CLOPIDOGREL Drug Interactions: What You Need to Know

INTERACTIONS

• CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. ( 7.1 )
• Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. ( 7.3 )
• Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7.4 , 7.5 , 7.6 )
• Other Antiplatelet Agents: Increases the risk of bleeding due to an additive effect. ( 7.7 )
• Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. ( 7.8 )

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span>. Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]</span>.

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . 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 clopidogrel 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 clopidogrel 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span>.

7.8 Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Clopidogrel increased repaglinide exposures by 3.9-fold to 5.1-fold <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> . Avoid concomitant use of repaglinide with clopidogrel. 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.

4 CONTRAINDICATIONS

• Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1 )
• Hypersensitivity to clopidogrel or any component of the product ( 4.2 )

4.1 Active Bleeding Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.

AND PRECAUTIONS

• CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. ( 5.1 )
• Bleeding: Clopidogrel tablets increases risk of bleeding. ( 5.2 )
• Discontinuation: Premature discontinuation increases risk of cardiovascular events.

Discontinue

5 days prior to elective surgery that has a major risk of bleeding. ( 5.3 )

• Thrombotic thrombocytopenic purpura (TTP) has been reported. ( 5.4 )
• Cross-reactivity among thienopyridines has been reported. ( 5.5 )

5.1 Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 <span class="opacity-50 text-xs">[see Boxed Warning]</span>. The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span>.

5.2 General Risk of Bleeding P2Y12 inhibitors (thienopyridines), including clopidogrel, increase the risk of bleeding. P2Y12 inhibitors (thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7 to 10 days). Because the half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective. Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid concomitant use of strong CYP2C19 inducers <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )]</span>. Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) <span class="opacity-50 text-xs">[see Drug Interactions ( 7.4 , 7.5 , 7.6 , 7.7 )]</span>.

5.3 Discontinuation of Clopidogrel Discontinuation of clopidogrel increases the risk of cardiovascular events. If clopidogrel must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy with clopidogrel for five days prior to such surgery. Resume clopidogrel as soon as hemostasis is achieved.

5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of clopidogrel, sometimes after a short exposure (&lt;2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span>.

5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines <span class="opacity-50 text-xs">[see Contraindications ( 4.2 ) and Adverse Reactions ( 6.2 )]</span>.