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Clopidogrel

Pronunciation

Pronunciation

(kloh PID oh grel)

Index Terms

  • Clopidogrel Bisulfate
  • Clopidogrel Hydrogen Sulfate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Plavix: 75 mg, 300 mg

Generic: 75 mg, 300 mg

Brand Names: U.S.

  • Plavix

Pharmacologic Category

  • Antiplatelet Agent
  • Antiplatelet Agent, Thienopyridine

Pharmacology

Clopidogrel requires in vivo biotransformation to an active thiol metabolite. The active metabolite irreversibly blocks the P2Y12 component of ADP receptors on the platelet surface, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet aggregation. Platelets blocked by clopidogrel are affected for the remainder of their lifespan (~7-10 days).

Absorption

Rapid, well absorbed

Metabolism

Extensively hepatic via esterase-mediated hydrolysis to a carboxylic acid derivative (inactive) and via CYP450-mediated (CYP2C19 primarily) oxidation to a thiol metabolite (active)

Excretion

Following administration of a single 14C-labeled clopidogrel oral dose; radioactivity measured over 5 days: Urine (50%); feces (46%)

Onset of Action

Onset of action: Inhibition of platelet aggregation (IPA): Dose-dependent:

300-600 mg loading dose: Detected within 2 hours

50-100 mg/day: Detected by the second day of treatment

Peak effect: Time to maximal IPA: Dose-dependent: Note: Degree of IPA based on adenosine diphosphate (ADP) concentration used during light aggregometry:

300-600 mg loading dose:

ADP 5 micromole/L: 20% to 30% IPA at 6 hours post administration (Montelescot, 2006)

ADP 20 micromole/L: 30% to 37% IPA at 6 hours post administration (Montelescot, 2006)

50-100 mg/day: ADP 5 micromole/L: 50% to 60% IPA at 5-7 days (Herbert, 1993)

Time to Peak

Serum: ~0.75 hours

Duration of Action

Platelet aggregation and bleeding time gradually return to baseline after ~5 days after discontinuation.

Half-Life Elimination

Parent drug: ~6 hours; Thiol derivatiove (active metabolite) ~30 minutes; carboxylic acid derivative (inactive; main circulating metabolite): ~8 hours; Note: A clopidogrel radiolabeled study has shown that covalent binding to platelets accounts for 2% of radiolabel and has a half-life of 11 days.

Protein Binding

Parent drug: 98%; Inactive metabolite (carboxylic acid derivative): 94%

Special Populations: Renal Function Impairment

After repeated doses of clopidogrel 75 mg/day, patients with severe (CrCl 5 to 15 mL/minute) and moderate (CrCl 30 to 60 mL/minute) renal impairment showed low (25%) inhibition of ADP-induced platelet aggregation.

Special Populations: Gender

Less inhibition of ADP-induced platelet aggregation was observed in women.

Use: Labeled Indications

Acute coronary syndrome:

Acute ST-segment elevation myocardial infarction: To reduce the rate of myocardial infarction and stroke in conjunction with aspirin in patients with acute ST-elevation MI (STEMI) who are to be managed medically.

Unstable angina/non-ST-segment elevation myocardial infarction: To decrease the rate of MI and stroke in conjunction with aspirin in patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-ST-elevation myocardial infarction [UA/NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization.

Recent myocardial infarction, recent stroke, or established peripheral arterial disease: To reduce the rate of MI and stroke in patients with a history of recent MI, recent stroke, or established peripheral arterial disease.

Off Label Uses

Adjunctive therapy to support reperfusion with primary percutaneous coronary intervention

Data from a prospective, randomized, double-blind, placebo-controlled trial supports the use of clopidogrel as an adjunctive therapy in this setting [Sabatine 2005b]. Additionally, a smaller study conducted in patients undergoing primary percutaneous coronary intervention (PCI) for STEMI demonstrated a reduction in infarct size (primary endpoint) with a 600 mg loading dose versus a 300 mg loading dose [Patti 2011].

Based on the American College of Cardiology Foundation/American Heart Association (ACCF/AHA) guidelines for the management of ST-elevation myocardial infarction, clopidogrel is an effective and recommended adjunctive antithrombotic agent to support reperfusion with primary PCI.

