PLAVIX Clopidogrel Bisulfate 75mg Film-Coated Tablet 1's
RXDRUG-DRP-5643-1pc
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Features
Brand
Plavix
Full Details
Dosage Strength
75 mg
Drug Ingredients
- Clopidogrel
Drug Packaging
Film-Coated Tablet 1's
Generic Name
Clopidogrel Bisulfate
Dosage Form
Film-Coated Tablet
Registration Number
DRP-5643
Drug Classification
Prescription Drug (RX)
Description
Indications/Uses
Clopidogrel is indicated in adults for the secondary prevention of atherothrombotic events in: 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 has 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.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction [MI]) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or (CABG), clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, reinfarction or stroke.
In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS): Clopidogrel in combination with ASA is indicated in: Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3) within 24 hours of either the TIA or IS event.
Clopidogrel is indicated in adults for the prevention of atherothrombotic and thromboembolic events in:
Atrial Fibrillation: In patients with atrial fibrillation (AF) at increased risk of vascular events who can take vitamin K antagonist (VKA) therapy, VKA has been shown to be associated with a better clinical benefit than acetylsalicylic acid (ASA) alone or the combination of clopidogrel and ASA for the reduction of stroke.
In patients with atrial fibrillation who have at least one risk factor for vascular events and who cannot take VKA therapy (e.g., specific risk of bleeding, physician assessment that patient is unable to comply with INR (international normalised ratio) monitoring or that VKA use is inappropriate), clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. Clopidogrel in combination with ASA has been shown to reduce the rate of the combined endpoint of stroke, myocardial infarction (MI), non-CNS systemic embolism, or vascular death, largely through a reduction in stroke.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction [MI]) including patients who are to be managed medically and those who are to be managed with percutaneous coronary intervention (with or without stent) or (CABG), clopidogrel has been shown to decrease the rate of a combined endpoint of cardiovascular death, MI or stroke as well as the rate of a combined endpoint of cardiovascular death, MI, stroke or refractory ischemia.
For patients with ST-segment elevation acute myocardial infarction, clopidogrel has been shown to reduce the rate of death from any cause and the rate of a combined endpoint of death, reinfarction or stroke.
In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS): Clopidogrel in combination with ASA is indicated in: Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3) within 24 hours of either the TIA or IS event.
Clopidogrel is indicated in adults for the prevention of atherothrombotic and thromboembolic events in:
Atrial Fibrillation: In patients with atrial fibrillation (AF) at increased risk of vascular events who can take vitamin K antagonist (VKA) therapy, VKA has been shown to be associated with a better clinical benefit than acetylsalicylic acid (ASA) alone or the combination of clopidogrel and ASA for the reduction of stroke.
In patients with atrial fibrillation who have at least one risk factor for vascular events and who cannot take VKA therapy (e.g., specific risk of bleeding, physician assessment that patient is unable to comply with INR (international normalised ratio) monitoring or that VKA use is inappropriate), clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke. Clopidogrel in combination with ASA has been shown to reduce the rate of the combined endpoint of stroke, myocardial infarction (MI), non-CNS systemic embolism, or vascular death, largely through a reduction in stroke.
Dosage/Direction for Use
General: Recent MI, Recent Stroke, or Established Peripheral Arterial Disease: Clopidogrel should be given as a single daily dose of 75 mg.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), clopidogrel should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Acetylsalicylic acid (ASA) (75 mg up to 325 mg once daily) should be initiated and continued in combination with clopidogrel. In CURE, most patients with Acute Coronary Syndrome also received heparin.
For patients with ST-segment elevation acute myocardial infarction, the recommended dose of clopidogrel is 75 mg once daily, administered in combination with ASA, with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose (300 mg was used in CLARITY).
Adult patients with moderate to high-risk TIA or minor IS: Adult patients with moderate to high-risk TIA (ABCD2 score ≥4) or minor IS (NIHSS ≤3) should be given a loading dose of clopidogrel 300 mg followed by clopidogrel 75 mg once daily and ASA (75 mg - 100 mg once daily). Treatment with clopidogrel and ASA should be started within 24 hours of the event and be continued for 21 days followed by single antiplatelet therapy.
Atrial Fibrillation: Clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel.
Pharmacogenetics: CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. A higher dose regimen (600-mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response (see Pharmacology: Pharmacokinetics under Actions). Consider the use of higher clopidogrel doses in patients who are poor CYP2C19 metabolizers. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Special Populations: Children: Safety and effectiveness in pediatric populations have not been established.
Elderly: No dosage adjustment is necessary in elderly patients.
Hepatic impairment: No dosage adjustment is necessary. See Precautions and Pharmacology: Pharmacokinetics, Special populations under Actions.
Renal impairment: No dosage adjustment is necessary. See Precautions and Pharmacology: Pharmacokinetics, Special populations under Actions.
Administration: Clopidogrel can be administered with or without food.
Acute Coronary Syndrome: For patients with non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave MI), clopidogrel should be initiated with a single 300-mg loading dose and then continued at 75 mg once daily. Acetylsalicylic acid (ASA) (75 mg up to 325 mg once daily) should be initiated and continued in combination with clopidogrel. In CURE, most patients with Acute Coronary Syndrome also received heparin.
For patients with ST-segment elevation acute myocardial infarction, the recommended dose of clopidogrel is 75 mg once daily, administered in combination with ASA, with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose (300 mg was used in CLARITY).
Adult patients with moderate to high-risk TIA or minor IS: Adult patients with moderate to high-risk TIA (ABCD2 score ≥4) or minor IS (NIHSS ≤3) should be given a loading dose of clopidogrel 300 mg followed by clopidogrel 75 mg once daily and ASA (75 mg - 100 mg once daily). Treatment with clopidogrel and ASA should be started within 24 hours of the event and be continued for 21 days followed by single antiplatelet therapy.
Atrial Fibrillation: Clopidogrel should be given as a single daily dose of 75 mg. ASA (75-100 mg daily) should be initiated and continued in combination with clopidogrel.
