- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.
|18.5 mg:||Each film-coated tablet contains lurasidone hydrochloride equivalent to 18.6 mg lurasidone.|
|37 mg:||Each film-coated tablet contains lurasidone hydrochloride equivalent to 37.2 mg lurasidone.|
|74 mg:||Each film-coated tablet contains lurasidone hydrochloride equivalent to 74.5 mg lurasidone.|
PosologyThe recommended starting dose of lurasidone is 37 mg once daily. No initial dose titration is required. It is effective in a dose range of 37 to 148 mg once daily. Dose increase should be based on physician judgement and observed clinical response. The maximum daily dose should not exceed 148 mg.Patients on doses higher than 111 mg once daily who discontinue their treatment for longer than 3 days should be restarted on 111 mg once daily and up-titrated to their optimal dose. For all other doses patients can be restarted on their previous dose without need for up-titration.
Elderly peopleDosing recommendations for elderly patients with normal renal function (CrCl ≥ 80 ml/min) are the same as for adults with normal renal function. However, because elderly patients may have diminished renal function, dose adjustments may be required according to their renal function status (see Renal impairment below).Limited data are available in elderly people treated with higher doses of lurasidone. No data are available in elderly people treated with Latuda 148 mg. Caution should be exercised when treating patients ≥65 years of age with higher doses of Latuda.
Renal impairmentNo dose adjustment of lurasidone is required in patients with mild renal impairment.In patients with moderate (Creatinine Clearance (CrCl) ≥ 30 and < 50 ml/min), severe renal impairment (CrCL >15 and < 30 ml/min) and End Stage Renal Disease (ESRD) patients (CrCl < 15 ml/min), the recommended starting dose is 18.5 mg and the maximum dose should not exceed 74 mg once daily. Latuda should not be used in patients with ESRD unless the potential benefits outweigh the potential risks. If used in ESRD, clinical monitoring is advised.
Hepatic impairmentNo dose adjustment of lurasidone is required in patients with mild hepatic impairment.Dose adjustment is recommended in moderate (Child-Pugh Class B) and severe hepatic impairment (Child-Pugh Class C) patients. The recommended starting dose is 18.5 mg. The maximum daily dose in moderate hepatic impairment patients should not exceed 74 mg and in severe hepatic impairment patients should not exceed 37 mg once daily.
Paediatric populationThe safety and efficacy of lurasidone in children aged less than 18 years have not been established. Current available data are described in section 5.2, but no recommendation on a posology can be made.
Dose adjustment due to interactionsA starting dose of 18.5 mg is recommended and the maximum dose of lurasidone should not exceed 74 mg once daily in combination with moderate CYP3A4 inhibitors. Dose adjustment of lurasidone may be necessary in combination with mild and moderate CYP3A4 inducers (see section 4.5). For strong CYP3A4 inhibitors and inducers see section 4.3.
Switching between antipsychotic medicinal productsDue to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinal products, supervision by a clinician is needed when switching to another antipsychotic product is considered medically appropriate.
Method of administrationLatuda film-coated tablets are for oral use, to be taken once daily together with a meal.If taken without food, it is anticipated that lurasidone exposure will be significantly lower as compared to when taken with food (see section 5.2).Latuda tablets should be swallowed whole, in order to mask the bitter taste. Latuda tablets should be taken at the same time every day to aid compliance.
SuicidalityThe occurrence of suicidal behaviour is inherent in psychotic illnesses and in some cases has been reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy.
Parkinson's diseaseIf prescribed to patients with Parkinson's disease, antipsychotic medicinal products may exacerbate the underlying parkinsonism symptoms. Physicians should therefore weigh the risks versus the benefits when prescribing Latuda to patients with Parkinson's disease.
