LATUDA Film-coated tablet Ref.[9812] Active ingredients: Lurasidone

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).

Co-administration 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 coadministration.

Co-administration 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.

Co-administration 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).

Co-administration of lurasidone with the strong CYP3A4 inducer rifampicin resulted in a 6-fold decrease in exposure of lurasidone.

Co-administration 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

Co-administration 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.

Co-administration of lurasidone with digoxin (a P-gp substrate) did not increase the exposure to digoxin and only slightly increased C_max (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.

Co-administration 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.

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:

^* 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:

^* 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.

Not applicable.