Apolets

Clopidogrel.

Each film-coated tablet contains Clopidogrel bisulfate 98.0 mg equivalent to 75 mg of clopidogrel base.
Clopidogrel bisulfate is an inhibitor of ADP-induced platelet aggregation acting by direct inhibition of adenosine diphosphate (ADP) binding to its receptor and of the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex. Chemically it is Methyl (+)-(S)-a-(o-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate,sulfate (1:1). The empirical formula of clopidogrel bisulfate is C₁₆H₁₆ClNO₂S·H₂SO₄ and its molecular weight is 419.90.
Clopidogrel bisulfate is a white to off-white powder. It is practically insoluble in water at neutral pH but freely soluble at pH 1. It also dissolves freely in methanol, dissolves sparingly in methylene chloride, and is practically insoluble in ethyl ether. It has a specific optical rotation of about +56°.
Excipients/Inactive Ingredients: Each tablet contains  anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate. The reddish brown film coating contains ferric oxide, hydroxypropyl cellulose, hypromellose 2910 E5, polyethylene glycol 8000 and titanium dioxide.

Pharmacotherapeutical group: Platelet aggregation inhibitors excluding heparin. ATC Code: B01AC/04.
Pharmacology: Pharmacodynamics: Mechanism of Action: Clopidogrel is a prodrug that is metabolized to the active form, (thiol derivative) that inhibits platelet aggregation by selectively and irreversibly binding to the adenosine diphosphate (ADP) P2Y12 receptor on platelets. This binding prevents activation of the ADP-mediated glycoprotein GPIIb/IIIa complex, which is necessary for platelet aggregation. This action is irreversible for the remainder of the platelet lifespan (7 to 10 days).
Pharmacodynamic Properties: Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel. Repeated doses of 75 mg per day inhibit ADP-induced platelet aggregation from the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg clopidogrel per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values after treatment was discontinued, generally in about 5 days.
Clinical Studies: The clinical evidence for the safety and efficacy in preventing vascular ischemic events has been evaluated in two randomized, double-blind, placebo-controlled trials: the CAPRIE study (Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events), a comparison of clopidogrel to aspirin, and the CURE study (Clopidogrel in Unstable Angina to Prevent Recurrent Ischemic Events), a comparison of clopidogrel to placebo, both given in combination with aspirin and other standard therapy.
The CAPRIE trial was a 19,185 patients, randomized, double-blind, parallel-group study comparing clopidogrel (75 mg) daily to aspirin (325 mg daily).
In patients with recent myocardial infarction (within 35 days), recent ischemic stroke (within 6 months) or established peripheral arterial disease. Patients received randomized treatment for an average of 1.91 years (maximum of 3 years).
The trial's primary outcome was the time to first occurrence of new ischemic stroke (fatal or not), new myocardial infarction (fatal or not), or other vascular death. Deaths not easily attributable to nonvascular causes were all classified as vascular. (See Table 1.)

Click on icon to see table/diagram/image

As shown in the table, clopidogrel was associated with a lower incidence of outcome events of every kind. The overall risk reduction (9.8% vs. 10.6%) was 8.7%, p = 0.045. Similar results were obtained when all-cause mortality and all-cause strokes were counted instead of vascular mortality and ischemic strokes (risk reduction 6.9%). In patients who survived an on-study stroke or myocardial infarction, the incidence of subsequent events was again lower in the clopidogrel group. The curves showing the overall event rate are shown in Figure 1. The event curves separated early and continued to diverge over the 3-year follow-up period. (See Figure 1.)

