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 in adults aged 18 years and older:

– for the treatment of schizophrenia;

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

– as adjunctive therapy with lithium or valproic acid for major depressive episodes due to bipolar affective disorder type I (bipolar depression).

Active ingredient

Lurazidone

Composition

Active ingredient:

Lurazidone 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 coating – Opadray® white* 4.128 mg, iron oxide yellow dye 0.08 mg, indigo carmine aluminum varnish 0.11 mg, carnauba wax 0.01 mg.

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

How to take, the dosage

For oral administration.

Latuda® film-coated tablets are taken orally once daily with a meal (at least 350 kcal). Expected exposure to lurazidone is significantly lower when taken on an empty stomach compared to when taken with a meal.

The tablets of Latuda® are recommended to be swallowed whole to mask the bitter taste. The tablets should be taken at the same time each day to follow the therapy regimen.

Schizophrenia

The recommended starting dose of Latuda® is 40 mg once daily. No dose titration is required. The effect is achieved in a dose range of 40 to 160 mg daily. The dose of lurazidone may be increased at the discretion of the physician based on clinical response. The maximum daily dose should not exceed 160 mg. Patients receiving Latuda® at a daily dose greater than 120 mg who have interrupted treatment for more than 3 days should resume starting at 120 mg and then increasing the dose to the optimal dose. Patients receiving other doses may resume starting at the previous dose without increasing the dose.

Depressive episodes due to bipolar affective disorder type I The recommended starting dose of Latuda® is 20 mg once daily as monotherapy or adjunctive therapy in combination with lithium and valproic acid. Initial dose titration is not required. Latuda has been shown to be effective over a dose range of 20 mg to 120 mg daily as monotherapy or adjunctive therapy in combination with lithium and valproic acid.

The recommended maximum dose of Latuda® for monotherapy or adjunctive therapy in combination with lithium and valproic acid is 120 mg daily. On average, monotherapy with the drug in the higher dose range (80 to 120 mg per day) did not result in additional efficacy compared to lower doses (20 to 60 mg per day).

Special patient groups

Elderly patients (65 years and older)

Dose adjustment is not required in elderly patients with preserved renal function (creatinine clearance ≥80 mL/min). However, in elderly patients with decreased renal function, dose adjustment may be required depending on the degree of renal failure.

There are limited data on treatment of elderly patients with high doses of lurazidone. There are no data on the use of Latuda® at a dose of 160 mg for the treatment of elderly patients. Caution should be exercised when treating patients 65 years of age and older with high doses of Latuda®.

Patients with impaired renal function

Patients with mild renal impairment do not require adjustment of the dose of lurazidone. In patients with moderate renal failure (creatinine clearance ≥ 30 and < 50 ml/min), severe renal failure (creatinine clearance > 15 and < 30 ml/min) and patients with terminal renal failure (creatinine clearance < 15 ml/min), the recommended starting dose is 20 mg; the maximum dose should not exceed 80 mg once daily. Latuda® is used in patients with terminal renal failure only if the potential benefit exceeds the potential risk of complications. Latuda® should only be used in patients with end-stage renal failure with appropriate clinical monitoring.

Patients with hepatic impairment

Patients with mild hepatic impairment do not require dosage adjustment of Latuda®.

Patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment require dose adjustment. The recommended starting dose is 20 mg. Maximum daily dose in patients with moderate hepatic insufficiency should not exceed 80 mg, in patients with severe hepatic insufficiency should not exceed 40 mg once a day.

Children

The safety and effectiveness of Latuda® in children under 18 years of age has not been established.

Dose adjustment depending on interactions

In concomitant use of Latuda® with moderate CYP3A4 isoenzyme inhibitors, the recommended starting dose is 20 mg; the maximum daily dose should not exceed 80 mg. Dose adjustment may be required when used in combination with weak and moderate CYP3A4 isoenzyme inducers. For concomitant use with strong CYP3A4 isoenzyme inhibitors and inducers, see “Contraindications”.

Transferring patients to treatment with other antipsychotics The pharmacodynamics and pharmacokinetics of different antipsychotics are not the same, so physicians should monitor patients carefully when transferring them from one antipsychotic to another.

