Clopidogrel Bisulfate (Page 6 of 8)

14.2 Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial Disease

CAPRIE

The CAPRIE trial was a 19,185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel bisulfate (75 mg daily) to aspirin (325 mg daily). To be eligible to enroll, patients had to have: 1) recent history of myocardial infarction (within 35 days); 2) recent histories of ischemic stroke (within 6 months) with at least a week of residual neurological signs; and/or 3) established peripheral arterial disease (PAD). 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.

Table 6: Outcome Events in the CAPRIE Primary Analysis

Patients

Clopidogrel bisulfate

Aspirin

n=9,599

n=9,586

Ischemic stroke (fatal or not)

438 (4.6%)

461 (4.8%)

MI (fatal or not)

275 (2.9%)

333 (3.5%)

Other vascular death

226 (2.4%)

226 (2.4%)

Total

939 (9.8%)

1,020 (10.6%)

As shown in Table 6, clopidogrel bisulfate was associated with a lower incidence of outcome events, primarily MI. The overall relative 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 lower in the clopidogrel bisulfate group.

The curves showing the overall event rate are shown in Figure 7. The event curves separated early and continued to diverge over the 3-year follow-up period.

Figure7:FatalorNonfatalVascularEventsintheCAPRIEStudy

fig 8
(click image for full-size original)

The statistical significance favoring clopidogrel bisulfate over aspirin was marginal (p=0.045). However, because aspirin is itself effective in reducing cardiovascular events in patients with recent myocardial infarction or stroke, the effect of clopidogrel bisulfate is substantial.

The CAPRIE trial enrolled a population that had recent MI, recent stroke, or PAD. The efficacy of clopidogrel bisulfate relative to aspirin was heterogeneous across these subgroups (p=0.043) (see Figure 8). Nonetheless, this difference may be a chance occurrence because the CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel bisulfate over aspirin in the individual patient subgroups. The benefit was most apparent in patients who were enrolled because of peripheral arterial disease and less apparent in stroke patients. In patients who were enrolled in the trial on the sole basis of a recent myocardial infarction, clopidogrel bisulfate was not numerically superior to aspirin.

Figure 8: Hazard Ratio and 95% CI by Baseline Subgroups in the CAPRIE Study

fig 5
(click image for full-size original)

14.3 No Demonstrated Benefit of clopidogrel bisulfate plus Aspirin in Patients with Multiple Risk Factors or Established Vascular Disease

CHARISMA

The CHARISMA trial was a 15,603 subject, randomized, double-blind, parallel group study comparing clopidogrel bisulfate (75 mg daily) to placebo for prevention of ischemic events in patients with vascular disease or multiple risk factors for atherosclerosis. All subjects were treated with aspirin 75 to 162 mg daily. The mean duration of treatment was 23 months. The study failed to demonstrate a reduction in the occurrence of the primary endpoint, a composite of CV death, MI, or stroke. A total of 534 (6.9%) patients in the clopidogrel bisulfate group versus 573 (7.4%) patients in the placebo group experienced a primary outcome event (p=0.22). Bleeding of all severities was more common in the subjects randomized to clopidogrel bisulfate.

16 HOW SUPPLIED/STORAGE AND HANDLING

Clopidogrel tablets, USP 75mg are available as light pink colored, round, beveled edge, biconvex film coated tablets printed “41” with black ink on one side and plain on the other side. Tablets are provided as follows:

Cartons of 100 Tablets (1 tablets each blister pack x 10), NDC 0904-6294-61

Store at 20° to 25° C (68° to 77° F); excursions permitted to 15° to 30° C (59° to 86° F) [See USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Advise patients to read FDA approved patient labeling (Medication Guide).

Discontinuation

Advise patients not to discontinue clopidogrel tablets without first discussing it with the health care provider who prescribed it [see Warnings and Precautions ( 5.3)] .

Bleeding

Advise patients that they:

will bruise and bleed more easily
will take longer than usual to stop bleeding
must report any unanticipated, prolonged, or excessive bleeding, or blood in their stool or urine [see Warnings and Precautions ( 5.2)] .

Thrombotic Thrombocytopenic Purpura

Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot otherwise be explained [see Warnings and Precautions ( 5.4)] .

Invasive Procedures

Advise patients to inform physicians and dentists that they are taking clopidogrel tablets before any surgery or dental procedure [see Warnings and Precautions ( 5.2, 5.3)] .

Proton Pump Inhibitors

Advise patients not to take omeprazole or esomeprazole while taking clopidogrel tablets. Dexlansoprazole, lansoprazole, and pantoprazole had less pronounced effects on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole [see Drug Interactions ( 7.1)] .

fig6

Manufactured by:

TORRENT PHARMACEUTICALS LTD., INDIA.

Manufactured for:

TORRENT PHARMA INC., Basking Ridge, NJ 07920

Distributed By:

MAJOR® PHARMACEUTICALS

Livonia, MI 48152

Refer to package label for Distributor’s NDC Number

8081783 Revised March 2021

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