LATUDA 18.5mg film-coated tablets medication leaflet

Latuda 18.5 mg film-coated tablets

Latuda 37 mg film-coated tablets

Latuda 74 mg film-coated tablets

Latuda 18.5 mg film-coated tablets

Each film-coated tablet contains lurasidone hydrochloride equivalent to18.6 mg lurasidone.

Latuda 37 mg film-coated tablets

Each film-coated tablet contains lurasidone hydrochloride equivalent to 37.2 mg lurasidone.

Latuda 74 mg film-coated tablets

Each film-coated tablet contains lurasidone hydrochloride equivalent to 74.5 mg lurasidone.

For the full list of excipients, see section 6.1.

Film-coated tablet (tablet).

Latuda 18.5 mg film-coated tablets

White to off-white, film-coated round tablets of 6 mm debossed with ‘LA’

Latuda 37 mg film-coated tablets

White to off-white, film-coated round tablets of 8 mm debossed with ‘LB’

Latuda 74 mg film-coated tablets

Pale green, film-coated oval tablets of 12 mm x 7 mm debossed with ‘LD’

Latuda is indicated for the treatment of schizophrenia in adults and adolescent aged 13 years and over.

Adult population

The recommended starting dose is 37 mg of lurasidone 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 physicianjudgement 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 than3 days should be restarted on 111 mg once daily and up-titrated to their optimal dose. For all otherdoses patients can be restarted on their previous dose without need for up-titration.

The recommended starting dose is 37 mg of lurasidone once daily. No initial dose titration is required.

It is effective in a dose range of 37 to 74 mg once daily. Dose increase should be based on physicianjudgement and observed clinical response. The maximum daily dose should not exceed 74 mg. Inchildren, lurasidone should be prescribed by an expert in paediatric psychiatry.

Dose adjustment due to interactions

A starting dose of 18.5 mg is recommended and the maximum dose of lurasidone should not exceed74 mg once daily in combination with moderate CYP3A4 inhibitors. Dose adjustment of lurasidonemay be necessary in combination with mild and moderate CYP3A4 inducers (see section 4.5). Forstrong CYP3A4 inhibitors and inducers see section 4.3.

Switching between antipsychotic medicinal products

Due to different pharmacodynamic and pharmacokinetic profiles among antipsychotic medicinalproducts, supervision by a clinician is needed when switching to another antipsychotic product isconsidered medically appropriate.

Elderly people

Dosing recommendations for elderly patients with normal renal function (CrCl ≥ 80 ml/min) are thesame as for adults with normal renal function. However, because elderly patients may have diminishedrenal function, dose adjustments may be required according to their renal function status (see “Renalimpairment” below).

Limited data are available in elderly people treated with higher doses of lurasidone. No data areavailable in elderly people treated with 148 mg of lurasidone. Caution should be exercised whentreating patients ≥65 years of age with higher doses of lurasidone.

No 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 renalimpairment (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 notexceed 74 mg once daily. Lurasidone should not be used in patients with ESRD unless the potentialbenefits outweigh the potential risks. If used in ESRD, clinical monitoring is advised.

No 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 dosein moderate hepatic impairment patients should not exceed 74 mg and in severe hepatic impairmentpatients should not exceed 37 mg once daily.

Latuda 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 comparedto when taken with food (see section 5.2).

Latuda tablets should be swallowed whole, in order to mask the bitter taste. Latuda tablets should betaken at the same time every day to aid compliance.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Concomitant administration of strong CYP3A4 inhibitors (e.g. boceprevir, clarithromycin,cobicistat, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, posaconazole,ritonavir, saquinavir, telaprevir, telithromycin, voriconazole) and strong CYP3A4 inducers (e.g.carbamazepine, phenobarbital, phenytoin, rifampicin, St John’s wort (Hypericum perforatum)(see section 4.5).

During antipsychotic treatment, improvement in the patient's clinical condition may take a few days tosome weeks. Patients should be closely monitored during this period.

Suicidality

The occurrence of suicidal behaviour is inherent in psychotic illnesses and in some cases has beenreported early after initiation or switch of antipsychotic therapy. Close supervision of high-riskpatients should accompany antipsychotic therapy.

Parkinson’s disease

If prescribed to patients with Parkinson’s disease, antipsychotic medicinal products may exacerbatethe underlying parkinsonism symptoms. Physicians should therefore weigh the risks versus thebenefits when prescribing lurasidone to patients with Parkinson’s disease.

Medicinal products with dopamine receptor antagonistic properties have been associated withextrapyramidal adverse reactions including rigidity, tremors, mask-like face, dystonias, drooling ofsaliva, drooped posture and abnormal gait. In placebo controlled clinical studies in adult patients withschizophrenia there was an increased occurrence of EPS following treatment with lurasidonecompared to placebo.

Medicinal products with dopamine receptor antagonistic properties have been associated with theinduction of tardive dyskinesia characterised by rhythmical involuntary movements, predominantly ofthe tongue and/or face. If signs and symptoms of tardive dyskinesia appear, the discontinuation of allantipsychotics, including lurasidone, should be considered.

Cardiovascular disorders/QT prolongation

Caution should be exercised when lurasidone is prescribed in patients with known cardiovasculardisease or family history of QT prolongation, hypokalaemia, and in concomitant use with othermedicinal products thought to prolong the QT interval.

Lurasidone should be used cautiously in patients with a history of seizures or other conditions thatpotentially lower the seizure threshold.

