Clopidogrel: Package Insert and Label Information (Page 3 of 5)

12.3 Pharmacokinetics

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of Food

Clopidogrel bisulfate can be administered with or without food. In a study in healthy male subjects when clopidogrel bisulfate 75 mg per day was given with a standard breakfast, mean inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC 0–24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite C max . Similar results were observed when a clopidogrel bisulfate 300 mg loading dose was administered with a high-fat breakfast.

Metabolism

Clopidogrel is extensively metabolized by two main metabolic pathways: one mediated by esterases and leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel to a 2-oxoclopidogrel 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 CYP3A. 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. In the 75 to 300 mg dose range, the pharmacokinetics of the active metabolite deviates from dose proportionality: 4-fold the dose results in 2.0-fold and 2.7-fold the C max and AUC, respectively.

Elimination

Following an oral dose of 14 C-labeled clopidogrel in humans, approximately 50% of total radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-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 about 30 minutes.

Drug Interactions

Effect of other drugs on Clopidogrel Bisulfate

Clopidogrel is metabolized to its active metabolite in part by CYP2C19.

CYP2C19 inducers

Concomitant use of strong inducers of CYP2C19 results in increased plasma concentration of the active metabolite of clopidogrel and an increase in platelet inhibition.

Rifampin: Coadministration of rifampin 300 mg twice daily for 7 days with 600 mg loading dose of clopidogrel in healthy adults increased the mean AUC and Cmax of clopidogrel’s thiol metabolites by 3.8-fold. Mean inhibition of platelet aggregation at 4 hours post-dose was 34% higher in the presence of rifampin compared to clopidogrel administered alone.

CYP2C19 inhibitors

Concomitant use of certain inhibitors of this enzyme results in reduced plasma concentrations of the active metabolite of clopidogrel and a reduction in platelet inhibition.

Proton pump inhibitors (PPI)

The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel bisulfate 75 mg evaluated in dedicated drug interaction studies is presented in Figure 1.

Figure 1: Exposure to Clopidogrel Active Metabolite Following Multiple Doses of Clopidogrel Bisulfate 75 mg Alone or with Proton Pump Inhibitors (PPIs)

                                                        Change relative to clopidogrel bisulfate administered alone
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Change relative to clopidogrel bisulfate administered alone

Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole.

Opioids

Co-administration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in healthy adults decreased the AUC and C max of clopidogrel’s thiol metabolites by 34%. Mean platelet aggregation was higher up to 2 to 4 hours with morphine co-administration.

Effect of Clopidogrel Bisulfate on other drugs

In vitro studies have shown that the glucuronide metabolite of clopidogrel is a strong inhibitor of CYP2C8. Concomitant administration of repaglinide with clopidogrel bisulfate increased the systemic exposure to repaglinide (AUC 0-∞ ) by 5.1-fold following the loading dose (300 mg) and by 3.9-fold on day 3 of the maintenance dose (75 mg) of clopidogrel bisulfate [see Drug Interactions (7.6)].

12.5 Pharmacogenomics

CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics and antiplatelet effects, as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotype. Patients who are homozygous for nonfunctional alleles of the CYP2C19 gene are termed “CYP2C19 poor metabolizers”. Approximately 2% of White and 4% of Black patients are poor metabolizers; the prevalence of poor metabolism is higher in Asian patients (e.g., 14% of Chinese). Tests are available to identify patients who are CYP2C19 poor metabolizers.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite exposure and diminished inhibition of platelet aggregation were observed in the poor metabolizers as compared to the other groups.

Table 3: Active Metabolite Pharmacokinetics and Antiplatelet Responses by CYP2C19 Metabolizer Status
Dose Poor (n=10) Intermediate* (n=10) Normal (n=10) Ultrarapid (n=10)
Values are mean (SD) *Intermediate metabolizers have one but not two nonfunctional alleles Ultrarapid metabolizers have at least one gain-of-function allele Inhibition of platelet aggregation with 5mcM ADP; larger value indicates greater platelet inhibition § Vasodilator-stimulated phosphoprotein – platelet reactivity index; smaller value indicates greater platelet inhibition Values are mean (SD).
C max (ng/mL) 300 mg (24 h) 11 (4) 23 (11) 32 (21) 24 (10)
600 mg (24 h) 17 (6) 39 (23) 44 (27) 36 (13)
75 mg (Day 5) 4 (1) 12 (5) 13 (7) 12 (6)
150 mg (Day 5) 7 (2) 18 (7) 19 (5) 16 (9)
IPA (%) 300 mg (24 h) 24 (26) 37 (21) 39 (28) 40 (21)
600 mg (24 h) 32 (25) 56 (22) 49 (23) 51 (28)
75 mg (Day 5) 37 (23) 60 (18) 58 (19) 56 (13)
150 mg (Day 5) 61 (14) 74 (14) 73 (9) 68 (18)
VASP-PRI (%) § 300 mg (24 h) 91 (12) 78 (12) 68 (16) 73 (12)
600 mg (24 h) 85 (14) 56 (26) 48 (20) 51 (20)
75 mg (Day 5) 83 (13) 50 (16) 39 (14) 40 (9)
150 mg (Day 5) 61 (18) 29 (11) 24 (10) 20 (10)

13 NONCLINICAL TOXICOLOGY

13.1 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 treated prior to pairing and throughout gestation at oral doses up to 400 mg/kg per day (52 times the recommended human dose on a mg/m 2 basis).

