Latuda, 80 mg 28 pcs

Antipsychotic medicine (neuroleptic)

ATX code: N05AE05

Pharmacological properties

The mechanism of action

Lurazidone is a selective dopamine and monoamine receptor antagonist with high affinity for D₂-dopamine and 5-NT_2A– and 5-NT₇-serotonin receptors (K_i = 0.994, 0.47 and 0.495 nM, respectively). Lurazidone also blocks α_2C– and α_2A-adrenoreceptors (affinity degree 10.8 and 40.7 nM, respectively), has partial agonism to 5-NT-_1A-serotonin receptors with an affinity degree of 6.38 nM. Lurazidone does not bind to histamine and muscarinic receptors.

The mechanism of action of the minor active metabolite of lurazidone, ID-14283, is the same as that of lurazidone.

Positron emission tomography data shows that administration of lurazidone at doses ranging from 9 to 74 mg (10 to 80 mg of lurazidone hydrochloride) in healthy volunteers resulted in a dose-dependent decrease in binding of 11C-raclopride, the D-ligandsub>2/D₃ receptors, in the caudate nucleus, shell, and ventral striatum.

Pharmacodynamics

Lurazidone was administered in doses ranging from 20 to 160 mg in the major clinical efficacy trials (KIs).

Clinical data

Schizophrenia

The efficacy of lurazidone in the treatment of schizophrenia has been demonstrated in 5 multicenter placebo-controlled, double-blind, 6-week CIs, in patients meeting the criteria of the Diagnostic and Statistical Manual of Mental Disorders, Revision IV (DSMR-IV). Doses of lurazidone, different in the five CIs, ranged from 40 to 160 mg once daily. In the short-term CIs, the primary efficacy measure was defined as the mean change in the sum of scores by 6 weeks of therapy relative to baseline as assessed by the Positive and Negative Syndrome Scale (PSSS, a validated questionnaire including 5 factors to assess positive symptoms, negative symptoms, disorganized thinking, uncontrollable hostility/excitement, and anxiety/depression).

Lurazidone demonstrated greater efficacy compared to placebo in phase 3 studies. Statistically significant differences from placebo were recorded as early as day 4 of therapy. In addition, lurazidone was superior to placebo on a predetermined secondary efficacy measure, the Overall Clinical Impression of Disease Severity Scale (OCIS-T). Efficacy was also confirmed by a secondary analysis of treatment response (reduction of ≥30% relative to baseline on the Total Clinical Impression Scale (TNIS) score). No persistent dose-response relationships were found in short-term studies.

The long-term efficacy of lurazidone at doses of 40 to 160 mg once daily was demonstrated in a 12-month study of no less efficacy than slow-release quetiapine (XR) (200 to 800 mg once daily). Lurazidone was no less effective than XR quetiapine in affecting the duration of remission of schizophrenia. After 12 months of lurazidone use, there was a relatively greater increase in body weight and BMI from baseline (mean (standard deviation:) 0.73 (3.36) kg and 0.28 (1 , 17) kg/m2, respectively) compared with quetiapine XR (1.23 (4.56) kg and 0.45 (1.63) kg/m2, respectively). Overall, lurazidone had little effect on weight and other metabolic parameters, including total cholesterol, triglycerides, and glucose concentrations.

In a long-term safety study, clinically stable patients received 40 to 120 mg of lurazidone or 2 to 6 mg of risperidone. In this study, the 12-month relapse rate was 20% with lurazidone and 16% with risperidone. This difference approached but did not reach statistical significance.

In long-term studies of duration of effect, the duration of symptom control and relapse-free schizophrenia was longer in patients receiving lurazidone compared to patients receiving placebo. After acute seizures were controlled and stabilized for 12 weeks with lurazidone, patients were randomized in a double-blind manner to continue lurazidone or placebo until schizophrenia symptoms relapsed.

The primary analysis of duration to relapse was performed by censoring data from those patients who completed the study before relapse. There was a longer relapse-free period in patients treated with lurazidone compared to patients in the placebo group (p=0,039). The Kaplan-Meier estimate of the probability of relapse at 28 weeks was 42.2% in the lurazidone group and 51.2% in the placebo group. The probability of discontinuing therapy for any reason at 28 weeks was 58.2% for patients in the lurazidone group and 69.9% for patients in the placebo group (p=0.072).

Depressive episodes due to bipolar affective disorder type I

Monotherapy

. The efficacy of lurazidone as monotherapy was studied in a 6-week, multicenter, randomized, double-blind, placebo-controlled trial in adult patients (mean age 41.5 years, range 18 to 74 years) who met criteria for a major depressive episode within bipolar affective disorder type I Revised DSMR-IV, with or without rapid cycling, and without evidence of psychosis (N=485). Patients were randomized to receive lurazidone in two dosing ranges (20 to 60 mg/day and 80 to 120 mg/day) or placebo.

In this study, the primary instrument for assessing depressive symptoms was the Montgomery-Asberg Depression Rating Scale (MADRS), a clinically ranked 10-item scale with a sum score ranging from 0 (no signs of depression) to 60 (maximum score). The primary endpoint was the change from baseline in the SHMAOD score by week 6. The instrument for assessing the secondary endpoint was the SHQA-T, a clinically ranked scale that assesses the current health status of a patient with bipolar illness on a 7-point scale; with the higher the total score, the more severe the illness.

For both dose intervals, lurazidone outperformed placebo in terms of reduction of the SHMAOD and SHOKV-T scores by week 6. Taking the drug at higher doses (80 to 120 mg per day), on average, provided no additional efficacy compared with lower doses (20 to 60 mg per day).

