Drug Interaction Report

GENERALLY AVOID: The hypotensive and bradycardic effects of lofexidine may be increased if it is used concurrently with other medications capable of these effects. Clinical trials reported orthostatic hypotension (29% and 42%), bradycardia (24% and 32%), and hypotension (30% and 30%) more frequently in patients on lofexidine 2.16 mg and 2.88 mg, respectively, compared to placebo (5%, 5%, and 1%, respectively).

MANAGEMENT: Concomitant use of lofexidine with medications that can decrease pulse rate or blood pressure should generally be avoided. If patients are using lofexidine in an outpatient setting, they should be capable of and counseled on self-monitoring for hypotension, orthostasis, and bradycardia. Patients should also be instructed to remain hydrated, rise carefully from a sitting or lying down position, and to contact their healthcare provider for guidance on dosing if hypotension or bradycardia occur.

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

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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: Coadministration with grapefruit juice may increase the plasma concentrations of macitentan, which is primarily metabolized by CYP450 3A4. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has not been studied with grapefruit juice but has been reported for ketoconazole, a potent CYP450 3A4 inhibitor. In ten healthy subjects, coadministration of a single 10 mg oral dose of macitentan on day 5 of treatment with ketoconazole (400 mg daily for 24 days) resulted in an approximately 2-fold increase in macitentan systemic exposure compared to administration alone. However, the clinical significance of the interaction is unclear. 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: Until further information is available, patients receiving macitentan therapy should avoid the consumption of grapefruit or grapefruit juice.