Drug Interaction Report

ADJUST DOSING INTERVAL: The concomitant use of antacids or oral products containing polyvalent cations (e.g., Mg, Al, Ca, Fe, Zn) may significantly decrease the plasma concentrations of elvitegravir. According to the elvitegravir manufacturer, the mechanism of the interaction may be related to local complexation in the gastrointestinal tract and not to changes in gastric pH. When 20 mL of an antacid containing magnesium and aluminum was given 2 hours before a 50 mg dose of elvitegravir with ritonavir (100 mg pharmacokinetic booster dose) to 11 study subjects, mean elvitegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) were reduced by 18%, 15%, and 10%, respectively. When the antacid was given 2 hours after elvitegravir to 10 study subjects, the mean elvitegravir Cmax, AUC, and Cmin decreased by approximately 20% each. When the antacid was given simultaneously with elvitegravir to 13 study subjects, the mean elvitegravir Cmax, AUC, and Cmin decreased by approximately 47%, 45%, and 41%, respectively. In contrast, when the antacid was given 4 hours before or 4 hours after elvitegravir, no significant differences were observed in elvitegravir pharmacokinetics compared to the administration of elvitegravir alone. The interaction has not been studied with other polyvalent cation-containing products, but they are expected to decrease elvitegravir plasma concentrations as well.

MANAGEMENT: Antacid and oral products containing polyvalent cations should be administered at least 2 hours before or 2 hours after the elvitegravir dose. Some experts recommend an interval of at least 4 hours. Alternatively, H2-receptor antagonists or proton pump inhibitors may be considered instead of antacids, with no dosage adjustment needed.

ADJUST DOSING INTERVAL: Food enhances the oral bioavailabilities of both elvitegravir and tenofovir. When a single dose of cobicistat/elvitegravir/emtricitabine/tenofovir (trade name Stribild) was given with a light meal (approximately 373 kcal; 20% fat), mean elvitegravir and tenofovir systemic exposures (AUCs) increased by 34% and 24%, respectively, relative to fasting conditions. When administered with a high-fat meal (approximately 800 kcal; 50% fat), the mean AUC of elvitegravir and tenofovir increased by 87% and 23%, respectively, relative to fasting conditions. The alterations in mean AUCs of cobicistat and emtricitabine were not clinically significant with either the light or high-fat meal.

MANAGEMENT: Cobicistat/elvitegravir/emtricitabine/tenofovir as a fixed-dose preparation should be administered once daily with food. Elvitegravir as a single-ingredient preparation should also be administered once daily with food.

GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.