. Complementary therapy with lithium or valproic acid The efficacy of lurazidone as complementary therapy with lithium or valproic acid was established in a 6-week, multicenter, randomized, double-blind placebo-controlled study in adult patients (mean age 41.7 years, range 18 to 72 years) who met criteria for a major depressive episode within bipolar affective disorder type I Revised RDSPR-IV, with or without rapid cycling, and without evidence of psychosis (N=340). Patients with persistent symptoms after treatment with lithium or valproic acid were randomized to receive lurazidone at doses of 20 to 120 mg/day or placebo.

The primary instrument for assessing depressive symptoms was the SMAOD. The primary endpoint was the change from baseline in the SHMAOD score by week 6 of treatment. The instrument for assessing the secondary endpoint was the SHOQ-T scale.

Lurazidone as adjunctive therapy with lithium and valproic acid was superior to placebo in terms of reduction of SHMAOD and SHOKV-T scores by week 6 of treatment.

Pharmacokinetics

Intake

The time to reach maximum concentration (C_max) in blood is 1 to 3 hours. The mean C_max and area under the concentration-time curve (AUC) were 2-3 and 1.5-2 times greater, respectively, after ingestion of lurazidone with food compared to values after fasting lurazidone.

Distribution

After oral administration of 40 mg of lurazidone, the average apparent volume of distribution was approximately 6000 L. Lurazidone is significantly (99%) bound to plasma proteins.

Metabolism

Lurazidone is metabolized primarily with the participation of the cytochrome P450 (CYP) 3A4 isoenzyme system. The main pathways of metabolism are oxidative N-dealkylation, hydroxylation of the nonbornan ring, and S-oxidation.

Lurazidone is metabolized to form two active metabolites (ID-14283 and ID- 14326) and two inactive metabolites (ID-20219 and ID-20220). Lurazidone 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 plasma radioactivity, respectively.

The active metabolite ID-14283 is metabolized primarily with the participation of the CYP3A4 isoenzyme.

Pharmacodynamic effects are due to the action of lurazidone and its active

metabolite ID-14283 on dopamine and serotonin receptors.

In in vitro studies it was found that lurazidone is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 isozymes.

In in vitro studies, lurazidone showed no direct or weak inhibitory effect (direct or time-dependent, IC>5.9 μmol) against the CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4 isoenzymes. Based on these data, the pharmacokinetics of drugs that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 isoenzymes are not expected to be affected by lurazidone. When prescribing drugs with a narrow therapeutic range, which are substrates of CYP3A4 isoenzyme, see section “Interaction with other medicinal products”.

In in vitro studies, lurazidone has been found to be a substrate for the efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP). Lurazidone is not a substrate for active transport by the transport polypeptides of the organic anions OATP1B1 and OATP1B3.

In vitro studies also show that lurazidone is an inhibitor of P-glycoprotein, BCRP and organic cation transporters type 1 (OCT1). Lurazidone has no clinically relevant inhibitory effect on OATP1B1, OATP1B3, organic cation transporters type 2 (OCT2), organic anion transporters type 1 (OAT1) and type 3 (OAT3), renal transporters MATE1 and MATE2K or bile acid export pump (BSEP).

The elimination half-life is approximately 20-40 hours. After ingestion of lurazidone labeled with the radioactive isotope, about 67% of the drug is excreted by the intestine and about 19% by the kidneys. Urine contains mostly metabolites due to minimal renal excretion of the parent compound.

Linearity/Nonlinearity

The pharmacokinetic parameters of lurazidone are dose proportional over a total daily dose range of 20 to 160 mg. Equilibrium concentrations of lurazidone are reached within 7 days of initiating therapy.

Pharmacokinetics in Special Patient Groups Elderly Patients

There are limited data on the pharmacokinetics of lurazidone in healthy elderly volunteers (≥65 years). According to the results obtained, the plasma concentration of lurazidone in elderly healthy volunteers is identical to that in the plasma of younger volunteers (younger than 65 years). However, an increase in plasma concentrations of lurazidone in elderly patients with impaired renal or hepatic function can be expected.

Patients with impaired hepatic function

In patients with mild (Child-Pugh Class A), moderate (Child-Pugh Class B) and severe (Child-Pugh Class C) hepatic impairment, the AUC of lurazidone is increased by 1.5; 1.7 and 3 times, respectively.

Patients with impaired renal function

In patients with mild, moderate and severe renal impairment the AUC of lurazidone is increased 1.5; 1.9 and 2.0 times, respectively. There are no clinical data on the use of lurazidone in patients with terminal renal failure (creatinine clearance < 15 ml/min).

Population pharmacokinetic analysis showed no clinically significant effect of gender in patients with schizophrenia on the pharmacokinetics of lurazidone.

Raciality

Population pharmacokinetic analysis showed no clinically significant effect of race in patients with schizophrenia on the pharmacokinetics of lurazidone. It was noted that healthy volunteers of mongoloid race had a 1.5-fold increase in AUC compared to volunteers of Caucasoid race.

Smoking

In vitro studies using human liver enzymes have shown that lurazidone is not a substrate of the CYP1A2 isoenzyme, so smoking should not affect the pharmacokinetics of lurazidone.

Children

The pharmacokinetic properties of lurazidone in a pediatric population were studied in 49 children aged 6-12 years and in 56 adolescents aged 13-17 years. Lurazidone was administered as lurazidone hydrochloride at daily doses of 20, 40, 80, 120 mg (6 -17 years old) or 160 mg (10-17 years old patients only) for 7 days. There was no clear correlation between plasma concentrations of lurazidone and age or body weight. Pharmacokinetic parameters of lurazidone in children aged 6-17 years were generally comparable to those in adults.

