Latuda - instructions for use, dose, side effects, contraindications

Active substanceLurasidoneLurasidone

Similar drugsTo uncover

Latuda®

pills inwards

Takeda Pharma A / S Denmark

Dosage form: & nbspTfilm-covered abeys.

Composition:

1 tablet of 20 mg contains:

Active substance: lurasidone hydrochloride 20 mg;

Excipients: core - mannitol 35.5 mg, pregelatinized starch 20 mg, croscarmellose sodium 1 mg, hypromellose 2910 2.5 mg, magnesium stearate 1 mg; film sheath - Opadrai® white * 1.638 mg, carnauba wax 0.01 mg.

1 tablet of 40 mg contains:

Active substance: lurasidone hydrochloride 40 mg;

Excipients: core - mannitol 71 mg, pregelatinized starch 40 mg, croscarmellose sodium 2 mg, hypromellose 2910 5 mg, magnesium stearate 2 mg; film sheath - Deficient white * 2.6 mg, carnauba wax 0.01 mg.

1 tablet of 80 mg contains:

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 sheath - Deficient white * 4,128 mg, iron oxide dye yellow 0.08 mg, indigocarmine lacquer aluminum 0.11 mg, carnauba wax 0.01 mg.

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

Description:

Tablets of 20 mg: round tablets, covered with a film shell from white to almost white, with an engraving "L 20 "on one side.

Tablets 40 mg: round tablets, covered with a film shell from white to almost white, with an engraving "L 40 "on one side.

Tablets 80 mg: oval tablets, covered with a film shell of light green color, with an engraving "L 80 "on one side.

Pharmacotherapeutic group:antipsychotic agent (antipsychotic)

ATX: & nbsp

Lurasidone

Pharmacodynamics:

Mechanism of action

Lurasidone is a selective antagonist of dopamine and monoamine receptors, which has a high affinity for D₂dopamine and 5HT_2A- and 5NT₇-serotonin receptors (K_i = 0.994, 0.47 and 0.495 nM, respectively). Lurasidone also blocks α₂c- and α₂a-adrenergic receptors (affinity level of 10.8 and 40.7 nM, respectively), has partial agonism to 5HT_1Aserotonin receptors with an affinity degree of 6.38 nM. Lurasidone does not bind to histamine and muscarinic receptors.

The mechanism of action of the secondary active metabolite of lourazidone, ID-14283, 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 binding ¹¹C-raclopride, ligand D₂/D₃ receptors, in the caudate nucleus, the shell and the ventral striatum.

Pharmacodynamics

In basic clinical studies (CI) of efficacy lourazidone administered at doses of 40 to 160 mg.

Clinical data

The efficacy of lurasidone in the treatment of schizophrenia was demonstrated in 5 multicenter, placebo-controlled, double-blind 6-week CIs in patients who meet the criteria for the Diagnostic and Statistical Manual of Mental Disorders, IV edition (RDPR-IV). Doses of lurasidone, different in five CIs, were 40 to 160 mg once a day. In the course of short-term CI, the primary efficacy index 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 demonstrated greater efficacy compared with placebo in phase 3 studies. Statistically significant differences from placebo were recorded as early as the 4th day of therapy. Besides, lourazidone was superior to placebo according to a predetermined 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 short-term studies, there was no evidence of dose-response dependence.

The long-term efficacy of lurasidone at doses of 40 to 160 mg once daily is demonstrated in a 12-month study of no less efficacy compared to quetiapine with sustained release (XR) (200 to 800 mg once a day). Lurasidone was no less effective than quetiapine XR, on the effect on the duration of remission of schizophrenia. After 12 months of application of lurasidone, a relatively larger increase in body weight and body mass index from the initial value (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). Generally, lourazidone 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 lourazidone or risperidone in 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 lourazidone, compared with 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 until the symptoms of schizophrenia recurred. 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 long duration of the disease-free period in patients who received lourazidone, compared with patients in the placebo group (p = 0.039).The probability of recurrence at 28 weeks 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

Time to reach the maximum concentration (C_mOh) in the blood is 1 to 3 hours. After taking lurasidone with food, the average C_mOh and the area under the "concentration-time" curve (AUC) increased in 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 lourazidone, the average apparent volume of distribution was approximately 6,000 liters. Lurasidone significantly (by 99%) is associated with plasma proteins.

Metabolism

Lurasidone is metabolized mainly with the participation of the isoenzyme of the cytochrome P system₄₅₀ (CYP) 3A4. The main ways of metabolism are oxidative N-dealkylation, hydroxylation of the non-boron ring, S-oxidation.