Neuroleptic Malignant Syndrome, characterised by hyperthermia, muscle rigidity, autonomicinstability, altered consciousness and elevated serum creatine phosphokinase levels, has been reportedto occur with lurasidone. Additional signs may include myoglobinuria (rhabdomyolysis) and acuterenal failure. In this event, lurasidone should be discontinued.

Lurasidone has not been studied in elderly patients with dementia.

In a meta-analysis of 17 controlled clinical trials, elderly patients with dementia treated with otheratypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine had anincreased risk of mortality compared to placebo.

Cerebrovascular accident

An approximately 3-fold increased risk of cerebrovascular adverse reactions has been seen inrandomised placebo-controlled clinical trials in the dementia population with some atypicalantipsychotics, including risperidone, aripiprazole and olanzapine. The mechanism for this increasedrisk is not known. An increased risk cannot be excluded for other antipsychotics or other patientpopulations. Lurasidone should be used with caution in elderly patients with dementia who have riskfactors for stroke.

Cases 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 possiblerisk factors for VTE should be identified before and during treatment with lurasidone and preventivemeasures undertaken.

Lurasidone elevates prolactin levels due to antagonism of dopamine D2 receptors. Patients should becounseled on signs and symptoms of elevated prolactin, such as gynecomastia, galactorrhea,amenorrhea and erectile dysfunction. Patient should be advised to seek medical attention if theyexperience any signs and symptoms.

Weight gain has been observed with atypical antipsychotic use. Clinical monitoring of weight isrecommended.

Rare cases of glucose related adverse reactions, e.g. increase in blood glucose, have been reported inclinical trials with lurasidone. Appropriate clinical monitoring is advisable in diabetic patients and inpatients with risk factors for the development of diabetes mellitus.

Orthostatic hypotension/syncope

Lurasidone 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 tohypotension.

Interaction with grapefruit juice

Grapefruit juice should be avoided during treatment with lurasidone (see section 4.5).

Serotonin syndrome

Concomitant administration of Latuda and other serotonergic agents, such as buprenorphine/opioids,

MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotonin norepinephrine re-uptakeinhibitors (SNRIs) or tricyclic antidepressants may result in serotonin syndrome, a potentially life-threatening condition (see section 4.5).

If concomitant treatment with other serotonergic agents is clinically warranted, careful observation ofthe patient is advised, particularly during treatment initiation and dose increases.

Symptoms of serotonin syndrome may include mental-status changes, autonomic instability,neuromuscular abnormalities, and/or gastrointestinal symptoms. If serotonin syndrome is suspected, adose reduction or discontinuation of therapy should be considered depending on the severity of thesymptoms.

This medicine contains less than 1 mmol sodium (23 mg) per one tablet, that is to say essentially‘sodium-free’.

Given the primary central nervous system effects of lurasidone, lurasidone should be used withcaution in combination with other centrally acting medicinal products and alcohol.

Caution is advised when prescribing lurasidone with medicinal products known to prolong the QTinterval, 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).

Latuda should be used cautiously when co-administered with other serotonergic agents, such asbuprenorphine/opioids, MAO inhibitors, selective serotonin re-uptake inhibitors (SSRIs), serotoninnorepinephrine re-uptake inhibitors (SNRIs) or tricyclic antidepressants as the risk of serotoninsyndrome, a potentially life-threatening condition, is increased (see section 4.4).

The concomitant administration of lurasidone and grapefruit juice has not been assessed. Grapefruitjuice inhibits CYP3A4 and may increase the serum concentration of lurasidone. Grapefruit juiceshould be avoided during treatment with lurasidone.

Potential for other medicinal products to affect lurasidone

Lurasidone and its active metabolite ID-14283 both contribute to the pharmacodynamic effect at thedopaminergic and serotonergic receptors. Lurasidone and its active metabolite ID-14283 are primarilymetabolised by CYP3A4.

Lurasidone 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- and6-fold increase in exposure of lurasidone and its active metabolite ID-14283 respectively.

Co-administration of lurasidone and posaconazole (strong CYP3A4 inhibitor) resulted in anapproximate 4-5 fold increase in lurasidone exposure. A persistent effect of posaconazole onlurasidone exposure was observed up to 2-3 weeks after stop of posaconazole co-administration.

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 CYP3A4inhibitor, 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 largerincrease in lurasidone exposure.

Lurasidone 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-folddecrease 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 duringco-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 oflurasidone needs to be carefully monitored and a dose adjustment may be needed.

Lurasidone 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 products

Coadministration of lurasidone with midazolam, a sensitive CYP3A4 substrate, resulted in a < 1.5-foldincrease in midazolam exposure. Monitoring is recommended when lurasidone and CYP3A4substrates 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 todigoxin and only slightly increased Cmax (1.3 -fold) and therefore, it is considered that lurasidone canbe coadministered with digoxin. Lurasidone is an in vitro inhibitor of the efflux transporter P-gp andthe clinical relevance of intestinal P-gp inhibition cannot be excluded. Concomitant administration ofthe 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 ofintestinal BCRP inhibition cannot be excluded. Concomitant administration of BCRP substrates mayresult in increases in the plasma concentrations of these substrates.

Coadministration of lurasidone with lithium indicated that lithium had clinically negligible effects onthe pharmacokinetics of lurasidone, therefore no dose adjustment of lurasidone is required whencoadministered with lithium. Lurasidone does not impact concentrations of lithium.

A clinical drug interaction study investigating the effect of coadministration of lurasidone on patientstaking oral combination contraceptives including norgestimate and ethinyl estradiol, indicated thatlurasidone had no clinically or statistically meaningful effects on the pharmacokinetics of thecontraceptive or sex hormone binding globulin (SHBG) levels. Therefore, lurasidone can becoadministered with oral contraceptives.

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of lurasidonein pregnant women. Animal studies are insufficient with respect to effects on pregnancy,embryonal/foetal development, parturition and postnatal development (see section 5.3). The potentialrisk for humans is unknown. Lurasidone should not be used during pregnancy unless clearlynecessary.

Neonates exposed to antipsychotics (including lurasidone) during the third trimester are at risk ofadverse reactions including extrapyramidal and/or withdrawal symptoms that may vary in severity andduration following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor,somnolence, respiratory distress, or feeding disorder. Consequently, newborns should be monitoredcarefully.

Lurasidone was excreted in milk of rats during lactation (see section 5.3). It is not known whetherlurasidone or its metabolites are excreted in human milk. Breast feeding in women receivinglurasidone should be considered only if the potential benefit of treatment justifies the potential risk tothe child.

Studies 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).

Lurasidone has minor influence on the ability to drive and use machines. Patients should be cautionedabout operating hazardous machines, including motor vehicles and cycles, until they are reasonablycertain that lurasidone does not affect them adversely (see section 4.8).

Regarding road safety, adolescents who may not be old enough to drive may nevertheless cycle.

The safety of lurasidone has been evaluated at doses of 18.5 -148 mg in clinical studies in patientswith schizophrenia treated for up to 52 weeks and in the post-marketing setting. The most commonadverse drug reactions (ADRs) (≥ 10%) were akathisia, nausea and insomnia.

Adverse drug reactions (ADRs) based upon pooled data are shown by system, organ class and bypreferred term are listed in Table 1 below. The incidence of ADRs reported in clinical trials istabulated by frequency category. The following terms and frequencies are applied: very common(≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to< 1/1,000), very rare (<1 /10,000) and not known (cannot be estimated from the available data).

Table 1: Adverse drug reactions (ADRs) Based Upon Pooled Data for Adults

System Organ Very Common Uncommon Rare Frequency not

Class Commo knownn

Infections and Nasopharyngitiinfestations s

Blood and Anaemia Eosinophilia Neutropenia***lymphatic Leukopenia *systemdisorders

Immune Hypersensitivitsystem ydisorders

Metabolism Weight Blood glucoseand nutrition increased increaseddisorders Decreased Hyponatraemiaappetite

Psychiatric Insomni Agitation Nightmare Suicidal Sleepdisorders a Anxiety Catatonia behaviour disorder****

Restlessness Panic attack

Nervous Akathisi Somnolence* Lethargy Neurolepticsystem a Parkinsonism* Dysarthria malignantdisorders * Tardive syndrome

Dizziness dyskinesia (NMS)

Dystonia*** Syncope Cerebrovascula

Dyskinesia Convulsion r accident

Eye disorders Blurred vision

Ear and Vertigolabyrinthdisorders

Cardiac Tachycardia Angina pectorisdisorders Atrioventricular block firstdegree

Bradycardia

System Organ Very Common Uncommon Rare Frequency not

Class Commo knownn

Vascular Hypertension Hypotensiondisorders Orthostatichypotension

Hot flush

Blood pressureincreased

Gastrointestina Nausea Diarrhoea Flatulencel disorders Vomiting Dysphagia

Dyspepsia Gastritis

Salivaryhypersecretion

Dry mouth

Upperabdominal pain

Stomachdiscomfort

Hepatobiliary Alaninedisorders aminotransferase increased

Skin and Rash Hyperhidrosis Angioedema Stevens-subcutaneous Pruritus Johnsontissue syndromedisorders

Musculoskelet Back pain Joint stiffness Rhabdomyolysal and Musculoskelet Myalgia isconnective al stiffness Neck paintissuedisorders

Renal and Serum Dysuria Renal failureurinary creatininedisorders increased

Pregnancy, Drugpuerperium withdrawaland perinatal syndromeconditions neonatal (see4.6)

Reproductive Blood prolactin Breast pain Breastsystem and increased Galactorrhoea enlargement***breast Erectile *disorders dysfunction

Amenorrhoea

Dysmenorrhoea

General Fatigue Gait Sudden deathdisorders and disturbanceadministrationsite conditions

System Organ Very Common Uncommon Rare Frequency not

Class Commo knownn

Investigations Bloodcreatininephosphokinaseincreased

*Somnolence includes adverse reaction terms: hypersomnia, hypersomnolence, sedation, and somnolence

**Parkinsonism includes adverse reaction terms: bradykinesia, cogwheel rigidity, drooling, extrapyramidal disorder,hypokinesia, muscle rigidity, parkinsonism, psychomotor retardation, and tremor

***Dystonia includes adverse reaction terms: dystonia, oculogyric crisis, oromandibular dystonia, tongue spasm, torticollis,and trismus.

****ADRs noted in Phase 2 and 3 controlled and uncontrolled studies; however, the incidence of occurrence for these are toolow to estimate frequencies.

