Luranis

INSTRUCTION for medical use of the medicinal product LURANIA® (Lurania)

Composition:

Active substance: lurazidone;

One film-coated tablet contains 20 mg of lurazidone hydrochloride, equivalent to 18.62 mg of lurazidone, or 40 mg of lurazidone hydrochloride, equivalent to 37.24 mg of lurazidone, or 80 mg of lurazidone hydrochloride, equivalent to 74.49 mg of lurazidone;

Excipients:

Intragranular: microcrystalline cellulose 101 (E 460), mannitol (E 421), hypromellose 2910 low-viscosity type E (E 464), sodium croscarmellose (E 468);

Extragranular: microcrystalline cellulose 102 (E 460), sodium croscarmellose (E 468), magnesium stearate (E 572);

Film coating of 18.5 mg and 37 mg tablets: hypromellose 2910 (E 464), titanium dioxide (E 171), polyethylene glycol MW 8000 (E 1521);

Film coating of 74 mg tablets: hypromellose 2910 (E 464), titanium dioxide (E 171), macrogol MW 8000 (E 1521), iron oxide yellow (E 172), FD&C blue № 2/lakes indigocarmine aluminum brilliant (E 132).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

18.5 mg: round film-coated tablets, white or almost white, with "LL" imprint on one side, smooth on the other side, 6.1 mm in diameter;

37 mg: round film-coated tablets, white or almost white, with "LI" imprint on one side, smooth on the other side, 8.1 mm in diameter;

74 mg: oval film-coated tablets, pale green to green, with "LH" imprint on one side, smooth on the other side, 12.1×7.1 mm in size.

Pharmacotherapeutic group. Antipsychotics. Indole derivatives. Lurasidone.

ATC code N05AE05.

Pharmacological Properties

Pharmacodynamics

Mechanism of action. Lurasidone is a selective blocker of dopamine and monoamine effects. Lurasidone binds with high affinity to dopaminergic D2 and serotonergic 5-HT2A and 5-HT7 receptors, with binding affinities of 0.994, 0.47, and 0.495 nM, respectively. It also blocks α2c-adrenergic and α2a-adrenergic receptors with binding affinities of 10.8 and 40.7 nM, respectively. Lurasidone also exhibits partial agonism at the 5-HT1A receptor with a binding affinity of 6.38 nM. Lurasidone does not bind to histaminergic or muscarinic receptors.

The mechanism of action of the minor active metabolite of lurasidone, ID-14283, is similar to that of lurasidone.

Doses of lurasidone ranging from 9 to 74 mg administered to healthy subjects caused dose-dependent reductions in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate nucleus, putamen, and ventral striatum, as measured by positron emission tomography.

Pharmacodynamic effects

In pivotal clinical efficacy studies, lurasidone was administered at doses of 37–148 mg.

Clinical efficacy

The efficacy of lurasidone in the treatment of schizophrenia was demonstrated in five multicenter, placebo-controlled, double-blind, 6-week studies involving subjects meeting the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). Lurasidone doses varied across the five studies from 37 to 148 mg once daily. In the short-term studies, the primary efficacy endpoint was defined as the mean change from baseline to Week 6 in total scores on the Positive and Negative Syndrome Scale (PANSS)—a validated multi-item questionnaire consisting of five factors used to assess positive symptoms, negative symptoms, disorganized thinking, uncontrolled hostility/agitation, and anxiety/depression. Lurasidone showed superior efficacy compared to placebo in three Phase 3 studies (see Table 1). Lurasidone demonstrated significant separation from placebo as early as Day 4. Furthermore, lurasidone was superior to placebo on a pre-specified secondary endpoint—the Clinical Global Impressions Severity scale (CGI-S). Efficacy was also confirmed in a secondary analysis of treatment response (defined as ≥30% reduction from baseline in PANSS total score).

Schizophrenia study in adults: Positive and Negative Syndrome Scale (PANSS) total score — change from baseline to Week 6 — MMRM method for studies D1050229, D1050231, and D1050233: intent-to-treat analysis

Table 1

Study statistics	Placebo	Lurasidone dose (b)				Active control (a)
		37 mg	74 mg	111 mg	148 mg
Study D1050229 Baseline mean (SD — standard deviation) Mean change, calculated by LS [least squares] (SE — standard error) Treatment difference compared to placebo Estimate (SE) p-value	N = 124 96.8 (11.1) -17.0 (1.8) -- --	N = 121 96.5 (11.6) -19.2 (1.7) -2.1 (2.5) 0.591	N = 118 96.0 (10.8) -23.4 (1.8) -6.4 (2.5) 0.034	N = 123 96.0 (9.7) -20.5 (1.8) -3.5 (2.5) 0.391	-- -- -- -- --	-- -- -- -- --
Study D1050231 Baseline mean (SD) Mean change, calculated by LS (SE) Treatment difference compared to placebo Estimate (SE) p-value	N = 114 95.8 (10.8) -16.0 (2.1) -- --	N = 118 96.6 (10.7) -25.7 (2.0) -9.7 (2.9) 0.002	-- -- -- -- --	N = 118 97.9 (11.3) -23.6 (2.1) -7.5 (3.0) 0.022	-- -- -- -- --	N = 121 96.3 (12.2) -28.7 (1.9) -12.6 (2.8) <0.001
Study D1050233 Baseline mean (SD) Mean change, calculated by LS (SE) Treatment difference compared to placebo Estimate (SE) p-value	N = 120 96.6 (10.2) -10.3 (1.8) -- --	-- -- -- -- --	N = 125 97.7 (9.7) -22.2 (1.8) -11.9 (2.6) <0.001	-- -- -- -- --	N = 121 97.9 (11.8) -26.5 (1.8) -16.2 (2.5) <0.001	N = 116 97.7 (10.2) -27.8 (1.8) -17.5 (2.6) <0.001

(a) Olanzapine 15 mg in study D1050231, extended-release quetiapine 600 mg in study D1050233. N — number of subjects in the model-based assessment.

