What are the potential drug interactions with Clopidogrel (Plavix)?

From the Guidelines

Clopidogrel should be used with caution when combined with proton pump inhibitors (PPIs), particularly omeprazole and esomeprazole, due to the potential reduction in clopidogrel's antiplatelet effect, and alternative acid suppressants like pantoprazole or H2-blockers should be considered if necessary, as recommended by the most recent guidelines 1.

Key Considerations

• The most significant interaction with clopidogrel occurs with PPIs, especially omeprazole and esomeprazole, which can inhibit the CYP2C19 enzyme responsible for converting clopidogrel to its active form 1.
• If acid suppression is required, pantoprazole or H2-blockers like famotidine are preferred alternatives to minimize the risk of reducing clopidogrel's effectiveness 1.
• Other important interactions include NSAIDs, which increase bleeding risk, warfarin and other anticoagulants, which significantly increase bleeding risk, and strong CYP2C19 inhibitors like fluconazole 1.
• Certain statins, particularly atorvastatin at high doses, may slightly reduce clopidogrel's effectiveness, while St. John's Wort can decrease clopidogrel's antiplatelet effects, and grapefruit juice may increase bleeding risk 1.

Clinical Recommendations

• Patients taking clopidogrel should inform all healthcare providers about their medication regimen before starting any new drugs 1.
• Healthcare providers should reevaluate the need for starting or continuing treatment with a PPI, including omeprazole, in patients taking clopidogrel, and consider alternative acid suppressants if necessary 1.
• Patients should not stop taking clopidogrel without medical advice, as this could increase the risk of serious cardiovascular events, especially in patients with recent stent placement 1.

From the FDA Drug Label

Effect of other drugs on clopidogrel Clopidogrel is metabolized to its active metabolite in part by CYP2C19. CYP2C19 inducers Concomitant use of strong inducers of CYP2C19 results in increased plasma concentration of the active metabolite of clopidogrel and an increase in platelet inhibition CYP2C19 inhibitors Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition Opioids Coadministration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C maxof clopidogrel’s thiol metabolites by 34% Effect of clopidogrel on other drugs In vitrostudies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of repaglinide with clopidogrel increased the systemic exposure to repaglinide (AUC 0-∞) by 5. 1-fold following the loading dose (300 mg) and by 3.9-fold on day 3 of the maintenance dose (75 mg) of clopidogrel

• Clopidogrel drug interactions include:
  • CYP2C19 inducers: increase levels of clopidogrel active metabolite and increase platelet inhibition 2
  • CYP2C19 inhibitors: decrease plasma concentrations of the active metabolite of clopidogrel and reduce platelet inhibition 2
  • Opioids: decrease exposure to clopidogrel 2, 2
  • Repaglinide: increase substrate plasma concentrations due to inhibition of CYP2C8 by clopidogrel 2
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): increase risk of bleeding 2
  • Other Antiplatelet Agents: increase the risk of bleeding due to an additive effect 2

From the Research

Clopidogrel Drug Interactions

• Clopidogrel is an antiplatelet prodrug that can cause bleeding, a major adverse effect, which can lead to drug discontinuation or noncompliance with therapy 3
• The use of clopidogrel with other antiplatelet agents such as aspirin and warfarin can increase the risk of bleeding 3
• Proton pump inhibitors (PPIs) are frequently administered in combination with clopidogrel to reduce the risk for gastrointestinal (GI) bleeding, but some PPIs may attenuate the antiplatelet effect of clopidogrel 4, 5, 6
• Omeprazole, a PPI, has been shown to decrease the antiplatelet effects of clopidogrel ex vivo, raising concerns about the cardiovascular safety of this drug combination 4, 5, 6
• Other PPIs do not appear to interact with clopidogrel 4
• The decision to administer PPIs to patients treated with clopidogrel should be individualized based on the patient's bleeding and cardiovascular risk 4, 5

Interactions with Other Antiplatelet Agents

• Aspirin and clopidogrel are well-known antiplatelet agents that are widely used across the spectrum of cardio- and cerebrovascular disease 7
• The use of aspirin and PPIs together may also attenuate the antiplatelet effect of aspirin 7
• Ibuprofen, a nonsteroidal anti-inflammatory drug (NSAID), can interact with aspirin and reduce its anti-platelet action 6
• Statins and calcium channel blockers may also interact with thienopyridines, such as clopidogrel, by inhibiting CYP3A4/5 6

Clinical Implications

• Clinicians should be aware of the potential interactions between clopidogrel and other medications, including PPIs and other antiplatelet agents 3, 4, 5, 6, 7
• Patients at high risk of bleeding or with a history of prior GI bleeding should be carefully monitored when taking clopidogrel with other medications 4, 5
• The use of high dose H2 antagonists instead of PPIs may be a reasonable strategy for patients taking clopidogrel 6