Table 2: Adverse Drug Reactions (ADRs) for Adolescents

System Organ Very Common Uncommon Rare Frequency

Class Common not known

Infections and Nasopharyngitisinfestations Rhinitis

Upper respiratorytract infection

Blood and Neutropenialymphaticsystemdisorders

Immune System Hypersensitivity

Disorders

Endocrine Hyperprolactinaemia Autoimmunedisorders (including blood thyroiditisprolactin increased) Hyperandrogenism

Metabolism and Decreased appetite Hyperinsulinemianutrition Increased appetitedisorders

Psychiatric Abnormal dreams Aggression

Disorders Agitation Apathy

Anxiety Confusional state

Depression Depressed mood

Insomnia Dissociation

Psychotic disorder Hallucination

Schizophrenia (auditory)

Tension Hallucination(visual)

Homicidalideation

Impulsivebehaviour

Initial insomnia

Libido decreased

Libido increased

Listless

Mental statuschanges

Obsessivethoughts

System Organ Very Common Uncommon Rare Frequency

Class Common not known

Panic Attack

Psychomotorhyperactivity

Restlessness

Sleep disorder

Suicidal ideation

Terminal insomnia

Thinkingabnormal

Nervous Akathisia Disturbance in Dizziness postural

System Headache attention Dysgeusia

Disorders Somnolence* Dizziness Hyperkinesia

Dyskinesia Memory

Dystonia*** impairment

Parkinsonism** Migraine

Paraesthesia

Psychomotorhyperactivity

Restless legssyndrome

Tension headache

Eye Disorders Accommodationdisorder

Vision blurred

Ear and Hyperacusislabyrinthdisorders

Cardiac Tachycardia Palpitationsdisorders Supraventricularextrasystoles

Vascular Orthostaticdisorders hypotension

Respiratory, Oropharyngealthoracic and painmediastinal Dyspnoeadisorders

Gastrointestinal Nausea Constipation Abdominaldisorders Dry mouth discomfort

Salivary Abdominal painhypersecretion upper

Vomiting Aptyalism

Dyspepsia

Lip dry

Toothache

Skin and Hyperhidrosis Alopeciasubcutaneous Hair growthtissue disorders abnormal

Urticaria

System Organ Very Common Uncommon Rare Frequency

Class Common not known

Musculoskeletal Muscle rigidity Arthralgiaand connective Muscle tightnesstissue disorders Musculoskeletalstiffness

Myalgia

Pain in extremity

Pain in jaw

Renal and Bilirubinuriaurinary Dysuriadisorders Micturitiondisorder

Polyuria

Proteinuria

Renal disorder

Reproductive Erectile dysfunction Amenorrhoeasystem and Breast painbreast disorders Ejaculationdisorder

Galactorrhoea

Gynaecomastia

Menstruationirregular

Oligomenorrhoea

Sexualdysfunction

Congenital, Tourette's disorderfamilial andgeneticdisorders

General Asthenia Chillsdisorders and Fatigue Gait disturbanceadministration Irritability Malaisesite conditions Non-cardiac chestpain

System Organ Very Common Uncommon Rare Frequency

Class Common not known

Investigations Blood creatine Alaninephosphokinase aminotransferaseincreased increased

Anti-thyroid

C-reactive protein antibody positiveincreased Aspartateaminotransferase

Weight decreased increased

Weight increased Blood alkalinephosphatasedecreased

Blood alkalinephosphokinaseincreased

Blood cholesterolincreased

Blood glucoseincreased

Blood insulinincreased

Blood testosteronedecreased

Blood thyroidstimulatinghormone increased

Bloodtriglyceridesincreased

Electrocardiogram

PR shortened

Haemoglobindecreased

High densitylipoproteindecreased

Low densitylipoproteindecreased

Injury, Intentionalpoisoning and overdoseproceduralcomplications

*Somnolence includes the following adverse reactions observed in adolescents: hypersomnia, sedation, and somnolence.

**Parkinsonism includes the following adverse reactions observed in adolescents: cogwheel rigidity, extrapyramidaldisorder, hypokinesia, parkinsonism, and tremor.

*** Dystonia includes the following adverse reactions observed in adolescents: dystonia, oculogyric crisis and torticollis.

Post marketing reports of clinically serious cases of skin and other hypersensitivity reactions havebeen reported in association with lurasidone treatment, including some reports of Stevens-Johnsonsyndrome.

Events of interest to the class

Extrapyramidal symptoms (EPS): In the adult short-term placebo-controlled studies, the incidence ofreported events related to EPS, excluding akathisia and restlessness, was 13.5% for lurasidone-treatedsubjects versus 5.8% for placebo-treated subjects. The incidence of akathisia for lurasidone-treatedsubjects was 12.9% versus 3.0% for placebo-treated subjects. In the adolescent short-term placebo-controlled study, the incidence of reported events related to EPS, excluding akathisia, was 5.1% forlurasidone-treated subjects versus 1.8% for placebo-treated subjects. The incidence of akathisia forlurasidone-treated subjects was 8.9% versus 1.8% for placebo-treated subjects.

Dystonia: Symptoms of dystonia, prolonged abnormal contractions of muscle groups, may occur insusceptible individuals during the first few days of treatment. Dystonic symptoms include: spasm ofthe neck muscles, sometimes progressing to tightness of the throat, difficulty swallowing, difficultybreathing, and/or protrusion of the tongue. While these symptoms can occur at low doses, they occurmore frequently and with greater severity, higher potency and at higher doses of first generationantipsychotic medicinal products. An elevated risk of acute dystonia is observed in males and youngerage groups.

