Interaction Considerations for Common OTC Drug Classes


Although OTC medications are generally considered safe when used as directed, there are some key drug interactions for pharmacists to keep in mind when helping patients choose an OTC product.

As we enter the fall and children are back at school, the oncoming flu season and the potential for a surge in COVID-19 cases may be top-of-mind. Still, patients dealing with fall allergies, occasional stomach upset, and other non-seasonal complaints will continue to visit the pharmacy for guidance on how to safely treat minor issues without seeing their physician.

Although OTC medications are generally considered safe when used as directed, there are some key drug interactions for pharmacists to keep in mind when helping patients choose an OTC product. Identifying these potential interactions and finding alternative treatment options, when possible, can be especially important when counseling elderly patients, who account for 30% of all OTC purchases. This population tends to be on a greater number of interacting prescription medications and could be more susceptible to drug adverse effects (AEs) in general.1

Having access to the latest drug reference resources and keeping up to date on important interactions for common OTC drug classes, such as the ones included here, can help pharmacists efficiently provide the most appropriate recommendations for care without a prescription.

Allergy Medications

Increased risk of central nervous system (CNS) depression and anticholinergic effects account for the main interaction concern with antihistamines used to treat seasonal allergies. Both first- and second-generation antihistamines could potentially interact with other CNS depressants, though the risk is greater with first-generation drugs, such as diphenhydramine.

Using antihistamines with other medications that have anticholinergic effects could enhance the risk of AEs, which can be especially concerning in elderly patients who already have an increased risk of urinary retention, sedation, and confusion with anticholinergic drugs. Medications with anticholinergic effects, including antihistamines, are also contraindicated with solid oral dosage forms of potassium due to risk of gastrointestinal irritation and ulceration.

Acid Suppressants

Acid suppressants have the potential to change the absorption rates of other medications by raising gastric pH. Although the risk of a significant interaction can vary significantly from class to class, orally administered kinase inhibitors, azole antifungals, non-nucleoside reverse transcriptase inhibitors, bisphosphonates, and the cephalosporins cefuroxime and cefditoren are among the drugs that are most affected by reduced stomach acidity.

Proton pump inhibitors (PPIs)

PPIs are the most potent and long-lasting of all acid-suppressing classes and, as a result, tend to introduce more substantial and unavoidable pH-related interactions. Although unlikely to have significant effects at lower OTC doses, omeprazole and esomeprazole are also weak CYP2C19 inhibitors.

They could potentially influence the activity of drugs metabolized through this enzyme pathway, including clopidogrel, which is a prodrug that is metabolized via CYP2C19 to its active form. Due to the risk of PPIs inhibiting production of the active metabolite and decreasing antiplatelet action, clopidogrel labeling recommends avoiding concomitant use of either omeprazole or esomeprazole.

Histamine-2 receptor antagonists (H2RAs)

H2RAs have relatively potent acid-suppressing activity, with a shorter duration of action than PPIs. Certain medications that should be avoided with PPI use can therefore be given with an H2RA if the doses are separated by an appropriate amount of time.

The H2RA cimetidine is also a weak inhibitor of the CYP1A2, CYP2C19, CYP2D6, and CYP3A4 enzymes as well as transporters such as OCT2 and MATE1/2. The clinical consequences of this inhibition at lower OTC cimetidine doses are uncertain, but patients using many other medications would likely benefit from instead using the H2RAs famotidine or nizatidine to avoid increasing the risk of enzyme pathway interactions.


Antacids share similar pH-related interaction concerns as PPIs and H2RAs. However, their quick onset and shorter duration of action often make it possible to avoid these interactions by separating the administration of the antacid and other medication by several hours (specific recommendations vary by medication).

Antacids can also cause chelation-type interactions, in which the polyvalent cation of the antacid binds to certain orally administered medications, such as levothyroxine, tetracyclines, or fluoroquinolones, decreasing the medication's absorption and therapeutic effects. As with pH-related interactions, chelation interactions can often be minimized by spacing administration of the antacid and other medication.

Other Gastrointestinal Medications


Although there are generally very few drug interactions involving laxatives, sodium phosphates—often sold under the brand name Fleet—have been associated with acute phosphate nephropathy (APhN). APhN is of particular concern when sodium phosphates are used in large oral doses for bowel preparation prior to colonoscopy or in patients taking medications that affect renal perfusion or function, such as diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers (ARBs), and non-steroidal anti-inflammatory drug (NSAIDs).

Additionally, oral sodium phosphates should be avoided with drugs that raise serum phosphate concentrations or those that require accurate or stable serum phosphate measurements for dose titration (e.g., erdafitinib, burosumab).


