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Clopidogrel (Monograph)

Brand name: Plavix
Drug class: Platelet-aggregation Inhibitors
ATC class: B01AC04
Chemical name: Methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate, sulfate
Molecular formula: C16H16ClNO2S • H2SO4
CAS number: 120202-66-6

Medically reviewed by Drugs.com on Dec 11, 2023. Written by ASHP.

Warning

    Diminished Antiplatelet Effect in Patients with 2 Loss-of-Function CYP2C19 Alleles

  • Clopidogrel is a prodrug; requires conversion to its active metabolite by the CYP enzyme system (primarily by CYP2C19).1 2 6 8 11 121

  • Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel.1 121 (See Reduced Efficacy in Poor CYP2C19 Metabolizers under Cautions.) Patients who are homozygous for nonfunctional alleles of CYP2C19 have reduced levels of the active clopidogrel metabolite and reduced antiplatelet effects.1 121

  • Genetic tests are available to identify patients who are poor CYP2C19 metabolizers.1 20 121 122

  • Consider use of another P2Y12 receptor antagonist (e.g., prasugrel, ticagrelor) in patients identified as poor CYP2C19 metabolizers.1 121

Introduction

Platelet-aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate (ADP)-receptor antagonist.1

Uses for Clopidogrel

Acute Coronary Syndrome

Used in combination with aspirin to reduce the risk of MI and stroke in patients with acute coronary syndrome (ACS), including those with non-ST-segment-elevation ACS (NSTE-ACS) being managed medically or with revascularization strategies (e.g., PCI with coronary stent implantation, coronary artery bypass grafting [CABG]) and those with acute ST-segment-elevation MI (STEMI) managed medically.1 5 18 31 35 36 991 992 993 994 1005 1010 (See Prevention of Stent Thrombosis under Uses.)

Dual antiplatelet therapy (DAPT) with a P2Y12 inhibitor (e.g., clopidogrel, prasugrel, ticagrelor) and aspirin is considered the current standard of care in patients with ACS.33 991 992 994 1005

American College of Cardiology (ACC)/American Heart Association (AHA) has issued guidelines for treatment options and duration of DAPT.991 992 994 1005 Aspirin should almost always be continued indefinitely; decisions about specific P2Y12 inhibitor and duration of P2Y12 inhibitor therapy should be based on risks of bleeding versus benefits of ischemic reduction, clinical judgment, and patient preference.1005

ACC/AHA generally recommends a shorter duration of DAPT for patients at reduced ischemic, but high bleeding, risk and a longer duration for patients at high ischemic, but reduced bleeding, risk.1005

In ACS patients managed medically (without revascularization or reperfusion therapy) or with PCI and stent implantation (bare-metal or drug-eluting), P2Y12 inhibitor therapy should be given for at least 12 months; in patients who have tolerated DAPT without bleeding complications and do not have a high risk of bleeding, continuation of such therapy for longer than 12 months may be reasonable.1005

With regard to the specific P2Y12 inhibitor, evidence supports use of clopidogrel or ticagrelor in medically-managed ACS patients; clopidogrel, prasugrel, or ticagrelor may be used in ACS patients treated with PCI.1005

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

If clopidogrel is given at hospital admission or diagnosis of ACS and the patient is subsequently scheduled for CABG, temporarily discontinue clopidogrel for at least 5 days prior to the procedure; if CABG is urgent, discontinue clopidogrel for at least 24 hours.1 35 40 991

Peripheral Arterial Disease or History of MI or Stroke

Used to reduce the risk of MI and stroke in patients with established peripheral arterial disease (PAD) or a history of recent MI or recent stroke.1 2 6 8 1009 1010 1101 1102 1103

Experts recommend antiplatelet therapy with either aspirin or clopidogrel in patients with stable ischemic heart disease (SIHD).1010 1101 Because of cost considerations, aspirin is generally preferred, and clopidogrel considered an alternative when aspirin is contraindicated.5 6 20 992 1101

Experts also recommend antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or TIA; options include aspirin monotherapy, clopidogrel, or aspirin in combination with extended-release dipyridamole.1009 1103 Some experts state that in patients with recent stroke or TIA attributable to severe stenosis (70-99%) of a major intracranial artery, the addition of clopidogrel to aspirin for 90 days may be reasonable.1103

