Drug Interactions between Hetlioz LQ and lorlatinib

GENERALLY AVOID: Grapefruit and grapefruit juice may significantly increase the plasma concentrations of lorlatinib. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall induced by certain compounds present in grapefruit. Because grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4, the magnitude of interaction is greatest for those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability). 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.

MANAGEMENT: Patients treated with lorlatinib should avoid consumption of grapefruit, grapefruit juice, and any supplement containing grapefruit extract. If coadministration is unavoidable, some authorities recommend reducing the initial dosage of lorlatinib from 100 mg orally once daily to 75 mg orally once daily. In patients who have had a dosage reduction to 75 mg orally once daily due to adverse reactions, the lorlatinib dosage should be further reduced to 50 mg orally once daily upon initiation of a potent CYP450 3A4 inhibitor. After 3 plasma half-lives following discontinuation of the potent CYP450 3A4 inhibitor, the lorlatinib dosage may be increased to that used prior to initiation of the inhibitor.

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

ADJUST DOSING INTERVAL: Food may delay the absorption and onset of action of tasimelteon. According to the product labeling, administration of tasimelteon with a high-fat meal decreased peak plasma concentration (Cmax) by 44% and delayed the median time to reach Cmax by approximately 1.75 hours compared to administration in the fasted state.

MONITOR: Smoking induces CYP450 1A2 and may reduce the plasma concentrations of tasimelteon, which is metabolized by the isoenzyme. According to the product labeling, tasimelteon systemic exposure was approximately 40% lower in smokers than in nonsmokers.

MANAGEMENT: Patients receiving tasimelteon should be advised to avoid or limit consumption of alcohol. Tasimelteon should be taken without food. Patients who smoke may have a reduced therapeutic response to tasimelteon.