Pharmacogenetics: CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to clopidogrel. A higher dose regimen (600-mg loading dose followed by 150 mg once daily) in poor metabolizers increases antiplatelet response (see Pharmacology: Pharmacokinetics under Actions). Consider the use of higher clopidogrel doses in patients who are poor CYP2C19 metabolizers. An appropriate dose regimen for this patient population has not been established in clinical outcome trials.
Special Populations: Children: Safety and effectiveness in pediatric populations have not been established.
Elderly: No dosage adjustment is necessary in elderly patients.
Hepatic impairment: No dosage adjustment is necessary. See Precautions and Pharmacology: Pharmacokinetics, Special populations under Actions.
Renal impairment: No dosage adjustment is necessary. See Precautions and Pharmacology: Pharmacokinetics, Special populations under Actions.
Administration: Clopidogrel can be administered with or without food.
Overdosage
Signs and Symptoms: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications.
Management: Appropriate therapy should be considered if bleeding is observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.
Management: Appropriate therapy should be considered if bleeding is observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reverse the effects of clopidogrel.
Administration
May be taken with or without food.
Contraindications
Hypersensitivity to the drug substance or any component of the product.
Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Special Precautions
Bleeding and haematological disorders: Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever such suspected clinical symptoms arise during the course of treatment (see Adverse Reactions). Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions, and in patients receiving treatment with acetylsalicylic acid, heparin, glycoprotein IIb/IIIa inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or selective serotonin reuptake inhibitors (SSRIs). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 to 7 days prior to surgery.
Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce gastrointestinal lesions (such as acetylsalicylic acid and Non-Steroidal Anti-Inflammatory Drugs) should be used with caution in patients taking clopidogrel.
Patients should be told that it may take longer than usual to stop bleeding when they take clopidogrel alone or in combination with ASA, and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Recent ischemic stroke: Initiation of therapy: In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy (clopidogrel and ASA) should be started no later than 24 hours after the event onset. There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acute minor IS or moderate to high-risk TIA patients, with a history of (non-traumatic) intracranial hemorrhage. In non-minor IS patients, clopidogrel monotherapy should be started only after the first 7 days of the event.
Non-minor IS patients (NIHSS >4): In view of the lack of data, use of dual antiplatelet therapy is not recommended.
Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned:There is no data to support the use of dual antiplatelet therapy in patients for whom treatment with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.
Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterized by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment, including plasmapheresis (plasma exchange).
Acquired haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.
Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolizers clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function (see Pharmacology: Pharmacokinetics under Actions). Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider the use of higher clopidogrel doses in patients who are known CYP2C19 poor metabolizers. (See General under Dosage & Administration.)
Cross-reactivity among thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported. Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.
Renal impairment: Experience with clopidogrel is limited in patients with severe renal impairment. Therefore, clopidogrel should be used with caution in this population.
Hepatic impairment: Experience is limited in patients with severe hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Driving a Vehicle or Performing other Hazardous Tasks: No impairment of driving or psychometric performance was observed following clopidogrel administration.
As with other anti-platelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions, and in patients receiving treatment with acetylsalicylic acid, heparin, glycoprotein IIb/IIIa inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), or selective serotonin reuptake inhibitors (SSRIs). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5 to 7 days prior to surgery.
Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce gastrointestinal lesions (such as acetylsalicylic acid and Non-Steroidal Anti-Inflammatory Drugs) should be used with caution in patients taking clopidogrel.
Patients should be told that it may take longer than usual to stop bleeding when they take clopidogrel alone or in combination with ASA, and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Recent ischemic stroke: Initiation of therapy: In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy (clopidogrel and ASA) should be started no later than 24 hours after the event onset. There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acute minor IS or moderate to high-risk TIA patients, with a history of (non-traumatic) intracranial hemorrhage. In non-minor IS patients, clopidogrel monotherapy should be started only after the first 7 days of the event.
Non-minor IS patients (NIHSS >4): In view of the lack of data, use of dual antiplatelet therapy is not recommended.
Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned:There is no data to support the use of dual antiplatelet therapy in patients for whom treatment with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.
Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterized by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment, including plasmapheresis (plasma exchange).
Acquired haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated Partial Thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists, and clopidogrel should be discontinued.
Cytochrome P450 2C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolizers clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function (see Pharmacology: Pharmacokinetics under Actions). Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider the use of higher clopidogrel doses in patients who are known CYP2C19 poor metabolizers. (See General under Dosage & Administration.)
Cross-reactivity among thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported. Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological reactions such as thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.
Renal impairment: Experience with clopidogrel is limited in patients with severe renal impairment. Therefore, clopidogrel should be used with caution in this population.
Hepatic impairment: Experience is limited in patients with severe hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Driving a Vehicle or Performing other Hazardous Tasks: No impairment of driving or psychometric performance was observed following clopidogrel administration.
Use In Pregnancy & Lactation
Pregnancy: Reproduction studies have been performed in rats at doses up to 500 mg/kg per day and in rabbits at doses up to 300 mg/kg per day and have revealed no evidence of impaired fertility or harm to the foetus due to clopidogrel. There are, however, no adequate and well controlled studies in pregnant women. Because animal reproduction studies are not always predictive of a human response, this drug should not be used during pregnancy, unless, in the opinion of the physician, there is a clear need.
Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to a nursing woman.
Lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to a nursing woman.
Adverse Reactions
Clinical Studies Experience: Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 12,000 patients treated for 1 year or more. Clopidogrel 75 mg/day was well tolerated compared to acetylsalicylic acid (ASA) 325 mg/day in CAPRIE. The overall tolerability of clopidogrel in this study was similar to ASA regardless of age, gender and ethnicity. The clinically relevant adverse effects observed in CAPRIE, CURE, CLARITY, COMMIT and ACTIVE-A are discussed as follows.
Hemorrhagic disorders: In CAPRIE, the overall incidence of bleeding on clopidogrel and ASA was the same (9.3%). The incidence of severe cases was 1.4% and 1.6% in the clopidogrel and ASA groups, respectively.
