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PLAVIX
clopidogrel bisulfate tablets
DESCRIPTION
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(4 H )-acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C 16 H 16 ClNO 2 S•H 2 SO 4 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 either 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 or pink, oblong, debossed film-coated tablets containing 391.5 mg of clopidogrel bisulfate which is the molar equivalent of 300 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.
CLINICAL PHARMACOLOGY
Mechanism of Action and Pharmacodynamic Properties Clopidogrel is a prodrug, one of whose metabolites 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 platelet function can reduce the event rate.
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Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible. Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
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.
Pharmacokinetics Absorption : After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Effect of Food : The effect of food on the bioavailability of the parent compound or active metabolite is currently not known.
Distribution : Clopidogrel and the main circulating inactive metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 mcg/mL.
Metabolism: Clopidogrel is extensively metabolized by the liver. In vitro and in viv o, clopidogrel is metabolized according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Cytochromes first oxidize clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2 oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. In vitro , this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
Elimination : Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post
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thrombosis compared to extensive metabolizers. In the fifth cohort study (n=2,208; Simon^7 ), the increased event rate was observed only in poor metabolizers.
(^1) Mega JL, Thakuria JV, Cannon CP, Sabatine MS. Sequence variations in CYP metabolism genes and
cardiovascular outcomes following treatment with clopidogrel: insights from the CLARITY-TIMI 28 genomic study. 2008; ACC Meeting Abstract (^2) Mega et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med 2009; 360:354- (^3) Trenk et al. Cytochrome P450 2C19 681G>A polymorphism and high on-clopidogrel platelet reactivity associated
with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol 2008; 51, 20: 1952 (^4) Collet JP et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial
infarction: a cohort study. The Lancet 2009; 373: 309- (^5) Sibbing D et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following
percutaneous coronary intervention. Eur Heart J 2009:1- (^6) Giusti et al. Relation of cytochrome P450 2C19 loss-of-function polymorphism to occurrence of drug-eluting
coronary stent thrombosis. Am J Cardiol 2009; 103:806– (^7) Simon et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med 2009;
360(4):363-
Pharmacogenetic testing can identify genotypes associated with variability in CYP2C19 activity.
There may be genetic variants of other CYP450 enzymes with effects on the ability to form clopidogrel’s active metabolite.
Special Populations The pharmacokinetics of clopidogrel’s active metabolite is not known in these special populations.
Geriatric Patients : In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Renally-Impaired Patients: After repeated doses of 75 mg Plavix per day in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min), inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers; however, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of Plavix per day.
Hepatically-Impaired Patients: After repeated doses of 75 mg Plavix per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.
Gender : In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
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Race : The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C metabolism differs according to race/ethnicity (see C LINICAL PHARMACOLOGY: Pharmacogenetics ).
CLINICAL STUDIES
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).
Recent Myocardial Infarction (MI), Recent Stroke or Established Peripheral Arterial Disease 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.
Table 2: Outcome Events in the CAPRIE Primary Analysis Plavix aspirin Patients 9599 9586 IS (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%) 1020 (10.6%)
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.
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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 3).
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 3).
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.
Table 3: Outcome Events in the CURE Primary Analysis Outcome Plavix Placebo Relative Risk (+ aspirin)* (+ aspirin)* Reduction (%) (95% CI) (n=6259) (n=6303)
Primary outcome 582 (9.3%) 719 (11.4%) 20% (Cardiovascular death, MI, Stroke)
P=0.
Co-primary outcome (^1035) (16.5%) 1187 (18.8%) 14% (Cardiovascular death, MI, Stroke, Refractory Ischemia) (6.2, 20.6) P=0.
All Individual Outcome Events:†
CV death 318 (5.1%) 345 (5.5%) 7% (-7.7, 20.6) MI 324 (5.2%) 419 (6.6%) 23% (11.0, 33.4) Stroke 75 (1.2%) 87 (1.4%) 14% (-17.7, 36.6)
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Refractory ischemia 544 (8.7%) 587 (9.3%) 7% (-4.0, 18.0)
- Other standard therapies were used as appropriate. † The individual components do not represent a breakdown of the primary and co-primary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
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.
