lurasidone: prescribing information – dosing, contraindications, interactions, side effects

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

Posology

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 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.

Paediatric 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 74 mg once daily. Dose increase should be based on physician

judgement and observed clinical response. The maximum daily dose should not exceed 74 mg. In children, 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 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 products
Due 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.

Elderly people
Dosing 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 148 mg of lurasidone. Caution should be exercised when treating patients ≥65 years of age with higher doses of lurasidone.

Renal impairment
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 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. Lurasidone 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 impairment
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 dose in moderate hepatic impairment patients should not exceed 74 mg and in severe hepatic impairment patients should not exceed 37 mg once daily.

Method of administration

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 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.

- 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).

Summary of the safety profile
The 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, nausea and insomnia.

Tabulated summary of adverse reactions
Adverse drug reactions (ADRs) based upon pooled data are shown by system, organ class and by preferred term are listed in Table 1 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 (≥ 1/1,000 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
Class
Very
Commo n
Common

Uncommon

Rare

Frequency not known
Infections and infestations

Nasopharyngiti s

Blood and lymphatic system disorders

Anaemia
Eosinophilia
Leukopenia
Neutropenia***
*
Immune system disorders

Hypersensitivit y

Metabolism and nutrition disorders

Weight increased
Decreased appetite

Blood glucose increased
Hyponatraemia

Psychiatric disorders

Insomni a

Agitation
Anxiety
Restlessness
Nightmare
Catatonia
Panic attack

Suicidal behaviour
Sleep disorder****
Nervous system disorders

Akathisi a

Somnolence*
Parkinsonism*
*
Dizziness
Dystonia***
Dyskinesia
Lethargy
Dysarthria
Tardive dyskinesia
Syncope
Convulsion
Neuroleptic malignant syndrome
(NMS)
Cerebrovascula r accident

Eye disorders

Blurred vision

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Tachycardia
Angina pectoris
Atrioventricula r block first degree
Bradycardia

System Organ
Class
Very
Commo n
Common

Uncommon

Rare

Frequency not known
Vascular disorders

Hypertension

Hypotension
Orthostatic hypotension
Hot flush
Blood pressure increased

Gastrointestina l disorders

Nausea

Diarrhoea
Vomiting
Dyspepsia
Salivary hypersecretion
Dry mouth
Upper abdominal pain
Stomach discomfort
Flatulence
Dysphagia
Gastritis

Hepatobiliary disorders

Alanine aminotransferas e increased

Skin and subcutaneous tissue disorders

Rash
Pruritus

Hyperhidrosis

Angioedema

Stevens-
Johnson syndrome
Musculoskelet al and connective tissue disorders

Back pain
Musculoskelet al stiffness

Joint stiffness
Myalgia
Neck pain

Rhabdomyolys is

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
Erectile dysfunction
Amenorrhoea
Dysmenorrhoea
Breast pain
Galactorrhoea
Breast enlargement***
*

General disorders and administration site conditions

Fatigue
Gait disturbance
Sudden death

System Organ
Class
Very
Commo n
Common

Uncommon

Rare

Frequency not known
Investigations

Blood creatinine phosphokinase increased

*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 too low to estimate frequencies.

Table 2: Adverse Drug Reactions (ADRs) for Adolescents

System Organ
Class
Very
Common
Common

Uncommon

Rare

Frequency not known
Infections and infestations

Nasopharyngitis
Rhinitis
Upper respiratory tract infection

Blood and lymphatic system disorders

Neutropenia

Immune System
Disorders

Hypersensitivity

Endocrine disorders

Hyperprolactinaemia
(including blood prolactin increased)

Autoimmune thyroiditis
Hyperandrogenism
Hypothyroidism

Metabolism and nutrition disorders

Decreased appetite
Increased appetite
Hyperinsulinemia

Psychiatric
Disorders

Abnormal dreams
Agitation
Anxiety
Depression
Insomnia
Psychotic disorder
Schizophrenia
Tension
Aggression
Apathy
Confusional state
Depressed mood
Dissociation
Hallucination
(auditory)
Hallucination
(visual)
Homicidal ideation
Impulsive behaviour
Initial insomnia
Libido decreased
Libido increased
Listlessness
Mental status changes
Obsessive thoughts

System Organ
Class
Very
Common
Common

Uncommon

Rare

Frequency not known
Panic Attack
Psychomotor hyperactivity
Restlessness
Sleep disorder
Suicidal ideation
Terminal insomnia
Thinking abnormal
Nervous
System
Disorders
Akathisia
Headache
Somnolence*
Disturbance in attention
Dizziness
Dyskinesia
Dystonia***
Parkinsonism**

Dizziness postural
Dysgeusia
Hyperkinesia
Memory impairment
Migraine
Paraesthesia
Psychomotor hyperactivity
Restless legs syndrome
Tardive dyskinesia
Tension headache

Eye Disorders

Accommodation disorder
Vision blurred

Ear and labyrinth disorders

Hyperacusis

Cardiac disorders

Tachycardia
Palpitations
Supraventricular extrasystoles

Vascular disorders

Orthostatic hypotension
Hypertension

Respiratory, thoracic and mediastinal disorders

Oropharyngeal pain
Dyspnoea

Gastrointestinal disorders
Nausea
Constipation
Dry mouth
Salivary hypersecretion
Vomiting
Abdominal discomfort
Abdominal pain upper
Aptyalism
Diarrhoea
Dyspepsia
Lip dry
Toothache