(b) p-values for lurasidone compared to placebo were adjusted for multiple comparisons. p-values for olanzapine and extended-release quetiapine compared to placebo were not adjusted.

In short-term studies, a consistent dose-response relationship was not observed.

Long-term maintenance of efficacy of lurasidone (37 to 148 mg lurasidone once daily) was demonstrated in a 12-month non-inferiority study versus extended-release quetiapine (200 to 800 mg once daily). Lurasidone was non-inferior to extended-release quetiapine in time to relapse of schizophrenia. With lurasidone treatment, there was a small increase in body weight and body mass index from baseline to 12 months (mean (SD): 0.73 (3.36) kg and 0.28 (1.17) kg/m², respectively) compared to extended-release quetiapine (1.23 (4.56) kg and 0.45 (1.63) kg/m², respectively). Overall, lurasidone had minimal effects on weight and other metabolic parameters, including levels of total cholesterol, triglycerides, and glucose.

In a long-term safety study, clinically stable patients received treatment with 37–111 mg lurasidone or 2–6 mg risperidone. In this study, the relapse rate over the 12-month period was 20% with lurasidone and 16% with risperidone. This difference approached statistical significance but did not reach it.

In a long-term study designed to evaluate maintenance of effect, lurasidone was superior to placebo in maintaining control of symptoms and delaying relapse of schizophrenia. After treatment of an acute episode and stabilization for at least 12 weeks with lurasidone, patients were randomized in a double-blind manner to continue lurasidone or switch to placebo until relapse of schizophrenia symptoms occurred. The primary analysis of time to relapse was conducted using censoring of data from patients who completed the study prior to relapse. A significantly longer relapse-free duration was observed in patients receiving lurasidone compared to those in the placebo group (p=0.039). The Kaplan-Meier estimate of relapse probability at Week 28 was 42.2% in the lurasidone group and 51.2% in the placebo group. The probability of discontinuation for any reason by Week 28 was 58.2% with lurasidone and 69.9% with placebo (p = 0.072).

Pediatric population

Schizophrenia. The efficacy of lurasidone was established in a 6-week, randomized, double-blind, placebo-controlled study involving adolescents (13 to 17 years of age) meeting DSM-IV-TR criteria for schizophrenia (N = 326). Patients were randomized to receive one of two fixed doses of lurasidone (37 or 74 mg/day) or placebo.

The primary instrument for assessing psychiatric signs and symptoms was the PANSS scale. The primary secondary instrument was the CGI-S scale.

In both lurasidone dose groups, lurasidone was superior to placebo in reduction of PANSS and CGI-S scores at Week 6. Overall, the 74 mg/day dose did not provide additional benefit compared to the 37 mg/day dose.

Primary efficacy results are presented in Table 2.

Primary efficacy results (PANSS total score) — change from baseline to Week 6 — MMRM method for adolescent schizophrenia study D1050301: intent-to-treat analysis set

Table 2

Study statistics	Placebo	Lu AA21054 dose (a)
		37 mg	74 mg
Study D1050301 Baseline mean (SD) Least-squares mean change (SE) Difference vs placebo Estimate (SE) p-value	N = 112 92.8 (11.08) -10.5 (1.59) -- --	N = 108 94.5 (10.97) -18.6 (1.59) -8.0 (2.21) 0.0006	N = 106 94.0 (11.12) -18.3 (1.60) -7.7 (2.22) 0.0008

N — number of subjects per model-based estimate.

(a) p-values for lurasidone compared to placebo were adjusted for multiple comparisons.

Improvement in CGI-S scores at Week 6 was significantly different from placebo both in the group treated with lurasidone 74 mg/day (–0.42 ± 0.130, adjusted p = 0.0015) and in the group treated with lurasidone 37 mg/day (–0.47 ± 0.130, adjusted p = 0.0008).

A 104-week extension study (Study D1050302) was designed to evaluate the long-term safety, tolerability, and efficacy of flexible-dose lurasidone (18.5, 37, 55.5, or 74 mg/day) in pediatric patients who completed the 6-week treatment period in three prior studies across various indications. Only results from the 271 patients with schizophrenia who were enrolled in Study D1050301 are presented below. Of these, 186 patients (68.6%) completed 52 weeks of treatment, and 156 (57.6%) completed 104 weeks of flexible-dose lurasidone treatment ranging from 18.5 to 74 mg/day.

In participants who continued treatment from Study D1050301, the mean change (95% CI [confidence interval]) from baseline of the double-blind study in PANSS score was –26.5 (–28.5, –24.5) at Week 28 (LOCF method), –28.2 (–30.2, –26.2) at Week 52 (LOCF), and –29.5 (–31.8, –27.3) at Week 104 (LOCF / end-of-open-label treatment [OL]); the mean change (95% CI) from OL baseline was –9.2 (–11.1, –7.2) at Week 28 (LOCF), –10.8 (–13.0, –8.7) at Week 52 (LOCF), and –12.2 (–14.5, –9.8) at the Week 104 endpoint (LOCF / post-OL).

