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Clopidogrel

Pronunciation

Pronunciation

(kloh PID oh grel)

Index Terms

  • Clopidogrel Bisulfate

Dosage Forms

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

Slideshow: Atrial Fibrillation - Stroke Prevention Guidelines & Treatment Options

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

Unstable angina/non-ST-segment elevation myocardial infarction: To decrease the rate of a combined end point of cardiovascular death, MI, or stroke, as well as the rate of a combined end point of cardiovascular death, MI, stroke, or refractory ischemia 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.

ST-segment elevation acute myocardial infarction: To reduce the rate of death from any cause and the rate of a combined end point of death, reinfarction, or stroke in patients with ST-elevation MI (STEMI).

Recent myocardial infarction, recent stroke, or established peripheral arterial disease: To reduce the rate of a combined end point of new ischemic stroke (fatal or nonfatal), new MI (fatal or nonfatal), and other vascular death in patients with a history of recent MI, recent stroke, or established peripheral arterial disease.

Canadian labeling: Additional use (not in U.S. labeling): Prevention of atherothrombotic and thromboembolic events, including stroke, in patients with atrial fibrillation with at least 1 risk factor for vascular events who are not suitable for treatment with an anticoagulant and are at a low risk for bleeding.

Use: Unlabeled

In patients with allergy or major gastrointestinal intolerance to aspirin, initial treatment of unstable angina/non-ST-elevation myocardial infarction (UA/NSTEMI) or prevention of coronary artery bypass graft closure (saphenous vein); stable coronary artery disease (in combination with aspirin); adjunctive therapy to support reperfusion with primary percutaneous coronary intervention (PCI); in patients having undergone peripheral artery percutaneous transluminal angioplasty; symptomatic carotid artery stenosis (including recent carotid endarterectomy)

Contraindications

Hypersensitivity to clopidogrel or any component of the formulation; active pathological bleeding such as peptic ulcer or intracranial hemorrhage

Canadian labeling: Additional contraindications (not in U.S. labeling): Significant liver impairment or cholestatic jaundice

Dosage

Oral: Adults:

Recent MI, recent stroke, or established peripheral arterial disease (PAD): 75 mg once daily. Note: The ACCF/AHA guidelines for PAD recommend clopidogrel as an alternative to aspirin (Class Ib recommendation) or in conjunction with aspirin for those who are not at an increased risk of bleeding but are of high cardiovascular risk (Class IIb recommendation). These recommendations also pertain to those with intermittent claudication or critical limb ischemia, prior lower extremity revascularization, or prior amputation for lower extremity ischemia (Rooke 2011).

Acute coronary syndrome (ACS):

Unstable angina, non-ST-segment elevation myocardial infarction (UA/NSTEMI): Initial: 300 mg loading dose, followed by 75 mg once daily for up to 12 months (in combination with aspirin indefinitely) (ACCF/AHA [Anderson 2013]). The American College of Chest Physicians recommends combination aspirin dose of 75 to 100 mg (Guyatt 2012).

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, UA/NSTEMI 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 for at least 12 months (in combination with aspirin 81 mg/day) (ACCF/AHA [Anderson 2013]; 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 (ACCF/AHA [Anderson 2013]; 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 and non-ACS indications: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. According to the ACCF/AHA/SCAI PCI guidelines, at least 12 months of clopidogrel is recommended for those with ACS receiving either stent type (bare metal [BMS] or drug eluting stent [DES]) or those receiving a DES for a non-ACS indication (ACCF/AHA/SCAI [Levine 2011]). The ACCF/AHA guidelines for the management of UA/NSTEMI recommend up to 12 months of clopidogrel in patients with ACS who receive a BMS (ACCF/AHA [Anderson 2013]). A duration >12 months may be considered in patients with DES placement. Recent data has demonstrated that continued dual antiplatelet therapy for a total of 30 months (compared to 12 months) significantly reduced the risk of stent thrombosis and major adverse cardiovascular/cerebrovascular events but was associated with a higher risk of bleeding (Mauri 2014). Those receiving a BMS for a non-ACS indication (ie, elective PCI) should be given clopidogrel for at least 1 month and ideally up to 12 months; if patient is at increased risk of bleeding, give for a minimum of 2 weeks (ACCF/AHA/SCAI [Levine 2011]).

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 (in patients not candidates for warfarin and at a low risk of bleeding) (Canadian labeling; ACTIVE Investigators 2009; off-label use in U.S.): 75 mg once daily (in combination with aspirin 75 to 100 mg once daily). Note: Combination may also be used as an alternative for patients with atrial fibrillation and mitral stenosis (Guyatt 2012).

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

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

Secondary prevention of cardioembolic stroke (patient not candidate for oral anticoagulation) (off-label use): 75 mg once daily (in combination with aspirin) (Guyatt 2012).

Dosing adjustment in 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).

Dosing adjustment in hepatic impairment: Use with caution; experience is limited. Note: Inhibition of ADP-induced platelet aggregation and mean bleeding time prolongation were similar in patients with severe hepatic impairment compared to healthy subjects after repeated doses of 75 mg once daily for 10 days.

