrovascular adverse events was approximately three times higher. The mechanism of this increased risk is unknown. An increased risk of CVAE cannot be excluded with other antipsychotics or in other patient populations. Cariprazine should be used cautiously in patients with risk factors for stroke.

Cardiovascular disorders

Blood pressure changes

Cariprazine may cause both orthostatic hypotension and hypertension (see section "Adverse reactions"). Cariprazine should be used cautiously in patients with a history of cardiovascular disorders who are predisposed to blood pressure fluctuations. Blood pressure should be monitored.

Electrocardiogram (ECG) changes

QT interval prolongation may occur in patients taking antipsychotics.

In a clinical study assessing QT interval prolongation, no QT prolongation was observed with cariprazine compared to placebo (see section "Pharmacodynamics"). In clinical trials, only a few cases of minor QT prolongation were reported with cariprazine (see section "Adverse reactions"). Therefore, cariprazine should be used cautiously in patients with a history of cardiovascular disease or familial QT prolongation, as well as in patients receiving medications known to prolong the QT interval (see section "Pharmacodynamics").

Venous thromboembolism (VTE)

Cases of VTE have been reported with antipsychotic use. Since patients taking antipsychotics often have acquired risk factors for VTE, all potential VTE risk factors should be identified before and during cariprazine treatment, and appropriate preventive measures should be taken.

Hyperglycemia and diabetes mellitus

Patients with diabetes mellitus or those with risk factors for developing diabetes (e.g., obesity, family history of diabetes) who initiate treatment with atypical antipsychotics should have serum glucose levels monitored. Adverse reactions related to glucose levels have been reported during clinical trials of cariprazine (see section "Pharmacodynamics").

Weight changes

Significant weight gain has been observed during cariprazine treatment. Patients should have their body weight monitored regularly (see section "Adverse reactions").

Concomitant use of moderate CYP3A4 inhibitors

Concomitant administration of cariprazine with moderate CYP3A4 inhibitors may lead to increased overall exposure to cariprazine. Monitoring of individual response and tolerability is recommended, and if necessary, the dose of cariprazine should be (temporarily) reduced, considering the potential increase in exposure (see section "Interaction with other medicinal products and other forms of interaction").

Excipients

Reagila, 3 mg, 4.5 mg, and 6 mg hard capsules, contain the azo dye Ponceau 4R (E 129), which may cause allergic reactions.

Use during pregnancy or breastfeeding.

Women of reproductive potential/ women using contraception

Women of reproductive potential should avoid pregnancy during treatment with Reagila. Female patients of reproductive potential must use highly effective contraceptive methods during treatment and for at least 10 weeks after the last dose of Reagila.

Pregnancy

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

Animal studies have shown reproductive toxicity, including developmental malformations in rats (see section "Preclinical safety data").

Reagila is not recommended during pregnancy and in women of reproductive potential who are not using effective contraception. Due to the slow elimination of active components after discontinuation of cariprazine, contraceptive methods should be used for at least 10 weeks after stopping treatment.

Neonates exposed to antipsychotics (including cariprazine) during the third trimester of pregnancy are at risk of developing adverse reactions such as extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration. Reported symptoms include agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress syndrome, and feeding disorders. The severity of these complications varies; while symptoms may resolve spontaneously in some cases, others may require intensive care treatment and prolonged hospitalization. Therefore, newborns should be closely monitored.

Breastfeeding

It is currently unknown whether cariprazine and its major metabolites are excreted in human milk. Cariprazine and its metabolites are excreted in the milk of lactating rats (see section "Preclinical safety data"). A potential effect on neonates/infants cannot be excluded. Breastfeeding must be discontinued during cariprazine treatment.

Fertility

The effect of cariprazine on human fertility has not been studied. In rat studies, reduced fertility and mating performance were observed in females (see section "Preclinical safety data").

Ability to affect reaction speed when driving or operating machinery.

Cariprazine has a mild to moderate effect on the ability of patients to drive or operate machinery. Patients should be cautioned against working with dangerous machinery, including driving, until they are fully confident that Reagila does not adversely affect them.

Method of Administration and Dosage

Dosage

The recommended initial dose of cariprazine is 1.5 mg once daily. The dose may subsequently be gradually increased by 1.5 mg, as needed, up to a maximum dose of 6 mg/day. The lowest effective dose should be maintained according to the physician's clinical assessment. Due to the long elimination half-life of cariprazine and its active metabolites, changes in dosing will not be fully reflected in plasma concentrations for several weeks. Patients should be monitored for the emergence of adverse reactions and response to treatment for several weeks after initiation of cariprazine and after each dosage adjustment (see section "Pharmacokinetics").

Switching from Other Antipsychotics to Cariprazine

When switching from other antipsychotics to cariprazine, a gradual cross-titration should be considered, with gradual discontinuation of the prior therapy while initiating cariprazine.

Switching from Cariprazine to Another Antipsychotic

When switching from cariprazine to another antipsychotic, gradual cross-titration is not required; the new antipsychotic may be initiated at its lowest dose while discontinuing cariprazine. Note that plasma concentrations of cariprazine and its active metabolites will decrease by approximately 50% within about 1 week (see section "Pharmacokinetics").

