Drug Interactions between Duo-Vil and entrectinib

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

GENERALLY AVOID: Entrectinib may 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. Of 355 patients who received entrectinib in clinical trials at dosages ranging from 100 mg to 2600 mg daily (75% received 600 mg orally once daily), 3.1% of patients with at least one post-baseline QTc measurement experienced QTcF interval prolongation of >60 msec and 0.6% had a QTcF interval >500 msec. 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: Coadministration of entrectinib with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) performed prior to initiation of entrectinib, after 1 month of treatment with entrectinib, and periodically during treatment as appropriate based on individual risk factors. Some authorities suggest that if the QTc interval is between 481 to 500 msec at any time during treatment, entrectinib should be withheld until QTc is recovered to baseline at which time treatment at the same dose may be resumed (AU, UK). If the QTc is greater than 500 msec, entrectinib should be withheld until the QTc interval recovers to baseline at which time the same dose may be resumed if factors that caused the QT prolongation are corrected. However, if these factors are not identified and corrected, entrectinib should be resumed at a reduced dose. Entrectinib should be permanently discontinued in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia such as torsade de pointes or polymorphic ventricular tachycardia. Because hypokalemia and hypomagnesemia are risk factors for ventricular arrhythmias, electrolyte levels should also be obtained prior to and during treatment, and any abnormalities corrected as necessary. 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: Entrectinib may 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. Of 355 patients who received entrectinib in clinical trials at dosages ranging from 100 mg to 2600 mg daily (75% received 600 mg orally once daily), 3.1% of patients with at least one post-baseline QTc measurement experienced QTcF interval prolongation of >60 msec and 0.6% had a QTcF interval >500 msec. 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: Coadministration of entrectinib with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have electrocardiograms (ECGs) performed prior to initiation of entrectinib, after 1 month of treatment with entrectinib, and periodically during treatment as appropriate based on individual risk factors. Some authorities suggest that if the QTc interval is between 481 to 500 msec at any time during treatment, entrectinib should be withheld until QTc is recovered to baseline at which time treatment at the same dose may be resumed (AU, UK). If the QTc is greater than 500 msec, entrectinib should be withheld until the QTc interval recovers to baseline at which time the same dose may be resumed if factors that caused the QT prolongation are corrected. However, if these factors are not identified and corrected, entrectinib should be resumed at a reduced dose. Entrectinib should be permanently discontinued in patients who develop QTc interval prolongation with signs or symptoms of life-threatening arrhythmia such as torsade de pointes or polymorphic ventricular tachycardia. Because hypokalemia and hypomagnesemia are risk factors for ventricular arrhythmias, electrolyte levels should also be obtained prior to and during treatment, and any abnormalities corrected as necessary. 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.