FDA label 510501a7-61be-4fa1-8120-4bd218a01d8d

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. ( 5.1 ) Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. ( 12.5 ) Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. ( 12.5 ) Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. ( 2.3 , 5.1 ) The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1) ] . Plavix 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 acute coronary syndrome or undergoing percutaneous coronary intervention treated with Plavix at recommended doses exhibit higher cardiovascular event rates than do 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 [see Clinical Pharmacology (12.5) ] . Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3) ] .

5 WARNINGS AND PRECAUTIONS Reduced effectiveness in impaired CYP2C19 function: Avoid concomitant use with drugs that inhibit CYP2C19 (e.g., omeprazole). ( 5.1 ) Bleeding: Plavix increases risk of bleeding. Discontinue 5 days prior to elective surgery. ( 5.2 ) Discontinuation of Plavix: Premature discontinuation increases risk of cardiovascular events. ( 5.3 ) Recent transient ischemic attack or stroke: Combination use of Plavix and aspirin in these patients was not shown to be more effective than Plavix alone, but was shown to increase major bleeding. ( 5.4 ) Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with Plavix, including fatal cases. ( 5.5 ) 5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19 [see Boxed Warning ] and by concomitant medications that interfere with CYP2C19. Avoid concomitant use of Plavix and drugs that inhibit CYP2C19 activity. Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart [see Drug Interactions (7.1) ] . 5.2 General Risk of Bleeding Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 5 days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7–10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. 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. 5.3 Discontinuation of Plavix Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events. 5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and Plavix has not been shown to be more effective than Plavix alone, but the combination has been shown to increase major bleeding. 5.5 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of Plavix, sometimes after a short exposure (<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 [see Adverse Reactions (6.2) ] .

6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: Bleeding [see Warnings and Precautions (5.2) ] Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.5) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more. The clinically important adverse reactions observed in trials comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below. Bleeding CURE In CURE, Plavix use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1 ). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise. The overall incidence of bleeding is described in Table 1. Table 1: CURE Incidence of Bleeding Complications (% patients) Event Plavix (+ aspirin) Other standard therapies were used as appropriate. Placebo (+ aspirin) p-value (n=6259) (n=6303) Major bleeding Life-threatening and other major bleeding. 3.7 Major bleeding event rate for Plavix + aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100–200 mg = 3.5%; >200 mg = 4.9% Major bleeding event rates for Plavix + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years = 5.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2.0%; 100–200 mg = 2.3%; >200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years = 3.6% 0.001 Life-threatening bleeding 2.2 1.8 0.13 Fatal 0.2 0.2 5 g/dL hemoglobin drop 0.9 0.9 Requiring surgical intervention 0.7 0.7 Hemorrhagic strokes 0.1 0.1 Requiring inotropes 0.5 0.5 Requiring transfusion (≥4 units) 1.2 1.0 Other major bleeding 1.6 1.0 0.005 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2–3 units of blood 1.3 0.9 Minor bleeding Led to interruption of study medication. 5.1 2.4 < 0.001 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results. COMMIT In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2 ). Table 2: Incidence of Bleeding Events in COMMIT (% patients) Type of bleeding Plavix (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value Major Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Plavix + aspirin by age were: <60 years = 0.3%, ≥60 to <70 years = 0.7%, ≥70 years = 0.8%. Event rates for placebo + aspirin by age were: <60 years = 0.4%, ≥60 to <70 years = 0.6%, ≥70 years = 0.7%. 0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.90 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Plavix vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo. In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse events (other than bleeding) was reported. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Plavix. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP) Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis General disorders and administration site condition : Fever, hemorrhage of operative wound Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis Nervous system disorders : Taste disorders, fatal intracranial bleeding Eye disorders : Eye (conjunctival, ocular, retinal) bleeding Psychiatric disorders: Confusion, hallucinations Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding Renal and urinary disorders: Glomerulopathy, increased creatinine levels Skin and subcutaneous tissue disorders: Maculopapular or erythematous rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, skin bleeding, lichen planus Vascular disorders: Vasculitis, hypotension