Indications

Latuda® is indicated for adults aged 18 years and older:

– for the treatment of schizophrenia;

– as monotherapy for major depressive episodes caused by bipolar affective disorder type I (bipolar depression);

– as additional therapy with lithium or valproic acid for major depressive episodes caused by bipolar affective disorder type I (bipolar depression).

Pharmacological effect

Antipsychotic (neuroleptic)

ATX code: N05AE05

PHARMACOLOGICAL PROPERTIES

Mechanism of action

Lurasidone is a selective dopamine and monoamine receptor antagonist with high affinity for D2-dopamine and 5-HT2A and 5-HT7 serotonin receptors (Ki = 0.994, 0.47 and 0.495 nM, respectively). Lurasidone also blocks α2C and α2A adrenergic receptors (affinity 10.8 and 40.7 nM, respectively), and has partial agonism to 5-HT-1A serotonin receptors with an affinity of 6.38 nM. Lurasidone does not bind to histamine and muscarinic receptors.

The mechanism of action of the minor active metabolite of lurasidone ID-14283 is the same as that of lurasidone.

Positron emission tomography data showed that lurasidone doses ranging from 9 to 74 mg (10 to 80 mg lurasidone hydrochloride) in healthy volunteers resulted in a dose-dependent decrease in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate nucleus, putamen, and ventral striatum.

Pharmacodynamics

In the main clinical studies (CTs) of efficacy, lurasidone was prescribed in doses ranging from 20 to 160 mg.

Clinical data

Schizophrenia

The effectiveness of lurasidone in the treatment of schizophrenia was demonstrated in 5 multicenter, placebo-controlled, double-blind, 6-week clinical trials in patients meeting Diagnostic and Statistical Manual of Mental Disorders, IV (DSM-IV) criteria. Lurasidone doses varied across the five trials, ranging from 40 to 160 mg once daily. During short-term clinical trials, the main outcome measure was defined as the mean change in the total score at week 6 of treatment from baseline as assessed using the Positive and Negative Syndrome Scale (PSNS – a validated questionnaire that includes 5 factors to assess positive symptoms, negative symptoms, disorganized thinking, uncontrolled hostility/arousal, and anxiety/depression).

Lurasidone demonstrated greater efficacy compared with placebo in phase 3 studies. Statistically significant differences from placebo were recorded already on the 4th day of therapy. In addition, lurasidone was superior to placebo on a prespecified secondary efficacy measure, the Clinical Global Impression of Illness Severity Scale (CGI-S) score. Efficacy was also confirmed in a secondary analysis of response to treatment (≥ 30% reduction from baseline in PNS scores). In short-term studies, no consistent dose-response relationship was found.

The long-term effectiveness of lurasidone at doses of 40 to 160 mg once daily was demonstrated in a 12-month noninferiority study compared with extended-release (XR) quetiapine (200 to 800 mg once daily). Lurasidone was no less effective than quetiapine XR in influencing the duration of remission of schizophrenia. After 12 months of lurasidone use, there was a relatively greater increase in body weight and body mass index from baseline (mean (standard deviation): 0.73 (3.36) kg and 0.28 (1, 17) kg/m2, respectively) compared with quetiapine XR (1.23 (4.56) kg and 0.45 (1.63) kg/m2, respectively). Overall, lurasidone had little effect on weight and other metabolic parameters, including total cholesterol, triglyceride, and glucose concentrations.

In a long-term safety study, clinically stable patients received lurasidone 40 to 120 mg or risperidone 2 to 6 mg. In this study, the relapse rate at 12 months was 20% with lurasidone and 16% with risperidone. This difference approached but did not reach statistical significance.

In long-term duration of effect studies, the duration of symptom control and relapse-free period of schizophrenia was longer in patients receiving lurasidone compared with patients receiving placebo. After resolution of acute attacks and stabilization for 12 weeks on lurasidone, patients were randomized in a double-blind manner to continue lurasidone or placebo until relapse of schizophrenic symptoms.

The primary analysis of time to relapse was performed by censoring data from those patients who completed the study before relapse. A longer relapse-free period was noted in patients receiving lurasidone compared with patients in the placebo group (p = 0.039). The Kaplan–Meier estimate of the probability of relapse at week 28 was 42.2% in the lurasidone group and 51.2% in the placebo group. The likelihood of discontinuation of therapy for any reason at week 28 was 58.2% for patients in the lurasidone group and 69.9% for patients in the placebo group (p=0.072).

Depressive episodes due to bipolar disorder type I

Monotherapy

The efficacy of lurasidone monotherapy was studied in a 6-week, multicenter, randomized, double-blind, placebo-controlled study in adult patients (mean age 41.5 years, range 18 to 74 years) who met the criteria for a major depressive episode in the Revised RDS-IV bipolar disorder type I, with or without rapid cycling, and without evidence of psychosis. (N=485). Patients were randomized to receive lurasidone in two dosing ranges (20 to 60 mg/day and 80 to 120 mg/day) or placebo.

In this study, the primary instrument for assessing depressive symptoms was the Montgomery-Åsberg Depression Inventory (MADS), a clinically rated 10-item scale with scores ranging from 0 (no signs of depression) to 60 (maximum score). The primary endpoint was change from baseline in the SMADP score to week 6. The instrument for assessing the secondary endpoint was the PCS-T, a clinically ranked scale that assesses the current health status of a patient with bipolar disease on a 7-point scale; Moreover, the higher the score, the more severe the disease.

For both dose intervals, lurasidone was superior to placebo in terms of reduction in SMAOD and SOCW-T scores at week 6. On average, higher doses (80 to 120 mg per day) provided no additional benefit compared with lower doses (20 to 60 mg per day).