Lurasidone is metabolized with the formation of two active metabolites (ID-14283 and ID- 14326) and two non-active metabolites (ID-20219 and ID-20220). The share of lourazidone and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 is about 11.4; 4.1; 0.4; 24 and 11% of the plasma radioactivity, respectively.

Active metabolite ID-14283 is metabolized, mainly with the participation of isoenzyme CYP3A4.

The pharmacodynamic effect is due to the action of lurasidone and its active metabolite ID-14283 on dopamine and serotonin receptors.

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

In studies in vitro lurasidone showed no direct or weak inhibitory effect (direct or time-dependent, 105.9 μmol) with respect to 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 isoenzymes CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. In the administration of drugs with a narrow therapeutic range, which are the substrates of the isoenzyme CYP3A4, see section "Interaction with other drugs".

In studies in vitro it was revealed that lourazidone is a substrate for efflux carriers of P-glycoprotein and breast cancer resistance protein (BCRP). Lurasidone is not a substrate for active transport using transport polypeptides of organic anions OATP1B1 and OATP1B3.

Also research in vitro show that lourazidone is an inhibitor of P-glycoprotein, BCRP and transporters of organic cations of the first type (OST1). Lurasidone has no clinically significant inhibitory effect on OATP1B1, OATP1B3, the transporters of organic cations of the second type (OCT2), the transporters of the organic anions of the first (OAT1) and the third type (OAT3), the renal transporter MATE1 and MATE2K or the exporting pump of bile acidsBSEP).

Excretion

The half-life is about 20-40 hours. After ingestion of lurasidone labeled with a radioactive isotope, about 67% of the drug 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. The equilibrium concentration of lourazidone is reached within 7 days from the start of therapy.

Pharmacokinetics in specific patient groups

Elderly patients

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, we can expect an increase in lurasidone concentration in the plasma of elderly patients with impaired renal or hepatic function.

Patients with impaired hepatic function

In patients with mild (Class A Child-Pugh classification), secondary (class B according to the Child-Pugh classification) and severe (class C according to the Child-Pugh classification), hepatic impairment AUC lurasidone is increased by 1.5; 1.7 and 3 times, respectively.

Patients with impaired renal function

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

Gender identity

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

Race

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 AUC increased by 1.5 times in comparison with the volunteers of the European race.

Smoking

Research in vitro using human hepatic enzymes have shown that lourazidone is not a substrate of 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, in general, were comparable to those of adults.

Indications:

For the treatment of schizophrenia in adults aged 18 years and older.

Contraindications:

- Hypersensitivity to the active substance or any other components of the drug listed in the "Composition" section;

- simultaneous application with strong inhibitors of isoenzyme CYP3A4 (for example, with bocepreviram, clarithromycin, cobicystate, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and with strong isoenzyme inducers CYP3A4 (for example, with carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort perforated);

- age under 18 years (efficiency and safety not established).

Pregnancy and lactation:

Application during pregnancy

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.

Preparation Latum® should not be used during pregnancy, except in cases of obvious need.

In the case of a woman taking antipsychotics, including lourazidone, 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.

Breastfeeding period

In animal studies, it was found that lourazidone excreted in the milk of rats. Information on the ability of lurasidone or its metabolites to penetrate into human milk is not available. The appointment of Latuda® to nursing 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 the drug on fertility, mainly associated with an increase in the concentration of prolactin, which is not related to human reproductive function.

Dosing and Administration:

For oral administration.

The drug Latuda® in film-coated tablets is taken orally once a day with meals.The expected exposure of lourazidone when taken on an empty stomach is significantly lower compared to the exposure when taken during meals (see section "Pharmacokinetics").

The tablet of the preparation Latuda® is recommended to be swallowed whole to mask the bitter taste. Tablets should be taken every day at the same time to adhere to the therapy regimen.

The recommended initial dose of lurasidone hydrochloride is 40 mg once a day. Titration is not required. The effect is achieved in the dose range from 40 to 160 mg per day. The dose of lurasidone can be increased by the doctor's decision on the basis of a clinical response.

The maximum daily dose should not exceed 160 mg.

Patients receiving a daily dose of more than 120 mg of lurasidone hydrochloride, who discontinued treatment for more than 3 days, should resume admission, starting at 120 mg, and then increasing the dose to the optimal dose.

Patients receiving other doses may resume admission, starting with the previous dose without increasing it.

Special patient groups

Patients of advanced age (65 years and older)

No dose adjustment is required in elderly patients with preserved renal function (creatinine clearance> 80 ml / min).However, with a decrease in renal function in elderly patients, dose adjustment may be required depending on the degree of renal failure (see subsection "Patients with impaired renal function" below).

