CYP2C19 Inhibitors: Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.
Proton Pump Inhibitors (PPI): Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Coadministration of clopidogrel bisulfate and NSAIDs increases the risk of gastrointestinal bleeding.
Warfarin (CYP2C9 Substrates): Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, co-administration of clopidogrel bisulfate with warfarin increases the risk of bleeding because of independent effects on hemostasis.
However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.
SSRIs and SNRIs: Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
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