Lurasidone

Registered South African indications:

• Schizophrenia
• Major depressive episodes associated with bipolar disorder (bipolar depression)

Registered South African contraindications

• Hypersensitivity to the active ingredient or any of its excipients
• Coadministration with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin, ritonavir, voriconazole, mibefradil, etc.)
• Coadministration with strong CYP3A4 inducers (e.g., rifampin, avasimibe, St. John’s wort, phenytoin, carbamazepine, etc.)

South African recommendations

Caution in the following patient groups

• Pregnancy
• Breastfeeding
• Moderate to severe renal impairment (CrCl<50ml/min)
• Moderate to severe hepatic impairment (Child-Pugh Score: 7 to 15)
• Elderly

Risk of suicide

• The occurrence of suicidal behaviour is inherent in psychotic illnesses and has been reported early after initiation or switch of antipsychotic therapy
• Close supervision of high-risk patients should accompany anti-psychotic therapy

Parkinson's disease

• If prescribed to patients with Parkinson's disease, lurasidone may exacerbate the underlying parkinsonism symptoms
• Physicians should weigh the risks versus the benefits when prescribing lurasidone to patients with Parkinson's disease

Extrapyramidal symptoms (EPS)

• Medicines such as lurasidone with dopamine receptor antagonistic properties have been associated with extrapyramidal adverse reactions
• In placebo-controlled clinical studies, there was an increased occurrence of EPS following treatment with lurasidone compared to placebo

Tardive dyskinesia

• Medicines such as lurasidone with dopamine receptor antagonistic properties have been associated with the induction of Tardive dyskinesia
• If signs and symptoms of tardive dyskinesia appear, 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, or in concomitant use with other medicines 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
• If NMS occurs, discontinue lurasidone immediately

Elderly patients with dementia

• Lurasidone has not been studied in elderly patients with dementia

Overall mortality

• In a meta-analysis, elderly patients with dementia treated with atypical antipsychotics, including risperidone, aripiprazole, olanzapine, and quetiapine, had an increased risk of mortality compared to placebo

Cerebrovascular accident

• Increased risk of cerebrovascular adverse reactions has been seen in dementia patients treated with atypical antipsychotics, including lurasidone

Venous thromboembolism

• Cases of venous thromboembolism (VTE) have been reported with antipsychotic medicines
• All possible risk factors for VTE should be identified before and during treatment with lurasidone

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 gynaecomastia, galactorrhoea, amenorrhoea, and erectile dysfunction

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. increased blood glucose, have been reported in clinical trials with lurasidone
• Clinical monitoring is advisable in diabetic patients and those with risk factors for diabetes mellitus

Orthostatic hypotension/syncope

• Lurasidone may cause orthostatic hypotension, potentially due to its α1-adrenergic receptor antagonism
• Monitoring of orthostatic vital signs should be considered in patients vulnerable to hypotension

Interaction with grapefruit juice

• Grapefruit juice should be avoided during treatment with lurasidone

Serotonin syndrome

• Concomitant administration of lurasidone and other serotonergic agents may result in serotonin syndrome
• If serotonin syndrome is suspected, a dose reduction or discontinuation of therapy should be considered

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

Forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Schizophrenia

• Oral (fct): Initial: 40mg, dly; Dose range (initial dose titration is not required): 40-160mg, dly; Max: 160mg/24hrs

Major depressive episodes associated with bipolar disorder (bipolar depression)
- As monotherapy or as adjunctive therapy with lithium or valproate

• Oral (fct): Initial: 20mg, dly; Dose range (initial dose titration is not required): 20-120mg, dly; Max: 120mg/24hrs

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Depressive episodes associated with bipolar I disorder
In the monotherapy study, the higher dose range (80mg to 120mg per day) did not provide additional efficacy, on average, compared to the lower dose range (20 to 60mg per day). The efficacy of lurasidone in the treatment of mania associated with bipolar disorder has not been established

Paed. forms avail. in SA and covered in this monograph: fct

South African registered indications and dosages

Schizophrenia

• Oral (fct): Initial: 40mg, dly; Dose range (initial dose titration is not required): 40-80mg, dly; Max: 80mg/24hrs

Pregnancy

South African recommendations

• Caution; not recommended
• Lurasidone should not be used during pregnancy unless clearly necessary (if the benefit to the mother clearly weighs the potential risk to the foetus). If women decide to become pregnant, the use of this product should be carefully re-evaluated

Breastfeeding

South African recommendations

• Caution
• Lurasidone was excreted in milk of rats during lactation. 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

South African recommendations

• 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

South African recommendations

• Mild: No dose adjustment recommended
• Moderate to severe: Caution; dose adjustment recommended
  Dose adjustment is recommended in moderate (CrCl: 30 to <50ml/min) and severe renal impairment (CrCl <30ml/min)
  Initial: 20mg/day; Max: 80mg/24hrs
  Subjects with ESRD (CrCl< 15 ml/min) have not been investigated