In patients receiving clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0% and required hospitalisation in 0.7%. In patients receiving ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs. 0.4%). The most frequent events reported were purpura/bruising and epistaxis. Other less frequently reported events were haematoma, haematuria and eye bleeding (mainly conjunctival).
The incidence of intracranial bleeding was 0.4% for clopidogrel compared to 0.5% for ASA.
In CURE, there was an increase in major and minor bleeding between the clopidogrel + ASA group compared with the placebo + ASA group (event rates 3.7% vs. 2.7%, for major, respectively, and 5.1% vs 2.4% for minor). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites.
The increase in life-threatening bleeding in the clopidogrel + ASA group compared to the placebo + ASA group was not statistically significant (2.2% vs 1.8%). There was no difference between the two groups in the rate of fatal bleeding (0.2% in both groups). The rate of non-life-threatening major bleeding was significantly higher in the clopidogrel + ASA group compared with the placebo + ASA group (1.6% vs 1%), and the incidence of intracranial bleeding was 0.1% in both groups.
The major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA (<100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + ASA vs. 5.3% placebo + ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + ASA, and 6.3% for placebo + ASA.
The overall incidence of bleeding is described in Table 2 for patients receiving both clopidogrel and ASA in CURE.
Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results (see Table 2).
In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin >5 g/dL) was similar between groups (1.3% versus 1.1% in the clopidogrel + ASA and in the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + ASA and in the placebo + ASA groups, respectively) and intracranial haemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups.
The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 3 (see Table 3).
In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly in the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (see Table 4) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups. (See Table 4.)
Haematological disorders: In CAPRIE, severe neutropaenia (<0.450G/L) was observed in 4 patients (0.04%) on clopidogrel and 2 patients (0.02%) on ASA.
Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophils counts of zero. Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other sign of infection.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopaenia (<80 G/L) was 0.2% on clopidogrel and 0.1% on ASA; very rare cases of platelet count <=30 G/L have been reported.
In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups.
Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE, CLARITY, COMMIT and ACTIVE-A studies with an incidence < 0.1% as well as all serious and relevant ADR with an incidence < 0.1 % are presented as follows.
The following CIOMS frequency rating is used, when applicable: Very common ≥ 10%; Common ≥ 1 to <10%; Uncommon ≥ 0.1 to <1%; Rare ≥ 0.01 to <0.1%; Very rare <0.01%; Unknown (cannot be estimated from available data).
Central and peripheral nervous system disorders: Uncommon: headache, dizziness, paraesthesia.
Rare: vertigo.
Gastrointestinal system disorders: Common: dyspepsia, abdominal pain, diarrhoea.
Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer.
Platelet, bleeding and clotting disorders: Uncommon: bleeding time increased, platelets decreased.
Skin and appendages disorders: Uncommon: rash, pruritus.
White cell and RES disorders: Uncommon: leucopenia, neutrophils decreased, eosinophilia.
Post-Marketing Experience: Adverse reactions have been ranked under heading of system-organ class. Frequencies for the following adverse reactions are not known (cannot be estimated from available data).
Blood and the lymphatic system disorders: Serious cases of bleeding, mainly skin, musculo-skeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding, epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage), agranulocytosis, aplastic anaemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired haemophilia A. Cardiac disorders: Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel.
Immune system disorders: Anaphylactoid reactions, serum sickness; Cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see Precautions); Insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population).
Psychiatric disorders: Confusion, hallucinations.
Nervous system disorders: Taste disturbances, ageusia.
Vascular disorders: Vasculitis, hypotension.
Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.
Hepato-biliary disorders: Hepatitis (non-infectious), acute liver failure.
Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis), acute generalised exanthematous pustulosis (AGEP)), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus.
Musculoskeletal, connective tissue and bone disorders: Arthralgia, arthritis, myalgia.
Renal and urinary disorders: Glomerulopathy.
Reproductive system and breast disorders: Gynaecomastia.
General disorders and administration site conditions: Fever.
Investigations: Abnormal liver function test, blood creatinine increase.
Hemorrhagic disorders: In CAPRIE, the overall incidence of bleeding on clopidogrel and ASA was the same (9.3%). The incidence of severe cases was 1.4% and 1.6% in the clopidogrel and ASA groups, respectively.
In patients receiving clopidogrel, gastrointestinal bleeding occurred at a rate of 2.0% and required hospitalisation in 0.7%. In patients receiving ASA, the corresponding rates were 2.7% and 1.1%, respectively.
The overall incidence of other bleeding disorders was higher in the clopidogrel group (7.3%) compared to ASA (6.5%). However, the incidence of severe events was similar in both treatment groups (0.6% vs. 0.4%). The most frequent events reported were purpura/bruising and epistaxis. Other less frequently reported events were haematoma, haematuria and eye bleeding (mainly conjunctival).
The incidence of intracranial bleeding was 0.4% for clopidogrel compared to 0.5% for ASA.
In CURE, there was an increase in major and minor bleeding between the clopidogrel + ASA group compared with the placebo + ASA group (event rates 3.7% vs. 2.7%, for major, respectively, and 5.1% vs 2.4% for minor). The principal sites for major bleeding included gastrointestinal and at arterial puncture sites.
The increase in life-threatening bleeding in the clopidogrel + ASA group compared to the placebo + ASA group was not statistically significant (2.2% vs 1.8%). There was no difference between the two groups in the rate of fatal bleeding (0.2% in both groups). The rate of non-life-threatening major bleeding was significantly higher in the clopidogrel + ASA group compared with the placebo + ASA group (1.6% vs 1%), and the incidence of intracranial bleeding was 0.1% in both groups.
The major bleeding event rate for clopidogrel + ASA was dose-dependent on ASA (<100 mg: 2.6%; 100-200 mg: 3.5%; >200 mg: 4.9%) as was the major bleeding event rate for placebo + ASA (<100 mg: 2.0%; 100-200 mg: 2.3%; >200 mg: 4.0%).