Adjunctive Therapy with Lithium or Valproic Acid The effectiveness of lurasidone as adjunctive therapy with lithium or valproic acid was established in a 6-week, multicenter, randomized, double-blind, placebo-controlled study in adult patients (mean age 41.7 years, range 18 to 72 years) who met criteria for a major depressive episode within bipolar disorder. affective disorder type I, revised RDSPR-IV, with or without rapid cycling, and without signs of psychosis (N=340). Patients with persistent symptoms after treatment with lithium or valproic acid were randomized to receive lurasidone at doses ranging from 20 to 120 mg/day or placebo.

The main instrument for assessing depressive symptoms was the SMADS. The primary endpoint was the change from baseline in the SMADP score to week 6 of treatment. The tool used to assess the secondary endpoint was the PCS-T score.

Lurasidone as an adjunctive therapy with lithium and valproic acid was superior to placebo in terms of the degree of reduction in SMAOD and SCHW-T scores by the 6th week of treatment.

Pharmacokinetics

Suction

The time to reach maximum concentration (Cmax) in the blood ranges from 1 to 3 hours. After administration of lurasidone with food, mean Cmax and area under the concentration-time curve (AUC) increased by 2-3 and 1.5-2 times, respectively, compared with values ​​after administration of lurasidone on an empty stomach.

Distribution

Following oral administration of 40 mg lurasidone, the mean apparent volume of distribution was approximately 6000 L. Lurasidone is significantly (99%) bound to plasma proteins.

Metabolism

Lurasidone is metabolized primarily through the cytochrome P450 (CYP) 3A4 isoenzyme. The main metabolic pathways are oxidative N-dealkylation, hydroxylation of the nonbornane 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). The share of lurasidone and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 accounts for approximately 11.4; 4.1; 0.4; 24 and 11% of plasma radioactivity, respectively.

The active metabolite ID-14283 is metabolized mainly with the participation of the CYP3A4 isoenzyme.

The pharmacodynamic effect is due to the action of lurasidone and its active

metabolite ID-14283 on dopamine and serotonin receptors.

In vitro studies revealed that lurasidone is not a substrate of the isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

In in vitro studies, lurasidone did not show direct or weak inhibitory effects (direct or time-dependent, IC>5.9 µmol) on the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Based on these data, no effect of lurasidone on the pharmacokinetics of drugs that are substrates of the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 is expected. When prescribing drugs with a narrow therapeutic range that are substrates of the CYP3A4 isoenzyme, see the section “Interaction with other drugs”.

In vitro studies have shown that lurasidone is a substrate for the efflux transporters P-glycoprotein and breast cancer resistance protein (BCRP). Lurasidone is not a substrate for active transport by the organic anion transport polypeptides OATP1B1 and OATP1B3.

In vitro studies also show that lurasidone is an inhibitor of P-glycoprotein, BCRP and organic cation transporter type 1 (OCT1). Lurasidone does not have a clinically significant inhibitory effect on OATP1B1, OATP1B3, organic cation transporter type 2 (OCT2), organic anion transporter type 1 (OAT1) and type 3 (OAT3), renal transporters MATE1 and MATE2K, or bile acid export pump (BSEP).

Removal

The half-life is approximately 20-40 hours. After oral administration of radiolabeled lurasidone, about 67% of the drug is excreted by the intestines and about 19% by the kidneys. Urine contains mainly metabolites due to minimal renal excretion of the parent compound.

Linearity/Nonlinearity

The pharmacokinetic parameters of lurasidone are dose proportional with a total daily dose range of 20 to 160 mg. Steady-state concentrations of lurasidone are achieved within 7 days from the start of therapy.

Pharmacokinetics in special groups of patients Elderly patients

Data on the pharmacokinetics of lurasidone in healthy elderly volunteers (≥ 65 years) are limited. According to the results obtained, the concentration of lurasidone in the plasma of elderly healthy volunteers is identical to its concentration in the plasma of younger volunteers (under 65 years of age). However, increased plasma concentrations of lurasidone can be expected in elderly patients with impaired renal or hepatic function.

Patients with liver dysfunction

In patients with mild (Child-Pugh class A), moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment, the AUC of lurasidone increases by 1.5; 1.7 and 3 times, respectively.

Patients with impaired renal function

In patients with mild, moderate and severe renal impairment, the AUC of lurasidone increases by 1.5; 1.9 and 2.0 times, respectively. There are no clinical data on the use of lurasidone in patients with end-stage renal failure (creatinine clearance < 15 ml/min).

Gender

Population pharmacokinetic analysis did not reveal a clinically significant effect of the gender of patients with schizophrenia on the pharmacokinetics of lurasidone.

Race

Population pharmacokinetic analysis did not reveal a clinically significant effect of the race of patients with schizophrenia on the pharmacokinetics of lurasidone. It was noted that in healthy volunteers of the Mongoloid race, the AUC value increased by 1.5 times compared to volunteers of the Caucasian race.

Smoking

In vitro studies using human liver enzymes have shown that lurasidone is not a substrate of the CYP1A2 isoenzyme, therefore smoking should not affect the pharmacokinetics of lurasidone.

Children

The pharmacokinetic properties of lurasidone in the pediatric population were studied in 49 children aged 6-12 years and in 56 adolescents aged 13-17 years. Lurasidone was prescribed as lurasidone hydrochloride in daily doses of 20, 40, 80, 120 mg (6-17 years old) or 160 mg (patients 10-17 years old only) for 7 days. There was no clear correlation between lurasidone plasma concentrations and age or body weight. Pharmacokinetic parameters of lurasidone in children aged 6-17 years were generally comparable to those in adults.

