Class: Platelet-aggregation Inhibitors
ATC Class: B01AC04
Medically reviewed on October 23, 2017
- Reduced Efficacy Associated with Impaired CYP2C19 Function
Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel.1 121 (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.) Higher rates of major adverse cardiovascular events (e.g., death, MI, stroke) have been reported in poor metabolizers of CYP2C19 receiving clopidogrel at recommended dosages following acute coronary syndrome (ACS) or PCI compared with those who have normal CYP2C19 function.1 121
Platelet-aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1
Uses for Clopidogrel Bisulfate
Reduction of Cardiovascular and Cerebrovascular Events
Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic stroke, and vascular death) in patients with a history of recent MI, recent ischemic stroke, or established peripheral arterial disease.1 2 6 8 527 1009 1010 1011
The American College of Chest Physicians (ACCP) recommends long-term antiplatelet therapy with either aspirin or clopidogrel in patients with established CAD.1010 Because of cost considerations, clopidogrel generally recommended as an alternative to aspirin in those with aspirin intolerance or contraindications (e.g., allergy).5 6 20 992
ACCP, the American Stroke Association (ASA), and AHA consider clopidogrel an acceptable antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or TIAs; other options include aspirin monotherapy, cilostazol, or the combination of aspirin and extended-release dipyridamole.990 1009
Oral anticoagulation (e.g., warfarin, dabigatran) rather than antiplatelet therapy is recommended in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients who cannot take or choose not to take oral anticoagulants (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with clopidogrel and aspirin is recommended.1009
Recommended by ACCP and other experts as an acceptable antiplatelet therapy for secondary prevention of cardiovascular events in patients with symptomatic peripheral arterial disease,992 1011 1017 including those with intermittent claudication and those undergoing revascularization procedures (peripheral artery percutaneous transluminal angioplasty or peripheral artery bypass graft surgery, carotid endarterectomy).1011
Recommended by ACCP as an option for long-term antiplatelet therapy in patients with symptomatic carotid stenosis†, including in patients who are intolerant of aspirin and those who have undergone recent carotid endarterectomy.1011 1017
Non-ST-Segment-Elevation ACS (NSTE ACS)
Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events in patients with NSTE ACS, including unstable angina and non-ST-segment-elevation MI (NSTEMI).1 5 18 35 992 993 994 1010 1100 Used in patients who are managed medically or with coronary revascularization (e.g., PCI with or without coronary artery stenting, CABG).1 5 18 35 992 993 994 1010
Experts state that aspirin should be administered as soon as possible after presentation (and continued indefinitely) in all patients with NSTE ACS unless contraindicated; in addition, a P2Y12-receptor antagonist should be administered for up to 12 months.1100
Ticagrelor or clopidogrel generally recommended as the P2Y12-receptor antagonist of choice in patients treated medically without stent placement; ticagrelor, clopidogrel, or prasugrel is recommended in patients undergoing PCI with stent placement (bare-metal or drug-eluting).992 993 994 1010
Efficacy of pretreatment with clopidogrel prior to diagnostic cardiac catheterization is controversial; balance potential benefit of pretreatment against increased risk of bleeding should emergency CABG be needed.35 994
ST-Segment-Elevation MI (STEMI)
In patients in whom CABG is planned, withhold clopidogrel for ≥5 days prior to surgery.1004
In patients with STEMI in whom PCI is planned†, experts recommend a loading dose of a P2Y12-receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) before or at the time of PCI in conjunction with aspirin therapy.994 Clopidogrel also has been used in patients with STEMI who are receiving delayed PCI after thrombolytic therapy.994
Continue therapy for ≥12 months after stent implantation (bare-metal or drug-eluting), unless risk of bleeding outweighs anticipated net benefit; continue aspirin therapy indefinitely.992 993 994 (See Risks of Premature Discontinuance of Therapy under Cautions.)