Bipolar Depression. Short-term efficacy of lurasidone was evaluated in a 6-week, multicenter, randomized, double-blind, placebo-controlled study involving children and adolescents (10–17 years of age) who met Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for a major depressive episode associated with bipolar I disorder, with or without rapid cycling, and without psychotic features (N = 350). Patients were randomized to receive flexible-dose lurasidone 18–74 mg once daily or placebo.

The primary efficacy endpoint was defined as the mean change from baseline to Week 6 in the total score on the Children's Depression Rating Scale–Revised (CDRS-R). A key secondary efficacy endpoint was the assessment of depression using the Clinical Global Impressions–Bipolar Version, Severity of Illness (CGI-BP-S). Statistically significant differences favoring lurasidone over placebo were demonstrated for these endpoints in the overall study population starting at Week 2 and were maintained at each visit throughout the study. However, the primary and key secondary efficacy endpoints were not met in younger patients (under 15 years of age). The placebo-adjusted mean change (95% CI), analyzed by MMRM, from baseline to Week 6 on the CDRS-R scale was –1.8 (–5.6; 2.0) in patients aged 10 to 14 years and –8.6 (–12.4; –4.8) in patients aged 15 to 17 years (see Table 3).

The safety profile of lurasidone in children included in this short-term study was generally consistent with that observed in adults treated for approved indications; however, differences in the frequency of the most common adverse reactions were observed in pediatric patients compared to adults: nausea (very common), diarrhea (common), and decreased appetite (common), compared to adults (common, unknown, and uncommon, respectively).

Study of Bipolar Depression in the Pediatric Population: Children's Depression Rating Scale–Revised (CDRS-R), total score, and Clinical Global Impressions–Bipolar Version, Severity of Illness (CGI-BP-S) depression assessment — change from baseline to Week 6 — MMRM method for Study D1050326: Intent-to-Treat Analysis Set

Table 3

Parameters	Study statistics	Placebo	Luvoxidone dose 18.5–74 mg (a) (b)
Primary endpoint: total CDRS-R score		N = 170	N = 173
	Baseline mean (SD)	58.6 (8.26)	59.2 (8.24)
	Mean change, calculated by ANCOVA (SE)	-15.3 (1.08)	-21.0 (1.06)
	Treatment difference compared to placebo
	Estimate (SE; 95% CI)	--	-5.7 (1.39; from -8.4 to -3.0)
	p-value	--	< 0.0001
Key secondary endpoint: CGI-BP-S depression rating		N = 170	N = 173
	Baseline mean (SD)	4.5	4.6
	Mean change, calculated by ANCOVA (SE)	-1.05 (0.087)	-1.49 (0.085)
	Treatment difference compared to placebo
	Estimate (SE; 95% CI)	--	-0.44 (0.112; from -0.66 to -0.22)
	p-value	--	< 0.0001

N — number of subjects studied.

(a) p-values for lurasidone compared to placebo were adjusted for multiple comparisons.

(b) Lurasidone doses of 18.5, 37, 55.5, and 74 mg are equivalent to 20, 40, 60, and 80 mg of lurasidone hydrochloride, respectively.

Pharmacokinetics

Absorption. Lurasidone reaches peak serum concentrations within 1–3 hours.

In a food-effect study, mean Cmax and AUC values of lurasidone increased approximately 2–3 times and 1.5–2 times, respectively, when administered with food compared to fasting conditions.

Distribution. Following a 37 mg dose of lurasidone, the mean apparent volume of distribution was approximately 6000 L. Lurasidone is highly bound (~99%) to serum proteins.

Biotransformation. Lurasidone is primarily metabolized by CYP3A4. The main biotransformation pathways are oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation.

Lurasidone is metabolized to form two active metabolites (ID-14283 and ID-14326) and two inactive metabolites (ID-20219 and ID-20220). Lurasidone and its metabolites ID-14283, ID-14326, ID-20219, and ID-20220 account for approximately 11.4, 4.1, 0.4, 24, and 11% of serum concentrations, respectively.

CYP3A4 is the primary enzyme responsible for the metabolism of the active metabolite ID-14283.

Lurasidone and its active metabolite ID-14283 contribute to the pharmacodynamic activity at dopaminergic and serotonergic receptors.

Based on in vitro studies, lurasidone is not a substrate for CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP2E1 enzymes.

In vitro, lurasidone did not show direct or time-dependent inhibition (IC50 > 5.9 µM) of cytochrome P450 (CYP) enzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Based on these data, lurasidone is not expected to affect the pharmacokinetics of drugs that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP2E1. Regarding concomitant use of drugs that are CYP3A4 substrates with a narrow therapeutic index, see section "Interaction with other medicinal products and other forms of interaction".

Lurasidone is a substrate in vitro for efflux transporters P-gp and BCRP. Lurasidone does not undergo active transport via OATP1B1 or OATP1B3.

Lurasidone is an inhibitor of P-gp, BCRP, and OCT1 in vitro (see section "Interaction with other medicinal products and other forms of interaction"). Based on in vitro data, lurasidone is not expected to clinically significantly inhibit transporters OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2K, or BSEP.

