Lurasidone Krono (Tablets) Instructions for Use

Marketing Authorization Holder

Kronopharm, LLC (Russia)

Manufactured By

Canonpharma Production, CJS (Russia)

ATC Code

N05AE05 (Lurasidone)

Active Substance

Lurasidone (Rec.INN registered by WHO)

Dosage Forms

	Lurasidone Krono	Film-coated tablets 20 mg
		Film-coated tablets 40 mg
		Film-coated tablets 80 mg

Dosage Form, Packaging, and Composition

Film-coated tablets

14 pcs. – blister packs (2) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4) – cardboard packs (56 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (4) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (8) – cardboard packs (56 pcs.) – By prescription

Film-coated tablets

14 pcs. – blister packs (2) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4) – cardboard packs (56 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (4) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (8) – cardboard packs (56 pcs.) – By prescription

Film-coated tablets

14 pcs. – blister packs (2) – cardboard packs (28 pcs.) – By prescription
14 pcs. – blister packs (4) – cardboard packs (56 pcs.) – By prescription
56 pcs. – jars – cardboard packs (56 pcs.) – By prescription
7 pcs. – blister packs (4) – cardboard packs (28 pcs.) – By prescription
7 pcs. – blister packs (8) – cardboard packs (56 pcs.) – By prescription

Pharmacotherapeutic Group

Psycholeptics; antipsychotic agents; indole derivatives

Pharmacological Action

Antipsychotic agent, a selective antagonist of dopamine and monoamine receptors, has high affinity for dopamine D₂ and serotonin 5-HT_2A and 5-HT₇ receptors (K_i = 0.994, 0.47 and 0.495 nM, respectively). Lurasidone also blocks α_2C– and α_2A-adrenergic receptors (affinity degree 10.8 and 40.7 nM, respectively), and is a partial agonist of serotonin 5-HT_1A 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 lurasidone, ID-14283, is the same as that of lurasidone. According to positron emission tomography data, the use of lurasidone in the dose range from 9 to 74 mg (from 10 to 80 mg of lurasidone hydrochloride) in healthy volunteers led to a dose-dependent decrease in the binding of ¹¹C-raclopride, a ligand for dopamine D₂/_D3 receptors, in the caudate nucleus, putamen, and ventral striatum.

Pharmacokinetics

After oral administration, the time to reach C_max in the blood is from 1 to 3 hours. After taking lurasidone with food, the mean C_max and AUC increased by 2-3 times and 1.5-2 times, respectively, compared to the values after taking lurasidone on an empty stomach.

After oral administration of 40 mg of lurasidone, the mean apparent V_d was approximately 6000 L. The binding of lurasidone to plasma proteins is high – 99%.

Lurasidone is metabolized mainly by the CYP3A4 isoenzyme system. The main pathways of metabolism are oxidative N-dealkylation, hydroxylation of the norbornane ring, and S-oxidation. Lurasidone is metabolized to form two active metabolites (ID-14283 and ID-14326) and two inactive metabolites (ID-20219 and ID-20220). The active metabolite ID-14283 is metabolized mainly by 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 have shown that Lurasidone is a substrate for the efflux transporters P-glycoprotein and Breast Cancer Resistance Protein (BCRP). In vitro studies have also shown that Lurasidone is an inhibitor of P-glycoprotein, BCRP, and Organic Cation Transporter type 1 (OCT1).

T_1/2 is about 20-40 hours. After oral administration of radiolabeled lurasidone, about 67% is excreted via the intestine and about 19% via the kidneys. Urine contains mainly metabolites due to minimal renal excretion of the parent compound.

The pharmacokinetic parameters of lurasidone are dose-proportional in the total daily dose range from 20 to 160 mg. C_ss of lurasidone is reached within 7 days from the start of therapy. Data on the pharmacokinetics of lurasidone in healthy elderly volunteers (≥65 years) are limited. According to the results obtained, the plasma concentration of lurasidone in elderly healthy volunteers is identical to its plasma concentration in younger volunteers (under 65 years). However, an increase in the plasma concentration of lurasidone in elderly patients with impaired renal or hepatic function can be expected.

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

In patients with mild, moderate, and severe renal impairment, the AUC of lurasidone increases by 1.5, 1.9, and 2.0 times, respectively.

