Drug Interactions between encorafenib and MKO Melt Dose Pack

GENERALLY AVOID: Coadministration with potent or moderate inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of encorafenib, which is primarily metabolized by the isoenzyme. When a single 50 mg dose of encorafenib (equivalent to 0.1 times the recommended dose) was administered with posaconazole, a potent CYP450 3A4 inhibitor, encorafenib peak plasma concentration (Cmax) increased by 68% and systemic exposure (AUC) increased by 3-fold. When the same dose of encorafenib was administered with diltiazem, a moderate CYP450 3A4 inhibitor, encorafenib Cmax increased by 45% and AUC increased by 2-fold. Increased exposure to encorafenib may increase the risk of serious and life-threatening adverse effects such as hemorrhage, uveitis, QT prolongation, hepatotoxicity, dermatologic reactions, and new malignancies.

MANAGEMENT: Concomitant use of encorafenib with grapefruit or grapefruit juice should generally be avoided. If coadministration is required, the manufacturer recommends reducing the encorafenib dose to one-third of the dose used prior to addition of a potent CYP450 3A4 inhibitor or one-half of the dose used prior to addition of a moderate CYP450 3A4 inhibitor. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, the encorafenib dose that was taken prior to initiating the inhibitor may be resumed.

MONITOR CLOSELY: Coadministration of ketamine with other central nervous system (CNS) depressants, including alcohol, may result in profound sedation, respiratory depression, coma, and death. In addition, opioid analgesics, barbiturates, and benzodiazepines may prolong the time to complete recovery from anesthesia.

MANAGEMENT: During concomitant use of ketamine with other CNS depressants, including alcohol, close monitoring of neurologic status and respiratory parameters, including respiratory rate and pulse oximetry, is recommended. Dosage adjustments should be considered according to the patient's clinical situation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of ketamine. Use in combination may result in additive central nervous system (CNS) depression and/or impairment of judgment, thinking, and psychomotor skills.

GENERALLY AVOID: Coadministration of oral ketamine with grapefruit juice may significantly increase the plasma concentrations of S(+) ketamine, the dextrorotatory enantiomer of ketamine. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. Inhibition of hepatic CYP450 3A4 may also contribute. When a single 0.2 mg/kg dose of S(+) ketamine was administered orally on study day 5 with grapefruit juice (200 mL three times daily for 5 days) in 12 healthy volunteers, mean S(+) ketamine peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 2.1- and 3.0-fold, respectively, compared to administration with water. In addition, the elimination half-life of S(+) ketamine increased by 24% with grapefruit juice, and the ratio of the main metabolite norketamine to ketamine was decreased by 57%. The pharmacodynamics of ketamine were also altered by grapefruit juice. Specifically, self-rated relaxation was decreased and performance in the digit symbol substitution test was increased with grapefruit juice, but other behavioral or analgesic effects were not affected.

MANAGEMENT: Patients receiving ketamine should not drink alcohol. Caution is advised when ketamine is used in patients with acute alcohol intoxication or a history of chronic alcoholism. Following anesthesia with ketamine, patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination, such as driving or operating hazardous machinery, for at least 24 hours and until they know how the medication affects them. Patients treated with oral ketamine should also avoid consumption of grapefruit and grapefruit juice during treatment. Otherwise, dosage reductions of oral ketamine should be considered.

GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.