<table width="100%" ID="table_1"> <caption>Table 1: CURE Incidence of Bleeding Complications (% patients)</caption> <col width="40%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th>Event</th> <th>Plavix (+ aspirin)<footnote ID="t1ft1">Other standard therapies were used as appropriate.</footnote> </th> <th>Placebo (+ aspirin)<footnoteRef IDREF="t1ft1"/> </th> <th>p-value</th> </tr> <tr> <th/> <th>(n=6259)</th> <th>(n=6303)</th> <th/> </tr> </thead> <tbody> <tr> <td>Major bleeding <footnote>Life-threatening and other major bleeding.</footnote> </td> <td>3.7 <footnote>Major bleeding event rate for Plavix + aspirin was dose-dependent on aspirin: &lt;100 mg = 2.6%; 100&#x2013;200 mg = 3.5%; &gt;200 mg = 4.9% Major bleeding event rates for Plavix + aspirin by age were: &lt;65 years = 2.5%, &#x2265;65 to &lt;75 years = 4.1%, &#x2265;75 years = 5.9%</footnote> </td> <td>2.7 <footnote>Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: &lt;100 mg = 2.0%; 100&#x2013;200 mg = 2.3%; &gt;200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: &lt;65 years = 2.1%, &#x2265;65 to &lt;75 years = 3.1%, &#x2265;75 years = 3.6%</footnote> </td> <td>0.001</td> </tr> <tr> <td> Life-threatening bleeding</td> <td>2.2</td> <td>1.8</td> <td>0.13</td> </tr> <tr> <td> Fatal</td> <td>0.2</td> <td>0.2</td> <td/> </tr> <tr> <td> 5 g/dL hemoglobin drop</td> <td>0.9</td> <td>0.9</td> <td/> </tr> <tr> <td> Requiring surgical intervention</td> <td>0.7</td> <td>0.7</td> <td/> </tr> <tr> <td> Hemorrhagic strokes</td> <td>0.1</td> <td>0.1</td> <td/> </tr> <tr> <td> Requiring inotropes</td> <td>0.5</td> <td>0.5</td> <td/> </tr> <tr> <td> Requiring transfusion (&#x2265;4 units)</td> <td>1.2</td> <td>1.0</td> <td/> </tr> <tr> <td>Other major bleeding</td> <td>1.6</td> <td>1.0</td> <td>0.005</td> </tr> <tr> <td> Significantly disabling</td> <td>0.4</td> <td>0.3</td> <td/> </tr> <tr> <td> Intraocular bleeding with significant loss of vision</td> <td>0.05</td> <td>0.03</td> <td/> </tr> <tr> <td> Requiring 2&#x2013;3 units of blood</td> <td>1.3</td> <td>0.9</td> <td/> </tr> <tr> <td>Minor bleeding <footnote>Led to interruption of study medication.</footnote> </td> <td>5.1</td> <td>2.4</td> <td>&lt; 0.001</td> </tr> </tbody> </table>

<table width="100%" ID="table_2"> <caption>Table 2: Incidence of Bleeding Events in COMMIT (% patients)</caption> <col width="40%" align="left" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <col width="20%" align="center" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule">Type of bleeding</th> <th styleCode="Rrule">Plavix (+ aspirin) (n=22961)</th> <th styleCode="Rrule">Placebo (+ aspirin) (n=22891)</th> <th styleCode="Rrule">p-value</th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule Rrule">Major<footnote>Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.</footnote> noncerebral or cerebral bleeding<footnote>The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Plavix + aspirin by age were: &lt;60 years = 0.3%, &#x2265;60 to &lt;70 years = 0.7%, &#x2265;70 years = 0.8%. Event rates for placebo + aspirin by age were: &lt;60 years = 0.4%, &#x2265;60 to &lt;70 years = 0.6%, &#x2265;70 years = 0.7%.</footnote> </td> <td styleCode="Rrule">0.6</td> <td styleCode="Rrule">0.5</td> <td styleCode="Rrule">0.59</td> </tr> <tr> <td styleCode="Lrule Rrule"> Major noncerebral</td> <td styleCode="Rrule">0.4</td> <td styleCode="Rrule">0.3</td> <td styleCode="Rrule">0.48</td> </tr> <tr> <td styleCode="Lrule Rrule"> Fatal</td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.90</td> </tr> <tr> <td styleCode="Lrule Rrule">Hemorrhagic stroke </td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.91</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule"> Fatal</td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.2</td> <td styleCode="Rrule">0.81</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Other noncerebral bleeding (non-major)</td> <td styleCode="Rrule">3.6</td> <td styleCode="Rrule">3.1</td> <td styleCode="Rrule">0.005</td> </tr> <tr> <td styleCode="Lrule Rrule">Any noncerebral bleeding</td> <td styleCode="Rrule">3.9</td> <td styleCode="Rrule">3.4</td> <td styleCode="Rrule">0.004</td> </tr> </tbody> </table>