4.1. Therapeutic indications

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

4.2. Posology and method of administration

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

Lurasidone 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).

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

4.3. Contraindications

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).

4.4. Special warnings and precautions for use

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 counselled on signs and symptoms of elevated prolactin, such as gynecomastia, galactorrhoea, amenorrhoea 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 Lurasidone 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.

Sodium

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

4.5. Interaction with other medicinal products and other forms of interaction

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).

Lurasidone 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.

4.6. Fertility, pregnancy and lactation

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).

4.7. Effects on ability to drive and use machines

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.

4.8. Undesirable effects

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 Common

Common

Uncommon

Rare

Frequency not known

Infections and infestations

Nasopharyngitis

Blood and lymphatic system disorders

Anaemia

Eosinophilia

Leukopenia

Neutropenia****

Immune system disorders

Hypersensitivity

Metabolism and nutrition disorders

Weight increased

Decreased appetite

Blood glucose increased

Hyponatraemia

Psychiatric disorders

Insomnia

Agitation

Anxiety

Restlessness

Nightmare

Catatonia

Panic attack

Suicidal behaviour

Sleep disorder****

Nervous system disorders

Akathisia

Somnolence*

Parkinsonism**

Dizziness

Dystonia***

Dyskinesia

Lethargy

Dysarthria

Tardive dyskinesia

Syncope

Convulsion

Neuroleptic malignant syndrome (NMS)

Cerebrovascular accident

Eye disorders

Blurred vision

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Tachycardia

Angina pectoris

Atrioventricular block first degree

Bradycardia

Vascular disorders

Hypertension

Hypotension

Orthostatic hypotension

Hot flush

Blood pressure increased

Gastrointestinal disorders

Nausea

Diarrhoea

Vomiting

Dyspepsia

Salivary hypersecretion

Dry mouth

Upper abdominal pain

Stomach discomfort

Flatulence

Dysphagia

Gastritis

Hepatobiliary disorders

Alanine aminotransferase increased

Skin and subcutaneous tissue disorders

Rash

Pruritus

Hyperhidrosis

Angioedema

Stevens- Johnson syndrome

Musculoskeletal and connective tissue disorders

Back pain

Musculoskeletal stiffness

Joint stiffness

Myalgia

Neck 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

Erectile dysfunction

Amenorrhoea

Dysmenorrhoea

Breast pain

Galactorrhoea

Breast enlargement****

General disorders and administration site conditions

Fatigue

Gait disturbance

Sudden death

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

Listless

Mental status changes

Obsessive thoughts

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

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

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 classExtrapyramidal 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 Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

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.