PLAVIX®
clopidogrel bisulfate tablets

PLAVIX (clopidogrel bisulfate) is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Chemically it is methyl (+)-(S)-α-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C₁₆H₁₆ClNO₂S•H₂SO₄ 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°.

PLAVIX for oral administration is provided as pink, round, biconvex, debossed film-coated tablets containing 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.

Each tablet contains hydrogenated castor oil, hydroxypropylcellulose, mannitol, microcrystalline cellulose and polyethylene glycol 6000 as inactive ingredients. The pink film coating contains ferric oxide, hypromellose 2910, lactose monohydrate, titanium dioxide and triacetin. The tablets are polished with Carnauba wax.

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.

Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of PLAVIX. Repeated doses of 75 mg PLAVIX per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg PLAVIX per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma.

Following an oral dose of ¹⁴C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.

The clinical evidence for the efficacy of PLAVIX is derived from four double-blind trials involving 81,090 patients: the CAPRIE study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events), a comparison of PLAVIX to aspirin, and the CURE (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), the COMMIT/CCS-2 (Clopidogrel and Metoprolol in Myocardial Infarction Trial / Second Chinese Cardiac Study) studies comparing PLAVIX to placebo, both given in combination with aspirin and other standard therapy and CLARITY-TIMI 28 (Clopidogrel as Adjunctive Reperfusion Therapy – Thrombolysis in Myocardial Infarction).

The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing PLAVIX (75 mg daily) to aspirin (325 mg daily). The patients randomized had: 1) recent histories of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; or 3) objectively established peripheral arterial disease. Patients received randomized treatment for an average of 1.6 years (maximum of 3 years).

The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular.

As shown in the table, PLAVIX (clopidogrel bisulfate) was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.8% vs. 10.6%) was 8.7%, P=0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the PLAVIX group.

The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure 1: Fatal or Non-Fatal Vascular Events in the CAPRIE Study

Although the statistical significance favoring PLAVIX over aspirin was marginal (P=0.045), and represents the result of a single trial that has not been replicated, the comparator drug, aspirin, is itself effective (vs. placebo) in reducing cardiovascular events in patients with recent myocardial infarction or stroke. Thus, the difference between PLAVIX and placebo, although not measured directly, is substantial.

The CAPRIE trial included a population that was randomized on the basis of 3 entry criteria. The efficacy of PLAVIX relative to aspirin was heterogeneous across these randomized subgroups (P=0.043). It is not clear whether this difference is real or a chance occurrence. Although the CAPRIE trial was not designed to evaluate the relative benefit of PLAVIX over aspirin in the individual patient subgroups, the benefit appeared to be strongest in patients who were enrolled because of peripheral vascular disease (especially those who also had a history of myocardial infarction) and weaker in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, PLAVIX was not numerically superior to aspirin.

In the meta-analyses of studies of aspirin vs. placebo in patients similar to those in CAPRIE, aspirin was associated with a reduced incidence of thrombotic events. There was a suggestion of heterogeneity in these studies too, with the effect strongest in patients with a history of myocardial infarction, weaker in patients with a history of stroke, and not discernible in patients with a history of peripheral vascular disease. With respect to the inferred comparison of PLAVIX to placebo, there is no indication of heterogeneity.

The CURE study included 12,562 patients with acute coronary syndrome without ST segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia. Patients were required to have either ECG changes compatible with new ischemia (without ST segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. The patient population was largely Caucasian (82%) and included 38% women, and 52% patients ≥65 years of age.

Patients were randomized to receive PLAVIX (300 mg loading dose followed by 75 mg/day) or placebo, and were treated for up to one year. Patients also received aspirin (75–325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the PLAVIX-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%–28%; p=0.00009) for the PLAVIX-treated group (see Table 2).

At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the PLAVIX-treated group and 1187 (18.83%) in the placebo-treated group, a 14% relative risk reduction (95% CI of 6%–21%, p=0.0005) for the PLAVIX-treated group (see Table 2).

In the PLAVIX-treated group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo-treated group.