It was noted that in healthy volunteers of Mongoloid race, the AUC value increased by 1.5 times compared to volunteers of Caucasian race.

Indications

Treatment of schizophrenia; as monotherapy for major depressive episodes associated with bipolar affective disorder type I (bipolar depression); as adjunctive therapy with lithium or valproate preparations for major depressive episodes associated with bipolar affective disorder type I (bipolar depression).

ICD codes

Dosage Regimen

Take orally once daily with food (at least 350 calories).

For schizophrenia, initiate at 40 mg daily. The recommended dose range is 40 mg to 160 mg daily.

For bipolar depression as monotherapy, initiate at 20 mg daily. The recommended dose range is 20 mg to 120 mg daily.

For bipolar depression as adjunctive therapy with lithium or valproate, initiate at 20 mg daily. The recommended dose range is 20 mg to 120 mg daily.

Do not exceed a maximum daily dose of 160 mg.

In patients with moderate or severe renal impairment (CrCl < 50 mL/min), the initial dose is 20 mg. The maximum dose is 80 mg.

In patients with moderate hepatic impairment (Child-Pugh B), the initial dose is 20 mg. The maximum dose is 80 mg.

In patients with severe hepatic impairment (Child-Pugh C), the initial dose is 20 mg. The maximum dose is 40 mg.

When co-administered with a moderate CYP3A4 inhibitor, the initial dose is 20 mg. The maximum dose is 80 mg.

Dose adjustments should be based on clinical response and tolerability.

Adverse Reactions

Blood and lymphatic system disorders rarely – eosinophilia, frequency unknown – leukopenia, neutropenia, anemia.

Metabolism and nutrition disorders often – weight increased, infrequently – decreased appetite, increased blood glucose, hyponatremia.

Psychiatric disorders often – insomnia, agitation, restlessness, anxiety, infrequently – nightmare, catatonia, frequency unknown – suicidal behavior, panic attack, sleep disorder.

Nervous system disorders: very often – akathisia, somnolence, often – parkinsonism, dizziness, dystonia, dyskinesia, infrequently – lethargy, dysarthria, tardive dyskinesia, rarely – neuroleptic malignant syndrome, frequency unknown – seizures.

Eye disorders infrequently – blurred vision, frequency unknown – vertigo.

Cardiac disorders infrequently – tachycardia, hypertension, hypotension, orthostatic hypotension, flushing, frequency unknown – angina pectoris, first-degree AV block, bradycardia.

Gastrointestinal disorders often – nausea, vomiting, dyspepsia, hypersalivation, dry mouth, upper abdominal pain, stomach discomfort, infrequently – flatulence, frequency unknown – diarrhea, dysphagia, gastritis.

Hepatobiliary disorders infrequently – increased ALT.

Skin and subcutaneous tissue disorders infrequently – hyperhidrosis, frequency unknown – rash, pruritus, angioedema, Stevens-Johnson syndrome.

Immune system disorders often – hypersensitivity.

Musculoskeletal and connective tissue disorders often – musculoskeletal stiffness, increased blood creatine phosphokinase, infrequently – joint stiffness, myalgia, neck pain, back pain, rarely – rhabdomyolysis.

Renal and urinary disorders often – increased blood creatinine, infrequently – dysuria, frequency unknown – renal failure.

Reproductive system and breast disorders infrequently – increased blood prolactin, frequency unknown – breast enlargement, breast pain, galactorrhea, erectile dysfunction, amenorrhea, dysmenorrhea.

General disorders and administration site conditions often – fatigue, infrequently – nasopharyngitis, gait disturbance.

Contraindications

Hypersensitivity to lurasidone; concomitant use with strong inhibitors of the CYP3A4 isoenzyme (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and with strong inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, phenobarbital, phenytoin), rifampicin, St. John’s wort; age under 18 years.

Use in Pregnancy and Lactation

Data on the use of lurasidone in pregnant women are limited. Animal studies are insufficient to assess the effects on pregnancy, embryonic and fetal development, childbirth, and postnatal development. The potential risk to humans is unknown.

Lurasidone should not be used during pregnancy except in cases of extreme necessity.

