Drug Interactions between escitalopram and letrozole / ribociclib

GENERALLY AVOID: Ribociclib 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 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).

MONITOR CLOSELY: 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: Coadministration of ribociclib with other drugs that can prolong the QT interval and are substrates of CYP450 3A4, particularly those with a narrow therapeutic range, should generally be avoided. Since the magnitude of QT prolongation may increase with increasing plasma concentrations of these drugs, caution and close clinical monitoring are recommended if concomitant use with these drugs is unavoidable. 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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

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MONITOR: Coadministration with inhibitors of CYP450 2C19 may increase the plasma concentrations of escitalopram, which is primarily metabolized by the isoenzyme. The interaction has been studied with omeprazole, a potent CYP450 2C19 inhibitor. In study subjects, administration of a single 20 mg dose of escitalopram on day 5 of treatment with omeprazole 30 mg once daily for 6 days resulted in increases of escitalopram peak plasma concentration (Cmax) and systemic exposure (AUC) by approximately 10% and 50%, respectively. High plasma levels of escitalopram may increase the risk of serious side effects such as QT prolongation, which may lead to arrhythmias including torsade de pointes and sudden death, as well as serotonin syndrome, which is a rare but potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucination, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

MANAGEMENT: Caution is advised when escitalopram is used concomitantly with CYP450 2C19 inhibitors. Pharmacologic response to escitalopram should be monitored more closely whenever a CYP450 2C19 inhibitor is added to or withdrawn from therapy, and the escitalopram dosage adjusted as necessary. This may be particularly important in patients receiving escitalopram at the upper end of the dosage range. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heartbeat, shortness of breath, or syncope. Patients should also be closely monitored for symptoms of the serotonin syndrome during treatment.

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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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