Instruction for use: Lurasidone

The Latin name of the substance Lurasidone

Lurasidonum (genus. Lurasidoni)

Chemical name

(3aR, 4S, 7R, 7aS) -2 - ((1R, 2R) -2- (4- (1,2-Benzothiazol-3-yl) piperazin-1-yl methylcyclohexylmethyl) hexahydro-4,7- 2H-isoindole-1,3-dione

Gross formula

C₂₈H₃₆N₄O₂S

Pharmacological group:

Neuroleptics

The nosological classification (ICD-10)

F20.9 Schizophrenia, unspecified: Delusions in schizophrenia; Sluggish schizophrenia with apathoabulic disorders; Schizophrenic disorders

CAS Code

367514-87-2

Pharmacology

Pharmacological action - antipsychotic, neuroleptic.

Mechanism of action. Selective antagonist of dopamine and monoamine receptors, which has a high affinity for D2-dopamine and 5HT2A- and 5HT7-serotonin receptors (Ki = 0.994, 0.47 and 0.495 nM, respectively). Lurasidone also blocks α2C- and α2A-adrenoreceptors (Ki = 10.8 and 40.7 nM, respectively), has partial agonism to 5HT1A-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 secondary active metabolite lurasidone, ID-14283, is the same as that of lurasidone.

According to positron emission tomography, the use of lurasidone in the dose range of 9 to 74 mg (10 to 80 mg of lurasidone hydrochloride) in healthy volunteers resulted in a dose-dependent decrease in the binding of 11C-rakloprid, the D2- / D3 receptor ligand, in the caudate nucleus, shell and ventral striatum.

Pharmacodynamics

In the main clinical trials of efficacy, lurasidone was administered at doses of 40 to 160 mg.

Clinical data. The efficacy of lourazidone in the treatment of schizophrenia was demonstrated in 5 multicenter, placebo-controlled, double-blind, 6-week clinical trials in patients meeting the criteria for the Diagnostic and Statistical Manual of Mental Disorders, IV edition (RDPR-IV). Dosages of lurasidone, different in five studies, were 40 to 160 mg once daily. In the case of short-term clinical trials, the primary efficacy was defined as the mean change in the score by the 6th week of therapy relative to the baseline value by the Scale of Positive and Negative Syndromes (SPMS, validated questionnaire, including 5 factors for assessing positive symptoms, negative symptoms, disorganized thinking, uncontrolled hostility / arousal and anxiety / depression). Lurasidone has been shown to be more effective than placebo in Phase III studies. Statistically significant differences from placebo were registered on the 4th day of therapy. In addition, lurasidone was superior to placebo according to a pre-determined secondary efficacy index-the Score of the General Clinical Impression of Severity (SHOCK-T). Efficacy was also confirmed by the results of a secondary analysis of the response to treatment (a decrease of> 30% relative to the baseline value for the sum of SPMS points). In the short-term studies, there was no consistent dose-response relationship.

The long-term efficacy of lurasidone at doses of 40 to 160 mg once daily is demonstrated in a 12-month efficacy study compared with quetiapine with sustained-release (XR) (200 to 800 mg once daily). Lurasidone was no less effective than quetiapine XR, due to the effect on the duration of the remission of schizophrenia. After 12 months of application of lurasidone, a relatively larger increase in body weight and a BMI from the baseline were observed, mean (standard deviation) of 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). In general, lurasidone had little effect on weight and other metabolic parameters, including the concentration of total cholesterol, triglycerides and glucose.

In a long-term safety study, clinically stable patients received 40 to 120 mg of lurasidone or risperidone at a dose of 2 to 6 mg. In this study, the relapse rate for 12 months was 20% with lurasidone and 16% with risperidone. This difference has approached statistically significant, but has not reached that.

In long-term studies of the duration of the effect, the duration of the symptom control period and the disease-free period of schizophrenia was greater in patients receiving lurasidone than in patients receiving placebo. After relief of acute attacks and stabilization of the condition for 12 weeks with lurasidone, patients were randomized with a double-blind method to continue taking lurasidone or placebo before relapse of symptoms of schizophrenia. A primary analysis of the duration of the period prior to relapse was carried out by censoring the data of those patients who completed the study before relapse. There was a greater duration of the disease-free period in patients receiving lurasidone, compared with patients in the placebo group (p = 0.039). The probability of recurrence at the 28th week by the Kaplan-Mayer method was 42.2% in the lurasidone group and 51.2% in the placebo group. The probability of discontinuing 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).