Special instructions

When treated with antipsychotic drugs, improvement in the patient’s clinical condition should be expected within a period of several days to several weeks. Proper monitoring of the patient’s condition during this period is necessary.

Suicidal intentions

A tendency to suicidal thoughts and attempts is characteristic of patients with psychosis. There are reports of similar cases at the beginning of therapy or when changing an antipsychotic drug. Therefore, antipsychotic drug therapy should be carried out under close medical supervision.

Parkinson’s disease

Caution should be exercised when using antipsychotic drugs in patients with Parkinson’s disease, because This group of patients has increased sensitivity to antipsychotic drugs and an increased risk of exacerbation of parkinsonian symptoms. Latuda® can be used in patients with Parkinson’s disease only in cases where the potential benefit outweighs the possible risk to the patient.

Extrapyramidal symptoms (EPS)

Drugs with dopamine receptor antagonist properties may cause unwanted extrapyramidal disturbances, including rigidity, tremor, mask-like face, dystonia, drooling, postural and gait disturbances. According to placebo-controlled clinical trials in adult patients with schizophrenia, lurasidone was associated with an increased incidence of extrapyramidal symptoms compared with placebo.

Tardive dyskinesia

Drugs with dopamine receptor antagonist properties may cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, especially of the tongue and/or face. If symptoms of tardive dyskinesia appear, a decision should be made about the advisability of discontinuing all antipsychotic drugs, including lurasidone.

Cardiovascular disease/QT prolongation

Caution should be exercised when prescribing lurasidone to patients with known cardiovascular disease or a prolonged QT interval in immediate family members, hypokalemia, or when used concomitantly with other drugs that prolong the QT interval.

Falls

Latuda® may cause drowsiness, orthostatic hypotension, motor and sensory instability, which can lead to falls and, as a result, fractures or other injuries. In patients with diseases, conditions, or drug therapy that may worsen these ADRs, a fall risk assessment should be performed before initiating antipsychotic therapy, and again in patients receiving long-term antipsychotic medications.

Convulsions

Caution should be exercised when prescribing lurasidone to patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Neuroleptic malignant syndrome

Cases of the development of neuroleptic malignant syndrome, characterized by hyperthermia, muscle rigidity, instability of autonomic functions, impaired consciousness and increased activity of creatine phosphokinase in the blood, have been reported with the use of antipsychotic drugs, including lurasidone. In addition, the development of myoglobinuria (rhabdomyolysis) and acute renal failure is possible. In such cases, it is necessary to discontinue all antipsychotic drugs, including lurasidone.

Exacerbation of mania/hypomania

Treatment with antidepressants may increase the risk of developing a manic or hypomanic episode, especially in patients with bipolar disorder. Patients should be monitored for such episodes.

Manic or hypomanic states in patients receiving Latuda® in studies of monotherapy and adjunctive therapy (with lithium or valproic acid) for bipolar depression occurred in less than 1% of participants in the Latuda® and placebo groups.

Elderly patients with dementia

Lurasidone has not been studied in elderly patients with dementia.

Overall mortality rate

In a meta-analysis of 17 controlled trials in elderly patients with dementia, treatment with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine, was associated with increased overall mortality compared with placebo.

Cerebrovascular disorders

In patients with dementia treated with atypical antipsychotics, including risperidone, aripiprazole, and olanzapine, there was an approximately 3-fold increase in the risk of cerebrovascular adverse reactions, the mechanism of which is unknown, in randomized placebo-controlled clinical trials. An increased risk of cerebrovascular disorders cannot be excluded for other antipsychotic drugs or other patient groups. Lurasidone should be used with caution in elderly patients with dementia who have risk factors for stroke.

Venous thromboembolism

Cases of venous thromboembolism have been reported with the use of antipsychotic drugs. Because patients taking antipsychotic drugs are often at risk for developing venous thromboembolism, all possible risk factors for venous thromboembolic events should be identified before and during treatment with lurasidone, and preventive measures should be taken.

Hyperprolactinemia

Lurasidone increases prolactin concentrations because it is an antagonist of D2-dopamine receptors.

Weight gain

Weight gain has been observed when taking atypical antipsychotic drugs. It is recommended to control body weight.

Hyperglycemia

According to clinical trials, the use of lurasidone in rare cases was accompanied by the development of adverse reactions associated with changes in glucose concentration, for example, hyperglycemia. Appropriate clinical monitoring is recommended when treating patients with diabetes mellitus and risk factors for diabetes mellitus when treating lurasidone.

Orthostatic hypotension/syncope

Orthostatic hypotension may develop due to the presence of lurasidone as an α1-adrenergic receptor antagonist. Appropriate monitoring for symptoms of orthostatic hypotension is recommended in patients at risk for low blood pressure.

Kidney failure

It is recommended to adjust the dose of lurasidone in patients with moderate, severe and end-stage renal failure. There are no data on the use of lurasidone in patients with end-stage renal failure, so lurasidone should only be used in cases where the potential benefit outweighs the possible risk. Treatment of patients with end-stage renal failure with lurasidone should be carried out under appropriate monitoring of the patient’s condition.

Liver failure

It is recommended to adjust the dose of lurasidone in patients with moderate to severe hepatic impairment (Child-Pugh class B and C, see sections “Dosage and Administration” and “Pharmacokinetics”). Proper monitoring of the patient’s condition is mandatory when lurasidone is used in patients with severe hepatic impairment.

Interaction with grapefruit juice

Grapefruit juice should be avoided when being treated with lurasidone (see section “Interactions with other drugs”).

