Drug Interaction Report

MONITOR: The risk of neurotoxicity may be increased when local anesthetics are used together with intraspinal ketamine. Animal and cell studies have shown that the combined neurotoxicity of lidocaine and ketamine are additive.

MANAGEMENT: Caution is advised during concomitant use of local anesthetics with intraspinal ketamine.

MONITOR: Coadministration with selpercatinib may increase the plasma concentrations of drugs that are primarily metabolized by the CYP450 3A4 isoenzyme. The mechanism is reduced clearance due to inhibition of CYP450 3A4 by selpercatinib. The interaction may be particularly important for sensitive substrates or those that demonstrate a narrow therapeutic index. When midazolam, a sensitive CYP450 3A4 substrate, was administered with selpercatinib, midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 39% and 54%, respectively. These results suggest weak inhibition of CYP450 3A4 by selpercatinib.

MANAGEMENT: Caution is advised when selpercatinib is used concomitantly with drugs that are substrates of 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as well as clinical and laboratory monitoring may be appropriate for some drugs whenever selpercatinib is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of selpercatinib. 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. The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors. When a single dose of selpercatinib (160 mg) was coadministered with multiple doses of itraconazole (200 mg once daily), a potent CYP450 3A4 inhibitor, selpercatinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 30% and 133%, respectively. Based on pharmacokinetic modeling, administration of multiple doses of selpercatinib (160 mg twice daily) with multiple doses of the moderate CYP450 3A4 inhibitors diltiazem (60 mg three times daily), fluconazole (200 mg once daily), or verapamil (80 mg three times daily) is predicted to increase selpercatinib Cmax by 46% to 76% and AUC by 60% to 99%. In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands. Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition. Increased exposure to selpercatinib may increase the risk of serious adverse effects such as QT interval prolongation, liver transaminase and bilirubin elevations, hypertension, hemorrhage, edema, and hypersensitivity reactions (e.g., fever, rash, arthralgias/myalgias with concurrent decreased platelets or transaminitis).

MANAGEMENT: Until further information is available, it may be advisable for patients to limit or avoid consumption of grapefruit and grapefruit juice during treatment with selpercatinib.

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 concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.