FDA label 2fbe4111-2cf5-4bcd-91cc-5879b077569a

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS The effectiveness of clopidogrel bisulfate is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1) ] . Clopidogrel bisulfate at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are CYP2C19 poor metabolizers. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy [see Clinical Pharmacology (12.5) ] . Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers [see Dosage and Administration (2.3) ] . WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS See full prescribing information for complete boxed warning. • Effectiveness of clopidogrel bisulfate depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. ( 5.1 ) • Poor metabolizers treated with clopidogrel bisulfate at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. ( 12.5 ) • Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. ( 12.5 ) • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. ( 2.3 , 5.1 )

5 WARNINGS AND PRECAUTIONS • Reduced effectiveness in impaired CYP2C19 function: Avoid concomitant use with omeprazole or esomeprazole. ( 5.1 ) • Bleeding: clopidogrel bisulfate increases risk of bleeding. Discontinue 5 days prior to elective surgery. ( 5.2 ) • Discontinuation of clopidogrel bisulfate: Premature discontinuation increases risk of cardiovascular events. ( 5.3 ) • Recent transient ischemic attack or stroke: Combination use of clopidogrel bisulfate and aspirin in these patients was not shown to be more effective than clopidogrel bisulfate alone, but was shown to increase major bleeding. ( 5.4 ) • Thrombotic thrombocytopenic purpura (TTP): TTP has been reported with clopidogrel bisulfate, including fatal cases. ( 5.5 ) 5.1 Diminished Antiplatelet Activity Due to 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 [see Boxed Warning] and by concomitant medications that interfere with CYP2C19. Proton Pump Inhibitors Avoid concomitant use of Clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Clopidogrel [see Drug Interactions (7.1) and Dosage and Administration (2.4) ]. 5.2 General Risk of Bleeding Thienopyridines, including clopidogrel bisulfate, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel bisulfate five days prior to surgery. In patients who stopped therapy more than five days prior to CABG the rates of major bleeding were similar (event rate 4.4% clopidogrel bisulfate + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel bisulfate + aspirin, and 6.3% for placebo + aspirin. Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so withholding a dose will not be useful in managing a bleeding event or the risk of bleeding associated with an invasive procedure. 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. 5.3 Discontinuation of Clopidogrel Bisulfate Avoid lapses in therapy, and if clopidogrel bisulfate must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel bisulfate may increase the risk of cardiovascular events. 5.4 Patients with Recent Transient Ischemic Attack (TIA) or Stroke In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel bisulfate has not been shown to be more effective than clopidogrel bisulfate alone, but the combination has been shown to increase major bleeding. 5.5 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, 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 [see Adverse Reactions (6.2) ]. 5.6 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction have been reported in patients receiving clopidogrel, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications (4.2) and Adverse Reactions (6.2) ].

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 (5.5) ] 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 1-800-667-4708 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 bisulfate 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 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. 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 Table 1: CURE Incidence of Bleeding Complications (% patients) Event Clopidogrel Bisulfate (+ aspirin) Other standard therapies were used as appropriate. Placebo (+ aspirin) (n=6259) (n=6303) Major bleeding Life-threatening and other major bleeding. 3.7 Major bleeding event rate for clopidogrel bisulfate + aspirin was dose-dependent on aspirin: <100 mg = 2.6%; 100–200 mg = 3.5%; >200 mg = 4.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg = 2.0%; 100–200 mg = 2.3%; >200 mg = 4.0% 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 2–3 units of blood 1.3 0.9 Minor bleeding Led to interruption of study medication. 5.1 2.4 COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin ( 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 Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Clopidogrel bisulfate + 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%. 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 CAPRIE (Clopidogrel bisulfate vs. Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate 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 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 post-approval 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. • Blood and lymphatic system disorders : Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP) • 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 • Renal and urinary disorders: Increased creatinine levels • Skin and subcutaneous tissue disorders: Maculopapular or erythematous rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, erythema multiforme, skin bleeding, lichen planus, generalized pruritus • Vascular disorders: Vasculitis, hypotension