Venous thromboembolism: Cases of venous thromboembolism, including cases of pulmonaryembolism and cases of deep vein thrombosis have been reported with antipsychotic drugs -Frequencyunknown.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

There is no specific antidote to lurasidone, therefore, appropriate supportive measures should beinstituted, and close medical supervision and monitoring should continue until the patient recovers.

Cardiovascular monitoring should commence immediately, including continuous electrocardiographicmonitoring for possible arrhythmias. If antiarrhythmic therapy is administered, disopyramide,procainamide, and quinidine carry a theoretical hazard of QT-prolonging effects when administered inpatients with an acute overdose of lurasidone. Similarly, the alpha-blocking properties of bretyliummight be additive to those of lurasidone, resulting in problematic hypotension.

Hypotension and circulatory collapse should be treated with appropriate measures. Adrenaline anddopamine should not be used, or other sympathomimetics with beta agonist activity, since betastimulation may worsen hypotension in the setting of lurasidone-induced alpha blockade. In case ofsevere extrapyramidal symptoms, anticholinergic medicinal products should be administered.

Gastric lavage (after intubation if patient is unconscious) and administration of activated charcoaltogether with a laxative should be considered.

The possibility of obtundation, seizures, or dystonic reaction of the head and neck following overdosemay create a risk of aspiration with induced emesis.

Pharmacotherapeutic group: Psycholeptics, antipsychotics. ATC code: N05AE05

Lurasidone is a selective blocking agent of dopamine and monoamine effects. Lurasidone bindsstrongly to dopaminergic D2- and to serotonergic 5-HT2A and 5-HT7- receptors with high bindingaffinity of 0.994, 0.47 and 0.495 nM, respectively. It also blocks α2c-adrenergic receptors andα2a-adrenergic receptors with a binding affinity of 10.8 and 40.7 nM respectively. Lurasidone alsoexhibits partial agonism at the 5HT-1A receptor with a binding affinity of 6.38 nM. Lurasidone doesnot bind to histaminergic or muscarinic receptors.

The mechanism of action of the minor active metabolite of lurasidone ID-14283 is similar to that oflurasidone.

Lurasidone doses ranging from 9 to 74 mg administered to healthy subjects produced adose-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.

In the main clinical efficacy studies, lurasidone was administered at doses of 37-148 mg lurasidone.

The 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 Manualof Mental Disorders, Fourth Edition (DSM-IV) criteria for schizophrenia. Lurasidone doses, whichvaried across the five trials, ranged from 37 to 148 mg lurasidone once daily. In the short-term trials,the primary efficacy endpoint was defined as the mean change from baseline to Week 6 in Positiveand Negative Syndrome Scale (PANSS) total scores, a validated multi-item inventory composed offive factors to evaluate positive symptoms, negative symptoms, disorganised thoughts, uncontrolledhostility/excitement, and anxiety/depression. Lurasidone demonstrated superior efficacy comparedwith placebo across Phase 3 studies (see Table 2). Lurasidone showed significant separation fromplacebo from as early as Day 4. Additionally, lurasidone was superior to placebo on the predefinedsecondary endpoint Clinical Global Impression - Severity (CGI-S) scale. Efficacy was also confirmedin a secondary analysis of treatment response (defined as ≥ 30% decrease from Baseline in PANSStotal score).

Table 3: Schizophrenia Adult Studies: Positive and Negative Syndrome Scale for

Schizophrenia (PANSS) Total Score - Change from Baseline to Week 6- MMRMfor Studies D1050229, D1050231, and D1050233: Intent-to-Treat Analysis Set

Study Statistic Placebo Lurasidone dose (b) Active37 mg 74 mg 111 mg 148 mg Control(a)

Study D1050229 N=124 N=121 N=118 N=123 -- --

Baseline Mean 96.8 96.5 96.0 -- --(SD) (11.1) (11.6) (10.8) 96.0 (9.7)

LS Mean Change -17.0 -19.2 -23.4 -20.5 -- --(SE) (1.8) (1.7) (1.8) (1.8)

Treatment Differencevs. placebo

Estimate (SE) -- -2.1 (2.5) -6.4 (2.5) -3.5 (2.5) -- --p-value -- 0.591 0.034 0.391 -- --

Study D1050231 N=114 N=118 -- N=118 -- N=121

Baseline Mean 95.8 96.6 -- 97.9 -- 96.3 (12.2)(SD) (10.8) (10.7) (11.3)

LS Mean Change -16.0 -25.7 -- -23.6 -- -28.7 (1.9)(SE) (2.1) (2.0) (2.1)

Treatment Differencevs. placebo

Estimate (SE) -- -9.7 (2.9) -- -7.5 (3.0) -- -12.6 (2.8)p-value -- 0.002 -- 0.022 -- <0.001

Study D1050233 N=120 -- N=125 -- N=121 N=116

Baseline Mean 96.6 -- 97.7 (9.7) -- 97.9 97.7 (10.2)(SD) (10.2) (11.8)

LS Mean Change -10.3 -- -22.2 -- -26.5 -27.8 (1.8)(SE) (1.8) (1.8) (1.8)

Treatment Differencevs. placebo

Estimate (SE) -- -- -11.9 -- -16.2 -17.5 (2.6)(2.6) (2.5)p-value -- -- <0.001 -- <0.001 <0.001(a) Olanzapine 15 mg in Study D1050231, quetiapine extended-release (XR) 600 mg in Study D1050233.