Remains of unused drug must be disposed of in accordance with local requirements.

INFLUENCE ON THE ABILITY TO DRIVE VEHICLES AND MECHANISMS

Lurasidone has a minor effect on the ability to drive and operate machines. Patients should be warned about the dangers of driving vehicles and operating machinery in cases where there is no convincing evidence of the absence of adverse reactions in each individual patient (see section “Side Effects”).

Active ingredient

Lurasidone

Composition

Active substance:

lurasidone hydrochloride 80 mg;

Excipients:

core – mannitol 142 mg,

pregelatinized starch 80 mg,

croscarmellose sodium 4 mg,

hypromellose 2910 10 mg,

magnesium stearate 4 mg;

film shell – Opadry® white* 4.128 mg, iron dye yellow oxide 0.08 mg, indigo carmine aluminum varnish 0.11 mg, carnauba wax 0.01 mg.

*Opadray® white (for tablets of all dosages) contains: hypromellose 2910 65%, titanium dioxide 20%, macrogol-8000 15%.

Pregnancy

Use during pregnancy

Data on the use of lurasidone in pregnant women are limited (fewer than 300 pregnancy outcomes have been assessed). Animal studies are insufficient to assess effects on pregnancy, embryonic and fetal development, childbirth and postnatal development. The potential risk to humans is unknown.

Latuda® should not be used during pregnancy unless clearly necessary.

If a woman takes antipsychotic drugs, including lurasidone, in the third trimester of pregnancy, there is a risk of adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome of varying severity. Agitation, hypertension, hypotension, tremor, somnolence, respiratory distress, or feeding disturbances have been reported. Therefore, in such cases, it is necessary to carefully monitor the newborns.

Breastfeeding period

Animal studies have shown that lurasidone is excreted into the milk of rats. There is no information on the ability of lurasidone or its metabolites to pass into human breast milk. Prescribing Latuda® to breastfeeding women is possible only in cases where the potential benefits of treatment for the mother outweigh the potential risk of complications for the child.

Fertility

Animal studies have shown an effect of the drug on fertility, mainly associated with an increase in the concentration of prolactin, which is not related to human reproductive function.

Contraindications

– hypersensitivity to the active substance or any other components of the drug listed in the “Composition” section;

– simultaneous use with strong inhibitors of the CYP3A4 isoenzyme (for example, with boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and with strong inducers isoenzyme CYP3A4 (for example, with carbamazepine, phenobarbital, phenytoin), rifampicin, St. John’s wort;

– age under 18 years (efficacy and safety have not been established).

Side Effects

Security Profile Summary

Schizophrenia

The safety of lurasidone was assessed against the background of its use in doses from 20 to 160 mg during a clinical trial in patients with schizophrenia for 52 weeks and in the post-registration period. The most common adverse drug reactions (ADRs) (≥ 10%) were akathisia and somnolence, which were dose-dependent when taking the drug in doses up to 120 mg per day.

The ADRs listed below are classified by organ system class and preferred terminology. The incidence of ADRs shown in Table 1 is based on data from clinical studies. The frequency of ADRs was determined according to the following classification: very common (≥ 1/10); often (from ≥ 1/100 to < 1/10); uncommon (from ≥1/1000 to <1/100); rare (from ≥ 1/10,000 to < 1/1000); very rare (<1/10,000), including isolated reports; frequency unknown (frequency cannot be determined from available data). Within each group, adverse reactions are presented in descending order of severity.

Table 1. Adverse drug reactions according to the results of the pooled analysis in patients with schizophrenia

Frequency

Very

often

Often

Uncommon

Rarely

Frequency

unknown

Organ system

Infectious and parasitic

diseases

Nasopharyngitis

Blood and lymphatic disorders

systems

Eosinophilia

Leukopenia**** Neutropenia****

Anemia****

Violations with

aspects of metabolism and nutrition

Weight gain

Decreased appetite Increased blood glucose Hyponatremia

Violations

psyche

Insomnia

Agitation Restlessness Anxiety

Nightmare

dreams catatonia

Suicidal

behavior**** Panic attack****

Sleep disturbance****

Nervous system disorders

Akathisia Somnolence *

Parkinsonism

** Dizziness

Dystonia *** Dyskinesia

Lethargy Dysarthria

Tardive dyskinesia

Malignant

neuroleptic syndrome

Convulsions****

Violations with

sides of the organ of vision

Blurred vision

Hearing disorders and

labyrinthine disorders

Vertigo****

Violations with

sides of the heart

Tachycardia

Angina**** Atrioventricular (AV) block 1st degree**** Bradycardia****

Violations with

aspects of the vascular system

Hypertension

Hypotension Orthostatic hypotension

“Hot flashes” Increased blood

pressure

Violations with

sides of the gastrointestinal tract

Nausea

Vomiting Dyspepsia Hypersalivation

Dry mouth Pain in the upper abdomen Feeling of discomfort in the stomach

Flatulence

Diarrhea****

Dysphagia****Gastritis****

Violations with

sides of the liver and biliary tract

Promotion

alanine amino transferase level

(ALT)

Skin and subcutaneous tissue disorders

Hyperhidrosis

Rash**** Itching**** Angioedema**** Stevens syndrome-

Johnson

Immune disorders

systems

Hypersensitivity*****

Musculoskeletal and connective tissue disorders

fabrics

Musculoskeletal

rigidity Increased creatine phosphokinase in the blood

Stiffness in the joints

Myalgia Neck pain Back pain

Rhabdomyoli s

Violations with

side of the kidneys and

urinary tract

Promotion

creatinine in blood

Dysuria

Renal

failure**

**

Pregnancy,

postpartum and perinatal conditions

Withdrawal syndrome in

newborns (see section

“Use during pregnancy and during

breastfeeding period”)

Violations with

sides of the genitals and mammary glands

Increase

prolactin in the blood

Increase

breast**** Breast pain**** Galactorrhea**** Erectile dysfunction**** Amenorrhea****

Dysmenorrhea****

General

disorders and disorders at the injection site

Fatigue

Violation

gait

Sudden death

associated with existing cardiovascular disease, observed during clinical

research****

* The term “somnolence” combines the terms NDR: hypersomnia, hypersomnolence, sedation and drowsiness.

