Drug Interactions between levomethadyl acetate and Tavneos

GENERALLY AVOID: The concurrent use of levomethadyl acetate and alcohol may result in additive CNS and respiratory depression, hypotension, sedation, or coma. Grapefruit juice may increase the plasma concentrations of orally administered drugs which are substrates of the CYP450 3A4 isoenzyme, such as levomethadyl acetate. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruits. The extent and clinical significance are unknown. Moreover, pharmacokinetic alterations associated with interactions involving grapefruit juice are often subject to a high degree of interpatient variability.

MANAGEMENT: Patients who are known to abuse alcohol should be warned of the risk of potentially fatal overdose if these substances are taken concurrently. Patients who regularly consume grapefruits and grapefruit juice should be monitored for adverse effects and altered plasma concentrations of levomethadyl acetate. A 12-lead ECG should be performed before initiating therapy, 12 to 14 days after initiating therapy, and periodically thereafter. Patients should be advised to immediately seek medical attention if they experience palpitations, dizziness, lightheadedness, fainting, or seizures. Grapefruits and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact.

ADJUST DOSING INTERVAL: Food significantly enhances the oral bioavailability of avacopan. When a 30 mg capsule of avacopan was administered with a high-fat, high-calorie meal, avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by approximately 8% and 72%, respectively, while the time to reach peak concentration (Tmax) was delayed by approximately 4 hours (from 2.0 hours to 6.0 hours).

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of avacopan. 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 itraconazole, a potent CYP450 3A4 inhibitor. When avacopan was administered with itraconazole (200 mg once daily for 4 days), avacopan peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 1.9-fold and 2.2-fold, respectively. 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. Pharmacokinetic interactions involving grapefruit juice are also subject to a high degree of interpatient variability, thus the extent to which a given patient may be affected is difficult to predict. Increased exposure to avacopan may increase the risk and/or severity of serious adverse reactions such as hepatotoxicity and infections.

MANAGEMENT: To ensure maximal oral absorption, avacopan should be administered with food. Patients should preferably avoid or limit consumption of grapefruit, grapefruit juice, or any supplement containing grapefruit extract during avacopan therapy.