Click on icon to see table/diagram/image

Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin.
The CURE study included 12,562 patients with acute coronary syndrome without ST-segment elevation (unstable angina or non-Q-wave myocardial infarction) and presenting within 24 hours of onset of the most recent episode of chest pain or symptoms consistent with ischemia.
Patients were required to have either ECG changes compatible with new ischemia (without ST-segment elevation) or elevated cardiac enzymes or troponin I or T to at least twice the upper limit of normal. Patients were randomized to receive clopidogrel (300 mg loading dose followed by 75 mg/day), (n=6,259) or placebo (n=6,303), and were treated for 3 to 12 months. Patients also received aspirin (75-325 mg once daily) and other standard therapies such as heparin (oral anticoagulants e.g. warfarin and long-term NSAIDs were not permitted). The use of GP IIb/IIIa inhibitors was not permitted for three days prior to randomization. The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.30%) in the clopidogrel-treated group and 719 (11.41%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p=0.00009) for the clopidogrel group (see Table 2).
At the end of 12 months, the number of patients experiencing the co-primary outcome (CV death, MI, stroke or refractory ischemia) was 1035 (16.54%) in the clopidogrel group and 1187 (18.83%) in the placebo group, a 14% relative risk reduction (95% CI of 6%-21%, p=0.0005) for the clopidogrel group (see Table 2).

Click on icon to see table/diagram/image

In the clopidogrel group, each component of the two primary endpoints (CV death, MI, stroke, refractory ischemia) occurred less frequently than in the placebo group. The benefits of clopidogrel were apparent as early as the first 24 hours after randomization and maintained throughout the course of the trial up to 12 months (see Figure 2).

Click on icon to see table/diagram/image

In CURE, the use of clopidogrel was associated with a lower incidence of CV death, MI or stroke in patient populations with different characteristics are shown in Figure 3. The benefits associated with clopidogrel tablets were independent of the use of other acute and long-term cardiovascular therapies, such as heparin/LMWH (low molecular weight heparin), IV glycoprotein IIb/IIIa (GP IIb/IIIa inhibitors), lipid-lowering drugs, beta-blockers, and ACE-inhibitors. The efficacy of clopidogrel was observed independently of the dose of aspirin (75-325 mg once daily). (See Figure 3.)

