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Clopidogrel Bisulfate

Pronunciation

Class: Platelet-aggregation Inhibitors
ATC Class: B01AC04
Brands: Plavix

Warning(s)

Special Alerts:

[Posted 11/16/2014] ISSUE: FDA is evaluating preliminary data from a clinical trial showing that treatment for 30 months with dual antiplatelet blood-thinning therapy decreased the risk of heart attacks and clot formation in stents, but there was an increased overall risk of death compared to 12 months of treatment. The clinical trial compared 30 months versus 12 months of treatment with dual antiplatelet therapy consisting of aspirin plus either clopidogrel (Plavix) or prasugrel (Effient), following implantation of drug-eluting coronary stents. These stents are small, medicine-coated tubes inserted into narrowed arteries in the heart to keep them open and maintain blood flow to the heart. Clopidogrel and prasugrel are important medicines used to prevent heart attacks, strokes, and other clot-related diseases.

FDA believes the benefits of clopidogrel (Plavix) and prasugrel (Effient) therapy continue to outweigh their potential risks when used for approved uses.

BACKGROUND: The Dual Antiplatelet Therapy (DAPT) trial was published in the New England Journal of Medicine on November 16, 2014. FDA has not reviewed the trial results or reached any conclusions based on the findings from this clinical trial. We are communicating this safety information while we continue to evaluate the results from this trial and other available data. We will communicate our final conclusions and recommendations when our evaluation is complete.

RECOMMENDATION: Health care professionals should not change the way they prescribe these drugs at this time. Patients should not stop taking these drugs because doing so may result in an increased risk of heart attacks, blood clots, strokes, and other major cardiovascular problems. For more information visit the FDA website at: and .

Warning(s)

  • Clopidogrel is a prodrug; requires activation by CYP enzyme system (principally by CYP2C19) to produce its pharmacologically active metabolite.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 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

  • Genetic tests are available to determine a patient’s CYP2C19 genotype; results of such tests may be used to guide treatment decisions.1 20 121 122

  • Consider use of other antiplatelet agents or alternative dosing strategies for clopidogrel in patients identified as CYP2C19 poor metabolizers.1 121

Introduction

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

Uses for Clopidogrel Bisulfate

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Cardiovascular Risk Reduction Following Recent MI or Stroke or in Established Peripheral Arterial Disease

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 23 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 23 992

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

Slideshow: Atrial Fibrillation - Stroke Prevention Guidelines & Treatment Options

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

Unstable Angina or Non-ST-Segment Elevation MI (NSTEMI)

Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events in patients with non-ST-segment elevation ACS, including unstable angina and NSTEMI.1 5 18 35 992 993 994 1010 Used in patients who are managed medically or with coronary intervention (e.g., PCI with or without coronary artery stenting, CABG).1 5 18 35 992 993 994 1010

Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist and aspirin is considered part of the current standard of care in patients with ACS.991 992 993 994 1010 The American College of Cardiology Foundation (ACCF), AHA, and other experts recommend antiplatelet therapy with a P2Y12-receptor antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and secondary prevention in patients with ACS, including those undergoing PCI.991 992 993 994 1010

Ticagrelor or clopidogrel generally is recommended 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

Experts generally recommend continuing treatment with a P2Y12-receptor antagonist for up to 12 months in patients managed medically without stenting and ≥12 months in those with coronary artery stents (bare-metal or drug-eluting); continue aspirin therapy indefinitely.992 993 994 1010

ACCP suggests use of ticagrelor over clopidogrel in patients with ACS, regardless of whether PCI is performed; other expert guidelines make no specific recommendations regarding P2Y12-receptor antagonist of choice.992 993 994 1010 When selecting an appropriate antiplatelet regimen, consider individual patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction potential) factors.140 141

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

Temporarily discontinue therapy ≥5 days prior to CABG.1 35 40 1004

ST-Segment Elevation MI (STEMI)

Used in combination with aspirin for reduction of the rate of ischemic cardiovascular and cerebrovascular events in patients with STEMI.1 31 36 134

Experts recommend treatment for 14–28 days in addition to aspirin, with or without reperfusion therapy (i.e., thrombolytic therapy, primary PCI), in patients with suspected STEMI.68

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

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

Chronic Stable Angina

May be used as an alternative to aspirin in patients with symptomatic chronic stable angina who cannot tolerate aspirin.96

Embolism Associated with Atrial Fibrillation and/or Valvular Heart Disease

Has been used in combination with aspirin as an alternative to warfarin for prevention of stroke and systemic embolism in patients with atrial fibrillation.995 997 1007

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

General

Timing of Treatment in Relation to PCI or CABG

  • In patients with ACS in whom PCI is planned, experts recommend administration of a loading dose of clopidogrel as early as possible before or at the time of the procedure.134 994

  • Temporarily discontinue therapy ≥5 days prior to CABG and resume as soon as possible after procedure.1 35 40 134 1004

Administration

Administer orally without regard to meals.1 6 8

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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.)

