Drug Interactions between calcium / ferrous fumarate / vitamin d and raltegravir

GENERALLY AVOID: Coadministration with aluminum-, magnesium-, and/or calcium-containing antacids may reduce the oral bioavailability of raltegravir. The proposed mechanism is chelation of raltegravir by polyvalent cations, but changes in solubility and lipophilicity of raltegravir related to pH increases may also contribute. In drug interaction studies, raltegravir peak plasma concentration (Cmax), systemic exposure (AUC) and trough plasma concentration (Cmin) decreased by 44%, 49% and 63%, respectively, when a single 20 mL dose of aluminum and magnesium hydroxide antacid was administered simultaneously with raltegravir (400 mg twice daily). The Cmax, AUC and Cmin of raltegravir decreased by 51%, 51% and 56%, respectively, when the antacid was given 2 hours before raltegravir, and by 22%, 30% and 57%, respectively, when the antacid was given 2 hours after raltegravir. When given 4 hours apart, raltegravir Cmax, AUC and Cmin decreased by 22%, 19% and 60% with antacid administered first, and by 30%, 32% and 62% with raltegravir administered first. Minimal changes in raltegravir Cmax and AUC were observed when administration was staggered by 6 hours; however, Cmin was still diminished by approximately 50% regardless of whether antacid was administered before or after raltegravir. When raltegravir 400 mg twice daily was given with a single dose of antacid containing calcium carbonate 3000 mg, raltegravir Cmax, AUC and Cmin decreased by 52%, 55% and 32%, respectively. These changes are not considered clinically significant by the manufacturer. However, when a single 1200 mg dose of raltegravir was coadministered with the calcium carbonate antacid, raltegravir Cmax, AUC and Cmin decreased by 74%, 72% and 58%, respectively. Staggering the doses by administering the calcium carbonate antacid 12 hours after raltegravir resulted in minimal changes in raltegravir Cmax and AUC, but Cmin was still reduced by 57%.

MANAGEMENT: Concomitant use of raltegravir with aluminum- and/or magnesium-containing antacids should generally be avoided, even if administration is staggered. Antacids containing calcium carbonate should not be used with once-daily raltegravir (HD formulation), but may be used without dose adjustment for other raltegravir products.

ADJUST DOSING INTERVAL: The bioavailability of orally administered iron may be reduced by concomitant administration of antacids or other agents with acid-neutralizing effects. The exact mechanism is unknown but may involve reduced iron solubility due to increase in gastric pH and/or reduced absorption due to complexation or precipitation of the iron. Based on existing data, sodium bicarbonate and calcium carbonate appear to have greater effects than antacids containing magnesium and aluminum hydroxides. In a study of patients with mild iron deficiency anemia, coadministration of ferrous sulfate with sodium bicarbonate 1 gram and calcium carbonate 500 mg reduced iron absorption by 50% and 67%, respectively, while 5 mL of an antacid containing magnesium and aluminum hydroxides had little effect. Another study also found no effect on iron absorption when ferrous sulfate (equivalent to 10 mg/kg of elemental iron) was coadministered with magnesium hydroxide (1 mg for every 5 mg of elemental iron ingested) in a group of healthy, fasting male subjects. In contrast, absorption of iron from ferrous sulfate and ferrous fumarate tablets was reduced by 37% and 31%, respectively, following administration of an antacid containing magnesium carbonate, magnesium hydroxide, and aluminum hydroxide in a study of healthy, iron-replete volunteers. Similarly, in a study of nine patients, coadministration of 5 mg of ferrous sulfate with a 35 gram dose of magnesium trisilicate was found to reduce iron absorption by an average of more than 70%. The interaction reportedly does not occur in the presence of ascorbic acid, which may competitively bind with iron and prevent the interference with iron absorption.

MANAGEMENT: To minimize the potential for interaction, it may be appropriate to administer oral iron preparations at least two hours apart from antacids or other agents with acid-neutralizing effects.