Click on icon to see table/diagram/image

The data show the consistency of the benefit of clopidogrel.
The use of clopidogrel in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel group, 126 patients [2%] in the placebo group; relative risk reduction of 43%, p=0.0001), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel group, 454 patients [7.2%] in the placebo group; relative risk reduction of 18%, p=0.003). There were significantly more patients with major bleeding in the clopidogrel group than in the placebo group (3.7% vs. 2.7%, relative risk 1.38, p=0.001), but there were not significantly more patients with episodes of life-threatening bleeding (2.1% vs. 1.8%, p=0.13) or hemorrhagic strokes.
In patients with acute ST-segment elevation MI, safety and efficacy of clopidogrel have been evaluated in 2 randomised, placebo-controlled, double-blind studies, Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) and Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT).
The CLARITY trial included 3,491 patients presenting within 12 hours after the onset of a ST-elevation MI and planned for thrombolytic therapy. Patients received clopidogrel (300 mg loading dose, followed by 75 mg once daily, n=1,752) or placebo (n=1,739), both in combination with ASA (150 to 325 mg as a loading dose, followed by 75 to 162 mg/day, a fibrinolytic agent and, when appropriate, heparin. The patients were followed for 30 days. The primary endpoint was the occurrence of the composite of an occluded infarct-related artery on the predischarge angiogram, or death or recurrent MI before coronary angiography. For patients who did not undergo angiography, the primary endpoint was death or recurrent myocardial infarction by Day 8 or by hospital discharge whichever came first. A total of 99.7% of patients received fibrinolytics (fibrin specific: 68.8%, non-fibrin specific: 31.1%), 89.5% heparin, 78.7% beta blockers, 54.7% ACE inhibitors and 63% statins.
Fifteen percent (15.0%) of patients in the clopidogrel group and 21.7% in the placebo group reached the primary endpoint, representing an absolute reduction of 6.7% in the rate and a 36% odds reduction in favor of clopidogrel (95% CI: 24, 47%; p < 0.001), mainly related to a reduction in occluded infarct-related arteries. This benefit was consistent across all prespecified subgroups including patients' age and gender, infarct location, and type of fibrinolytic or heparin used.
COMMIT trial included 45,852 patients presenting within 24 hours of the onset of the symptoms of suspected MI with supporting ECG abnormalities (i.e. ST elevation, ST depression or left bundle-branch block). Patients received clopidogrel (75 mg/day, n=22,961) or placebo (n=22,891), in combination with ASA (162 mg/day), for 28 days or until hospital discharge. The co-primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death. The population included 54.5% patients who received fibrinolytics.
Clopidogrel significantly reduced the relative risk of death from any cause by 7% (p=0.029), and the relative risk of the combination of re-infarction, stroke or death by 9% (p=0.002), representing an absolute reduction of 0.5% and 0.9%, respectively. This benefit was consistent across age, gender and with or without fibrinolytics, and was observed as early as 24 hours.
The ACTIVE-W and ACTIVE-A studies, separate trials in the ACTIVE program, included patients with atrial fibrillation (AF) who had at least one risk factor for stroke. Based on enrollment criteria, physicians enrolled patients in ACTIVE-W if they were candidates for vitamin K antagonist (VKA) therapy (such as warfarin). The ACTIVE-A study included patients who could not receive VKA therapy because they were unable or unwilling to receive the treatment.
The ACTIVE-W study demonstrated that anticoagulant treatment with vitamin K antagonists was more effective than with clopidogrel and ASA.
The ACTIVE-A study (n=7,554) was a multicenter, randomized, double-blind, placebo-controlled study which compared clopidogrel (75 mg once daily) + ASA (n=3,772) to placebo + ASA (n=3,782). The recommended dose for ASA was 75 to 100 mg/day. Patients were treated for up to 5 years.
A total of 23.0% of patients received anti-arrhythmics, 52.1% beta-blockers, 54.6% ACE inhibitors, and 25.4% statins.
The number of patients who reached the primary endpoint (time to first occurrence of stroke, MI, non-CNS systemic embolism or vascular death) was 832 (22.1%) in the group treated with clopidogrel + ASA and 924 (24.4%) in the placebo + ASA group (relative risk reduction of 11.1%; 95%CI of 2.4% to 19.1%; p=0.013), primarily due to a large reduction in the incidence of strokes. Strokes occurred in 296 (7.8%) patients receiving clopidogrel + ASA and 408 (10.8%) patients receiving placebo + ASA (relative risk reduction of 28.4%; 95%CI, 16.8% to 38.3%; p=0.00001).
Pharmacokinetics: After repeated 75 mg oral doses of clopidogrel, plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing.
Effect of Food: Administration of clopidogrel with meals did not significantly modify the bioavailability of active form, (thiol derivative).
Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel metabolites.
Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100 µg/mL.
Metabolism: Clopidogrel is extensively metabolised by the liver by 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 enzymes. 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. In vitro, this metabolic pathway is mediated by CYP3A4, CYP2C19, CYP1A2 and CYP2B6. The active thiol metabolite binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation for the lifespan of the platelet.
The C_max 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. C_max 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 feces 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 half-life of the active metabolite is approximately 30 minutes. The elimination half-life of the main circulating (inactive) metabolite was 8 hours after single and repeated administration.
Special Populations: Geriatric Patients: Plasma concentrations of the main circulating metabolite are significantly higher in elderly (≥75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.
Renal impairment: After repeated doses of 75 mg clopidogrel per day in patients with moderate (creatinine clearance from 30 to 60 ml/minute) and severe (creatinine clearance from 5 to 15 ml/minute) renal impairment, inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, however, the prolongation of bleeding time was similar to that seen in healthy subjects receiving 75 mg of clopidogrel/day.
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.
Pediatric population: Clopidogrel should not be used in children because safety and efficacy in children have not been established.
Gender: No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. 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. Aspirin 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.
Race: The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethnicity. From literature limited data in Asian populations are available to assess the clinical implication of genotyping of the CYP on clinical outcome events.