South African recommendations

• Mild: No dose adjustment recommended
• Moderate (Child-Pugh Score: 7 to 9): Caution; dose adjustment recommended
  Initial: 20mg/day; Max: 80mg/24hrs
• Severe (Child-Pugh Score: 10 to 15): Caution; dose adjustment recommended
  Initial: 20mg/day; Max: 40mg/24hrs

South African recommendations

• Caution; no dose adjustment recommended
  Limited data have been collected in healthy subject’s ≥ 65 years. Of the data collected, similar exposure was obtained compared with subjects < 65 years. However, an increase in exposure in elderly subjects may be expected for patients if they have impaired renal or hepatic function

Adults

Infections and Infestations

Less frequent

• Nasopharyngitis

Blood and Lymphatic System Disorders

Less frequent

• Anaemia
• Eosinophilia
• Leukopenia

Frequency unknown

• Neutropenia

Immune System Disorders

Frequent

• Hypersensitivity

Metabolism and Nutrition Disorders

Frequent

• Weight increased
• Decreased appetite

Less frequent

• Blood glucose increased
• Hyponatraemia

Psychiatric Disorders

Frequent

• Insomnia
• Agitation
• Anxiety
• Restlessness

Less frequent

• Nightmares
• Catatonia
• Panic attack
• Suicidal behaviour

Frequency unknown

• Sleep disorder

Nervous System Disorders

Frequent

• Akathisia
• Somnolence
• Parkinsonism
• Dizziness
• Dystonia
• Dyskinesia

Less frequent

• Lethargy
• Dysarthria
• Tardive dyskinesia
• Syncope
• Convulsion
• Neuroleptic malignant syndrome (NMS)
• Cerebrovascular accident

Eye Disorders

Less frequent

• Blurred vision

Cardiac Disorders

Frequent

• Tachycardia

Less frequent

• Angina pectoris
• Atrioventricular block first degree
• Bradycardia

Vascular Disorders

Frequent

• Hypertension

Less frequent

• Hypotension
• Orthostatic hypotension
• Hot flush
• Blood pressure increased

Gastrointestinal Disorders

Frequent

• Nausea
• Diarrhoea
• Vomiting
• Dyspepsia
• Salivary hypersecretion
• Dry mouth
• Upper abdominal pain
• Stomach discomfort

Less frequent

• Flatulence
• Dysphagia
• Gastritis

Hepatobiliary Disorders

Less frequent

• Alanine aminotransferase increased

Skin and Subcutaneous Tissue Disorders

Frequent

• Rash
• Pruritis

Less frequent

• Hyperhidrosis
• Angioedema

Frequency unknown

• Stevens Johnson syndrome

Musculoskeletal and Connective Tissue Disorders

Frequent

• Back pain
• Musculoskeletal stiffness

Less frequent

• Joint stiffness
• Myalgia
• Neck pain
• Rhabdomyolysis

Renal and Urinary Disorders

Frequent

• Serum creatinine increased

Less frequent

• Dysuria
• Renal failure

Pregnancy, Puerperium and Perinatal Conditions

Frequency unknown

• Neonatal drug withdrawal syndrome

Reproductive System and Breast Disorders

Less frequent

• Blood prolactin increased
• Erectile dysfunction
• Amenorrhoea
• Dysmenorrhoea
• Breast pain
• Galactorrhoea

Frequency unknown

• Breast enlargement

General Disorders and Administration Site Conditions

Frequent

• Fatigue

Less frequent

• Gait disturbance
• Sudden death

Investigations

Frequent

• Blood creatinine phosphokinase increased

Adolescents

Infections and Infestations

Less frequent

• Nasopharyngitis
• Rhinitis
• Upper respiratory tract infection

Blood and Lymphatic System Disorders

Less frequent

• Neutropenia

Immune System Disorders

Less frequent

• Hypersensitivity

Endocrine Disorders

Frequent

• Hyperprolactinaemia (including blood prolactin increased)

Less frequent

• Autoimmune thyroiditis
• Hyperandrogenism
• Hypothyroidism

Metabolism and Nutrition Disorders

Frequent

• Decreased appetite
• Increased appetite

Less frequent

• Hyperinsulinaemia

Psychiatric Disorders

Frequent

• Abnormal dreams
• Agitation
• Anxiety
• Depression
• Insomnia
• Psychotic disorder
• Schizophrenia
• Tension

Less frequent

• Aggression
• Apathy
• Confusional state
• Depressed mood
• Dissociation
• Hallucination (auditory, 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

Frequent

• Akathisia
• Headache
• Somnolence
• Disturbance in attention
• Dizziness
• Dyskinesia
• Dystonia
• Parkinsonism

Less frequent

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

Eye Disorders

Less frequent

• Accommodation disorders
• Blurred vision

Ear and labyrinth disorders

Less frequent

• Hyperacusis

Cardiac Disorders

Frequent

• Tachycardia

Less frequent

• Palpitations
• Supraventricular extra systoles

Vascular Disorders

Frequent

• Hypertension

Less frequent

• Hypotension
• Orthostatic hypertension

Respiratory, Thoracic and Mediastinal Disorders

Less frequent

• Oropharyngeal pain
• Dyspnoea

Gastrointestinal Disorders

Frequent

• Nausea
• Vomiting
• Dry mouth
• Salivary hypersecretion

Less frequent

• Abdominal discomfort
• Abdominal pain upper
• Aptyalism
• Diarrhoea
• Dyspepsia
• Lip dry
• Toothache

