Clopidogrel bisulfate

1 INDICATIONS AND 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 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 DOSAGE AND ADMINISTRATION 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 DOSAGE FORMS AND STRENGTHS • Clopidogrel Tablets, USP 75 mg tablets: Pink colored, Round shaped, biconvex, film coated tablets de-bossed on one side with SG and 124 on other side. • Clopidogrel Tablets, USP 300 mg tablets: Pink colored, Modified oval shaped, film coated tablets de-bossed on one side with SG and 121 on other side. Tablets: 75 mg, 300 mg ( )

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

6 ADVERSE REACTIONS 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: 200 mg = 4.9%. Major bleeding event rates for clopidogrel + aspirin by age were: 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 h …

7 DRUG INTERACTIONS CYP2C19 inducers: Increases levels of clopidogrel active metabolite and increases platelet inhibition. ( 7.1 ) Opioids: Decreased exposure to clopidogrel. Consider use of parenteral antiplatelet agent. ( 7.3 ) Nonsteroidal anti-inflammatory drugs (NSAIDs), warfarin, selective serotonin and serotonin norepinephrine reuptake inhibitors (SSRIs, SNRIs): Increases risk of bleeding. ( 7.4 , 7.5 , 7.6 ) Other Antiplatelet Agents: Increases the risk of bleeding due to an additive effect. ( 7.7 ) Repaglinide (CYP2C8 substrates): Increases substrate plasma concentrations. ( 7.8 ) 7.1 CYP2C19 Inducers Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampin strongly induces CYP2C19 resulting to both an increase level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. 7.2 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 tablets with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of clopidogrel tablets when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel tablets. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of clopidogrel tablets than did omeprazole or esomeprazole [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.3 )]. 7.3 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. 7.4 Nonsteroidal Anti-inflammatory Drugs (NSAIDs) Coadministration of clopidogrel tablets and NSAIDs increases the risk of gastrointestinal bleeding. 7.5 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 tablets with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitr o, clopidogrel inhibits CYP2C9. 7.6 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. 7.7 Other Antiplatelet Agents Coadministration of antiplatelet agents increase the risk of bleeding due to an additive effect. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with other antiplatelet agents [see Warnings and Precautions (5.2 )]. 7.8 Repaglinide (CYP2C8 Substrates) The acyl-β-glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Clopidogrel tablets can increase the systemic exposure to drugs that are primarily cleared by CYP2C8, thereby needing dose adjustment and appropriate monitoring. Clopidogrel tablets increased repaglinide exposures by 3.9-fold to …

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 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 [see Data] .There are risks to the pregnant woman and fetus associated with myocardial infarction and stroke [see Clinical Considerations ]. 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 [see Data]. 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. 8.2 Lactation Risk Summary There are no data on the presence of clopidogrel in human milk or the effects on milk production. No adverse effects on breastfed infants have been observed with maternal clopidogrel use during lactation in a small number of postmarketing cases. Studies in rats have shown that clopidogrel and/or its metabolites are present in the milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breastfeeding should be considered along with mother's clinical need for clopidogrel tablets and any potential adverse effects on the breastfed infant from clopidogrel tablets or from underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric populations have not been established. A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin, and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population. 8.5 Geriatric Use Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel tablets were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel tablets were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel tablets plus aspirin versus placeb …

12.1 Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets.

11 DESCRIPTION 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(4 H )-acetate sulfate (1:1). The molecular formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO 4 and its molecular weight is 419.9. 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 for oral administration is provided as pink, round, biconvex, imprinted, film-coated tablets containing 97.875 mg of clopidogrel bisulfate, USP which is the molar equivalent of 75 mg of clopidogrel base. Each tablet contains mannitol, microcrystalline cellulose, low substituted hydroxypropylcellulose, polyethylene glycol and hydrogenated castor oil as inactive ingredients. The pink film coating contains hypromellose, iron oxide red, lactose monohydrate, titanium dioxide and triacetin. Imprinting ink contains shellac glaze, black iron oxide, N-butyl alcohol, propylene glycol, ammonium hydroxide. spl-clopidogrel-chemical-structure

10 OVERDOSAGE Platelet inhibition by clopidogrel tablets is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in bleeding complications. A single oral dose of clopidogrel at 1,500 or 2,000 mg/kg was lethal to mice and to rats and at 3,000 mg/kg to baboons. Symptoms of acute toxicity were vomiting, prostration, difficult breathing, and gastrointestinal hemorrhage in animals. Based on biological plausibility, platelet transfusion may restore clotting ability.

16 HOW SUPPLIED/STORAGE AND HANDLING Clopidogrel tablets USP, 75 mg are pink, round, coated tablets, 7 debossed on one side, plain on the other side and free from physical defects. Tablets are provided as follows: Bottles of 30 NDC 43598-121-30 Bottles of 90 NDC 43598-121-90 Bottles of 500 NDC 43598-121-05 Bottles of 1000 NDC 43598-121-10 Clopidogrel tablets USP, 300 mg are pink, oval, coated tablets, 3H debossed on one side, plain on the other side and free from physical defects. Tablets are provided as follows: Bottles of 30 NDC 43598-122-30 Bottles of 500 NDC 43598-122-05 Unit dose package of 30 (5 x 6) NDC 43598-122-59 Preserve in well-closed containers. . Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature].