Omeprazole interacts with more medications than most other acid reducers. That’s for two main reasons. First, it blocks a liver enzyme called CYP2C19, which raises the levels of some drugs and stops others from being activated. Second, by lowering stomach acid, it changes how well certain drugs are absorbed.

The most important omeprazole drug interactions are with clopidogrel (Plavix), methotrexate, certain HIV medications (atazanavir, nelfinavir and rilpivirine), citalopram and escitalopram, warfarin, tacrolimus, some antifungals and cancer drugs, levothyroxine, and the herbal supplement St John’s wort.

Most of these can still be managed safely, often by adjusting a dose, monitoring a level, separating doses or switching to a PPI with fewer interactions, like pantoprazole. But you should never start, stop or combine these medications without checking with your doctor or pharmacist first.

Key Takeaways

Omeprazole has a higher potential for drug interactions than most PPIs because it strongly inhibits the liver enzyme CYP2C19 and moderately affects CYP3A4.
Pantoprazole and famotidine generally have fewer interactions, which is why they’re often used as alternatives.
Clopidogrel (Plavix) is the best-known interaction. Omeprazole reduces its activation, so regulators advise avoiding the combination, although a large trial didn’t show more heart events.
Omeprazole can raise levels of citalopram and escitalopram by 35 to 50% or more, which can increase side effects and QT prolongation risk.
Some HIV drugs, including atazanavir and rilpivirine, need stomach acid to absorb and shouldn’t be taken with omeprazole.
High-dose methotrexate may be cleared more slowly alongside PPIs, and many cancer centers pause PPIs during treatment.
Acid suppression can reduce absorption of levothyroxine, iron, some antifungals and some cancer drugs.
St John’s wort and rifampin can make omeprazole much less effective.

Why Omeprazole Interacts With Other Drugs

Before I go through the list, it helps to understand the two ways omeprazole causes interactions, because it makes it much easier to spot potential problems with medications that aren’t on any list.

1. It blocks liver enzymes

Omeprazole is broken down in the liver mainly by an enzyme called CYP2C19, with some help from CYP3A4. While it’s being processed, it also slows that enzyme down for other drugs that use the same pathway.

That has two possible effects:

Drugs cleared by CYP2C19 build up, leading to higher levels and potentially more side effects (for example, citalopram, escitalopram, diazepam and phenytoin).
Prodrugs activated by CYP2C19 work less well, because they can’t be converted into their active form (the main example is clopidogrel).

A review of PPI interactions concluded that omeprazole carries considerable potential for interactions because of its high affinity for CYP2C19 and moderate affinity for CYP3A4, while pantoprazole appears to have a lower potential [Wedemeyer & Blume, Drug Safety, 2014]. Esomeprazole (Nexium), which is closely related to omeprazole, shares most of the same interactions. If you’re weighing the two up, see my comparison of Prilosec vs Nexium.

2. It changes stomach pH

Some drugs need an acidic stomach to dissolve and be absorbed. When omeprazole raises your stomach pH, less of these drugs get into your bloodstream. Other drugs break down in acid, so less acid means more of them get absorbed.

This pH effect applies to all acid reducers, including other PPIs and, to a lesser degree, H2 blockers like famotidine. So switching PPI won’t fix this type of interaction.

Major Omeprazole Drug Interactions

Clopidogrel (Plavix)

This is the interaction most people have heard of. Clopidogrel is a blood thinner used after heart attacks, stents and strokes. It’s a prodrug, meaning your liver has to convert it into its active form, and CYP2C19 does much of that work. By blocking CYP2C19, omeprazole reduces how much active clopidogrel you make, and lab tests show weaker platelet inhibition.

Regulators in the US and Europe advise avoiding omeprazole and esomeprazole with clopidogrel. The review I mentioned above found this CYP2C19 interaction has been shown to be clinically important for omeprazole and esomeprazole, but it isn’t a class effect across all PPIs [Wedemeyer & Blume, Drug Safety, 2014].

Interestingly, the one large randomized trial on this found no apparent increase in cardiovascular events. In COGENT, 3,761 heart patients on clopidogrel and aspirin were given omeprazole or placebo. Omeprazole significantly reduced gastrointestinal bleeding, with no clear rise in heart attacks, strokes or cardiac death, although the authors said a meaningful difference couldn’t be ruled out [Bhatt et al., The New England Journal of Medicine, 2010].

In practice, if you need both a PPI and clopidogrel, doctors usually choose pantoprazole. Don’t stop clopidogrel or change your PPI without speaking to your cardiologist or GP.

