Platelet inhibition by Roclas is irreversible and will last for the life of the platelet. Overdose following clopidogrel administration may result in 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, prostration, difficult breathing, and gastrointestinal hemorrhage in animals.
Based on biological plausibility, platelet transfusion may restore clotting ability.
Roclas is contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
HypersensitivityRoclas is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product.
The following serious adverse reactions are discussed below and elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions and durations of follow-up, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
Roclas has been evaluated for safety in more than 54,000 patients, including over 21,000 patients treated for one year or more. The clinically important adverse reactions observed in trials comparing Roclas plus aspirin to placebo plus aspirin and trials comparing Roclas alone to aspirin alone are discussed below.
Bleeding CUREIn CURE, Roclas use with aspirin was associated with an increase in major bleeding (primarily gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both groups. Other bleeding events that were reported more frequently in the clopidogrel group were epistaxis, hematuria, and bruise.
The overall incidence of bleeding is described in Table 1.
Table 1: CURE Incidence of Bleeding Complications (% patients)
| Event | Roclas (+ aspirin) (n=6259) | Placebo (+ aspirin) (n=6303) |
| Major bleeding* | 3.7 | 2.7 |
| Life-threatening bleeding | 2.2 | 1.8 |
| Fatal | 0.2 | 0.2 |
| 5 g/dL hemoglobin drop | 0.9 | 0.9 |
| Requiring surgical intervention | 0.7 | 0.7 |
| Hemorrhagic strokes | 0.1 | 0.1 |
| Requiring inotropes | 0.5 | 0.5 |
| Requiring transfusion (≥ 4 units) | 1.2 | 1.0 |
| Other major bleeding | 1.6 | 1.0 |
| Significantly disabling | 0.4 | 0.3 |
| Intraocular bleeding with significant loss of vision | 0.05 | 0.03 |
| Requiring 2-3 units of blood | 1.3 | 0.9 |
| Minor bleeding† | 5.1 | 2.4 |
| * Life-threatening and other major bleeding. † Led to interruption of study medication. |
In COMMIT, similar rates of major bleeding were observed in the Roclas and placebo groups, both of which also received aspirin (see Table 2).
Table 2: Incidence of Bleeding Events in COMMIT (% patients)
| Type of Bleeding | Roclas (+ aspirin) (n=22961) | Placebo (+ aspirin) (n=22891) | p-value |
| Major* noncerebral or cerebral bleeding | 0.6 | 0.5 | 0.59 |
| Major noncerebral | 0.4 | 0.3 | 0.48 |
| Fatal | 0.2 | 0.2 | 0.90 |
| Hemorrhagic stroke | 0.2 | 0.2 | 0.91 |
| Fatal | 0.2 | 0.2 | 0.81 |
| Other noncerebral bleeding (nonmajor) | 3.6 | 3.1 | 0.005 |
| Any noncerebral bleeding | 3.9 | 3.4 | 0.004 |
| * Major bleeds were cerebral bleeds or noncerebral bleeds thought to have caused death or that required transfusion. |
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking Roclas versus 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for Roclas compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the Roclas group were epistaxis and hematoma.
Other Adverse EventsIn CURE and CHARISMA, which compared Roclas plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between Roclas and placebo.
In CAPRIE, which compared Roclas to aspirin, pruritus was more frequently reported in those taking Roclas. No other difference in the rate of adverse events (other than bleeding) was reported.
Postmarketing ExperienceThe following adverse reactions have been identified during postapproval use of Roclas. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hemorrhages, including those with fatal outcome, have been reported in patients treated with Roclas.
In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke Roclas is indicated to reduce the rate of MI and stroke.
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 P2Y12 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 Roclas. Repeated doses of 75 mg Roclas 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 Roclas 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.
Geriatric PatientsElderly (≥ 75 years) and young healthy subjects had similar effects on platelet aggregation.
