Drug Interaction Report

Talk to your doctor before using macitentan together with fedratinib. Fedratinib may increase the blood levels of macitentan. In some cases, this may increase the risk and/or severity of side effects such as headache, anemia and liver problems, especially during prolonged treatment. Your doctor may be able to prescribe alternatives that do not interact. Call your doctor immediately if you have fever, chills, joint pain or swelling, unusual bleeding or bruising, skin rash, itching, loss of appetite, fatigue, nausea, vomiting, abdominal pain, dark colored urine, light colored stools, and/or yellowing of the skin or eyes, as these may be signs and symptoms of liver damage. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.

Consumer information for this interaction is not currently available.

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.

Grapefruit juice can increase the blood levels of fedratinib. This may increase the risk of serious side effects such as Wernicke's encephalopathy, a potentially fatal condition of the brain associated with thiamine (vitamin B1) deficiency; low blood cell counts, which can lead to anemia, bleeding, and infections; severe diarrhea, nausea, and vomiting; problems in the liver or pancreas; and development of other cancers. You should avoid the consumption of grapefruit and grapefruit juice during treatment with fedratinib. You may take the medication with or without food, but taking it with a high-fat meal may help reduce nausea and vomiting. Talk to your doctor or pharmacist if you have questions on how to take this or other medications you are prescribed. It is important to tell your doctor about all other medications you use, including vitamins and herbs. Do not stop using any medications without first talking to your doctor.