Clopidogrel is indicated for the reduction of atherothrombotic events as follows: 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 acute coronary syndrome (unstable angina/non-Q-wave MI) including patients who are to be managed medically and those who are to be managed with 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 in combination with aspirin is used to reduce the rate of ischemic cardiovascular events (e.g. death, reinfarction, stroke).
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation: In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.

Recommended Doses: Recent MI, Recent Stroke or Established Peripheral Arterial Disease: The recommended daily dose of clopidogrel tablets is 75 mg once daily.
Acute Coronary Syndrome: For patients with 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. Aspirin (75 mg - 325 mg daily) should be initiated and continued in combination with clopidogrel.
Since a higher dose of ASA was associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical data support use up to 12 months, and the maximum benefit was seen at 3 months.
For patients with ST-segment elevation acute myocardial infarction, the recommended dose of clopidogrel is 75 mg once daily, administered in combination with aspirin, with or without thrombolytics. Clopidogrel may be initiated with or without a loading dose 300 mg.
For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least 4 weeks. The benefit of the combination of clopidogrel with ASA beyond 4 weeks has not been studied in this setting.
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation: In patients with 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.
If a Dose is Missed: If the patient misses a dose or forgets to use the medicine, use as soon as the patient can.
If it is almost time for the next dose, wait until then to use the medicine and skip the missed dose.
Do not use extra medicine to make up for a missed dose.
Dose Adjustments: Renal impairment: Experience is limited in patients with moderate (creatinine clearance of 30-60 mL/minute) or severe (creatinine clearance of 5-15 mL/minute) renal impairment; use with caution. Inhibition of ADP-induced platelet aggregation may be decrease by 25%, but prolongation of bleeding time is similar in patients with renal impairment compared with that in healthy individuals.
Hepatic Insufficiency: Dosage adjustments are not necessary in patients with hepatic impairment. No dosage adjustment is necessary for mild to moderate cirrhosis.
Geriatric Patients: No dosage adjustments are necessary.
Other Disease States: CYP2C19 Poor Metabolizers: Patients who are CYP2C19 poor metabolizers have lower antiplatelet response to clopidogrel. Higher dosages of 600 mg loading dose followed by 150 mg once daily in this patient population had resulted in higher antiplatelet response. However, an appropriate dosage regimen has not been established.
Mode of administration: Clopidogrel oral tablets can be administered with or without food.

Overdose: Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications.
A single oral dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and to rats and at 3000 mg/kg to baboons. Symptoms of acute toxicity were vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all animals.
Recommendations about Specific Treatment: Based on biological plausibility, platelet transfusion may be appropriate to reverse the pharmacological effects of clopidogrel bisulfate if quick reversal is required.

The use of clopidogrel is contraindicated in the following conditions: Hypersensitivity to the drug substance or any component of the product; Active pathological bleeding such as peptic ulcer or intracranial hemorrhage; Severe hepatic impairment.

Thrombotic thrombocytopenic purpura (TTP): TTP has been reported rarely following use of clopidogrel, sometimes after a short exposure (<2 weeks). TTP is a serious potentially fatal condition and requires urgent referral to a hematologist for prompt treatment. It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral blood smear), neurological findings, renal dysfunction, and fever. TTP was not seen during clopidogrel's clinical trials, which included over 17,500 clopidogrel-treated patients. In worldwide post marketing experience, however, TTP has been reported at a rate of about four cases per million patients exposed, or about 11 cases per million patient-years. The background rate is thought to be about four cases per million person-years (See Adverse Reactions).

