Platelet Aggregation Inhibitor
Action And Clinical Pharmacology: Mechanism of Action: The role of platelets in the pathophysiology of atherosclerotic disease and thrombotic events has been established. Long-term prophylactic use of antiplatelet drugs has shown consistent benefit in the prevention of ischemic stroke, myocardial infarction and vascular death in patients at increased risk of such outcomes, including those with established atherosclerosis or a history of atherothrombosis. Clopidogrel is a specific inhibitor of ADP-induced platelet aggregation.
Pharmacodynamics: Clopidogrel inhibits selectively the binding of adenosine-diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the GPIIb-IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation. An active metabolite responsible for the activity of the drug has not been identified. Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.
Clopidogrel acts by modifying irreversibly the platelet ADP receptor. Consequently, platelets exposed to a single dose of clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover (approximately 7 days). Single administration is not sufficient to reach a desired therapeutic effect.
Statistically significant and dose-dependent inhibition of platelet aggregation was noted 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg/day produced inhibition of ADP-induced platelet aggregation from the first day. Steady state was reached between Day 3 and Day 7. At steady state, with a dose of 75 mg/day, the average inhibition level observed was between 40 and 60%. The aggregation level and bleeding time gradually returned to baseline values within 5 to 7 days after treatment was discontinued. The precise correlation between inhibition of platelet aggregation, prolongation of bleeding time and prevention of atherothrombotic events has not been established.
Pharmacokinetics and Metabolism: Following repeated 75 mg oral doses of clopidogrel (base), plasma concentrations of the parent compound are very low and generally below the quantification limit (0.00025 mg/mL) beyond 2 hours after dosing. Clopidogrel is extensively metabolised by the liver to an unknown pharmacodynamically active chemical moiety. The main circulating metabolite (the carboxylic acid derivative), is inactive and represents about 85% of the circulating metabolites in plasma. The relationship between platelet aggregation and the concentration of the main circulating metabolite has not been established.
Clopidogrel is rapidly absorbed after oral administration of repeated 75 mg clopidogrel (base), with peak plasma levels (approx. 3 mg/L) of the main circulating metabolite occurring at approximately 1 hour after dosing. The pharmacokinetics of the carboxylic acid metabolite are linear (plasma concentrations increase in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50%, based on urinary excretion of clopidogrel-related metabolites.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is non saturable in vitro up to a concentration of 100 Âµg/mL.
Following an oral dose of 4-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 the radiolabel with a half-life of 11 days.
Administration of clopidogrel with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.
Special Populations: Geriatric Patients: Although plasma concentrations of the main circulating metabolite are significantly higher in elderly (Â³75 years) as compared to young healthy subjects, there were no differences in platelet aggregation and bleeding time (see Dosage).
Patients with Renal Impairment: After repeated doses of 75 mg/day, plasma levels of the main circulating metabolite were significantly lower in subjects with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min). Since no differences in Cmax, for both clopidogrel and the main circulating metabolite were observed, a compensatory phenomenon, i.e., biliary excretion, which has been observed in animals, may explain the lower values of AUC observed in subjects with severe chronic renal failure. The inhibition of ADP-induced platelet aggregation was lower (25%) than what was observed in healthy subjects in other clinical studies (see Dosage).
Sex Differences: No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women (n=10 males and 10 females), less inhibition of ADP-induced platelet aggregation was observed in women. In the CAPRIE study (for details see below), the incidence of clinical outcome events was similar in men and women.
Clinical Studies: The safety and efficacy of clopidogrel in preventing atherothrombotic events has been evaluated in a blinded comparison with ASA (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events; CAPRIE). This was a 19 185-patient, 304-center, international, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg daily) ASA (325 mg daily). Patients ranged in age from 21 to 94 years (mean 62 years). The study was composed of 72.4% men and 27.6% women and included patients with established atherosclerosis or history of atherothrombosis as manifested by myocardial infarction, ischemic stroke or peripheral arterial disease. Patients received randomized treatment for up to 3 years (mean treatment period 1.6 years) and were followed to 3 years or study termination, irrespective of whether study drug had been discontinued (mean follow-up 1.9 years).
The primary outcome of the trial was an intent to treat analysis of 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.
Clopidogrel was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.78% vs. 10.64%) 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 clopidogrel group.
The CAPRIE trial was not designed to evaluate the relative benefit of clopidogrel in the individual patient subgroups. The benefit appeared to be strongest in patients who were enrolled because of peripheral arterial disease (PAD), followed by patients with stroke and then those with recent myocardial infarction.
