Important Clopidogrel (PLAVIX) Drug Interactions

Patients taking the drug clopidogrel (PLAVIX) should be aware that it has clinically important interactions with many other prescription and over-the-counter medications.

Clopidogrel is a widely used drug that inhibits platelets and, therefore, prevents clot formation. It is approved by the Food and Drug Administration to reduce the risk of having a new heart attack or stroke in the following patient groups:

• Patients who have a condition known as acute coronary syndrome and who are to be treated with medicines, a stent (a tubeshaped metal mesh device placed in a coronary artery vessel to keep it open) or coronary artery bypass surgery. Acute coronary syndrome consists of unstable angina (worsening chest pain due to inadequate blood flow to the heart) or changes on an electrocardiogram (EKG) that suggest a heart attack is occurring.
• Patients who have definitive changes on an EKG indicating that an acute heart attack is occurring and who are to be treated with medicines.
• Patients who have a history of a recent heart attack or stroke or have established peripheral vascular disease (for example, evidence of narrowed or blocked arteries in the legs or neck).[1]

For the first two groups of patients, clopidogrel should be taken in combination with aspirin, another platelet-inhibiting drug.

Public Citizen’s Health Research Group has designated clopidogrel as a Limited Use drug.

Drugs that block clopidogrel activation

Like many drugs, clopidogrel is metabolized (broken down or chemically modified) by substances in the liver called enzymes. Notably, clopidogrel itself is not able to inhibit platelets. To be effective, it first must be converted after ingestion into an active form by enzymes in the liver.

When clopidogrel is taken concomitantly with other drugs that block one of the liver enzymes that activate clopidogrel, patients may not achieve the desired level of platelet inhibition necessary to prevent blood clots that can cause heart attacks and strokes. Table 1 (below) lists drugs that good-to-excellent evidence shows block clopidogrel activation by the liver and thereby decrease its antiplatelet effects.[2]

Table 1: Examples of Drugs That Block Clopidogrel Activation and Decrease Its Effectiveness as a Platelet Inhibitor

*Designated as Limited Use
**Combination drug that contains at least one other active ingredient not listed
†Over-the-counter product

Four commonly used — and often misused and overused — proton pump inhibitors (PPIs) have been shown to interfere with the activation of clopidogrel. PPIs, which are available in both prescription and over-the-counter forms, suppress the production of stomach acid and are used to treat heartburn and a number of other conditions. Two of these drugs, omeprazole (PRILOSEC, PRILOSEC OTC, ZEGERID, ZEGERID OTC) and esomeprazole (NEXIUM, NEXIUM 24HR, VIMOVO), have been shown to inhibit one of the enzymes in the liver that plays a key role in the activation of clopidogrel. The product labeling for clopidogrel warns against concomitant use of the drug with esomeprazole or omeprazole.[3]

Importantly, several large observational studies have found that in patients taking clopidogrel for one of its approved uses, concomitant use of a PPI was associated with an increased risk of serious adverse cardiovascular events, such as a heart attack, stroke or death from cardiovascular causes.[4],[5],[6],[7] These findings strongly suggest that concomitant use of PPIs with clopidogrel can cause clinically important reductions in the beneficial antiplatelet effects of clopidogrel.

Other drugs that have been found to interfere with the activation of clopidogrel include two antidepressants and three calcium channel blockers that are used to treat high blood pressure.

Drugs that increase clopidogrel’s risk of bleeding

As with other antiplatelet drugs, one of the major adverse effects of clopidogrel is bleeding, which can be life-threatening in severe cases. Table 2 (below) provides examples of commonly used drugs that can interfere with platelet function and augment the antiplatelet effects of clopidogrel, thus increasing the risk of bleeding complications.

The examples include two types of commonly used antidepressants — selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (such as venlafaxine [EFFEXOR XR]).[8],[9] Of note, two SSRI antidepressants — fluoxetine (PROZAC, SARAFEM, SELFEMRA, SYMBYAX) and fluvoxamine (LUVOX) — also were listed in Table 1 as drugs that can block the activation of clopidogrel, which makes their interactions with clopidogrel particularly complex.

Concomitant use of clopidogrel with nonsteroidal anti-inflammatory drugs (for example, ibuprofen [ADVIL]), which can interfere with platelet function and damage the inner lining of the stomach, increases the risk of gastrointestinal bleeding.[10]

Table 2: Examples of Drugs That Can Increase the Risk of Bleeding When Taken Concomitantly With Clopidogrel

*Designated as Limited Use
**Combination drug that contains at least one other active ingredient not listed
*** Designated as Do Not Use
†Over-the-counter product

Other drugs that can interact with clopidogrel

Taking clopidogrel with the anticoagulant warfarin (COUMADIN, JANTOVEN) can increase the risk of bleeding.

Finally, dangerously low blood sugar levels can occur when the diabetes drug repaglinide (PRANDIMET, PRANDIN) and clopidogrel are taken together because clopidogrel increases the amount of repaglinide in the blood. Severe drops in blood sugar can cause loss of consciousness, seizures, brain damage and even death.[11]

What You Can Do

These types of potentially dangerous drug interactions reinforce the importance of bringing all of the drugs that you take each time you visit any doctor. Because many drugs, including others not listed in this article, affect the activity of the enzymes that metabolize clopidogrel or interact with it in other ways, you should find out from your doctor whether any other drugs that you are taking could interact with your clopidogrel treatment.

References

[1] Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Label: clopidogrel bisulfate (PLAVIX). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020839s070lbl.pdf. Accessed October 23, 2018.

[2] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Accessed October 6, 2018.

[3] Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Label: clopidogrel bisulfate (PLAVIX). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020839s070lbl.pdf. Accessed October 23, 2018.

[4] Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA. 2009;301(9):937-44.

[5] Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ. 2009;180(7):713-718.

[6] Kreutz RP, Stanek EJ, Aubert R, et al. Impact of proton pump inhibitors on the effectiveness of clopidogrel after coronary stent placement: The Clopidogrel Medco Outcomes Study. Pharmacotherapy. 2010;30(8):787-796.

[7] Bhurke SM, Martin BC, Li C, et al. Effect of the clopidogrel-proton pump inhibitor drug interaction on adverse cardiovascular events in patients with acute coronary syndrome. Pharmacotherapy. 2012;32(9):809-818.

[8] IBM Micromedex. Drug interactions. http://www.micromedexsolutions.com/home/dispatch. Accessed October 6, 2018.

[9] Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Label: clopidogrel bisulfate (PLAVIX). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020839s070lbl.pdf. Accessed October 23, 2018.

[10] Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. Label: clopidogrel bisulfate (PLAVIX). May 2018. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/020839s070lbl.pdf. Accessed October 23, 2018.

[11] Health Canada Warns of Dangerous Drug Interaction. Worst Pills, Best Pills News. January 2016. /newsletters/view/1007. Accessed October 23, 2018.