Atrial fibrillation (primary prevention of thromboembolism)

Two large randomized controlled trials evaluated the use of dual antiplatelet therapy (ie, clopidogrel and aspirin) in patients with atrial fibrillation. While the use of warfarin was found to be clearly superior to the use of dual antiplatelet therapy in the ACTIVE W trial, data from the ACTIVE A trial supports the use of clopidogrel (in combination with aspirin) for the prevention of major vascular events, especially stroke, in patients with atrial fibrillation with at least 1 risk factor for stroke who in the uncommon scenario cannot take oral anticoagulants for reasons other than elevated risk of bleeding (ACTIVE Investigators 2006; ACTIVE Investigators 2009). In a subsequent analysis of the ACTIVE trials, the addition of clopidogrel to aspirin in patients with AF for whom warfarin was unsuitable resulted in only modest net benefit. The patient with an elevated bleeding risk who is not a candidate for oral anticoagulation would not be a candidate for dual antiplatelet therapy given the comparable risk of bleeding events (Connolly 2011).

Based on the 2012 American College of Chest Physicians antithrombotic guidelines, the combination of clopidogrel and aspirin is an alternative antithrombotic strategy in patients with AF who are at intermediate to high risk of stroke; however, the use of oral anticoagulation is preferred in patients especially if the patient has multiple risk factors for stroke. For those patients who are unsuitable for or choose not to take an oral anticoagulant (for reasons other than concerns for bleeding), clopidogrel in combination with aspirin is recommended. Based on the 2014 American Heart Association/American College of Cardiology/Heart Rhythm Society guidelines on the management of patients with atrial fibrillation, the selection of an antithrombotic agent should be based on the shared decision making with the patient taking into consideration multiple factors (eg, cost, tolerability). No specific recommendation regarding the use of clopidogrel and aspirin as an alternative was made.

Coronary artery bypass graft (CABG) surgery (secondary prevention)

Based on the American Heart Association (AHA) scientific statement for the secondary prevention after coronary artery bypass graft surgery, clopidogrel is a reasonable alternative to aspirin for patients who are intolerant or allergic to aspirin. Additionally, in patients following off-pump CABG, clopidogrel in combination with aspirin should be administered for 1 year to reduce graft occlusion. In patients following on-pump CABG (without recent acute coronary syndrome), clopidogrel in combination with aspirin may be considered but benefits are not well established.

Non-ST-elevation acute coronary syndromes in patients with allergy or major gastrointestinal intolerance to aspirin

Based on the American Heart Association/American College of Cardiology (AHA/ACC) guidelines for the management of patients with non-ST-elevation acute coronary syndromes (NSTE-ACS), clopidogrel (given initially and continued indefinitely) may be used as an alternative for patients with allergy or major gastrointestinal intolerance to aspirin.

Percutaneous coronary intervention (PCI), non-acute coronary syndrome (ie, stable ischemic heart disease)

Based on the 2011 American College of Cardiology Foundation/American Heart Association/Society for Cardiovascular Angiography and Interventions (ACCF/AHA/SCAI) percutaneous coronary intervention guidelines, clopidogrel is an effective and recommended adjunctive oral antithrombotic agent for patients with non-ACS (ie, stable ischemic heart disease [SIHD]) undergoing PCI.

Peripheral artery percutaneous transluminal angioplasty

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy and prevention of thrombosis, clopidogrel is an effective and recommended treatment option for patients undergoing peripheral artery percutaneous transluminal angioplasty with or without stenting.

Secondary prevention of cardiovascular disease (patients with diabetes and an aspirin allergy)

Based on the American Diabetes Association (ADA) Standards of Medical Care in Diabetes, clopidogrel is effective and recommended for the secondary prevention of cardiovascular disease in patients with diabetes and atherosclerotic disease who have a documented aspirin allergy.

Symptomatic carotid artery stenosis (including recent carotid endarterectomy)

Based on the American College of Chest Physicians (ACCP) guidelines for antithrombotic therapy and prevention of thrombosis, clopidogrel is effective and recommended for patients with symptomatic carotid stenosis (including recent carotid endarterectomy).

Contraindications

Hypersensitivity (eg, anaphylaxis) to clopidogrel or any component of the formulation; active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage).

