21 Potentially Dangerous OTC Medication Combinations to Avoid

Many of us tend to think about over-the-counter (OTC) drugs as being safer than their prescription counterparts, maybe because there are no gatekeepers holding us back from using them at our discretion. In truth, over-the-counter medication is still medication and each can have serious health risks of their own but this is especially true when we combine them with other drugs. Though this list is not intended to be exhaustive, here are 21 combinations that could be especially dangerous.


NSAID Interactions

How many of us take ibuprofen, naproxen or another NSAID whenever pain or inflammation hits without any worry about how the med might mix with others in our regimens? Well it's probably time to rethink how often and how easily we take NSAIDs as these drugs have several interactions users need to be aware of:

  • NSAIDs taken with other NSAIDS can be a dangerous mix because it can increase the risks of side effects. The biggest threat is gastrointestinal damage but there are others so best not compound these.
  • Anticoagulants can add to the increased blood-thinning effects NSAIDs can cause, potentially leading to dangerous bleeding.
  • Blood pressure medications may be less effective if taken with NSAIDs, which can increase blood pressure.
  • Corticosteroids increase the risks of gastrointestinal bleeding and damage, and this may be exacerbated by NSAID use.
  • SSRIs also increase bleeding risks so combining with NSAIDs is ill-advised.
  • Lithium can build to toxic levels in the body when it’s used alongside NSAIDs.
  • Methotrexate may also build up to toxic levels when NSAIDs are also present in the body.
  • Multi-symptom cold remedies often contain acetaminophen, so taking them with any other products that contain that drug can lead to dangerous overdoses.


Aspirin Interactions

Even low-dose aspirin can interact with medications in dangerous ways. Here are a few:

  • Ibuprofen and naproxen can interact with aspirin’s antiplatelet effects, making it less effective for cardiovascular protection.
  • NSAIDs, in general, when taken with aspirin, can increase bleeding risks.
  • Antidiabetic medications like sulfonylureas can become overly effective with aspirin, leading to hypoglycemia.
  • SSRIs, when mixed with aspirin, can increase bleeding risks.
  • Acetazolamide and aspirin can compete for clearance through the kidneys, raising levels of both medications in the body.
  • Valproate levels can also rise to dangerous levels when used with aspirin.


Antihistamine Interactions

Antihistamines are generally safe when taken at recommended doses, but there are a few interactions users should know about:

  • Alcohol and sedatives can significantly increase drowsiness and driving impairment effects of diphenhydramine (Benadryl).
  • Dramamine, which many people use to control motion sickness, can also cause increased sedation when taken with diphenhydramine, warns Men’s Health.
  • Macrolide antibiotics and antifungals can lead to heart problems when combined with terfenadine or astemizole, two nonsedating antihistamines.


Antacid Interactions

Antacids containing calcium and other minerals can have a chelating effect on certain medications, affecting their potency. Some interactions include:

  • Antibiotics and antifungals can become significantly less effective when taken within 2-4 hours of using antacids.
  • Glucocorticoids may also lose potency.
  • Antidiarrheal medications may become ineffective with some antacids due to the stool-softening nature of both calcium and magnesium.
  • NSAID levels in the blood may increase if used alongside magnesium-based antacids; aluminum-based medications may decrease medication absorption.

Most OTC medications are safe when taken occasionally, as directed, and at their lowest effective doses. But serious risks increase with every medication a person adds to their regimen and OTC medications are not exempt from causing problems—in fact, because they're often taken without medical supervision and so casually, they may actually be more dangerous than adding a newly prescribed medication. 

Consumers should always check medication labels for warnings, and for those with existing prescribed medications, never add an over-the-counter remedy without first consulting your doctor and a pharmacist. 

Copyright 2025, Wellness.com

3/31/2025 4:00:00 AM
Wellness Editor
Written by Wellness Editor
Wellness Exists to Empower Health Conscious Consumers. Wellness.com helps people live healthier, happier and more successful lives by connecting them with the best health, wellness and lifestyle information and resources on the web.
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