Extrapyramidal symptoms (EPS)Medicinal products with dopamine receptor antagonistic properties have been associated with extrapyramidal adverse reactions including rigidity, tremors, mask-like face, dystonias, drooling of saliva, drooped posture and abnormal gait. In placebo controlled clinical studies in adult patients with schizophrenia there was an increased occurrence of EPS following treatment with lurasidone compared to placebo.
Tardive dyskinesiaMedicinal products with dopamine receptor antagonistic properties have been associated with the induction of tardive dyskinesia characterised by rhythmical involuntary movements, predominantly of the tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of all antipsychotics, including lurasidone, should be considered.
Cardiovascular disorders/QT prolongationCaution should be exercised when lurasidone is prescribed in patients with known cardiovascular disease or family history of QT prolongation, hypokalaemia, and in concomitant use with other medicinal products thought to prolong the QT interval.
SeizuresLurasidone should be used cautiously in patients with a history of seizures or other conditions that potentially lower the seizure threshold.
Neuroleptic malignant syndrome (NMS)Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomic instability, altered consciousness and elevated serum creatine phosphokinase levels, has been reported to occur with antipsychotics including lurasidone. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, all antipsychotics, including lurasidone, should be discontinued.
Elderly patients with dementiaLurasidone has not been studied in elderly patients with dementia.
Overall mortalityIn a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with other atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had an increased risk of mortality compared to placebo.
Cerebrovascular accidentAn approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen in randomised placebo-controlled clinical trials in the dementia population with some atypical antipsychotics, including risperidone, aripiprazole and olanzapine. The mechanism for this increased risk is not known. An increased risk cannot be excluded for other antipsychotics or other patient populations. Lurasidone should be used with caution in elderly patients with dementia who have risk factors for stroke.
Venous thromboembolismCases of venous thromboembolism (VTE) have been reported with antipsychotic medicinal products. Since patients treated with antipsychotics often present with acquired risk factors for VTE, all possible risk factors for VTE should be identified before and during treatment with lurasidone and preventive measures undertaken.
HyperprolactinaemiaLurasidone elevates prolactin levels due to antagonism of dopamine D2 receptors.
Weight gainWeight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight is recommended.
HyperglycaemiaRare cases of glucose related adverse reactions, e.g. increase in blood glucose, have been reported in clinical trials with lurasidone. Appropriate clinical monitoring is advisable in diabetic patients and in patients with risk factors for the development of diabetes mellitus.
Orthostatic hypotension/syncopeLurasidone may cause orthostatic hypotension, perhaps due to its α1-adrenergic receptor antagonism. Monitoring of orthostatic vital signs should be considered in patients who are vulnerable to hypotension.
Renal impairmentDose adjustment is recommended for patients with moderate and severely impaired renal function and in patients with ESRD. Use in patients with ESRD has not been investigated and therefore lurasidone should not be used in patients with ESRD unless the potential benefits outweigh the potential risks. If used in patients with ESRD, clinical monitoring is advised (see sections 4.2 and 5.2).
Hepatic impairmentDose adjustment is recommended for patients with moderate and severely impaired hepatic function (Child-Pugh Class B and C) (see sections 4.2 and 5.2). Caution is recommended in patients with severely impaired hepatic function.
Interaction with Grapefruit juiceGrapefruit juice should be avoided during treatment with lurasidone (see section 4.5).
Pharmacodynamic interactionsGiven the primary central nervous system effects of lurasidone, lurasidone should be used with caution in combination with other centrally acting medicinal products and alcohol.Caution is advised when prescribing lurasidone with medicinal products known to prolong the QT interval, e.g. class IA antiarrhythmics (e.g. quinidine, disopyramide) and class III antiarrhythmics (e.g. amiodarone, sotalol), some antihistaminics, some other antipsychotics and some antimalarials (e.g. mefloquine).
Pharmacokinetic interactionsThe concomitant administration of lurasidone and grapefruit juice has not been assessed. Grapefruit juice inhibits CYP 3A4 and may increase the serum concentration of lurasidone. Grapefruit juice should be avoided during treatment with lurasidone.
