Drug Interactions between ivacaftor / lumacaftor and relugolix

GENERALLY AVOID: Coadministration with inhibitors of the P-glycoprotein (P-gp) efflux transporter may increase the plasma concentrations of relugolix, particularly when the inhibitors are given orally. Relugolix is a substrate for intestinal P-gp. In vitro, it is metabolized primarily by CYP450 3A and, to a lesser extent, by CYP450 2C8. When relugolix was coadministered with erythromycin, a combined P-gp and moderate CYP450 3A inhibitor, relugolix peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 6.2-fold. Increased exposure to relugolix may increase the risk and/or severity of adverse effects such as hot flushes; weight gain; decreased sex drive; erectile function difficulties; QT interval prolongation; musculoskeletal pain; constipation; diarrhea; increases in glucose, triglyceride, and liver transaminase levels; and decreased hemoglobin. No clinically significant differences in the pharmacokinetics of relugolix were observed when coadministered with voriconazole, a strong CYP450 3A inhibitor that does not inhibit P-gp.

MANAGEMENT: Concomitant use of relugolix with orally administered P-gp inhibitors should generally be avoided. If coadministration is required, the manufacturer recommends taking relugolix first and separating the dosing by at least 6 hours. Patients should be monitored more frequently for adverse effects. Alternatively, when relugolix is used as monotherapy for the treatment of prostate cancer, the prescribing information states that treatment with relugolix may be interrupted for up to two weeks if a short course of treatment with a P-gp inhibitor is necessary. Following interruption of relugolix for more than 7 days, the manufacturer recommends restarting therapy with a loading dose of 360 mg on the first day, then continuing with a dose of 120 mg once daily.

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MONITOR: Based on in vitro data demonstrating both inhibition and induction of P-glycoprotein (P-gp) efflux transporter, lumacaftor has the potential to alter the plasma concentrations of drugs that are substrates of P-gp. Additionally, a clinical study with ivacaftor monotherapy showed that ivacaftor is a weak inhibitor of P-gp. Therefore, concomitant use of lumacaftor/ivacaftor with P-gp substrates may alter the systemic exposure to these substrates.

MANAGEMENT: Caution is advised when lumacaftor is used concurrently with medications that are substrates of the P-glycoprotein efflux transporter, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever lumacaftor is added to or withdrawn from therapy.

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