There was no excess in major bleeds within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (4.4% clopidogrel + ASA vs. 5.3% placebo + ASA). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + ASA, and 6.3% for placebo + ASA.
The overall incidence of bleeding is described in Table 2 for patients receiving both clopidogrel and ASA in CURE.
Ninety-two percent (92%) of the patients in the CURE study received heparin/LMWH, and the rate of bleeding in these patients was similar to the overall results (see Table 2).
In CLARITY, the incidence of major bleeding (defined as intracranial bleeding or bleeding associated with a fall in hemoglobin >5 g/dL) was similar between groups (1.3% versus 1.1% in the clopidogrel + ASA and in the placebo + ASA groups, respectively). This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytics or heparin therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the clopidogrel + ASA and in the placebo + ASA groups, respectively) and intracranial haemorrhage (0.5% versus 0.7%, respectively) was low and similar in both groups.
The overall rate of noncerebral major bleeding or cerebral bleeding in COMMIT was low and similar in both groups as shown in Table 3 (see Table 3).
In ACTIVE-A, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo + ASA group), mainly in the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (see Table 4) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups. (See Table 4.)
Haematological disorders: In CAPRIE, severe neutropaenia (<0.450G/L) was observed in 4 patients (0.04%) on clopidogrel and 2 patients (0.02%) on ASA.
Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received ASA had neutrophils counts of zero. Although the risk of myelotoxicity with clopidogrel appears to be quite low, this possibility should be considered when a patient receiving clopidogrel demonstrates fever or other sign of infection.
One case of aplastic anaemia occurred on clopidogrel treatment.
The incidence of severe thrombocytopaenia (<80 G/L) was 0.2% on clopidogrel and 0.1% on ASA; very rare cases of platelet count <=30 G/L have been reported.
In CURE and CLARITY, the number of patients with thrombocytopenia or neutropenia was similar in both groups.
Other clinically relevant adverse drug reactions pooled from CAPRIE and CURE, CLARITY, COMMIT and ACTIVE-A studies with an incidence < 0.1% as well as all serious and relevant ADR with an incidence < 0.1 % are presented as follows.
The following CIOMS frequency rating is used, when applicable: Very common ≥ 10%; Common ≥ 1 to <10%; Uncommon ≥ 0.1 to <1%; Rare ≥ 0.01 to <0.1%; Very rare <0.01%; Unknown (cannot be estimated from available data).
Central and peripheral nervous system disorders: Uncommon: headache, dizziness, paraesthesia.
Rare: vertigo.
Gastrointestinal system disorders: Common: dyspepsia, abdominal pain, diarrhoea.
Uncommon: nausea, gastritis, flatulence, constipation, vomiting, gastric ulcer, duodenal ulcer.
Platelet, bleeding and clotting disorders: Uncommon: bleeding time increased, platelets decreased.
Skin and appendages disorders: Uncommon: rash, pruritus.
White cell and RES disorders: Uncommon: leucopenia, neutrophils decreased, eosinophilia.
Post-Marketing Experience: Adverse reactions have been ranked under heading of system-organ class. Frequencies for the following adverse reactions are not known (cannot be estimated from available data).
Blood and the lymphatic system disorders: Serious cases of bleeding, mainly skin, musculo-skeletal, eye (conjunctival, ocular, retinal) and respiratory tract bleeding, epistaxis, haematuria and haemorrhage of operative wound; cases of bleeding with fatal outcome (especially intracranial, gastrointestinal and retroperitoneal haemorrhage), agranulocytosis, aplastic anaemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired haemophilia A. Cardiac disorders: Kounis syndrome (vasospastic allergic angina / allergic myocardial infarction) in the context of a hypersensitivity reaction due to clopidogrel.
Immune system disorders: Anaphylactoid reactions, serum sickness; Cross-reactive drug hypersensitivity among thienopyridines (such as ticlopidine, prasugrel) (see Precautions); Insulin autoimmune syndrome, which can lead to severe hypoglycemia, particularly in patients with HLA DRA4 subtype (more frequent in the Japanese population).
Psychiatric disorders: Confusion, hallucinations.
Nervous system disorders: Taste disturbances, ageusia.
Vascular disorders: Vasculitis, hypotension.
Respiratory, thoracic and mediastinal disorders: Bronchospasm, interstitial pneumonitis, eosinophilic pneumonia.
Gastrointestinal disorders: Colitis (including ulcerative or lymphocytic colitis), pancreatitis, stomatitis.
Hepato-biliary disorders: Hepatitis (non-infectious), acute liver failure.
Skin and subcutaneous tissue disorders: Maculopapular, erythematous or exfoliative rash, urticaria, pruritus, angioedema, bullous dermatitis (erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis), acute generalised exanthematous pustulosis (AGEP)), drug-induced hypersensitivity syndrome, drug rash with eosinophilia and systemic symptoms (DRESS), eczema, lichen planus.
Musculoskeletal, connective tissue and bone disorders: Arthralgia, arthritis, myalgia.
Renal and urinary disorders: Glomerulopathy.
Reproductive system and breast disorders: Gynaecomastia.
General disorders and administration site conditions: Fever.
Investigations: Abnormal liver function test, blood creatinine increase.
Drug Interactions
Drugs associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect. The concomitant administration of drugs associated with bleeding risk should be undertaken with caution.
Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin are co-administered with acetylsalicylic acid.
Glycoprotein IIb/IIIa inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.
Injectable anticoagulants: In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. As a pharmacodynamic interaction between clopidogrel and heparin is possible, concomitant use should be undertaken with caution.
Oral anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Acetylsalicylic acid: Acetylsalicylic acid did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of acetylsalicylic acid twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, concomitant use should be undertaken with caution. However, clopidogrel and ASA (75-325 mg once daily) have been administered together for up to one year.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs and clopidogrel should be co administered with caution.
Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.
Other Concomitant Therapy: Inducers of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see Precautions).
