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Clopidogrel

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
Brands: Plavix

Medically reviewed by Drugs.com on Dec 21, 2021. 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).

  • Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel. (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.

  • Genetic tests are available to identify patients who are poor CYP2C19 metabolizers.

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

Introduction

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

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. (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.

American College of Cardiology (ACC)/American Heart Association (AHA) has issued guidelines for treatment options and duration of DAPT. 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.

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.

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.

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.

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.

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.

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.

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

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. 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.

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.

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

Prevention of Stent Thrombosis

Has been used in combination with aspirin (DAPT) to prevent stent thrombosis following implantation of coronary artery stents.

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. Therefore, current recommendations for duration of DAPT apply principally to the use of newer-generation stents.

DAPT should be given to patients with ACS who receive a BMS or DES for at least 12 months. 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. (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.

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

Embolism Associated with Atrial Fibrillation

Has been used in combination with aspirin for prevention of stroke and systemic embolism in patients with atrial fibrillation. 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).

Has been used in patients with atrial fibrillation and ACS. 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. If triple therapy is considered in patients with high thrombotic risk and low bleeding risk, the shortest possible duration of therapy should be used.

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.

Clopidogrel Dosage and Administration

Administration

Administer orally without regard to meals.

Dosage

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

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).

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.

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. Initiate clopidogrel therapy before or with the thrombolytic agent. Continue therapy at 75 mg once daily for ≥14 days and up to 1 year.

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.

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

Peripheral Arterial Disease or History of MI or Stroke
Oral

75 mg once daily.

Special Populations

Hepatic Impairment

No dosage adjustment necessary.

Geriatric Patients

No dosage adjustment necessary.

Cautions for Clopidogrel

Contraindications

  • Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).

  • Known hypersensitivity to clopidogrel or any ingredient in the formulation.

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. 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.

Genetic tests are available to identify patients with variant CYP2C19 genotypes. (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.

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

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. CPIC also recommends consideration of alternative anticoagulation in patients with an intermediate CYP2C19 phenotype.

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. (See Proton-Pump Inhibitors under Interactions.) Reduced effectiveness in preventing cardiovascular events possible.

Concomitant use of other drugs that inhibit CYP2C19 also may decrease response to clopidogrel. (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Other Warnings and Precautions

Bleeding

Increased risk of bleeding.

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

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.

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.

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. However, consider possibility of reduced antiplatelet effects when clopidogrel is used concomitantly with certain proton-pump inhibitors (e.g., omeprazole, esomeprazole). (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. Stent thrombosis with potentially fatal sequelae, particularly with drug-eluting stents (DES), associated with premature discontinuance of dual antiplatelet therapy .

Before stent implantation, assess patients for likelihood of compliance with prolonged dual-drug antiplatelet therapy. 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.

At least 12 months of dual antiplatelet therapy is recommended following placement of any type of coronary artery stent (bare-metal or drug-eluting). 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). 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.

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.

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.

Thrombotic Thrombocytopenic Purpura (TTP)

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

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.

Specific Populations

Pregnancy

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

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

Lactation

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

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.

Pediatric Use

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

Has been used in some neonates and infants with certain cardiac conditions that predispose them to thrombosis.

Geriatric Use

In patients ≥75 years of age, no difference in platelet aggregation observed compared with younger healthy individuals. In a clinical trial, geriatric patients were at greater risk for thrombotic events and major bleeding than younger patients.

Hepatic Impairment

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

Renal Impairment

Experience limited in patients with moderate or severe renal impairment.

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.

Common Adverse Effects

Bleeding.

Interactions for Clopidogrel

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Converted to active metabolite in part by CYP2C19. (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. Avoid concomitant use of drugs known to be potent inhibitors or inducers of CYP2C19.

Appears to inhibit CYP2C9 in vitro at high concentrations.

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). Increased risk of adverse cardiovascular events possible.

If concomitant proton-pump inhibitor therapy is necessary, consider using an agent with little or no CYP2C19-inhibitory activity. (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.