Potential for other medicinal products to affect lurasidoneLurasidone and its active metabolite ID-14283 both contribute to the pharmacodynamic effect at the dopaminergic and serotonergic receptors. Lurasidone and its active metabolite ID-14283 are primarily metabolised by CYP3A4.
CYP3A4 inhibitorsLurasidone is contraindicated with strong CYP3A4 inhibitors (e.g. boceprevir, clarithromycin, cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) (see section 4.3).Coadministration of lurasidone with the strong CYP3A4 inhibitor ketoconazole resulted in a 9- and 6-fold increase in exposure of lurasidone and its active metabolite ID-14283 respectively.Coadministration of lurasidone with medicinal products that moderately inhibit CYP3A4 (e.g. diltiazem, erythromycin, fluconazole verapamil) may increase exposure to lurasidone. Moderate CYP3A4 inhibitors are estimated to result in a 2-5 fold increase in exposure of CYP3A4 substrates.Coadministration of lurasidone with diltiazem (slow-release formulation), a moderate CYP3A4 inhibitor, resulted in a 2.2 and 2.4-fold increase in exposure of lurasidone and ID-14283 respectively (see section 4.2). The use of an immediate release formulation of diltiazem could result in a larger increase in lurasidone exposure.
CYP3A4 inducersLurasidone is contraindicated with strong CYP3A4 inducers (e.g. carbamazepine, phenobarbital, phenytoin, rifampicin, St John's wort (Hypericum perforatum)) (see section 4.3).Coadministration of lurasidone with the strong CYP3A4 inducer rifampicin resulted in a 6-fold decrease in exposure of lurasidone.Coadministration of lurasidone with mild (e.g. armodafinil, amprenavir, aprepitant, prednisone, rufinamide) or moderate (e.g. bosentan, efavirenz, etravirine, modafinil, nafcillin) inducers of CYP3A4 would be expected to give a <2-fold reduction in lurasidone exposure during co-administration and for up to 2 weeks after discontinuation of mild or moderate CYP3A4 inducers.When lurasidone is coadministered with mild or moderate CYP3A4 inducers, the efficacy of lurasidone needs to be carefully monitored and a dose adjustment may be needed.
TransportersLurasidone is a substrate of P-gp and BCRP in vitro and the in vivo relevance of this is unclear. Coadministration of lurasidone with P-gp and BCRP inhibitors may increase exposure to lurasidone.
Potential for lurasidone to affect other medicinal productsCoadministration of lurasidone with midazolam, a sensitive CYP3A4 substrate, resulted in a < 1.5-fold increase in midazolam exposure. Monitoring is recommended when lurasidone and CYP3A4 substrates known to have a narrow therapeutic index (e.g. astemizole, terfenadine, cisapride, pimozide, quinidine, bepridil or ergot alkaloids [ergotamine, dihydroergotamine]) are coadministered.Coadministration of lurasidone with digoxin (a P-gp substrate) did not increase the exposure to digoxin and only slightly increased Cmax (1.3 fold) and therefore, it is considered that lurasidone can be coadministered with digoxin. Lurasidone is an in vitro inhibitor of the efflux transporter P-gp and the clinical relevance of intestinal P-gp inhibition cannot be excluded. Concomitant administration of the P-gp substrate dabigatran etexilate may result in increased dabigatran plasma concentrations.Lurasidone is an in vitro inhibitor of the efflux transporter BCRP and the clinical relevance of intestinal BCRP inhibition cannot be excluded. Concomitant administration of BCRP substrates may result in increases in the plasma concentrations of these substrates.Coadministration of lurasidone with lithium indicated that lithium had clinically negligible effects on the pharmacokinetics of lurasidone, therefore no dose adjustment of lurasidone is required when coadministered with lithium. Lurasidone does not impact concentrations of lithium.A clinical drug interaction study investigating the effect of coadministration of lurasidone on patients taking oral combination contraceptives including norgestimate and ethinyl estradiol, indicated that lurasidone had no clinically or statistically meaningful effects on the pharmacokinetics of the contraceptive or sex hormone binding globulin (SHBG) levels. Therefore, lurasidone can be coadministered with oral contraceptives.