Oral anticoagulation (e.g., warfarin, direct oral anticoagulants [DOACs]) rather than antiplatelet therapy is recommended in patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation.1007 1009 1014

AHA/ACC recommends antiplatelet therapy with either aspirin or clopidogrel in patients with symptomatic PAD.1102 1107 Dual antiplatelet therapy may be considered in some patients.1102

Prevention of Stent Thrombosis

Has been used in combination with aspirin (DAPT) to prevent stent thrombosis following implantation of coronary artery stents† [off-label].43 44 45 46 50 51 52 54 992 993 994 1005 1010

Various drug-eluting stents are available; however, newer-generation (e.g., everolimus- or zotarolimus-eluting) stents have demonstrated lower risk of stent thrombosis and MI compared with first-generation (e.g., sirolimus- and paclitaxel-eluting) stents, which are rarely, if ever, used in current practice.1005 1105 1106 Therefore, current recommendations for duration of DAPT apply principally to the use of newer-generation stents.1005

DAPT should be given to patients with ACS who receive a BMS or DES for at least 12 months.1005 Continuation of DAPT beyond 12 months may be reasonable in patients who have tolerated such therapy without a bleeding complication and who are not at high bleeding risk.1005 (See Acute Coronary Syndrome under Uses.) If patients with a DES develop a high risk of bleeding or have a high risk of severe bleeding, discontinuation of a P2Y12 inhibitor after 3 months may be reasonable.1005

Recommendations are also provided by ACC/AHA for patients with stable ischemic heart disease (SIHD) who undergo stent implantation.1005

Embolism Associated with Atrial Fibrillation

Has been used in combination with aspirin for prevention of stroke and systemic embolism in patients with atrial fibrillation† [off-label].995 997 1007 1014 However, oral anticoagulants are currently recommended for antithrombotic therapy in these patients; antiplatelet therapy should not be used alone for stroke prevention, but may be added if the patient has other indications for use (e.g., ACS, PCI with stenting).1007 1014

Has been used in patients with atrial fibrillation and ACS.993 1014 1015 Because of the high risk of bleeding associated with triple antithrombotic therapy (aspirin, a P2Y12 inhibitor, and an oral anticoagulant), experts generally recommend against this approach and instead favor a dual strategy (an oral anticoagulant and a P2Y12 inhibitor) for most patients with atrial fibrillation who present with ACS and/or undergo PCI.33 993 1014 1015 If triple therapy is considered in patients with high thrombotic risk and low bleeding risk, the shortest possible duration of therapy should be used.33 993 1014 1015

Has been used in combination with low-dose rivaroxaban (15 mg daily) instead of triple therapy to reduce the risk of bleeding in patients with atrial fibrillation who have undergone PCI with stenting.1014

Clopidogrel Dosage and Administration

Administration

Administer orally without regard to meals.1 6 8

Dosage

Available as clopidogrel bisulfate; dosage expressed in terms of clopidogrel.1

Adults

ACS
Oral

In ACS patients who need an antiplatelet effect within hours, manufacturer recommends 300-mg initial loading dose followed by 75 mg once daily given concomitantly with aspirin (75–325 mg once daily).1

ACC/AHA guidelines recommend clopidogrel loading dose of 300 or 600 mg, followed by 75 mg daily in patients with NSTE-ACS who are treated with an early invasive or ischemia-guided strategy.991

In patients with STEMI receiving thrombolytic therapy, experts recommend a 300-mg loading dose in patients ≤75 years of age; loading dose not recommended in patients >75 years of age.992 Initiate clopidogrel therapy before or with the thrombolytic agent.992 Continue therapy at 75 mg once daily for ≥14 days and up to 1 year.992

In patients undergoing PCI, a 600-mg loading dose should be administered before the procedure, followed by 75 mg once daily for at least 12 months in those who receive a coronary stent.146 991 992 994

Temporarily discontinue therapy ≥5 days prior to CABG and resume as soon as possible after procedure.1

Peripheral Arterial Disease or History of MI or Stroke
Oral

75 mg once daily.1 2 3 5 6 8

Special Populations

Hepatic Impairment

No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Detailed Clopidogrel dosage information

