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Pronunciation:

(kloh PID oh grel)

U.S. Brand Names:

Plavix®

Synonyms:

Clopidogrel Bisulfate

Generic Available:

Canadian Brand Names:

Plavix®

Use:

Reduce atherosclerotic events (myocardial infarction, stroke, vascular deaths) in patients with atherosclerosis documented by recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease; prevention of thrombotic complications after coronary stenting; acute coronary syndrome (unstable angina or non-Q-wave MI)

Use - Unlabeled/Investigational:

In aspirin-allergic patients, prevention of coronary artery bypass graft closure (saphenous vein)

Pregnancy Risk Factor:

Lactation:

Excretion in breast milk unknown/not recommended

Contraindications:

Hypersensitivity to clopidogrel or any component of the formulation; active pathological bleeding such as PUD or intracranial hemorrhage; coagulation disorders

Warnings/Precautions:

Use with caution in patients who may be at risk of increased bleeding, including patients with peptic ulcer disease, trauma, or surgery. Consider discontinuing 5 days before elective surgery. Use caution in mixing with other antiplatelet drugs. Use with caution in patients with severe liver disease (experience is limited). Cases of thrombotic thrombocytopenic purpura (usually occurring within the first 2 weeks of therapy) have been reported.

Adverse Reactions:

As with all drugs which may affect hemostasis, bleeding is associated with clopidogrel. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the concurrent use of multiple agents which alter hemostasis and patient susceptibility.

>10%: Gastrointestinal: The overall incidence of gastrointestinal events (including abdominal pain, vomiting, dyspepsia, gastritis and constipation) has been documented to be 27% compared to 30% in patients receiving aspirin.

3% to 10%:

Cardiovascular: Chest pain (8%), edema (4%), hypertension (4%)

Central nervous system: Headache (3% to 8%), dizziness (2% to 6%), depression (4%), fatigue (3%), general pain (6%)

Dermatologic: Rash (4%), pruritus (3%)

Endocrine & metabolic: Hypercholesterolemia (4%)

Gastrointestinal: Abdominal pain (2% to 6%), dyspepsia (2% to 5%), diarrhea (2% to 5%), nausea (3%)

Genitourinary: Urinary tract infection (3%)

Hematologic: Purpura (5%), epistaxis (3%)

Hepatic: Liver function test abnormalities (<3%; discontinued in 0.11%)

Neuromuscular & skeletal: Arthralgia (6%), back pain (6%)

Respiratory: Dyspnea (5%), rhinitis (4%), bronchitis (4%), cough (3%), upper respiratory infection (9%)

Miscellaneous: Flu-like syndrome (8%)

1% to 3%:

Cardiovascular: Atrial fibrillation, cardiac failure, palpitation, syncope

Central nervous system: Fever, insomnia, vertigo, anxiety

Dermatologic: Eczema

Endocrine & metabolic: Gout, hyperuricemia

Gastrointestinal: Constipation, GI hemorrhage, vomiting

Genitourinary: Cystitis

Hematologic: Hematoma, anemia

Neuromuscular & skeletal: Arthritis, leg cramps, neuralgia, paresthesia, weakness

Ocular: Cataract, conjunctivitis

<1% (Limited to important or life-threatening): Agranulocytosis, allergic reaction, anaphylactoid reaction, angioedema, aplastic anemia, bilirubinemia, bronchospasm, bullous eruption, fatty liver, granulocytopenia, hematuria, hemoptysis, hemothorax, hepatitis, hypochromic anemia, intracranial hemorrhage (0.4%), ischemic necrosis, leukopenia, maculopapular rash, menorrhagia, neutropenia (0.05%), ocular hemorrhage, pulmonary hemorrhage, purpura, retroperitoneal bleeding, thrombocytopenia, thrombotic thrombocytopenic purpura, urticaria

Overdosage/Toxicology:

Symptoms of acute toxicity include vomiting, prostration, difficulty breathing, and gastrointestinal hemorrhage. Only one case of overdose with clopidogrel has been reported to date, no symptoms were reported with this case and no specific treatments were required.

Based on its pharmacology, platelet transfusions may be an appropriate treatment when attempting to reverse the effects of clopidogrel. After decontamination, treatment is symptomatic and supportive.

Drug Interactions:

Substrate (minor) of CYP1A2, 3A4; Inhibits CYP2C8/9 (weak)

Anticoagulants or other antiplatelet agents may increase the risk of bleeding. Use with heparin in acute coronary syndrome is clinically accepted.