PregnancyThere are no or limited amount of data (less than 300 pregnancy outcomes) from the use of lurasidone in pregnant women. Animal studies are insufficient with respect to effects on pregnancy, embryonal/fetal development, parturition and postnatal development (see section 5.3). The potential risk for humans is unknown. Lurasidone should not be used during pregnancy unless clearly necessary.Neonates exposed to antipsychotics (including lurasidone) during the third trimester are at risk of adverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity and duration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitored carefully.
Breast-feedingLurasidone was excreted in milk of rats during lactation (see section 5.3). It is not known whether lurasidone or its metabolites are excreted in human milk. Breast feeding in women receiving Latuda should be considered only if the potential benefit of treatment justifies the potential risk to the child.
FertilityStudies in animals have shown a number of effects on fertility, mainly related to prolactin increase, which are not considered to be relevant to human reproduction (see section 5.3).
Summary of the safety profileThe safety of lurasidone has been evaluated at doses of 18.5 -148 mg in clinical studies in patients with schizophrenia treated for up to 52 weeks and in the post-marketing setting. The most common adverse drug reactions (ADRs) (≥ 10%) were akathisia and somnolence, which were dose-related up to 111 mg daily.
Tabulated summary of adverse reactionsAdverse drug reactions (ADRs) based upon pooled data are shown by system, organ class and by preferred term are listed below. The incidence of ADRs reported in clinical trials is tabulated by frequency category. The following terms and frequencies are applied: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (<1 /10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
|System Organ Class||Very Common||Common||Uncommon||Rare||Frequency not known|
|Infections and infestations||Nasopharyngitis|
|Blood and lymphatic system disorders||Eosinophilia||Leukopenia**** Neutropenia**** Anemia****|
|Immune system disorders||Hypersensitivity#|
|Metabolism and nutrition disorders||Weight increased||Decreased appetite Blood glucose increased|
|Psychiatric disorders||Insomnia Agitation Anxiety Restlessness||Nightmare Catatonia||Suicidal behaviour**** Panic attack**** Sleep disorder****|
|Nervous system disorders||Akathisia Somnolence*||Parkinsonism** Dizziness Dystonia*** Dyskinesia||LethargyDysarthriaTardive dyskinesia||Neuroleptic malignant syndrome (NMS)||Convulsion****|
|Eye disorders||Blurred vision|
|Ear and labyrinth disorders||Vertigo****|
|Cardiac disorders||Tachycardia||Angina**** AV block first degree**** Bradycardia****|
|Vascular disorders||Hypertension Hypotension Orthostatic hypotension Hot flush Blood pressure increased|
|Gastrointestinal disorders||Nausea Vomiting Dyspepsia Salivary hypersecretion Dry mouth Upper abdominal pain Stomach discomfort||Flatulence||Diarrhoea**** Dysphagia**** Gastritis****|
|Hepatobiliary disorders||Alanine aminotransferase increased|
|Skin and subcutaneous tissue disorders||Hyperhidrosis||Rash**** Pruritus**** Angioedema****Stevens-Johnson syndrome|
|Musculoskeletal and connective tissue disorders||Musculoskeletal stiffness Blood creatine phosphokinase increase||Joint stiffness Myalgia Neck pain Back pain||Rhabdomyolysis|
|Renal and urinary disorders||Serum creatinine increased||Dysuria||Renal failure****|
|Pregnancy, puerperium and perinatal conditions||Drug withdrawal syndrome neonatal (see 4.6)|
|Reproductive system and breast disorders||Blood prolactin increased||Breast enlargement**** Breast pain**** Galactorrhoea**** Erectile dysfunction**** Amenorrhoea**** Dysmenorrhoea****|
|General disorders and administration site conditions||Fatigue||Gait disturbance||Sudden death attributable to underlying cardiovascular disease observed during the clinical development programme****|
Events of interest to the classExtrapyramidal symptoms (EPS): In the short-term placebo controlled studies, the incidence of reported events related to EPS, excluding akathisia and restlessness, was 13.5% for lurasidone-treated subjects versus 5.8% for placebo-treated subjects. The incidence of akathisia for lurasidone-treated subjects was 12.9% versus 3.0% for placebo-treated subjects.Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur in susceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm of the neck muscles, sometimes progressing to tightness of the throat, difficulty swallowing, difficulty breathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occur more frequently and with greater severity, higher potency and at higher doses of first generation antipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and younger age groups.Venous thromboembolism: Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis have been reported with antipsychotic drugs -Frequency unknown.