Canadian labeling: Additional contraindications (not in US labeling): Significant liver impairment or cholestatic jaundice; concomitant use of repaglinide.

Dosing: Adult

Acute coronary syndrome (ACS): Oral:

Unstable angina, non-ST-segment elevation myocardial infarction (UA/NSTEMI) (also referred to as NSTE-ACS): Initial: 300 mg or 600 mg loading dose, followed by 75 mg once daily for up to 12 months in combination with aspirin, followed by aspirin indefinitely (ACC/AHA [Amsterdam 2014]). Note: If patient is to undergo PCI, see Percutaneous coronary intervention (PCI) for acute coronary syndrome dosing.

ST-segment elevation myocardial infarction (STEMI) receiving fibrinolytic therapy (in combination with aspirin and appropriate anticoagulant) (ACCF/AHA [O'Gara 2013]): Note: If patient is to undergo primary PCI, see Percutaneous coronary intervention (PCI) for acute coronary syndrome dosing.

Age ≤75 years: Loading dose of 300 mg followed by 75 mg once daily for at least 14 days up to 1 year (in the absence of bleeding).

Age >75 years: 75 mg once daily (no loading dose) for at least 14 days up to 1 year (in the absence of bleeding).

Percutaneous coronary intervention (PCI) for acute coronary syndrome (eg, NSTE-ACS or STEMI) (off-label use): 600 mg (loading dose) given as early as possible before or at the time of PCI, followed by 75 mg once daily (in combination with aspirin) for at least 12 months (bare metal or drug-eluting stent) (ACC/AHA [Amsterdam 2014]); ACC/AHA [Levine 2016]; ACCF/AHA/SCAI [Levine 2011]; ACCF/AHA [O'Gara 2013]).

PCI after fibrinolytic therapy (ACCF/AHA [O'Gara 2013]):

Fibrinolytic administered with a loading dose of clopidogrel: Continue 75 mg once daily and do not administer an additional loading dose.

Fibrinolytic administered within previous 24 hours without a loading dose of clopidogrel: Administer 300 mg loading dose before or at the time of PCI.

Fibrinolytic administered more than 24 hours ago without a loading dose of clopidogrel: Administer 600 mg loading dose before or at the time of PCI.

Higher versus standard maintenance dosing: May consider a maintenance dose of 150 mg once daily for 6 days, then 75 mg once daily thereafter in patients not at high risk for bleeding (CURRENT-OASIS 7 Investigators 2010); however, in another study, in patients with high on-treatment platelet reactivity, the use of 150 mg once daily for 6 months did not demonstrate a difference in 6-month incidence of death from cardiovascular causes, nonfatal MI, or stent thrombosis compared to standard dose therapy (Price 2011).

Duration of clopidogrel (in combination with aspirin) after stent placement for ACS: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. According to the ACC/AHA Duration of Dual Antiplatelet Therapy (DAPT) guidelines, at least 12 months of a P2Y12 inhibitor (eg, clopidogrel) is recommended for those with ACS receiving either stent type (bare metal [BMS] or drug eluting stent [DES]). The DAPT score may be useful in determining whether to prolong or extend DAPT in patients with stent placement (Yeh 2016). In patients with DES placement with a high risk of bleeding or significant overt bleeding on DAPT, it may be reasonable to discontinue clopidogrel after 6 months of therapy (ACC/AHA [Levine 2016]).

CYP2C19 poor metabolizers (ie, CYP2C19*2 or *3 carriers): Although routine genetic testing is not recommended in patients treated with clopidogrel undergoing PCI, testing may be considered to identify poor metabolizers who would be at risk for poor outcomes while receiving clopidogrel; if identified, these patients may be considered for an alternative P2Y12 inhibitor (Levine 2011). An appropriate regimen for this patient population has not been established in clinical outcome trials. Although a 600 mg loading dose, followed by 150 mg once daily produced greater active metabolite exposure and antiplatelet response compared to the 300 mg/75 mg regimen, it does not appear that this dosing strategy improves outcomes for this patient population (Price 2011; Simon 2011).