14 CLINICAL STUDIES

14.1 Acute Coronary Syndrome

CURE

The CURE study included 12,562 patients with ACS without ST-elevation (UA or NSTEMI) 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-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 bisulfate (300-mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year. Patients also received aspirin (75 to 325 mg once daily) and other standard therapies such as heparin. The use of GPIIb/IIIa inhibitors was not permitted for three days prior to randomization.

The patient population was largely White (82%) and included 38% women, and 52% age ≥ 65 years of age. Only about 20% of patients underwent revascularization during the initial hospitalization and few underwent emergent or urgent revascularization.

The number of patients experiencing the primary outcome (CV death, MI, or stroke) was 582 (9.3%) in the clopidogrel bisulfate-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10% to 28%; p < 0.001) for the clopidogrel bisulfate-treated group (see Table 4).

Table 4: Outcome Events in the CURE Primary Analysis
Outcome Clopidogrel bisulfate (+ aspirin) *(n=6259) Placebo (+ aspirin) *(n=6303) Relative Risk Reduction (%) (95% CI)
*
Other standard therapies were used as appropriate.
The individual components do not represent a breakdown of the primary and coprimary outcomes, but rather the total number of subjects experiencing an event during the course of the study.
Primary outcome (Cardiovascular death, MI, stroke) 582 (9.3%)719 (11.4%)20% (10.3, 27.9) p < 0.001
All Individual Outcome Events:
CV death 318 (5.1%)345 (5.5%)7% (-7.7, 20.6)
MI324 (5.2%)419 (6.6%)23% (11.0, 33.4)
Stroke75 (1.2%)87 (1.4%)14% (-17.7, 36.6)

Most of the benefit of clopidogrel bisulfate occurred in the first two months, but the difference from placebo was maintained throughout the course of the trial (up to 12 months) (see Figure 2).

Figure 2: Cardiovascular Death, Myocardial Infarction, and Stroke in the CURE Study

Figure
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The effect of clopidogrel bisulfate did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with clopidogrel bisulfate were independent of the use of other acute and long-term cardiovascular therapies, including heparin/LMWH, intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs, beta-blockers, and ACE inhibitors. The efficacy of clopidogrel bisulfate was observed independently of the dose of aspirin (75 to 325 mg once daily). The use of oral anticoagulants, nonstudy antiplatelet drugs, and chronic NSAIDs was not allowed in CURE.

Figure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study

Figure
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The use of clopidogrel bisulfate in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel bisulfate group, 126 patients [2.0%] in the placebo group; relative risk reduction of 43%), and GPIIb/IIIa inhibitors (369 patients [5.9%] in the clopidogrel bisulfate group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%). The use of clopidogrel bisulfate in CURE did not affect the number of patients treated with CABG or PCI (with or without stenting), (2253 patients [36.0%] in the clopidogrel bisulfate group, 2324 patients [36.9%] in the placebo group; relative risk reduction of 4.0%).

COMMIT

In patients with STEMI, the safety and efficacy of clopidogrel bisulfate were evaluated in the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included 45,852 patients presenting within 24 hours of the onset of the symptoms of myocardial infarction with supporting ECG abnormalities ( i.e. , ST-elevation, ST-depression or left bundle-branch block). Patients were randomized to receive clopidogrel bisulfate (75 mg once daily) or placebo, in combination with aspirin (162 mg per day), for 28 days or until hospital discharge, whichever came first.

The primary endpoints were death from any cause and the first occurrence of re-infarction, stroke or death.

The patient population was 28% women and 58% age ≥ 60 years (26% age ≥ 70 years). Fifty-five percent (55%) of patients received thrombolytics and only 3% underwent PCI.

As shown in Table 5 and Figure 4 and Figure 5 below, clopidogrel bisulfate 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).

Table 5: Outcome Events in COMMIT
EventClopidogrel bisulfate (+ aspirin) (N=22961) Placebo (+ aspirin) (N=22891) Odds ratio (95% CI) p-value
* 9 patients (2 clopidogrel and 7 placebo) suffered both a nonfatal stroke and a nonfatal MI. Nonfatal MI and nonfatal stroke exclude patients who died (of any cause).
Composite endpoint: Death, MI, or Stroke * 2121 (9.2%)2310 (10.1%)0.91 (0.86, 0.97)0.002
Death 1726 (7.5%)1845 (8.1%)0.93 (0.87, 0.99)0.029
Nonfatal MI 270 (1.2%)330 (1.4%)0.81 (0.69, 0.95)0.011
Nonfatal Stroke 127 (0.6%)142 (0.6%)0.89 (0.70, 1.13)0.33

Figure 4: Cumulative Event Rates for Death in the COMMIT Study 1

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Figure 5: Cumulative Event Rates for the Combined Endpoint Re-Infarction, Stroke or Death in the COMMIT Study 2

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The effect of clopidogrel bisulfate did not differ significantly in various prespecified subgroups as shown in Figure 6. The effect was also similar in non-prespecified subgroups including those based on infarct location, Killip class or prior MI history. Such subgroup analyses should be interpreted cautiously.

Figure 6: Effects of Adding Clopidogrel Bisulfate to Aspirin on the Combined Primary Endpoint across Baseline and Concomitant Medication Subgroups for the COMMIT Study 3

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