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme website: www.mhra.gov.uk/yellowcard.
Management of overdoseThere is no specific antidote to lurasidone, therefore, appropriate supportive measures should be instituted and close medical supervision and monitoring should continue until the patient recovers. Cardiovascular monitoring should commence immediately, including continuous electrocardiographic monitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide, procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects when administered in patients with an acute overdose of lurasidone. Similarly the alpha-blocking properties of bretylium might be additive to those of lurasidone, resulting in problematic hypotension.Hypotension and circulatory collapse should be treated with appropriate measures. Adrenaline and dopamine should not be used, or other sympathomimetics with beta agonist activity, since beta stimulation may worsen hypotension in the setting of lurasidone-induced alpha blockade. In case of severe extrapyramidal symptoms, anticholinergic medicinal products should be administered.Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoal together with a laxative should be considered.The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdose may create a risk of aspiration with induced emesis.
Mechanism of actionLurasidone is a selective blocking agent of dopamine and monoamine effects. Lurasidone binds strongly to dopaminergic D2- and to serotonergic 5-HT2A and 5-HT7- receptors with high binding affinity of 0.994, 0.47 and 0.495 nM, respectively. It also blocks α2c-adrenergic receptors and α2a-adrenergic receptors with a binding affinity of 10.8 and 40.7 nM respectively. Lurasidone also exhibits partial agonism at the 5HT-1A receptor with a binding affinity of 6.38 nM. Lurasidone does not bind to cholinergic or muscarinic receptors.The mechanism of action of the minor active metabolite of lurasidone ID-14283 is similar to that of lurasidone.Lurasidone doses ranging from 9 to 74 mg (10-80 mg lurasidone hydrochloride) administered to healthy subjects produced a dose-dependent reduction in the binding of 11C-raclopride, a D2/D3 receptor ligand, in the caudate, putamen and ventral striatum detected by positron emission tomography.
Pharmacodynamic effectsIn the main clinical efficacy studies, lurasidone was administered at doses of 37-148 mg lurasidone (equivalent to 40-160 mg lurasidone hydrochloride).
Clinical efficacyThe efficacy of lurasidone in the treatment of schizophrenia was demonstrated in five multi-centre, placebo-controlled, double-blind, 6-week trials in subjects who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia. Lurasidone doses, which varied across the five trials, ranged from 37 to 148 mg lurasidone (equivalent to 40-160 mg lurasidone hydrochloride) once daily. In the short-term trials, the primary efficacy endpoint was defined as the mean change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) total scores, a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolled hostility/excitement, and anxiety/depression. Lurasidone demonstrated superior efficacy compared with placebo across Phase 3 studies (see Table 2). Lurasidone showed significant separation from placebo from as early as Day 4. Additionally, lurasidone was superior to placebo on the predefined secondary endpoint Clinical Global Impression Severity (CGI-S) scale. Efficacy was also confirmed in a secondary analysis of treatment response (defined as ≥ 30% decrease from Baseline in PANSS total score).