Elimination. After administration, the elimination half-life of lurasidone ranged from 20 to 40 hours. Following oral administration of a radiolabeled dose, approximately 67% of the dose was excreted in feces and 19% in urine. Urine contained predominantly metabolites with minimal amounts of parent compound.

Linearity/Non-linearity. The pharmacokinetics of lurasidone are dose-proportional over the total daily dose range of 18.5 mg to 148 mg. Steady-state concentrations of lurasidone are achieved within 7 days after initiation of dosing.

Pharmacokinetics in special patient populations

Elderly. Limited data are available in healthy subjects aged ≥65 years. According to these data, lurasidone exposure was similar to that in subjects aged <65 years. However, increased exposure may be expected in elderly patients with impaired renal or hepatic function.

Hepatic impairment. Serum concentrations of lurasidone increase in healthy subjects with Child-Pugh classes A, B, and C hepatic impairment, with exposure increased by 1.5, 1.7, and 3 times, respectively.

Renal impairment. Serum concentrations of lurasidone increase in healthy subjects with mild, moderate, and severe renal impairment, with exposure increased by 1.5, 1.9, and 2 times, respectively. Patients with chronic renal failure (GFR [glomerular filtration rate] <15 mL/min) have not been studied.

Gender. In a population pharmacokinetic analysis of lurasidone pharmacokinetics in patients with schizophrenia, no clinically significant differences were observed between genders.

Race. No clinically significant differences in lurasidone pharmacokinetics were identified in a population pharmacokinetic analysis in patients with schizophrenia. However, exposure to lurasidone was observed to be 1.5 times higher in Asian patients compared to Caucasian patients.

Smoking. Based on in vitro studies using human liver enzymes, lurasidone is not a substrate for CYP1A2; therefore, smoking is not expected to affect lurasidone pharmacokinetics.

Pediatric population. The pharmacokinetics of lurasidone in pediatric patients were evaluated in 47 children aged 6–12 years and 234 adolescents aged 13–17 years. Lurasidone was administered as lurasidone hydrochloride at daily doses of 20, 40, 80, 120 mg (6–17 years) or 160 mg (10–17 years) for 42 days. No clear correlation was observed between serum concentration and age or body weight. The pharmacokinetics of lurasidone in children aged 6 to 17 years were generally comparable to those in adults.

Clinical Characteristics

Indications. For the treatment of schizophrenia in adults and adolescents aged 13 years and older.

Contraindications

• Hypersensitivity to the active substance or to any of the excipients of Luania®.
• Concomitant use of strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort [Hypericum perforatum]) (see section "Interaction with other medicinal products and other types of interactions").

Interaction with other medicinal products and other types of interactions

Pharmacodynamic interactions. Given the primary effect of lurasidone on the central nervous system, lurasidone should be used with caution in combination with other centrally acting medicinal products and alcohol.

Lurasidone should be prescribed with caution together with medicinal products that prolong the QT interval, particularly class IA (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), certain antihistamines, certain other antipsychotics, and certain antimalarial agents (e.g., mefloquine).

Lurasidone should be used with caution in combination with other serotonergic agents such as buprenorphine/opioids, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, due to an increased risk of serotonin syndrome, a potentially life-threatening condition (see section "Special precautions for use").

Pharmacokinetic interactions. The concomitant use of lurasidone and grapefruit juice has not been studied. Grapefruit juice inhibits CYP3A4 and may increase lurasidone serum concentrations. Consumption of grapefruit juice should be avoided during treatment with lurasidone.

Potential effect of other medicinal products on lurasidone. Lurasidone and its active metabolite ID-14283 contribute to the pharmacodynamic effects on dopaminergic and serotonergic receptors. Lurasidone and its active metabolite ID-14283 are metabolized primarily via CYP3A4.

CYP3A4 inhibitors

Lurasidone is contraindicated with strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) (see section "Contraindications").

Concomitant administration of lurasidone with the strong CYP3A4 inhibitor ketoconazole resulted in a 9-fold and 6-fold increase in exposure to lurasidone and its active metabolite ID-14283, respectively.

Concomitant use of lurasidone and posaconazole (a strong CYP3A4 inhibitor) resulted in approximately a 4–5 fold increase in lurasidone exposure. The effect of posaconazole on lurasidone exposure persisted for up to 2–3 weeks after discontinuation of posaconazole.

Concomitant use of lurasidone with medicinal products that moderately inhibit CYP3A4 (e.g., diltiazem, erythromycin, fluconazole, verapamil) may increase lurasidone exposure. Moderate CYP3A4 inhibitors are estimated to increase exposure to CYP3A4 substrates by 2–5 fold.

Concomitant use of lurasidone with diltiazem (extended-release formulation), a moderate CYP3A4 inhibitor, resulted in a 2.2-fold and 2.4-fold increase in exposure to lurasidone and ID-14283, respectively (see section "Method of administration and dosage"). Use of immediate-release diltiazem formulations may lead to even greater increases in lurasidone exposure.

CYP3A4 inducers

Lurasidone is contraindicated with strong CYP3A4 inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort [Hypericum perforatum]) (see section "Contraindications").

Concomitant use of lurasidone with the strong CYP3A4 inducer rifampicin resulted in a 6-fold decrease in lurasidone exposure.