Skin and subcutaneous tissue disorders

Hyperhidrosis
Alopecia
Hair growth abnormal
Rash
Urticaria

System Organ
Class
Very
Common
Common

Uncommon

Rare

Frequency not known
Musculoskeletal and connective tissue disorders

Muscle rigidity
Arthralgia
Muscle tightness
Musculoskeletal stiffness
Myalgia
Pain in extremity
Pain in jaw

Renal and urinary disorders

Bilirubinuria
Dysuria
Micturition disorder
Polyuria
Proteinuria
Renal disorder

Reproductive system and breast disorders

Erectile dysfunction
Amenorrhoea
Breast pain
Ejaculation disorder
Galactorrhoea
Gynaecomastia
Menstruation irregular
Oligomenorrhoea
Sexual dysfunction

Congenital, familial and genetic disorders

Tourette's disorder

General disorders and administration site conditions

Asthenia
Fatigue
Irritability
Chills
Gait disturbance
Malaise
Non-cardiac chest pain
Pyrexia

System Organ
Class
Very
Common
Common

Uncommon

Rare

Frequency not known
Investigations

Blood creatine phosphokinase increased

C-reactive protein increased

Weight decreased
Weight increased
Alanine aminotransferase increased
Anti-thyroid antibody positive
Aspartate aminotransferase increased
Blood alkaline phosphatase decreased
Blood alkaline phosphokinase increased
Blood cholesterol increased
Blood glucose increased
Blood insulin increased
Blood testosterone decreased
Blood thyroid stimulating hormone increased
Blood triglycerides increased
Electrocardiogram
PR shortened
Haemoglobin decreased
High density lipoprotein decreased
Low density lipoprotein decreased

Injury, poisoning and procedural complications

Intentional overdose

*Somnolence includes the following adverse reactions observed in adolescents: hypersomnia, sedation, and somnolence.
**Parkinsonism includes the following adverse reactions observed in adolescents: cogwheel rigidity, extrapyramidal disorder, hypokinesia, parkinsonism, and tremor.
*** Dystonia includes the following adverse reactions observed in adolescents: dystonia, oculogyric crisis and torticollis.

Description of selected adverse reactions
Post marketing reports of clinically serious cases of skin and other hypersensitivity reactions have been reported in association with lurasidone treatment, including some reports of Stevens-Johnson syndrome.

Events of interest to the class
Extrapyramidal symptoms (EPS): In the adult 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. In the adolescent short-term placebo- controlled study, the incidence of reported events related to EPS, excluding akathisia, was 5.1% for lurasidone-treated subjects versus 1.8% for placebo-treated subjects. The incidence of akathisia for lurasidone-treated subjects was 8.9% versus 1.8% 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 reactions
Reporting 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 national reporting system listed in Appendix V.

During antipsychotic treatment, improvement in the patient's clinical condition may take a few days to some 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 been reported early after initiation or switch of antipsychotic therapy. Close supervision of high-risk patients should accompany antipsychotic therapy.

Parkinson’s disease
If 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 lurasidone 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 dyskinesia
Medicinal 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 prolongation
Caution 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.

Seizures
Lurasidone 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 lurasidone. Additional signs may include myoglobinuria (rhabdomyolysis) and acute renal failure. In this event, lurasidone should be discontinued.

Elderly patients with dementia
Lurasidone has not been studied in elderly patients with dementia.

Overall mortality
In 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 accident
An 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 thromboembolism
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 possible risk factors for VTE should be identified before and during treatment with lurasidone and preventive measures undertaken.

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

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

Hyperglycaemia
Rare 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/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 to hypotension.

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-uptake inhibitors (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 of the 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, a dose reduction or discontinuation of therapy should be considered depending on the severity of the symptoms.

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

Pharmacodynamic interactions
Given 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).

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

Pharmacokinetic interactions
The concomitant administration of lurasidone and grapefruit juice has not been assessed. Grapefruit juice inhibits CYP3A4 and may increase the serum concentration of lurasidone. Grapefruit juice should 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 the dopaminergic and serotonergic receptors. Lurasidone and its active metabolite ID-14283 are primarily metabolised by CYP3A4.

CYP3A4 inhibitors
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- and 6-fold increase in exposure of lurasidone and its active metabolite ID-14283 respectively.

Co-administration of lurasidone and posaconazole (strong CYP3A4 inhibitor) resulted in an approximate 4-5 fold increase in lurasidone exposure. A persistent effect of posaconazole on lurasidone 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 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 inducers
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-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.

Transporters
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-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.

Pregnancy
There 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/foetal 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-feeding
Lurasidone 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 lurasidone should be considered only if the potential benefit of treatment justifies the potential risk to the child.

Fertility
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 cautioned about operating hazardous machines, including motor vehicles and cycles, until they are reasonably certain 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.

Management of overdose
There 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.

5.
PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Psycholeptics, antipsychotics. ATC code: N05AE05

Mechanism of action
Lurasidone 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 histaminergic 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 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 effects
In the main clinical efficacy studies, lurasidone was administered at doses of 37-148 mg lurasidone.

Clinical efficacy
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 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 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).

Table 3:
Schizophrenia Adult 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)
Active
Control
(a)
37 mg
74 mg
111 mg
148 mg
Study D1050229
N=124
N=121
N=118
N=123
--
--
Baseline Mean
(SD)

Absorption
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 and 1.5-2-times, respectively, when administered with food compared to the levels observed under fasting conditions.

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

Biotransformation
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-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.

In vitro, lurasidone demonstrated no direct, or weak inhibition (direct or time-dependent) (IC50>5.9 μM) 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 the pharmacokinetics 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.