Atrial fibrillation, primary prevention of thromboembolism (off-label use): Oral: 75 mg once daily (in combination with aspirin 75 to 100 mg once daily) (ACTIVE Investigators 2009). Note: Oral anticoagulation is preferred; clopidogrel and aspirin may be used in patients who cannot take oral anticoagulation and are at low bleeding risk (ACCP [You 2012]). The patient with an elevated bleeding risk who is not a candidate for oral anticoagulation would not be a candidate for dual antiplatelet therapy given the comparable risk of bleeding events (Connolly 2011)

Carotid artery stenosis, symptomatic (including recent carotid endarterectomy) (off-label use): Oral: 75 mg once daily (ACCP [Guyatt 2012])

Coronary artery bypass graft surgery (secondary prevention) (off-label use) (AHA [Kulik 2015]):

Following off-pump CABG: 75 mg once daily (in combination with aspirin) for 1 year

Aspirin-allergic or -intolerant patients: 75 mg once daily; continue indefinitely

Coronary artery disease (CAD), established (off-label use): Oral: 75 mg once daily. Note: Established CAD defined as patients 1-year post ACS, with prior revascularization, coronary stenosis >50% by angiogram, and/or evidence for cardiac ischemia on diagnostic testing (includes patients after the first year post-ACS and/or with prior CABG surgery) (ACCP [Guyatt 2012]).

Percutaneous coronary intervention (PCI), non-acute coronary syndrome (ie, stable ischemic heart disease) (off-label use): 600 mg (loading dose) given as early as possible before or at the time of PCI, followed by 75 mg once daily (in combination with aspirin) for at least 1 month (bare metal stent) or for at least 6 months (drug-eluting stent) (ACC/AHA [Levine 2016]; ACCF/AHA/SCAI [Levine 2011]).

Duration of clopidogrel (in combination with aspirin) after stent placement for stable ischemic heart disease (SIHD): Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. According to the ACC/AHA Duration of Dual Antiplatelet Therapy (DAPT) guidelines, those receiving a newer generation DES, at least 6 months of clopidogrel therapy is recommended. Those receiving a BMS should be given clopidogrel for a minimum of 1 month. The DAPT score may be useful in determining whether to prolong or extend DAPT in patients with stent placement (Yeh 2016). In patients with DES placement with a high risk of bleeding or significant overt bleeding on DAPT, it may be reasonable to discontinue clopidogrel after 3 months of therapy (ACC/AHA [Levine 2016]).

Peripheral artery percutaneous transluminal angioplasty (with or without stenting) or peripheral artery bypass graft surgery, postprocedure (off-label use): Oral: 75 mg once daily. Note: For below-knee bypass graft surgery with prosthetic grafts, combine with aspirin 75-100 mg/day (ACCP [Guyatt 2012]).

Recent MI, recent stroke, or established peripheral arterial disease (PAD): Oral: 75 mg once daily.

Guideline recommendations regarding concomitant therapy and durations of therapy (off-label):

Minor ischemic stroke or TIA, secondary prevention: The combination of clopidogrel and aspirin might be considered within 24 hours of a minor ischemic stroke or TIA and continued for 21 days (AHA/ASA [Kernan 2014]).

Intracranial atherosclerosis (70% to 99% stenosis of a major intracranial artery), secondary prevention: The combination of clopidogrel and aspirin for 90 days is recommended in patients with recent stroke/TIA (within 30 days) due to severe stenosis [70% to 99%]) (AHA/ASA [Kernan 2014]).

PAD: Clopidogrel is recommended as an alternative to aspirin or in conjunction with aspirin for those who are not at an increased risk of bleeding but are of high cardiovascular risk. These recommendations also pertain to those with intermittent claudication or critical limb ischemia, prior lower extremity revascularization, or prior amputation for lower extremity ischemia (ACCF/AHA [Rooke 2011]).

Secondary prevention of cardioembolic stroke (patient not candidate for oral anticoagulation): The combination of clopidogrel and aspirin is recommended (ACCP [Guyatt 2012])

Secondary prevention of cardiovascular disease (patients with diabetes and an aspirin allergy) (off-label use): Oral: 75 mg once daily (ADA 2017)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No dosage adjustment necessary (Basra 2011). Note: GFR stage 5 (ie, ESRD or an eGFR <15 mL/minute) is associated with higher residual platelet reactivity with maintenance dosing (Muller 2012).

