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Product Name
:
CLOPID
Chemical Name
:
Clopidogrel (Bisulfate)
Therapeutic Category
:
Cardiovascular drugs
Pharmacologic Category
:
Antiplatelet Agent, Thienopyridine
Pharmaceutical Form
:
Tablets
Composition
:
Clopidogrel (Bisulfate) 75mg
Monitoring Parameters
Dosing
 
Dosing: Adult
Recent MI, recent stroke, or established peripheral arterial disease (PAD): Oral: 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:
Unstable angina, non-ST-segment elevation myocardial infarction (UA/NSTEMI): Initial: 300 mg loading dose, followed by 75 mg once daily for at least 1 month and ideally up to 12 months (in combination with aspirin 75-162 mg once daily indefinitely) (Wright, 2011).
ST-segment elevation myocardial infarction (STEMI): 75 mg once daily (in combination with aspirin 162-325 mg initially followed by 81-162 mg/day). Note: CLARITY-TIMI 28 used a 300 mg loading dose (with thrombolysis) demonstrating an improvement in the patency rate of the infarct related artery and reduction in ischemic complications. The duration of therapy was <28 days (usually until hospital discharge) unless nonprimary percutaneous coronary intervention (PCI) was performed (Sabatine, 2005).
The American College of Chest Physicians (Goodman, 2008) recommends:
Patients ≤75 years: Initial: 300 mg loading dose, followed by 75 mg once daily for up to 28 days (in combination with aspirin)
Patients >75 years: 75 mg once daily for up to 28 days (with or without thrombolysis)
Percutaneous coronary intervention (PCI) for UA/NSTEMI or STEMI: Loading dose: 300-600 mg (600 mg may be preferred for early invasive strategy with UA/NSTEMI) given as early as possible before or at the time of PCI, followed by 75 mg once daily. Note: If an initial loading dose of 300 mg was given prior to PCI, a supplemental loading dose of 300 mg (total loading dose of 600 mg) may be administered (Kushner, 2009). For patients with UA/NSTEMI, it has been recommended that the loading dose be given at least 2 hours (or 24 hours in patients unable to take aspirin) prior to PCI (Chest guidelines, 2008).
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; Wright, 2011); 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: Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal MI. With STEMI, clopidogrel for at least 12 months regardless of stent type (ie, either bare metal or drug eluting stent) is recommended (Kushner, 2009). With UA/NSTEMI, at least 12 months of clopidogrel is recommended in patients receiving a drug eluting stent (DES) unless the risk of bleeding outweighs the benefits. For bare metal stent (BMS) placement, at least 1 month and ideally up to 12 months duration is recommended unless the risk of bleeding outweighs the benefits then a minimum of 2 weeks is recommended (Wright, 2011). In either setting, a duration >15 months may be considered in patients with DES placement (Kushner, 2009; Wright 2011). For patients without ongoing ACS, clopidogrel should be continued for at least 1 month (for BMS) or at least 12 months (for DES) (Becker, 2008).
CYP2C19 poor metabolizers (ie, CYP2C19*2 or *3 carriers): An appropriate regimen for this patient population has not been established in clinical outcome trials. Although the manufacturer suggests a 600 mg loading dose, followed by 150 mg once daily, it does not appear that this dosing strategy improves outcomes for this patient population (Price, 2011).
Atrial fibrillation (in patients not candidates for warfarin and at a low risk of bleeding) (Canadian labeling; not in U.S. labeling): Oral: 75 mg once daily (in combination with aspirin 75-100 mg once daily)
Prevention of coronary artery bypass graft closure (saphenous vein) [Chest guidelines, 2008]: Aspirin-allergic patients (unlabeled use): Oral: Loading dose: 300 mg administered 6 hours following procedure; maintenance: 75 mg once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

No adjustment is necessary.

Dosing: 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.
Use
 
Reduces rate of atherothrombotic events (myocardial infarction, stroke, vascular deaths) in patients with recent MI or stroke, or established peripheral arterial disease; reduces rate of atherothrombotic events in patients with unstable angina (UA) or non-ST-segment elevation (NSTEMI) managed medically or with percutaneous coronary intervention (PCI) (with or without stent) or CABG; reduces rate of death and atherothrombotic events in patients with ST-segment elevation MI (STEMI) managed medically
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/Investigational
In patients with allergy or major gastrointestinal intolerance to aspirin, initial treatment of acute coronary syndromes (ACS) or prevention of coronary artery bypass graft closure (saphenous vein)
Adverse Reactions
 
