clopidogrel (Rx)

1-10%

Upper respiratory tract infection (8.7%)

Chest pain (8.3%)

Headache (7.6%)

Flulike syndrome (7.5%)

Arthralgia (6%)

Pain (6%)

Dizziness (6%)

Diarrhea (4.5%)

Rash (4.2%)

Rhinitis (4.2%)

Depression (3.6%)

Urinary tract infection (3.1%)

<1%

Severe neutropenia

Thrombotic thrombocytopenic purpura

Acute liver failure

Aplastic anemia

Hypotension

Hepatitis

Myalgia

Eczema

Erythema

Agranulocytosis

Postmarketing Reports

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

Contraindications

Hypersensitivity

Active pathologic bleeding (eg, peptic ulcer, intracranial hemorrhage)

Cautions

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

P2Y12 inhibitors (thienopyridines), including clopidogrel, inhibit platelet aggregation for lifetime of platelet (7-10 days); because half-life of clopidogrel’s active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of loading dose or 2 hours of the maintenance dose may be less effective

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
• Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate bleeding risk; as a precaution, avoid concomitant use of strong CYP2C19 inducers

Pregnancy

Available data from cases reported over two decades in published literature and postmarketing surveillance have not identified any drug-associated risks for major birth defects or miscarriage; there are risks to pregnant woman and fetus associated with myocardial infarction and stroke

Myocardial infarction and stroke are medical emergencies; therapy for pregnant woman should not be withheld because of potential concerns regarding effects of clopidogrel on the fetus

Labor or delivery

• Therapy during labor or delivery will increase risk of maternal bleeding and hemorrhage; avoid neuraxial blockade during clopidogrel use because of risk of spinal hematoma; when possible, discontinue therapy 5-7 days prior to labor, delivery, or neuraxial blockade

Animal data

• Embryo-fetal development studies performed showed no evidence of fetotoxicity when drug administered to pregnant rats and rabbits during organogenesis at doses corresponding to 65 and 78 times the recommended daily human dose

Lactation

There are no data on presence of drug in human milk or effects on milk production; no adverse effects on breastfed infants observed during lactation in a small number of postmarketing cases; studies in rats have shown that clopidogrel and/or its metabolites are present in milk; when a drug is present in animal milk, it is likely that the drug will be present in human milk; consider developmental and health benefits of breastfeeding along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug or underlying maternal condition

Pregnancy Categories

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

Absorption

Bioavailability: >50%

Onset: 2 hr

Peak serum time: 0.75 hr

Peak plasma concentration: 3 mg/L

Distribution

Protein bound: 98%

Metabolism

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

Elimination

Half-life: 6 hr (parent drug); 30 min (active metabolite)

Excretion: Urine (50%), feces (46%)