Aspirin: Clopidogrel may increase the antiplatelet effect of aspirin; bleeding time is not prolonged relative to clopidogrel alone. Concurrent use is accepted in clinical practice (particularly in ACS treatment).

Atorvastatin: Atorvastatin may attenuate the effects of clopidogrel; monitor.

Drotrecogin alfa may increase the risk of bleeding.

Macrolide antibiotics: CYP3A4-inhibiting macrolides may attenuate the effects of clopidogrel. These include clarithromycin, erythromycin, and troleandomycin. Monitor.

NSAIDs: Concurrent use with clopidogrel may increase gastrointestinal effects, including GI blood loss. NSAID use was excluded in ACS trial (CURE).

Rifampin: Rifampin may increase the effects of clopidogrel; monitor.

Thrombolytics may increase the risk of bleeding.

Ethanol/Nutrition/Herb Interactions:

Herb/Nutraceutical: Avoid cat's claw, dong quai, evening primrose, feverfew, garlic, ginger, ginkgo, red clover, horse chestnut, green tea, ginseng (all have additional antiplatelet activity).

Stability:

Store at 25°C (77°F); excursions permitted to 15°C to 3°C (59°F to 86°F).

Mechanism of Action:

Blocks the ADP receptors, which prevent fibrinogen binding at that site and thereby reduce the possibility of platelet adhesion and aggregation

Pharmacodynamics/Kinetics:

Onset of action: Inhibition of platelet aggregation detected: 2 hours after 300 mg administered; after second day of treatment with 50-100 mg/day

Peak effect: 50-100 mg/day: Bleeding time: 5-6 days; Platelet function: 3-7 days

Absorption: Well absorbed

Metabolism: Extensively hepatic via hydrolysis; biotransformation primarily to carboxyl acid derivative (inactive). The active metabolite that inhibits platelet aggregation has not been isolated.

Half-life elimination: ~8 hours

Time to peak, serum: ~1 hour

Excretion: Urine

Dosage:

Oral: Adults:

Recent MI, recent stroke, or established arterial disease: 75 mg once daily

Acute coronary syndrome: Initial: 300 mg loading dose, followed by 75 mg once daily (in combination with aspirin 75-325 mg once daily). Note: A loading dose of 600 mg has been used in some investigations; limited research exists comparing the two doses.

Prevention of coronary artery bypass graft closure (saphenous vein): Aspirin-allergic patients (unlabeled use): Loading dose: 300 mg 6 hours following procedure; maintenance: 50-100 mg/day

Dosing adjustment in renal impairment and elderly: None necessary

Monitoring Parameters:

Signs of bleeding; hemoglobin and hematocrit periodically

Dietary Considerations:

May be taken without regard to meals.

Patient Education:

Take as directed. May cause headache or dizziness; use caution when driving or engaging in tasks that require alertness until response to drug is known. It may take longer than usual to stop bleeding. Small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may reduce nausea or vomiting. Mild analgesics may reduce arthralgia or back pain. Inform physicians and dentists that you are taking this medication prior to scheduling any surgery or dental procedure. Report immediately unusual or acute chest pain or respiratory difficulties; skin rash; unresolved bleeding, diarrhea, or GI distress; nosebleed; or acute headache. Breast-feeding precaution: Breast-feeding is not recommended.

Anesthesia and Critical Care Concerns/Other Considerations:

Withhold clopidogrel for 5-7 days prior to elective CABG surgery.

Cardiovascular Considerations:

Acute Coronary Syndromes (ACS): The 2002 ACC/AHA guidelines for unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) recommend administration of clopidogrel to hospitalized patients who are unable to take aspirin because of hypersensitivity or major gastrointestinal intolerance (Class 1; level of evidence: A). In certain situations, patients may even be desensitized to aspirin so that they may receive aspirin and clopidogrel concurrently. In hospitalized patients in whom an early noninterventional approach is planned, clopidogrel should be added to aspirin as soon as possible. In patients taking clopidogrel in whom elective CABG is planned, the drug should be withheld for 5-7 days before surgery.

Percutaneous Coronary Intervention (PCI): The 2004 ACC/AHA guidelines for ST-elevation myocardial infarction (STEMI) suggests that clopidogrel be continued for at least 1 month after bare-metal stent implantation, for several months after drug-eluting stent implantation (3 months for sirolimus, 6 months for paclitaxel), and for up to 12 months in patients who are not at high risk for bleeding.