There are limited data on the treatment of elderly patients with high doses of lurasidone. Information about the use of the drug Latuda® at a dose of 160 mg for the treatment of elderly patients is absent. Care should be taken when treating patients aged 65 years and older with high doses of Latuda®.

Patients with impaired renal function

Patients with mild renal insufficiency are not required to adjust the dose of lourazidone. In patients with moderate renal insufficiency (creatinine clearance> 30 and <50 ml / min), severe severity (creatinine clearance> 15 and <30 ml / min) and patients with terminal renal insufficiency (creatinine clearance <15 ml / min ) the recommended initial dose is 20 mg; The maximum dose should not exceed 80 mg once a day. Latuda ® is used in patients with terminal renal failure only if the potential benefit exceeds the potential risk of complications.The use of Latuda® in patients with terminal renal insufficiency follows only with proper clinical monitoring.

Patients with impaired hepatic function

Patients with hepatic insufficiency of mild severity of dose adjustment of Latuda® are not required.

Patients with hepatic insufficiency secondary (class B according to the Child-Pugh classification) and severe severity (class C according to the Child-Pugh classification) are recommended dose adjustment. The recommended initial dose is 20 mg. The maximum daily dose in patients with moderate-level liver failure should not exceed 80 mg, in patients with severe hepatic insufficiency should not exceed 40 mg once a day.

Children

Safety and efficacy of Latuda® in children under the age of 18 years have not been established.

Correction of dose depending on the interaction

With simultaneous application of the drug Latuda® with moderate inhibitors of isoenzyme CYP3A4 the recommended initial dose is 20 mg, the maximum daily dose should not exceed 80 mg.

Dose adjustment may be required when used in combination with mild to moderate inducers of isoenzyme CYP3A4 (cm.section "Interaction with other drugs").

Concerning simultaneous application with strong inhibitors and inducers of isoenzyme CYP3A4 see the section "Contraindications".

Transfer of patients to treatment with other antipsychotic drugs

Pharmacodynamics and pharmacokinetics of various antipsychotics are not the same, so doctors should closely monitor the condition of patients when transferring them from one antipsychotic to another.

Side effects:

Security Profile Summary

The safety of lurasidone was evaluated against the background of its application in doses of 20 to 160 mg during CI in patients with schizophrenia for 52 weeks and post-marketing period. The most frequent adverse reactions (HP) (≥ 10%) had akathisia and drowsiness, which were dose-dependent when taking the drug at doses up to 120 mg per day. HP, listed below, are classified according to the class of organ systems and preferred terminology. Frequency HP, given in Table 1, was determined from the data of clinical studies.

Frequency HP was determined in accordance with the recommendations of the World Health Organization: very often (≥ 1/10); often (from ≥ 1/100 to <1/10); infrequently (from ≥1 / 1000 to <1/100); rarely (from ≥ 1/10 000 to <1/1000); very rarely (<1/10 000),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.

Table 1. Undesirable reactions from the combined analysis

Frequency	Often	Often	Infrequently	Rarely	Frequency unknown
System of organs
Infectious and parasitic diseases			Nasopharyngitis
Violations of the blood and lymphatic system				Eosinophilia	Leukopenia ** Neutropenia Anemia**
Disorders from the metabolism and nutrition		Weight gain	Decreased appetite Increase in blood glucose
Disorders of the psyche		Insomnia Agitation Anxiety Anxiety	Nightmarish dreams Catatonia		Suicidal behavior ** Panic attack Sleep disturbance**
Disturbances from the nervous system	Akathisia Drowsiness*	Parkinsonism Dizziness Dystonia * Dyskinesia	Lethargy Dysatria Late dyskinesia	Malignant neuroleptic syndrome	Seizures ****
Disturbances on the part of the organ of sight			Blurred vision
Hearing disorders and labyrinthine disorders					Vertigo ****
Heart Disease			Tachycardia		Angina pectoris ** Atrioventricular (AV) block of 1st degree Bradycardia **
Disorders from the vascular system			Hypertension Hypotension Orthostatic hypotension "Tides" High blood pressure
Disorders from the gastrointestinal tract		Nausea Vomiting Dyspepsia Hypersalivation Dry mouth Pain in the upper abdomen Feeling of discomfort in the stomach	Flatulence		Diarrhea** Dysphagia Gastritis**
Disturbances from the liver and bile ducts			An increase in the level of alanine aminotransferase (ALT)
Disturbances from the skin and subcutaneous tissues			Hyperhidrosis		Rash** Itching Angioedema, edema ** Stevens-Johnson Syndrome
Immune system disorders					Hypersensitivity *****
Disturbances from musculoskeletal and connective tissue		Musculoskeletal rigidity Increase of creatine phosphokinase in the blood	Stiffness in the joints Myalgia Pain in the neck Backache	Rhabdomyolysis
Disorders from the kidneys and urinary tract		Increased creatinine in the blood	Dizuria		Renal failure ****
Pregnancy, postpartum and perinatal conditions					The withdrawal syndrome in newborns (see the section "Application during pregnancy and during breastfeeding")
Violations of the genitals and mammary glands			Increased prolactin in the blood		Breast augmentation ** Pain in the mammary gland Galactorrhea Erectile disfunction Amenorrhea Dysmenorrhea **
General disorders and disorders at the site of administration		Fatigue	Violation of gait		Sudden death associated with an existing cardiovascular disease, observed during clinical trials ****

