Drug Interaction Report

MONITOR: Coadministration with berotralstat may increase the plasma concentrations and effects of drugs that are substrates of CYP450 3A4 and/or 2D6. The mechanism is decreased clearance due to inhibition of CYP450 3A4 and 2D6 activity by berotralstat. Berotralstat is considered a moderate inhibitor of CYP450 3A4 and 2D6. In drug interaction studies, berotralstat reportedly increased the peak plasma concentration (Cmax) and systemic exposure (AUC) of the sensitive CYP450 3A4 substrate midazolam by approximately 1.5-fold and 2.25-fold, respectively, and the CYP450 3A4 substrate amlodipine by approximately 1.5-fold and 1.75-fold, respectively. It increased the Cmax and AUC of the sensitive CYP450 2D6 substrate dextromethorphan by approximately 2.9-fold and 2.7-fold, respectively, and the CYP450 2D6 substrate desipramine by 1.7-fold and 1.9-fold, respectively. Clinical data are not available.

MANAGEMENT: Caution is advised when berotralstat is coadministered with drugs that are substrates of CYP450 3A4 and/or 2D6, particularly those with a narrow therapeutic index. Clinical and laboratory monitoring are recommended following the initiation of berotralstat, and the individual dosages of the concomitant agents adjusted as needed.

GENERALLY AVOID: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.