Dental Health: Effects on Dental Treatment:

If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 7 days prior to surgery only upon approval via a medical consult with prescribing physician. As with all drugs which may affect hemostasis, bleeding is associated with clopidogrel. Hemorrhage may occur at virtually any site; risk is dependent on multiple variables, including the concurrent use of multiple agents which alter hemostasis and patient susceptibility.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions:

No information available to require special precautions

Mental Health: Effects on Mental Status:

May cause depression, dizziness, confusion, hallucinations, insomnia, or anxiety

Mental Health: Effects on Psychiatric Treatment:

GI side effects are common; concurrent use with SSRIs and/or valproic acid may produce additive effects. Flu-like syndrome may occur and present like SSRI-discontinuation symptoms. Hematologic side effects have rarely been reported; monitor with clozapine, carbamazepine, and valproate.

Dosage Forms:

Tablet [film coated]: 75 mg

International Brand Names:

Iscover® (ES); Plavix® (AR, CA, ES, FR, ID, RU, SG, TH)

References

"A Randomized, Blinded, Trial of Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE). CAPRIE Steering Committee,"Lancet, 1996, 348(9083):1329-39.

Antman EM, Anbe SC, Alpert JS, et al, "ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction - Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of Patients With Acute Myocardial Infarction),"Circulation, 2004, 110:588-636. Available at: http://www.circulationaha.org/cgi/content/full/110/5/588. Last accessed August 26, 2004.

Bal dit Sollier C, Mahe I, Berge N, et al, "Reduced Thrombus Cohesion in an ex vivo Human Model of Arterial Thrombosis Induced by Clopidogrel Treatment: Kinetics of the Effect and Influence of Single and Double Loading-Dose Regimens,"Thromb Res, 2003, 111(1-2):19-27.

Berger PB, Bell MR, Rihal CS, et al, "Clopidogrel Versus Ticlopidine After Intracoronary Stent Placement,"J Am Coll Cardiol, 1999, 34(7):1891-4.

Bertrand ME, Rupprecht HJ, Urban P, et al, "Double-Blind Study of the Safety of Clopidogrel With and Without a Loading Dose in Combination With Aspirin Compared With Ticlopidine in Combination With Aspirin After Coronary Stenting,"Circulation, 2000, 102(6):624-9.

Braunwald E, Antman EM, Beasley JW, et al, "ACC/AHA 2002 Guideline Update for the Management of Patients With Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction - Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina),"J Am Coll Cardiol, 2002, 40(7):1366-74. Available at: http://www.acc.org/clinical/guidelines/unstable/incorporated/index.htm. Accessed May 20, 2003.

Kastrati A, Mehilli J, Schuhlen H, et al, "A Clinical Trial of Abciximab in Elective Percutaneous Coronary Intervention After Pretreatment With Clopidogrel,"N Engl J Med, 2004, 350(3):232-8.

Lange RA and Hillis LD, "Antiplatelet Therapy for Ischemic Heart Disease,"N Engl J Med, 2004, 350(3):277-80.

Lidell C, Svedberg LE, Lindell P, et al, "Clopidogrel and Warfarin: Absence of Interaction in Patients Receiving Long-Term Anticoagulant Therapy for Non-Valvular Atrial Fibrillation,"Thromb Haemost, 2003, 89(5):842-6.

Mehta SR, Yusuf S, Peters RJ, et al, "Effects of Pretreatment With Clopidogrel and Aspirin Followed by Long-Term Therapy in Patients Undergoing Percutaneous Coronary Intervention: The PCI-CURE Study,"Lancet, 2001, 358(9281):527-33.

Mishkel GJ, Aguirre FV, Ligon RW, et al, "Clopidogrel as Adjunctive Antiplatelet Therapy During Coronary Stenting,"J Am Coll Cardiol, 1999, 34(7):1884-90.

Moussa I, Oetgen M, Roubin G, et al, "Effectiveness of Clopidogrel and Aspirin Versus Ticlopidine and Aspirin in Preventing Stent Thrombosis After Coronary Stent Implantation,"Circulation, 1999, 99(18):2364-6.

"Seventh ACCP Consensus Conference on Antithrombotic and Thrombolytic Therapy,"Chest, 2004, 126(3 Suppl):172-608.

Steinhubl SR, Berber PB, Mann JT, et al, "Early and Sustained Dual Oral Antiplatelet Therapy Following Percutaneous Coronary Intervention. A Randomized Controlled Trial,"JAMA, 2002, 288(19):2411-20.

Yusef S, Zhao F, Mehta SR, et al, "Effects of Clopidogrel in Addition to Aspirin in Patients With Acute Coronary Syndromes Without ST-Segment Elevation,"N Engl J Med, 2001, 345(7):494-502.

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