An on-treatment efficacy analysis was also performed in which clopidogrel demonstrated a significant relative risk reduction in the overall event rate compared to ASA of 9.4% (p=0.046). The event curves separated early and continued to diverge over the 3-year, follow-up period.
Indications And Clinical Uses: For the secondary prevention of vascular ischemic events (myocardial infarction, stroke, vascular death) in patients with a history of symptomatic atherosclerotic disease.
Contra-Indications: Hypersensitivity to the drug substance or any component of the product. Active bleeding such as peptic ulcer and intracranial hemorrhage. Significant liver impairment or cholestatic jaundice.
Manufacturers’ Warnings In Clinical States: Active Gastrointestinal Lesions: Clopidogrel prolongs bleeding time. Although clopidogrel has shown a lower incidence of gastrointestinal bleeding compared to ASA in a large controlled clinical trial (CAPRIE), clopidogrel should not be used in patients who have lesions with a propensity to bleed (such as ulcers). In patients taking clopidogrel, drugs that might induce such lesions (such as ASA and NSAIDs) should only be used under medical supervision, after carefully assessing the risks.
Anticoagulant Drugs: In view of the possible increased risk of bleeding, anticoagulant drugs should be used with caution as tolerance and safety of simultaneous administration with clopidogrel has not been established (See Precautions, Drug interactions). Risk factors should be assessed for individual patients before using clopidogrel.
The safety of the coadministration of clopidogrel with warfarin has not been established. Consequently, concomitant administration of these two agents should be undertaken with caution.
Pregnancy: There are no adequate and well-controlled studies in pregnant women.
Reproduction studies have been performed in rats at doses up to 500 mg/kg/day and in rabbits at doses up to 300 mg/kg/day and have revealed no evidence of impaired fertility or harm to the fetus due to clopidogrel. Because animal reproduction studies are not always predictive of a human response, clopidogrel should be used during pregnancy only if the potential benefits outweigh the potential risks to the fetus.
Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in milk. Therefore, clopidogrel should not be used by lactating women.
Children: Safety and effectiveness in subjects below the age of 18 have not been established.
Precautions: General: As with other antiplatelet agents, when considering prescribing clopidogrel, physicians should inquire whether the patient has a history of bleeding. Clopidogrel should be used with caution in patients who may be at risk of increased bleeding from recent trauma, surgery or other pathological condition(s). If a patient is to undergo elective surgery, consideration should be given to discontinue clopidogrel 7 days prior to surgery to allow for the reversal of the effect.
Platelet transfusion may be used to reverse the pharmacological effects of clopidogrel when quick reversal is required.
Patients with Renal Impairment: Therapeutic experience with clopidogrel is limited in patients with severe and moderate renal impairment. Therefore clopidogrel should be used with caution in these patients.
Patients with Hepatic Impairment: Experience is limited in patients with moderate hepatic impairment who may have bleeding diatheses. As with any patient exhibiting hepatic impairment, liver function should be carefully monitored and clopidogrel should be used with caution.
In the CAPRIE study, there were 344 hepatically impaired patients (Alkaline phosphatase >300 U/l, or ALT>120 U/l, or AST>75 U/l) and 168 received clopidogrel for a mean duration of 18 months. The adverse events were more common in this population, compared to the rest of the CAPRIE population, and more common in the clopidogrel (n=168) than in the ASA (n=176) group (any bleeding disorders, n=17 vs n=14; any rash, n=11 vs n=6; diarrhea, n=8 vs n=3, respectively).
Drug Interactions: Study of specific drug interactions yielded the following results.
ASA: ASA (2´500 mg once) did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. The safety of chronic concomitant administration of ASA and clopidogrel has not been established.
NSAIDs: The short-term concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss in a clinical study conducted in healthy volunteers. Consequently, there is a potential increased risk of gastrointestinal bleeding (See Warnings).
Heparin: Clopidogrel did not modify the effect of heparin on coagulation in a clinical study conducted in healthy volunteers. Coadministration of heparin had no effect on platelet aggregation inhibition induced by clopidogrel. However, the safety of this combination has not been established (See Warnings).
Warfarin: The safety of the coadministration of clopidogrel with warfarin has not been established. Consequently, concomitant administration of these two agents should be undertaken with caution (See Warnings).