Use of lurasidone with weak (e.g., armodafinil, amprenavir, aprepitant, prednisone, rufinamide) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) CYP3A4 inducers is expected to reduce lurasidone exposure by more than 2-fold during concomitant use and for up to 2 weeks after discontinuation of weak or moderate CYP3A4 inducers.

When lurasidone is used concomitantly with weak or moderate CYP3A4 inducers, careful monitoring of lurasidone efficacy is recommended, and dose adjustment may be necessary.

Transporters

Lurasidone is a substrate of P-gp (P-glycoprotein) and BCRP (breast cancer resistance protein) in vitro, but the clinical relevance of this is unclear in vivo. Concomitant use of lurasidone with inhibitors of P-gp and BCRP may increase lurasidone exposure.

Potential effect of lurasidone on other medicinal products

Concomitant use of lurasidone with midazolam, a sensitive CYP3A4 substrate, resulted in more than a 1.5-fold increase in midazolam exposure. Appropriate monitoring is recommended when lurasidone is used concomitantly with CYP3A4 substrates that have a narrow therapeutic index (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids [ergotamine, dihydroergotamine]).

Concomitant administration of lurasidone with digoxin (a P-gp substrate) did not increase digoxin exposure and only slightly increased Cmax (by 1.3-fold); therefore, lurasidone can be considered suitable for concomitant use with digoxin. Lurasidone is an inhibitor of the efflux transporter P-gp in vitro, and clinically significant inhibition of intestinal P-gp cannot be excluded. Concomitant use of the P-gp substrate dabigatran etexilate may lead to increased plasma concentrations of dabigatran.

Lurasidone is an inhibitor of the efflux transporter BCRP in vitro, and clinically significant inhibition of intestinal BCRP cannot be excluded. Concomitant use of BCRP substrates may lead to increased plasma concentrations of these substrates.

Concomitant use of lurasidone with lithium showed that lithium has a clinically insignificant effect on the pharmacokinetics of lurasidone; therefore, dose adjustment of lurasidone is not required when used concomitantly with lithium. Lurasidone does not affect lithium concentrations.

In a clinical study evaluating the effect of concomitant use of lurasidone and combined oral contraceptives, specifically norgestimate and ethinyl estradiol, lurasidone did not have a clinically or statistically significant effect on the pharmacokinetics of the contraceptive or on sex hormone-binding globulin levels. Therefore, lurasidone may be used concomitantly with oral contraceptives.

Special precautions for use

Improvement in the patient's clinical condition during treatment with antipsychotics may take from several days to several weeks. During this period, patients should remain under close supervision.

Suicidal behavior. Suicidal behavior is inherent to psychiatric disorders, and in some cases has been reported in the early stages after initiation or change of antipsychotic therapy. Antipsychotic therapy should be accompanied by careful monitoring of patients at high risk.

Parkinson's disease. In patients with Parkinson's disease, antipsychotic drugs may exacerbate the core symptoms of parkinsonism. Therefore, physicians should carefully weigh the risks and benefits when prescribing lurasidone to patients with Parkinson's disease.

Extrapyramidal symptoms (EPS). Medicinal products that are dopamine receptor antagonists have been associated with extrapyramidal adverse reactions, including rigidity, tremor, mask-like face, dystonia, drooling, stooping posture, and gait disturbances. In placebo-controlled clinical trials in adult patients with schizophrenia, an increased incidence of EPS was observed after treatment with lurasidone compared to placebo.

Tardive dyskinesia. Medicinal products that are dopamine receptor antagonists are associated with induction of tardive dyskinesia, characterized by rhythmic involuntary movements, predominantly of the tongue and/or face. If symptoms of tardive dyskinesia occur, discontinuation of all antipsychotic agents, including lurasidone, should be considered.

Cardiovascular disorders / QT interval prolongation. Lurasidone should be prescribed cautiously to patients with cardiovascular diseases or a family history of QT interval prolongation, patients with hypokalemia, and when used concomitantly with other medicinal products that prolong the QT interval.

Seizures. Lurasidone should be used with caution in patients with a history of seizures or other conditions that may potentially lower the seizure threshold.

Neuroleptic malignant syndrome (NMS). Cases of neuroleptic malignant syndrome, characterized by hyperthermia, muscle rigidity, autonomic instability, altered consciousness, and elevated serum creatine phosphokinase levels, have been reported with lurasidone. Additional features may include myoglobinuria (rhabdomyolysis) and acute renal failure. In such cases, lurasidone should be discontinued.

Elderly patients with dementia. Lurasidone has not been studied in elderly patients with dementia.

Overall mortality. In a meta-analysis of 17 controlled clinical trials in elderly patients with dementia who received other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine, an increased risk of mortality was observed compared to placebo.

Cerebrovascular events. In randomized, placebo-controlled clinical trials in a population of patients with dementia, treatment with certain atypical antipsychotics, including risperidone, aripiprazole, and olanzapine, was associated with approximately a threefold increased risk of cerebrovascular adverse reactions. The mechanism of this increased risk is unknown. An increased risk cannot be excluded when other antipsychotics are used or in other patient populations. Lurasidone should be used with caution in elderly patients with dementia who have risk factors for stroke.

Venous thromboembolism (VTE). Cases of venous thromboembolism (VTE) have been reported with the use of antipsychotic medicinal products. Since patients treated with antipsychotics often have acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with lurasidone, and preventive measures should be taken.