Hemodialysis: Not dialyzable (NCS/SCCM [Frontera 2016])

Dosing: Hepatic Impairment

No dosage adjustment necessary.

Extemporaneously Prepared

A 5 mg/mL oral suspension may be made using tablets. Crush four 75 mg tablets and reduce to a fine powder. Add a small amount of a 1:1 mixture of Ora-Sweet® and Ora-Plus® and mix to a uniform paste; mix while adding the vehicle in geometric proportions to almost 60 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 60 mL. Label "shake well". Stable 60 days at room temperature or under refrigeration.

Skillman KL, Caruthers RL, and Johnson CE, "Stability of an Extemporaneously Prepared Clopidogrel Oral Suspension," Am J Health Syst Pharm, 2010, 67(7):559-61.20237383

Administration

Administer without regard to meals.

Dietary Considerations

Avoid or minimize the consumption of grapefruit juice (Holmberg, 2013).

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Agents with Antiplatelet Properties (e.g., P2Y12 inhibitors, NSAIDs, SSRIs, etc.): May enhance the antiplatelet effect of other Agents with Antiplatelet Properties. Monitor therapy

Amiodarone: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

Amodiaquine: CYP2C8 Inhibitors may increase the serum concentration of Amodiaquine. Avoid combination

Anticoagulants: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Anticoagulants. Monitor therapy

Apixaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Apixaban. Specifically, the risk for bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

BuPROPion: CYP2B6 Inhibitors (Weak) may increase the serum concentration of BuPROPion. Monitor therapy

Calcium Channel Blockers: May diminish the therapeutic effect of Clopidogrel. Exceptions: Clevidipine. Monitor therapy

Cangrelor: May diminish the antiplatelet effect of Clopidogrel. More specifically, while the use of Cangrelor is expected to increase total platelet inhibition in patients who have previously received Clopidogrel, Cangrelor is expected to decrease binding of Clopidogrel metabolites to P2Y12 receptors and thus reduce the extent of irreversible platelet inhibition. Management: Avoid administration of clopidogrel until cangrelor infusion is discontinued. Consider therapy modification

Cephalothin: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Cephalothin. Specifically, the risk for bleeding may be increased. Monitor therapy

Collagenase (Systemic): Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Monitor therapy

CYP2C19 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a moderate CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CYP2C19 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to a risk for impaired clopidogrel effectiveness with such a combination, carefully consider the need for a strong CYP2C19 inhibitor in patients receiving clopidogrel. Monitor patients closely for evidence of a diminished response to clopidogrel. Consider therapy modification

CYP2C8 Substrates: CYP2C8 Inhibitors (Moderate) may decrease the metabolism of CYP2C8 Substrates. Monitor therapy

Dabigatran Etexilate: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Dabigatran Etexilate. Specifically, the risk of bleeding may be increased. Antiplatelet Agents (P2Y12 Inhibitors) may increase the serum concentration of Dabigatran Etexilate. Specifically, clopidogrel may increase dabigatran serum concentrations. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Dasatinib: May enhance the anticoagulant effect of Agents with Antiplatelet Properties. Monitor therapy

Deoxycholic Acid: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Deoxycholic Acid. Specifically, the risk for bleeding or bruising in the treatment area may be increased. Monitor therapy

Dexlansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Edoxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Edoxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider the anticipated risks and benefits of this combination. If combined, increased monitoring for bleeding is recommended. Consider therapy modification

Erythromycin (Systemic): May diminish the antiplatelet effect of Clopidogrel. Monitor therapy

Esomeprazole: May diminish the antiplatelet effect of Clopidogrel. Esomeprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Clopidogrel prescribing information recommends avoiding concurrent use with esomeprazole. Rabeprazole or pantoprazole may be lower-risk alternatives to esomeprazole. Consider therapy modification

FluvoxaMINE: May enhance the adverse/toxic effect of Clopidogrel. Specifically, the risk for bleeding may be increased. FluvoxaMINE may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Monitor therapy

Glucosamine: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Grapefruit Juice: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Advise patients receiving clopidogrel to minimize consumption of grapefruit and grapefruit juice. Consumption of three 200 mL glasses of grapefruit juice a day may substantially reduce clopidogrel antiplatelet effects. Consider therapy modification