General: Bleeding: Clopidogrel prolongs the bleeding time and therefore should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery, or other pathological conditions (particularly gastrointestinal and intraocular). If a patient is to undergo elective surgery and an antiplatelet effect is not desired, clopidogrel should be discontinued 5-10 days prior to surgery. Due to the risk of bleeding and undesirable hematological 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. The concomitant administration of clopidogrel with oral anticoagulants (e.g. warfarin) is not recommended since it may increase the intensity of bleeding (See Adverse Reactions).
In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.
Patients should be told that they may bleed more easily and it may take them longer than usual to stop bleeding when they take clopidogrel or clopidogrel combined with aspirin, and that they should report any unusual bleeding to their physician. Patients should inform physicians and dentists that they are taking clopidogrel and/or any other product known to affect bleeding before any surgery is scheduled and before any new drug is taken.
GI Bleeding: In CAPRIE, clopidogrel was associated with a rate of gastrointestinal bleeding of 2% vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal bleeding was 1.3% vs. 0.7% (clopidogrel + aspirin vs. placebo + aspirin, respectively). Clopidogrel should be used with caution in patients who have lesions with a propensity to bleed (such as ulcers). Drugs that might induce such lesions should be used with caution in patients taking clopidogrel.
Carcinogenesis, Mutagenesis, Impairment of Fertility: There was no evidence of tumorigenicity when clopidogrel was administered for 78 weeks to mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which afforded plasma exposures >25 times that in humans at the recommended daily dose of 75 mg.
Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes, gene mutation assay in Chinese hamster fibroblasts, and metaphase chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral route in mice).
Clopidogrel was found to have no effect on fertility of male and female rats at oral doses up to 400 mg/kg per day) 52 times the recommended human dose on a mg/m² basis).

Pregnancy: Pregnancy Category B. Reproduction studies performed in rats and rabbits at doses up to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended daily human dose on a mg/m² basis), revealed no evidence of impaired fertility or fetotoxicity 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, clopidogrel should not be used in women during pregnancy.
Nursing Mothers: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in breast 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 the nursing woman.

Clopidogrel has been evaluated for safety in more than 44,000 patients, including over 12,000 patients treated for 1 year or more. The overall tolerability of clopidogrel 75 mg/day in CAPRIE was similar to that of aspirin (325 mg/day) regardless of age, gender and race, with an approximately equal incidence (13%) of patients withdrawing from treatment because of adverse reactions. The clinically important adverse events observed in CAPRIE and CURE are discussed as follows.
Hemorrhagic: In CAPRIE patients receiving clopidogrel, gastrointestinal hemorrhage occurred at a rate of 2%, and required hospitalization in 0.7%. In patients receiving aspirin, the corresponding rates were 2.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel compared to 0.5% for aspirin.
In CURE, clopidogrel use with aspirin was associated with an increase in bleeding compared to placebo with aspirin (see Table 3). There was an excess in major bleeding in patients receiving clopidogrel plus aspirin compared with placebo plus aspirin, primarily gastrointestinal and at puncture sites. The incidences of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%), were the same in both groups.
The overall incidence of bleeding is described in Table 3 for patients receiving both clopidogrel and aspirin in CURE. (See Table 3.)

