CLOPIDOGREL BISULFATE

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 molecular formula of clopidogrel bisulfate is C 16 H 16 Cl NO 2 S•H 2 SO 4 and its molecular weight is 419.9. The structural formula is as follows: Clopidogrel bisulfate, USP is a white to off-white powder. It is freely soluble in methanol practically insoluble in ether. It has a specific optical rotation of about +56°. Clopidogrel for oral administration is provided as either pink colored, round shaped, biconvex, de-bossed, film coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base or pink colored, modified oval shaped, de-bossed film coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 mg of clopidogrel base. Each tablet contains microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxy propyl cellulose, hydroxy propyl methyl cellulose and hydrogenated castor oil as inactive ingredients. The film coating contains hypromellose, titanium dioxide, polyethylene glycol and red iron oxide. structure

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 decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. (1.1) - For patients with ST-elevation myocardial infarction (STEMI), CLOPIDOGREL has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary PCI is unknown. (1.1) 2. Recent MI, recent stroke, or established peripheral arterial disease. CLOPIDOGREL has been shown to reduce the combined endpoint of new ischemic stroke, new MI, and other vascular death. ( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) • For 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 has been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia. • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke. The benefit for patients who undergo primary percutaneous coronary intervention is unknown. The optimal duration of clopidogrel therapy in ACS is unknown. 1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel has been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

2. Acute coronary syndrome ( 2.1 ) - UA/NSTEMI: 300 mg loading dose followed by 75 mg once daily, in combination with aspirin (75 to 325 mg once daily) - STEMI: 75 mg once daily, in combination with aspirin (75-325 mg once daily), with or without a loading dose 2. Recent MI, recent stroke, or established peripheral arterial disease: 75 mg once daily ( 2.2 ) 2.1 Acute Coronary Syndrome Clopidogrel can be administered with or without food [see Clinical Pharmacology (12.3) ] 1. For patients with non-ST-elevation ACS (UA/NSTEMI), initiate clopidogrel with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75 to 325 mg once daily) and continue in combination with clopidogrel [see Clinical Studies (14.1) ]. 2. For patients with STEMI, the recommended dose of clopidogrel is 75 mg once daily orally, administered in combination with aspirin (75 to 325 mg once daily), with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose [see Clinical Studies (14.1) ]. 2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease The recommended daily dose of clopidogrel is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3 ) ]. 2.3 CYP2C19 Poor Metabolizers CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5 ) ], an appropriate dose regimen for this patient population has not been established. 2.4 Use with Proton Pump Inhibitors (PPI) Avoid using omeprazole or esomeprazole with clopidogrel. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of clopidogrel. When concomitant administration of a PPI is required, consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite [see Warnings and Precautions (5.1) , Drug Interactions (7.1) and Clinical Pharmacology ( 12.3 ) ].

3. Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage ( 4.1 ) 4. Hypersensitivity to CLOPIDOGREL or any component of the product ( 4.2 ) 4.1 Active Bleeding Clopidogrel is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage. 4.2 Hypersensitivity Clopidogrel are 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: 1. Bleeding [see Warnings and Precautions (5.2) ] 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 ScieGen Pharmaceuticals Inc at 1-855-724-3436 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. Clopidogrel 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 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 br/uise. The overall incidence of bleeding is described in Table 1. Table 1: CURE Incidence of Bleeding Complications (% patients) Event Clopidogrel (+ aspirin)* (n=6259) Placebo (+ aspirin)* (n=6303) * Other standard therapies were used as appropriate. † Life-threatening and other major bleeding. ‡ Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100 to 200 mg = 3.5%; >200 mg = 4.9%. Major bleeding event rates for clopidogrel + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥75 years = 5.9%. § Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2.0%; 100 to 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%. ¶ Led to interruption of study medication. 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 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 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 (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 * Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. ** The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for clopidogrel + 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%. CAPRIE (Clopidogrel vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0 % in those taking clopidogrel 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 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 post-approval 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. • Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A • Eye disorders: Eye (conjunctival, ocular, retinal) bleeding • Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis,gastric/duodenal ulcer, diarrhea • 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,headache • Psychiatric disorders: Confusion, hallucinations • Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, 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, skin bleeding, lichen planus, generalized pruritus • Vascular disorders: Vasculitis, hypotension

2. Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. (7.2 ) (7.3 ) (7.4 ) 7.1 CYP2C19 Inhibitors Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain 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) and Dosage and Administration (2.4) ]. Proton Pump Inhibitors (PPI) Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole [see Dosage and Administration ( 2.4 ), Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 ) ]. 7.2 Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding. 7.3 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 with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. 7.4 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.