Inhibitors of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be discouraged (see Precautions, Pharmacology: Pharmacokinetics under Actions and Pharmacogenetics under Dosage & Administration). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as pantoprazole.
Proton Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with 5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In a second interaction study with omeprazole 80 mg administered 12 hours apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.
In a third interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600-mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.
In a crossover clinical study, healthy subjects were administered clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (Day 1) and 14% (Day 5) when clopidogrel and pantoprazole were administered together. Mean inhibition of platelet aggregation was diminished by 15% (24 hours) and 11% (Day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
The CURRENT trial compared 2 dosing regimens of clopidogrel (600-mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs. 300-mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18,432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.
A number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies (ART) are at high risk of vascular events.
A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir-or cobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who have experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitant use of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boosted therapies should be discouraged.
CYP2C8 substrate drugs: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g, repaglinide, paclitaxel) should be undertaken with caution.
In addition to the previously mentioned specific interaction studies, patients entered into large clinical studies (CAPRIE and CURE) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin), anti-epileptic agents, GPIIb/IIIa antagonists and hormone replacement therapy, without evidence of clinically significant adverse interactions.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.
Thrombolytics: The safety of the concomitant administration of clopidogrel, thrombolytics and heparin was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytics and heparin are co-administered with acetylsalicylic acid.
Glycoprotein IIb/IIIa inhibitors: As a pharmacodynamic interaction between clopidogrel and glycoprotein IIb/IIIa inhibitors is possible, concomitant use should be undertaken with caution.
Injectable anticoagulants: In a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. As a pharmacodynamic interaction between clopidogrel and heparin is possible, concomitant use should be undertaken with caution.
Oral anticoagulants: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution.
Acetylsalicylic acid: Acetylsalicylic acid did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of acetylsalicylic acid on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of acetylsalicylic acid twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. As a pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, concomitant use should be undertaken with caution. However, clopidogrel and ASA (75-325 mg once daily) have been administered together for up to one year.
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): In a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs, it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs and clopidogrel should be co administered with caution.
Selective Serotonin Reuptake Inhibitors (SSRIs): Since SSRIs affect platelet activation and increase the risk of bleeding, the concomitant administration of SSRIs with clopidogrel should be undertaken with caution.
Other Concomitant Therapy: Inducers of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel.
Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong CYP2C19 inducers should be discouraged (see Precautions).
Inhibitors of CYP2C19: Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. Concomitant use of strong or moderate CYP2C19 inhibitors (e.g., omeprazole) should be discouraged (see Precautions, Pharmacology: Pharmacokinetics under Actions and Pharmacogenetics under Dosage & Administration). If a proton pump inhibitor is to be used concomitantly with clopidogrel, consider using one with less CYP2C19 inhibitory activity, such as pantoprazole.
Proton Pump Inhibitors (PPI): In a crossover clinical study, clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with omeprazole (80 mg at the same time as clopidogrel) were administered for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 45% (Day 1) and 40% (Day 5) when clopidogrel and omeprazole were administered together. Mean inhibition of platelet aggregation (IPA) with 5 μM ADP was diminished by 39% (24 hours) and 21% (Day 5) when clopidogrel and omeprazole were administered together.
In a second interaction study with omeprazole 80 mg administered 12 hours apart from the clopidogrel standard regimen, the results were similar, indicating that administering clopidogrel and omeprazole at different times does not prevent their interaction that is likely to be driven by the inhibitory effect of omeprazole on CYP2C19.
In a third interaction study with omeprazole 80 mg administered with a higher dose regimen of clopidogrel (600-mg loading dose followed by 150 mg/day), a degree of interaction was observed similar to that noted in the other omeprazole interaction studies. However, active metabolite formation and platelet aggregation were at the same level as clopidogrel administered alone at the standard dose regimen.
In a crossover clinical study, healthy subjects were administered clopidogrel (300-mg loading dose followed by 75 mg/day) alone and with pantoprazole (80 mg at the same time as clopidogrel) for 5 days. The exposure to the active metabolite of clopidogrel was decreased by 20% (Day 1) and 14% (Day 5) when clopidogrel and pantoprazole were administered together. Mean inhibition of platelet aggregation was diminished by 15% (24 hours) and 11% (Day 5) when clopidogrel and pantoprazole were administered together. These results indicate that clopidogrel can be administered with pantoprazole.
The CURRENT trial compared 2 dosing regimens of clopidogrel (600-mg loading dose, then 150 mg/day for 6 days followed by 75 mg/day up to 30 days vs. 300-mg loading dose followed by 75 mg/day up to 30 days). A subanalysis (n=18,432) correlated PPI use (mainly omeprazole and pantoprazole) at randomization and hospital discharge and demonstrated no interaction between clopidogrel and PPI use for the primary endpoint (CV death, MI or stroke) or any secondary endpoints, including stent thrombosis.
A number of other clinical studies have been conducted with clopidogrel and other concomitant medications to investigate the potential for pharmacodynamic and pharmacokinetic interactions. No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Furthermore, the pharmacodynamic activity of clopidogrel was not significantly influenced by the co-administration of phenobarbital or oestrogen.
The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. However, at high concentrations in vitro, clopidogrel inhibits CYP2C9. It is unlikely that clopidogrel may interfere with the metabolism of drugs such as phenytoin and tolbutamide and the NSAIDs, which are metabolised by cytochrome P450 2C9. Data from the CAPRIE study indicate that phenytoin and tolbutamide can be safely co-administered with clopidogrel.
Boosted anti-retroviral therapy (ART): HIV patients treated with boosted anti-retroviral therapies (ART) are at high risk of vascular events.
A significantly reduced platelet inhibition has been shown in HIV patients treated with ritonavir-or cobicistat-boosted ART. Although the clinical relevance of these findings is uncertain, there have been spontaneous reports of HIV-infected patients treated with ritonavir boosted ART, who have experienced re-occlusive events after de-obstruction or have suffered thrombotic events under a clopidogrel loading treatment schedule. Average platelet inhibition can be decreased with concomitant use of clopidogrel and ritonavir. Therefore, concomitant use of clopidogrel with ART boosted therapies should be discouraged.
