Dosing & Uses
Dosage Forms & Strengths
Acute Coronary Syndrome
Unstable angina, non-ST-segment elevation MI (NSTEMI): 300 mg loading dose; initiating therapy without a loading dose will delay establishment of antiplatelet effect by several days; following the loading dose, administer 75 mg/day PO for up to 12 months; may administer beyond 12 months if used in combination with aspirin (75-100 mg/day); long-term combination therapy with aspirin, following stent placement, is individualized depending on how a patient tolerates long-term dual antiplatelet therapy (DAPT), whether they have stable coronary artery disease, and do NOT have risk factors (eg, TIA or stroke, age >75 years, bleeding risk, low body wt, concurrent medications)
ST-segment elevation MI (STEMI): 75 mg/day PO in combination with aspirin 162-325 mg/day and then 81-162 mg/day
- 300 mg loading dose followed by 75 mg for 14 days up to 12 months (if no bleeding)
- Concomitant therapy with aspirin: Administer in combination with aspirin 75-325 mg qDay with or without thrombolytics
- No loading dose
- 75 mg for 14 days up to 12 months (if no bleeding)
Recent MI, Stroke, or Established Peripheral Arterial Disease
75 mg PO qDay without a loading dose; recommended as alternative to aspirin or concomitantly with aspirin if patient not at increased risk for bleeding but at high risk for cardiovascular disease
Coronary Artery Disease
75 mg PO qDay
Prophylaxis if patient not candidate for oral anticoagulation
75 mg/day PO
Carotid Artery Stenting (Off-label)
300 mg PO plus aspirin 81-325 mg for 1 dose on day before carotid artery stenting (CAS), then 75 mg/day PO plus aspirin 81-325 mg/day for at least 30 days after CAS
Alternative: 300-600 mg PO once, then 75 mg/day for 4 days before CAS in combination with aspirin 81-325 mg/day
Renal impairment: Dose adjustment not necessary
Hepatic impairment: Use caution; experience limited
CYP2C19 poor metabolizers associated with diminished antiplatelet response to clopidogrel; although higher-dose regimen (600 mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response, no appropriate dosing regimen for poor metabolizers has been established in clinical outcome trials
Serious - Use Alternative
Significant - Monitor Closely
Upper respiratory tract infection (8.7%)
Chest pain (8.3%)
Flulike syndrome (7.5%)
Urinary tract infection (3.1%)
Thrombotic thrombocytopenic purpura
Acute liver failure
Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A
Eye disorders: Eye (conjunctival, ocular, retinal) bleeding
Gastrointestinal disorders: Gastrointestinal and retroperitoneal hemorrhage with fatal outcome, colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis, gastric/duodenal ulcer, diarrhea
General disorders and administration site condition: Fever, hemorrhage of operative wound
Hepato-biliary disorders: Acute liver failure, hepatitis (non-infectious), abnormal liver function test
Immune system disorders: Hypersensitivity reactions, anaphylactoid reactions, serum sickness
Musculoskeletal, connective tissue and bone disorders: Musculoskeletal bleeding, myalgia, arthralgia, arthritis
Nervous system disorders: Taste disorders, fatal intracranial bleeding, headache
Psychiatric disorders: Confusion, hallucinations
Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, respiratory tract bleeding, eosinophilic pneumonia
Renal and urinary disorders: Increased creatinine levels
Skin and subcutaneous tissue disorders: Maculopapular, erythematous, or exfoliative rash, urticaria, bullous dermatitis, eczema, toxic epidermal necrolysis, Stevens-Johnson syndrome, angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus, acute generalized exanthematous pustulosis (AGEP)
Vascular disorders: Vasculitis, hypotension
Black Box Warnings
Clopidogrel's antiplatelet activity is dependent on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19
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
Active pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage)
Use with caution in patients with bleeding or platelet disorders
Premature discontinuation increases risk of cardiovascular events; discontinue 5 days prior to elective surgery that has a major risk of bleeding
Use caution in patients with atrial fibrillation; assess bleeding risk carefully; significant increase in major bleeding events reported in patients receiving clopidogrel plus aspirin instead of aspirin alone
Patients allergic to aspirin who are undergoing PCI; see American Heart Association (AHA)/American College of Chest Physicians (ACCP)/American College of Cardiology (ACC) recommendations
Rare but potentially fatal thrombotic thrombocytopenic purpura associated with use
Risk of bleeding with potentially fatal outcome
Hepatic or renal impairment
Allergic cross-reactivity including rash, angioedema, or hematologic reaction among thienopyridines (eg, ticlopidine, prasugrel) reported; evaluate patient for history of hypersensitivity
Use caution in patients with severe hepatic or renal impairment
Use caution or avoid in patients with hypersensitivity or hematologic reactions to previous thienopyridine use, including ticlopidine and prasugrel
Use caution in patients receiving either anticoagulants, including heparin and warfarin, or other platelet aggregation inhibitors; risk of bleeding increases
Premature interruption of therapy may result in stent thrombosis with subsequent fatal and nonfatal myocardial infarction; duration of therapy is determined by type of stent placed
May increase risk of major hemorrhage in patients with recent lacunar stroke
CYP2C19 inhibition & poor metabolizers
- Metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19
- Clopidogrel is a prodrug and requires CYP2C19 to convert to active metabolite; inhibition of platelet aggregation is entirely due to active metabolite
- CYP2C19*2 and *3 alleles have no functional metabolism of clopidogrel to active metabolite; CYP2C19*4, *5, *6, *7, and *8 may be associated with absent or reduced metabolism of clopidogrel but are less frequent than CYP2C19*2 and *3
- >50% of Asians have CYP2C19 genetic variants that inhibit clopidogrel metabolism
- Use of CYP2C19 inhibitors (eg, proton pump inhibitors [PPIs]) or use in poor metabolizers may decrease formation of active metabolite, thereby decreasing antiplatelet effect; observational studies and 1 randomized clinical trial have shown concomitant use of clopidogrel and PPIs to have inconsistent effects on cardiovascular outcomes
Pregnancy & Lactation
Pregnancy: There are no adequate and well-controlled studies in pregnant women; because animal reproduction studies are not always predictive of human response, clopidogrel should be used during pregnancy only if clearly needed
Lactation: Not known whether drug is excreted in human milk; because many drugs are excreted in human milk and because of potential for serious adverse reactions in nursing infants from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue drug, taking into account importance of drug to mother
A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.
C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.
D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.
X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.
NA:Information not available.
Mechanism of Action
Inhibitor of adenosine diphosphate (ADP)-induced pathway for platelet aggregation
Onset: 2 hr
Peak serum time: 0.75 hr
Peak plasma concentration: 3 mg/L
Protein bound: 98%
Metabolized in liver by hepatic CYP450 enzymes (in vitro by CYP3A4, CYP2C19 [predominantly], others) to generate active metabolite and also by esterase to generate inactive metabolite
Metabolites: Thiol (active); further activation of thiol metabolite is required through hydrolysis via paraoxonase-1 (PON-1); allele variation of PON-1 may inhibit activation and increase risk for stent thrombosis
Half-life: 6 hr (parent drug); 30 min (active metabolite)
Excretion: Urine (50%), feces (46%)
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