Digoxin, Theophylline, Antacids: There was no modification of the pharmacokinetics of digoxin or theophylline with the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Other: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered in clinical studies to investigate drug interaction with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of clopidogrel was slightly enhanced by the coadministration of phenobarbital, however this was not considered to be clinically significant. Pharmacodynamic activity of clopidogrel was not changed with the coadministration of cimetidine. Pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of estrogen.
Clinically significant adverse interactions were not detected in the CAPRIE study where patients received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, coronary vasodilators, antidiabetic agents, antiepileptic agents and hormone replacement therapy. Patients on HMG CoA reductase inhibitors and clopidogrel experienced a higher incidence of bleeding events (primarily epistaxis). There is no known pathophysiological or pharmacological explanation for this observation. Patients on HMG CoA reductase inhibitors and ASA experienced a higher incidence of intracranial hemorrhage.
At high concentrations in vitro, clopidogrel inhibits cytochrome P450 (2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many nonsteroidal anti-inflammatory agents. 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 clopidogrel.
Laboratory Test Interactions : None known.
Information to be Provided to the Patient: Patients should be informed that it may take longer than usual to stop bleeding when they take clopidogrel, and that they should report any unusual and prolonged bleeding to their physician before starting and during clopidogrel therapy. Patients should be told to inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is prescribed.
Adverse Reactions: Clopidogrel has been evaluated for safety in more than 11 300 patients, including over 7 000 patients treated for 1 year or more. Clopidogrel was well tolerated compared to ASA in a large controlled clinical trial (CAPRIE). The overall tolerability of clopidogrel was similar regardless of age, gender and race. However, in women there was a slightly higher incidence of bleeding disorders, primarily epistaxis, in the clopidogrel group (11.36% vs 9.88%).
A summary of selected adverse effects, regardless of incidence observed in CAPRIE are presented in Table II. In CAPRIE, patients with a known intolerance to ASA were excluded from the study.
The following rare events were reported in CAPRIE although there was no difference in the incidence between clopidogrel and ASA. Clopidogrel was not associated with an increase in the incidence of thrombocytopenia and neutropenia.
White Cell Disorders: Granulocytopenia
Platelet, Bleeding and Clotting Disorders: One case of Henoch-Schonlein purpura (acute visceral symptoms: vomiting, diarrhea, abdominal distension, hematuria, renal colic) was reported in a patient taking clopidogrel. The patient recovered without sequelae within 1 month.
Skin Disorders: There was no notable difference between treatment groups in the incidence of bullous eruptions (0.23% clopidogrel versus 0.16% ASA). One case of a severe bullous eruption was reported in a patient taking clopidogrel.
Allergic Disorders: Three anaphylactic reactions were reported, 2 in the clopidogrel group and 1 in the ASA group. The patients recovered without sequelae. No anaphylactic shock was reported in either treatment group.
Symptoms And Treatment Of Overdose: Symptoms: One case of deliberate overdosage with clopidogrel was reported: a 34 year old woman took a single 1 050 mg dose of clopidogrel (equivalent to 14 standard 75 mg tablets). There were no associated adverse events. No special therapy was instituted, and she recovered without sequelae.
No adverse reactions were reported after single oral administration of 600 mg (equivalent to 8 standard 75 mg tablets) of clopidogrel in healthy volunteers. The bleeding time was prolonged by a factor of 1.7, which is similar to that typically observed with the therapeutic dose of 75 mg/day.
A single oral dose of clopidogrel at 1 500 or 2 000 mg/kg was lethal to mice and rats, and at 3 000 mg/kg to baboons.
Treatment: Platelet transfusion may be used to reverse the pharmacological effects of clopidogrel when quick reversal is required.
Dosage And Administration: The recommended dose of clopidogrel is 75 mg once daily with or without food.
No dosage adjustment is necessary for elderly patients or patients with renal impairment (see Pharmacology).
Availability And Storage: Each round, pink, film-coated tablet, engraved on one side with the number 75, contains: clopidogrel 75 mg. Nonmedicinal ingredients: anhydrous lactose, hydrogenated castor oil, microcrystalline cellulose, pregelatinized starch and polyethylene glycol 6000; coating: carnauba wax, ferric oxide (red), hydroxypropyl methylcellulose 2910, polyethylene glycol 6000 and titanium dioxide. Blister cards of 28, cartons of 1. Store away from heat and humidity. Store between 15 and 30°C.
PLAVIX Sanofi/Bristol-Myers Squibb Clopidogrel Bisulfate Platelet Aggregation Inhibitor