Herbs (Anticoagulant/Antiplatelet Properties) (eg, Alfalfa, Anise, Bilberry): May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Bleeding may occur. Consider therapy modification

Ibritumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Ibritumomab. Both agents may contribute to impaired platelet function and an increased risk of bleeding. Monitor therapy

Ibrutinib: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Monitor therapy

Lansoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Limaprost: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Morphine (Liposomal): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Liposomal) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Morphine (Systemic): May diminish the antiplatelet effect of Antiplatelet Agents (P2Y12 Inhibitors). Morphine (Systemic) may decrease the serum concentration of Antiplatelet Agents (P2Y12 Inhibitors). Management: Consider alternative anti-ischemic/analgesic therapies (eg, beta-blockers, nitroglycerin) in patients with acute coronary syndromes treated with a P2Y12 inhibitor when possible. The risks associated with other opioids are unknown. Consider therapy modification

Multivitamins/Fluoride (with ADE): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Multivitamins/Minerals (with AE, No Iron): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Obinutuzumab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Obinutuzumab. Specifically, the risk of serious bleeding-related events may be increased. Monitor therapy

Omega-3 Fatty Acids: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Omeprazole: May diminish the antiplatelet effect of Clopidogrel. Omeprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Clopidogrel labeling recommends avoiding concurrent omeprazole due to a possible decrease in clopidogrel effectiveness. Rabeprazole or pantoprazole may be lower-risk alternatives to omeprazole. Consider therapy modification

PACLitaxel (Conventional): Clopidogrel may increase the serum concentration of PACLitaxel (Conventional). Monitor therapy

PACLitaxel (Protein Bound): Clopidogrel may increase the serum concentration of PACLitaxel (Protein Bound). Monitor therapy

Pantoprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Pentosan Polysulfate Sodium: May enhance the adverse/toxic effect of Agents with Antiplatelet Properties. Specifically, the risk of bleeding may be increased by concurrent use of these agents. Monitor therapy

Pentoxifylline: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Pioglitazone: Clopidogrel may increase the serum concentration of Pioglitazone. Monitor therapy

Prostacyclin Analogues: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

RABEprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Due to the possible risk for impaired clopidogrel effectiveness, clinicians should carefully consider the need for proton pump inhibitor therapy in patients receiving clopidogrel. Other acid-lowering therapies do not appear to share this interaction. Consider therapy modification

Repaglinide: Clopidogrel may increase the serum concentration of Repaglinide. Management: Avoid use of clopidogrel and repaglinide if possible; if the combination must be used, limit total repaglinide daily dose to no more than 4 mg. This is contraindicated in some non-US labeling. Consider therapy modification

Rifamycin Derivatives: May enhance the adverse/toxic effect of Clopidogrel. Specifically,clopidogrel antiplatelet effects may be enhanced. Monitor therapy

Rivaroxaban: Antiplatelet Agents (P2Y12 Inhibitors) may enhance the adverse/toxic effect of Rivaroxaban. Specifically, the risk of bleeding may be increased. Management: Carefully consider risks and benefits of this combination and monitor closely; Canadian labeling recommends avoiding prasugrel or ticagrelor. Consider therapy modification

Rosuvastatin: Clopidogrel may increase the serum concentration of Rosuvastatin. Monitor therapy

Salicylates: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Salicylates. Increased risk of bleeding may result. Monitor therapy

Selexipag: CYP2C8 Inhibitors (Moderate) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Moderate) may increase the serum concentration of Selexipag. Management: If initiating selexipag in a patient on a moderate CYP2C8 inhibitor, consider a less frequent dosing regimen (ie, once daily). If initiating a moderate CYP2C8 inhibitor in a patient on selexipag, consider a selexipag dose reduction. Consider therapy modification

Thrombolytic Agents: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Thrombolytic Agents. Monitor therapy

Tipranavir: May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Tositumomab and Iodine I 131 Tositumomab: Agents with Antiplatelet Properties may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Monitor therapy

Urokinase: Agents with Antiplatelet Properties may enhance the anticoagulant effect of Urokinase. Avoid combination

Vitamin E (Systemic): May enhance the antiplatelet effect of Agents with Antiplatelet Properties. Monitor therapy

Warfarin: Clopidogrel may enhance the anticoagulant effect of Warfarin. Consider therapy modification

Adverse Reactions

As with all drugs that may affect hemostasis, bleeding is associated with clopidogrel. Hemorrhage may occur at virtually any site. Risk is dependent on multiple variables, including the concurrent use of multiple agents that alter hemostasis and patient susceptibility. Frequency not always defined.

