Drug Interactions between crizotinib and estradiol / norethindrone / 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.

GENERALLY AVOID: Long-term androgen deprivation therapy, including relugolix, can prolong the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In a single, active-controlled, clinical study comparing abarelix to LHRH (luteinizing hormone releasing hormone) agonist plus nonsteroidal antiandrogen therapy, both therapies were found to prolong the mean Fridericia-corrected QT interval (QTcF) by more than 10 msec from baseline. In approximately 20% of patients in both groups, there were either changes from baseline QTc of greater than 30 msec or end-of-treatment QTc values exceeding 450 msec. Similar results were observed in two other Phase 3 studies with abarelix and the active-control treatments. In a randomized, active-controlled trial comparing degarelix to leuprolide, three patients (<1%) in the pooled degarelix group and four patients (2%) in the leuprolide 7.5 mg group had a QTcF of 500 ms or greater. From baseline to end of study, the median change was 12.3 msec for degarelix and 16.7 msec for leuprolide. Investigators believe that long-term androgen deprivation is responsible for these changes, as testosterone has been found to shorten ventricular repolarization. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Concomitant use of relugolix with orally administered P-gp inhibitors should be avoided when possible. In addition, the benefits of androgen deprivation therapy such as relugolix should be carefully assessed against the potential risk in patients receiving other drugs known to prolong the QT interval, many of which are also P-gp inhibitors (e.g., amiodarone, azithromycin, bepridil, cabozantinib, clarithromycin, crizotinib, dronedarone, elagolix, erythromycin, ketoconazole, lapatinib, mifepristone, nilotinib, osimertinib, propafenone, quinidine, quinine, ranolazine, tacrolimus, telithromycin, valbenazine, vemurafenib). If coadministration is required, the manufacturer recommends taking relugolix first and separating the dosing by at least 6 hours. Electrolyte abnormalities should be corrected prior to initiating therapy, and periodic monitoring of electrocardiograms and electrolytes should be considered. 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.