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

May be administered without regard to meals.

Dietary Considerations

May be taken without regard to meals. Avoid 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 (Moderate) may increase the serum concentration of BuPROPion. Management: Monitor patients for altered clinical responses to bupropion. The maximum recommended adult dose of naltrexone/bupropion (8 mg/90 mg) tablets is one tablet twice daily when used with moderate or strong CYP2B6 inhibitors. 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

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

Cyclophosphamide: CYP2B6 Inhibitors (Moderate) may decrease serum concentrations of the active metabolite(s) of Cyclophosphamide. More specifically, moderate CYP2B6 inhibitors may decrease the rate of cyclophosphamide conversion to its primary active metabolite, 4-hydroxycyclophosphamide. Monitor therapy

CYP2B6 Substrates: CYP2B6 Inhibitors (Moderate) may decrease the metabolism of CYP2B6 Substrates. 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 (Strong) may decrease the metabolism of CYP2C8 Substrates. Consider therapy modification

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

Dabrafenib: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Dabrafenib. Avoid combination

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

Enzalutamide: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Enzalutamide. Management: Avoid concurrent use of strong CYP2C8 inhibitors and enzalutamide if possible. If the combination must be used, reduce enzalutamide to 80 mg once daily. Avoid combination

Esomeprazole: May diminish the antiplatelet effect of Clopidogrel. Esomeprazole may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Avoid combination

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

Luliconazole: May increase the serum concentration of CYP2C19 Substrates. Monitor therapy

Macrolide Antibiotics: May diminish the therapeutic effect of Clopidogrel. Exceptions: Azithromycin (Systemic); Fidaxomicin; Roxithromycin; Spiramycin. Monitor therapy

Morphine (Liposomal): May diminish the antiplatelet effect of Clopidogrel. Morphine (Liposomal) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Consider alternatives to morphine in clopidogrel treated patients, or the use of other P2Y12 receptor antagonists (e.g., prasugrel or ticagrelor) if morphine use is necessary. The risk of alternative opioids is presently unclear. Consider therapy modification

Morphine (Systemic): May diminish the antiplatelet effect of Clopidogrel. Morphine (Systemic) may decrease serum concentrations of the active metabolite(s) of Clopidogrel. Management: Consider alternatives to morphine in clopidogrel treated patients, or the use of other P2Y12 receptor antagonists (e.g., prasugrel or ticagrelor) if morphine use is necessary. The risk of alternative opioids is presently unclear. 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

Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Ombitasvir, Paritaprevir, Ritonavir, and Dasabuvir. Specifically, the serum concentrations of dasabuvir may increase significantly. Avoid combination

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. Avoid combination

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: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Pioglitazone. Management: Limit pioglitazone adult maximum dose to 15 mg/day when used in combination with any strong CYP2C8 inhibitor. Consider therapy modification

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: Consider a repaglinide dose adjustment and monitor for increased repaglinide effects (eg, hypoglycemia) if combined with clopidogrel. Canadian labeling states that this combination is contraindicated. 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 (Strong) may increase serum concentrations of the active metabolite(s) of Selexipag. CYP2C8 Inhibitors (Strong) may increase the serum concentration of Selexipag. Avoid combination

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

Treprostinil: CYP2C8 Inhibitors (Strong) may increase the serum concentration of Treprostinil. Management: Reduce the initial treprostinil extended release tablet dose to 0.125 mg twice daily, titrating by 0.125 mg twice daily every 3 to 4 days. No preemptive dose adjustment is recommended for other treprostinil products. Consider therapy modification

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

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

Vitamin E (Oral): 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, anasarca, aplastic anemia, arthralgia, bullous rash, chronic gastric ulcer with perforation, colitis (including ulcerative or lymphocytic), confusion, decreased neutrophils, decreased platelet count, dermal hemorrhage, DRESS syndrome, drug-induced hypersensitivity (to other thienopyridines [eg, ticlopidine, prasugrel]), duodenal ulcer, eczema, eosinophilia, eosinophilic pneumonitis, erythema multiforme, erythematous rash, exfoliative dermatitis, gastric ulcer, gastritis, glomerulopathy, granulocytopenia, gynecomastia, hallucination, 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, musculoskeletal disease (bleeding), myalgia, pancreatitis, pancytopenia, paresthesia, prolonged bleeding time, pulmonary embolism, pulmonary hemorrhage, purpura, respiratory tract hemorrhage, retroperitoneal hemorrhage, serum sickness, Stevens-Johnson syndrome, stomatitis, thrombotic thrombocytopenic purpura, toxic epidermal necrolysis, upper gastrointestinal tract ulcer (hemorrhagic), vasculitis, wound hemorrhage

ALERT: U.S. Boxed Warning

Diminished effectiveness in poor metabolizers:

The effectiveness of clopidogrel is dependent on its activation to an active metabolite by the cytochrome P450 (CYP-450) system, principally CYP2C19. Clopidogrel at recommended doses forms less of that metabolite and has a smaller effect on platelet function in patients who are poor metabolizers of CYP2C19. Poor metabolizers who also have acute coronary syndrome or who are undergoing percutaneous coronary intervention and are being treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates than patients with normal CYP2C19 function. Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. Consider alternative treatment or treatment strategies 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 or 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 PUD, severe hepatic impairment), body weight <60 kg, CABG or other surgical procedure, concomitant use of medications that increase risk of bleeding (eg, warfarin, NSAIDs). 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.

