Applies to clopidogrel: oral tablets.
Warning
-
Diminished Antiplatelet Effect in Patients with 2 Loss-of-Function CYP2C19 Alleles
- Clopidogrel is a prodrug; requires conversion to its active metabolite by the CYP enzyme system (primarily by CYP2C19).1 2 6 8 11 121
- Genetic variations of CYP2C19 can result in impaired metabolism and reduced effectiveness of clopidogrel.1 121 (See Reduced Efficacy in Poor CYP2C19 Metabolizers under Cautions.) Patients who are homozygous for nonfunctional alleles of CYP2C19 have reduced levels of the active clopidogrel metabolite and reduced antiplatelet effects.1 121
- Genetic tests are available to identify patients who are poor CYP2C19 metabolizers.1 20 121 122
- Consider use of another P2Y12 receptor antagonist (e.g., prasugrel, ticagrelor) in patients identified as poor CYP2C19 metabolizers.1 121
Side effects include:
Bleeding.
For Healthcare Professionals
Applies to clopidogrel: oral tablet.
General
The most commonly reported adverse effect was bleeding, including life threatening and fatal bleeding.[Ref]
Hematologic
Uncommon (0.1% to 1%): Fatal bleeding, eosinophilia, leucopenia, increased bleeding time, thrombocytopenia
Rare (0.01% to 0.1%): Neutropenia
Very rare (less than 0.01%): Decreased platelet count
Postmarketing reports: Serious cases of bleeding (mainly skin), hemarthrosis, hematoma, hemorrhage of operative wound, fatal hemorrhage (intracranial, gastrointestinal, and retroperitoneal), thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A, aplastic anemia, pancytopenia, agranulocytosis, granulocytopenia, anemia[Ref]
In the COMMIT study (n=45,852), the incidence of major non-cerebral or cerebral bleeding was 0.6% in clopidogrel plus aspirin treated patients, with 0.4% classified as major non-cerebral (0.2% fatal) and 0.2% as hemorrhagic stroke (0.2% fatal). Non-major noncerebral bleeding or any noncerebral bleeding occurred in 3.6% and 3.9% of patients receiving this drug plus aspirin, respectively. Major bleeds were defined as cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.
In the CURE study (n=12,562), the incidence of fatal bleeding (0.2%) and intracranial hemorrhage (0.1%) was the same between clopidogrel with aspirin and placebo with aspirin groups.[Ref]
Gastrointestinal
Common (1% to 10%): Abdominal pain, gastrointestinal hemorrhage, dyspepsia, diarrhea, nausea, gastritis
Uncommon (0.1% to 1%): Vomiting, flatulence, constipation, gastric, peptic, or duodenal ulcer
Rare (0.01% to 0.1%): Retroperitoneal hemorrhage
Postmarketing reports: Colitis (ulcerative or lymphocytic), pancreatitis, stomatitis[Ref]
In the CAPRIE study (n=19,185), gastrointestinal hemorrhage occurred in 2% of patients taking clopidogrel compared to 2.7% taking aspirin. Bleeding requiring hospitalization occurred in 0.7% clopidogrel-treated and 1.1% aspirin-treated patients.[Ref]
Hypersensitivity
Postmarketing reports: Angioedema, anaphylactic reactions, cross reactive hypersensitivity among thienopyridines (e.g. ticlopidine, prasugrel), hypersensitivity reactions[Ref]
Cardiovascular
Common (1% to 10%): Chest pain, hypertension, angina pectoris, coronary artery disorder, peripheral ischemia
Very rare (less than 0.01%): Hematoma
Postmarketing reports: Hypotension, syncope, vasculitis[Ref]
Nervous system
Common (1% to 10%): Dizziness, headache
Uncommon (0.1% to 1%): Paresthesia
Rare (0.01% to 0.1%): Vertigo, intracranial hemorrhage
Postmarketing reports: Taste disturbances, ageusia[Ref]
Musculoskeletal
Common (1% to 10%): Arthralgia, back pain
Postmarketing reports: Arthritis, myalgia, musculoskeletal bleeding[Ref]
Psychiatric
Common (1% to 10%): Depression
Postmarketing reports: Hallucinations, confusion[Ref]
Respiratory
Common (1% to 10%): Upper respiratory tract infection, dyspnea, rhinitis, coughing, bronchitis, epistaxis
Postmarketing reports: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia, respiratory tract bleeding (hemoptysis, pulmonary hemorrhage)[Ref]
Dermatologic
Common (1% to 10%): Rash, purpura, pruritus, bruising
Postmarketing reports: Maculopapular, erythematous, or exfoliative rash, urticaria, bullous dermatitis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus[Ref]
In CAPRIE (n=19,185), 4.2% of patients receiving clopidogrel developed a rash compared to 3.5% in the aspirin group. In CURE (n=12,562), 1.3% treated with clopidogrel and aspirin compared to 1.1% placebo, as well as 0.7% of patients in CLARITY (n=3491) reported a rash. Drug discontinuation due to skin disorders in CAPRIE was 0.8% and in CURE 0.4% of patients.[Ref]
Hepatic
Postmarketing reports: Hepatitis (noninfectious), acute liver failure, abnormal liver function tests[Ref]
Metabolic
Common (1% to 10%): Hypercholesterolemia[Ref]
Genitourinary
Common (1% to 10%): Urinary tract infection
Postmarketing reports: Hematuria[Ref]
Ocular
Postmarketing reports: Eye bleeds (conjunctival, ocular, retinal)[Ref]
Other
Common (1% to 10%): Accidental/inflicted injury, influenza-like symptoms, pain, fatigue, infection
Postmarketing reports: Fever[Ref]
Renal
Uncommon (0.1% to 1%): Hematuria
Postmarketing reports: Glomerulopathy, serum creatinine increase[Ref]
Immunologic
Postmarketing reports: Serum sickness, insulin autoimmune syndrome[Ref]
Endocrine
Postmarketing reports: Gynecomastia[Ref]
Local
Common (1% to 10%): Puncture site bleeding[Ref]