Interaction

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

We should use Latuda® concomitantly with QT prolongers such as class IA antiarrhythmic drugs (e.g., quinidine, disopyramide) and class III drugs (e.g., amiodarone, sotalol), some antihistamines, some other antipsychotics and some antimalarials (e.g., mefloquine).

Pharmacokinetic interaction

The concomitant use of lurazidone and grapefruit juice has not been studied. Grapefruit juice inhibits the CYP3A4 isoenzyme and may increase the blood concentration of lurazidone. Grapefruit juice should be avoided during treatment with lurazidone.

The ability of other drugs to affect Latuda®

The pharmacodynamic effects of lurazidone and its active metabolite ID-14283 are mediated by interaction with dopamine and serotonin receptors. Lurazidone and its active metabolite ID-14283 are metabolized primarily with participation of CYP3A4 isoenzyme.

Inhibitors of CYP3A4 isoenzyme

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

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

The concomitant use of lurazidone with moderate CYP3A4 isoenzyme inhibitors (e.g. diltiazem, erythromycin, fluconazole, verapamil) may increase exposure to lurazidone. Moderate CYP3A4 isoenzyme inhibitors are expected to result in a 2-5-fold increase in exposure to CYP3A4 isoenzyme substrates when used concomitantly.

The concomitant use of lurazidone with diltiazem (delayed release dosage form), a moderate CYP3A4 isoenzyme inhibitor, results in a 2.2-fold and 2.4-fold increase in exposure of lurazidone and ID-14283 respectively (see section “Dosage and administration”). Administration of diltiazem in a fast-release dosage form may result in a more pronounced increase in lurazidone exposure.

CYP3A4 isoenzyme inducers

The concomitant use of lurazidone with strong CYP3A4 isoenzyme inducers (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s Wort, see section “Contraindications”) is contraindicated.

The concomitant use of lurazidone with the strong inducer of the CYP3A4 isoenzyme, rifampicin, results in a 6-fold decrease in lurazidone exposure.

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

When co-administered with mild to moderate CYP3A4 isoenzyme inducers, the effectiveness of lurazidone should be carefully monitored and the dose adjusted if necessary.

Lithium

There is no need to adjust the dose of lurazidone when co-administered with lithium preparations.

Valproic acid

There is no need to adjust the dose of lurazidone when co-administered with valproic acid preparations. There have been no studies to investigate interdrug interactions between valproate and Latuda®. Based on pharmacokinetic data from bipolar depression studies, valproic acid concentration had no effect on lurazidone concentration and vice versa.

Lurazidone 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 lurazidone with P-glycoprotein and BCRP inhibitors may increase exposure to lurazidone.

The ability of lurazidone to affect other drugs

Concomitant use of lurazidone with midazolam, a sensitive substrate of the CYP3A4 isoenzyme, results in less than 1.5-fold increase in exposure to midazolam.

A proper monitoring is recommended when using lurazidone and

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

Lurazidone can be used in combination with digoxin (a P-glycoprotein substrate) because their concomitant use did not increase digoxin exposure and only slightly increased C_max (1.3-fold). Lurazidone in vitro is an inhibitor of efflux P-glycoprotein transporter, so the clinical significance of inhibition of P-glycoprotein in the gut cannot be excluded. Simultaneous use of the P-glycoprotein substrate dabigatran etexilate can lead to increased blood concentrations of dabigatran.

Lurazidone in vitro is an inhibitor of the BCRP efflux transporter, so the clinical significance of BCRP inhibition in the intestine cannot be excluded. Concomitant use of lurazidone with BCRP substrates may result in increased concentrations of these substrates in the blood.

The concomitant use of lurazidone with lithium preparations has shown that lithium has no clinically significant effect on the pharmacokinetics of lurazidone. Thus, no dose adjustment of lurazidone is required when used in combination with lithium preparations. Lurazidone has no effect on the concentration of lithium. No dose adjustment of valproic acid drugs is required when used in combination with lurazidone.

