Do pantoprazole (Protonix) and Synthroid (levothyroxine) interact with each other?

Pantoprazole and Levothyroxine Interaction: Clinical Implications

Pantoprazole and levothyroxine (Synthroid) do interact, with concomitant use leading to significant elevation in TSH levels in treated patients, regardless of administration timing. 1

Mechanism of Interaction

The interaction between pantoprazole and levothyroxine occurs primarily through:

1. Gastric pH alteration: Levothyroxine absorption is highly dependent on gastric acidity. Pantoprazole and other PPIs reduce gastric acid secretion, creating a less acidic environment that impairs levothyroxine dissolution and absorption 2, 1.

2. Timing-independent effect: Recent research demonstrates that both morning and evening administration of pantoprazole similarly affect thyroid function tests in patients taking levothyroxine 1.

Clinical Evidence

The most recent and highest quality evidence from a 2023 prospective crossover study showed:

• Concomitant use of pantoprazole for just 6 weeks led to significant elevation in serum TSH in levothyroxine-treated patients who were previously biochemically euthyroid 1.
• This effect occurred regardless of whether pantoprazole was taken in the morning simultaneously with levothyroxine or in the evening 1.

Management Recommendations

1. Separate administration times:

   • Administer levothyroxine at least 4 hours before pantoprazole 2.
   • The FDA label for levothyroxine specifically mentions that gastric acidity is essential for adequate absorption, and PPIs may reduce levothyroxine absorption 2.

2. Consider alternative formulations:

   • If separation of dosing is not possible, consider switching to a soft gel capsule formulation of levothyroxine, which has been shown to be less affected by changes in gastric pH compared to tablet formulations 3.

3. Monitor thyroid function:

   • More frequent monitoring of TSH levels is recommended when initiating, changing, or discontinuing pantoprazole in patients on levothyroxine therapy 2.
   • Dose adjustments of levothyroxine may be necessary to maintain euthyroid status 1, 3.

4. Consider alternative acid-suppressing medications:

   • H2-receptor antagonists like famotidine may have less impact on levothyroxine absorption than PPIs, though the evidence is mixed 4.

Special Considerations

• Pantoprazole vs. other PPIs: While pantoprazole has a lower potential for drug interactions via the CYP450 system compared to other PPIs like omeprazole 5, 6, 7, its effect on gastric pH still impacts levothyroxine absorption.

• Patients at higher risk:

  • Elderly patients
  • Patients with poor compliance
  • Patients with narrow therapeutic window for levothyroxine
  • Patients with difficulty maintaining stable TSH levels

Practical Algorithm

1. First option: Separate administration times

   • Take levothyroxine in the morning on an empty stomach
   • Take pantoprazole at least 4 hours later

2. If separation is not possible:

   • Consider levothyroxine soft gel capsule formulation
   • Increase monitoring frequency of thyroid function tests
   • Adjust levothyroxine dose as needed

3. If TSH remains unstable:

   • Consider alternative acid-suppressing medication
   • Consult with endocrinologist for specialized management

Pitfalls to Avoid

• Don't assume all PPIs have identical interaction profiles: While all PPIs affect gastric pH similarly, pantoprazole has fewer drug interactions via CYP450 pathways than omeprazole or esomeprazole 5, 6.

• Don't overlook the need for monitoring: Even with separated administration times, monitoring of thyroid function is essential when both medications are used concurrently.

• Don't underestimate the clinical significance: The interaction can lead to suboptimal control of hypothyroidism, which may have important clinical consequences if not addressed.