** The term “parkinsonism” combines the terms NDR: bradykinesia, rigidity type

cogwheel, drooling, extrapyramidal disorders, hypokinesia, muscle rigidity, parkinsonism, slow psychomotor activity and tremor.

*** The term “dystonia” combines the terms NDR: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis and trismus.

**** ADRs identified during controlled and uncontrolled phase 2 and 3 clinical trials, but the small number of cases does not allow us to estimate the frequency.

***** Hypersensitivity may include symptoms such as laryngeal swelling, tongue swelling, urticaria or symptoms of angioedema, rash or pruritus (listed in Table 1 under Skin and Subcutaneous Tissue Disorders).

Bipolar depression (monotherapy)

The data presented below are based on short-term, placebo-controlled, pre-registration studies of bipolar depression in patients receiving Latuda® in doses ranging from 20 mg to 120 mg per day (n=331).

The most commonly observed ADRs (new incidence rate ≥ 5% and at least twice as common as placebo) in patients receiving Latuda® were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea and anxiety. There were no ADRs that led to treatment discontinuation and were observed in at least 2% of participants receiving Latuda® and occurred at least 2 times more often than when taking placebo.

Adjunctive therapy with lithium or valproic acid Data presented are based on two short-term, placebo-controlled, pre-registration studies of bipolar depression in patients receiving Latuda as adjunctive therapy with lithium and valproic acid at doses ranging from 20 to 120 mg per day (n=360).

The most commonly observed ADRs (new incidence rate ≥ 5% and at least twice as common as placebo) in patients receiving Latuda® were akathisia and somnolence.

There were no ADRs that led to treatment discontinuation and were observed in at least 2% of participants receiving Latuda® and occurred at least 2 times more often than when taking placebo.

Description of selected adverse reactions

Clinically significant skin reactions and other hypersensitivity reactions associated with lurasidone have been reported during post-marketing surveillance, including several reports of Steven-Johnson syndrome.

Reactions of particular interest for this class of drugs

Extrapyramidal symptoms (EPS)

Schizophrenia

In short-term placebo-controlled studies, the incidence of reported events related to extrapyramidal disorders, excluding akathisia and restlessness, was 13.5% in patients receiving lurasidone and 5.8% in patients receiving placebo. The incidence of akathisia in patients receiving lurasidone was 12.9% and 3.0% in patients receiving placebo.

Bipolar depression Monotherapy

In short-term, placebo-controlled studies of bipolar depression in patients receiving Latuda monotherapy, the incidence of EPS-related ADRs, excluding akathisia and restlessness, was 6.9% compared with 2.4% in patients receiving placebo. The incidence of akathisia in patients receiving Latuda® was 9.4% compared to 2.4% in patients receiving placebo.

Additional therapy with lithium or valproic acid

In short-term, placebo-controlled studies of Latuda as adjunctive therapy for bipolar depression in patients receiving lithium and valproic acid, the incidence of EPS-related ADRs excluding akathisia and restlessness was 13.9% compared with 8.7% in patients receiving placebo.

The incidence of akathisia in patients receiving Latuda® was 10.8% compared to 4.8% in patients receiving placebo.

Dystonia

Symptoms of dystonia, prolonged pathological contractions of muscle groups, may be observed in predisposed patients during the first few days of treatment. Symptoms of dystonia include spasms of the neck muscles, sometimes a tightening of the throat, difficulty swallowing, difficulty breathing, and/or protrusion of the tongue. Although these symptoms may occur when using the drug in low doses, they occur more often and with greater severity when using first-generation antipsychotic drugs in high doses. The risk of developing acute dystonia is increased in men and in younger patients.

Venous thromboembolism

Cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported with the use of antipsychotic drugs. The incidence of venous thromboembolism is unknown.

If any of the side effects indicated in the instructions get worse, or you notice any other side effects not listed in the instructions, tell your doctor.

Interaction

Pharmacodynamic interaction

Since Latuda® acts primarily on the central nervous system, caution must be exercised when using the drug in combination with other centrally acting drugs and alcohol.

Caution should be exercised when using Latuda® concomitantly with drugs that prolong the QT interval, such as Class IA (e.g., quinidine, disopyramide) and Class III antiarrhythmic drugs (e.g., amiodarone, sotalol), certain antihistamines, certain other antipsychotic drugs, and certain antimalarial drugs (e.g., mefloquine).

Pharmacokinetic interaction

Concomitant use of lurasidone and grapefruit juice has not been studied. Grapefruit juice inhibits CYP3A4 and may increase blood concentrations of lurasidone. Grapefruit juice should be avoided during treatment with lurasidone.

The ability of other drugs to affect Latuda®

The pharmacodynamic effect of lurasidone and its active metabolite ID-14283 is mediated by interaction with dopamine and serotonin receptors. Lurasidone and its active metabolite ID-14283 are metabolized mainly by the CYP3A4 isoenzyme.

CYP3A4 isoenzyme inhibitors

The use of lurasidone with strong CYP3A4 inhibitors (for example, boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated (see. section “Contraindications”).

