Drug Interactions between letrozole / ribociclib and Quineprox

GENERALLY AVOID: Chloroquine and hydroxychloroquine 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. 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 advanced age, 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). Currently available data seem to suggest a significantly higher risk of QTc prolongation (>= 60 msec increase from baseline or absolute QTc >=500 msec ) in COVID-19 patients treated with hydroxychloroquine or chloroquine, with or without azithromycin, than has been previously reported in other settings. Because COVID-19 may disproportionately affect the elderly and individuals with preexisting heart disease, and cardiac complications such as myocarditis and cardiomyopathy as well as organ failure may occur in patients with severe COVID-19, it appears likely that hospitalized patients with COVID-19 may represent a particularly susceptible and high-risk population, and other, less critically ill patients may not have the same arrhythmic risk.

MANAGEMENT: Coadministration of chloroquine or hydroxychloroquine with other drugs that can prolong the QT interval should generally be avoided, particularly in patients with baseline QT prolongation (e.g., QTc >=500 msec) or congenital long QT syndrome. Close monitoring of QTc interval, electrolyte levels, and renal and hepatic function is recommended if concomitant use is required and benefits are anticipated to outweigh the risks. Electrolyte abnormalities should be corrected prior to initiating treatment with chloroquine or hydroxychloroquine. 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. Because chloroquine and hydroxychloroquine are eliminated slowly from the body, the potential for drug interactions should be observed for a prolonged period following their discontinuation.

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MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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