CYP2C8 substrate drugs: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g, repaglinide, paclitaxel) should be undertaken with caution.
In addition to the previously mentioned specific interaction studies, patients entered into large clinical studies (CAPRIE and CURE) received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting enzyme inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, anti-diabetic agents (including insulin), anti-epileptic agents, GPIIb/IIIa antagonists and hormone replacement therapy, without evidence of clinically significant adverse interactions.
As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel presumably because of slowed gastric emptying. The clinical relevance is unknown. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.
Storage
Store at temperatures not exceeding 30°C.
Action
Pharmacology: Pharmacodynamics: Mode of Action: Clopidogrel is a prodrug, one of whose metabolites is an inhibitor of platelet aggregation. Clopidogrel must be metabolised by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Due to the irreversible binding, platelets exposed are affected for the remainder of their lifespan (approximately 7-10 days) and recovery of normal platelet function occurs at a rate consistent with platelet turnover. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Repeated doses of 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.
Clinical efficacy and safety: The safety and efficacy of clopidogrel have been evaluated in 7 double-blind studies involving over 100,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT, CHANCE, POINT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.
De-escalation of P2Y12 Inhibitor Agents in Acute Coronary Syndrome:Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after acute phase in Acute Coronary Syndrome (ACS) has been evaluated in two randomized investigator-sponsored studies (ISS)-TOPIC and TROPICAL-ACS- with clinical outcome data.
The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their pivotal studies is related to a significant reduction in recurrent ischemic events (including acute and subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although the ischemic benefit was consistent throughout the first year, greater reduction in ischemic recurrence after ACS was observed during the initial days following the treatment initiation. In contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding events while maintaining efficacy.
TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome): This randomized, open-label trial included ACS patients requiring percutaneous coronary intervention (PCI). Patients on aspirin and a more potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose aspirin plus clopidogrel (de-escalated dual antiplatelet therapy (DAPT)) or continuation of their drug regimen (unchanged DAPT).
Overall, 645 of 646 patients with ST-elevation-MI (STEMI) or non-ST-elevation-MI (NSTEMI) or unstable angina were analyzed (de-escalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients (98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. The characteristics of the studied cohort were similar in the 2 groups.
The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding events, with no difference reported in ischemic endpoints (p=0.36), while BARC ≥2 bleeding occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).
TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes): This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1306), or prasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), in combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The prasugrel-only patients were continued on prasugrel for 11.5 months.
The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and were followed for one year.
The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 at 12 months) was met showing non-inferiority. Ninety-five patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group (p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14).
Dual Antiplatelet Therapy (DAPT) in Acute Minor IS or Moderate to High-risk TIA: DAPT with combination clopidogrel and ASA as a treatment to prevent stroke after an acute minor IS or moderate to high-risk TIA has been evaluated in two randomized investigator-sponsored studies (ISS) - CHANCE and POINT- with clinical safety and efficacy outcome data.
CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events): This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 5,170 Chinese patients with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS ≤3). Patients in both groups received open-label ASA on day 1 (with the dose ranging from 75 to 300 mg, at the discretion of the treating physician). Patients randomly assigned to the clopidogrel-ASA group received a loading dose of 300 mg of clopidogrel on day 1, followed by a dose of 75 mg of clopidogrel per day on days 2 through 90, and ASA at a dose of 75 mg per day on days 2 through 21. Patients randomly assigned to the ASA group received a placebo version of clopidogrel on days 1 through 90 and ASA at a dose of 75 mg per day on days 2 through 90.
The primary efficacy outcome was any new stroke event (ischemic and hemorrhagic) in the first 90 days after acute minor IS or high-risk TIA. This occurred in 212 patients (8.2%) in the clopidogrel-ASA group compared with 303 patients (11.7%) in the ASA group (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.57 to 0.81; P<0.001). IS occurred in 204 patients (7.9%) in the clopidogrel-ASA group compared with 295 (11.4%) in the ASA group (HR, 0.67; 95% CI, 0.56 to 0.81; P<0.001). Hemorrhagic stroke occurred in 8 patients in each of the two study groups (0.3% of each group). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-ASA group and in eight (0.3%) in the ASA group (P = 0.73). The rate of any bleeding event was 2.3% in the clopidogrel-ASA group as compared with 1.6% in the ASA group (HR, 1.41; 95% CI, 0.95 to 2.10; P = 0.09).
POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke): This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 4,881 international patients with acute TIA (ABCD2 score ≥4) or minor stroke (NIHSS ≤3). All patients in both groups received open-label ASA on day 1 to 90 (50-325 mg depending upon the discretion of the treating physician). Patients randomly assigned to the clopidogrel group received a loading dose of 600 mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day on days 2 through 90. Patients randomly assigned to the placebo group received clopidogrel placebo on days 1 through 90.
The primary efficacy outcome was a composite of major ischemic events (IS, MI or death from an ischemic vascular event) at day 90. This occurred in 121 patients (5.0%) receiving clopidogrel plus ASA compared with 160 patients (6.5%) receiving ASA alone (HR, 0.75; 95% CI, 0.59 to 0.95; P = 0.02). The secondary outcome of IS occurred in 112 patients (4.6%) receiving clopidogrel plus ASA compared with 155 patients (6.3%) receiving ASA alone (HR, 0.72; 95% CI, 0.56 to 0.92; P = 0.01). The primary safety outcome of major hemorrhage occurred in 23 of 2,432 patients (0.9%) receiving clopidogrel plus ASA and in 10 of 2,449 patients (0.4%) receiving ASA alone (HR, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). Minor hemorrhage occurred in 40 patients (1.6%) receiving clopidogrel plus ASA and in 13 (0.5%) receiving ASA alone (HR, 3.12; 95% CI, 1.67 to 5.83; P = 0.001).
