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Rx pill bottle and Rx prescription pad: Clopidogrel interactions
Drug Info

Clopidogrel interactions to avoid

Be cautious when taking clopidogrel in combination with antidepressants as this medication can intensify blood-thinning effects
Chad Shaffer, MD, medical writer and reviewer for SingleCare
By | Feb. 8, 2024

Key takeaways

  • Proton pump inhibitors (PPIs) are a widely used class of medications for acid reflux and stomach ulcers, and along with other CYP enzyme inhibitors, they have been implicated in reducing the effectiveness of Plavix.

  • Coupling clopidogrel with any variety of anticoagulants raises the risk of bleeding, which may be worth it in some situations but warrants caution.

  • A number of different antidepressants can amplify the blood-thinning action of clopidogrel, so watch out for bleeding with this combination.

  • Taking a calcium channel blocker for hypertension or heart rate control in coronary artery disease or atrial fibrillation is not uncommon, but this drug class can diminish the potency of Plavix.

  • Grapefruit juice, one of the foods most implicated in drug interactions, lessens clopidogrel efficacy as a blood thinner, and as with all of these key interactions, it warrants a discussion with your healthcare provider about whether a change needs to be made.

Drug interactions | Food interactions | Other interactions | Avoiding interactions | When to see a doctor

Avoiding a heart attack and stroke is at the top of everyone’s priority list for their health, particularly for those who have suffered one in the past or have a coronary stent in place. Clopidogrel can be an ally in that endeavor, but only if drug interactions do not compromise the medication’s action. Clopidogrel functions as an antiplatelet agent by blocking the glycoprotein IIb/IIIa receptor activation. Inhibiting platelet blood cells makes the blood thinner, and how the drug is metabolized in the body makes clopidogrel susceptible to interactions with various medications and even some foods. If you are about to start or are already taking clopidogrel, better known by its brand name Plavix, you need to know these interactions.

Clopidogrel drug interactions

Either amplifying or minimizing the action of clopidogrel can be a big deal when it comes to drug-drug interactions. You certainly don’t want to be at risk of hemorrhaging from too much platelet inhibition, but you also want clopidogrel to be able to do its thing by helping to prevent cardiovascular events. These grave events could include acute coronary syndromes, unstable angina, and myocardial infarctions.

Proton pump inhibitors

PPIs are probably one of the more used (and overused) drug classes, partly because acid reflux is common, plus they work well and are hard to discontinue. For these reasons, they end up on many patient’s medication lists. Their ubiquitous presence should not be misconstrued as being innocuous, and their interaction with clopidogrel is a perfect example.

PPIs can nullify the antiplatelet effects of clopidogrel, which could heighten the risk of a cardiovascular event. The mechanism of the interaction is thought to be the inhibition of a liver enzyme, CYP2C19, which is required to convert clopidogrel to its active state. 

Among the PPIs, Prilosec (omeprazole) and Nexium (esomeprazole) are felt to be the biggest offenders and are usually avoided in combination with Plavix. Prevacid (lansoprazole) and Protonix (pantoprazole) may have less negative interaction, and Aciphex (rabeprazole) and Dexilant (dexlansoprazole) could be most preferable if a PPI is needed, based on having the least interaction. The need for both a PPI and Plavix should be reviewed with the prescribing providers to discuss any potential PPI or clopidogrel alternatives. If price is an issue in switching, check out the SingleCare discount card for savings.

CYP enzyme inhibitors

CYP enzymes are frequently involved in the metabolism of drugs, including clopidogrel. Besides PPIs, other drugs can influence clopidogrel metabolism through CYP enzyme inhibition and lead to less antiplatelet action. Members of the azole antifungal class, including Diflucan (fluconazole) and Ketodan (ketoconazole) may negatively affect Plavix activity, and ritonavir, one of the components of Paxlovid (nirmatrelvir-ritonavir) which is used for treating COVID-19, can do so as well. Get input from your medical provider about whether these interactions with clopidogrel require a change to be made.