Schizophrenia Studies: Positive and Negative Syndrome Scale for Schizophrenia (PANSS) Total Score - Change From Baseline to Week 6- MMRM for Studies D1050229, D1050231, and D1050233: Intent-to-Treat Analysis Set
|Study Statistic||Placebo||Lurasidone dose (b) (c)||Active Control (a)|
|37 mg||74 mg||111 mg||148 mg|
|Study D1050229 Baseline Mean (SD) LS Mean Change (SE) Treatment Difference vs. placebo Estimate (SE) p-value||N=124 96.8 (11.1) -17.0 (1.8) |
|N=121 96.5 (11.6) -19.2 (1.7) |
-2.1 (2.5) 0.591
|N=118 96.0 (10.8) -23.4 (1.8) |
-6.4 (2.5) 0.034
|N=123 96.0 (9.7) -20.5 (1.8) |
-3.5 (2.5) 0.391
|-- -- -- |
|-- -- -- |
|Study D1050231 Baseline Mean (SD) LS Mean Change (SE) Treatment Difference vs. placebo Estimate (SE) p-value||N=114 95.8 (10.8) -16.0 (2.1) |
|N=118 96.6 (10.7) -25.7 (2.0) |
-9.7 (2.9) 0.002
|-- -- -- |
|N=118 97.9 (11.3) -23.6 (2.1) |
-7.5 (3.0) 0.022
|-- -- -- |
|N=121 96.3 (12.2) -28.7 (1.9) |
-12.6 (2.8) <0.001
|Study D1050233 Baseline Mean (SD) LS Mean Change (SE) Treatment Difference vs. placebo Estimate (SE) p-value||N=120 96.6 (10.2) -10.3 (1.8) |
|-- -- -- |
|N=125 97.7 (9.7) -22.2 (1.8) |
-11.9 (2.6) <0.001
|-- -- -- |
|N=121 97.9 (11.8) -26.5 (1.8) |
-16.2 (2.5) <0.001
|N=116 97.7 (10.2) -27.8 (1.8) |
-17.5 (2.6) <0.001
AbsorptionLurasidone reaches peak serum concentrations in approximately 1-3 hours.In a food effect study, lurasidone mean Cmax and AUC increased approximately by 2-3-times and 1.5-2-times, respectively, when administered with food compared to the levels observed under fasting conditions.
DistributionFollowing administration of 37 mg of lurasidone (equivalent to 40 mg lurasidone hydrochloride), the mean approximate apparent volume of distribution was 6000 L. Lurasidone is highly bound (~99%) to serum proteins.
BiotransformationLurasidone is metabolised mainly via CYP3A4. The major biotransformation pathways are oxidative N-dealkylation, hydroxylation of norbornane ring, and S-oxidation.Lurasidone is metabolised into two active metabolites (ID-14283 and ID-14326) and two non-active metabolites (ID-20219 and ID-20220). Lurasidone and its metabolites ID-14283, ID-14326, ID-20219 and ID-20220 correspond to approximately 11.4, 4.1, 0.4, 24 and 11% respectively, of serum radioactivity respectively.CYP3A4 is the major enzyme responsible for metabolism of the active metabolite ID-14283. Lurasidone and its active metabolite ID-14283 both contribute to the pharmacodynamic effect at the dopaminergic and serotonergic receptors.Based on in vitro studies lurasidone is not a substrate of CYP1A1, CYP1A2, CYP2A6, CYP4A11, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP2E1 enzymes.Lurasidone is an in vitro substrate of the efflux transporters P-gp and BCRP. Lurasidone is not subject to active uptake transport by OATP1B1 or OATP1B3.Lurasidone is an inhibitor of P-gp, BCRP and OCT1 in vitro (see section 4.5). Lurasidone is not expected to have a clinically relevant inhibitory potential on transporters OATP1B1, OATP1B3, OCT2, OAT1, OAT3, MATE1, MATE2K or BSEP based on in vitro data.
