Drug Interaction Report

ADJUST DOSING INTERVAL: Coadministration with medications containing polyvalent cations such as aluminum, calcium, iron, or magnesium may decrease the oral bioavailability of dolutegravir. The mechanism of interaction likely involves chelation of dolutegravir by the polyvalent cation in the gastrointestinal tract. In 16 study subjects, administration of a single 50 mg dose of dolutegravir simultaneously with an antacid containing magnesium and aluminum decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 72%, 74% and 74%, respectively, compared to administration without the antacid. When the antacid was administered 2 hours after dolutegravir, the Cmax, AUC and Cmin of dolutegravir decreased by just 18%, 26% and 30%, respectively. Administration of single-dose dolutegravir simultaneously with a multivitamin decreased the Cmax, AUC and Cmin of dolutegravir by 35%, 33% and 32%, respectively. Coadministration of dolutegravir with calcium carbonate or ferrous fumarate under fed conditions counteracted the interaction and provided plasma exposures comparable to dolutegravir alone under fasted conditions.

MANAGEMENT: Dolutegravir should be administered 2 hours before or 6 hours after medications containing polyvalent cations such as antacids, laxatives, or mineral supplements. When taken with food, dolutegravir and supplements or multivitamins containing calcium or iron can be taken at the same time.

ADJUST DOSING INTERVAL: Coadministration with medications containing polyvalent cations such as aluminum, calcium, iron, or magnesium may decrease the oral bioavailability of dolutegravir. The mechanism of interaction likely involves chelation of dolutegravir by the polyvalent cation in the gastrointestinal tract. In 16 study subjects, administration of a single 50 mg dose of dolutegravir simultaneously with an antacid containing magnesium and aluminum decreased dolutegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin; 24 hours post-dose) by 72%, 74% and 74%, respectively, compared to administration without the antacid. When the antacid was administered 2 hours after dolutegravir, the Cmax, AUC and Cmin of dolutegravir decreased by just 18%, 26% and 30%, respectively. Administration of single-dose dolutegravir simultaneously with a multivitamin decreased the Cmax, AUC and Cmin of dolutegravir by 35%, 33% and 32%, respectively. Coadministration of dolutegravir with calcium carbonate or ferrous fumarate under fed conditions counteracted the interaction and provided plasma exposures comparable to dolutegravir alone under fasted conditions.

MANAGEMENT: Dolutegravir should be administered 2 hours before or 6 hours after medications containing polyvalent cations such as antacids, laxatives, or mineral supplements. When taken with food, dolutegravir and supplements or multivitamins containing calcium or iron can be taken at the same time.

GENERALLY AVOID: The concomitant administration of aluminum-containing products (e.g., antacids and phosphate binders) and citrates may significantly increase serum aluminum concentrations, resulting in toxicity. Citrates or citric acid are contained in numerous soft drinks, citrus fruits, juices, and effervescent and dispersible drug formulations. Citrates enhance the gastrointestinal absorption of aluminum by an unknown mechanism, which may involve the formation of a soluble aluminum-citrate complex. Various studies have reported that citrate increases aluminum absorption by 4.6- to 50-fold in healthy subjects. Patients with renal insufficiency are particularly at risk of developing hyperaluminemia and encephalopathy. Fatalities have been reported. Patients with renal failure or on hemodialysis may also be at risk from soft drinks and effervescent and dispersible drug formulations that contain citrates or citric acid. It is unknown what effect citrus fruits or juices would have on aluminum absorption in healthy patients.

MANAGEMENT: The concomitant use of aluminum- and citrate-containing products and foods should be avoided by renally impaired patients. Hemodialysis patients should especially be cautioned about effervescent and dispersible over-the-counter remedies and soft drinks. Some experts also recommend that healthy patients should separate doses of aluminum-containing antacids and citrates by 2 to 3 hours.

ADJUST DOSING INTERVAL: The administration of aluminum-containing antacids with enteral nutrition may result in precipitation, formation of bezoars, and obstruction of feeding tubes. The proposed mechanism is the formation of an insoluble complex between the aluminum and the protein in the enteral feeding. Several cases of esophageal plugs and nasogastric tube obstructions have been reported in patients receiving high-protein liquids and an aluminum hydroxide-magnesium hydroxide antacid or an aluminum hydroxide antacid.

MANAGEMENT: Some experts recommend that antacids should not be mixed with or given after high protein formulations, that the antacid dose should be separated from the feeding by as much as possible, and that the tube should be thoroughly flushed before administration.

Food increases the extent of absorption and slows the rate of absorption of dolutegravir. When administered with a low-, moderate- or high-fat meal, dolutegravir peak plasma concentration (Cmax) increased by 46%, 52% and 67%, systemic exposure (AUC) increased by 33%, 41% and 66%, and time to reach Cmax (Tmax) increased from 2 hours to 3, 4 and 5 hours, respectively, compared to administration under fasted conditions. Dolutegravir may be taken with or without food.