Clopidogrel

Plavix is a P2Y 12 platelet inhibitor indicated for: Acute coronary syndrome – For patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), Plavix has been shown to reduce the rate of myocardial infarction (MI) and stroke. – For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of MI and stroke. Recent MI, recent stroke, or established peripheral arterial disease. Plavix has been shown to reduce the rate of MI and stroke.

1.1Acute Coronary Syndrome

(ACS) Plavix is indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with non–ST-segment elevation ACS (unstable angina [UA]/non–ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. Plavix should be administered in conjunction with aspirin. Plavix is indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically.

Plavix should be administered in conjunction with aspirin.

1.2Recent MI, Recent Stroke, or Established

Peripheral Arterial Disease In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Plavix is indicated to reduce the rate of MI and stroke.

Acute coronary syndrome – Initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. – Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days. Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily orally without a loading dose.

2.1Acute Coronary Syndrome In

patients who need an antiplatelet effect within hours, initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiating Plavix without a loading dose will delay establishment of an antiplatelet effect by several days .

2.2Recent MI, Recent Stroke, or Established

Peripheral Arterial Disease 75 mg once daily orally without a loading dose .

5 WARNINGS AND PRECAUTIONS CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. Bleeding: Plavix increases risk of bleeding. Discontinuation: Premature discontinuation increases risk of cardiovascular events. Discontinue 5 days prior to elective surgery that has a major risk of bleeding. Thrombotic thrombocytopenic purpura (TTP) has been reported. Cross-reactivity among thienopyridines has been reported.

5.1Diminished 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 . The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole.

Avoid concomitant use of Plavix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Plavix .

5.2General Risk of Bleeding P2Y12

inhibitors (thienopyridines), including Plavix, increase the risk of bleeding. P2Y12 inhibitors (thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7–10 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 . 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) .

5.3Discontinuation of Plavix Discontinuation of Plavix

increases the risk of cardiovascular events. If Plavix 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 Plavix for five days prior to such surgery. Resume Plavix as soon as hemostasis is achieved.

5.4Thrombotic 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 .

5.5Cross-Reactivity

among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving Plavix, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines .

Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage Hypersensitivity to clopidogrel or any component of the product

4.1Active Bleeding Plavix

is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2Hypersensitivity Plavix

is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product .

8.1Pregnancy Risk Summary Available

data from cases reported in published literature and postmarketing surveillance with clopidogrel use in pregnant women have not identified any drug-associated risks for major birth defects or miscarriage . There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke . No evidence of fetotoxicity was observed when clopidogrel was administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose . The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Myocardial infarction and stroke are medical emergencies. Therapy for the pregnant woman should not be withheld because of potential concerns regarding the effects of clopidogrel on the fetus. Labor or delivery Clopidogrel use during labor or delivery will increase the risk of maternal bleeding and hemorrhage.

Avoid neuraxial blockade during clopidogrel use because of the risk of spinal hematoma. When possible, discontinue clopidogrel 5 to 7 days prior to labor, delivery, or neuraxial blockade. Data Human data The available data from published case reports over two decades of postmarketing use have not identified an association with clopidogrel use in pregnancy and major birth defects, miscarriage, or adverse fetal outcomes.

Animal data Embryo-fetal developmental toxicology studies were performed in pregnant rats and rabbits with doses up to 500 and 300 mg/kg/day, respectively, administered during organogenesis. These doses, corresponding to 65 and 78 times the recommended daily human dose, respectively, on a mg/m 2 basis, revealed no evidence of impaired fertility or fetotoxicity due to clopidogrel.

The following serious adverse reactions are discussed below and elsewhere in the labeling: Bleeding Thrombotic thrombocytopenic purpura Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis U.S. LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials 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 one 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 . 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) (n=6259) Placebo (+ aspirin) (n=6303) Major bleeding Life-threatening and other major bleeding. 3.7

2.7Life-threatening

bleeding 2.2

1.8Fatal

0.2 0.2 5 g/dL hemoglobin drop 0.9

0.9Requiring

surgical intervention 0.7

0.7Hemorrhagic

strokes 0.1

0.1Requiring

inotropes 0.5

0.5Requiring

transfusion (≥4 units) 1.2

1.0Other

major bleeding 1.6

1.0Significantly

disabling 0.4

0.3Intraocular

bleeding with significant loss of vision 0.05

0.03Requiring

2–3 units of blood 1.3

0.9Minor

bleeding Led to interruption of study medication. 5.1

2.4COMMIT In COMMIT,

similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin . 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 noncerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding 0.6 0.5

0.59Major

noncerebral 0.4 0.3

0.48Fatal

0.2 0.2

0.90Hemorrhagic

stroke 0.2 0.2

0.91Fatal

0.2 0.2

0.81Other

noncerebral bleeding (nonmajor) 3.6 3.1

0.005Any

noncerebral bleeding 3.9 3.4

0.004CAPRIE

(Plavix vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix versus 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.

6.2Postmarketing Experience The

following adverse reactions have been identified during postapproval 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. Hemorrhages, including those with fatal outcome, have been reported in patients treated with Plavix.

Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea General disorders and administration site condition: Fever Hepatobiliary disorders: Acute liver failure, hepatitis (noninfectious), abnormal liver function test Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness, insulin autoimmune syndrome, which can lead to severe hypoglycemia Musculoskeletal, connective tissue and bone disorders: Myalgia, arthralgia, arthritis Nervous system disorders: Taste disorders, headache, ageusia Psychiatric disorders: Confusion, hallucinations Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia Renal and urinary disorders: Increased creatinine levels Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, lichen planus, generalized pruritus Vascular disorders: Vasculitis, hypotension