DESCRIPTION

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)-α-(2-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 419.9.

The structural formula is as follows:

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°.

Clopidogrel Tablets 75 mgfor oral administrationare provided as reddish-brown, round, unscored, film coated tablets, imprinted "APO" on one side and "CL" over "75" on the other side. The tabletscontain 97.875 mg of clopidogrel bisulfate which is the molar equivalent of 75 mg of clopidogrel base.

Each tablet contains anhydrous lactose, colloidal silicon dioxide, crospovidone, methylcellulose and zinc stearate as inactive ingredients. Thereddish-brown film coating contains ferric oxide, hydroxypropyl cellulose, hypromellose 2910 15 CPS, polyethylene glycol 8000 and titanium dioxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.

Pharmacodynamic Properties

Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity.

Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan.

Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel bisulfate. Repeated doses of 75 mg clopidogrel bisulfate per day inhibit ADP-induced platelet aggregation on 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 bisulfate per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.

Pharmacokinetics and Metabolism

After repeated 75 mg oral doses of clopidogrel (base), 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. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma.

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.

Effect of Food

Administration of clopidogrel bisulfate with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.

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-related 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 and Elimination

In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.

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.

Renally Impaired Patients

After repeated doses of 75 mg clopidogrel bisulfate per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of clopidogrel bisulfate per day.

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 pl