Clopidogrelinteractions

CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition.

Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding.

Other Antiplatelet Agents: Increases the risk of bleeding due to an additive effect. Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations.

7.1 CYP2C19

Inducers Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers.

7.2 CYP2C19

Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of 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. Omeprazole or Esomeprazole Avoid concomitant use of Plavix with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of Plavix when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole.

7.3 Opioids

As with other oral P2Y 12 inhibitors, coadministration of opioid agonists delay and reduce the absorption of clopidogrel, presumably because of slowed gastric emptying, resulting in reduced exposure to its metabolites. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists.

7.4 Nonsteroidal

Anti-inflammatory Drugs (NSAIDs) Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.

7.5 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, coadministration of Plavix with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

7.6 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.

7.7 Other Antiplatelet

Agents Coadministration of antiplatelet agents increase the risk of bleeding due to an additive effect. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with other antiplatelet agents.

7.8 Repaglinide (CYP2C8

Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Plavix can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Plavix increased repaglinide exposures by 3.9-fold to 5.1-fold. Avoid concomitant use of repaglinide with Plavix. If concomitant use cannot be avoided, initiate repaglinide at 0.5 mg before each meal and do not exceed a total daily dose of 4 mg. Increased frequency of glucose monitoring may be required during concomitant use.