The benefits of PLAVIX (clopidogrel bisulfate) were maintained throughout the course of the trial (up to 12 months).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study

In CURE, the use of PLAVIX was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics, as shown in Figure 3. The benefits associated with PLAVIX were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of PLAVIX was observed independently of the dose of aspirin (75–325 mg once daily). The use of oral anticoagulants, non-study anti-platelet drugs and chronic NSAIDs was not allowed in CURE.

Figure 3. Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study

The use of PLAVIX in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the PLAVIX group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%, P=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the PLAVIX group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%, P=0.003). The use of PLAVIX in CURE did not impact the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the PLAVIX group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%, P=0.1658).

In patients with ST-segment elevation acute myocardial infarction, the safety and efficacy of clopidogrel have been evaluated in two randomized, placebo-controlled, double-blind studies, COMMIT- a large outcome study conducted in China - and CLARITY- a supportive study with a surrogate endpoint conducted internationally.

The randomized, double-blind, placebo-controlled, 2×2 factorial design COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected myocardial infarction with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients were randomized to receive PLAVIX (75 mg/day) or placebo, in combination with aspirin (162 mg/day), for 28 days or until hospital discharge whichever came first.

The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population included 28% women and 58% patients ≥60 years (26% patients ≥70 years) and 55% patients who received thrombolytics, 68% received ace-inhibitors, and only 3% had percutaneous coronary intervention (PCI).

As shown in Table 3 and Figures 4 and 5 below, PLAVIX significantly reduced the relative risk of death from any cause by 7% (p = 0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p = 0.002).

Figure 4: Cumulative Event Rates for Death in the COMMIT Study*

*All treated patients received aspirin.

Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study*

*All treated patients received aspirin.

The effect of PLAVIX did not differ significantly in various pre-specified subgroups as shown in Figure 6. Additionally, the effect was similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history (see Figure 7). Such subgroup analyses should be interpreted very cautiously.

Figure 6: Effects of Adding PLAVIX to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study

*Three similar-sized prognostic index groups were based on absolute risk of primary composite outcome for each patient, calculated from baseline prognostic variables (excluding allocated treatments) with a Cox regression model.

Figure 7: Effects of Adding PLAVIX to Aspirin in Non-Prespecified Subgroups in the COMMIT Study

The randomized, double-blind, placebo-controlled CLARITY trial included 3,491 patients, 5% U.S., presenting within 12 hours of the onset of a ST-elevation myocardial infarction and planned for thrombolytic therapy. Patients were randomized to receive PLAVIX (300-mg loading dose, followed by 75 mg/day) or placebo until angioplasty, discharge, or Day 8. Patients also received aspirin (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day), a fibrinolytic agent and, when appropriate, heparin for 48 hours.The patients were followed for 30 days.

The primary endpoint was the occurrence of the composite of an occluded infarct-related artery (defined as TIMI Flow Grade 0 or 1) on the predischarge angiogram, or death or recurrent myocardial infarction by the time of the start of coronary angiography.

The patient population was mostly Caucasian (89.5%) and included 19.7% women and 29.2% patients ≥65 years. A total of 99.7% of patients received thrombolytics (fibrin specific: 68.7%, non- fibrin specific: 31.1%), 89.5% heparin, 78.7% beta-blockers, 54.7% ACE inhibitors and 63% statins.

The number of patients who reached the primary endpoint was 262 (15.0%) in the PLAVIX-treated group and 377 (21.7%) in the placebo group,but most of the events related to the surrogate endpoint of vessel patency.

PLAVIX (clopidogrel bisulfate) is indicated for the reduction of atherothrombotic events as follows:

• 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.

• Acute Coronary Syndrome

  For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or CABG, PLAVIX has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI, or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
   

  For patients with ST-segment elevation acute myocardial infarction, 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. This benefit is not known to pertain to patients who receive primary angioplasty.

The use of PLAVIX is contraindicated in the following conditions:

• Hypersensitivity to the drug substance or any component of the product.
• Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

Thrombotic thrombocytopenic purpura (TTP):

TTP has been reported rarely following use of PLAVIX, sometimes after a short exposure (<2 weeks). TTP is a serious condition that can be fatal and 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.)

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