EliminationFollowing administration of lurasidone, the elimination half-life was 20-40 hours. Following oral administration of a radiolabelled dose, approximately 67% dose was recovered in faeces and 19% in urine. Urine comprised mostly of a number of metabolites with minimal renal excretion of parent compound.
Linearity/non-linearityThe pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 18.5 mg to 148 mg (equivalent to 20 to 160 mg lurasidone hydrochloride). Steady-state concentrations of lurasidone are reached within 7 days of starting lurasidone.
Pharmacokinetics in special patient groups:
Elderly peopleLimited data have been collected in healthy subjects ≥ 65years. Of the data collected, similar exposure was obtained compared with subjects < 65 years. However, an increase in exposure in elderly subjects may be expected for patients if they have impaired renal or hepatic function.
Hepatic impairmentThe serum concentrations of lurasidone are increased in healthy subjects with Child-Pugh Class A, B and C hepatic impairment with an increased exposure of 1.5-, 1.7- and 3-fold respectively.
Renal impairmentThe serum concentrations of lurasidone are increased in healthy subjects with mild, moderate and severe renal impairment with an increased exposure of 1.5, 1.9 and 2.0-fold respectively. Subjects with ESRD (CrCl<15 ml/min) have not been investigated.
GenderThere were no clinically relevant differences between genders in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia.
RaceThere were no clinically relevant differences in the pharmacokinetics of lurasidone in a population pharmacokinetic analysis in patients with schizophrenia. It was noted that Asian subjects had 1.5 fold increased exposure to lurasidone compared to Caucasian subjects.
SmokingBased on in vitro studies utilising human liver enzymes, lurasidone is not a substrate for CYP1A2; smoking should, therefore, not have an effect on the pharmacokinetics of lurasidone.Paediatric populationThe pharmacokinetics of lurasidone in paediatric patients was investigated in 49 children aged 6-12 years and 56 adolescents aged 13-17 years. Lurasidone was administered as lurasidone hydrochloride at daily doses of either 20, 40, 80, 120 mg (6-17 years) or 160 mg (10-17 years only) for 7 days. There was no clear correlation between obtained plasma exposure and age or body weight. The pharmacokinetics of lurasidone in paediatric patients aged 6-17 years was generally comparable to those observed in adults.
CoreMannitol (E 421) Starch, pregelatinised Croscarmellose sodium (E 468) Hypromellose 2910 (E 464) Magnesium stearate (E 470b) Tablet coatingHypromellose 2910 (E 464) Titanium dioxide (E 171) Macrogol 8000Carnauba wax (E 903)
74 mgIron oxide, Yellow (E 172) Indigotine (E 132)
|18.5 mg||14 film coated tablets: 28 film coated tablets: 30 film coated tablets: 56 film coated tablets: 60 film coated tablets: 90 film coated tablets: 98 film coated tablets:||EU/1/14/913/001 EU/1/14/913/002 EU/1/14/913/003 EU/1/14/913/004 EU/1/14/913/005 EU/1/14/913/006 EU/1/14/913/007|
|37 mg||14 film coated tablets: 28 film coated tablets: 30 film coated tablets: 56 film coated tablets: 60 film coated tablets: 90 film coated tablets: 98 film coated tablets:||EU/1/14/913/008 EU/1/14/913/009 EU/1/14/913/010 EU/1/14/913/011 EU/1/14/913/012 EU/1/14/913/013 EU/1/14/913/014|
|74 mg||14 film coated tablets: 28 film coated tablets: 30 film coated tablets: 56 film coated tablets: 60 film coated tablets: 90 film coated tablets: 98 film coated tablets:||EU/1/14/913/015 EU/1/14/913/016 EU/1/14/913/017 EU/1/14/913/018 EU/1/14/913/019 EU/1/14/913/020 EU/1/14/913/021|
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