The addition of warfarin to antiplatelet therapy is recommended in STEMI patients who have indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli, extensive wall-motion abnormality, mechanical heart valves).993 1007 1010
Triple antithrombotic therapy† with clopidogrel, low-dose aspirin, and warfarin (target INR 2–3) is suggested by ACCP in patients with anterior MI and left ventricular thrombus (or at high risk for such thrombi) undergoing stent implantation; recommended duration of triple antithrombotic therapy is dependent on whether patient has a bare-metal or drug-eluting stent.1010
Suggested by the American Diabetes Association (ADA) as alternative to aspirin for primary prevention of MI† in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity, albuminuria, elevated blood cholesterol or triglyceride concentrations).95
Some evidence suggests benefits of an even longer duration of dual-drug antiplatelet therapy (e.g., at least 30 months), but such prolonged therapy has been associated with an increased risk of bleeding.1019
Chronic Stable Angina
May be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin†.96 1101 In certain high-risk patients, combination therapy with aspirin and clopidogrel may be beneficial.1101
Embolism Associated with Atrial Fibrillation and/or Valvular Heart Disease
In patients with atrial fibrillation at increased risk of stroke who cannot or choose not to take oral anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination therapy with clopidogrel and aspirin rather than aspirin alone is recommended.998 1007
In patients with atrial fibrillation and mitral stenosis† who cannot or choose not to take warfarin therapy for reasons other than concerns about major bleeding, ACCP recommends combination therapy with clopidogrel and aspirin rather than aspirin alone.1007
Clopidogrel Bisulfate Dosage and Administration
Timing of Treatment in Relation to PCI or CABG
Available as clopidogrel bisulfate; dosage expressed in terms of clopidogrel.1
Pharmacogenomic factors can influence response to clopidogrel; although a higher dosage or administration of additional loading doses may increase the antiplatelet response in patients who are poor metabolizers, manufacturer states that an appropriate dosage of the drug in such patients has not been determined.1 121 123 130 (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.)
Reduction of Cardiovascular and Cerebrovascular Events
Patients undergoing PCI: Optimal dosage uncertain.993 994 Some experts suggest a 600-mg loading dose, administered as early as possible prior to or at time of the procedure, then 75 mg once daily.146 993 994 No apparent benefit with higher loading doses (e.g., 900 mg).147 994
Manufacturer states that optimal duration of therapy unknown;1 other experts recommend administering clopidogrel for up to 12 months in patients being managed medically and for ≥12 months in those undergoing PCI with coronary artery stent placement; continue aspirin indefinitely.992 993 994 1010
In patients receiving a bare-metal stent for a non-ACS indication, administer clopidogrel for up to 12 months unless patient has an increased risk of bleeding; in this situation, give clopidogrel with aspirin for a minimum of 2 weeks.994
Manufacturer recommends 75 mg once daily with or without a loading dose in combination with aspirin.1
Patients receiving thrombolytic therapy: Experts recommend a 300-mg loading dose in patients ≤75 years of age.527 Loading dose not recommended in patients >75 years of age.527 Initiate clopidogrel therapy before or with the thrombolytic agent.527 Continue therapy at 75 mg once daily for ≥14 days and up to 1 year.527
Patients undergoing primary PCI: Some experts recommend a 600-mg loading dose, administered as early as possible prior to or at time of the procedure, then 75 mg once daily.146 527 994 No apparent benefit with higher loading doses (e.g., 900 mg).147 994
Patients undergoing delayed PCI after thrombolytic therapy who have not received previous clopidogrel loading dose: Experts recommend a loading dose of 300 or 600 mg depending on the timing of PCI in relation to thrombolytic therapy, then 75 mg once daily.527
Patients undergoing delayed PCI after thrombolytic therapy who have received previous clopidogrel loading dose: Do not administer additional clopidogrel loading dose.527 Continue clopidogrel therapy with dosage of 75 mg once daily.527
Manufacturer states that optimal duration of therapy unknown.1 Some experts generally recommend dual antiplatelet therapy (e.g., clopidogrel and aspirin) for 12 months following ACS, and possibly longer in those undergoing PCI with stent placement.992 994 1010
No dosage adjustment necessary.1
No dosage adjustment necessary.1
Cautions for Clopidogrel Bisulfate
Known hypersensitivity to clopidogrel or any ingredient in the formulation.1
Reduced Efficacy Associated with Impaired CYP2C19 Function
Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to genetic polymorphism of CYP2C19 or concurrent use of drugs (e.g., omeprazole, esomeprazole) that inhibit CYP2C19.1 72 76 78 79 80 81 82 83 84 85 86 100 101 121 350 351 352 356 Consider use of other antiplatelet agents (e.g., prasugrel, ticagrelor) or alternative dosing strategies for clopidogrel in patients identified as potential poor metabolizers of CYP2C19.1 121 123 140 143 (See Boxed Warning.)
Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) associated with reduced metabolism of and diminished antiplatelet response to clopidogrel; data on clinical outcomes are conflicting, but higher rates of major adverse cardiovascular events (e.g., death, MI, stroke, stent thrombosis) reported in patients receiving recommended dosages of clopidogrel who possess such alleles.1 76 78 79 80 82 83 88 89 90 92 104 117 118 121 (See Actions.)
Genetic tests are available to identify patients with variant CYP2C19 genotypes.1 20 121 122 143 145 While such tests are appropriate for any patient currently receiving or considering treatment with clopidogrel, the need for pharmacogenetic testing should be determined individually.121 122 123 143 Genetic variants of other CYP isoenzymes (e.g., CYP2C19*17, CYP2B6) also may affect response to clopidogrel.1 78 123 131
Concurrent use of clopidogrel with omeprazole or esomeprazole (potent CYP2C19 inhibitors) also shown to reduce antiplatelet effects of clopidogrel.1 72 79 84 88 89 98 100 101 102 103 109 350 351 352 (See Proton-Pump Inhibitors under Interactions.) Clinical importance not fully elucidated, but reduced effectiveness in preventing cardiovascular events possible.1 73 74 81 89 91 92 98 100 101 102 103 115 Concomitant use of other drugs that inhibit CYP2C19 also may decrease response to clopidogrel.1 100 101 (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Avoid concomitant therapy with known inhibitors of CYP2C19 activity.1 20 101
Other Warnings and Precautions
Risks of Premature Discontinuance of Therapy
In general, because of the increased risk of cardiovascular events, do not prematurely discontinue treatment with a thienopyridine derivative (e.g., clopidogrel, prasugrel).1 45 Stent thrombosis with potentially fatal sequelae, particularly with drug-eluting stents (DES), associated with premature discontinuance of therapy with a thienopyridine derivative and aspirin.43 44 45 46 47 48 49 54 (See Non-ST-Segment-Elevation MI [NSTEMI] under Uses.)
Before implantation of a DES, carefully assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy.45 59 1004 Consider avoiding use of a DES in patients who are not expected to comply.45 59 (See Advice to Patients.) In patients who are likely to require invasive or surgical procedures ≤12 months after DES implantation, consider implantation of a bare-metal stent or use of balloon angioplasty with provisional stent implantation instead.45 1004
At least 12 months of dual antiplatelet therapy is recommended following placement of any type of coronary artery stent (bare-metal or drug-eluting).993 994 1010 Preliminary evidence from a randomized controlled study (Dual Antiplatelet Therapy [DAPT] study) suggests that an even longer duration (at least 30 months) of dual antiplatelet therapy may be beneficial in reducing stent thrombosis and other cardiovascular events in patients with a drug-eluting stent; however, such prolonged therapy was associated with increased bleeding and an unexpected finding of increased noncardiovascular mortality (principally related to trauma or cancer).1019 1020 These adverse mortality findings were not observed during FDA's final review of the DAPT study and other clinical studies evaluating the long-term use of clopidogrel.1021 FDA review found no evidence of either a harmful or beneficial effect of clopidogrel on all-cause mortality or cancer-related deaths in a population with, or at risk for, CAD.1021
Clinicians performing invasive procedures must understand the consequences of premature discontinuance of thienopyridine derivative therapy in patients with DES.45 If issues about a patient’s antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such professionals should contact the patient’s cardiologist.45 Defer elective procedures with substantial bleeding risk until completion of dual-drug antiplatelet therapy.45 If an invasive procedure is required, temporarily discontinue clopidogrel 5 days prior to the procedure.1 For non-elective procedures that mandate discontinuance of thienopyridine-derivative therapy, continue aspirin therapy if at all possible.45 Restart clopidogrel therapy as soon as possible after the procedure.1 45
May restore hemostasis with exogenous administration of platelets; however, platelet transfusions within 4 hours of a loading dose or within 2 hours of a maintenance dose may have reduced effectiveness.1
Bleeding is unlikely to be resolved or prevented by withholding a dose of clopidogrel because of the drug’s prolonged inhibitory effects on platelet function.1
American College of Cardiology Foundation/American College of Gastroenterology/American Heart Association (ACCF/ACG/AHA) recommends prophylactic proton-pump inhibitor therapy to reduce risk of ulcer complications and GI bleeding in patients with additional GI risk factors receiving clopidogrel and aspirin.81 87 89 136 However, consider possibility of reduced antiplatelet effects when clopidogrel is used concomitantly with certain proton-pump inhibitors (e.g., omeprazole, esomeprazole).1 76 100 101 350 351 352 356 (See Proton-Pump Inhibitors under Interactions.)
