PLAVIX — clopidogrel bisulfate tablet, film coated
Physicians Total Care, Inc.
The effectiveness of Plavix is dependent on its activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1)]. Plavix 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 Plavix 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)].
- 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.
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.
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)].
The recommended daily dose of Plavix is 75 mg once daily orally, with or without food [see Clinical Pharmacology (12.3)].
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.
Avoid using omeprazole or esomeprazole with Plavix. Omeprazole and esomeprazole significantly reduce the antiplatelet activity of Plavix. 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)].
- 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
Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Plavix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)].
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 Plavix with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Plavix [see Drug Interactions (7.1) and Dosage and Administration (2.4)].
Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue Plavix 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% 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.
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.
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.
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)].
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)]
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 1 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.
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.
|Event||Plavix (+ aspirin)*||Placebo (+ aspirin)*|
|Major bleeding †||3.7 ‡||2.7 §|
|5 g/dL hemoglobin drop||0.9||0.9|
|Requiring surgical intervention||0.7||0.7|
|Requiring transfusion (≥4 units)||1.2||1.0|
|Other major bleeding||1.6||1.0|
|Intraocular bleeding with significant loss of vision||0.05||0.03|
|Requiring 2–3 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.
In COMMIT, similar rates of major bleeding were observed in the Plavix and placebo groups, both of which also received aspirin (see Table 2).
|Type of bleeding||Plavix(+ aspirin)(n=22961)||Placebo(+ aspirin)(n=22891)||p-value|
|Major * noncerebral or cerebral bleeding †||0.6||0.5||0.59|
|Other noncerebral bleeding (non-major)||3.6||3.1||0.005|
|Any noncerebral bleeding||3.9||3.4||0.004|
CAPRIE (Plavix vs. Aspirin)
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Plavix 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 Plavix compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the Plavix group were epistaxis and hematoma.
Other Adverse Events
In CURE and CHARISMA, which compared Plavix plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Plavix and placebo.
In CAPRIE, which compared Plavix to aspirin, pruritus was more frequently reported in those taking Plavix. No other difference in the rate of adverse events (other than bleeding) was reported.
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