Cautions for Clopidogrel

Contraindications

Warnings/Precautions

Warnings

Reduced Efficacy in Poor CYP2C19 Metabolizers

Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to genetic polymorphism of CYP2C19.1 72 76 78 79 80 81 82 83 84 85 86 100 101 121 350 351 356 1000 In patients who are homozygous for nonfunctional alleles of CYP2C19 (poor metabolizers of CYP2C19), reduced conversion to the active metabolite of clopidogrel can occur resulting in reduced antiplatelet activity.1 1000

Genetic tests are available to identify patients with variant CYP2C19 genotypes.1 20 121 122 143 145 (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; 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 1000

Relationship between CYP2C19 genotype and clopidogrel response is particularly evident in ACS patients undergoing PCI.1000 Increased risk of major cardiovascular events and stent thrombosis has been observed in such patients who are CYP2C19*2 heterozygotes or homozygotes.1000

When considering use of clopidogrel in patients with ACS being managed with PCI, the Clinical Pharmacogenetics Implementation Consortium (CPIC) strongly recommends using an alternative antiplatelet agent (e.g., prasugrel, ticagrelor) in poor metabolizers of CYP2C19.1000 CPIC also recommends consideration of alternative anticoagulation in patients with an intermediate CYP2C19 phenotype.1000

Reduced Efficacy with Concomitant Use of Omeprazole or Esomeprazole

Concurrent use of clopidogrel with omeprazole or esomeprazole (potent CYP2C19 inhibitors) may reduce antiplatelet effects of clopidogrel and should be avoided.1 72 79 84 88 89 98 100 101 102 103 109 350 351 (See Proton-Pump Inhibitors under Interactions.) 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.)

Other Warnings and Precautions

Bleeding

Increased risk of bleeding.1 136 138

Temporarily discontinue clopidogrel ≥5 days prior to elective surgery (e.g., CABG) and ≥24 hours prior to urgent CABG.1 35 43 991

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 of clopidogrel 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 76 100 101 350 351 356 (See Proton-Pump Inhibitors under Interactions.)

Risks of Premature Discontinuance of Therapy

In general, because of the increased risk of cardiovascular events, do not prematurely discontinue treatment with a P2Y12 inhibitor.1 45 Stent thrombosis with potentially fatal sequelae, particularly with drug-eluting stents (DES), associated with premature discontinuance of dual antiplatelet therapy .43 44 45 46 47 48 49 54

Before stent implantation, assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy.45 59 Some experts recommend that PCI with coronary stenting should not be performed in patients not likely to tolerate or comply with dual antiplatelet therapy for the appropriate duration of treatment based on the type of stent implanted.994

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 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).1006 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.806

Advise patients to not discontinue dual-drug antiplatelet therapy without first consulting with their cardiologist, even if instructed to do so by another health-care professional.1 45

AHA/ACC guidelines provide recommendations for timing of elective surgical procedures in patients treated with PCI and stenting to minimize bleeding and risk of stent thrombosis.1005

Thrombotic Thrombocytopenic Purpura (TTP)

Rarely reported, sometimes after short exposure (<2 weeks) to the drug.1 11 12 Potentially fatal; requires urgent treatment, including plasmapheresis.1

Cross-Reactivity Among Thienopyridines

Patients with a history of hypersensitivity or hematologic reaction to other thienopyridines have experienced hypersensitivity, including rash, angioedema, or hematologic reaction, after receiving clopidogrel.1

Specific Populations

Pregnancy

Available data have not identified any drug-associated risk of major birth defects or miscarriage.1 No evidence of fetotoxicity in animal studies.1

Neuraxial blockade during clopidogrel use should be avoided because of the risk of spinal hematoma.1 When possible, discontinue clopidogrel 5–7 days prior to labor, delivery, or neuraxial blockade.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1

Consider benefits of breast-feeding along with importance of the drug to the mother and any adverse effects on the infant from the drug or underlying maternal condition.1

Pediatric Use

Manufacturer states that safety and efficacy not established in pediatric patients.1

Has been used in some neonates and infants† [off-label] with certain cardiac conditions that predispose them to thrombosis.97

Geriatric Use

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

Hepatic Impairment

Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to be similar to that observed in healthy individuals.1

Renal Impairment

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

Bleeding.1

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Converted to active metabolite in part by CYP2C19.1 72 78 80 81 82 83 (See Metabolism under Pharmacokinetics.) Potential pharmacokinetic (decreased or increased concentrations of active metabolite) and pharmacodynamic (reduced or increased antiplatelet effects) interaction with inhibitors or inducers of CYP2C19.1 72 76 81 88 89 Avoid concomitant use of drugs known to be potent inhibitors or inducers of CYP2C19.1 20 101 356

