Clopidogrel Side Effects:
Common adverse reactions include rash (4%), diarrhea (5%), abdominal pain (6%), dyspepsia (5%), intracranial hemorrhage (0.4%), gastrointestinal bleeding (2%), and severe neutropenia (0.04%). These effects are similar to those of aspirin. They are primarily based on the results evaluated in the large clinical trial CAPRIE. In this study, the overall tolerability of clopidogrel was comparable to that of ASA (aspirin), irrespective of age, race, and gender. Hemorrhagic disorders include gastrointestinal bleeding, purpura, bruising, hematoma, epistaxis, hematuria, ocular bleeding (mainly conjunctival), and intracranial hemorrhage. The incidence of severe bleeding in patients treated with clopidogrel was 1.4%. Hematologic: includes severe neutropenia, aplastic anemia, and severe thrombocytopenia, all of which are relatively rare.
Clopidogrel’s safety was assessed in over 11,300 patients, with more than 7,000 treated for one year or longer. In the large clinical study CAPRIE, patients taking 75 mg/day of clopidogrel had good tolerability compared to those taking 325 mg/day of aspirin. Clopidogrel’s overall tolerability was similar to aspirin regardless of age, gender, and race. The main adverse reactions discussed in the CAPRIE trial are as follows:
(1)Bleeding-clopidogrel side effects:
The total incidence of bleeding in patients treated with clopidogrel or aspirin was 9.3%. The incidence of severe bleeding events was 1.4% for clopidogrel and 1.6% for aspirin.
Patients treated with clopidogrel had a 2.0% rate of gastrointestinal bleeding, with 0.7% requiring hospitalization, compared to 2.7% and 1.1%, respectively, for aspirin.
Compared to aspirin, patients taking clopidogrel had a higher incidence of other bleeding events (7.3% vs. 6.5%), but the rate of severe events was similar between the two treatment groups (0.6% vs. 0.4%). The most common adverse events in both treatment groups were purpura/bruising/hematoma and epistaxis, along with hematoma, hematuria, and ocular bleeding (mainly conjunctival).
The incidence of intracranial hemorrhage was 0.4% for clopidogrel and 0.5% for aspirin.
(2)Hematologic Disorders-clopidogrel side effects:
Six patients experienced severe neutropenia (neutrophil count < 0.45×10^9/L), four in the clopidogrel group (0.04%) and two in the aspirin group (0.02%). Among 9,599 patients in the clopidogrel group, two had an absolute neutrophil count of zero, while none of the 9,586 patients in the aspirin group experienced this. There was one case of aplastic anemia in the clopidogrel group.
The incidence of severe thrombocytopenia (platelet count < 80×10^9/L) was 0.2% in the clopidogrel group and 0.1% in the aspirin group; cases with platelet counts ≤ 30×10^9/L were extremely rare.
(3)Gastrointestinal Reactions-clopidogrel side effects:
Overall, the incidence of gastrointestinal reactions (such as abdominal pain, dyspepsia, gastritis, and constipation) was 27.1% in the clopidogrel group and 29.8% in the aspirin group. Moreover, 3.2% of the clopidogrel group discontinued treatment due to gastrointestinal side effects, compared to 4.0% in the aspirin group. However, there was no statistical difference in the incidence of clinically serious adverse reactions between the groups (3.0% vs. 3.6%). The most common adverse events in both treatment groups were abdominal pain, dyspepsia, diarrhea, and nausea. Other events included constipation, dental conditions, vertigo, and gastritis.
The incidence of diarrhea was 4.5% in the clopidogrel group, significantly higher than in the aspirin group (3.4%). The incidence of severe diarrhea was similar between the two treatment groups (0.2% vs. 0.1%). The incidence of gastrointestinal, gastric, and duodenal ulcers was 0.7% in the clopidogrel group, compared to 1.2% in the aspirin group.
(4)Rash and Other Skin Disorders-clopidogrel side effects:
The incidence of skin and subcutaneous tissue disorders was 15.8% (0.7% severe) in the clopidogrel group, significantly higher than in the aspirin group (4.2% vs. 3.5%). The incidence of pruritus in the clopidogrel group was also higher than in the aspirin group (3.3% vs. 1.6%).