• 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.

• 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:

• Atrial fibrillation: Approved indication in Canadian labeling (not in U.S. labeling): Assess bleeding risk carefully prior to initiating therapy in patients with atrial fibrillation; in clinical trials, a significant increase in major bleeding events (including intracranial hemorrhage and fatal bleeding events) were observed in patients receiving clopidogrel plus aspirin versus aspirin alone. Vitamin K antagonist (VKA) therapy (in suitable patients) has demonstrated a greater benefit in stroke reduction than aspirin (with or without clopidogrel).

• Bleeding disorders: Use with caution in patients with platelet disorders, bleeding disorders and/or at increased risk for bleeding (eg, PUD, trauma, or surgery).

• Hepatic impairment: Use with caution in patients with severe hepatic impairment (experience is limited). Use in patients with severe hepatic impairment or cholestatic jaundice is contraindicated in the Canadian labeling.

• 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 severe renal impairment (experience is limited).

Concurrent drug therapy issues:

• Anticoagulants and platelet aggregation inhibitors: Use with caution in patients receiving either anticoagulants (eg, heparin, warfarin) or other platelet aggregation inhibitors; bleeding risk is increased.

• Aspirin: Concurrent use of aspirin and clopidogrel is not recommended for secondary prevention of ischemic stroke or TIA in patients unable to take oral anticoagulants due to hemorrhagic risk (Furie, 2011).

• CYP2C19 inhibitors: Concurrent use with drugs known to inhibit CYP2C19 (eg, proton pump inhibitors) may reduce levels of active metabolite and subsequently reduce clinical efficacy and increase the risk of cardiovascular events; if possible, avoid concurrent use of moderate-to-strong CYP2C19 inhibitors. In patients requiring antacid therapy, consider use of an acid-reducing agent lacking (eg, ranitidine/famotidine) or with less CYP2C19 inhibition. According to the manufacturer, avoid concurrent use of omeprazole (even when scheduled 12 hours apart) or esomeprazole; if a PPI is necessary, the use of an agent with comparatively less effect on the antiplatelet activity of clopidogrel is recommended. Of the PPIs, pantoprazole has the lowest degree of CYP2C19 inhibition in vitro (Li, 2004) and has been shown to have has less effect on conversion of clopidogrel to its active metabolite compared to omeprazole (Angiolillo, 2011). Although lansoprazole exhibits the most potent CYP2C19 inhibition in vitro (Li, 2004; Ogilvie, 2012), an in vivo study of extensive CYP2C19 metabolizers showed less reduction of the active metabolite of clopidogrel by lansoprazole/dexlansoprazole compared to esomeprazole/omeprazole (Frelinger, 2012). Avoidance of rabeprazole appears prudent due to potent in vitro CYP2C19 inhibition and lack of sufficient comparative in vivo studies with other PPIs. In contrast to these warnings, others have recommended the continued use of PPIs, regardless of the degree of inhibition, in patients with multiple risk factors for GI bleeding who are also receiving clopidogrel since no evidence has established clinically meaningful differences in outcome; however, a clinically-significant interaction cannot be excluded in those who are poor metabolizers of clopidogrel. Staggering PPIs with clopidogrel is not recommended until further evidence is available (Abraham, 2010).

Special populations:

• Reduced CYP2C19 function: [U.S. Boxed Warning]: Patients with one or more copies of the variant CYP2C19*2 and/or CYP2C19*3 alleles (and potentially other reduced-function variants) may have reduced conversion of clopidogrel to its active thiol metabolite. Lower active metabolite exposure may result in reduced platelet inhibition and, thus, a higher rate of cardiovascular events following MI or stent thrombosis following PCI. Although evidence is insufficient to recommend routine genetic testing, tests are available to determine CYP2C19 genotype and may be used to determine therapeutic strategy; alternative treatment or treatment strategies may be considered if patient is identified as a CYP2C19 poor metabolizer. 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).

Other warnings/precautions:

• Appropriate use: 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]).

• 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.

Monitoring Parameters

Signs of bleeding; hemoglobin and hematocrit periodically. May consider platelet function testing to determine platelet inhibitory response or genotyping for CYP2C19 loss of function variant if results of testing may alter management (ACCF/AHA [Anderson, 2013]).

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events were not 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; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), angina, severe headache, shortness of breath, illogical thinking, skin discoloration, pharyngitis, arrhythmia, 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; feeling very tired or weak; dark urine or yellow skin or eyes; pale skin; change in the amount of urine passed; vision changes; change in strength on 1 side is greater than the other, trouble 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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