Thrombotic Thrombocytopenic Purpura (TTP)
In neonates and infants† up to 24 months of age with systemic to pulmonary artery shunts or other cardiac conditions predisposing to thrombosis, clopidogrel 0.2 mg/kg daily for 1–4 weeks achieved similar inhibition of platelet aggregation as a 75-mg daily dosage in adults; no serious hemorrhagic events reported.97
In patients ≥75 years of age, no difference in platelet aggregation observed compared with younger healthy individuals.1 In a clinical trial, geriatric patients were at greater risk for thrombotic events and major bleeding than younger patients.1
Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to be similar to that observed in healthy individuals.1
Experience limited in patients with moderate or severe renal impairment.1
Inhibition of ADP-induced platelet aggregation is decreased in patients with moderate (Clcr 30–60 mL/minute) or severe (Clcr 5–15 mL/minute) renal impairment.1
Common Adverse Effects
Chest pain,1 6 accidental injury,1 6 influenza-like symptoms,1 6 pain,1 6 headache,1 6 dizziness,1 6 abdominal pain,1 6 8 dyspepsia,1 2 3 6 8 diarrhea,1 2 3 6 8 11 nausea,1 2 3 6 arthralgia,1 6 back pain,1 6 purpura,1 6 upper respiratory tract infection,1 6 rash,1 2 3 6 8 11 pruritus.1 6
Interactions for Clopidogrel Bisulfate
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Converted to active metabolite by CYP2C19.1 72 78 80 81 82 83 (See Metabolism under Pharmacokinetics.) Potential pharmacokinetic (decreased concentrations of active metabolite) and pharmacodynamic (reduced antiplatelet effects) interaction with inhibitors of CYP2C19.1 72 76 81 88 89 Avoid concomitant use of drugs known to be potent inhibitors of CYP2C19.1 20 101 352 356
Potential for reduced systemic exposure to clopidogrel’s active metabolite and reduced antiplatelet effects with certain proton-pump inhibitors (e.g., omeprazole, esomeprazole) (via inhibition of CYP2C19 by proton-pump inhibitor).1 20 72 73 74 79 84 86 88 89 91 100 101 102 103 106 107 109 350 351 352 356 (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions and see Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.) Conflicting data on clinical outcomes reported, but increased risk of adverse cardiovascular events possible.1 72 73 74 81 91 98 102 103 104 105 107 108 110 111 112 113 115 119
If concomitant proton-pump inhibitor therapy is considered necessary, consider using an agent with little or no CYP2C19-inhibitory activity.81 89 92 102 103 109 111 112 114 350 352 (See Specific Drugs under Interactions.) In healthy individuals, dexlansoprazole, lansoprazole, or pantoprazole had less effect on clopidogrel's antiplatelet activity than did omeprazole or esomeprazole; of these proton-pump inhibitors, dexlansoprazole appeared to have the least potential to interact with clopidogrel.350 351 352
Weigh risks and benefits of concomitant use of any proton-pump inhibitor in individual patients.102 103 112 119 ACCF/ACG/AHA states that use of a proton-pump inhibitor concomitantly with dual antiplatelet therapy may provide the optimal balance of risk and benefit in patients with ACS who have a history of upper GI bleeding.136 Risk/benefit tradeoff may favor concomitant use of dual antiplatelet therapy and a proton-pump inhibitor in stable patients with a history of GI bleeding who undergo coronary revascularization and receive a coronary stent.136 ACCF/ACG/AHA states that the risk reduction with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding (e.g., advanced age; concomitant use of warfarin, corticosteroids, or NSAIAs; H. pylori infection) and may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a drug–drug interaction.136 In patients without such risk factors for GI bleeding, risk/benefit balance may favor use of antiplatelet therapy without a concomitant proton-pump inhibitor.136 Alternatively, consider concomitant therapy with antacids or H2-receptor antagonists (i.e., ranitidine, famotidine, nizatidine), except for cimetidine (also a potent CYP2C19 inhibitor).1 81 89 92 100 103 112
No evidence that antacids interfere with antiplatelet effects of clopidogrel101
Caution advised; monitor bleeding times during concurrent administration93
No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of dexlansoprazole353
Histamine H2-receptor antagonists (ranitidine, famotidine, nizatidine)
May consider H2-receptor antagonist (except cimetidine) as alternative to proton-pump inhibitor for gastric protection in patients receiving clopidogrel, but may not be as effective81 89 92 101 103 112 136
No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of lansoprazole354
Potential increased risk of bleeding1
No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of pantoprazole355
FDA states insufficient information available to make specific recommendations about concomitant use with clopidogrel100
Clopidogrel Bisulfate Pharmacokinetics
Following oral administration of a single dose, dose-dependent platelet aggregation inhibition can be observed in 2 hours.1
In healthy men, administration with a high-fat or standard meal decreased mean inhibition of platelet aggregation by <9%.1 Although food decreased peak plasma concentrations of the active metabolite by 57%, systemic exposure to the active metabolite was unaffected.1
Peak plasma concentrations and exposure to clopidogrel’s active metabolite decreased by 30–50% in patients with genetically reduced CYP2C19 function.1 (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.)