Click on icon to see table/diagram/image

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. There was no excess in major bleeds within seven days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery (event rate 4.4% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.
Neutropenia/Agranulocytosis: Ticlopidine, a drug chemically similar to clopidogrel, is associated with a 0.8% rate of severe neutropenia (less than 450 neutrophils/µL). In CAPRIE severe neutropenia was observed in six patients, four on clopidogrel and two on aspirin. Two of the 9599 patients who received clopidogrel and none of the 9586 patients who received aspirin had neutrophil counts of zero. One of the four clopidogrel patients in CAPRIE was receiving cytostatic chemotherapy, and another recovered and returned to the trial after only temporarily interrupting treatment with clopidogrel. In CURE, the numbers of patients with thrombocytopenia or neutropenia were similar in both clopidogrel + aspirin and placebo + aspirin groups. 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.
Gastrointestinal: Overall, the incidence of gastrointestinal events (e.g. abdominal pain, dyspepsia, gastritis and constipation) patients receiving clopidogrel was 27.1%, compared to 29.8% in those receiving aspirin in the CAPRIE trial. In the CURE trial the incidence of these gastrointestinal events for patients receiving clopidogrel + aspirin was 11.7% compared to 12.5% for those receiving placebo + aspirin.
In the CAPRIE trial, the incidence of peptic, gastric or duodenal ulcers was 0.7% for clopidogrel and 1.2% for aspirin. In the CURE trial the incidence of peptic, gastric or duodenal ulcers was 0.4% for clopidogrel + aspirin and 0.3% for placebo + aspirin.
Cases of diarrhea were reported in the CAPRIE trial in 4.5% of patients in the clopidogrel group compared to 3.4% in the aspirin group. However, these were rarely severe (clopidogrel = 0.2% and aspirin = 0.1%). In the CURE trial, the incidence of diarrhea for patients receiving clopidogrel + aspirin was 2.1% compared to 2.2% for those receiving placebo + aspirin.
In the CAPRIE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 3.2% for clopidogrel and 4% for aspirin. In the CURE trial, the incidence of patients withdrawing from treatment because of gastrointestinal adverse reactions was 0.9% for clopidogrel + aspirin compared with 0.8% for placebo + aspirin.
Rash and Other Skin Disorders: In the CAPRIE trial, the incidence of skin and appendage disorders in patients receiving clopidogrel was 15.8% (0.7% serious); the corresponding rate in aspirin patients was 13.1% (0.5% serious). In the CURE trial the incidence of rash or other skin disorders in patients receiving clopidogrel + aspirin was 4.2% compared to 3.5% for those receiving placebo + aspirin.
In the CAPRIE trial, the overall incidence of patients withdrawing from treatment because of skin and appendage disorders adverse reactions was 1.5% for clopidogrel and 0.8% for aspirin. In the CURE trials, the incidence of patients withdrawing because of skin and appendage disorders adverse reactions was 0.7% for clopidogrel + aspirin compared with 0.3% for placebo + aspirin.
Adverse reactions that occurred either during clinical studies or that were spontaneously reported are presented in the table as follows. Their frequency is defined using the following conventions: common (≥1/100 to <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to 1/1,000); very rare (<1/10,000). Within each system organ class, adverse reactions are presented in order of decreasing seriousness. (See Table 4.)

Click on icon to see table/diagram/image

Other adverse experiences of potential importance occurring in 1% to 2.5% of patients receiving clopidogrel in the CAPRIE or CURE controlled clinical trials are listed as follows regardless of relationship to clopidogrel. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in CURE).
Autonomic Nervous System Disorders: Syncope, palpitation. Body as a Whole-general disorders: Asthenia, fever, hernia. Cardiovascular disorders: Cardiac failure. Central and peripheral nervous system disorders: Cramps legs, hypoaesthesia, neuralgia, paraesthesia, vertigo. Gastrointestinal system disorders: Constipation, vomiting. Heart rate and rhythm disorders: Atrial fibrillation. Liver and biliary system disorders: Hepatic enzymes increased. Metabolic and nutritional disorders: Gout, hyperuricemia, non-protein nitrogen (NPN) increased. Musculo-skeletal system disorders: Arthritis, arthrosis. Platelet, bleeding & clotting disorders: GI hemorrhage, hematoma, platelets decreased. Psychiatric disorders: Anxiety, insomnia. Red blood cell disorders: Anemia. Respiratory system disorders: Pneumonia, sinusitis. Skin and appendage disorders: Eczema, skin ulceration. Urinary system disorders: Cystitis. Vision disorders: Cataract, conjunctivitis.
Other potentially serious adverse events which may be of clinical interest but were rarely reported (<1%) in patients who received clopidogrel bisulfate in the CAPRIE or CURE controlled clinical trials are listed as follows regardless of relationship to clopidogrel. In general, the incidence of these events was similar to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin (in CURE).
Body as a whole: Allergic reaction, necrosis ischemic. Cardiovascular disorders: Edema generalized. Gastrointestinal system disorders: Gastric ulcer perforated, gastritis hemorrhagic, upper GI ulcer hemorrhagic. Liver and Biliary system disorders: Bilirubinemia, hepatitis infectious, liver fatty. Platelet, bleeding and clotting disorders: hemarthrosis, hematuria, hemoptysis, hemorrhage intracranial, hemorrhage retroperitoneal, hemorrhage of operative wound, ocular hemorrhage, pulmonary hemorrhage, purpura allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic, anemia hypochromic. Reproductive disorders, female: Menorrhagia. Respiratory system disorders: Hemothorax. Skin and appendage disorders: Bullous eruption, rash erythematous, rash maculopapular, urticaria. Urinary system disorders: Abnormal renal function, acute renal failure. White cell and reticuloendothelial system disorders: Agranulocytosis, granulocytopenia, leukemia, leukopenia, neutrophils decreased.