If a woman is taking antipsychotic drugs, including Lurasidone, in the third trimester of pregnancy, there is a risk of adverse reactions in newborns, including extrapyramidal disorders and/or withdrawal syndrome of varying severity. Agitation, hypertension, hypotension, tremor, drowsiness, respiratory disorders, or feeding disorders have been reported. Therefore, in such cases, careful monitoring of newborns should be carried out.

Experimental studies have shown that Lurasidone is excreted in the milk of lactating rats. There are no data on excretion in human breast milk. The use of lurasidone in nursing women is possible only in cases where the expected benefit of therapy for the mother outweighs the potential risk of complications for the child.

Use in Hepatic Impairment

Dose adjustment of lurasidone is recommended in patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Proper monitoring of the patient’s condition is mandatory when using lurasidone in patients with severe hepatic impairment.

Use in Renal Impairment

Dose adjustment of lurasidone is recommended in patients with moderate, severe, and end-stage renal impairment. There are no data on the use of lurasidone in patients with end-stage renal impairment, therefore Lurasidone can be used only in cases where the potential benefit outweighs the possible risk. Treatment of patients with end-stage renal impairment with lurasidone should be carried out under proper monitoring of the patient’s condition.

Pediatric Use

The drug is contraindicated for use in children and adolescents under 18 years of age.

Special Precautions

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

A tendency to suicidal thoughts and attempts is characteristic of patients with psychosis. There have been reports of such cases at the beginning of therapy or when replacing an antipsychotic drug. Therefore, drug antipsychotic therapy should be carried out under careful medical supervision.

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

Drugs with dopamine receptor antagonist properties can cause undesirable extrapyramidal disorders, including rigidity, tremor, mask-like face, dystonia, drooling, impaired posture and gait. According to placebo-controlled clinical studies in adult patients with schizophrenia, taking lurasidone was accompanied by an increased incidence of extrapyramidal symptoms compared to placebo.

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

Caution is required when using lurasidone in patients with diagnosed cardiovascular diseases or a prolonged QT interval in close relatives, hypokalemia, as well as when used concomitantly with other drugs that prolong the QT interval.

Lurasidone may cause drowsiness, orthostatic hypotension, and motor and sensory instability, which may lead to falls and, as a result, fractures or other injuries. In patients with diseases, conditions, or drug therapy that may exacerbate these adverse drug reactions, a fall risk assessment should be performed before starting antipsychotic therapy, and again in patients receiving long-term antipsychotic treatment.

Use with caution in patients with a history of seizures or other conditions that potentially lower the seizure threshold.

Cases of NMS development, characterized by hyperthermia, muscle rigidity, autonomic instability, impaired consciousness, and increased serum CPK activity, have been reported with the use of antipsychotic drugs, including lurasidone. In addition, myoglobinuria (rhabdomyolysis) and acute renal failure may develop. In such cases, it is necessary to discontinue all antipsychotic drugs, including Lurasidone.

Treatment with antidepressants may increase the risk of developing a manic or hypomanic episode, especially in patients with bipolar disorder.

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

Cases of venous thromboembolism have been noted with the use of antipsychotic drugs. Since patients taking antipsychotic drugs often have a risk of developing venous thromboembolism, all possible risk factors for venous thromboembolic complications should be identified before and during treatment with lurasidone, and preventive measures should be taken.

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

Weight gain has been observed with the use of atypical antipsychotic drugs. It is recommended to monitor body weight.

According to clinical studies, the use of lurasidone was rarely accompanied by the development of adverse reactions associated with changes in glucose concentration, such as hyperglycemia. Proper clinical monitoring is recommended when treating patients with diabetes and risk factors for diabetes with lurasidone.

Orthostatic hypotension may develop due to the α₁-adrenergic receptor antagonist properties of lurasidone. Proper monitoring for symptoms of orthostatic hypotension is recommended in patients at risk of decreased blood pressure.

Dose adjustment of lurasidone is recommended in patients with moderate, severe, and end-stage renal impairment. There are no data on the use of lurasidone in patients with end-stage renal impairment, therefore Lurasidone can be used only in cases where the potential benefit outweighs the possible risk. Treatment of patients with end-stage renal impairment with lurasidone should be carried out under proper monitoring of the patient’s condition.