Citalopram and escitalopram

These common antidepressants are cleared partly by CYP2C19. When healthy volunteers took omeprazole, exposure to a single dose of escitalopram rose by 51% and its half-life was prolonged [Malling et al., British Journal of Clinical Pharmacology, 2005].

Real-world data shows the same pattern. In a large therapeutic drug monitoring study, citalopram levels were 35% higher in patients also taking omeprazole, and the authors suggested considering a 50% dose reduction of escitalopram when combined with omeprazole or esomeprazole [Gjestad et al., Therapeutic Drug Monitoring, 2015].

Why it matters: higher citalopram and escitalopram levels increase the risk of side effects and QT prolongation, a change in heart rhythm. Both drugs and omeprazole can also lower sodium levels. That’s why the recommended maximum dose of citalopram is lower in people taking omeprazole, often 20mg a day. Sertraline is less affected.

HIV medications

Several antiretrovirals need stomach acid to be absorbed properly. Omeprazole can dramatically lower their levels, which risks treatment failure and drug resistance.

Rilpivirine: contraindicated with PPIs.
Atazanavir: in the prescribing data, omeprazole 40mg cut atazanavir exposure by 94%. The combination isn’t recommended.
Nelfinavir: levels fall significantly. Not recommended.
Saquinavir: the opposite effect. Levels rise, so monitoring is needed.

If you’re on HIV treatment, always check with your HIV clinic before taking any acid reducer, including over-the-counter ones.

Methotrexate

Methotrexate is used at high doses for some cancers and at low doses for conditions like rheumatoid arthritis and psoriasis. PPIs may slow how quickly the kidneys clear it.

In a French study of 197 cycles of high-dose methotrexate, PPIs were taken in 53% of the cycles where methotrexate elimination was delayed, compared with 15% of cycles with normal elimination. PPI use was identified as a major risk factor for delayed elimination [Santucci et al., Anticancer Research, 2010]. However, not all studies agree. A US study of patients on high-dose methotrexate found PPI use wasn’t a significant predictor of delayed elimination [Reeves et al., British Journal of Clinical Pharmacology, 2014].

Because the consequences of methotrexate toxicity can be serious, many oncology teams pause PPIs around high-dose treatment, often switching to an H2 blocker. The risk at low weekly doses seems much smaller, but it’s still worth your prescriber knowing you take omeprazole.

Warfarin

Omeprazole can slightly raise levels of warfarin and increase its blood-thinning effect in some people. There have been reports of raised INR and bleeding. If you start or stop omeprazole while on warfarin, your INR should be checked more closely for a few weeks.

Tacrolimus

Tacrolimus, used after organ transplants, can build up with omeprazole, particularly in people who are poor CYP2C19 metabolizers. Transplant teams usually monitor tacrolimus levels when a PPI is started or stopped.

Cilostazol, diazepam and phenytoin

These are all cleared partly through CYP2C19, so omeprazole can raise their levels:

Cilostazol (for leg circulation): a lower cilostazol dose is often recommended.
Diazepam: may last longer and cause more drowsiness.
Phenytoin: levels can rise, so monitoring may be needed when omeprazole is started or stopped.

Clozapine

This one goes the other way. Omeprazole can speed up the CYP1A2 enzyme that breaks down clozapine, potentially lowering clozapine levels. A review of omeprazole interactions recommended close monitoring of clozapine levels or choosing pantoprazole instead [Li et al., Therapeutics and Clinical Risk Management, 2013].

St John’s wort and rifampin

St John’s wort, a popular herbal remedy for low mood, and the antibiotic rifampin both speed up the enzymes that break down omeprazole. They can lower omeprazole levels so much that it stops controlling your reflux. Avoid combining them.

Drugs Affected by Lower Stomach Acid

These interactions happen with any acid reducer, not just omeprazole.

Levothyroxine

Levothyroxine, the main treatment for an underactive thyroid, absorbs best in an acidic stomach. In a study of people with hypothyroidism on stable levothyroxine doses, TSH (a marker that rises when thyroid replacement isn’t enough) went up significantly after starting a PPI [Sachmechi et al., Endocrine Practice, 2007].

Not everyone is affected, but if you start omeprazole and you’re on levothyroxine, it’s sensible to have your thyroid levels checked after 6 to 8 weeks. Liquid and soft-gel forms of levothyroxine seem to be less affected. I’ve covered the wider link in thyroid problems and acid reflux.

Antifungals

Ketoconazole, itraconazole capsules and posaconazole suspension need acid for absorption, so omeprazole can make them less effective. Fluconazole isn’t affected in the same way. Fluconazole actually raises omeprazole levels by blocking its breakdown.

Some cancer drugs

Several targeted cancer drugs, including erlotinib, dasatinib, nilotinib and some others, absorb poorly when stomach acid is low. Oncology teams often advise avoiding PPIs or carefully timing doses with these treatments.