Pharmacokinetics

Suction. Tmax in the blood is 1 to 3 hours. After taking lurasidone with food, the average Cmax and AUC increased 2-3 and 1.5-2 times, respectively, compared with the values after taking lurasidone on an empty stomach.

Distribution. After oral administration of 40 mg of lurasidone, the average apparent Vd was approximately 6,000 liters. Lurasidone is significantly (by 99%) bound by plasma proteins.

Metabolism. Lurasidone is metabolized mainly with the participation of the CYP3A4 isoenzyme. The main ways of metabolism are oxidative N-dealkylation, hydroxylation of the non -bornane ring, S-oxidation.

Lurasidone is metabolized with the formation of two active metabolites (ID-14283 and ID-14326) and two inactive metabolites (ID-20219 and ID-20220). The share of lourazidone and its metabolites (ID-14283, ID-14326, ID-20219 and ID-20220) accounted for approximately 11.4; 4.1; 0.4; 24 and 11% of the radioactivity of the plasma, 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, it was found that lurasidone is not a substrate for the isoenzymes CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1.

In in vitro studies, lourazidone showed no direct or weak inhibitory effect (direct or time-dependent, 105.9 μmol) for the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. Based on these data, the effect of lurasidone on the pharmacokinetics of drugs that are substrates of the isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1 is not expected.

In vitro studies, it was found that lurasidone is a substrate for the efflux carriers of P-gp and BCRP. Lurasidone is not a substrate for active transport by transport polypeptides of organic anions OATP1B1 and OATP1B3.

In vitro studies also show that lurasidone is an inhibitor of P-gp, BCRP, and organic-type transporters of the first type (OCT1). Lurasidone does not have a clinically significant inhibitory effect on OATP1B1, OATP1B3, the transporters of organic cations of the second type (OCT2), the transporters of organic anions of the first (OAT1) and the third type (OAT3), the renal transporter MATE1 and MATE2K or the exporting bile acid pump (BSEP).

Excretion. T1 / 2 is about 20-40 hours. After ingestion of lurasidone labeled with a radioactive isotope, about 67% of the dose is excreted by the intestine 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 proportional to the dose in the range of the total daily dose of 20 to 160 mg. Cs lurasidone is reached within 7 days of the initiation of therapy.

Special patient groups

Patients of advanced age. Data on the pharmacokinetics of lurasidone in healthy elderly volunteers (> 65 years) are limited. According to the obtained results, the concentration of lurasidone in the plasma of elderly healthy volunteers is identical to its concentration in the plasma of volunteers of younger age (under 65 years). However, one can expect an increase in lurasidone concentration in the plasma of elderly patients with impaired renal or hepatic function.

Violation of the function of the liver. In patients with mild (class A on the Child-Pugh scale), secondary (class B on the Child-Pugh scale) and severe (class C on the Child-Pugh scale), heuricidone AUC increases by 1.5; 1.7 and 3 times, respectively.

Impaired renal function. In patients with mild, moderate and severe renal insufficiency, the AUC of lurasidone is increased by 1.5; 1.9 and 2 times, respectively. There are no clinical data on the use of lourazidone in patients with terminal renal failure (Cl creatinine <15 mL / min).

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

Race affiliation. Population pharmacokinetic analysis did not reveal a clinically significant effect of the racial affiliation of schizophrenic patients on the pharmacokinetics of lurasidone. It was noted that in healthy volunteers of the Mongoloid race the AUC increased 1.5 times as compared to volunteers of the European race.

Smoking. In vitro studies using human hepatic enzymes have shown that lurasidone is not a substrate for the isoenzyme CYP1A2, so 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 at a daily dose of 20, 40, 80, 120 mg (6-17 years) or 160 mg (only to patients 10-17 years old) for 7 days. There was no clear correlation between the concentration of lurasidone in plasma and age or body weight. The pharmacokinetic parameters of lurasidone in children aged 6-17 years were generally comparable to those of adults.

Application of substance Lurasidone

Schizophrenia in adults (aged 18 and over).

Contraindications

Hypersensitivity; simultaneous application with strong inhibitors of the isoenzyme CYP3A4 (eg, bocetrevir, clarithromycin, cobicystate, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and strong inducers of the isoenzyme CYP3A4 (eg carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort pitted); age to 18 years (efficacy and safety not established).