According to drug interaction studies, the combined use of lurazidone and combined oral contraceptives, including norgestim and ethinylestradiol, did not result in clinically and statistically significant effects of lurazidone on contraceptive pharmacokinetics or on sex hormone-binding globulin concentrations. Therefore, lurazidone can be used in combination with oral contraceptives.

Special Instructions

In treatment with antipsychotics, improvement in the patient’s clinical condition should be expected within a few days to a few weeks. Proper monitoring of the patient’s condition during this period is necessary.

Suicidal ideation

Suicidal thoughts and attempts are common in patients with psychosis. There are reports of such cases at the beginning of therapy or when the antipsychotic medication is replaced. Therefore, drug antipsychotic therapy should be administered under close medical supervision.

Parkinson’s disease

Cautious use of antipsychotic medications should be used in patients with Parkinson’s disease because this group of patients has an increased sensitivity to antipsychotic medications and an increased risk of exacerbation of Parkinsonian symptoms. Latuda® should only be used in patients with Parkinson’s disease when the potential benefit is greater than the possible risk to the patient.

Extrapyramidal symptoms (EPS)

Drugs with dopamine receptor antagonist properties may cause unwanted extrapyramidal disorders, including rigidity, tremor, mask-like face, dystonia, salivation, posture and gait disorders. According to placebo-controlled CIs in adult patients with schizophrenia, administration of lurazidone was accompanied by an increased incidence of extrapyramidal symptoms compared to placebo.

Late 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. When symptoms of tardive dyskinesia appear, a decision should be made as to whether it is appropriate to withdraw all antipsychotic medications, including lurazidone.

Cardiovascular disease/QT interval prolongation

Patients with diagnosed cardiovascular disease or prolonged QT interval in immediate family members, hypokalemia, and concomitant use with other QT interval prolonging medications should be cautious when prescribing lurazidone.

Falls

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

Convulsions

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

Malignant neuroleptic syndrome

Cases of malignant neuroleptic syndrome characterized by hyperthermia, muscle rigidity, instability of autonomic functions, impaired consciousness and elevated blood creatine phosphokinase activity have been reported when using antipsychotic drugs, including lurazidone. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may develop. In such cases, all antipsychotic drugs, including lurazidone, should be discontinued.

An exacerbation of mania/hypomania

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

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

Elderly patients with dementia

The use of lurazidone has not been studied in elderly patients with dementia.

The overall mortality rate

In a meta-analysis of 17 controlled observational studies in older 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

Randomized placebo-controlled trials in dementia patients treated with atypical antipsychotics, including risperidone, aripiprazole and olanzapine, have shown an approximately 3-fold increased risk of cerebrovascular adverse reactions, the mechanism of which is unknown. An increased risk of cerebrovascular events cannot be ruled out for other antipsychotics or other patient groups. Lurazidone 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 medications are often at risk for venous thromboembolism, all possible risk factors for venous thromboembolic complications should be identified before and during treatment with lurazidone, and preventive measures should be taken.

Hyperprolactinemia

Lurazidone increases prolactin concentration because it is a D₂-dopamine receptor antagonist.

Body weight increase

An increase in body weight has been observed when taking atypical antipsychotic drugs. It is recommended to control body weight.

Hyperglycemia

The use of lurazidone has rarely been associated with adverse reactions associated with changes in glucose concentrations, such as hyperglycemia. Appropriate clinical monitoring is recommended when treating patients with diabetes mellitus and risk factors for diabetes mellitus with lurazidone.

Orthostatic hypotension/fainting

The development of orthostatic hypotension is possible due to the α₁ adrenoreceptor antagonist properties of lurazidone. Proper monitoring of orthostatic hypotension symptoms in patients at risk of decreased blood pressure is recommended.

Renal insufficiency

Adjustment of the dose of lurazidone is recommended in patients with moderate, severe and terminal renal insufficiency. There are no data on the use of lurazidone in patients with terminal renal failure, so lurazidone should only be used when the potential benefit exceeds the possible risk. Treatment with lurazidone in patients with terminal renal failure should be performed under proper patient monitoring.