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The randomized, double-blind, placebo-controlled, 2x2 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, 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 4 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).
Table 4: Outcome Events in the COMMIT Analysis Event Plavix (+ aspirin) (N=22961)
Placebo (+ aspirin) (N=22891)
Odds ratio (95% CI)
p-value
*Composite endpoint: Death, MI, or Stroke ^ 2121 (9.2%) 2310 (10.1%) 0.91 (0.86, 0.97) 0. Death Non-fatal MI Non-fatal Stroke
*The difference between the composite endpoint and the sum of death+non-fatal MI+non-fatal stroke indicates that 9
patients (2 clopidogrel and 7 placebo) suffered both a non-fatal stroke and a non-fatal MI. ** (^) Non-fatal MI and non-fatal stroke exclude patients who died (of any cause).
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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
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Figure 7: Effects of Adding PLAVIX to Aspirin in the 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 angiography, 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 fibrinolytics (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.
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Table 5: Event Rates for the Primary Composite Endpoint in the CLARITY Study
Clopidogrel 1752
Placebo 1739
OR 95% CI
Number (%) of patients reporting the composite endpoint 262 (15.0%) 377 (21.7%) 0.64 0.53, 0. Occluded IRA N (subjects undergoing angiography) n (%) patients reporting endpoint
Death n (%) patients reporting endpoint 45 (2.6%) 38 (2.2%) 1.18 0.76, 1. Recurrent MI n (%) patients reporting endpoint 44 (2.5%) 62 (3.6%) 0.69 0.47, 1. *The total number of patients with a component event (occluded IRA, death, or recurrent MI) is greater than the number of patients with a composite event because some patients had more than a single type of component event.
INDICATIONS AND USAGE
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.
CONTRAINDICATIONS
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.
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Use in Hepatically-Impaired Patients : Experience is limited in patients with severe hepatic disease, who may have bleeding diatheses. Plavix should be used with caution in this population.
Use in Renally-Impaired Patients : Experience is limited in patients with severe renal impairment. Plavix should be used with caution in this population.
Information for Patients Patients should be told that while taking Plavix or Plavix combined with aspirin:
- it may take them longer than usual to stop bleeding;
- they may bruise and/or bleed more easily;
- they should report any unusual bleeding to their physician;
- they should tell their physician about any other medications they are taking, including prescription or over-the-counter omeprazole;
- they should inform physicians and dentists that they are taking Plavix and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.
Drug Interactions 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. Avoid concomitant use of drugs that inhibit CYP2C19, including omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine (see WARNINGS ).
Studies of specific drug interactions yielded the following results:
Omeprazole : In a crossover clinical study, 72 healthy subjects were administered Plavix (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as Plavix) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 46% (Day 1) and 42% (Day 5) when Plavix and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) was diminished by 47% (24 hours) and 30% (Day 5) when Plavix and omeprazole were administered together. In another study 72 healthy subjects were given the same doses of Plavix and omeprazole but the drugs were administered 12 hours apart; the results were similar indicating that administering Plavix and omeprazole at different times does not prevent their interaction (see WARNINGS ).
Aspirin : Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by Plavix. Plavix potentiated the effect of aspirin on collagen-induced platelet aggregation. Plavix and aspirin have been administered together for up to one year.
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Heparin : In a study in healthy volunteers, Plavix did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by Plavix.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) : In healthy volunteers receiving naproxen, concomitant administration of Plavix was associated with increased occult gastrointestinal blood loss. NSAIDs and Plavix should be coadministered with caution.
Warfarin : Because of the increased risk of bleeding, the concomitant administration of warfarin with Plavix should be undertaken with caution (See PRECAUTIONS: General ).
Other Concomitant Therapy : No clinically significant pharmacodynamic interactions were observed when PLAVIX was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of Plavix was also not significantly influenced by the coadministration of phenobarbital or estrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the coadministration of Plavix (clopidogrel bisulfate).
At high concentrations in vitro , clopidogrel inhibits P 450 (2C9). Accordingly, Plavix may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with Plavix.