Skin and Subcutaneous Tissue Disorders

Frequent

• Hyperhidrosis

Less frequent

• Alopecia
• Hair growth abnormal
• Rash
• Urticaria

Musculoskeletal and Connective Tissue Disorders

Frequent

• Muscle rigidity

Less frequent

• Arthalagia
• Muscle tightness
• Musculoskeletal stiffness
• Myalgia
• Pain in extremity
• Pain in jaw

Renal and Urinary Disorders

Less frequent

• Bilirubinuria
• Dysuria
• Micturition disorder
• Polyuria
• Proteinuria
• Renal disorder

Reproductive System and Breast Disorders

Frequent

• Erectile dysfunction

Less frequent

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

Congenital, Familial and Genetic Disorders

Less frequent

• Tourette's disorder

General Disorders and Administration Site Conditions

Frequent

• Asthenia
• Fatigue
• Irritability

Less frequent

• Chills
• Gait disturbance
• Malaise
• Non- cardiac chest pain
• Pyrexia

Investigations

Frequent

• Blood creatinine phosphokinase increased
• C-reactive protein increased
• Weight decreased
• Weight increased

Less frequent

• 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

Less frequent

• Intentional overdose

• Other centrally acting medicines
• Medicines known to prolong the QT interval
• Strong CYP3A4 inhibitors
• Strong CYP3A4 inducers
• Mibefradil
• Avasimibe
• Class I antiarrhythmics
• Quinidine
• Disopyramide
• Class III antiarrhythmics
• Amiodarone
• Sotalol
• Antimalarials
• Mefloquine
• Other serotonergic agents
• Buprenorphine
• Opioids
• Monoamine oxidase (MAO) inhibitors
• Selective serotonin reuptake inhibitors (SSRIs)
• Serotonin-norepinephrine reuptake inhibitors (SNRIs)
• Tricyclic antidepressants
• Boceprevir
• Clarithromycin
• Cobicistat
• Indinavir
• Itraconazole
• Ketoconazole
• Nefazodone
• Nelfinavir
• Posaconazole
• Ritonavir
• Saquinavir
• Telaprevir
• Telithromycin
• Voriconazole
• Moderate CYP3A4 inhibitors
• Diltiazem
• Erythromycin
• Fluconazole
• Verapamil
• Carbamazepine
• Phenobarbital
• Phenytoin
• Rifampicin
• Armodafinil
• Amprenavir
• Aprepitant
• Prednisone
• Rufinamide
• Bosentan
• Efavirenz
• Etravirine
• Modafinil
• Nafcillin
• Antihistaminics
• Astemizole
• Terfenadine
• Cisapride
• Pimozide
• Quinidine
• Bepridil
• Ergot alkaloids
• Ergotamine
• Dihydroergotamine
• Digoxin
• Dabigatran
• Lithium
• Norgestimate
• Ethinyl estradiol

Other interactions

• Alcohol
• St. John's wort
• Grapefruit juice

• Blood chemistries (annually)
  • Electrolytes
  • Renal function
  • Hepatic function
  • TSH
• Fasting plasma glucose / HbA1c
  • 4 months after initiation; annually. Check more frequently if abnormal
• Lipid panel
  • 4 months after initiation; annually. Check more frequently if abnormal
• Weight, height, and BMI
  • 8 and 12 weeks after initiation and dose change; quarterly
• Waist circumference
  • Consider at baseline and annually, especially in patients with or at risk for metabolic syndrome
• Vital signs
  • Every visit (at least weekly during the first 3 to 4 weeks of treatment); 4 weeks after dose change

Specific cases may require

• Full blood count
  • As clinically indicated; check frequently during the first few months in patients with preexisting low WBC or history of drug-induced leukopenia/neutropenia
• Prolactin
  • Ask about symptoms at every visit until dose is stable. Check prolactin level if symptoms are reported

Additional observations

• Metabolic syndrome history (annually)
  • Evaluate for personal and family history of obesity, diabetes, dyslipidaemia, hypertension, or cardiovascular disease
• Adherence (every visit)
• Mental status and alertness (every visit)
• Extrapyramidal symptoms
  • Every visit; 4 weeks after initiation and dose change; annually. Use a formalised rating scale at least annually or every 6 months if high risk
• Tardive dyskinesia
  • Every visit; annually. Use a formalised rating scale at least annually or every 6 months if high risk
• Fall risk (every visit)

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 0.495nm, respectively. It also blocks α2c-adrenergic receptors and α2a-adrenergic receptors with a binding affinity of 10.8 and 40.7nM respectively. Lurasidone also exhibits partial agonism at the 5HT-1A receptor with a binding affinity of 6.38nm. 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 74mg 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.