Drug Interaction Report

MONITOR: Fostemsavir can cause dose-related prolongation of 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. At therapeutic doses, fostemsavir did not prolong the QT interval to any clinically relevant extent. At 4 times the recommended dosage (2400 mg twice daily), the mean QTcF increase was 11.2 milliseconds (upper 90% confidence interval 13.3 milliseconds). The observed increase in QTcF was concentration-dependent on temsavir, the active moiety of fostemsavir. Therefore, the risk may be increased during concomitant treatment with potent CYP450 3A4 and/or P-glycoprotein (P-gp) inhibitors, which may increase systemic exposure to temsavir. 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: Caution is recommended if fostemsavir is used in combination with other drugs that can prolong the QT interval. Consider obtaining electrocardiogram and serum electrolyte levels prior to initiating fostemsavir therapy and periodically thereafter, particularly in patients with risk factors for torsade de pointes and/or receiving one or more potent CYP450 3A4 inhibitors (e.g., azole antifungal agents; cobicistat; protease inhibitors; ketolide and certain macrolide antibiotics; ceritinib; idelalisib; nefazodone) or P-gp inhibitors (e.g., cyclosporine; diltiazem; quinidine; quinine; tacrolimus; verapamil). Correct hypokalemia and/or hypomagnesemia before starting treatment and as indicated during treatment, as they may be risk factors for ventricular arrhythmias. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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.