Do PPIs Interact With Levothyroxine?

Darrell Hulisz, PharmD


May 18, 2011


I have a number of patients who need to take both a PPI and levothyroxine. Do I need to be aware of any potential interactions?

Response from Darrell Hulisz, PharmD
Associate Professor, Case Western Reserve University School of Medicine; Clinical Specialist in Family Medicine, University Hospitals, Case Medical Center, Cleveland, Ohio

The product labeling for levothyroxine recommends that it not be simultaneously coadministered with antacids. If concurrent use is necessary, administration of the agents should be separated by 4 hours.[1] Several case studies report increased thyroid-stimulating hormone (TSH) levels and/or decreases in thyroxine (T4) associated with concurrent use of calcium-containing antacids and supplements in patients previously stabilized on levothyroxine.[2,3,4,5]

The intestinal absorption of oral thyroxine is 62%-82% and occurs at the level of the jejunum and ileum.[6] The mechanism of interaction is likely due to adsorption of levothyroxine to calcium in the acidic environment of the gut lumen. In one study, separating the administration of calcium carbonate and levothyroxine avoided the interaction completely.[7]

Similar effects have been demonstrated with simultaneous administration of levothyroxine and aluminum hydroxide.[8] Because of the known interaction between calcium- and aluminum-containing antacids with levothyroxine, the question arises as to whether this interaction extends to other acid-reducing agents, such as proton-pump inhibitors (PPIs).

Centanni and colleagues[6] examined the need for increased levothyroxine dosing in euthyroid patients with nontoxic, multinodular goiter who had conditions associated with increased gastric pH. Of 123 patients with gastritis, 53 patients had Helicobacter pylori infection, 60 patients had atrophic gastritis, and 10 patients had gastroesophageal reflux disease requiring omeprazole 40 mg daily. Patients were treated with levothyroxine to reach a goal TSH level of 0.05-0.2 mU/L and were studied for a minimum of 30 months. A control group of 135 patients with multinodular goiter and no gastric disorders was used for reference.

The median levothyroxine dose in the gastritis group was significantly higher than in the control group at 125 µg/day vs 100 µg/day (P < .001). In patients treated with omeprazole, the TSH goal was met by increasing the levothyroxine dose by an average of 37%. However, the change in dosage was not needed until after 6 months of omeprazole treatment. The authors concluded that patients with impaired gastric acid secretion require an increased dose of oral thyroxine, which suggests that normal acid secretion is necessary for effective oral absorption of thyroxine.

Sachmechi and colleagues[9] retrospectively studied the effect of PPI therapy on TSH levels in patients with hypothyroidism. The study group (N = 37) consisted of euthyroid patients who had received stable levothyroxinereplacement for at least 6 months and in whom lansoprazole was later initiated. TSH levels were collected before and at least 2 months after the PPI treatment was started. The control group (N = 55) consisted of euthyroid patients with a history of hypothyroidism who had received stable levothyroxinefor at least 6 months and did not take a PPI during the study period.

In the study group, the mean change in TSH level from before to at least 2 months after initiation of PPI therapy was significant at 0.69 ± 1.9 µIU/mL (P = .035). The mean change in the TSH level in the control group was 0.11 ± 1.06 µIU/mL (P = .45). In the study group, the mean TSH level increased after 2-6 months of lansoprazole therapy, and 19% of patients required an increase of levothyroxine. The mean increase in levothyroxine dose was 35%.

In contrast with the aforementioned studies, Dietrich and colleagues[10] failed to demonstrate a change in levothyroxine absorption associated with administration of pantoprazole 40 mg daily. However, this study was limited in that it included only 20 healthy euthyroid volunteers in a crossover design over a 1-week period. No alteration in levothyroxine absorption was noted.

Patients with hypothyroidism receiving levothyroxine who are euthyroid may need subsequent thyroid function tests following the initiation of a PPI, especially if symptoms of hypothyroidism emerge. Although the precise effect of PPIs on levothyroxine pharmacokinetics has not been fully elucidated, patients may require an increase in their levothyroxine dose several months into PPI therapy. This interaction is not completely predictable, but it appears to be more likely after 6 months of PPI therapy. Future studies should control for the many confounding variables known to influence levothyroxine absorption.


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