Missed Dose

If a dose is missed, the patient should take the missed tablet as soon as possible. However, if the next scheduled dose is due soon, the missed dose should be skipped and the next dose taken according to the regular schedule. A double dose should not be taken to compensate for a missed dose.

Special Patient Populations

Renal Impairment

Patients with mild to moderate renal impairment (creatinine clearance [CrCl] ≥ 30 mL/min and < 89 mL/min) do not require dose adjustments. The safety and efficacy of cariprazine in patients with severe renal impairment (CrCl < 30 mL/min) have not been evaluated. Cariprazine is not recommended in patients with severe renal impairment (see section "Pharmacokinetics").

Hepatic Impairment

Patients with mild to moderate hepatic impairment (Child–Pugh score 5–9) do not require dose adjustments. The safety and efficacy of cariprazine in patients with severe hepatic impairment (Child–Pugh score 10–15) have not been evaluated. Cariprazine is not recommended in patients with severe hepatic impairment (see section "Pharmacokinetics").

Elderly Patients

There are insufficient data on the use of cariprazine in elderly patients (≥ 65 years) to determine whether their response differs from younger patients (see section "Pharmacokinetics"). Dose selection for elderly patients should be cautious.

Method of Administration

The medicinal product Reagila should be administered orally once daily at the same time each day, regardless of food intake.

Alcohol consumption should be avoided during treatment with cariprazine (see section "Interaction with Other Medicinal Products and Other Forms of Interaction").

Children

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

Overdose

Symptoms

One case of accidental acute overdose (48 mg/day) has been reported. In this patient, orthostasis and sedative effects occurred. The patient fully recovered on the same day.

Management of Overdose

Management of overdose should be supportive, including maintenance of a patent airway, oxygenation, and ventilation, as well as symptomatic treatment. Cardiovascular monitoring should begin immediately and include electrocardiographic monitoring to detect possible arrhythmias. In the event of severe extrapyramidal symptoms, anticholinergic medications should be administered. Since cariprazine is highly protein-bound, hemodialysis is not expected to be effective in treating overdose. Close medical supervision and monitoring should continue until the patient recovers.

Cariprazine has no specific antidote.

Adverse reactions

The most commonly reported adverse reactions during treatment with cariprazine in the dose range of 1.5–6 mg were akathisia (19%) and parkinsonism (17.5%). Most of these reactions were of mild to moderate severity.

Tabulated list of adverse reactions

Adverse drug reactions (ADRs), based on pooled data from schizophrenia treatment studies with cariprazine, are listed by system organ class and using the preferred terms in Table 3.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from the available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Table 3. Adverse reactions occurring in patients with schizophrenia

System organ classes by MedDRA	Very common (≥ 1/10)	Common (from ≥ 1/100 to < 1/10)	Uncommon (from ≥ 1/1,000 to < 1/100)	Rare (from ≥ 1/10,000 to < 1/1,000)	Frequency not known
Blood and lymphatic system			Anaemia Eosinophilia	Neutropenia
Immune system				Increased sensitivity
Endocrine system			Decreased blood level of thyroid-stimulating hormone	Hypothyroidism
Metabolism and nutrition		Dyslipidaemia Increased body weight Decreased appetite Increased appetite	Abnormal blood sodium levels Diabetes mellitus Increased blood glucose
Psychiatric disorders		Sleep disorders1 Anxiety	Suicidal behaviour Delirium Depression Decreased libido Increased libido Erectile dysfunction
Nervous system	Akathisia2 Parkinsonism3	Sedation Dizziness Dystonia4 Other extrapyramidal and movement disorders5	Tardive dyskinesia Dyskinesia6 Dysesthesia Sluggishness	Seizures/ Convulsions Amnesia Aphasia	Malignant neuroleptic syndrome
Eye disorders		Blurred vision	Increased intraocular pressure Accommodation disorder Decreased visual acuity Eye irritation	Cataract Photophobia
Ear and labyrinth disorders			Vertigo
Cardiac disorders		Tachyarrhythmia	Cardiac conduction abnormalities Bradycardia QT interval prolongation on electrocardiogram Pathological T wave on electrocardiogram
Vascular disorders		Arterial hypertension	Arterial hypotension
Respiratory, thoracic and mediastinal disorders			Hiccups
Gastrointestinal disorders		Vomiting Nausea Constipation	Gastroesophageal reflux disease	Dysphagia
Hepatobiliary disorders		Elevated liver enzymes	Elevated blood bilirubin		Toxic hepatitis
Skin and subcutaneous tissue			Pruritus Rash
Musculoskeletal and connective tissue		Elevated blood creatine phosphokinase		Rhabdomyolysis
Renal and urinary disorders			Dysuria Frequency of urination
Pregnancy, puerperium and perinatal conditions					Neonatal abstinence syndrome (see section "Use during pregnancy or breastfeeding")
General disorders and administration site conditions		Fatigue	Thirst

1 Sleep disorders: insomnia, abnormal dreams, nightmares, circadian rhythm sleep disorder, dysomnia, hypersomnia, sleep onset disturbance, middle-of-the-night awakening, night terrors, sleep disorders, somnambulism, awakening disturbance.