Mycophenolate

Omeprazole can reduce how much mycophenolate mofetil (used in transplants and autoimmune conditions) is absorbed. Your specialist may monitor for this.

Iron, B12 and magnesium

Lower stomach acid reduces how well you absorb iron from tablets and food, and long-term PPI use is linked with lower B12 and magnesium levels. If you’re treating iron deficiency, your doctor may need to monitor your response. I’ve covered these in detail in omeprazole and B12 deficiency and omeprazole and low magnesium.

Low magnesium also matters for drug interactions in its own right. It increases the risk of heart rhythm problems with digoxin and with QT-prolonging drugs like citalopram, and diuretics can lower magnesium further.

Digoxin

Omeprazole can slightly increase digoxin absorption. Usually this is minor, but because digoxin has a narrow safety margin, monitoring is sensible, especially in older adults or anyone with low magnesium.

Does Omeprazole Interact With Common Everyday Medicines?

Here are some of the combinations people ask about most often:

Ibuprofen and naproxen: no harmful interaction. Omeprazole is often prescribed alongside NSAIDs to protect the stomach.
Aspirin: no harmful interaction. PPIs are commonly used with low-dose aspirin to reduce ulcer risk.
Paracetamol (acetaminophen): no significant interaction.
Antibiotics like amoxicillin and clarithromycin: these are used with omeprazole in H. pylori treatment. Clarithromycin raises omeprazole levels a little, which is expected and not usually a problem.
Statins: generally fine.
Blood pressure medications: most are fine. Diuretics plus long-term PPIs can increase the risk of low magnesium.
Antihistamines: no significant interaction. More in my article on antihistamines and acid reflux.
GLP-1 drugs (Ozempic, Wegovy, Mounjaro): no direct drug interaction, but they slow stomach emptying and can worsen reflux. I’ve covered omeprazole or famotidine with Ozempic and Mounjaro separately.
Alcohol: no direct drug interaction, but alcohol worsens reflux and irritates the stomach, which works against the medication.

Always tell your pharmacist about any supplements or herbal remedies too. They’re easy to forget, and St John’s wort in particular is a real problem with omeprazole.

Omeprazole Alternatives With Fewer Interactions

If you’re on a medication that interacts with omeprazole, there are usually good options:

Pantoprazole: the PPI with the lowest interaction potential via liver enzymes. It’s usually the first choice for people on clopidogrel. However, it still has the pH-related interactions all PPIs share.
Famotidine: an H2 blocker that doesn’t meaningfully inhibit liver enzymes (unlike the older H2 blocker cimetidine). It has milder pH effects than a PPI. More in famotidine vs omeprazole.
Alginates: products like Gaviscon Advance work physically in the stomach and aren’t absorbed in a way that causes enzyme interactions. Separate them from other medications by a couple of hours, as antacid ingredients can bind some drugs. More in my guide to alginates for acid reflux.
Vonoprazan (Voquezna): a newer acid blocker with its own interaction profile, mainly through CYP3A4. Here’s my guide to vonoprazan for acid reflux.

And of course, the fewer medications you need, the fewer interactions you have to worry about. Getting your diet right is the most powerful way to reduce how much acid suppression you rely on, which is exactly what the Wipeout Diet Plan is built around. If you’ve been on omeprazole for a long time, it may be worth discussing whether you still need it. My guide to getting off PPIs and avoiding acid rebound covers how to do this safely.

How to Stay Safe

Keep an up-to-date list of every medication, supplement and herbal remedy you take, and show it to every doctor and pharmacist.
Ask specifically, “Does this interact with omeprazole?” when you’re prescribed something new.
Don’t swap PPIs or start over-the-counter omeprazole if you’re on clopidogrel, HIV medication, methotrexate, tacrolimus or warfarin without checking first.
If you’re on levothyroxine, ask about a thyroid blood test after starting or stopping omeprazole.
Report new symptoms, like unusual drowsiness, bruising, palpitations or a return of thyroid symptoms, after starting omeprazole.

Conclusion

Omeprazole is one of the most widely used drugs in the world and is generally very safe, but it has more interactions than many people realize. It affects other drugs by blocking the CYP2C19 liver enzyme and by lowering stomach acid. The interactions that matter most are with clopidogrel, citalopram and escitalopram, certain HIV medications, methotrexate, warfarin, tacrolimus, levothyroxine, some antifungals and cancer drugs, and St John’s wort. Most can be managed with a dose change, monitoring or a switch to pantoprazole or famotidine.