Adults

Cardiovascular Risk Reduction Following Recent MI or Stroke or in Established Peripheral Arterial Disease
Oral

75 mg once daily.1 2 3 5 6 8 23

Acute Coronary Syndromes
Unstable Angina or NSTEMI
Oral

Manufacturer recommends 300-mg initial loading dose promptly at diagnosis, then 75 mg once daily given concomitantly with aspirin.1 18 20 22

Patients undergoing PCI: 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

STEMI
Oral

Manufacturer recommends 75 mg once daily with or without a loading dose in combination with aspirin.1

Patients undergoing 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.146 994 No apparent benefit with higher loading doses (e.g., 900 mg).147 994

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

Special Populations

Hepatic Impairment

No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Cautions for Clopidogrel Bisulfate

Contraindications

  • Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage).1 6

  • Known hypersensitivity to clopidogrel or any ingredient in the formulation.1

Warnings/Precautions

Warnings

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

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).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 Unstable Angina or 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

Advise patients to never stop taking dual-drug antiplatelet therapy without first consulting with their cardiologist, even if instructed to do so by another health-care professional.1 45

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

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

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

General Precautions

Bleeding

Increased risk of bleeding.1 136 138

Temporarily discontinue clopidogrel ≥5 days prior to elective surgery (e.g., CABG) if antiplatelet effect is undesirable.1 23 35 43 68 1004

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.)

Specific Populations

Pregnancy

Category B.1

Lactation

Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or the drug.1

Pediatric Use

Manufacturer states that safety and efficacy not established in patients <21 years of age.1 20

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

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

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

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

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

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 91 100 101 102 103 106 107 109 350 351 352 356 (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

Specific Drugs

Drug

Interaction

Comments

Antacids

No evidence that antacids interfere with antiplatelet effects of clopidogrel101

Cilostazol

Potential additive antiplatelet effects93 94

Pharmacokinetic interaction unlikely19 93

Caution advised; monitor bleeding times during concurrent administration93

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 effect101 350 352

Avoid concomitant use101 352

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 92 101 103 112 128 136

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

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 100 101 106 114 350 352

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

Warfarin

Possible increased risk of bleeding1 6 8

Use caution6 8

Clopidogrel Bisulfate 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 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

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 Associated with Impaired CYP2C19 Function 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 1

Active metabolite: 30 minutes.1

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30 °C).1

Actions

  • 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

  • ADP receptor is irreversibly modified, so platelets exposed to clopidogrel remain affected for the remainder of their lifespan (about 7–10 days).1 2 4 6 62

  • 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.1 6

Advice to Patients

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

  • 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 any unanticipated, prolonged, or excessive bleeding, or blood in urine or stool.1 6

  • 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.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Clopidogrel Bisulfate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

75 mg (of clopidogrel)

Plavix

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

300 mg (of clopidogrel)

Plavix

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 12/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Plavix 300MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$749.95 or 90/$2,199.95

Plavix 75MG Tablets (B-M SQUIBB U.S. (PRIMARY CARE)): 30/$204.99 or 90/$590.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions November 17, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

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

References

1. Sanofi-Aventis/Bristol-Myers Squibb. Plavix, (clopidogrel bisulfate) tablets prescribing information. New York, NY; 2010 Mar.

2. Coukell AJ, Markham A. Clopidogrel. Drugs. 1997; 54:745- 50. [PubMed 9360060]

3. Gent M, Beaumont D, Blanchard J et al. The CAPRIE Steering Committee. Randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet. 1996; 348:1329-39. [IDIS 376382] [PubMed 8918275]

4. Mills DC, Puri R, Hu CJ et al. Clopidogrel inhibits the binding of ADP analogues to the receptor mediating inhibition of platelet adenylate cyclase. Arterioscler Thromb. 1992; 12:430-6. [PubMed 1558834]

5. Pepine CJ. Aspirin and newer orally active antiplatelet agents in the treatment of the post-myocardial infarction patient. J Am Coll Cardiol. 1998; 32:1126-8. [IDIS 415365] [PubMed 9768742]

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