Hyperprolactinemia. Lurasidone increases prolactin levels due to antagonism of dopamine D2 receptors. Patients should be advised about symptoms of elevated prolactin levels, such as gynecomastia, galactorrhea, amenorrhea, and erectile dysfunction. Patients should be instructed to seek medical attention if they experience any such symptoms.

Weight gain. Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of body weight is recommended.

Hypoglycemia. In clinical trials of lurasidone, rare adverse reactions related to glucose, such as increased blood glucose levels, have been reported. Appropriate clinical monitoring is recommended for patients with diabetes mellitus and for patients with risk factors for developing diabetes.

Orthostatic hypotension / syncope. Lurasidone may cause orthostatic hypotension, possibly due to α1-adrenergic receptor antagonism. Monitoring of orthostatic vital signs should be considered in patients predisposed to hypotension.

Interaction with grapefruit juice. Grapefruit juice should be avoided during treatment with lurasidone (see section "Interaction with other medicinal products and other forms of interaction").

Serotonin syndrome. Concomitant use of lurasidone and other serotonergic agents, such as buprenorphine/opioids, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants, may lead to serotonin syndrome, a potentially life-threatening condition (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant treatment with other serotonergic agents is clinically justified, close monitoring of the patient is recommended, especially at the beginning of treatment and when increasing the dose.

Symptoms of serotonin syndrome may include changes in mental status, autonomic instability, neuromuscular disturbances, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, consideration should be given to reducing the dose or discontinuing therapy, depending on the severity of symptoms.

Use during pregnancy or breastfeeding

Pregnancy. Data on the use of lurasidone in pregnant women are lacking or limited (fewer than 300 pregnancy outcomes). Animal studies on the effects on pregnancy, embryonic/fetal development, delivery, and postnatal development are insufficient. The potential risk to humans is unknown. Lurasidone should not be used during pregnancy except in cases of clear medical necessity.

Newborns exposed to antipsychotics (including lurasidone) during the third trimester are at risk of developing adverse reactions, including extrapyramidal symptoms and/or withdrawal symptoms, which may vary in severity and duration after delivery. Cases of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorders have been reported. Therefore, newborns should be closely monitored.

Breastfeeding. Lurasidone was excreted in the milk of lactating rats. It is unknown whether lurasidone or its metabolites are excreted in human milk. The use of lurasidone in women who are breastfeeding should only be considered if the potential benefit of treatment justifies the potential risk to the infant.

Fertility. Animal studies have shown several effects on fertility, primarily related to increased prolactin levels, which are not considered relevant to human reproductive function.

Ability to influence reaction speed when driving vehicles or operating machinery

Lurasidone has a minor influence on the ability to drive or operate machinery. Patients should be advised not to drive or operate dangerous machinery, including motor vehicles and bicycles, until they are sufficiently assured that lurasidone does not adversely affect them (see section "Adverse reactions").

Dosage and Administration

Adults

The recommended initial dose is 37 mg of lurazidone once daily. Dose titration of the initial dose is not required. The drug is effective in the dose range of 37 to 148 mg once daily. Dose increases should be based on physician assessment and observed clinical response. The daily dose should not exceed 148 mg.

For patients taking doses higher than 111 mg once daily who discontinue treatment for more than 3 days, treatment should be resumed at a dose of 111 mg once daily and titrated to the optimal dose. If the dose does not exceed 111 mg, patients may resume treatment at the previous dose without titration.

Children

The recommended initial dose is 37 mg of lurazidone once daily. Dose titration of the initial dose is not required. The drug is effective in the dose range of 37 to 74 mg once daily. Dose increases should be based on physician assessment and observed clinical response. The daily dose should not exceed 74 mg. Lurazidone should be prescribed to children by a specialist in child psychiatry.

Dose Adjustment for Drug Interactions

When co-administered with moderate CYP3A4 inhibitors, the recommended initial dose of lurazidone is 18.5 mg, and the maximum dose is 74 mg once daily.

When co-administered with weak and moderate CYP3A4 inducers, dose adjustment of lurazidone may be required (see section "Interaction with Other Medicinal Products and Other Forms of Interaction"). Regarding strong inhibitors and inducers of CYP3A4 (see section "Contraindications").

Switching from One Antipsychotic Medicinal Product to Another

Medical supervision is required when switching from one antipsychotic to another due to differences in pharmacodynamic and pharmacokinetic profiles of antipsychotic medicinal products.

Elderly Patients

Dosage recommendations for elderly patients with normal renal function (creatinine clearance (CrCl) ≥ 80 mL/min) are the same as for adults with normal renal function. However, since renal function may be reduced in elderly patients, dose adjustment according to renal function status may be necessary (see "Renal Impairment" below).

Limited data are available for elderly patients receiving higher doses of lurazidone. There are no data for elderly patients receiving 148 mg of lurazidone. Caution should be exercised when treating patients aged ≥ 65 years with higher doses of lurazidone.

Renal Impairment

Dose adjustment of lurazidone is not required for patients with mild renal impairment.

For patients with moderate (creatinine clearance (CrCl) ≥ 30 and < 50 mL/min), severe (CrCl >15 and < 30 mL/min) renal impairment, and end-stage renal disease (ESRD) (CrCl < 15 mL/min), the recommended initial dose is 18.5 mg, and the maximum dose is 74 mg once daily. Lurazidone should be used in patients with ESRD only when the potential benefit outweighs the potential risk. Clinical monitoring is recommended when used in ESRD.

