Drug Interaction Report

GENERALLY AVOID: Coadministration with tucatinib may increase the plasma concentrations of CYP450 3A4 substrates. The mechanism involves tucatinib-mediated inhibition of CYP450 3A isoenzymes. When a single 2 mg dose of midazolam, a CYP450 3A substrate, was administered with tucatinib (300 mg twice daily), midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 3-fold and 5.7-fold, respectively. Increased exposure to the CYP450 3A substrate may increase the risk of toxicity.

MANAGEMENT: Concomitant use of tucatinib with CYP450 3A substrates, particularly those with a narrow therapeutic index, should be avoided. If coadministration is required, a reduction in the dosage of the CYP450 3A substrate in accordance with product labeling is recommended.

GENERALLY AVOID: Some beverages such as tonic water contain varying amounts of quinine. Coadministration of a single 430 mg dose of quinine has been shown to increase plasma concentrations of astemizole and its metabolite, desmethylastemizole. Elevated levels of these agents may cause a prolongation of the electrocardiographic QT interval and potentially fatal ventricular arrhythmias. Although pharmacokinetic data have indicated that the amounts of quinine in beverages (up to 80 mg quinine in 32 oz of tonic water) are not sufficient to produce a significant effect, the potential for an interaction exists if large amounts of tonic water are ingested. Also, grapefruit juice has been shown to inhibit CYP450 enzymes, which may lead to increased serum astemizole concentrations. The risk of life-threatening ventricular arrhythmias may be increased.

MANAGEMENT: Patients should be counseled to limit consumption of quinine-containing beverages and avoid grapefruit juice while they are taking astemizole.