As with all drugs which 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 which alter hemostasis and patient susceptibility.
3% to 10%:
Dermatologic: Rash (4%), pruritus (3%)
Hematologic: Bleeding (major 4%; minor 5%), purpura/bruising (5%), epistaxis (3%)
1% to 3%:
Gastrointestinal: GI hemorrhage (2%)
Hematologic: Hematoma
<1% (Limited to important or life-threatening): Acute liver failure, agranulocytosis, anaphylactoid reaction, angioedema, aplastic anemia, arthralgia, arthritis, bronchospasm, bullous eruption, colitis (including ulcerative or lymphocytic), confusion, creatinine increased, eczema, erythema multiforme, fever, glomerulopathy, hallucination, hemorrhagic stroke (≤0.2%), hepatitis, hypersensitivity reaction, hypotension, interstitial pneumonitis, intracranial hemorrhage (≤0.4%), lichen planus, liver function tests (abnormal), musculoskeletal bleeding, myalgia, ocular bleeding (including conjunctival and retinal), pancreatitis, pancytopenia, pulmonary hemorrhage, rash (erythematous or maculopapular), retroperitoneal hemorrhage, serum sickness, Stevens-Johnson syndrome, stomatitis, taste disorder, thrombotic thrombocytopenic purpura (TTP), toxic epidermal necrolysis, vasculitis, wound hemorrhage
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
Warnings / Precautions Drug
 
Boxed warnings:
• Reduced CYP2C19 function: See “Special populations” below.
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.
• 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.
• 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) or with less CYP2C19 inhibition. If a PPI is necessary, the use of pantoprazole, a weak CYP2C19 inhibitor, has been shown to have less of an effect on the pharmacologic activity of clopidogrel. Of the PPIs, lansoprazole exhibits the most potent CYP2C19 inhibitory effects (Li, 2004).
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:
• 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.
• Elective surgery: 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).
Metabolism/Transport Effects
Substrate of CYP2C19, 3A4, 1A2 (minor); Inhibits CYP2B6 (moderate), 2C9 (weak)
Interactions
 
Amiodarone: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk C: Monitor therapy
Anticoagulants: Antiplatelet Agents may enhance the anticoagulant effect of Anticoagulants. Risk C: Monitor therapy
Antiplatelet Agents: May enhance the anticoagulant effect of other Antiplatelet Agents. Risk C: Monitor therapy
Collagenase (Systemic): Antiplatelet Agents may enhance the adverse/toxic effect of Collagenase (Systemic). Specifically, the risk of injection site bruising and/or bleeding may be increased. Risk C: Monitor therapy
CYP2B6 Substrates: CYP2B6 Inhibitors (Moderate) may decrease the metabolism of CYP2B6 Substrates. Risk C: Monitor therapy
CYP2C19 Inhibitors (Moderate): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
CYP2C19 Inhibitors (Strong): May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: Avoid combination
Esomeprazole: 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. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Macrolide Antibiotics: May diminish the therapeutic effect of Clopidogrel. Exceptions: Azithromycin; Azithromycin (Systemic); Fidaxomicin (Systemic); Spiramycin. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May enhance the adverse/toxic effect of Antiplatelet Agents. An increased risk of bleeding may occur. Nonsteroidal Anti-Inflammatory Agents may diminish the cardioprotective effect of Antiplatelet Agents. This interaction is likely specific to aspirin, and not to other antiplatelet agents. Risk C: Monitor therapy
Omeprazole: May decrease serum concentrations of the active metabolite(s) of Clopidogrel. Risk X: 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. Risk D: Consider therapy modification
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. Risk D: Consider therapy modification
Thrombolytic Agents: Antiplatelet Agents may enhance the anticoagulant effect of Thrombolytic Agents. Risk C: Monitor therapy
Tositumomab and Iodine I 131 Tositumomab: Antiplatelet Agents may enhance the adverse/toxic effect of Tositumomab and Iodine I 131 Tositumomab. Specifically, the risk of bleeding-related adverse events may be increased. Risk C: Monitor therapy
Vitamin E: May enhance the antiplatelet effect of Antiplatelet Agents. Risk C: Monitor therapy
Warfarin: Clopidogrel may enhance the anticoagulant effect of Warfarin. Risk D: Consider therapy
Pregnancy
 
B
Pregnancy Implications
Teratogenic effects were not observed in animal studies. Use during pregnancy only if clearly needed.
Lactation
 
Excretion in breast milk unknown/not recommended
Dietary Considerations
May be taken without regard to meals.
Mechanism of Action
 
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).
Pharmacodynamics / Kinetics
 
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)
Absorption: Well absorbed
Protein binding: Parent drug: 98%; Inactive metabolite: 94%
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)
Half-life elimination: Parent drug: ~6 hours; Active metabolite: ~30 minutes
Time to peak, serum: ~0.75 hours
Excretion: Urine (50%); feces (46%
 
   
 
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