* The term "drowsiness" combines the terms HP: hypersomnia, hypersomnolence, sedation and drowsiness.

** The term "parkinsonism" combines terms HP: bradykinesia, rigidity as a "cogwheel", drooling, extrapyramidal disorders, hypokinesia, muscle rigidity, parkinsonism, slowing of psychomotor activity and tremor.

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

**** HP, detected in the course of controlled and uncontrolled CI 2 and 3 phases, but a small number of cases does not allow us to estimate the frequency.

***** Hypersensitivity may include symptoms such as laryngeal edema, tongue edema, urticaria, or symptoms of angioedema, rash or itching (listed in Table 1 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.

Reactions of particular interest to this class of drugs

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 lourazidone, and 5.8% in patients receiving placebo. The incidence of akathisia in patients who received lourazidone, was 12.9%, in patients receiving placebo, 3.0%.

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 with the use of the drug in low doses, they are observed more often and with greater severity with the use of antipsychotic drugs of the first generation in high doses. The risk of developing acute dystonia in men and in younger patients is increased.

Venous thromboembolism

When using antipsychotic drugs, cases of venous thromboembolism, including pulmonary embolism and deep vein thrombosis, have been reported. The frequency of venous thromboembolism is unknown.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

Overdose:

Treatment

Specific antidote for lurasidone does not exist, 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, potentially can increase the interval QT in patients with acute overdose of lurasidone. The alpha-blocking effect of brethilia can be summarized with a similar effect of lurasidone and lead to hypotension.

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

Interaction:

Pharmacodynamic interaction

Since Latuma® acts primarily on the central nervous system, caution should be exercised when using the drug in combination with other central-action drugs and with alcohol.

Caution should be exercised while using Latuda® with drugs that extend the interval QT, such as antiarrhythmic drugs of the class IA (eg, quinidine, disopyramide) and class III (for example, amiodarone, sotalol), some antihistamines, some other antipsychotics and some anti-malarial drugs (eg, mefloquine).

Pharmacokinetic interaction

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

The ability of other drugs to influence the drug Latuda®

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 isoenzyme CYP3A4.

Inhibitor inhibitors CYP3A4

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

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

Simultaneous use of lourazidone with diltiazem (a sustained-release dosage form), a moderate isoenzyme inhibitor CYP3A4, increases the exposure of lourazidone and ID-14283 in 2.2 and 2.4 times, respectively (see section "Method of administration and dose"). 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 simultaneous use of lurasidone with strong isoenzyme inducers CYP3A4 (for example, carbamazepine, phenobarbital, phenytoin, rifampicin, St. John's wort, see the section "Contraindications").

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

The use of lurasidone in combination with weak (eg, ardomafinil, amprenavir, aprepitant, prednisolone, rubinamide) or moderate (eg, bosentan, efavirenz, etravirine, modafinil, nafcillin) isoenzyme inducers CYP3A4, presumably, can lead to less,than 2-fold decrease in lurasidone exposure, at the time of application and for up to two weeks after discontinuation of taking isoenzyme inducers CYP3A4.

When combined with weak and moderate isoenzyme inducers CYP3A4, the effectiveness of lourazidone should be carefully monitored and the dosage adjusted if necessary.

Conveyors

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

The ability of the drug Latuda® to influence other drugs

Simultaneous reception of lurasidone with midazolam, a sensitive isoenzyme substrate CYP3A4, leads to an increase in the exposure of midazolam by less than 1.5 times. It is recommended that proper monitoring be done when combined with lourazidone and isoenzyme substrates CYP3A4 with a known narrow therapeutic range (eg, astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]).

