Lurasidone - Drug Monograph

Introduction

Lurasidone hydrochloride is an atypical antipsychotic medication approved by the FDA in 2010. It belongs to the benzisothiazol class and is characterized by its unique receptor binding profile. Lurasidone is primarily used in the treatment of psychiatric conditions, particularly schizophrenia and bipolar depression, offering a favorable metabolic side effect profile compared to some other antipsychotic agents.

Mechanism of Action

Lurasidone exerts its therapeutic effects through potent antagonism at dopamine D₂ and serotonin 5-HT₂A receptors. Additionally, it acts as a partial agonist at serotonin 5-HT₁A receptors and demonstrates antagonist activity at adrenergic α₂C receptors. The drug's antidepressant properties are attributed to its high affinity for 5-HT₇ receptors, which may contribute to its efficacy in bipolar depression. Unlike many other antipsychotics, lurasidone has minimal affinity for muscarinic M₁, histamine H₁, and adrenergic α₁ receptors, which accounts for its reduced risk of anticholinergic effects, sedation, and orthostatic hypotension.

Indications

• Treatment of schizophrenia in adults and adolescents (13-17 years)
• Monotherapy treatment of bipolar I depression in adults and pediatric patients (10-17 years)
• Adjunctive therapy with lithium or valproate for bipolar I depression in adults

Dosage and Administration

• Initial dose: 40 mg once daily
• Maintenance range: 40-80 mg daily
• Maximum dose: 160 mg daily (not shown to be more effective than lower doses)

• Initial dose: 20 mg once daily
• Recommended dose: 20-120 mg daily
• Should be taken with food (at least 350 calories) to enhance absorption

• Renal impairment: Maximum dose 40 mg daily for moderate-to-severe impairment
• Hepatic impairment: Maximum dose 40 mg daily for moderate-to-severe impairment
• Elderly: Consider lower starting doses due to potential for increased sensitivity
• Pediatrics: Dosing based on weight and clinical response

Pharmacokinetics

• Absorption: Bioavailability approximately 9-19% when taken with food; Tmax: 1-3 hours
• Distribution: Volume of distribution: ~6173 L; >99% protein bound
• Metabolism: Primarily hepatic via CYP3A4; active metabolite (ID-14283) present in low concentrations
• Elimination: Half-life: ~18 hours; excreted primarily in feces (80%) and urine (9%)

Contraindications

• Hypersensitivity to lurasidone or any component of the formulation
• Concomitant use with strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin)
• Concomitant use with strong CYP3A4 inducers (e.g., rifampin, carbamazepine)

Warnings and Precautions

• Increased mortality in elderly patients with dementia-related psychosis
• Suicidality: Monitor for emergence of suicidal thoughts and behaviors
• Neuroleptic malignant syndrome: Monitor for hyperpyrexia, muscle rigidity, autonomic instability
• Tardive dyskinesia: May be irreversible; monitor for involuntary movements
• Metabolic changes: Monitor blood glucose, lipids, and weight
• Hyperprolactinemia: May occur due to dopamine blockade
• Orthostatic hypotension: Monitor especially during initial dosing
• Seizures: Use with caution in patients with seizure history
• Dysphagia: Esophageal dysmotility and aspiration risk
• Cognitive and motor impairment: Caution when operating machinery

Drug Interactions

• Strong CYP3A4 inhibitors: Contraindicated (increases lurasidone exposure up to 9-fold)
• Strong CYP3A4 inducers: Contraindicated (decreases lurasidone exposure up to 7-fold)
• Moderate CYP3A4 inhibitors: Reduce lurasidone dose by 50%
• CNS depressants: Additive sedation with alcohol, benzodiazepines, opioids
• Other dopamine antagonists: Increased risk of extrapyramidal symptoms

Adverse Effects

• Somnolence (22-27%)
• Akathisia (13-22%)
• Nausea (10-17%)
• Parkinsonism (8-14%)
• Restlessness (5-10%)

• Neuroleptic malignant syndrome (<0.1%)
• Tardive dyskinesia (cumulative incidence ~5% per year)
• Hyperglycemia/diabetes mellitus
• Orthostatic hypotension (2-5%)
• Seizures (<1%)
• Leukopenia/neutropenia (<1%)

Monitoring Parameters

• Baseline: Weight, BMI, blood pressure, fasting glucose, lipid profile, CBC
• Ongoing:

- Mental status and symptom improvement - Extrapyramidal symptoms and akathisia (at each visit) - Weight (monthly for first 3 months, then quarterly) - Blood glucose and lipids (at 3 months, then annually) - Prolactin levels (if symptomatic) - Treatment adherence - Suicidal ideation and behaviors

Patient Education

• Take with food (at least 350 calories) to ensure proper absorption
• Avoid grapefruit and grapefruit juice during treatment
• Do not abruptly discontinue medication without medical supervision
• Report any unusual movements, muscle stiffness, or restlessness
• Monitor for signs of high blood sugar (increased thirst, urination, hunger)
• Be aware of potential sedation and avoid driving until effects are known
• Rise slowly from sitting/lying position to prevent dizziness
• Inform all healthcare providers about lurasidone use
• Avoid alcohol and other CNS depressants
• Keep all follow-up appointments for monitoring

References

1. FDA prescribing information: Latuda (lurasidone hydrochloride) 2. Loebel A, et al. Efficacy and safety of lurasidone 80 mg/day and 160 mg/day in the treatment of schizophrenia. J Clin Psychiatry. 2013 3. Sanford M. Lurasidone: a review of its use in schizophrenia. Drugs. 2013 4. Loebel A, et al. Lurasidone as adjunctive therapy with lithium or valproate for the treatment of bipolar I depression. Am J Psychiatry. 2014 5. Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2011 6. Meyer JM, et al. The metabolic safety of lurasidone. J Clin Psychiatry. 2013