Hepatic failure

Patients with moderate to severe hepatic impairment (Child-Pugh class B and C, see sections “Administration and Dose” and “Pharmacokinetics”) should have their doses adjusted. Proper patient monitoring is required when using lurazidone in patients with severe hepatic impairment.

Interaction with Grapefruit Juice

Grapefruit juice should be avoided during treatment with lurazidone (see section “Interaction with other medicinal products”).

The remainder of the unused medication must be disposed of in accordance with local requirements.

Impact on the ability to operate vehicles, machinery

Lurazidone has little effect on the ability to operate vehicles and machinery. Patients should be warned about the dangers of driving and operating machinery in cases where there is no conclusive evidence of no adverse reactions in each individual patient (see section “Adverse effects”).

Synopsis

Oval, film-coated tablets with light green color, engraved “L 80” on one side.

Contraindications

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

– concomitant use with strong CYP3A4 isoenzyme inhibitors (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole ritonavir, saquinavir, telaprevir, telithromycin, voriconazole ) and with strong CYP3A4 isoenzyme inducers (e.g., carbamazepine, phenobarbital, phenytoin), rifampicin, St. John’s Wort;

– age less than 18 years (effectiveness and safety not established).

Side effects

Safety Profile Summary

Schizophrenia

The safety of lurazidone was evaluated at doses ranging from 20 to 160 mg in a 52-week follow-up study in patients with schizophrenia and in the post-registration period. The most common adverse drug reactions (ADRs) (≥10%) were akathisia and somnolence, which were dose-dependent at doses up to 120 mg per day.

The NLDs listed below are classified by organ system class and preferred terminology. The frequency of NLDs listed in Table 1 is based on clinical trial data. The frequency of NERs was defined according to the following classification: very common (≥1/10); common (≥1/100 to < 1/10); infrequent (≥1/1000 to < 1/100); rare (≥1/10 000 to < 1/1000); very rare (< 1/10 000), including individual 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 by pooled analysis in patients with schizophrenia

Blurred vision

table border=”1″ cellspacing=”0″ cellpadding=”0″>

Disorders from

Gastrointestinal tract side

Nausea

Vomiting Dyspepsia Hyper-salivation

Mouth dryness Upper abdominal pain A feeling of discomfort in the stomach

Meteorism

Diarrhea****

Dysphagia**** Gastritis****

Disorders with

Liver and biliary tract disorders

Elevation of alanine amino transferase

(ALT)

Skin and subcutaneous tissue disorders

Hyperhidrosis

Rash**** Pruritus**** Angioneurotic edema**** Stevens-

Johnson syndrome

Disorders of the immune system

/td>

Hypersensitivity*****

Skeletal muscular and connective tissue disorders

Skeletal-muscular

stiffness Increased creatine phospho-kinase in the blood

Joint stiffness

Myalgia Neck pain Back pain

Rhabdomyolysis

Disorders from

the renal and

/p>

urinary tract disorders

Increased

creatinine in the blood

Dysuria

Renal

dysuria**

/p>

**

Pregnancy,

Postpartum and perinatal conditions

Newborn withdrawal syndrome in

newborns (see Use in pregnancy and during

breastfeeding

)

Disorders from

the genital and mammary gland side

Increased

/p>

prolactin in the blood

Increased

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

Dysmenorrhea****

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

** The term “parkinsonism” combines the NLD terms: bradykinesia, cogwheel stiffness, drooling, extrapyramidal disorders, hypokinesia, muscle rigidity, parkinsonism, slowed psychomotor activity, and tremor.

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

**** NLRs identified in controlled and uncontrolled phase 2 and 3 CIs, but the small number of cases does not allow frequency estimates.

***** Hypersensitivity may include symptoms such as laryngeal edema, tongue swelling, urticaria, or symptoms of angioedema, rash, or itching (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 daily (n=331).

The most frequently observed HRDs (incidence of new cases ≥ 5% and at least twice as often as for placebo) in patients receiving Latuda® were akathisia, extrapyramidal symptoms, somnolence, nausea, vomiting, diarrhea, and anxiety. There were no reported NLDs that led to treatment discontinuation and occurred in at least 2% of participants who received Latuda® and occurred at least twice as often as with placebo.