Anticoagulants

Going the other direction with a clopidogrel interaction, anticoagulants can cause bleeding when taken alongside the antiplatelet agent. This duo is often necessary and recommended by cardiologists and neurologists. Nonetheless, you need to be aware of it and talk to these specialists or your primary care provider about the balance of side effects and benefits.

Drugs that could additively thin the blood with clopidogrel include anticoagulants and antiplatelet agents, including nonsteroidal anti-inflammatory drugs (NSAIDs). Examples of drugs in these different categories include:

Antidepressants

A little-known attribute of numerous antidepressants is their tendency to impair the function of platelet cells. The effect may not be strong enough to be meaningful in most cases, but when paired with a powerful antiplatelet drug like Plavix, the action takes on more relevance. The fear is that the combination could tip the scale toward excess bleeding risk. Talk to your healthcare provider about whether the benefits of both drug types warrant their use together; often, it does.

Antidepressants from the popular selective serotonin reuptake inhibitor (SSRI) and serotonin norepinephrine reuptake inhibitor (SNRI) classes are included in this cautionary note, as well as Wellbutrin XL (bupropion extended-release). Members of the SSRI and SNRI classes include:

Calcium channel blockers

Hypertension and heart disease are conditions that can often call for the use of both a calcium channel blocker to control blood pressure and heart rate and clopidogrel to reduce the likelihood of another heart attack or stroke. Unfortunately, a concomitant calcium channel blocker decreases the effectiveness of clopidogrel. Whether this potential interaction is significant enough to justify an adjustment to your medication regimen is a matter you can bring up with your team of healthcare professionals.

The calcium channel blocker drug category includes the following members:

Clopidogrel food interactions

A dose of clopidogrel can be taken with or without food. One exception is grapefruit juice, a food item that often rears its head in drug interaction warnings.

Clopidogrel and grapefruit juice

Grapefruit juice inhibits CYP enzymes, which are required to turn clopidogrel from a pro-drug into an active metabolite. Consequently, too much grapefruit juice could nullify your clopidogrel-based prevention efforts against heart attacks and strokes. Whoever is prescribing your Plavix can guide you on whether any amount of grapefruit juice is acceptable.

Other clopidogrel interactions

Clopidogrel and surgery

You need to be able to form blood clots during surgery to prevent excessive bleeding. Because clopidogrel blocks platelets from helping to make clots, the drug can be problematic during operations. If you are scheduled for surgery, your surgeon may request that you go off of it for five days beforehand. Check with your cardiologist for medical advice to see if you can discontinue Plavix preoperatively and for how long. 

Clopidogrel and caffeine

Caffeine may thin the blood a bit. To limit bleeding risk, a reduction in caffeine intake may be worthwhile during clopidogrel therapy. Before you get too upset about this, check with your healthcare provider to see if any change in your coffee consumption is actually advised.

Clopidogrel and omega-3 fatty acids

Omega-3 fatty acids are a popular dietary supplement, often labeled as fish oil capsules. They are a great example of why you need to keep your healthcare providers informed about what supplements you take. Little known to most people, omega-3 fatty acids inhibit platelet activity. Putting them together with antiplatelet drugs like Plavix or aspirin may lead to an increased risk of bleeding problems.

How to minimize clopidogrel interactions

Keeping your team of medicine prescribers and pharmacists updated on all the different prescription drugs, over-the-counter products, and dietary supplements is required. You should not be passive and assume they all know your medication list. Despite all the technology and computerized records in use today, the fact remains that this essential information does not always flow to the healthcare professionals who need it. By maintaining a list on your own and regularly sharing it with your medical team, you can help ensure that everyone is on the same page and reduce the risk of interactions.

When to talk to a healthcare provider about clopidogrel interactions

Don’t miss an opportunity to ask about drug interactions. When you are prescribed clopidogrel, regularly during treatment with the drug, and anytime a new medicine is added on, speak up and ask the prescriber about whether any interactions exist on your med list. It’s your health and well-being at stake. By all means, your active engagement in decision-making should always be welcome.