In an adult without liver disease, renal impairment, or drug hypersensitivity, do omeprazole, esomeprazole, or famotidine interfere with levothyroxine absorption, and how should the medications be timed?

Levothyroxine Interactions with Acid-Suppressing Medications

Omeprazole and esomeprazole (proton pump inhibitors) may reduce levothyroxine absorption and should be separated from levothyroxine by at least 4 hours, while famotidine (H2-antagonist) does not appear to significantly interfere with levothyroxine absorption based on controlled studies. 1

Evidence for Proton Pump Inhibitors (Omeprazole/Esomeprazole)

Proton pump inhibitors are recognized as clinically significant interacting agents that decrease levothyroxine absorption. 2 The mechanism involves reduced gastric acidity, which impairs the dissolution and absorption of levothyroxine in the gastrointestinal tract. 3

Clinical Implications:

• Patients taking levothyroxine with PPIs concomitantly may require increased levothyroxine doses to maintain euthyroid status. 4, 2
• Closer monitoring of thyroid-stimulating hormone (TSH) and free T4 levels is necessary when PPIs are initiated or discontinued in patients on levothyroxine. 2
• The interaction is established and clinically significant, requiring dose adjustments in many patients. 2

Evidence for H2-Antagonists (Famotidine)

A controlled study in 30 healthy volunteers found no significant differences in levothyroxine absorption after 1 week of famotidine therapy. 1 Peak hormone levels and area under the curve (AUC) measurements for T4, T3, and free T4 index remained unchanged before and after famotidine administration. 1

Important Caveat:

While this single controlled study showed no interaction, the evidence for H2-antagonists remains contradictory in the broader literature, with some sources suggesting potential interactions. 2 However, the direct experimental evidence from controlled testing favors no clinically significant interaction with famotidine specifically. 1

Medication Timing Recommendations

When PPIs cannot be avoided, separate levothyroxine administration from the PPI by at least 4 hours to minimize absorption interference. 4 The optimal approach is:

• Take levothyroxine on an empty stomach, typically in the morning upon waking 5
• Administer the PPI at least 4 hours after levothyroxine 4
• Consider taking levothyroxine at bedtime (at least 3-4 hours after the last meal) if morning administration conflicts with other medications 2

For famotidine, based on available evidence, strict separation may not be necessary, though taking levothyroxine on an empty stomach remains the standard recommendation. 1

Monitoring Strategy

When initiating or discontinuing acid-suppressing medications in patients on levothyroxine:

• Check TSH and free T4 levels 6-12 weeks after any change in acid-suppressing therapy 5
• The long half-life of levothyroxine (approximately 7 days) means dose adjustments should only be considered after 6-12 weeks of stable therapy 5
• Be alert for signs of hypothyroidism (fatigue, weight gain, cold intolerance) or hyperthyroidism (tachycardia, tremor, sweating) during medication transitions 5

Additional Considerations

Other medications that significantly impair levothyroxine absorption and require separation include calcium supplements, iron supplements, cholestyramine, colesevelam, and aluminum-containing antacids. 4, 2 These should be taken at least 4 hours apart from levothyroxine. 4

Gastrointestinal conditions that reduce gastric acidity (atrophic gastritis, H. pylori infection) may also impair levothyroxine absorption, making the addition of PPIs particularly problematic in these patients. 2