Appears to inhibit CYP2C9 in vitro at high concentrations.1 8 20

Proton-Pump Inhibitors

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 91 100 101 102 103 106 107 109 350 351 356 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 necessary, consider using an agent with little or no CYP2C19-inhibitory activity.81 89 92 102 103 109 111 112 114 350 (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

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 who have a history of upper GI bleeding.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

Specific Drugs

Drug

Interaction

Comments

Antacids

No evidence that antacids interfere with antiplatelet effects of clopidogrel101

Dexlansoprazole

Effects on exposure to clopidogrel's active metabolite and on clopidogrel-induced platelet inhibition not considered clinically important350 353

No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of dexlansoprazole353

Esomeprazole

Decreased plasma concentrations of clopidogrel’s active metabolite and diminished antiplatelet effect1 101 350

Avoid concomitant use1 101

Histamine H2-receptor antagonists (ranitidine, famotidine, nizatidine)

No evidence that H2-receptor antagonists (except cimetidine) interfere with antiplatelet effects of clopidogrel76 100

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

Lansoprazole

Effects on exposure to clopidogrel's active metabolite and on clopidogrel-induced platelet inhibition not considered clinically important350 354

No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of lansoprazole354

NSAIAs

Potential increased risk of bleeding1

Omeprazole

Decreased plasma concentrations of clopidogrel’s active metabolite and diminished antiplatelet effect1 72 79 81 84 88 91 92 100 101 102 103 106 107 109

Avoid concomitant use1 100 101

Separation of administration times does not avoid interaction1 20 100 101 123 351 356

Opiate agonists

Possible delayed or reduced absorption of clopidogrel’s active metabolite because of slowed gastric emptying1

Consider use of a parenteral antiplatelet agent1

Pantoprazole

Effects on exposure to clopidogrel's active metabolite and on clopidogrel-induced platelet inhibition not considered clinically important351 355

No clopidogrel dosage adjustment required if used concomitantly with FDA-labeled dosages of pantoprazole355

Rabeprazole

Reduced efficacy observed with concomitant clopidogrel and omeprazole or esomeprazole; extent to which rabeprazole may interfere with clopidogrel’s effects unknown1 100 101 106 114 350

FDA states insufficient information available to make specific recommendations about concomitant use with clopidogrel100

Repaglinide

Potential increased exposure to repaglinide1

Avoid concomitant use or initiate repaglinide at 0.5 mg before each meal and do not exceed total daily dose of 4 mg1

SSRIs/SNRIs

Potential increased risk of bleeding via pharmacodynamic interaction1

Warfarin

Possible increased risk of bleeding1 6 8

Use caution6 8
Clopidogrel drug interactions (more detail)

Clopidogrel Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration;1 ≥50% of an oral dose is absorbed.1 Peak plasma concentrations of the active metabolite occur approximately 30–60 minutes following an oral dose.1

Onset

Following oral administration of a single dose, dose-dependent platelet aggregation inhibition can be observed in 2 hours.1

Repeated dosage (75 mg daily) causes inhibition of ADP-induced platelet aggregation on the first day, and steady-state inhibition (40–60%) occurs in 3–7 days.1 2 6

Duration

After discontinuance, platelet aggregation and bleeding times gradually return to baseline in about 5 days.1 2 6

Food

In healthy males, 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

Special Populations

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 in Poor CYP2C19 Metabolizers under Cautions.)

Elimination

Metabolism

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

Elimination Route

Excreted in urine (50%) and in feces (46%).1

Half-life

Clopidogrel: Approximately 6 hours following single oral dose of 75 mg.1

Active metabolite: 30 minutes.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30 °C).1

Actions

Advice to Patients

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Clopidogrel Bisulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

75 mg (of clopidogrel)*

Clopidogrel Tablets

Plavix

Sanofi-Aventis (also promoted by Bristol-Myers Squibb)

300 mg (of clopidogrel)*

Clopidogrel Tablets

Plavix

Sanofi-Aventis (also promoted by Bristol-Myers Squibb)

AHFS DI Essentials™. © Copyright 2024, Selected Revisions December 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

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