CHANCE and POINT Time Course Analysis There was no efficacy benefit of continuing DAPT beyond 21 days. A time-course distribution of major ischemic events and major hemorrhages by treatment assignment was done to analyze the impact of the short-term time-course of DAPT. (See Table 1.)
Pharmacokinetics: Absorption: After single and repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is non-saturable in vitro up to a concentration of 100 mg/L.
Metabolism: Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing.
Elimination: Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.
Special Population: The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.
Gender: In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. ASA in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
Elderly: In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Pediatric: No information available.
Hepatic Impairment: After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.
Renal Impairment: After repeated doses of 75 mg clopidogrel per day in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min), inhibition of ADP induced platelet aggregation was lower (25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of clopidogrel per day.
Ethnicity:The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to ethnicity. From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.
Because the active metabolite is formed by CYP450 enzymes, some of which are polymorphic or subject to inhibition by other drugs, not all patients will have adequate platelet inhibition.
Repeated doses of 75 mg/day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg/day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.
Clinical efficacy and safety: The safety and efficacy of clopidogrel have been evaluated in 7 double-blind studies involving over 100,000 patients: the CAPRIE study, a comparison of clopidogrel to ASA, and the CURE, CLARITY, COMMIT, CHANCE, POINT and ACTIVE-A studies comparing clopidogrel to placebo, both medicinal products given in combination with ASA and other standard therapy.
De-escalation of P2Y12 Inhibitor Agents in Acute Coronary Syndrome:Switching from a more potent P2Y12 receptor inhibitor to clopidogrel in association with aspirin after acute phase in Acute Coronary Syndrome (ACS) has been evaluated in two randomized investigator-sponsored studies (ISS)-TOPIC and TROPICAL-ACS- with clinical outcome data.
The clinical benefit provided by the more potent P2Y12 inhibitors, ticagrelor and prasugrel, in their pivotal studies is related to a significant reduction in recurrent ischemic events (including acute and subacute stent thrombosis (ST), myocardial infarction (MI), and urgent revascularization). Although the ischemic benefit was consistent throughout the first year, greater reduction in ischemic recurrence after ACS was observed during the initial days following the treatment initiation. In contrast, post-hoc analyses demonstrated statistically significant increases in the bleeding risk with the more potent P2Y12 inhibitors, occurring predominantly during the maintenance phase, after the first month post-ACS. TOPIC and TROPICAL-ACS were designed to study how to mitigate the bleeding events while maintaining efficacy.
TOPIC (Timing Of Platelet Inhibition after acute Coronary syndrome): This randomized, open-label trial included ACS patients requiring percutaneous coronary intervention (PCI). Patients on aspirin and a more potent P2Y12 blocker and without adverse event at one month were assigned to switch to fixed-dose aspirin plus clopidogrel (de-escalated dual antiplatelet therapy (DAPT)) or continuation of their drug regimen (unchanged DAPT).
Overall, 645 of 646 patients with ST-elevation-MI (STEMI) or non-ST-elevation-MI (NSTEMI) or unstable angina were analyzed (de-escalated DAPT (n=322); unchanged DAPT (n=323)). Follow-up at one year was performed for 316 patients (98.1%) in the de-escalated DAPT group and 318 patients (98.5%) in the unchanged DAPT group. The median follow-up for both groups was 359 days. The characteristics of the studied cohort were similar in the 2 groups.
The primary outcome, a composite of cardiovascular death, stroke, urgent revascularization, and BARC (Bleeding Academic Research Consortium) bleeding ≥2 at 1 year post ACS, occurred in 43 patients (13.4%) in the de-escalated DAPT group and in 85 patients (26.3%) in the unchanged DAPT group (p<0.01). This statistically significant difference was mainly driven by fewer bleeding events, with no difference reported in ischemic endpoints (p=0.36), while BARC ≥2 bleeding occurred less frequently in the de-escalated DAPT group (4.0%) versus 14.9% in the unchanged DAPT group (p<0.01). Bleeding events defined as all BARC occurred in 30 patients (9.3%) in the de-escalated DAPT group and in 76 patients (23.5%) in the unchanged DAPT group (p<0.01).
TROPICAL-ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes): This randomized, open-label trial included 2,610 biomarker-positive ACS patients after successful PCI. Patients were randomized to receive either prasugrel 5 or 10 mg/d (Days 0-14) (n=1306), or prasugrel 5 or 10 mg/d (Days 0-7) then de-escalated to clopidogrel 75 mg/d (Days 8-14) (n=1304), in combination with ASA (<100 mg/day). At Day 14, platelet function testing (PFT) was performed. The prasugrel-only patients were continued on prasugrel for 11.5 months.
The de-escalated patients underwent high platelet reactivity (HPR) testing. If HPR≥46 units, the patients were escalated back to prasugrel 5 or 10 mg/d for 11.5 months; if HPR<46 units, the patients continued on clopidogrel 75 mg/d for 11.5 months. Therefore, the guided de-escalation arm had patients on either prasugrel (40%) or clopidogrel (60%). All patients were continued on aspirin and were followed for one year.
The primary endpoint (the combined incidence of CV death, MI, stroke and BARC bleeding grade ≥2 at 12 months) was met showing non-inferiority. Ninety-five patients (7%) in the guided de-escalation group and 118 patients (9%) in the control group (p non-inferiority=0.0004) had an event. The guided de-escalation did not result in an increased combined risk of ischemic events (2.5% in the de-escalation group vs 3.2% in the control group; p non-inferiority=0.0115), nor in the key secondary endpoint of BARC bleeding ≥2 ((5%) in the de-escalation group versus 6% in the control group (p=0.23)). The cumulative incidence of all bleeding events (BARC class 1 to 5) was 9% (114 events) in the guided de-escalation group versus 11% (137 events) in the control group (p=0.14).