In addition to the above specific interaction studies, patients entered into clinical trials with Plavix received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (including insulin ) , thrombolytics, heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence of clinically significant adverse interactions.
There are no data on the concomitant use of oral anticoagulants, non study oral anti-platelet drugs and chronic NSAIDs with clopidogrel.
Drug/Laboratory Test Interactions None known.
Carcinogenesis, Mutagenesis, Impairment of Fertility There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures
25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
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corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Plavix compared to 0.5% for aspirin.
In CURE, Plavix use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 6). There was an excess in major bleeding in patients receiving Plavix plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidence of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%), were the same in both groups.
The overall incidence of bleeding is described in Table 6 for patients receiving both Plavix and aspirin in CURE.
Table 6: CURE Incidence of bleeding complications (% patients)
Event Plavix Placebo P-value (+ aspirin)* (+ aspirin)* (n=6259) (n=6303) Major bleeding † 3.7 ‡ 2.7 § 0.
Life-threatening bleeding 2.2 1.8 0. Fatal 0.2 0. 5 g/dL hemoglobin drop 0.9 0. Requiring surgical intervention 0.7 0. Hemorrhagic strokes 0.1 0. Requiring inotropes 0.5 0. Requiring transfusion (≥4 units) 1.2^ 1. Other major bleeding 1.6 1.0 0. Significantly disabling 0.4 0. Intraocular bleeding with 0.05 0. significant loss of vision Requiring 2-3 units of blood 1.3 0.
Minor bleeding ¶ 5.1 2.4 (^) <0.
*Other standard therapies were used as appropriate. †Life threatening and other major bleeding. ‡Major bleeding event rate for Plavix + aspirin was dose-dependent on aspirin: <100 mg=2.6%; 100-200 mg= 3.5%;
200 mg=4.9% Major bleeding event rates for PLAVIX + aspirin by age were: <65 years = 2.5%, ≥65 to <75 years = 4.1%, ≥ 75 years = 5.9% §Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: <100 mg=2.0%; 100-200 mg= 2.3%; >200 mg=4.0% Major bleeding event rates for placebo + aspirin by age were: <65 years = 2.1%, ≥65 to <75 years = 3.1%, ≥75 years = 3.6% ¶Led to interruption of study medication.
Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results.
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There was no excess in major bleeds within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for Plavix + aspirin, and 6.3% for placebo + aspirin.
In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin > 5 g/dL) was similar between groups (1.3% versus 1.1% in the Plavix + aspirin and in the placebo + aspirin groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the Plavix + aspirin and in the placebo + aspirin groups, respectively) and intracranial hemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups.
The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 7 below.
Table 7: Number (%) of Patients with Bleeding Events in COMMIT Type of bleeding Plavix (+ aspirin) (N=22961)
Placebo (+ aspirin) (N=22891)
P-value
Major* noncerebral or cerebral bleeding** Major noncerebral Fatal Hemorrhagic stroke Fatal
Other noncerebral bleeding (non-major) 831 (3.6%) 721 (3.1%) 0. Any noncerebral bleeding 896 (3.9%) 777 (3.4%) 0.
- Major bleeds are cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion. ** The relative rate of major noncerebral or cerebral bleeding was independent of age. Event rates for Plavix + aspirin by age were: <60 years = 0.3%, ≥60 to <70 years = 0.7%, ≥70 years = 0.8%. Event rates for placebo + aspirin by age were: <60 years = 0.4%, ≥60 to <70 years = 0.6%, ≥70 years = 0.7%.
Adverse events occurring in ≥2.5% of patients on Plavix in the CAPRIE controlled clinical trial are shown below regardless of relationship to Plavix. The median duration of therapy was 20 months, with a maximum of 3 years.
Table 8: Adverse Events Occurring in ≥ 2.5% of Plavix Patients in CAPRIE % Incidence (% Discontinuation) Body System Plavix Aspirin Event [n=9599] [n=9586] Body as a Whole – general disorders Chest Pain 8.3 (0.2) 8.3 (0.3) Accidental/Inflicted Injury 7.9 (0.1) 7.3 (0.1)
