Clopidogrel
Generic: CLOPIDOGREL
Basic Information
Manufacturer
Proficient Rx LP
Product Type
HUMAN PRESCRIPTION DRUG
Route of Administration
ORAL
FDA Set ID
25ed3120-7960-4e87-8422-de5c2026062c
Indications & Usage
1 INDICATIONS AND USAGE Clopidogrel tablets USP are a P2Y 12 platelet inhibitor indicated for: • Acute coronary syndrome • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], clopidogrel tablets USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
( 1.1 ) • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke.
The benefit for patients who undergo primary PCI is unknown.
( 1.1 ) • Recent MI, recent stroke, or established peripheral arterial disease.
Clopidogrel tablets USP have been shown to reduce the combined endpoint of new ischemic stroke, new MI, and other vascular death.
( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel tablets USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
• For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke.
The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
The optimal duration of clopidogrel tablet USP therapy in ACS is unknown.
1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel tablets USP have been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
( 1.1 ) • For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke.
The benefit for patients who undergo primary PCI is unknown.
( 1.1 ) • Recent MI, recent stroke, or established peripheral arterial disease.
Clopidogrel tablets USP have been shown to reduce the combined endpoint of new ischemic stroke, new MI, and other vascular death.
( 1.2 ) 1.1 Acute Coronary Syndrome (ACS) • For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)], including patients who are to be managed medically and those who are to be managed with coronary revascularization, clopidogrel tablets USP have been shown to decrease the rate of a combined endpoint of cardiovascular death, myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke, or refractory ischemia.
• For patients with ST-elevation myocardial infarction (STEMI), clopidogrel tablets USP have been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, re-infarction, or stroke.
The benefit for patients who undergo primary percutaneous coronary intervention is unknown.
The optimal duration of clopidogrel tablet USP therapy in ACS is unknown.
1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease For patients with a history of recent myocardial infarction (MI), recent stroke, or established peripheral arterial disease, clopidogrel tablets USP have been shown to reduce the rate of a combined endpoint of new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.
Adverse Reactions
6 ADVERSE REACTIONS The following serious adverse reactions are discussed below and elsewhere in the labeling: • Bleeding [ see Warnings and Precautions ( 5.2 ) ] • Thrombotic thrombocytopenic purpura [ see Warnings and Precautions ( 5.5 ) ] Bleeding, including life-threatening and fatal bleeding, is the most commonly reported adverse reaction.
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more.
The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below.
Bleeding CURE In CURE, clopidogrel use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1 ).
The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups.
Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1 .
Table 1: CURE Incidence of Bleeding Complications (% Patients) Event Clopidogrel (+ aspirin) Other standard therapies were used as appropriate.
(n = 6259) Placebo (+ aspirin) (n = 6303) Major bleeding Life-threatening and other major bleeding.
3.7 Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: < 100 mg = 2.6%; 100 to 200 mg = 3.5%; > 200 mg = 4.9% Major bleeding event rates for clopidogrel + aspirin by age were: < 65 years = 2.5%, ≥ 65 to < 75 years = 4.1%, ≥ 75 years = 5.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: < 100 mg = 2.0%; 100 to 200 mg = 2.3%; > 200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: < 65 years = 2.1%, ≥ 65 to < 75 years = 3.1%, ≥ 75 years = 3.6% Life-threatening bleeding 2.2 1.8 Fatal 0.2 0.2 5 g/dL hemoglobin drop 0.9 0.9 Requiring surgical intervention 0.7 0.7 Hemorrhagic strokes 0.1 0.1 Requiring inotropes 0.5 0.5 Requiring transfusion (≥ 4 units) 1.2 1.0 Other major bleeding 1.6 1.0 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2 to 3 units of blood 1.3 0.9 Minor bleeding Led to interruption of study medication.
5.1 2.4 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.
COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (see Table 2 ).
Table 2: Incidence of Bleeding Events in COMMIT (% Patients) Type of bleeding Clopidogrel (+ aspirin) (n = 22961) Placebo (+ aspirin) (n = 22891) p-value Major Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.
noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age.
Event rates for clopidogrel + aspirin by age were: < 60 years = 0.3%, ≥ 60 to < 70 years = 0.7%, ≥ 70 years = 0.8%.
Event rates for placebo + aspirin by age were: < 60 years = 0.4%, ≥ 60 to < 70 years = 0.6%, ≥ 70 years = 0.7%.