Application in pregnancy and lactation

Data on the use of lurasidone in pregnant women are limited (estimated less than 300 pregnancy outcomes). Animal studies are not sufficient to assess the impact on pregnancy, fetal and fetal development, childbirth and postnatal development. The potential risk to humans is unknown.

Lurazidone should not be used during pregnancy, except in cases of obvious need.

In the case of a woman taking antipsychotic drugs, including lurasidone, in the third trimester of pregnancy in newborns there is a risk of developing unwanted reactions, including extrapyramidal disorders and / or withdrawal syndrome of varying severity. There was agitation, hypertension, hypotension, tremor, drowsiness, respiratory disorders or disturbances in the feeding process. Therefore, in such cases it is necessary to carry out careful monitoring of newborns.

In animal studies, it was found that lurasidone is excreted into the milk of rats. Information on the ability of lurasidone or its metabolites to penetrate into human milk is not available. The appointment of lurasidone to lactating women is possible only in cases where the potential benefit of treatment for the mother exceeds the potential risk of complications for the child.

Fertility. Studies in animals have shown the effect of lurasidone on fertility, mainly associated with an increase in the concentration of prolactin, which is not related to human reproductive function.

Side effects of Lurasidone

Security Profile Summary

The safety of lurasidone was evaluated against the background of its use in doses of 20 to 160 mg in clinical trials in patients with schizophrenia for 52 weeks and in the post-marketing period. The most frequent adverse reactions (> 10%) were akathisia and drowsiness, which were dose-dependent when taken at doses up to 120 mg per day. The adverse reactions listed below are classified according to the class of organ systems and preferred terminology. The frequency of these reactions is determined from clinical trials and is given in accordance with WHO recommendations: very often (≥1 / 10); often (from ≥1 / 100 to <1/10); infrequently (from ≥1 / 1000 to <1/100); rarely (from> 1/10000 to <1/1000); very rarely (<1/10000), including individual messages; the frequency is unknown (the frequency can not be determined from the available data). Within each group, undesirable reactions are presented in order of decreasing severity.

Infectious and parasitic diseases: infrequently - nasopharyngitis.

On the part of the blood and lymphatic system: rarely - eosinophilia; frequency unknown - leukopenia1, neutropenia1, anemia1.

From the side of metabolism and nutrition: often - an increase in body weight; infrequently - decreased appetite, increased blood glucose levels.

Disorders of the psyche: often - insomnia, agitation, anxiety, anxiety; infrequently - nightmarish dreams, catatonia; frequency unknown - suicidal behavior1, panic attack1, sleep disturbance1.

From the nervous system: very often - akathisia, drowsiness; often - parkinsonism3, dizziness, dystonia4, dyskinesia; infrequently - lethargy, diazartria, tardive dyskinesia; rarely - malignant neuroleptic syndrome; frequency is unknown - convulsions1.

From the side of the organ of vision: infrequently - blurred vision.

From the side of the hearing organ and labyrinthine disturbances: the frequency is unknown - vertigo1.

From the heart: infrequently - tachycardia; the frequency is unknown - angina pectoris1, AV blockade of I degree1, bradycardia1.

From the side of the vessels: infrequently - hypertension, hypotension, orthostatic hypotension, hot flashes, increased blood pressure.

From the digestive system: often - nausea, vomiting, indigestion, hypersalivation, dry mouth, pain in the upper abdomen, a feeling of discomfort in the stomach; infrequently - flatulence; frequency unknown - diarrhea1, dysphagia1, gastritis1.

From the side of the liver and bile ducts: infrequently - increase in ALT level.

From the skin and subcutaneous tissues: infrequently - hyperhidrosis; frequency unknown - rash1, itching1, angioedema, Stevens-Johnson syndrome.

From the side of the immune system: the frequency is unknown - hypersensitivity5.

From the musculoskeletal system and connective tissue: often - musculoskeletal rigidity, elevation of the level of CK in the blood; infrequent - stiffness in the joints, myalgia, neck pain, back pain; rarely rhabdomyolysis.

From the side of the kidneys and urinary tract: often - an increase in the level of creatinine in the blood; infrequently - dysuria; frequency unknown - renal failure1.