2 Akathisia: akathisia, psychomotor hyperactivity, agitation.

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

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

5 Other extrapyramidal and movement disorders: impaired balance, bruxism, drooling, dysarthria, gait disturbance, abnormal glabellar reflex, hyporeflexia, movement disorders, restless legs syndrome, hypersalivation, tongue movement disorders.

6 Dyskinesia: choreoathetosis, dyskinesia, grimacing, gaze spasm, tongue protrusion.

Description of some adverse reactions

Lens opacity / Cataract

Cataract development was observed during preclinical studies of cariprazine (see section "Preclinical safety data"). Therefore, cataract formation was monitored using slit-lamp examinations, and patients with pre-existing cataracts were excluded from the study. During the clinical development program of cariprazine in patients with schizophrenia, several cases of cataract were reported, characterized by mild lens opacity without visual impairment (13/3192; 0.4%). Some of these patients had risk factors. The most frequently reported ocular adverse effect was blurred vision (placebo: 1/683, 0.1%; cariprazine: 22/2048, 1.1%).

Extrapyramidal symptoms (EPS)

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

In the placebo-controlled phase of the long-term maintenance study, the incidence of EPS was 13.7% in the cariprazine group compared to 3.0% in the placebo group. Akathisia occurred in 3.9% of patients treated with cariprazine versus 2.0% in the placebo group. Parkinsonism was observed in 7.8% and 1.0% in the cariprazine and placebo groups, respectively.

In the study on negative symptoms, EPS were reported in 14.3% of the cariprazine group and 11.7% of the risperidone group. Akathisia occurred in 10.0% of patients treated with cariprazine and 5.2% in the risperidone group. Parkinsonism occurred in 5.2% and 7.4% in the cariprazine and risperidone groups, respectively. Most EPS cases were mild to moderate in severity and were managed with standard medications for EPS treatment. The discontinuation rate due to EPS related to the investigational product was low.

Venous thromboembolism (VTE)

Cases of VTE, including pulmonary embolism and deep vein thrombosis, have been reported with the use of antipsychotics. Frequency is unknown.

Elevated liver transaminases

Elevated liver transaminase levels (alanine aminotransferase (ALT), aspartate aminotransferase (AST)) are commonly observed during antipsychotic treatment. In clinical studies of cariprazine, increases in ALT and AST levels occurred in 2.2%, 1.6%, and 0.4% of patients treated with cariprazine, risperidone, and placebo, respectively. None of the patients treated with cariprazine had any evidence of liver injury.

Changes in body weight

In short-term studies, slightly greater mean increases in body weight were observed in the cariprazine group compared to the placebo group: 1 kg and 0.3 kg, respectively. In long-term maintenance studies, there was no clinically significant difference in body weight change from baseline to end of treatment (1.1 kg with cariprazine and 0.9 kg with placebo). During the 20-week open-label phase of the study, potentially clinically significant (PCS) weight gain (defined as ≥ 7% increase) occurred in 9.0% of patients treated with cariprazine. During the subsequent 20-week double-blind phase following open-label cariprazine treatment, PCS weight gain occurred in 9.8% of patients continuing cariprazine versus 7.1% of patients randomized to placebo. In the study on negative symptoms, mean body weight change was –0.3 kg in the cariprazine group and +0.6 kg in the risperidone group, and PCS weight gain occurred in 6% of patients in the cariprazine group and 7.4% of patients in the risperidone group.

QT interval prolongation

In a clinical study assessing QT interval prolongation with cariprazine, no QT prolongation was observed compared to placebo (see section "Pharmacodynamics"). In other clinical studies, only a few cases of minor QT prolongation were reported with cariprazine. During long-term open-label treatment, 3 patients (0.4%) had a Bazett-corrected QT interval > 500 ms, and one of them also had a Fridericia-corrected QT interval > 500 ms. QT prolongation of > 60 ms from baseline in the Bazett-corrected QT interval was observed in 7 patients (1%), and in the Fridericia-corrected QT interval in 2 patients (0.3%). In the long-term maintenance study, during the open-label phase, QT prolongation of > 60 ms from baseline in the Bazett-corrected QT interval was observed in 12 patients (1.6%), and in the Fridericia-corrected QT interval in 4 patients (0.5%). During the double-blind treatment phase, QT prolongation of > 60 ms from baseline in the Bazett-corrected QT interval was observed in 3 patients (3.1%) treated with cariprazine and in 2 patients (2%) receiving placebo.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.

Shelf life.

5 years.

Storage conditions.

Keep in the original packaging to protect from light.

The medicinal product does not require special storage temperature conditions.

Keep out of the reach of children.

Packaging.

1.5 mg or 3 mg: 7 capsules in a blister; 1 or 4 blisters in a cardboard box.

4.5 mg or 6 mg: 7 capsules in a blister; 4 blisters in a cardboard box.

Prescription category.

Prescription only.

Manufacturer.

Gedeon Richter Plc., Hungary.

Manufacturer's address and location of its business operations.

H-1103 Budapest, Demréni Street 19-21, Hungary.