After repeated doses of Clopidogrel 75 mg per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance 5–15 ml/min) compared to those with moderate renal impairment (creatinine clearance 30–60 ml/min) or healthy subjects. No dosage adjustment is needed in renally impaired patients. However, Clopidogrel should be used with caution in patients with hepatic impairment.

Safety and effectiveness in pediatric patients have not been established.

Animal studies have not shown evidence of impaired fertility or fetal toxicity due to Clopidogrel. However, there are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Clopidogrel should be used during pregnancy only if clearly necessary.

Studies on specific drug interactions have shown:

Aspirin: Does not modify the Clopidogrel-mediated inhibition of ADP-induced platelet aggregation but potentiates the effect of Aspirin on collagen-induced platelet aggregation.

Heparin: Clopidogrel does not necessitate a modification of the heparin dose and does not alter the effect of heparin on coagulation. Co-administration of heparin has no effect on the inhibition of platelet aggregation induced by Clopidogrel.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs): Concomitant administration of Clopidogrel increases occult gastrointestinal blood loss. Therefore, NSAIDs and Clopidogrel should be co-administered with caution.

Warfarin: The safety of co-administration of Clopidogrel and Warfarin has not been established. Thus, their concomitant use should be undertaken with caution.

No adverse events have been reported after a single oral administration of 600 mg (equivalent to eight standard 75 mg tablets) of Clopidogrel in healthy volunteers. The bleeding time was prolonged by 1.7 times, which is comparable to what is typically observed with the therapeutic dose (75 mg/day).

Store in a cool, dry place below 30°C. Protect from light.

Medicine: Keep out of reach of children.

Clopidogrel is an inhibitor of ADP-induced platelet aggregation, acting through the direct inhibition of adenosine diphosphate (ADP) binding to its receptor and the subsequent ADP-mediated activation of the glycoprotein GP IIb/IIIa complex. Aspirin is also an antiplatelet agent that works by irreversibly inhibiting the cyclooxygenase enzyme, leading to a decrease in thromboxane A2 formation and the inhibition of platelet aggregation.

After repeated 75 mg oral doses of Clopidogrel (base), plasma concentrations of the parent compound, which has no platelet-inhibiting effect, remain very low and are generally below the quantification limit (0.00025 mg/L) beyond two hours after dosing. Clopidogrel is extensively metabolized in the liver, with its main circulating metabolite being a carboxylic acid derivative, which has no effect on platelet aggregation and constitutes about 85% of the circulating drug-related compounds in plasma. Following an oral dose of 14C-labeled Clopidogrel in humans, approximately 50% is excreted in the urine and 46% in the feces within five days after dosing. The elimination half-life of the main circulating metabolite is eight hours after both single and repeated administration. Co-administration of Clopidogrel with meals does not significantly alter its bioavailability, as assessed by the pharmacokinetics of the main circulating metabolite.

Absorption and Distribution: Clopidogrel is rapidly absorbed after oral administration of repeated 75 mg doses, with peak plasma levels (3 mg/L) of the main circulating metabolite occurring approximately one hour after dosing. The pharmacokinetics of the main circulating metabolite are linear, meaning plasma concentrations increase proportionally with dose in the range of 50 mg to 150 mg of Clopidogrel. Absorption is at least 50%, based on the urinary excretion of Clopidogrel-related metabolites. Clopidogrel and its main circulating metabolite bind reversibly to human plasma proteins (98% and 94%, respectively), and this binding remains nonsaturable in vitro at concentrations of up to 100 µg/mL.

Metabolism and Elimination: In vitro and in vivo, Clopidogrel undergoes rapid hydrolysis to form its carboxylic acid derivative. In plasma and urine, the glucuronide conjugate of the carboxylic acid derivative is also observed.

Replet® or Replet® Plus is indicated for the reduction of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent stroke, recent myocardial infarction, or established peripheral arterial disease. It is also indicated for patients with acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction).

The recommended dose of Clopidogrel is 75 mg once daily, with or without food. No dosage adjustment is necessary for elderly patients or those with renal impairment. For patients with acute coronary syndrome (unstable angina/non-Q-wave myocardial infarction), Clopidogrel should be initiated with a single 300 mg loading dose, followed by 75 mg once daily. Aspirin (75 mg–325 mg once daily) should be initiated and continued in combination with Clopidogrel. Studies have shown that most patients with acute coronary syndrome also received heparin acutely.

Replet® or Replet® Plus is contraindicated in the following conditions:

Hypersensitivity to the active drug or any component of the product.
Active pathological bleeding, such as peptic ulcer or intracranial hemorrhage.

As with other antiplatelet agents, Clopidogrel or Aspirin should be used with caution in patients at risk of increased bleeding due to trauma, surgery, or other pathological conditions. If a patient is scheduled for elective surgery and an antiplatelet effect is not required, the drug should be discontinued five days prior to surgery. Clopidogrel and Aspirin prolong bleeding time; therefore, patients should be informed that it may take longer than usual to stop bleeding. Any unusual bleeding should be reported to a physician.