Drug Interactions between st. john's wort and Truseltiq

ADJUST DOSING INTERVAL: Food may increase the oral bioavailability of infigratinib. Coadministration with a high-fat, high-calorie meal (800 to 1,000 calories, with approximately 50% of total calories from fat) in healthy subjects increased mean infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 60% to 80% and 80% to 120%, respectively, and increased the median time to Cmax from 4 hours to 6 hours. When coadministered with a low-fat, low-calorie meal (approximately 330 calories, with 20% of total calories from fat), mean infigratinib Cmax and AUC increased by 90% and 70%, respectively, while the median time to Cmax did not change.

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of infigratinib and one of its active metabolites, BHS697, both of which are primarily metabolized by CYP450 3A4 in vitro. 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 other CYP450 3A4 inhibitors. Coadministration of infigratinib with multiple doses of itraconazole, a potent CYP450 3A4 inhibitor, increased infigratinib peak plasma concentration (Cmax) and total systemic exposure (AUC) by 164% and 622%, respectively, and the AUC for the active metabolite, BHS697, by 174%. 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. Increased exposure to infigratinib and BHS697 may increase the incidence and severity of serious adverse reactions such as infections, anemia, pyrexia, abdominal pain, hypercalcemia, hyperphosphatemia, ocular toxicity (e.g., retinal pigment epithelial detachment), sepsis, stomatitis, diarrhea, palmar-plantar erythrodysesthesia syndrome, increased blood creatinine, increased lipase, and onycholysis.

MANAGEMENT: Infigratinib should be administered on an empty stomach at least one hour before or two hours after food. Patients should avoid consumption of grapefruit, grapefruit juice, or supplements that contain grapefruit during treatment with infigratinib.

GENERALLY AVOID: An isolated case report suggests that foods containing large amounts of tyramine may precipitate a hypertensive crisis in patients treated with St. John's wort. The mechanism of interaction is unknown, as St. John's wort is not thought to possess monoamine oxidase (MAO) inhibiting activity at concentrations achieved in vivo. The case patient was a 41-year-old man who had been taking St. John's wort for seven days prior to presentation at the emergency room with confusion and disorientation. The patient recalled last eating aged cheese and having a glass of red wine approximately 10 hours prior to admission. No other cause of delirium or hypertension could be identified. In addition, alcohol may potentiate some of the pharmacologic effects of St. John's wort. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Until further information is available, patients treated with St. John's wort should consider avoiding consumption of protein foods in which aging or breakdown of protein is used to increase flavor. These foods include cheese (particularly strong, aged or processed cheeses), sour cream, wine (particularly red wine), champagne, beer, pickled herring, anchovies, caviar, shrimp paste, liver (particularly chicken liver), dry sausage, figs, raisins, bananas, avocados, chocolate, soy sauce, bean curd, yogurt, papaya products, meat tenderizers, fava beans, protein extracts, and dietary supplements. Caffeine may also precipitate hypertensive crisis so its intake should be minimized as well. Patients should also be advised to avoid or limit consumption of alcohol.