Hepatic generation of active metabolite Pharmacogenetics of Cardiovascular Antithrombotic Therapy CYP = cytochrome P450. GP = glycoprotein. MDR = multidrug resistance protein. Marín F, et al. J Am Coll Cardiol. 2009;54: Intestinal absorption Platelet inhibition MDR-1 Platelet Membrane Receptors P2Y 12, GPIIb/IIIa, GPIa Platelet Membrane Receptors P2Y 12, GPIIb/IIIa, GPIa Genetic targets CYP Enzyme System Two sequential steps: One step: CYP3A4, CYP3A5, CYP2C9, CYP1A2 Both steps: CYP2B6, CYP2C19 CYP Enzyme System Two sequential steps: One step: CYP3A4, CYP3A5, CYP2C9, CYP1A2 Both steps: CYP2B6, CYP2C19 N S O Cl O CH 3 C N O Cl O CH 3 C HS HOOC Clopidogrel (oral ingestion of pro-drug)

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with ACS or who are undergoing PCI treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. ACS = acute coronary syndrome. PCI = percutaneous coronary intervention. Plavix ® (clopidogrel bisulfate) tablets [package insert]. Bridgewater, NJ: Bristol-Myers Squibb Company/sanofi-aventis Partnership; Clopidogrel ─ Pharmacogenetic Information

Genotyping Platforms/Kits for Cytochrome P450 Testing FDA-approved – Not point-of-care tests: Roche Molecular Systems – AmpliChip ® CYP450 Test (includes CYP2C19*2, *3, and CYP2D6 variant allele testing) AutoGenomics – Infiniti ® CYP2C19 Assay (includes CYP2C19*2, *3, and *17 variant allele testing) Not approved by the FDA – Point-of-care tests: Spartan Bioscience Inc. – Spartan RX CYP2C19 Test Kit (only CYP2C19*2 variant allele testing) Nanosphere, Inc. – Verigene CYP2C19 Test (includes CYP2C19*2A and 3 variant allele testing) FDA = United States Food and Drug Administration. Scott SA, et al. Clin Pharmacol Ther. 2011;90: Spartan Bioscience Inc. Available at: Accessed September 18, Nanosphere, Inc.. Available at: Accessed September 18, 2012.

2009 Updated Labeling for Clopidogrel – PPI Interaction FDA-required label changes 1,2 : Warning: Co-administration of clopidogrel with omeprazole, a PPI that is an inhibitor of CYP2C19, reduces the pharmacological activity of clopidogrel if given concomitantly or if given 12 hours apart. Drug-drug interactions: Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. Based on PK/PD studies showing that concomitant omeprazole reduced clopidogrel active metabolite and effect on platelets. 1 –Did not include COGENT study data 2 EMEA warning extends to discourage concomitant use of all PPIs. 3 –Concomitant use of drugs that inhibit CYP2C19 discouraged; concomitant use of any PPI should be avoided unless absolutely necessary. 4 5 EMEA = European Medicines Agency. PD = pharmacodynamic. PK = pharmacokinetic. PPI = proton pump inhibitor. 1. FDA. Available at: InformationforHeathcareProfessionals/ucm htm. Accessed September 22, Plavix ® (clopidogrel bisulfate) tablets [package insert]. Bridgewater, NJ: Bristol-Myers Squibb Company/sanofi-aventis Partnership; Wathion N. Available at: Accessed September 22, Plavix ® (clopidogrel bisulfate) tablets [summary of product characteristics]. Paris, France: Bristol-Myers Squibb Company/sanofi-aventis Partnership; 2009.

ACC/AHA/SCAI Guideline Recommendations Regarding Genetic Testing and Concurrent Use of PPI and Antiplatelet Therapy Genetic Testing: Genetic testing might be considered to identify whether a patient at high risk for poor clinical outcomes is predisposed to inadequate platelet inhibition with clopidogrel – Class IIb - Level C evidence When a patient predisposed to inadequate platelet inhibition with clopidogrel is identified by genetic testing, treatment with an alternate P2Y 12 inhibitor (eg, prasugrel or ticagrelor) might be considered – Class IIb - Level C evidence Routine clinical use of genetic testing to screen patients treated with clopidogrel who are undergoing PCI is not recommended – Class III (no benefit) - Level C evidence PPI Use: PPIs should be used in patients with a history of prior GI bleeding who require dual antiplatelet therapy – Class I - Level C evidence PPI use is reasonable in patients with increased risk of gastrointestinal bleeding (advanced age, concomitant use of warfarin, steroids, NSAIDs, H. pylori infection, etc.) who require dual antiplatelet therapy – Class IIa - Level C evidence Routine use of a PPI is not recommended for patients at low risk of GI bleeding who have much less potential to benefit from prophylactic therapy – Class III (no benefit) - Level C evidence GI = gastrointestinal. NSAIDs = nonsteroidal anti-inflammatory drugs. Levine GN, et al. J Am Coll Cardiol. 2011;58:e44-e122.