Lurasidone

Class

Second Generation Antipsychotic

Neuroscience-based Nomenclature (NbN)

Pharmacological Target

Dopamine, serotonin

Mode of Action

Receptor Antagonist (D2, 5-HT2)

Brand Name

Latuda

Monograph

Monograph Link

Adverse Reactions

  Sedation
  Dizziness
  EPS
  Galactorrhea
  Weight gain (low)
  Risk of tardive dyskinesia
  NMS

Warnings

  Class Warning: Increased Mortality in Elderly Patients with Dementia Elderly patients with dementia treated with atypical antipsychotic drugs are at an increased risk of death compared to placebo. Analyses of thirteen placebo-controlled trials with various atypical antipsychotics (modal duration of 10 weeks) in these patients showed a mean 1.6-fold increase in the death rate in the drug-treated patients. Although the causes of death were varied, most of the deaths appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectious (e.g., pneumonia) in nature.
  Class Warning: Atypical antipsychotic drugs have been associated with metabolic changes that include hyperglycemia/diabetes mellitus, dyslipidemia, and body weight gain. While all of the drugs in the class have been shown to produce some metabolic changes, each drug has its own specific risk profile.

Smoking

Bioavailability

9-19%

Volume of distribution (Vd)

88.2 L/Kg

Protein Binding

99.8%

Elimination half-life

18 hours

Time to peak (Tmax)

1 – 3 hours

Metabolism

Primarily hepatic (CYP3A4)

Excretion

Following administration of a single radiolabeled dose, about 89% of the dose was recovered; approximately 80% recovered in feces and 9% in urine.

Special populations

  Renal impairment: caution should be exercised when starting lurasidone in patients with renal impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate and severe renal impairment (Clcr ?10 mL/min to <50 mL/min). The dose should not exceed 80 mg/day in patients with moderate and severe renal impairment
  Hepatic impairment: caution should be exercised when starting lurasidone in patients with hepatic impairment. The recommended starting dose is 20 mg. Patients should be treated with the lowest effective dose that provides optimal clinical response and tolerability, which is expected to be 20-40 mg once daily for most patients with moderate or severe hepatic impairment (Child Pugh Class B and C). The dose should not exceed 40 mg/day in patients with severe hepatic impairment, and 80 mg/day in patients with moderate hepatic impairment

Potential for Other Drugs to Affect Lurasidone

  Cytochrome P450 enzyme inhibitors or inducers Lursidone is predominantly metabolized by CYP3A4; interaction of lurasidone with strong and moderate inhibitors or inducers of this enzyme has been observed (i.e., Ketoconazole, diltiazem, rifampin). Lurasidone is contraindicated in combination with strong inhibitors or inducers of this enzyme

Potential for Lurasidone to Affect Other Drugs

  Midazolam (CYP3A4 substrate): Coadministration of lurasidone (120 mg/day) at steady state with a single dose of 5 mg midazolam increased midazolam Cmax and AUC(0-24) by approximately 21% and 44%, respectively, relative to midazolam alone. Midazolam dose adjustment is not required when coadministered with lursidone.
  Oral Contraceptive (estrogen/progesterone): Coadministration of lurasidone (40 mg/day) at steady state with an oral contraceptive (OC) containing ethinyl estradiol and norelgestromin resulted in equivalent AUC0-24 and Cmax of ethinyl estradiol and norelgestromin relative to OC administration alone. Also, sex hormone binding globulin levels were not meaningfully affected by coadministration of lurasidone and OC. Dose adjustment of OC dose is not required when coadministered with lurasidone.
  Transporters substrates: Coadministration of lurasidone (120 mg/day) at steady state with a single 0.25 mg dose of digoxin, a P-gp substrate, increased mean Cmax and AUC(0-24) for digoxin by approximately 9% and 13%, respectively, relative to digoxin alone. Digoxin dose adjustment is not generally required when coadministered with lurasidone.
  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.