Drug Interactions: Studies of specific drug interactions yielded the following results: Aspirin: Aspirin did not modify the clopidogrel-mediated inhibition of ADP-induced platelet aggregation, but clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation. Concomitant administration of 500 mg of aspirin twice a day for 1 day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. A pharmacodynamic interaction between clopidogrel and ASA is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. Clopidogrel and aspirin have been administered together for up to one year.
Heparin: In a clinical study in healthy volunteers, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation. Coadministration of heparin had no effect on inhibition of platelet aggregation induced by clopidogrel.
A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore concomitant use should be undertaken with caution.
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): In healthy volunteers receiving naproxen, concomitant administration of clopidogrel was associated with increased occult gastrointestinal blood loss. NSAIDs including COX-2 inhibitors and clopidogrel should be coadministered with caution.
Warfarin: Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel is not recommended since it may increase the intensity of bleeding (See General under PRECAUTIONS).
Glycoprotein IIb/IIIa Inhibitors: Clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors.
Proton Pump Inhibitors (PPIs): 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 5µM 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.
Other Concomitant Therapy: No clinically significant pharmacodynamic interactions were observed when clopidogrel was coadministered with atenolol, nifedipine, or both atenolol and nifedipine. The pharmacodynamic activity of clopidogrel was also not significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline was not modified by the coadministration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption.
Medicines metabolized by CYP₄₅₀ 2C9: At high concentrations in vitro, clopidogrel inhibits CYP₄₅₀(2C9). Accordingly, clopidogrel may interfere with the metabolism of phenytoin, tamoxifen, tolbutamide, warfarin, torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no data with which to predict the magnitude of these interactions. Caution should be used when any of these drugs is coadministered with clopidogrel. However, data from the CAPRIE study indicates that phenytoin and tolbutamide which are metabolized by CYP2C9 can be safely coadministered with cloipidogrel.
Since clopidogrel is metabolized 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 and a reduction in clinical efficacy. Concomitant use of drugs that strongly or moderately inhibit CYP2C19 (e.g., omeprazole, esomeprazole should be avoided).
In addition to the previously mentioned specific interaction studies, patients entered into clinical trials with clopidogrel received a variety of concomitant medications including diuretics, beta-blocking agents, ACE inhibitors, calcium antagonists, cholesterol lowering agents, coronary vasodilators, antidiabetic agents (Hypoglycemic Agents including insulin), antiepileptic agents, hormone replacement therapy, heparins (unfractionated and LMWH) and GPIIb/IIIa antagonists without evidence of clinically significant adverse interactions. The use of oral anticoagulants, non-study antiplatelet drug and chronic NSAIDs was not allowed in CURE and there are no data on their concomitant use with clopidogrel.
Drug/Laboratory Test Interactions: No data.

Stored at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F).

Anticoagulants, Antiplatelets & Fibrinolytics (Thrombolytics)

B01AC04 - clopidogrel ; Belongs to the class of platelet aggregation inhibitors excluding heparin. Used in the treatment of thrombosis.

D