You can apply lourazidone in combination with digoxin (P-glycoprotein substrate), since, with their simultaneous use, the digoxin exposure did not increase, and C only slightly increased_mOh (1.3 times). Lurasidone in vitro is an inhibitor of the efflux transporter of P-glycoprotein, therefore the clinical significance of P-glycoprotein inhibition in the intestine can not be ruled out. Simultaneous use of the substrate of the D-glycoprotein dabigatran etexilate can lead to an increase in the concentration of dabigatran in the blood.

Lurasidone in vitro is an efflux transporter inhibitor BCRP, therefore it is impossible to exclude the clinical significance of inhibition BCRP in the intestine. Simultaneous use of lourazidone with substrates BCRP can lead to an increase in 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, there is no need to adjust the dose of lurasidone when used in combination with lithium preparations. Lurasidone does not affect the concentration of lithium.

According to studies of drug interactions, the combined use of lourazidone and combined oral contraceptives, including norgestim and ethinyl estradiol, did not lead to a clinically and statistically significant effect of lurasidone on the pharmacokinetics of contraceptives or on the concentration of globulin binding sex hormones. Consequently, lourazidone can be used in combination with oral contraceptives.

Special instructions:

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 antipsychotics in patients with Parkinson's disease. in this group of patients sensitivity to antipsychotic drugs is increased, and the risk of exacerbation of parkinsonism symptoms is increased.The drug Latum can be used in patients with Parkinson's disease only in cases where the potential benefit exceeds the possible risk for the patient.

Extrapyramidal symptoms (EPS)

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 CI in adult patients with schizophrenia, lurasidone was associated with an increase in the incidence of extrapyramidal symptoms compared with placebo.

Late dyskinesia

Drugs 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 antipsychotics, including lurasidone, should be withdrawn.

Cardiovascular disease / lengthening interval QT

Caution should be exercised in prescribing lourazidone to patients with diagnosed cardiovascular disease or an elongated interval QT near relatives, hypokalemia, and also with simultaneous use with other drugs that extend the interval QT.

Convulsions

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

Malignant neuroleptic syndrome

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

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 CIs in elderly patients with dementia in the treatment of other atypical antipsychotics, including risperidone, aripiprazole, olanzapine and quetipine, reported an increase in the overall mortality rate compared with placebo.

Cerebrovascular disorders

According to randomized placebo-controlled CI in patients with dementia in the treatment of atypical antipsychotics, including risperidone, aripiprazole and olanzapine, there was an approximately 3-fold increase in the risk of cerebrovascular unwanted reactions, the mechanism of which is unknown. It is not possible to exclude an increased risk of cerebrovascular disorders for other antipsychotics or other groups of patients. Lurasidone should be used with caution in elderly patients with dementia who have risk factors for stroke.

Venous thromboembolism

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

Hyperprolactinemia

Lurasidone increases the concentration of prolactin, since it is an antagonist D₂dopamine receptors.

Weight gain

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

Hyperglycaemia

According to the CI data, the use of lurasidone in rare cases was accompanied by the development of undesirable reactions associated with changes in glucose concentration, for example, hyperglycemia. Proper 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 antagonist α₁adrenoreceptors. It is recommended that proper monitoring of symptoms of orthostatic hypotension in patients at risk of lowering blood pressure.

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 lourazidone It 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

Recommended lurasidone dose adjustment in patients with hepatic failure secondary to severe (Class B and C of the classification of Child-Pugh. See sections "Dosage and Administration" and "Pharmacokinetics"). Required proper control over the patient's condition in the application of lurasidone in patients with liver failure and severe.

Interaction with grapefruit juice

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

The remains of the unused product must be disposed of in accordance with local requirements.

Effect on the ability to drive transp. cf. and fur:

Lurasidone has little effect on the ability to drive and work with machinery. Patients should be warned about the dangers of driving a vehicle and using machinery in caseswhen there is no conclusive evidence that there are no undesirable reactions in each individual patient (see the "Side effect" section).

Form release / dosage:

Film coated tablets, 20 mg, 40 mg and 80 mg.

Packaging:

For 14 tablets coated with a film sheath are placed in an aluminum blister.

2 or 4 blisters together with instructions for use are placed in a cardboard box.

Storage conditions:

At a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

3 of the year.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003794

Date of registration:18.08.2016

Expiration Date:18.08.2021

The owner of the registration certificate:Takeda Pharma A / STakeda Pharma A / S Denmark

Manufacturer: & nbsp

TAKEDA IRELAND, Ltd. Ireland

Representation: & nbspTakeda Pharmaceuticals Ltd.Takeda Pharmaceuticals Ltd.

Information update date: & nbsp09.10.2016

Illustrated instructions

Instructions

Latuda® (Latuda®)