<table ID="_RefTABLE1" width="100%"> <caption>Table 1: CURE Incidence of Bleeding Complications (% patients) </caption> <col width="53%"/> <col width="23%"/> <col width="23%"/> <thead> <tr styleCode="Toprule"> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">Event</content> </th> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">Clopidogrel Bisulfate</content> <content styleCode="bold"> (+ aspirin)</content> <footnote ID="_RefT1FT1">Other standard therapies were used as appropriate.</footnote> </th> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold"> (+ aspirin)</content> <footnoteRef IDREF="_RefT1FT1"/> </th> </tr> <tr> <th align="left" styleCode="Lrule Botrule " valign="top"/> <th align="center" styleCode="Lrule Botrule " valign="top"> <content styleCode="bold">(n=6259)</content> </th> <th align="center" styleCode="Botrule " valign="top"> <content styleCode="bold">(n=6303)</content> </th> </tr> </thead> <tbody> <tr> <td> <paragraph>Major bleeding <footnote ID="_RefIDAJICMG">Life-threatening and other major bleeding.</footnote> </paragraph> </td> <td align="center"> <paragraph>3.7 <footnote ID="_Ref385226999">Major bleeding event rate for clopidogrel bisulfate + aspirin was dose-dependent on aspirin: &lt;100 mg = 2.6%; 100&#x2013;200 mg = 3.5%; &gt;200 mg = 4.9%</footnote> </paragraph> </td> <td align="center"> <paragraph>2.7 <footnote ID="_Ref385227016">Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: &lt;100 mg = 2.0%; 100&#x2013;200 mg = 2.3%; &gt;200 mg = 4.0%</footnote> </paragraph> </td> </tr> <tr> <td> <paragraph>Life-threatening bleeding</paragraph> </td> <td align="center"> <paragraph>2.2</paragraph> </td> <td align="center"> <paragraph>1.8</paragraph> </td> </tr> <tr> <td> <paragraph>Fatal</paragraph> </td> <td align="center"> <paragraph>0.2</paragraph> </td> <td align="center"> <paragraph>0.2</paragraph> </td> </tr> <tr> <td> <paragraph>5 g/dL hemoglobin drop</paragraph> </td> <td align="center"> <paragraph>0.9</paragraph> </td> <td align="center"> <paragraph>0.9</paragraph> </td> </tr> <tr> <td> <paragraph>Requiring surgical intervention</paragraph> </td> <td align="center"> <paragraph>0.7</paragraph> </td> <td align="center"> <paragraph>0.7</paragraph> </td> </tr> <tr> <td> <paragraph>Hemorrhagic strokes</paragraph> </td> <td align="center"> <paragraph>0.1</paragraph> </td> <td align="center"> <paragraph>0.1</paragraph> </td> </tr> <tr> <td> <paragraph>Requiring inotropes</paragraph> </td> <td align="center"> <paragraph>0.5</paragraph> </td> <td align="center"> <paragraph>0.5</paragraph> </td> </tr> <tr> <td> <paragraph>Requiring transfusion (&#x2265;4 units)</paragraph> </td> <td align="center"> <paragraph>1.2</paragraph> </td> <td align="center"> <paragraph>1.0</paragraph> </td> </tr> <tr> <td> <paragraph>Other major bleeding</paragraph> </td> <td align="center"> <paragraph>1.6</paragraph> </td> <td align="center"> <paragraph>1.0</paragraph> </td> </tr> <tr> <td> <paragraph>Significantly disabling</paragraph> </td> <td align="center"> <paragraph>0.4</paragraph> </td> <td align="center"> <paragraph>0.3</paragraph> </td> </tr> <tr> <td> <paragraph>Intraocular bleeding with significant loss of vision</paragraph> </td> <td align="center"> <paragraph>0.05</paragraph> </td> <td align="center"> <paragraph>0.03</paragraph> </td> </tr> <tr> <td> <paragraph>Requiring 2&#x2013;3 units of blood</paragraph> </td> <td align="center"> <paragraph>1.3</paragraph> </td> <td align="center"> <paragraph>0.9</paragraph> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Botrule "> <paragraph>Minor bleeding <footnote ID="_Ref385227097">Led to interruption of study medication. </footnote> </paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>5.1</paragraph> </td> <td align="center" styleCode="Botrule "> <paragraph>2.4</paragraph> </td> </tr> </tbody> </table>

<table ID="_RefTABLE2" width="100%"> <caption>Table 2: Incidence of Bleeding Events in COMMIT (% patients) </caption> <col width="45%"/> <col width="15%"/> <col width="15%"/> <col width="15%"/> <thead> <tr styleCode="Toprule"> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">Type of bleeding</content> </th> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">Clopidogrel bisulfate</content> <content styleCode="bold">(+ aspirin)</content> <content styleCode="bold">(n=22961)</content> </th> <th align="center" styleCode="Botrule Lrule " valign="top"> <content styleCode="bold">Placebo</content> <content styleCode="bold">(+ aspirin)</content> <content styleCode="bold">(n=22891)</content> </th> <th align="center" styleCode="Rrule Botrule Lrule " valign="top"> <content styleCode="bold">p-value</content> </th> </tr> </thead> <tbody> <tr> <td styleCode="Lrule "> <paragraph>Major<footnote ID="_RefIDAIOCMG">Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.</footnote> noncerebral or cerebral bleeding<footnote ID="_RefIDAKOCMG">The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Clopidogrel bisulfate + aspirin by age were: &lt;60 years = 0.3%, &#x2265;60 to &lt;70 years = 0.7%, &#x2265;70 years = 0.8%. Event rates for placebo + aspirin by age were: &lt;60 years = 0.4%, &#x2265;60 to &lt;70 years = 0.6%, &#x2265;70 years = 0.7%.</footnote> </paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.6</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.5</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.59</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Major noncerebral</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.4</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.3</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.48</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Fatal</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.90</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Hemorrhagic stroke </paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.91</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Fatal</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>0.2</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.81</paragraph> </td> </tr> <tr> <td styleCode="Lrule "> <paragraph>Other noncerebral bleeding (non-major)</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>3.6</paragraph> </td> <td align="center" styleCode="Lrule "> <paragraph>3.1</paragraph> </td> <td align="center" styleCode="Rrule Lrule "> <paragraph>0.005</paragraph> </td> </tr> <tr styleCode="Botrule"> <td styleCode="Botrule Lrule "> <paragraph>Any noncerebral bleeding</paragraph> </td> <td align="center" styleCode="Botrule Lrule "> <paragraph>3.9</paragraph> </td> <td align="center" styleCode="Botrule Lrule "> <paragraph>3.4</paragraph> </td> <td align="center" styleCode="Rrule Botrule Lrule "> <paragraph>0.004</paragraph> </td> </tr> </tbody> </table>