Pregnancy, postpartum and perinatal conditions: the frequency is unknown - withdrawal syndrome in newborns (see "Application in pregnancy and lactation").

From the genitals and mammary glands: infrequently - an increase in the level of prolactin in the blood; frequency unknown - breast enlargement1, pain in the mammary gland1, galactorrhea1, erectile dysfunction1, amenorrhea1, dysmenorrhea1.

General disorders and disorders at the injection site: often - fatigue; infrequently - gait disturbance; frequency unknown - sudden death associated with an existing cardiovascular disease, observed during clinical trials1.

1 Unfavorable reactions revealed in controlled and uncontrolled clinical trials of Phase II and III, but a small number of cases do not allow for the frequency assessment.

2The term "drowsiness" combines the terms "hypersomnia", "hypersomnolence", "sedation" and "drowsiness".

The term "parkinsonism" combines the terms "bradykinesia", "stiffness" like "cogwheel", "drooling", "extrapyramidal disorders", "hypokinesia", "muscle stiffness", "parkinsonism", "slowing of psychomotor activity" and "tremor" .

4The term "dystonia" combines the terms "dystonia", "oculogic crisis", "oromandibular dystonia," "spasm of the tongue," "torticollis," and "trismus."

5Hypersensitivity may include symptoms such as laryngeal edema, swelling of the tongue, urticaria, or symptoms of angioedema, rash or itching (listed under Skin and subcutaneous tissue disorders).

Description of individual adverse reactions

In the postgrade monitoring process, clinically relevant skin reactions and other hypersensitivity reactions associated with lurasidone have been reported, including several reports of the development of Stephen-Johnson syndrome.

Extrapyramidal symptoms. According to data from short-term placebo-controlled studies, the incidence of reported phenomena associated with extrapyramidal disorders, except for akathisia and anxiety, 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%, in patients receiving placebo, 3%.

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

VTE. When using antipsychotic drugs, cases of VTE, incl. PE and deep vein thrombosis. The frequency of VTE development is unknown.

Interaction

Pharmacodynamic interaction

Since lourazidone acts primarily on the central nervous system, care must be taken when it is used in combination with other central-action drugs and alcohol.

Caution should be exercised when concomitantly administering lurasidone with drugs extending the QT interval, such as class IA antiarrhythmics (eg, quinidine, disopyramide) and III (eg amiodarone, sotalol), certain antihistamines, other antipsychotic and antimalarial drugs (eg mefloquine).

Pharmacokinetic interaction

Simultaneous use of lourazidone and grapefruit juice has not been studied. Grapefruit juice inhibits the isoenzyme CYP3A4 and can increase the concentration of lurasidone in the blood. Avoid the use of grapefruit juice during treatment with lurasidone.

The effect of other drugs on lurasidone

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 with the participation of the CYP3A4 isoenzyme.

Inhibitors of the isoenzyme CYP3A4. Contraindicated the use of lurasidone with strong inhibitors of the isoenzyme CYP3A4 (for example, bocepreviir, clarithromycin, cobicystate, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) (see Contraindications).

Simultaneous use of lurasidone with a strong inhibitor of the CYP3A4 isoenzyme ketoconazole results in a 9- and 6-fold increase in the effect of lurasidone and its active metabolite ID-14283, respectively.

Simultaneous use of lurasidone with moderate inhibitors of the CYP3A4 isoenzyme (eg diltiazem, erythromycin, fluconazole, verapamil) may increase the exposure of lurasidone. It is assumed that with simultaneous use, moderate inhibitors of the CYP3A4 isoenzyme result in a 2-5 fold increase in the exposure of the CYP3A4 isoenzyme substrates.

Simultaneous use of lourazidone with delayed release diltiazem (moderate inhibitor CYP3A4) leads to an increase in the exposure of lurasidone and ID-14283 by 2.2 and 2.4 times, respectively. The administration of diltiazem in a rapid-release dosage form may result in a more pronounced increase in lurasidone exposure.

Inductors of isoenzyme CYP3A4. Contraindicated the simultaneous use of lurasidone with strong inducers of the isoenzyme CYP3A4 (eg carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort) (see "Contraindications").

Simultaneous use of lurasidone with a strong inducer of CYP3A4 isoenzyme rifampicin results in a 6-fold decrease in lurasidone exposure.