Dual Antiplatelet Therapy (DAPT) in Acute Minor IS or Moderate to High-risk TIA: DAPT with combination clopidogrel and ASA as a treatment to prevent stroke after an acute minor IS or moderate to high-risk TIA has been evaluated in two randomized investigator-sponsored studies (ISS) - CHANCE and POINT- with clinical safety and efficacy outcome data.
CHANCE (Clopidogrel in High-risk patients with Acute Non-disabling Cerebrovascular Events): This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 5,170 Chinese patients with acute TIA (ABCD2 score ≥4) or acute minor stroke (NIHSS ≤3). Patients in both groups received open-label ASA on day 1 (with the dose ranging from 75 to 300 mg, at the discretion of the treating physician). Patients randomly assigned to the clopidogrel-ASA group received a loading dose of 300 mg of clopidogrel on day 1, followed by a dose of 75 mg of clopidogrel per day on days 2 through 90, and ASA at a dose of 75 mg per day on days 2 through 21. Patients randomly assigned to the ASA group received a placebo version of clopidogrel on days 1 through 90 and ASA at a dose of 75 mg per day on days 2 through 90.
The primary efficacy outcome was any new stroke event (ischemic and hemorrhagic) in the first 90 days after acute minor IS or high-risk TIA. This occurred in 212 patients (8.2%) in the clopidogrel-ASA group compared with 303 patients (11.7%) in the ASA group (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.57 to 0.81; P<0.001). IS occurred in 204 patients (7.9%) in the clopidogrel-ASA group compared with 295 (11.4%) in the ASA group (HR, 0.67; 95% CI, 0.56 to 0.81; P<0.001). Hemorrhagic stroke occurred in 8 patients in each of the two study groups (0.3% of each group). Moderate or severe hemorrhage occurred in seven patients (0.3%) in the clopidogrel-ASA group and in eight (0.3%) in the ASA group (P = 0.73). The rate of any bleeding event was 2.3% in the clopidogrel-ASA group as compared with 1.6% in the ASA group (HR, 1.41; 95% CI, 0.95 to 2.10; P = 0.09).
POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke): This randomized, double-blinded, multicenter, placebo-controlled clinical trial included 4,881 international patients with acute TIA (ABCD2 score ≥4) or minor stroke (NIHSS ≤3). All patients in both groups received open-label ASA on day 1 to 90 (50-325 mg depending upon the discretion of the treating physician). Patients randomly assigned to the clopidogrel group received a loading dose of 600 mg of clopidogrel on day 1, followed by 75 mg of clopidogrel per day on days 2 through 90. Patients randomly assigned to the placebo group received clopidogrel placebo on days 1 through 90.
The primary efficacy outcome was a composite of major ischemic events (IS, MI or death from an ischemic vascular event) at day 90. This occurred in 121 patients (5.0%) receiving clopidogrel plus ASA compared with 160 patients (6.5%) receiving ASA alone (HR, 0.75; 95% CI, 0.59 to 0.95; P = 0.02). The secondary outcome of IS occurred in 112 patients (4.6%) receiving clopidogrel plus ASA compared with 155 patients (6.3%) receiving ASA alone (HR, 0.72; 95% CI, 0.56 to 0.92; P = 0.01). The primary safety outcome of major hemorrhage occurred in 23 of 2,432 patients (0.9%) receiving clopidogrel plus ASA and in 10 of 2,449 patients (0.4%) receiving ASA alone (HR, 2.32; 95% CI, 1.10 to 4.87; P = 0.02). Minor hemorrhage occurred in 40 patients (1.6%) receiving clopidogrel plus ASA and in 13 (0.5%) receiving ASA alone (HR, 3.12; 95% CI, 1.67 to 5.83; P = 0.001).
CHANCE and POINT Time Course Analysis There was no efficacy benefit of continuing DAPT beyond 21 days. A time-course distribution of major ischemic events and major hemorrhages by treatment assignment was done to analyze the impact of the short-term time-course of DAPT. (See Table 1.)
Pharmacokinetics: Absorption: After single and repeated oral doses of 75 mg/day, clopidogrel is rapidly absorbed. Mean peak plasma levels of unchanged clopidogrel (approximately 2.2-2.5 ng/mL after a single 75-mg oral dose) occurred approximately 45 minutes after dosing. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.
Distribution: Clopidogrel and the main circulating (inactive) metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is non-saturable in vitro up to a concentration of 100 mg/L.
Metabolism: Clopidogrel is extensively metabolised by the liver. In vitro and in vivo, clopidogrel is metabolised according to two main metabolic pathways: one mediated by esterases and leading to hydrolysis into its inactive carboxylic acid derivative (85% of circulating metabolites), and one mediated by multiple cytochromes P450. Clopidogrel is first metabolised to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-clopidogrel intermediate metabolite results in formation of the active metabolite, a thiol derivative of clopidogrel. The active metabolite is formed mostly by CYP2C19 with contributions from several other CYP enzymes, including CYP1A2, CYP2B6 and CYP3A4. The active thiol metabolite which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation.
The Cmax of the active metabolite is twice as high following a single 300-mg clopidogrel loading dose as it is after four days of 75-mg maintenance dose. Cmax occurs approximately 30 to 60 minutes after dosing.
Elimination: Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.
Special Population: The pharmacokinetics of the active metabolite of clopidogrel is not known in these special populations.
Gender: In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. In the large, controlled clinical study (Clopidogrel vs. ASA in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.
Elderly: In elderly (≥75 years) volunteers compared to young healthy volunteers, there were no differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Pediatric: No information available.
Hepatic Impairment: After repeated doses of 75 mg clopidogrel per day for 10 days in patients with severe hepatic impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in healthy subjects. The mean bleeding time prolongation was also similar in the two groups.
Renal Impairment: After repeated doses of 75 mg clopidogrel per day in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min), inhibition of ADP induced platelet aggregation was lower (25%) than that observed in healthy volunteers, however, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of clopidogrel per day.
Ethnicity:The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to ethnicity. From literature, limited data in Asian populations are available to assess the clinical implication of genotyping of this CYP on clinical outcome events.
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