Concomitant use of lurasidone with a strong CYP3 A4 inhibitor, ketoconazole, results in a 9- and 6-fold increase in exposure to lurasidone and its active metabolite ID-14283, respectively.

Concomitant use of lurasidone with moderate isoenzyme inhibitors

CYP3A4 (eg, diltiazem, erythromycin, fluconazole, verapamil) may increase lurasidone exposure. It is assumed that, when used concomitantly, moderate inhibitors of the CYP3A4 isoenzyme lead to a 2-5 fold increase in exposure to CYP3A4 isoenzyme substrates.

Concomitant use of lurasidone with diltiazem (extended-release dosage form), a moderate inhibitor of the CYP3A4 isoenzyme, increases the exposure of lurasidone and ID-14283 by 2.2 and 2.4 times, respectively (see Dosage and Administration). Administration of diltiazem in an immediate-release dosage form may result in a greater increase in lurasidone exposure.

Inducers of the CYP3A4 isoenzyme

The simultaneous use of lurasidone with strong inducers of the CYP3A4 isoenzyme (for example, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort, see section “Contraindications”) is contraindicated.

Concomitant use of lurasidone with a strong inducer of the CYP3A4 isoenzyme, rifampicin, leads to a 6-fold decrease in lurasidone exposure.

Use of lurasidone in combination with weak (e.g., armodafinil, amprenavir, aprepitant, prednisone, rufinamide) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) CYP3A4 inducers is expected to result in less than a 2-fold reduction in exposure. lurasidone, during use and for up to two weeks after discontinuation of inducers of the CYP3A4 isoenzyme.

When used together with weak and moderate inducers of the CYP3A4 isoenzyme, it is necessary to carefully monitor the effectiveness of lurasidone and adjust the dose if necessary.

Lithium

When used together with lithium preparations, there is no need to adjust the dose of lurasidone.

Valproic acid

When used together with valproic acid preparations, there is no need to adjust the dose of lurasidone. Studies aimed at studying drug-drug interactions between valproate and Latuda® have not been conducted. Based on pharmacokinetic data obtained in studies of bipolar depression, the concentration of valproic acid did not affect the concentration of lurasidone, and vice versa.

Conveyors

Lurasidone is a substrate of P-glycoprotein and BCRP (breast cancer resistance protein) in vitro, but the significance of this property in vivo has not been established. Concomitant use of lurasidone with P-glycoprotein and BCRP inhibitors may increase lurasidone exposure.

The ability of lurasidone to affect other drugs

Concomitant use of lurasidone with midazolam, a sensitive substrate of the CYP3A4 isoenzyme, results in an increase in midazolam exposure by less than 1.5 times.

Appropriate monitoring is recommended during concomitant use of lurasidone and

CYP3A4 substrates with a known narrow therapeutic index (eg, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids [ergotamine, dihydroergotamine]).

Lurasidone can be used in combination with digoxin (a P-glycoprotein substrate), since their simultaneous use did not increase digoxin exposure and only slightly increased Cmax (1.3 times). Lurasidone is an inhibitor of the P-glycoprotein efflux transporter in vitro, so the clinical significance of P-glycoprotein inhibition in the intestine cannot be excluded. Concomitant use of the P-glycoprotein substrate dabigatran etexilate may result in increased blood concentrations of dabigatran.

Lurasidone is an in vitro inhibitor of the BCRP efflux transporter, so clinical relevance of BCRP inhibition in the intestine cannot be ruled out. Concomitant use of lurasidone with BCRP substrates may result in increased blood concentrations of these substrates.

The simultaneous use of lurasidone with lithium preparations showed that lithium does not have a clinically significant effect on the pharmacokinetics of lurasidone. Thus, no dose adjustment of lurasidone is required when used in combination with lithium preparations. Lurasidone does not affect lithium concentrations. No dose adjustment of valproic acid is required when used together with lurasidone.

Based on drug interaction studies, coadministration of lurasidone and combined oral contraceptives, including norgestim and ethinyl estradiol, did not result in a clinically or statistically significant effect of lurasidone on contraceptive pharmacokinetics or on sex hormone binding globulin concentrations. Therefore, lurasidone can be used in combination with oral contraceptives.

Overdose

Treatment

There is no specific antidote for lurasidone; therefore, in case of overdose, appropriate symptomatic therapy must be carried out. Appropriate monitoring of the patient’s condition and vital signs should continue until recovery. Cardiovascular monitoring should be started immediately, including continuous ECG recording to identify possible arrhythmias. If antiarrhythmic therapy is necessary, be aware that drugs such as disopyramide, procainamide and quinidine may potentially prolong the QT interval in patients with acute overdose of lurasidone. The alpha-blocking effect of bretylium may be additive with that of lurasidone and lead to hypotension.

Hypotension and vascular collapse can be controlled with appropriate therapy. Beta-adrenergic stimulating drugs may exacerbate hypotension in the setting of lurasidone-induced alpha-adrenergic blockade; therefore, epinephrine, dopamine, and other beta-adrenergic stimulating sympathomimetics should not be used in cases of lurasidone overdose. If severe extrapyramidal symptoms occur, anticholinergic drugs should be administered.

In certain situations, gastric lavage is indicated (after intubation, if the patient is unconscious), administration of activated charcoal and laxatives.

Possible decreased sensitivity to pain, cramps or dystonia of the head and neck muscles due to overdose may create a risk of aspiration if vomiting occurs.

Storage conditions

At a temperature not exceeding 25 °C.

Keep out of the reach of children.

Shelf life

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

Manufacturer

Bushu Pharmaceuticals Ltd., Misato Factory, Japan