Renally Impaired PatientsAfter repeated doses of 75 mg Roclas 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.
Hepatically Impaired PatientsAfter repeated doses of 75 mg Roclas 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.
GenderIn a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women.
Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and inactive metabolites.
AbsorptionAfter 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
Roclas can be administered with or without food. In a study in healthy male subjects when Roclas 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 AUC0-24 was unchanged in the presence of food, while there was a 57% decrease in active metabolite Cmax. Similar results were observed when a Roclas 300 mg loading dose was administered with a high-fat breakfast.
MetabolismClopidogrel 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-oxoclopidogrel 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 Cmax 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. Cmax 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 Cmax and AUC, respectively.
EliminationFollowing an oral dose of 14C-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.
Included as part of the PRECAUTIONS section.
PRECAUTIONS Diminished Antiplatelet Activity In Patients With Impaired CYP2C19 FunctionClopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through an active metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic variations in CYP2C19.
The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of Roclas with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of Roclas.
General Risk Of BleedingThienopyridines, including Roclas, increase the risk of bleeding.
Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days). Because the half-life of clopidogrel's active metabolite is short, it may be possible to restore hemostasis by administering exogenous platelets; however, platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may be less effective.
Discontinuation Of RoclasDiscontinuation of Roclas increases the risk of cardiovascular events. If Roclas must be temporarily discontinued (e.g., to treat bleeding or for surgery with a major risk of bleeding), restart it as soon as possible. When possible, interrupt therapy with Roclas for five days prior to such surgery. Resume Roclas as soon as hemostasis is achieved.
Thrombotic Thrombocytopenic Purpura (TTP)TTP, sometimes fatal, has been reported following use of Roclas, sometimes after a short exposure (<2 weeks). TTP is a serious condition that requires urgent treatment including plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological findings, renal dysfunction, and fever.
Cross-Reactivity Among ThienopyridinesHypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving Roclas, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines.
Patient Counseling InformationAdvise patients to read FDA approved patient labeling (Medication Guide).
DiscontinuationAdvise patients not to discontinue Roclas without first discussing it with the healthcare provider who prescribed it.
BleedingAdvise patients that they:
Instruct patients to get prompt medical attention if they experience symptoms of TTP that cannot otherwise be explained.
Invasive ProceduresAdvise patients to inform physicians and dentists that they are taking Roclas before any surgery or dental procedure.
Proton Pump InhibitorsAdvise patients not to take omeprazole or esomeprazole while taking Roclas. Dexlansoprazole, lansoprazole and pantoprazole had less pronounced effects on the antiplatelet activity of Roclas than did omeprazole or esomeprazole.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityThere 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).
Use In Specific Populations Pregnancy Pregnancy Category BReproduction 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, respectively, 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, Roclas should be used during pregnancy only if clearly needed.
Nursing MothersStudies in rats have shown that clopidogrel and/or its metabolites are excreted in the 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 from clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseSafety and effectiveness in pediatric populations have not been established.
A randomized, placebo-controlled trial (CLARINET) did not demonstrate a clinical benefit of clopidogrel in neonates and infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary arterial shunt. Possible factors contributing to this outcome were the dose of clopidogrel, the concomitant administration of aspirin and the late initiation of therapy following shunt palliation. It cannot be ruled out that a trial with a different design would demonstrate a clinical benefit in this patient population.
Geriatric UseOf the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with Roclas were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with Roclas were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with Roclas plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively. No dosage adjustment is necessary in elderly patients.
Renal ImpairmentExperience is limited in patients with severe and moderate renal impairment.
Hepatic ImpairmentNo dosage adjustment is necessary in patients with hepatic impairment.
In patients who need an antiplatelet effect within hours, initiate Roclas with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating Roclas without a loading dose will delay establishment of an antiplatelet effect by several days.
Recent MI, Recent Stroke, Or Established Peripheral Arterial Disease75 mg once daily orally without a loading dose.