N is number of subjects per model estimate.(b) p-values for lurasidone vs. placebo were adjusted for multiple comparisons. P-values for olanzapine and quetiapine XRvs. placebo were unadjusted.

In the short-term studies there was no consistent dose-response correlation observed.

Long-term maintenance efficacy of lurasidone (37 to 148 mg lurasidone once daily) was demonstratedin a 12 month non-inferiority trial with quetiapine extended release (200 to 800 mg once daily).

Lurasidone was non-inferior to quetiapine extended release in time to relapse of schizophrenia.

Lurasidone had a small increase from baseline to Month 12 in body weight and body mass index(Mean (SD): 0.73 (3.36) kg and 0.28 (1.17) kg/m2, respectively) compared to quetiapine extendedrelease (1.23 (4.56) kg and 0.45 (1.63) kg/m2, respectively). Overall, lurasidone had a negligible effecton weight and other metabolic parameters including total cholesterol, triglycerides, and glucose levels.

In a long-term safety study clinically stable patients were treated using 37 - 111 mg lurasidone orrisperidone 2 - 6 mg. In that study the rate of relapse over a 12-month period was 20% for lurasidoneand 16% for risperidone. This difference neared, but did not reach, statistical significance.

In a long-term trial designed to assess the maintenance of effect, lurasidone was more effective thanplacebo in maintaining symptom control and delaying relapse of schizophrenia. After having beentreated for an acute episode and stabilized for a minimum of 12 weeks with lurasidone, patients werethen randomised in a double-blind manner to either continue on lurasidone or on placebo until theyexperienced a relapse in schizophrenia symptoms. In the primary analysis of time to relapse in whichpatients that withdrew without relapse were censored at the time of withdrawal, patients on lurasidoneshowed a significantly longer time to relapse compared with patients on placebo (p=0.039). The

Kaplan-Meier estimates of the probability of relapse at Week 28 were 42.2% for lurasidone and 51.2%for placebo. The probability of all-cause discontinuation at Week 28 were 58.2% for lurasidone and69.9% for placebo (p=0.072).

Schizophrenia

The efficacy of Latuda, was established in a 6-week, randomized, double-blind, placebo-controlledstudy of adolescents (13 to 17 years) who met DSM-IV-TR criteria for schizophrenia (N=326).

Patients were randomized to one of two fixed-doses of Latuda (37 or 74 mg/day) or placebo.

The primary rating instrument used to assess psychiatric signs and symptoms was the PANSS. Thekey secondary instrument was the CGI-S.

For both dose groups, Latuda was superior to placebo in reduction of PANSS and CGI-S scores at

Week 6. On average, the 74 mg/day dose did not provide additional benefit compared to the 37mg/day dose.

The primary efficacy results are provided in Table 4.

Table 4 Primary Efficacy Results (PANSS Total Score) - Change From Baseline to Week6- MMRM for the Adolescent Schizophrenia Study D1050301: Intent-to-Treat

Analysis Set

Study Statistic Placebo Lurasidone dose (a)37 mg 74 mg

Study D1050301 N=112 N=108 N=106

Baseline Mean (SD) 92.8 (11.08) 94.5 (10.97) 94.0 (11.12)

LS Mean Change (SE) -10.5 (1.59) -18.6 (1.59) -18.3 (1.60)

Treatment Difference vs.placebo

Estimate (SE) -- -8.0 (2.21) -7.7 (2.22)p-value -- 0.0006 0.0008

N is number of subjects per model estimate.(a) p-values for lurasidone vs. placebo were adjusted for multiple comparisons.

The improvements in the CGI-S scores at Week 6 were significantly different from placebo for boththe lurasidone 74 mg/day (-0.42 ± 0.130, adjusted p = 0.0015) and lurasidone 37 mg/day (-0.47 ±0.130, adjusted p = 0.0008) treatment groups.

A 104-week extension study (Study D1050302) was designed to evaluate the long-term safety,tolerability, and effectiveness of flexibly dosed lurasidone (18.5, 37, 55.5, or 74 mg/day) in paediatricsubjects who completed a 6-week treatment period in three preceding studies of various indications.

Only results for 271 subjects with schizophrenia who enrolled from Study D1050301 are hereinafterpresented. Of these, 186 subjects (68.6%) completed through 52 weeks and 156 (57.6%) subjectscompleted 104 weeks of flexible dosing with lurasidone 18.5 to 74 mg/day.

For subjects who continued from D1050301, the mean (95% CI) in PANSS total score from DB

Baseline was -26.5 (-28.5, -24.5) at Week 28 LOCF, -28.2 (-30.2, -26.2) at Week 52 LOCF, and -29.5(-31.8, -27.3) at Week 104 LOCF/post-OL Endpoint, and mean change (95% CI) from OL Baselinewas -9.2 (-11.1, -7.2) at Week 28 LOCF, -10.8 (-13.0, -8.7) at Week 52 LOCF, and -12.2 (-14.5, -9.8)at Week 104 LOCF/post-OL Endpoint.

Bipolar Depression

The short-term efficacy of lurasidone was studied in a 6-week multicentre, randomized, double-blind,placebo-controlled, study of children and adolescent patients (10-17 years of age) who met Diagnosticand Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) criteria for a major depressiveepisode associated with bipolar I disorder, with or without rapid cycling, and without psychoticfeatures (N=350). Patients were randomized to flexibly dosed lurasidone 18-74 mg once daily orplacebo.