Dose adjustment of lurasidone is recommended in patients with moderate and severe hepatic impairment (Child-Pugh class B and C). Proper monitoring of the patient’s condition is mandatory when using lurasidone in patients with severe hepatic impairment.

Effect on ability to drive vehicles and operate machinery

Lurasidone has a minor effect on the ability to drive vehicles and operate machinery. Patients should be warned about the dangers of driving vehicles and operating machinery in cases where there is no convincing evidence of the absence of adverse reactions in each specific patient.

Drug Interactions

Since Lurasidone acts primarily on the CNS, caution should be exercised when using it in combination with other centrally acting drugs, as well as with ethanol.

Caution is advised with the concomitant use of lurasidone with drugs that prolong the QT interval, such as class IA antiarrhythmics (e.g., quinidine, disopyramide) and class III antiarrhythmics (e.g., amiodarone, sotalol), some antihistamines, some other antipsychotic drugs, and some antimalarial drugs (e.g., mefloquine).

Grapefruit juice inhibits the CYP3A4 isoenzyme and may increase the blood concentration of lurasidone. Consumption of grapefruit juice should be avoided during treatment with 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 primarily by the CYP3A4 isoenzyme.

The use of lurasidone with strong inhibitors of the CYP3A4 isoenzyme (e.g., boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) is contraindicated. Concomitant use of lurasidone with the strong CYP3A4 isoenzyme inhibitor ketoconazole results in a 9-fold and 6-fold increase in exposure to lurasidone and its active metabolite ID-14283, respectively.

Concomitant use of lurasidone with moderate inhibitors of the CYP3A4 isoenzyme (e.g., diltiazem, erythromycin, fluconazole, verapamil) may increase lurasidone exposure. It is assumed that concomitant use of moderate CYP3A4 isoenzyme inhibitors leads to a 2- to 5-fold increase in exposure to CYP3A4 isoenzyme substrates. Concomitant use of lurasidone with diltiazem (extended-release formulation), a moderate CYP3A4 isoenzyme inhibitor, results in a 2.2-fold and 2.4-fold increase in exposure to lurasidone and ID-14283, respectively. Administration of diltiazem in an immediate-release formulation may lead to a more pronounced increase in lurasidone exposure.

Concomitant use of lurasidone with strong inducers of the CYP3A4 isoenzyme (e.g., carbamazepine, phenobarbital, phenytoin, rifampicin, St. John’s wort) is contraindicated. Concomitant use of lurasidone with the strong CYP3A4 isoenzyme inducer rifampicin results in a 6-fold decrease in lurasidone exposure.

The use of lurasidone in combination with weak (e.g., armodafinil, amprenavir, aprepitant, prednisone, rufinamide) or moderate (e.g., bosentan, efavirenz, etravirine, modafinil, nafcillin) inducers of the CYP3A4 isoenzyme is presumed to result in less than a 2-fold decrease in lurasidone exposure during use and for up to 2 weeks after discontinuation of the CYP3A4 isoenzyme inducers. When used concomitantly with weak and moderate CYP3A4 isoenzyme inducers, the effectiveness of lurasidone should be carefully monitored and the dose adjusted if necessary.

Lurasidone is a substrate of P-glycoprotein and BCRP (Breast Cancer Resistance Protein) in vitro, but the significance of this property in vivo is not established. Concomitant use of lurasidone with inhibitors of P-glycoprotein and BCRP may increase lurasidone exposure.

Concomitant administration of lurasidone with midazolam, a sensitive substrate of the CYP3A4 isoenzyme, results in less than a 1.5-fold increase in midazolam exposure. Appropriate monitoring is recommended when lurasidone is used concomitantly with substrates of the CYP3A4 isoenzyme with a known narrow therapeutic range (e.g., astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil, or ergot alkaloids [ergotamine, dihydroergotamine]).

Lurasidone is an inhibitor of the efflux transporter P-glycoprotein in vitro, so the clinical significance of P-glycoprotein inhibition in the intestine cannot be ruled out. Concomitant use with the P-glycoprotein substrate dabigatran etexilate may lead to an increased blood concentration of dabigatran.

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

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.