0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.90 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel vs.
Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel vs.
2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively.
The incidence of intracranial hemorrhage was 0.4% for clopidogrel compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma.
Other Adverse Events In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo.
In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel.
No other difference in the rate of adverse events (other than bleeding) was reported.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel.
Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• 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, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus • Vascular disorders: Vasculitis, hypotension
( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-866-832-8537 or drug.safety@tevapharm.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Studies Experience Because clinical trials are conducted under widely varying conditions and durations of follow up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Clopidogrel has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for 1 year or more.
The clinically important adverse reactions observed in trials comparing clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel alone to aspirin alone are discussed below.
Bleeding CURE In CURE, clopidogrel use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1 ).
The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups.
Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1 .
Table 1: CURE Incidence of Bleeding Complications (% Patients) Event Clopidogrel (+ aspirin) Other standard therapies were used as appropriate.
(n = 6259) Placebo (+ aspirin) (n = 6303) Major bleeding Life-threatening and other major bleeding.
3.7 Major bleeding event rate for clopidogrel + aspirin was dose-dependent on aspirin: < 100 mg = 2.6%; 100 to 200 mg = 3.5%; > 200 mg = 4.9% Major bleeding event rates for clopidogrel + aspirin by age were: < 65 years = 2.5%, ≥ 65 to < 75 years = 4.1%, ≥ 75 years = 5.9% 2.7 Major bleeding event rate for placebo + aspirin was dose-dependent on aspirin: < 100 mg = 2.0%; 100 to 200 mg = 2.3%; > 200 mg = 4.0% Major bleeding event rates for placebo + aspirin by age were: < 65 years = 2.1%, ≥ 65 to < 75 years = 3.1%, ≥ 75 years = 3.6% Life-threatening bleeding 2.2 1.8 Fatal 0.2 0.2 5 g/dL hemoglobin drop 0.9 0.9 Requiring surgical intervention 0.7 0.7 Hemorrhagic strokes 0.1 0.1 Requiring inotropes 0.5 0.5 Requiring transfusion (≥ 4 units) 1.2 1.0 Other major bleeding 1.6 1.0 Significantly disabling 0.4 0.3 Intraocular bleeding with significant loss of vision 0.05 0.03 Requiring 2 to 3 units of blood 1.3 0.9 Minor bleeding Led to interruption of study medication.
5.1 2.4 Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.
COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel and placebo groups, both of which also received aspirin (see Table 2 ).
Table 2: Incidence of Bleeding Events in COMMIT (% Patients) Type of bleeding Clopidogrel (+ aspirin) (n = 22961) Placebo (+ aspirin) (n = 22891) p-value Major Major bleeds were cerebral bleeds or non-cerebral bleeds thought to have caused death or that required transfusion.
noncerebral or cerebral bleeding The relative rate of major noncerebral or cerebral bleeding was independent of age.
Event rates for clopidogrel + aspirin by age were: < 60 years = 0.3%, ≥ 60 to < 70 years = 0.7%, ≥ 70 years = 0.8%.
Event rates for placebo + aspirin by age were: < 60 years = 0.4%, ≥ 60 to < 70 years = 0.6%, ≥ 70 years = 0.7%.
0.6 0.5 0.59 Major noncerebral 0.4 0.3 0.48 Fatal 0.2 0.2 0.90 Hemorrhagic stroke 0.2 0.2 0.91 Fatal 0.2 0.2 0.81 Other noncerebral bleeding (non-major) 3.6 3.1 0.005 Any noncerebral bleeding 3.9 3.4 0.004 CAPRIE (Clopidogrel vs.
Aspirin) In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel vs.
2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively.
The incidence of intracranial hemorrhage was 0.4% for clopidogrel compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis and hematoma.
Other Adverse Events In CURE and CHARISMA, which compared clopidogrel plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel and placebo.
In CAPRIE, which compared clopidogrel to aspirin, pruritus was more frequently reported in those taking clopidogrel.
No other difference in the rate of adverse events (other than bleeding) was reported.
6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of clopidogrel.
Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• 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, acute generalized exanthematous pustulosis (AGEP), angioedema, drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), erythema multiforme, skin bleeding, lichen planus, generalized pruritus • Vascular disorders: Vasculitis, hypotension