Extensively metabolized via 2-step pathway: 1) esterase-mediated hydrolysis to inactive carboxylic acid derivative 2) formation of active thiol metabolite mediated by CYP isoenzymes (e.g., 2C19, 3A4, 2B6, 1A2).1
Excreted in urine (50%) and in feces (46%).1
Active metabolite: 30 minutes.1
25°C (may be exposed to 15–30 °C).1
Prodrug; platelet-aggregation inhibitory activity is dependent on hepatic transformation to an active metabolite.1 2 6 8 11 72 78 80 81 82 83 Metabolism influenced by CYP2C19 polymorphism.1 78 79 80 82 83 Patients with one or more variant CYP2C19 alleles (e.g., CYP2C19*2, CYP2C19*3) are described as poor or intermediate metabolizers; lower concentrations of active metabolite, diminished antiplatelet effects, and higher incidence of major adverse cardiovascular events observed in such patients receiving clopidogrel.1 78 79 80 81 82 83 90 117 118 Approximately 2–14% of the population is estimated to be poor metabolizers of CYP2C19; however, there is wide variability among different racial/ethnic populations.121 (See Reduced Efficacy Associated with Impaired CYP2C19 Function under Cautions.)
Active metabolite binds selectively and noncompetitively to platelet surface low-affinity platelet P2Y12 ADP-receptor binding site.1 2 4 6 11 Inhibits ADP binding to the receptor and subsequent receptor activation of the platelet glycoprotein (GP IIb/IIIa) complex necessary for fibrinogen-platelet binding.1 2 4
Advice to Patients
Importance of counseling patients about potential risks versus benefits of clopidogrel.1
Importance of informing patients that they may bleed more easily and that a longer than normal time will be required to stop bleeding when taking clopidogrel.1
Before implantation of drug-eluting stent (DES), determine likelihood of patient compliance with ≥12 months of aspirin–clopidogrel combination therapy.45
Importance of informing patients prior to hospital discharge about risks associated with premature discontinuance of such combination therapy.45 Importance of informing patient not to discontinue therapy without consulting their prescribing clinician, even if instructed to do so by another health-care professional (e.g., dentist).1 45
Importance of patient informing clinician about clopidogrel therapy before any surgery is scheduled.1 6 Prior to scheduling an invasive procedure, patients should inform their clinicians (including dentists) that they are currently taking clopidogrel; clinicians performing the invasive procedure should consult with the prescribing clinician before discontinuing clopidogrel therapy.1
Importance of patient informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly omeprazole (including Prilosec OTC) or esomeprazole and drugs that affect bleeding (e.g., warfarin, NSAIAs).1 76 100 101 102 114 352
Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1
Importance of informing patients of other important precautionary information.1 (See Cautions.)
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
75 mg (of clopidogrel)
Sanofi-Aventis (also promoted by Bristol-Myers Squibb)
300 mg (of clopidogrel)
Sanofi-Aventis (also promoted by Bristol-Myers Squibb)
AHFS DI Essentials. © Copyright 2018, Selected Revisions October 23, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
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