The use of lourazidone in combination with the weak (eg armomofinil, amprenavir, aprepitant, prednisolone, rubinamide) or moderate (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) inductors of the isoenzyme CYP3A4 presumably may result in less than 2-fold decrease in lurasidone exposure during administration and for up to 2 weeks after the cessation of reception of inducers of the isoenzyme CYP3A4.

When combined with weak and moderate inductors of the CYP3A4 isoenzyme, the effectiveness of lurasidone should be carefully monitored and the dose adjusted if necessary.

Conveyors. Lurasidone is a substratum of P-gp and BCRP in vitro, but the significance of this property in vivo is not established. Simultaneous use of lourazidone with P-gp and BCRP inhibitors may increase the exposure of lurasidone.

Effect of lurasidone on other drugs

Simultaneous reception of lurasidone with midazolam, a sensitive substrate of the isoenzyme CYP3A4, leads to an increase in the exposure of midazolam by less than 1.5 times. It is recommended that appropriate monitoring is observed when sharing lurasidone and substrates of the CYP3A4 isoenzyme with a known narrow therapeutic range (for example, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids (ergotamine, dihydroergotamine).

You can use lourazidone in combination with digoxin (substrate P-gp), tk. with the simultaneous use of these substances, the exposure of digoxin did not increase and only Cmax increased by a factor of 1.3. Lurasidone in vitro is an inhibitor of the efflux P-gp transporter, so the clinical significance of Pgp inhibition in the intestine can not be ruled out. Simultaneous use of the substrate P-gp dabigatran etexilate can lead to an increase in the concentration of dabigatran in the blood.

Lurasidone in vitro is an inhibitor of the efflux transporter BCRP, so the clinical significance of inhibition of BCRP in the intestine can not be ruled out. The simultaneous use of lurasidone with BCRP substrates may increase the concentration of these substrates in the blood.

Simultaneous use of lourazidone with lithium preparations showed that lithium does not have a clinically significant effect on the pharmacokinetics of lurasidone. Thus, dose adjustment of lourazidone is not required when used in combination with lithium preparations. Lurasidone does not affect the concentration of lithium.

According to drug interaction studies, the combined use of lurasidone and COC, including norgestim and ethinylestradiol, did not result in a clinically and statistically significant effect of lurasidone on the pharmacokinetics of contraceptives or the concentration of SHBG. Consequently, lurasidone can be used in combination with oral contraceptives.

Overdose

Treatment: there is no specific antidote for lurasidone, therefore, in case of an overdose, appropriate symptomatic therapy should be performed. Proper monitoring of the patient's condition and basic physiological functions must be continued until they are restored. It is necessary to immediately begin monitoring of cardiovascular activity, including continuous registration of the ECG in order to identify possible arrhythmias. If antiarrhythmic therapy is necessary, it should be borne in mind that drugs such as disopyramide, procainamide, and quinidine can potentially increase the QT interval in patients with acute overdose of lurasidone. The alpha-blocking effect of brethil tosylate can be added to the similar action of lurasidone and lead to hypotension.

Hypotension and vascular collapse are treated with appropriate therapy. Drugs that stimulate beta-adrenergic receptors may aggravate hypotension in conditions of lurasidone-induced blockade of alpha-adrenergic receptors, therefore epinephrine, dopamine and other sympathomimetics stimulating beta-adrenoreceptors should not be used in case of an overdose of lurasidone. When severe extrapyramidal symptoms occur, anticholinergics should be administered.

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

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

Routes of administration

Inside.

Precautions for the substance Lurasidone

In the treatment of antipsychotic drugs, the improvement in the clinical state of the patient should be expected within a few days to several weeks. Proper monitoring of the patient's condition during this period is necessary.

Suicidal intentions

Propensity to suicidal thoughts and attempts is characteristic for patients with psychosis. There are reports of such cases at the beginning of therapy or when replacing an antipsychotic drug. Therefore, drug antipsychotic therapy should be conducted under close medical supervision.

Parkinson's disease

Caution should be exercised when using antipsychotic drugs in patients with Parkinson's disease. in this group of patients sensitivity to antipsychotic drugs and the risk of exacerbation of parkinsonism symptoms are increased. Lurasidone can be used in patients with Parkinson's disease only in cases where the potential benefit exceeds the possible risk to the patient.