The primary efficacy endpoint was defined as the mean change from baseline to Week 6 in Children's

Depression Rating Scale, Revised (CDRS-R) Total Score. The key secondary endpoint was Clinical

Global Impression - Bipolar Version, Severity of Illness (CGI-BP-S) Depression Score. Statisticallysignificant differences favouring lurasidone over placebo were shown for these endpoints for the totalpopulation studied, beginning at Week 2 and were maintained at each study visit through to the end ofthe study. However, the primary and key secondary efficacy endpoints were not met in youngerpatients (below 15 years of age). Placebo-adjusted LS mean change (95% CI) from Baseline to Week6 LOCF in CDRS-R total score for the lurasidone group was -1.8 (-5.6, 2.0) for subjects in the 10- to14-year-old age patients and was -8.6 (-12.4, -4.8) for subjects in the 15- to 17-year-old age patients(Table 5).

The safety profile of lurasidone in children included in this short-term study is in general consistentwith that observed when treated within the approved indication in adults, however, differences infrequency of the most commonly occurred adverse reactions have been observed in paediatric patientsfor nausea (very common), diarrhea (common) and decreased appetite (common), compared withadults (common, unknown, and uncommon, respectively).

Table 5 Bipolar Depression Paediatric Study: Children's Depression Rating Scale,

Revised (CDRS-R) Total Score and Clinical Global Impression-Bipolar Version,

Severity of Illness (CGI-BP-S) Depression Score (Depression) - Change From

Baseline to Week 6 - MMRM for Study D1050326: Intent-to-Treat Analysis Set

Parameters Study Statistic Placebo Lurasidone dose 18.5-74mg (a) (b)

Primary Endpoint: N=170 N=173

CDRS-R Total Baseline Mean (SD) 58.6 (8.26) 59.2 (8.24)

Score LS Mean Change (SE) -15.3 (1.08) -21.0 (1.06)

Treatment Difference vs.placebo

Estimate (SE; 95% CI) -- -5.7 (1.39; -8.4 to -3.0)p-value -- <0.0001

Key Secondary N=170 N=173

Endpoint: Baseline Mean (SD) 4.5 4.6

CGI-BP-S LS Mean Change (SE) -1.05 (0.087) -1.49 (0.085)

Depression Score Treatment Difference vs.

placebo

Estimate (SE; 95% CI) -- -0.44 (0.112; -0.66 to -0.22)p-value -- <0.0001

N is number of subjects.(a) p-values for lurasidone vs. placebo were adjusted for multiple comparisons.(b) Lurasidone doses of 18.5, 37, 55.5, 74 mg are equivalent to 20, 40, 60 and 80 amounts of lurasidone hydrochloride.

Lurasidone 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 and1.5-2-times, respectively, when administered with food compared to the levels observed under fastingconditions.

Following administration of 37 mg of lurasidone, the mean approximate apparent volume ofdistribution was 6000 L. Lurasidone is highly bound (~99%) to serum proteins.

Lurasidone 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-activemetabolites (ID-20219 and ID-20220). Lurasidone and its metabolites ID-14283, ID-14326, ID-20219and ID-20220 correspond to approximately 11.4, 4.1, 0.4, 24 and 11% respectively, of serumradioactivity 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 thedopaminergic 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.

In vitro, lurasidone demonstrated no direct, or weak inhibition (direct or time-dependent) (IC50>5.9μM) of the enzymes cytochrome P450 (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19,

CYP2D6, CYP2E1, and CYP3A4. Based on this data, lurasidone is not expected to affect thepharmacokinetics of medicinal products that are substrates of CYP1A2, CYP2B6, CYP2C8, CYP2C9,

CYP2C19, CYP2D6, and CYP2E1. For administration of medicinal products that are substrates of

CYP3A4 with a narrow therapeutic range, see section 4.5.

Lurasidone is an in vitro substrate of the efflux transporters P-gp and BCRP. Lurasidone is not subjectto 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 notexpected to have a clinically relevant inhibitory potential on transporters OATP1B1, OATP1B3,

OCT2, OAT1, OAT3, MATE1, MATE2K or BSEP based on in vitro data.

Following administration of lurasidone, the elimination half-life was 20-40 hours. Following oraladministration of a radiolabelled dose, approximately 67% dose was recovered in faeces and 19% inurine. Urine comprised mostly of a number of metabolites with minimal renal excretion of parentcompound.

The pharmacokinetics of lurasidone is dose-proportional within a total daily dose range of 18.5 mg to148 mg. Steady-state concentrations of lurasidone are reached within 7 days of starting lurasidone.

Elderly people

Limited data have been collected in healthy subjects ≥ 65 years. Of the data collected, similarexposure was obtained compared with subjects < 65 years. However, an increase in exposure inelderly subjects may be expected for patients if they have impaired renal or hepatic function.

The serum concentrations of lurasidone are increased in healthy subjects with Child-Pugh Class A, Band C hepatic impairment with an increased exposure of 1.5-, 1.7- and 3-fold respectively.

The serum concentrations of lurasidone are increased in healthy subjects with mild, moderate andsevere renal impairment with an increased exposure of 1.5, 1.9 and 2.0-fold respectively. Subjectswith ESRD (CrCl<15 ml/min) have not been investigated.

There were no clinically relevant differences between genders in the pharmacokinetics of lurasidone ina population pharmacokinetic analysis in patients with schizophrenia.

