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

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.

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Antacids and some aluminum, calcium, and magnesium salts may decrease the plasma concentrations of H2-receptor antagonists during oral coadministration. The mechanism of interaction is unknown, but may involve reduced oral absorption due to increased gastric pH. Study data vary, with no changes to nearly 60% reductions in systemic exposures (AUCs) reported for cimetidine, famotidine, and ranitidine. The clinical significance has not been established. As a precaution, patients may consider taking H2-receptor antagonists one to two hours before antacids.

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Cimetidine may interfere with the metabolism of vitamin D in the liver to its biologically active form. The proposed mechanism is inhibition of hepatic vitamin D 25-hydroxylase by cimetidine. However, since the formation of active vitamin D metabolites in the kidneys is not affected, the interaction is likely to be of limited clinical importance in the general population.

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Limited data have suggested that concurrent administration of cimetidine may reduce the bioavailability of orally administered iron. In one study, dose-related reductions in the absorption of iron occurred following single oral doses of cimetidine (300 mg to 900 mg) compared to baseline. There has also been a case report of persistent inadequate response to iron therapy for the treatment of anemia during concomitant use of cimetidine 1 gm and ferrous sulfate 600 mg daily. Hematologic improvement was noted within a month after reducing the cimetidine dosage to 400 mg daily. Some investigators have suggested that cimetidine-induced increases in gastric pH may reduce the solubility of iron salts, which leads to decreased absorption. However, a study in patients with iron deficiency or iron-deficiency anemia found that response to iron therapy (iron succinyl-protein complex 2400 mg twice daily) was not affected by H2-receptor antagonists such as famotidine, nizatidine, or ranitidine. In another study, stable serum iron concentrations were observed in 64 patients receiving chronic therapy with cimetidine 400 mg to 800 mg/day. Based on existing evidence, no intervention (e.g., separating times of administration) appears to be necessary during concomitant use of cimetidine and iron products unless an interaction is suspected.

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