The bigger picture is that the less you need to rely on medication, the fewer of these trade-offs you have to juggle. That’s what the Wipeout Diet Plan is designed to help with. I built it first and foremost for LPR, the stubborn throat-based form of reflux, but because it targets the same root causes, it works just as well for GERD and classic heartburn. It gives you a clear, step-by-step plan for what to eat, what to avoid and how to reintroduce foods, so you can control symptoms with diet and work with your doctor towards the lowest dose of medication you need.

If you’d prefer to start with something lighter, the Wipeout Food Reference Guide is the essential companion, listing the foods and drinks that are safe for acid reflux and LPR along with their pH values, so you can check anything at a glance.

Frequently Asked Questions

What drugs should not be taken with omeprazole?

The main ones to avoid or use only under close supervision are clopidogrel, rilpivirine, atazanavir, nelfinavir, St John’s wort, rifampin and high-dose methotrexate. Others, like citalopram, escitalopram, warfarin, tacrolimus, cilostazol and levothyroxine, can usually be taken together with a dose adjustment or monitoring.

Can I take omeprazole with clopidogrel?

Regulators advise avoiding omeprazole and esomeprazole with clopidogrel because they reduce clopidogrel’s activation. Pantoprazole is usually used instead. A large trial didn’t find more heart events with omeprazole, but most doctors still prefer pantoprazole. Never stop clopidogrel without speaking to your doctor.

Can I take omeprazole with antidepressants?

Most antidepressants are fine, but omeprazole can raise levels of citalopram and escitalopram, which increases side effect and QT prolongation risk. A lower dose may be needed. Sertraline is less affected. Check with your prescriber.

Can I take omeprazole and ibuprofen together?

Yes. There’s no harmful interaction, and omeprazole is often prescribed with NSAIDs like ibuprofen to protect the stomach lining from ulcers.

Does omeprazole interact with levothyroxine?

It can. Levothyroxine absorbs best in an acidic stomach, and some people need a higher dose after starting a PPI. A thyroid blood test 6 to 8 weeks after starting or stopping omeprazole is a good idea.

Which PPI has the fewest drug interactions?

Pantoprazole has the lowest potential for enzyme-based interactions among PPIs. All PPIs share the interactions caused by lower stomach acid, though, like reduced absorption of some HIV drugs, antifungals and iron.

Is famotidine safer than omeprazole for drug interactions?

Generally, yes. Famotidine doesn’t meaningfully block liver enzymes, unlike omeprazole and the older H2 blocker cimetidine. It still reduces acid, so it can affect drugs that need acid to absorb, though usually less than a PPI.

Research & References

[Wedemeyer & Blume, Drug Safety, 2014] — Review of PPI drug interactions concluding omeprazole has considerable interaction potential through CYP2C19 and CYP3A4, pantoprazole has lower potential, and the clopidogrel interaction is not a class effect.
[Bhatt et al., The New England Journal of Medicine, 2010] — COGENT trial in 3,761 patients on clopidogrel and aspirin, finding omeprazole reduced GI bleeding with no apparent cardiovascular interaction, though a meaningful difference couldn’t be excluded.
[Malling et al., British Journal of Clinical Pharmacology, 2005] — In 16 healthy volunteers, omeprazole 30mg daily increased exposure to escitalopram by 51% and prolonged its half-life.
[Gjestad et al., Therapeutic Drug Monitoring, 2015] — Drug monitoring study finding citalopram levels were 35% higher with omeprazole and recommending considering a 50% escitalopram dose reduction with omeprazole or esomeprazole.
[Santucci et al., Anticancer Research, 2010] — Analysis of high-dose methotrexate cycles identifying PPI co-administration as a major risk factor for delayed methotrexate elimination.
[Reeves et al., British Journal of Clinical Pharmacology, 2014] — Retrospective study in patients receiving high-dose methotrexate finding PPI use was not a significant predictor of delayed elimination.
[Li et al., Therapeutics and Clinical Risk Management, 2013] — Systematic review of omeprazole’s interactions with adverse consequences, with management advice including pantoprazole as an alternative and monitoring of drugs like clozapine.
[Sachmechi et al., Endocrine Practice, 2007] — In people with hypothyroidism on stable levothyroxine, TSH rose significantly after starting PPI therapy, with no significant change in controls.

David Gray

12 years living with LPR · Consultant & researcher

Every claim sourced to peer-reviewed research Editorial policy

I've lived with LPR for twelve years — the misdiagnoses, the PPI courses that did nothing, the slow work of figuring out what actually helps. Wipeout Reflux is where I translate the research into plain terms for people stuck in the same place. Every claim here is sourced to peer-reviewed work, and I consult one-to-one with LPR sufferers.

View all articles by David Gray

Omeprazole Drug Interactions: What Not to Take With It