Hepatic Impairment

Dose adjustment of lurazidone is not required for patients with mild hepatic impairment.

Dose adjustment is recommended for patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. The recommended initial dose is 18.5 mg. The maximum daily dose for patients with moderate hepatic impairment is 74 mg, and for patients with severe hepatic impairment is 37 mg once daily.

Administration

Lurania® tablets, film-coated, are intended for oral use.

Take once daily with food.

Lower concentrations of lurazidone are expected when taken without food compared to administration with food (see section "Pharmacokinetics").

Due to the bitter taste of the tablet, it should be swallowed whole.

Lurania® should be taken at the same time each day.

Children. Lurania® may be used in children aged 13 years and older.

Overdose

Treatment of Overdose. There is no specific antidote for lurazidone; therefore, appropriate supportive measures should be implemented, and careful medical supervision and monitoring should be continued until recovery.

Cardiovascular monitoring, including electrocardiographic monitoring to detect possible arrhythmias, should be initiated immediately. When antiarrhythmic therapy is indicated, disopyramide, procainamide, and quinidine carry a theoretical risk of QT interval prolongation in patients with acute lurazidone overdose. Similarly, the alpha-blocking effect of bretylium may be additive to that of lurazidone, potentially leading to problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures. Epinephrine and dopamine or other sympathomimetics with beta-agonist activity should not be used, as beta-stimulation may exacerbate hypotension in the presence of alpha-blockade caused by lurazidone. In cases of severe extrapyramidal symptoms, anticholinergic drugs should be administered.

Gastric lavage (after intubation if the patient is unconscious) and administration of activated charcoal together with a laxative should be considered.

The potential for altered mental status, seizures, or dystonic reactions of head and neck muscles following overdose creates a risk of aspiration during vomiting.

Adverse reactions

The safety of lurasidone was evaluated in clinical trials at doses of 18.5–148 mg in patients with schizophrenia who received treatment for up to 52 weeks, as well as during the post-marketing period. The most common adverse reactions (≥ 10%) were akathisia, nausea, and insomnia.

Adverse reactions of the medicinal product based on pooled data are presented in Table 4 by system organ classes and frequency: 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), and not known (cannot be estimated from the available data).

Adverse reactions of the medicinal product in adults based on pooled data

Table 4

System organ classes	Very common	Common	Uncommon	Rare	Frequency not known
Infections and infestations			Nasopharyngitis
Blood and lymphatic system disorders			Anaemia	Eosinophilia Leukopenia	Neutropenia****
Immune system disorders		Hypersensitivity
Metabolism and nutrition disorders		Weight increased Decreased appetite	Increased blood glucose Hypoaesthesia
Psychiatric disorders	Insomnia	Agitated state Anxiety Excitement	Nightmares Catatonia Panic attacks	Suicidal behaviour	Sleep disorder****
Nervous system disorders	Akathisia	Somnolence* Parkinsonism** Dizziness Dystonia*** Dyskinesia	Lethargy Dysarthria Tardive dyskinesia Unconsciousness Convulsion	Neuroleptic malignant syndrome Cerebrovascular disorder
Eye disorders			Blurred vision
Ear and labyrinth disorders			Dizziness
Cardiac disorders		Tachycardia	Angina pectoris First-degree atrioventricular block Bradycardia
Vascular disorders		Hypertension	Hypotension Orthostatic hypotension Flushing Blood pressure increased
Gastrointestinal disorders	Nausea	Diarrhoea Vomiting Dyspepsia Increased salivation Dry mouth Upper abdominal pain Stomach discomfort	Flatulence Dysphagia Gastritis
Hepatobiliary disorders			Increased alanine aminotransferase
Skin and subcutaneous tissue disorders		Rash Pruritus	Hyperhidrosis	Angioedema	Stevens-Johnson syndrome
Musculoskeletal and connective tissue disorders		Back pain Musculoskeletal stiffness	Joint stiffness Myalgia Neck pain	Rhabdomyolysis
Renal and urinary disorders		Increased serum creatinine	Dysuria	Renal failure
Pregnancy, puerperium and perinatal conditions					Neonatal abstinence syndrome (see section "Use during pregnancy or breastfeeding")
Reproductive system and breast disorders			Increased blood prolactin Erectile dysfunction Amenorrhoea Dysmenorrhoea	Breast pain Galactorrhoea	Increased breast size****
General disorders and administration site conditions		Fatigue	Gait disturbance	Sudden death
Investigations		Increased blood creatine phosphokinase

* Somnolence includes the following adverse reaction terms: hypersomnia, somnolence, somnolence effect, and sedative effect.

** Parkinsonism includes the following adverse reaction terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder, hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor.

*** Dystonia includes the following adverse reaction terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis, and trismus.

**** Adverse reactions observed in controlled and uncontrolled phase 2 and 3 studies; however, the frequency of occurrence was too low to allow estimation.

