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

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.

MONITOR: Inhibitors of the proton pump (PPIs or potassium-competitive acid blockers [PCABs]) may impair the gastrointestinal absorption of nonheme iron, a process that is dependent on an acidic environment. The interaction was suspected in two patients with iron deficiency anemia due to gastrointestinal blood loss that were unresponsive to oral iron replacement therapy, even after the bleeding had apparently stopped. Both patients had been on omeprazole for six months while being treated with ferrous sulfate. An iron-loading test was performed on one of the patients and indicated iron malabsorption. Within two months after discontinuation of omeprazole, notable improvements in hemoglobin level and mean corpuscular volume (MCV) were observed in both patients, and iron absorption was significantly increased in the patient who underwent absorption testing. In a case review of patients with hereditary hemochromatosis treated at one institution, investigators observed a reduced requirement for maintenance phlebotomy in seven patients following initiation of PPI therapy (mean 2.5 L blood removed/year before PPI therapy vs. 0.5 L/year during PPI therapy), presumably due to reduced tissue iron accumulation stemming from impaired absorption of dietary nonheme iron. Mean annual phlebotomy requirement during PPI therapy in these patients was also lower than that in controls who had never taken a PPI (mean 2.3 L blood removed/year). The same group of investigators also studied iron absorption in 14 patients fed an iron-loaded meal before and after PPI therapy for one week. PPI therapy was associated with a 51% reduction in area under the serum iron concentration-time curve (AUC 0 to 4 hours); a 55% reduction in maximum increase of serum iron following ingestion of iron-loaded meal; and a 46% reduction in percent recovery of administered iron at peak serum iron concentration. Interestingly, the interaction has not been reported in healthy, iron-replete individuals. In a study of 109 patients with Zollinger-Ellison syndrome who had not undergone gastric resection, omeprazole treatment for an average of 5.7 years did not significantly decrease body iron stores or cause iron deficiency compared to H2-receptor antagonist therapy or no gastric acid-suppressant treatment. It is possible that the interaction may not affect people with healthy iron stores because of compensation by dietary heme iron, which typically comprises only a small fraction of dietary iron but whose absorption is not dependent on gastrointestinal pH. In contrast, dietary heme iron alone may not be sufficient to restore normal iron balance in patients with anemia or those with defective regulatory mechanisms of iron absorption.

MANAGEMENT: Patients with iron deficiency may not respond adequately to oral iron replacement therapy during coadministration of PPIs or PCABs. If an interaction is suspected after ruling out other causes, it may be appropriate to discontinue the PPI or PCAB or consider administering iron parenterally.