Central and Peripheral Nervous System Disorders: The overall incidence of central and peripheral nervous system disorders (such as headache, vertigo, lightheadedness, and paresthesia) was significantly lower in the clopidogrel group compared to the aspirin group (22.3% vs. 23.8%).
(5)Hepatic and Biliary Disorders-clopidogrel side effects:
The overall incidence of hepatic and biliary disorders was similar between the two treatment groups (3.5% vs. 3.4%).
Post-Marketing Experience: Post-marketing surveillance has confirmed the safety profile of clopidogrel, with reported allergic symptoms mainly including skin reactions (maculopapular or erythematous rashes, urticaria…) and/or pruritus. There have been fewer reports of bronchospasm, angioedema, or anaphylactoid reactions. Post-marketing, there have been very few cases of thrombotic thrombocytopenic purpura (TTP) reported (1 in 200,000 patients).
Contraindications:
Hypersensitivity to the drug or any of its components.
Active pathological bleeding, such as peptic ulcers or intracranial hemorrhage.
Precautions:
- Clopidogrel is not recommended for patients with acute myocardial infarction during the first few days of the acute event.
- Due to the lack of relevant data, the use of clopidogrel is not actively recommended for unstable angina, PTCA (with stenting), CABG, and acute ischemic stroke (less than 7 days).
- Clopidogrel should be used with caution in patients who may have an increased risk of bleeding due to trauma, surgery, or other pathological causes.
- In patients scheduled for elective surgery who do not require antiplatelet therapy, clopidogrel should be discontinued one week before the procedure.
- Clopidogrel prolongs bleeding time and should be used with caution in patients prone to bleeding, especially in the gastrointestinal tract and eyes.
- Patients should be aware that their bleeding time may be longer than usual when taking clopidogrel and should report any unusual bleeding to their doctor.
- Patients should inform their doctor that they are taking clopidogrel before surgery and before starting any new medications.
- Due to limited experience with clopidogrel in patients with renal impairment, caution is advised when using this medication.
- Patients with severe liver disease may have a tendency to bleed, and there is limited experience with the use of this drug in such patients, so clopidogrel should be used with caution.
- The concurrent use of warfarin is not recommended due to the risk of bleeding; therefore, it is not advised to take warfarin while on clopidogrel.
- The simultaneous use of other antiplatelet drugs, nonsteroidal anti-inflammatory drugs (NSAIDs), heparin, and thrombolytics can increase the risk of bleeding, so their concurrent use is not recommended.
- Patients taking medications that may cause gastrointestinal damage (such as NSAIDs) should use clopidogrel with caution. There is no evidence that clopidogrel affects driving or psychometric tests.
Clopidogrel is an antiplatelet drug that mainly works by antagonizing the adenosine diphosphate (ADP) P2Y12 receptor, interfering with ADP-mediated platelet activation, exerting antiplatelet aggregation effects, and inhibiting the formation of arterial thrombosis. Clopidogrel is a prodrug that does not have antiplatelet activity itself. It must undergo hepatic enzyme metabolism activation to generate active metabolites that can inhibit platelet aggregation.
It is used to prevent arterial atherosclerotic thrombotic events, such as recent myocardial infarction, ischemic stroke, or peripheral arterial disease, and is also suitable for patients with acute coronary syndrome, such as those who have undergone percutaneous coronary intervention with stent placement. Clopidogrel needs to be taken for at least 6-12 months to prevent stent thrombosis when used in combination with aspirin.
American manufacturers of Clopidogrel
Clopidogrel is a generic drug and is manufactured by several companies in the United States. Some of the manufacturers of clopidogrel in the US include:
- Apotex Corp.
- Aurobindo Pharma USA, Inc.
- Dr. Reddy’s Laboratories, Inc.
- Mylan Pharmaceuticals, Inc.
- Teva Pharmaceuticals USA, Inc.