Adverse drug reactions in adolescents

Table 5

Body systems	Very common	Common	Uncommon
Infections and infestations			Nasopharyngitis Rhinitis Upper respiratory tract infection
Blood and lymphatic system disorders			Neutropenia
Immune system disorders			Hypersensitivity
Endocrine disorders		Hyperprolactinemia (including increased prolactin levels in blood)	Autoimmune thyroiditis Hyperandrogenism Hypothyroidism
Metabolism and nutrition disorders		Decreased appetite Increased appetite	Hyperinsulinemia
Psychiatric disorders		Abnormal dreams Agitation Anxiety Depression Insomnia Psychotic disorder Schizophrenia Tension	Aggression Apathy Confusional state Depressed mood Dissociation Hallucination (auditory) Visual hallucinations Homicidal ideation Impulsive behavior Difficulty falling asleep Decreased libido Increased libido Apathy Mental status changes Obsessive thoughts Panic attacks Psychomotor hyperactivity Restlessness Sleep disorder Suicidal ideation Terminal insomnia Thought disorder
Nervous system disorders	Akathisia Headache Somnolence*	Attention disturbance Dizziness Dyskinesia Dystonia*** Parkinsonism**	Postural dizziness Dysgeusia Hyperkinesia Memory impairment Migraine Paresthesia Psychomotor hyperactivity Restless legs syndrome Tardive dyskinesia Tension headache
Eye disorders			Accommodation disorder Blurred vision
Ear and labyrinth disorders			Hyperacusis
Cardiac disorders		Tachycardia	Pounding heartbeat Supraventricular extrasystoles
Vascular disorders			Orthostatic hypotension Hypertension
Respiratory, thoracic and mediastinal disorders			Oropharyngeal pain Dyspnea
Gastrointestinal disorders	Nausea	Constipation Dry mouth Increased salivation Vomiting	Abdominal discomfort Upper abdominal pain Aptyalism Diarrhea Dyspepsia Lip dryness Toothache
Skin and subcutaneous tissue disorders		Hyperhidrosis	Alopecia Abnormal hair growth Rash Urticaria
Musculoskeletal and connective tissue disorders		Muscle rigidity	Arthralgia Muscle tension Myalgia Limb pain Jaw pain
Renal and urinary disorders			Bilirubinuria Dysuria Urination disorder Polyuria Proteinuria Renal disorders
Reproductive system and breast disorders		Erectile dysfunction	Amenorrhea Breast pain Ejaculation disorder Galactorrhea Gynecomastia Irregular menstruation Oligomenorrhea Sexual dysfunction
Congenital, familial and genetic disorders			Tourette syndrome
General disorders and administration site conditions		Asthenia Malaise Irritability	Chills Gait disturbance Malaise Non-cardiac chest pain Pyrexia
Investigations		Increased blood creatine phosphokinase Elevated C-reactive protein Weight decreased Weight increased	Alanine aminotransferase increased Antithyroid antibodies positive Aspartate aminotransferase increased Alkaline phosphatase in blood decreased Alkaline phosphatase in blood increased Blood cholesterol increased Blood glucose increased Insulin in blood increased Testosterone in blood decreased Thyrotropin in blood increased Triglycerides in blood increased PR interval shortening on electrocardiogram Hemoglobin decreased High-density lipoprotein decreased Low-density lipoprotein decreased
Injury, poisoning and procedural complications			Intentional overdose

* Somnolence includes the following adverse reactions observed in adolescents: hypersomnia, sedative effect, and somnolence.

** Parkinsonism includes the following adverse reactions observed in adolescents: rigidity, extrapyramidal disorder, hypokinesia, parkinsonism, and tremor.

*** Dystonia includes the following adverse reactions observed in adolescents: dystonia, oculogyric crisis, and torticollis.

Description of selected adverse reactions

Clinically significant cases of skin and other hypersensitivity reactions have been reported during the post-marketing period with lurasidone treatment, including Stevens-Johnson syndrome.

Extrapyramidal symptoms (EPS). In short-term, placebo-controlled trials in adults, the incidence of adverse reactions related to EPS, excluding akathisia and restlessness, was 13.5% in patients receiving lurasidone compared to 5.8% in patients receiving placebo. The incidence of akathisia in patients receiving lurasidone was 12.9% compared to 3.0% in patients receiving placebo. In a short-term, placebo-controlled trial in adolescents, the incidence of adverse reactions related to EPS, excluding akathisia, was 5.1% in patients receiving lurasidone compared to 1.8% in patients receiving placebo. The incidence of akathisia in patients receiving lurasidone was 8.9% compared to 1.8% in patients receiving placebo.

Dystonia. Dystonic symptoms, characterized by prolonged abnormal contractions of muscle groups, may occur in susceptible individuals within the first few days of treatment. Dystonic symptoms include neck muscle spasm, sometimes progressing to throat constriction, difficulty in swallowing, breathing difficulty, and/or tongue protrusion. Although these symptoms may occur with low-dose administration, they are more frequent, pronounced, and severe with higher doses of first-generation antipsychotics. The risk of acute dystonia is increased in males and younger age groups.

Venous thromboembolism. Cases of venous thromboembolism, including pulmonary artery embolism and deep vein thrombosis, have been reported with the use of antipsychotic drugs — frequency unknown.

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, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. No special storage conditions required. Keep out of reach of children.

Packaging. 14 tablets in a blister. 2 blisters in a carton.

Prescription status. Prescription only.

Manufacturer. Elpen Pharmaceutical Co. Inc. (manufacturing, primary and secondary packaging, quality control, batch release of the medicinal product).

Manufacturer's address. Maratonos Avenue 95, Pikermi, 190 09, Greece.

Marketing Authorization Holder. JSC "Farmak".

Address of the Marketing Authorization Holder. 63, Kyrylivska Street, Kyiv, 04080, Ukraine.