Clopidogrel

1 INDICATIONS & USAGE Clopidogrel 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]), clopidogrel has been shown to reduce the rate of myocardial infarction (MI) and stroke. ( 1.1 ) - For patients with ST-elevation myocardial infarction (STEMI), clopidogrel has been shown to reduce the rate of MI and stroke. ( 1.1 ) • Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel has been shown to reduce the rate of MI and stroke. ( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) • Clopidogrel 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. Clopidogrel should be administered in conjunction with aspirin. • Clopidogrel 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. Clopidogrel should be administered in conjunction with aspirin. 1.2 Recent 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 clopidogrel is indicated to reduce the rate of MI and stroke.

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 ( 5.4 )] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Macleods Pharma USA, Inc. at 1-888-943-3210 or 1-855-926-3384 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical 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. Clopidogrel 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 clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel 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 Clopidogrel (+ aspirin) Placebo (+ aspirin) (n=6259) (n=6303) Major bleeding* 3.7 2.7 Life-threatening bleeding 2.2 1.8 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 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2 to 3 units of blood 1.3 0.9 Minor bleeding † 5.1 2.4 * Life-threatening and other major bleeding. † Led to interruption of study medication. COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (see Table 2). Table 2: Incidence of Bleeding Events in COMMIT (% patients) Type of Bleeding Clopidogrel (+ aspirin) (n=22961) Placebo (+ aspirin) (n=22891) p-value Major* noncerebral or cerebral bleeding 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 (nonmajor) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 * Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. CAPRIE (Clopidogrel vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel 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 clopidogrel compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo. In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel. 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 postapproval use of clopidogrel. 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 clopidogrel. • 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