There were no clinically relevant differences in the pharmacokinetics of lurasidone in a populationpharmacokinetic analysis in patients with schizophrenia. It was noted that Asian subjects had 1.5-foldincreased exposure to lurasidone compared to Caucasian subjects.

Smoking

Based 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.

The pharmacokinetics of lurasidone in paediatric patients was evaluated in 47 children aged 6-12 yearsand 234 adolescents aged 13-17 years. Lurasidone was administered as lurasidone hydrochloride atdaily doses of either 20, 40, 80, 120 mg (6-17 years) or 160 mg (10-17 years only) for up to 42 days.

There was no clear correlation between obtained serum exposure and age or body weight. Thepharmacokinetics of lurasidone in paediatric patients aged 6-17 years was generally comparable tothose observed in adults.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Major findings inrepeat-dose toxicity studies of lurasidone were centrally-mediated endocrine changes resulting fromserum prolactin elevations in rats, dogs and monkeys. High serum prolactin levels in long-termrepeat-dose studies in female rats were associated with effects on bones, adrenal glands, andreproductive tissues. In a long-term dog repeat-dose study, high serum prolactin levels were associatedwith effects on male and female reproductive tissues.

In rats, lurasidone had no effect on male and female reproduction at oral doses of 150 and0.1 mg/kg/day lurasidone hydrochloride, respectively, or on early embryonic development at an oraldose of 15 mg/kg/day lurasidone hydrochloride.

A fertility study in female rats resulted in prolonged oestrous cycle and delayed copulation at≥1.5 mg/kg/day lurasidone hydrochloride, whilst the copulation and fertility indices, and the numbersof corpora lutea, implantations and live foetuses were decreased at 150 mg/kg/day lurasidonehydrochloride. These effects were due to the hyperprolactinemia following lurasidone treatment,affecting the oestrous cycle and copulatory behaviour as well as the maintenance of corpus luteum ofthe female rats, resulting in a decrease in implantation and the number of live foetuses. Theseprolactin-related effects are not considered to be relevant to human reproduction.

A single dose of 10 mg/kg lurasidone hydrochloride to pregnant rats resulted in fetal exposure. In adose range finding study in pregnant rats, 150 mg/kg/day lurasidone hydrochloride caused fetal growthretardation without signs of teratogenicity. Lurasidone was not teratogenic in rats or rabbits at anexposure similar to or below the maximum recommended human dose (148 mg lurasidone).

In the definitive juvenile rat toxicity study, no increased sensitivity of juvenile animals to lurasidone-related effects on body weight, food consumption, and clinical observations were apparent, but similareffects as in adult rat were noted (delays in growth and development and hyperprolactinaemia).

Hyperactivity that was evident at ≥3 mg/kg/day during the post-treatment period has also beenreported for other D2 receptor antagonists. Slightly lower birth weights and body weights/body weightgains during the postnatal period were noted in the offspring of juvenile rats previously treated with≥30 mg/kg/day. At the NOAEL of 3 mg/kg/day, the exposures of lurasidone and most metaboliteswere lower than that achieved at the recommended clinical dose in adolescents aged 13 years orabove.

Lurasidone was excreted in milk of rats during lactation.

Lurasidone was not genotoxic in a battery of tests. Mammary gland and/or pituitary gland tumourswere observed in the mouse and rat carcinogenicity studies and are most likely due to the increasedblood prolactin levels. These findings are common in rodents treated with antipsychotic medicinalproducts with dopamine D2 blocking activity and are considered to be rodent-specific.

Latuda 18.5 mg film-coated tablets

Core

Mannitol (E 421)

Starch, pregelatinised

Croscarmellose sodium (E468)

Hypromellose 2910 (E 464)

Magnesium stearate (E 470b)

Hypromellose 2910 (E 464)

Titanium dioxide (E 171)

Macrogol 8000

Carnauba wax (E 903)

Latuda 37 mg film-coated tablets

Core

Mannitol (E 421)

Starch, pregelatinised

Croscarmellose sodium (E468)

Hypromellose 2910 (E 464)

Magnesium stearate (E 470b)

Hypromellose 2910 (E 464)

Titanium dioxide (E 171)

Macrogol 8000

Carnauba wax (E 903)

Latuda 74 mg film-coated tablets

Core

Mannitol (E 421)

Starch, pregelatinised

Croscarmellose sodium (E468)

Hypromellose 2910 (E 464)

Magnesium stearate (E 470b)

Hypromellose 2910 (E 464)

Titanium dioxide (E 171)

Macrogol 8000

Iron oxide, Yellow (E 172)

Indigotine (E 132)

Carnauba wax (E 903)

Not applicable.

5 years

Store in the original package in order to protect from light.

Cartons contain 14 x 1, 28 x 1, 30 x 1, 56 x 1, 60 x 1, 90 x 1 or 98 x 1 tablets in aluminium/aluminiumperforated unit dose blisters.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Aziende Chimiche Riunite Angelini Francesco - A.C.R.A.F. S.p.A.

Viale Amelia 70, 00181

Rome - Italy

Latuda 18.5 mg film-coated tablet

EU/1/14/913/001-007

Latuda 37 mg film-coated tablet

EU/1/14/913/008-014

Latuda 74 mg film-coated tablet

EU/1/14/913/015-021

Date of first authorisation: 21 March 2014

Date of latest renewal: 14 November 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.