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Over-the-Counter Heartburn/GERD Medication in Patients with Epilepsy

Considerations and Recommendations for Healthcare Providers

Patients with a history of seizures or epilepsy must exercise caution when taking medications for heartburn, gastroesophageal reflux disease (GERD), or acid reflux. Certain OTC heartburn medications can interact with antiseizure medications (ASMs), potentially leading to increased seizure activity or adverse side effects. 


Mechanism of Action and Clinical Implications

 

Antacids

Mechanism of Action:

Antacids neutralize stomach acid and provide quick relief from heartburn by increasing the pH of the stomach contents.

Clinical Implication:

Antacids can impair the absorption of phenytoin. It is recommended that patients wait at least two hours after taking phenytoin before consuming antacids to ensure proper medication absorption and efficacy.1

 

H2 Receptor Antagonists

 

Cimetidine:

Mechanism of Action:

Cimetidine inhibits histamine action at H2 receptors on gastric parietal cells, reducing stomach acid production. They may be metabolized by the same cytochromes as ASMs.

Clinical Implication:
Cimetidine can inhibit the metabolism of several ASMs, leading to elevated plasma levels and increased risk of side effects such as somnolence, ataxia, nystagmus, and cognitive disturbances.  

 

  • The inhibition is the strongest for phenytoin, which is dose dependent.2 Higher doses of cimetidine (e.g., 1000-1200 mg/day) appear to affect phenytoin more than lower doses. Cimetidine 200 mg twice/day caused no change in average phenytoin concentrations in one study.2
  • Other ASMs, which levels can be affected by the concomitant use of cimetidine includes carbamazepine (via CYP3A4)3, (clobazam (via interaction with CYP2C19)4, midazolam (CYP3A4)5,6, diazepam (CYP2C19), gabapentin (cimetidine-mediated inhibition of the organic cation transporter-2 transporter)7, and tiagabine.8 

 

Famotidine:

Mechanism of Action:

Similar to cimetidine, famotidine blocks H2 receptors but with fewer drug interactions.

Clinical Implication:
Famotidine is generally considered a safer alternative than cimetidine as it has a lower potential for drug interactions.

 

Proton Pump Inhibitors (PPIs):

Mechanism of Action:

Omeprazole irreversibly inhibits the H+/K+ ATPase enzyme system of gastric parietal cells, effectively reducing stomach acid production.

Clinical Implication:
Omeprazole can increase the plasma concentrations of phenytoin, clobazam, and diazepam by inhibiting the activity of CYP2C19 as well as carbamazepine through an unknown mechanism. Elevated levels of these ASMs can enhance the risk of dose-related side effects such as dizziness, nausea, and toxicity.9 Monitoring ASM levels and adjusting doses may be necessary when initiating or discontinuing omeprazole.

Expert Opinion and Recommendations for Healthcare Providers

 

Antacid Use: Antacids containing calcium carbonate, aluminum hydroxide and magnesium, may lower the levels of certain antiseizure medicines, specifically phenytoin, if taken at the same time. Antacids should be taken at least two hours after taking ASMs to prevent absorption interference.

H2 Receptor Antagonists: Famotidine is generally considered a safer option than cimetidine to avoid increasing the plasma levels of ASMs and phenytoin specifically. It is recommended to consider alternatives to cimetidine when prescribed concomitantly with phenytoin. Drug monitoring is recommended when cimetidine is taken with carbamazepine, clobazam, midazolam (CYP3A4), and diazepam (CYP2C19). 

Proton Pump Inhibitors: Omeprazole and esomeprazole may slow the metabolism of certain antiseizure medicines, like phenytoin, carbamazepine, clobazam, and diazepam.

 

Resources & References

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OTC medicine abuse resources

References arrow_drop_down

1 Carter BL, Garnett WR, Pellock JM, Stratton MA, Howell JR. Effect of antacids on phenytoin bioavailability. Ther Drug Monit. 1981;3(4):333-340. doi:10.1097/00007691-198104000-00003

2 Rafi JA, Frazier LM, Driscoll-Bannister SM, O'Hara KA, Garnett WR, Pugh CB. Effect of over-the-counter cimetidine on phenytoin concentrations in patients with seizures. Ann Pharmacother. 1999;33(7-8):769-774. doi:10.1345/aph.18314

3 Dalton MJ, Powell JR, Messenheimer JA Jr, Clark J. Cimetidine and carbamazepine: a complex drug interaction. Epilepsia. 1986;27(5):553-558. doi:10.1111/j.1528-1157.1986.tb03583.x

4 Walzer M, Bekersky I, Blum RA, Tolbert D. Pharmacokinetic drug interactions between clobazam and drugs metabolized by cytochrome P450 isoenzymes. Pharmacotherapy. 2012;32(4):340-353. doi:10.1002/j.1875-9114.2012.01028.x

5 Midazolam [prescribing information]. Berkeley Heights, NJ: Hikma Pharmaceuticals USA Inc.; November 2022.

6 Locniskar A, Greenblatt DJ, Harmatz JS, Zinny MA, Shader RI. Interaction of diazepam with famotidine and cimetidine, two H2-receptor antagonists. J Clin Pharmacol. 1986;26(4):299-303. doi:10.1002/j.1552-4604.1986.tb03527.x

7 Lal R, Sukbuntherng J, Luo W, et al. Clinical pharmacokinetic drug interaction studies of gabapentin enacarbil, a novel transported prodrug of gabapentin, with naproxen and cimetidine. Br J Clin Pharmacol. 2010;69(5):498-507. doi:10.1111/j.1365-2125.2010.03616.x

8 Gabitril (tiagabine) [prescribing information]. North Wales, PA: Teva Pharmaceuticals USA, Inc.; November 2015.

9 The Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. 2016;176(2):238-246. doi:10.1001/jamainternmed.2015.7193

 
This information was curated by the AES Treatments Committee to offer providers guidance on approved over-the-counter (OTC) drugs with an emphasis on their use by people with epilepsy. The information presented on this page is designed to be informational for a broad audience and is not medical advice. For personalized recommendations, speak to a pharmacist or healthcare provider.