Extrapyramidal symptoms

Drugs that have the properties of dopamine receptor antagonists can cause unwanted extrapyramidal disorders, including rigidity, tremor, masculine face, dystonia, drooling, violation of posture and gait. According to placebo-controlled clinical trials in adults with schizophrenia, lurasidone was associated with an increase in the incidence of extrapyramidal symptoms compared with placebo.

Late dyskinesia

LS with the properties of dopamine receptor antagonists can cause tardive dyskinesia, which is characterized by rhythmic involuntary movements, especially of the tongue and / or face. When symptoms of tardive dyskinesia appear, it should be decided whether all antipsychotic drugs should be withdrawn, incl. lurasidone.

Cardiovascular diseases / QT interval prolongation

Caution should be exercised when administering lourazidone to patients with diagnosed cardiovascular diseases or an extended QT interval in the immediate family, hypokalemia, and also with simultaneous use with other drugs extending the QT interval.

Convulsions

Caution should be exercised in prescribing lurasidone to patients with seizures in the anamnesis or other conditions that potentially reduce the threshold of convulsive activity.

Malignant neuroleptic syndrome

There have been reports of malignant neuroleptic syndrome, characterized by hyperthermia, muscle rigidity, unstable autonomic functions, impaired consciousness and increased activity of CK in the blood with the use of antipsychotic drugs, incl. lurasidone. In addition, the development of myoglobinuria (rhabdomyolysis) and acute renal failure is possible. In such cases, it is necessary to cancel all antipsychotic drugs, including lurasidone.

Elderly patients with dementia

In elderly patients with dementia, the use of lourazidone has not been studied.

Total mortality rate

According to a meta-analysis of 17 controlled clinical trials, in elderly patients with dementia in the treatment of other atypical antipsychotic drugs, including risperidone, aripiprazole, olanzapine and quetipine, an increase in the overall mortality rate was noted compared with placebo.

Cerebrovascular disorders

According to randomized, placebo-controlled clinical trials, patients with dementia in the treatment of atypical antipsychotic drugs, including risperidone, aripiprazole and olanzapine, experienced an approximately 3-fold increase in the risk of cerebrovascular unwanted reactions, the mechanism of which is unknown. It is impossible to exclude an increased risk of cerebrovascular disorders for other antipsychotic drugs or other groups of patients. Lurazidone should be used with caution in elderly patients with dementia who have risk factors for stroke.

VTE

When using antipsychotic drugs, cases of VTE were noted. Since patients who take antipsychotic drugs often have a risk of developing VTE, all possible risk factors for venous thromboembolic complications should be identified before and during treatment with lurasidone and preventive measures should be taken.

Hyperprolactinemia

Lurasidone increases the concentration of prolactin, tk. is an antagonist of D2-dopamine receptors.

Weight gain

When taking atypical antipsychotic drugs, there was an increase in body weight. It is recommended to control body weight.

Hyperglycaemia

According to clinical studies, the use of lurasidone in rare cases was accompanied by the development of unwanted reactions associated with changes in glucose concentration, for example, hyperglycemia. Appropriate clinical control is recommended in the treatment of lurasidone in patients with diabetes mellitus and risk factors for diabetes mellitus.

Orthostatic hypotension / syncope

Perhaps the development of orthostatic hypotension due to the presence of lurasidone properties of the α 1 -adrenoreceptor antagonist. It is recommended to properly monitor the symptoms of orthostatic hypotension in patients at risk of BP reduction.

Renal insufficiency

It is recommended to correct the dose of lourazidone in patients with moderate, severe and terminal renal insufficiency. There is no data on the use of lourazidone in patients with terminal renal insufficiency, so lurasidone can be used only in cases where the potential benefit exceeds the possible risk. Lurasidone treatment of patients with terminal renal insufficiency should be performed under proper control of the patient's condition.

Liver failure

It is recommended to correct the dose of lurasidone in patients with moderate and severe hepatic insufficiency (class B and C on the Child-Pugh scale). Proper monitoring of the patient's condition with lurasidone in patients with severe hepatic impairment is mandatory.

Interaction with grapefruit juice

Avoid the use of grapefruit juice when treated with lurasidone (see "Interaction").

Influence on the ability to drive vehicles and work with machinery. Lurasidone has little effect on the ability to drive vehicles and work with machinery. Patients should be warned about the danger of driving vehicles and working with mechanisms in cases where there is no conclusive evidence that there are no undesirable reactions in each individual patient (see "Side effects").