CLOPIDOGREL

Clopidogrel bisulfate is a thienopyridine class inhibitor of P2Y 12 ADP platelet receptors. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO 4 and its molecular weight is 419.9 g/mol. The structural formula is as follows: Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°. Clopidogrel tablets, USP 75 mg for oral administration are provided as pink, round, biconvex, film coated tablets, engraved “APO” on one side, “CL” over “75” on the other side. The tablets contain 97.875 mg of clopidogrel bisulfate, which is the molar equivalent of 75 mg of clopidogrel base. Clopidogrel tablets, USP 300 mg for oral administration are provided as pink, oblong, biconvex, film coated tablets engraved "APO" on one side and "CL 300" on the other side. The tablets contain 392.0 mg of clopidogrel bisulfate, which is the molar equivalent of 300 mg of clopidogrel base. Each tablet contains anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate as inactive ingredients. The pink film coating contains ferric oxide red, hydroxypropyl cellulose, hypromellose, polyethylene glycol and titanium dioxide. clopiodgrel-01.jpg

Clopidogrel bisulfate is a P2Y12 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 bisulfate has been shown to reduce the rate of myocardial infarction (MI) and stroke. ( 1.1 ) - For patients with ST-elevation myocardial infarction (STEMI), clopidogrel bisulfate has been shown to reduce the rate of MI and stroke. ( 1.1 ) Recent MI, recent stroke, or established peripheral arterial disease. Clopidogrel bisulfate has been shown to reduce the rate of MI and stroke. ( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) Clopidogrel tablets are 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 tablets are 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 bisulfate 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 bisulfate is indicated to reduce the rate of MI and stroke.

Acute coronary syndrome ( 2.1 ) Initiate clopidogrel with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel 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 ( 2.2 ) 2.1 Acute Coronary Syndrome In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 )] . 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease 75 mg once daily orally without a loading dose [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )] .

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 bisulfate is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel bisulfate is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions ( 6.2 )] .

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 Apotex Inc. at 1-800-706-5575 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 bisulfate 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 bisulfate alone to aspirin alone are discussed below. Bleeding CURE In CURE, clopidogrel bisulfate 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 Bisulfate (+ aspirin ) (n=6259) Placebo (+ aspirin ) (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 bisulfate 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 bisulfate (+ 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 (non-major) 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 bisulfate vs Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate 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 bisulfate compared to 0.5% for aspirin. Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma. Other Adverse Events In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo. In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. 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 bisulfate. 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

Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. ( 7.2 ) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7.3, 7.4, 7.5 ) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. ( 7.6 ) 7.1 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 [see Warnings and Precautions ( 5.1 )]. Omeprazole or Esomeprazole Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel bisulfate when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel bisulfate. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel bisulfate than did omeprazole or esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ]. 7.2 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 [see Clinical Pharmacology ( 12.3 )] . Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring coadministration of morphine or other opioid agonists. 7.3 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministration of clopidogrel bisulfate and NSAIDs increases the risk of gastrointestinal bleeding. 7.4 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 bisulfate with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitr o , clopidogrel inhibits CYP2C9. 7.5 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. 7.6 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 [see Clinical Pharmacology ( 12.3 )] . 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.