Dermatologic: Pruritus

Gastrointestinal: Gastrointestinal hemorrhage (2%)

Hematologic & oncologic: Hematoma

Respiratory: Epistaxis

<1%, postmarketing, and/or case reports (Limited to important or life-threatening): Abdominal pain, abnormal hepatic function tests, acute generalized exanthematous pustulosis, acute hepatic failure, agranulocytosis, anaphylactoid reaction, anasarca, angioedema, aplastic anemia, arthralgia, arthritis, bronchospasm, bullous rash, colitis (including ulcerative or lymphocytic), confusion, constipation, decreased neutrophils, decreased platelet count, dermal hemorrhage, diarrhea, dizziness, DRESS syndrome, drug-induced hypersensitivity (to other thienopyridines [eg, ticlopidine, prasugrel]), duodenal ulcer, dyspepsia, eczema, eosinophilia, eosinophilic pneumonitis, erythema multiforme, erythematous rash, exfoliative dermatitis, fever, flatulence, gastric ulcer, gastritis, glomerulopathy, granulocytopenia, gynecomastia, hallucination, headache, hemarthrosis, hematuria, hemophilia A (acquired), hemophthalmos (including conjunctival and retinal), hemoptysis, hemothorax, hepatitis (noninfectious), hepatitis A, hyperbilirubinemia, hypermenorrhea, hypersensitivity reaction, hypochromic anemia, hypotension, IgA vasculitis, increased serum creatinine, interstitial pneumonitis, intracranial hemorrhage, ischemic necrosis, leukopenia, lichen planus, liver steatosis, maculopapular rash, major hemorrhage (requiring hospitalization), musculoskeletal disease (bleeding), myalgia, nausea, pancreatitis, pancytopenia, paresthesia, peripheral ischemia (potentially leading to necrosis), prolonged bleeding time, pulmonary embolism, pulmonary hemorrhage, purpura, renal function abnormality, respiratory tract hemorrhage, retroperitoneal hemorrhage, serum sickness, Stevens-Johnson syndrome, stomatitis, taste disorder, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, upper gastrointestinal tract ulcer (hemorrhagic), urticaria, vasculitis, vertigo, vomiting, wound hemorrhage

ALERT: U.S. Boxed Warning

Diminished antiplatelet effect in patients with two loss-of-function alleles of the CYP2C19 gene:

The effectiveness of clopidogrel results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP-450) system, principally CYP2C19. Clopidogrel at recommended doses forms less of the active metabolite and has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 genes (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.

Warnings/Precautions

Concerns related to adverse effects:

• Bleeding: Clopidogrel increases the risk of bleeding. Use is contraindicated in patients with active pathological bleeding (eg, peptic ulcer, intracranial hemorrhage). Additional risk factors for bleeding include age ≥75 years, propensity to bleed (eg, recent trauma or surgery, recent or recurrent GI bleeding, active peptic ulcer disease, severe hepatic impairment), body weight <60 kg, CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs). Use with caution in patients with platelet disorders, bleeding disorders and/or at increased risk for bleeding. Bleeding should be suspected if patient becomes hypotensive after undergoing recent coronary angiography, PCI, CABG, or other surgical procedure even if overt signs of bleeding do not exist. It may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.

• Thienopyridine hypersensitivity: Because of structural similarities, cross-reactivity has been reported among the thienopyridines (clopidogrel, prasugrel, and ticlopidine); use with caution or avoid in patients with hypersensitivity or hematologic reactions to previous thienopyridine use. Use of clopidogrel is contraindicated in patients with hypersensitivity to clopidogrel. Although desensitization may be considered for mild-to-moderate hypersensitivity, do not desensitize patients with prior life-threatening allergic reactions to clopidogrel (eg, toxic epidermal necrolysis, exfoliative dermatitis, Stevens-Johnson syndrome, TTP) (Lokhandwala 2011).

