Plavix: what the label says

Plavix 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]), Plavix has been shown to reduce the rate of myocardial infarction (MI) and stroke. ( 1.1 ) – For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to reduce the rate of MI and stroke. ( 1.1 ) Recent MI, recent stroke, or established peripheral arterial disease. Plavix has been shown to reduce the rate of MI and stroke. ( 1.2 )

1.1 Acute Coronary Syndrome (ACS) Plavix 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. Plavix should be administered in conjunction with aspirin. Plavix 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. Plavix 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 Plavix is indicated to reduce the rate of MI and stroke.

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 Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity Plavix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2) ] .

CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. ( 5.1 ) Bleeding: Plavix increases risk of bleeding. ( 5.2 ) Discontinuation: Premature discontinuation increases risk of cardiovascular events. Discontinue 5 days prior to elective surgery that has a major risk of bleeding. ( 5.3 ) Thrombotic thrombocytopenic purpura (TTP) has been reported. ( 5.4 ) Cross-reactivity among thienopyridines has been reported. ( 5.5 )

5.1 Diminished Antiplatelet Activity in Patients with 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 ] . The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of Plavix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Plavix [see Drug Interactions (7.1) ] .

5.2 General Risk of Bleeding P2Y12 inhibitors (thienopyridines), including Plavix, increase the risk of bleeding. P2Y12 inhibitors (thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7–10 days). 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. Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Drug Interactions (7.1) and Clinical Pharmacology (12.3) ] . Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) [see Drug Interactions (7.4 , 7.5 , 7.6 , 7.7) ].

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 sanofi-aventis U.S. LLC at 1-800-633-1610 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. Plavix 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 Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin alone are discussed below. Bleeding CURE In CURE, Plavix 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 Plavix (+ aspirin) (n=6259) Placebo (+ aspirin) (n=6303) Major bleeding Life-threatening and other major bleeding. 3.7

Acute coronary syndrome ( 2.1 ) – Initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. – Initiating Plavix 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 Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiating Plavix 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) ] .

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Plavix were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Plavix were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with Plavix plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1) ] . No dosage adjustment is necessary in elderly patients.

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 Plavix with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce significantly the antiplatelet activity of Plavix when given concomitantly or 12 hours apart. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with Plavix. Dexlansoprazole, lansoprazole, and pantoprazole had less effect on the antiplatelet activity of Plavix than did omeprazole or esomeprazole [see Warnings and Precautions (5.1) and Clinical Pharmacology (12.3) ] .