Drug Interaction Report

MONITOR: Concomitant use of ashwagandha with other agents that are known to induce hepatotoxicity may theoretically increase the risk of hepatotoxicity. There are case reports of adverse effects on liver functions associated with ashwagandha use. In a case report, a 20-year-old man in Japan developed liver dysfunction and hyperbilirubinemia after using ashwagandha in combination with multiple antianxiety drugs. In additional case reports, three men and two women, age range 21 to 62 years who reportedly took supplements containing 450 to 1,350 mg ashwagandha daily over the course of one week to four months when signs of liver injury, such as jaundice, pruritus, nausea, lethargy, abdominal discomfort, and hyperbilirubinemia, appeared.

MANAGEMENT: Liver function tests should be monitored, and patients should be advised to report any symptoms such as abdominal pain, jaundice, dark urine, light stools, fever, or unusual fatigue.

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.