Weigh risks and benefits of concomitant use of any proton-pump inhibitor in individual patients. 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. Alternatively, consider concomitant therapy with antacids or H2-receptor antagonists (i.e., ranitidine, famotidine, nizatidine), except for cimetidine (also a potent CYP2C19 inhibitor).

Specific Drugs

Drug

Interaction

Comments

Antacids

No evidence that antacids interfere with antiplatelet effects of clopidogrel

Dexlansoprazole

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

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

Esomeprazole

Decreased plasma concentrations of clopidogrel’s active metabolite and diminished antiplatelet effect

Avoid concomitant use

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

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

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 effective

Lansoprazole

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

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

NSAIAs

Potential increased risk of bleeding

Omeprazole

Decreased plasma concentrations of clopidogrel’s active metabolite and diminished antiplatelet effect

Avoid concomitant use

Separation of administration times does not avoid interaction

Opiate agonists

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

Consider use of a parenteral antiplatelet agent

Pantoprazole

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

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

Rabeprazole

Reduced efficacy observed with concomitant clopidogrel and omeprazole or esomeprazole; extent to which rabeprazole may interfere with clopidogrel’s effects unknown

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

Repaglinide

Potential increased exposure to repaglinide

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

SSRIs/SNRIs

Potential increased risk of bleeding via pharmacodynamic interaction

Warfarin

Possible increased risk of bleeding

Use caution

Clopidogrel Pharmacokinetics

Absorption

Bioavailability

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

Onset

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

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.

Duration

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

Food

In healthy males, administration with a high-fat or standard meal decreased mean inhibition of platelet aggregation by <9%. Although food decreased peak plasma concentrations of the active metabolite by 57%, systemic exposure to the active metabolite was unaffected.

Special Populations

Peak plasma concentrations and exposure to clopidogrel’s active metabolite decreased by 30–50% in patients with genetically reduced CYP2C19 function. (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).

Elimination Route

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

Half-life

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

Active metabolite: 30 minutes.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30 °C).

Actions

  • Prodrug; platelet-aggregation inhibitory activity is dependent on hepatic transformation to an active metabolite.

  • Pharmacogenomics: Genetic polymorphism of CYP2C19 can affect pharmacokinetic and pharmacodynamic response to clopidogrel. Patients with at least one loss-of-function variant CYP2C19 allele (e.g., CYP2C19*2, CYP2C19*3) are described as poor or intermediate metabolizers of clopidogrel and have lower plasma concentrations of active metabolite and diminished antiplatelet response. Approximately 2–14% of the population is estimated to be poor metabolizers of CYP2C19; however, there is wide variability among different racial/ethnic populations. (See Reduced Efficacy in Poor CYP2C19 Metabolizers under Cautions.)

  • Active metabolite binds selectively and noncompetitively to platelet surface low-affinity platelet P2Y12 ADP-receptor binding site. Inhibits ADP binding to the receptor and subsequent receptor activation of the platelet glycoprotein (GP IIb/IIIa) complex necessary for fibrinogen-platelet binding.

  • ADP receptor is irreversibly modified, so platelets exposed to clopidogrel remain affected for the remainder of their lifespan (about 7–10 days).

  • Also inhibits ADP-mediated release of platelet dense granule (e.g., ADP, calcium, serotonin) and alpha granule (e.g., fibrinogen, thrombospondin) contents that augment platelet aggregation.

Advice to Patients

  • Importance of counseling patients about potential risks versus benefits of clopidogrel.

  • 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.

  • Importance of informing patient not to discontinue therapy without consulting their prescribing clinician.

  • Importance of patient informing clinician about any unanticipated, prolonged, or excessive bleeding, or blood in urine or stool.

  • Importance of patient informing clinician about clopidogrel therapy before any surgery is scheduled.

  • Advise patients not to take omeprazole or esomeprazole while taking clopidogrel.

  • Importance of patient informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs, particularly omeprazole or esomeprazole and drugs that affect bleeding (e.g., warfarin, NSAIAs).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

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 2022, Selected Revisions December 21, 2021. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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

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