1 INDICATIONS AND USAGE

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, Plavix 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), Plavix 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 Plavix 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, Plavix 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

2.1 Acute Coronary Syndrome

Plavix can be administered with or without food [see Clinical Pharmacology (12.3)]

• For patients with non-ST-elevation ACS (UA/NSTEMI), initiate Plavix with a single 300 mg oral loading dose and then continue at 75 mg once daily. Initiate aspirin (75–325 mg once daily) and continue in combination with Plavix [see Clinical Studies (14.1)].
• For patients with STEMI, the recommended dose of Plavix is 75 mg once daily orally, administered in combination with aspirin (75–325 mg once daily), with or without thrombolytics. Plavix 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 Plavix 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 (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response [see Clinical Pharmacology (12.5)], an appropriate dose regimen for this patient population has not been established in clinical outcome trials.

3 DOSAGE FORMS AND STRENGTHS

• 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with "75" on one side and "1171" on the other
• 300 mg tablets: Pink, oblong, film-coated tablets debossed with "300" on one side and "1332" on the other

4 CONTRAINDICATIONS

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)].

5 WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is entirely due to 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. Avoid concomitant use of Plavix and drugs that inhibit CYP2C19 activity. Co-administration of Plavix with omeprazole, a proton pump inhibitor that is an inhibitor of CYP2C19, reduces the pharmacological activity of Plavix if given concomitantly or if given 12 hours apart [see Drug Interactions (7.1)].

5.2 General Risk of Bleeding

Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 5 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% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for Plavix + 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 Plavix

Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as possible. Premature discontinuation of Plavix 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 Plavix has not been shown to be more effective than Plavix 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 Plavix, 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)].

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed below and el