Drug Interactions between Cotellic and Promacta

ADJUST DOSING INTERVAL: Food may reduce the oral bioavailability of eltrombopag. In healthy volunteers, a standard high-fat breakfast significantly decreased plasma eltrombopag peak plasma concentration (Cmax) by 65% and systemic exposure (AUC) by 59% and delayed Tmax by one hour. The calcium content of this meal may have also contributed to this decrease in exposure. In another study, adult subjects administered a single 25 mg dose of eltrombopag for oral suspension with a high-calcium, moderate-fat, moderate-calorie meal exhibited a 79% decrease in Cmax and 75% decrease in AUC of eltrombopag. Administration of eltrombopag 2 hours after the high-calcium meal decreased eltrombopag Cmax by 48% and AUC by 47%, while administration 2 hours before the high-calcium meal decreased eltrombopag Cmax by 14% and AUC by 20%.

ADJUST DOSING INTERVAL: Polyvalent cations such as aluminum, calcium, iron, magnesium, and zinc can significantly reduce the gastrointestinal absorption of eltrombopag due to chelation. In one clinical trial, administration of a single 75 mg dose of eltrombopag with an antacid containing 1524 mg aluminum hydroxide and 1425 mg magnesium carbonate resulted in an approximately 70% decrease in eltrombopag Cmax and AUC.

MANAGEMENT: Eltrombopag should be taken on an empty stomach one hour before or two hours after a meal. Additionally, eltrombopag should be taken at least 2 hours before or 4 hours after any products that contain polyvalent cations such as antacids, mineral supplements, dairy products, and fortified juices.

MONITOR: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.