Additional therapy with lithium or valproic acid The 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 of 20 to 120 mg daily (n=360).

The most frequently observed NLDs (incidence of new cases ≥ 5% and at least twice as often as for placebo) in patients treated with Latuda® were akathisia and somnolence.

There were no reported ADHDs that led to treatment discontinuation and occurred in at least 2% of participants receiving Latuda® and occurred at least twice as often as with placebo.

Description of Individual Adverse Reactions

In post-registration follow-up, clinically significant skin reactions and other hypersensitivity reactions associated with lurazidone have been reported, including several reports of the development of Stephen-Johnson syndrome.

Reactions of particular interest for this class of drugs

Extrapyramidal symptoms (EPS)

Schizophrenia

. In short-term placebo-controlled studies, the reported incidence of phenomena associated with extrapyramidal disorders, excluding akathisia and anxiety, was 13.5% in patients receiving lurazidone and 5.8% in patients receiving placebo. The incidence of akathisia was 12.9% in patients receiving lurazidone and 3.0% in patients receiving placebo.

Bipolar Depression Monotherapy

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

Additional therapy with lithium or valproic acid preparations

. In short-term placebo-controlled studies of Latuda® as adjunctive therapy for bipolar depression in patients treated with lithium and valproic acid, the incidence of EPS-related NDD, excluding akathisia and anxiety, was 13.9% compared to 8.7% in patients who received placebo.

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

Dystonia

Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may be seen in predisposed patients during the first few days of treatment. Symptoms of dystonia include neck muscle spasm, sometimes developing a feeling of throat constriction, difficulty swallowing, difficulty breathing, and/or tongue protrusion. Although these symptoms may appear at low doses, they occur more frequently and with greater severity when first-generation antipsychotic medications are used at high doses. There is an increased risk of acute dystonia 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 listed in the instructions worsen, or if you notice any other side effects not listed in the instructions, tell your doctor.

Overdose

Treatment

There is no specific antidote for lurazidone; therefore, in case of overdose, appropriate symptomatic therapy should be given. Proper monitoring of the patient’s condition and basic physiological functions should be continued until they are restored. Cardiovascular monitoring should be started immediately, including continuous ECG recording in order to detect possible arrhythmias. If antiarrhythmic therapy is necessary, it should be taken into account that drugs such as disopyramide, procainamide and quinidine may potentially prolong the QT interval in patients with acute lurazidone overdose. The alpha-blocking effect of bretylium may combine with the same effect of lurazidone and lead to hypotension.

Hypotension and vascular collapse are controlled with appropriate therapy. Drugs that stimulate beta-adrenoreceptors may exacerbate hypotension with lurazidone-induced alpha-adrenoreceptor blockade, so adrenaline, dopamine and other sympathomimetics that stimulate beta-adrenoreceptors should not be used in case of lurazidone 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 pain sensitivity, seizures, or head and neck dystonia due to overdose may create a risk of aspiration when vomiting occurs.

Pregnancy use

Use in pregnancy

Data on the use of lurazidone in pregnant women are limited (less than 300 pregnancy outcomes have been evaluated). There are insufficient animal studies to evaluate the effects on pregnancy, embryonic and fetal development, delivery, and postnatal development. The potential risk to humans is not known.

Latuda® should not be used in pregnancy unless clearly needed.

If a woman takes antipsychotic drugs, including lurazidone, in the third trimester of pregnancy, there is a risk of adverse reactions, including extrapyramidal disorders and/or withdrawal syndrome of varying severity, in the newborn. Agitation, hypertension, hypotension, tremor, somnolence, respiratory disturbances, or feeding disturbances have been reported. Consequently, careful monitoring of newborns in such cases is necessary.

Breast-feeding period

Lurazidone has been found to be excreted into the milk of rats in animal studies. There is no information about the ability of lurazidone or its metabolites to penetrate into human breast milk. Administration of Latuda® to breastfeeding women is possible only when the potential benefit to the mother is greater than the potential risk of complications to the baby.

Fertility

Animal studies have shown effects of the drug on fertility mainly related to an increase in prolactin concentration, which is not related to human reproduction.