• Thrombotic thrombocytopenic purpura (TTP): Cases of TTP (usually occurring within the first 2 weeks of therapy), resulting in some fatalities, have been reported; urgent plasmapheresis is required.

Disease-related concerns:

• Lacunar stroke: In patients with recent lacunar stroke (within 180 days), the use of clopidogrel in addition to aspirin did not significantly reduce the incidence of the primary outcome of stroke recurrence (any ischemic stroke or intracranial hemorrhage) compared to aspirin alone; the use of clopidogrel in addition to aspirin did however increase the risk of major hemorrhage and the rate of all-cause mortality (SPS3 Investigators, 2012).

• Renal impairment: Use with caution in patients with moderate to severe renal impairment (experience is limited).

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2C19 poor metabolizers: [US Boxed Warning]: Effectiveness of clopidogrel results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the CYP-450 system, principally CYP2C19. In patients who are homozygous for nonfunctional alleles of the CYP2C19 genes (termed “CYP2C19 poor metabolizers”), clopidogrel at recommended doses forms less of the active metabolite and has a reduced effect on platelet activity. Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. Genetic testing may be considered prior to initiating clopidogrel in patients at moderate or high risk for poor outcomes (eg, PCI in patients with extensive and/or very complex disease). The optimal dose for CYP2C19 poor metabolizers has yet to be determined. After initiation of clopidogrel, functional testing (eg, VerifyNow® P2Y12 assay) may also be done to determine clopidogrel responsiveness (Holmes, 2010).

• Lower GI bleed patients: An individualized and multidisciplinary approach should be utilized to determine therapy discontinuation and management in patients with acute lower GI bleed (LGIB) who are on antiplatelet medications; risk of ongoing bleeding should be weighed with risk of thromboembolic events. In patients receiving dual antiplatelet therapy (aspirin plus P2Y12 receptor blocker [eg, clopidogrel, prasugrel, ticagrelor, ticlopidine]) or thienopyridine monotherapy, the thienopyridine should generally be resumed as soon as possible and at least within 7 days, taking into account control of bleeding and cardiovascular risk (aspirin should not be discontinued); however, dual antiplatelet therapy should not be discontinued in the 90 days post-acute coronary syndrome or 30 days post-coronary stenting (Strate 2016).

• Surgical patients: Consider discontinuing 5 days before elective surgery (except in patients with cardiac stents that have not completed their full course of dual antiplatelet therapy; patient-specific situations need to be discussed with cardiologist; AHA/ACC/SCAI/ACS/ADA Science Advisory provides recommendations). Discontinue at least 5 days before elective CABG; when urgent CABG is necessary, the ACCF/AHA CABG guidelines recommend discontinuation for at least 24 hours prior to surgery (ACCF/AHA [Hillis, 2011]). The ACCF/AHA STEMI guidelines recommend discontinuation for at least 24 hours prior to on-pump CABG if possible; off-pump CABG may be performed within 24 hours of clopidogrel administration if the benefits of prompt revascularization outweigh the risks of bleeding (ACCF/AHA [O'Gara, 2013]).

Other warnings/precautions:

• Coronary artery stents: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. Duration of therapy, in general, is determined by the type of stent placed (bare metal or drug eluting) and whether an ACS event was ongoing at the time of placement (ACC/AHA [Levine 2016]; AHA/ACC/SCAI/ACS/ADA [Grines 2007]).

Monitoring Parameters

Signs of bleeding; hemoglobin and hematocrit periodically.

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Information related to use during pregnancy is limited (Bauer 2012; DeSantis 2011; Myers 2011).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Have patient report immediately to prescriber signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; hematuria; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), angina, severe headache, shortness of breath, confusion, skin discoloration, pharyngitis, abnormal heartbeat, seizures, back pain, urinary retention, change in amount of urine passed, weight loss, or signs of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (bruising or bleeding; severe loss of strength and energy; dark urine or jaundice; pale skin; change in amount of urine passed; vision changes; change in strength on one side is greater than the other, difficulty speaking or thinking, or change in balance; or fever) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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