Clopidogrel 300 mg Tablet, 500-count — NDC 52605-083-05 (Billing 52605-0083-05)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets.

12.2Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible.

Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel tablets.

Repeated doses of 75 mg clopidogrel tablets 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 tablets 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.

G e r i a t r i c Patients Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation. Renally Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation. H e pa ti c a ll y I m pa i r e d Patients After repeated doses of 75 mg clopidogrel tablets 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.

G e n d e r In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.

12.3Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. A b s o r p ti o n 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 tablets can be administered with or without food. In a study in healthy male subjects when clopidogrel tablets 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 tablet 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-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. 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 si… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding of its active metabolite to the P2Y 12 class of ADP receptors on platelets.

12.3Pharmacokinetics Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites. A b s o r p ti o n 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 tablets can be administered with or without food. In a study in healthy male subjects when clopidogrel tablets 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 tablet 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-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. 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 tablets 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 C max 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. P r o t o n pump inhibitors (PPI) The effect of proton pump inhibitors (PPI) on the systemic exposure to the clopidogrel active metabolite following multiple doses of clopidogrel tablets 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 Tablets 75 mg Alone or with Proton Pump Inhibitors (PPIs) Change relative to Clopidogrel Tablets administered alone Pharmacodynamic and pharmacokinetic parameters measured in these studies showed that the interaction was highest with omeprazole and least with dexlansoprazole. O p i o i d s Coadministration of 5 mg intravenous morphine with 600 mg loading dose of clopidogrel in… [Excerpted — this section continues on DailyMed.]

12.2Pharmacodynamics Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor and the subsequent ADP- mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. This action is irreversible.

Consequently, platelets exposed to clopidogrel’s active metabolite are affected for the remainder of their lifespan (about 7 to 10 days). Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Dose-dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of clopidogrel tablets.

Repeated doses of 75 mg clopidogrel tablets 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 tablets 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.

G e r i a t r i c Patients Elderly (≥75 years) and young healthy subjects had similar effects on platelet aggregation. Renally Impaired Patients After repeated doses of 75 mg clopidogrel tablets per day, patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) and moderate renal impairment (creatinine clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet aggregation. H e pa ti c a ll y I m pa i r e d Patients After repeated doses of 75 mg clopidogrel tablets 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.

G e n d e r In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.

14 CLINICAL STUDIES

14.1Acute Coronary Syndrome C U R E 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 tablets (300 mg loading dose followed by 75 mg once daily) or placebo, and were treated for up to one year.

Patients also received aspirin (75-325 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 tablets-treated group and 719 (11.4%) in the placebo-treated group, a 20% relative risk reduction (95% CI of 10%-28%; p < 0.001) for the clopidogrel tablets-treated group (see Table 4). T a b l e 4: Outcome Events in the CURE Primary Analysis Outcome Clopidogrel Tablets (+ aspirin) * (n=6259) Placebo (+ aspirin) * ( n=6303) Relative Risk Reduction (%) (95 % CI) 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) MI 324 (5.2 %) 419 (6.6%) 23 % (11.0, 33.4) Stroke 75 (1.2 %) 87 (1.4%) 14 % (-17.7, 36.6) * 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.

Most of the benefit of clopidogrel tablets 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 The effect of clopidogrel tablets did not differ significantly in various subgroups, as shown in Figure 3. The benefits associated with clopidogrel tablets 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 tablets was observed independently of the dose of aspirin (75-325 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 F i gure 3: Hazard Ratio for Patient Baseline Characteristics and On-Study Concomitant Medications/Interventions for the CURE Study (continued) The use of clopidogrel tablets in CURE was associated with a decrease in the use of thrombolytic therapy (71 patients [1.1%] in the clopidogrel tablets 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 tablets group, 454 patients [7.2%] in the placebo group, relative risk reduction of 18%).

The use of clopidogrel tablets 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 tablets 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 tablets were evaluated in the randomized, placebo-controlled, double-blind study, C… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis & 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).