Loperamide is a substrate of CYP3A4, CYP2C8, and the efflux transporter P-glycoprotein (P-gp), but concomitant use of drugs that inhibit these CYP enzymes or P-gp is of little clinical concern at typical loperamide doses. However, when loperamide is given at high doses or abused for its opioid-like effects, concomitant use of such inhibitors can lead to CNS depression, QTc interval prolongation, or other serious toxicities.

It’s also worth noting that bismuth subsalicylate contains a salicylate, so its drug interaction concerns are similar to those of aspirin and other salicylates. Due to antiplatelet effects, bismuth subsalicylate may increase bleeding risk when combined with other antiplatelet therapies, NSAIDs, or anticoagulants.

Salicylates can also reduce the uricosuric effects of drugs used to treat gout (e.g., probenecid), enhance the risk of metabolic acidosis with carbonic anhydrase inhibitors, or increase methotrexate concentrations and risk of toxicities. These effects are less likely to occur with occasional or intermittent use of bismuth subsalicylate, but warrant concern with routine or excessive use.


Levonorgestrel is available without a prescription for emergency contraception. Enzyme-inducing products, including barbiturates, carbamazepine, oxcarbazepine, phenytoin, topiramate, efavirenz, rifampin, and St John’s wort, may decrease plasma levonorgestrel concentrations and compromise its efficacy.

Recommendations outside of the United States suggest doubling the standard dose of levonorgestrel to 3 mg in women who have used enzyme-inducing drugs in the 4 weeks prior to levonorgestrel administration for the purpose of emergency contraception.2

Vitamins and Minerals

Primary concerns around vitamin and mineral interactions include chelation with polyvalent cations (e.g., iron, zinc, magnesium, calcium) and increased risk of toxicities when supplements are combined with medications that increase concentrations or effects of that specific vitamin or mineral. Examples of the latter include increased vitamin A, calcium, and potassium levels with retinoic acid derivatives, thiazide diuretics, and ACE inhibitors or potassium-sparing diuretics, respectively.

Vitamin E has been reported to have antiplatelet effects and may be a concern when combined with antiplatelet medications or anticoagulants. Conversely, vitamin K may antagonize the action of the anticoagulant warfarin, increasing the risk of therapeutic failure and clotting.


Armed with a basic understanding of interactions involving frequently used OTC drug classes, pharmacists can quickly identify many of the potential issues patients will encounter when seeking treatment without a prescription. Maintaining reliable access to current, regularly updated evidence and references is also critical to fill in the gaps for less common interactions involving the >300,000 marketed OTC products from >80 different therapeutic classes.3

Studies have demonstrated the value of accurate, updated drug databases, such as Lexicomp, in helping health care professionals identify key drug-drug interactions, particularly for newer medications with interaction profiles that are less understood and evolving.4 With a pharmacist’s knowledge and training backed by these reliable resources, patients can trust the recommendations they receive in the OTC aisles will lead to the safest possible self-care for a wide range of minor health conditions.

About the Authors

Dr. Daniel S. Streetman, PharmD, is the manager of referential content in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health. He completed a residency at the VA Medical Center in Huntington, WV and a research fellowship in clinical pharmacology at Bassett Healthcare in Cooperstown, NY, and was a clinical faculty member at the University of Michigan for several years prior to joining Wolters Kluwer. Dr. Streetman continues to maintain an academic relationship with several schools.

Dr. Carrie W. Nemerovski, PharmD, is a senior clinical content specialist in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health. She completed her PharmD, a PGY1 residency, and PGY2 residency in cardiology at the University of Michigan. She worked as a clinical faculty member at Wayne State University and as a clinical pharmacy specialist at Henry Ford Hospital prior to joining Wolters Kluwer. Dr. Nemerovski continues to maintain an academic relationship with the University of Michigan, serves as a regular peer reviewer, and is active in professional pharmacy organizations.


  1. OTC Medications and Older Adults.The Gerontological Society of America. Accessed March 7, 2022.
  2. CEU Statement: Use of double dose (3mg) levonorgestrel emergency contraception by women taking enzyme-inducing medications. Faculty of Sexual and Reproductive Healthcare. Accessed March 17, 2022.
  3. Drug Applications for Over-the-Counter (OTC) Drugs.U.S. Food and Drug Administration. Accessed March 7, 2022.
  4. Bossaer JB, Eskens D, Gardner A. Sensitivity and specificity of drug interaction databases to detect interactions with recently approved oral antineoplastics. J Oncol Pharm Pract. 2022 Jan;28(1):82-86. doi: 10.1177/1078155220984244. Epub 2021 Jan 12. PMID: 33435823.
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