CLOPIDOGREL- clopidogrel bisulfate tablet, film coated
Accord Healthcare Inc.
WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE
The effectiveness of clopidogrel bisulfate results from its antiplatelet activity, which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19 [see Warnings and Precautions (5.1) , Clinical Pharmacology (12.3)] . Clopidogrel bisulfate at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers [see Clinical Pharmacology (12.5)] . Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
- Clopidogrel tablets are indicated to reduce the rate of myocardial infarction (MI) and stroke in patients with non-ST-segment elevation ACS (unstable angina [UA]/non-ST-elevation myocardial infarction [NSTEMI]), including patients who are to be managed medically and those who are to be managed with coronary revascularization. Clopidogrel tablets should be administered in conjunction with aspirin.
- Clopidogrel tablets are indicated to reduce the rate of myocardial infarction and stroke in patients with acute ST-elevation myocardial infarction (STEMI) who are to be managed medically. Clopidogrel tablets should be administered in conjunction with aspirin.
In patients with established peripheral arterial disease or with a history of recent myocardial infarction (MI) or recent stroke clopidogrel tablets are indicated to reduce the rate of MI and stroke.
In patients who need an antiplatelet effect within hours, initiate clopidogrel tablets with a single 300-mg oral loading dose and then continue at 75 mg once daily. Initiating clopidogrel tablets without a loading dose will delay establishment of an antiplatelet effect by several days [see Clinical Pharmacology (12.3) and Clinical Studies (14.1)] .
- 75 mg tablets: Pink colored, round, biconvex, film-coated tablets debossed with “CI” on one side and plain on other side.
- 300 mg tablets: Pink colored, oval, biconvex, beveled edged, film-coated tablets debossed with “CL” on one side and plain on other side.
Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.
Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)] .
Clopidogrel 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 [see Boxed Warning].
The metabolism of clopidogrel can also be impaired by drugs that inhibit CYP2C19, such as omeprazole or esomeprazole. Avoid concomitant use of clopidogrel bisulfate with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel bisulfate [see Drug Interactions (7.1)].
P2Y12 inhibitors (Thienopyridines), including clopidogrel bisulfate, increase the risk of bleeding.
P2Y12 inhibitors (Thienopyridines), inhibit platelet aggregation for the lifetime of the platelet (7 to 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.
Use of drugs that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogrel and might potentiate the bleeding risk. As a precaution, avoid concomitant use of strong CYP2C19 inducers [see Drug Interactions (7.1) and Clinical Pharmacology (12.3).
Discontinuation of clopidogrel bisulfate increases the risk of cardiovascular events. If clopidogrel bisulfate 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 clopidogrel bisulfate for five days prior to such surgery. Resume clopidogrel bisulfate as soon as hemostasis is achieved.
TTP, sometimes fatal, has been reported following use of clopidogrel bisulfate, 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 [see Adverse Reactions (6.2)].
Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving clopidogrel bisulfate, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications(4.2) and Adverse Reactions(6.2)].
The following serious adverse reactions are discussed below and elsewhere in the labeling:
- Bleeding [see Warnings and Precautions (5.2)]
- Thrombotic thrombocytopenic purpura [see Warnings and Precautions (5.4)]
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.
Clopidogrel bisulfate 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 clopidogrel bisulfate plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.
In CURE, clopidogrel bisulfate 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.
|Event||Clopidogrel Bisulfate (+ aspirin) (n=6259)||Placebo (+ aspirin) (n=6303)|
|* Life-threatening and other major bleeding. † Led to interruption of study medication.|
|Major bleeding *||3.7||2.7|
|5 g/dL hemoglobin drop||0.9||0.9|
|Requiring surgical intervention||0.7||0.7|
|Requiring transfusion (≥4 units)||1.2||1.0|
|Other major bleeding||1.6||1.0|
|Intraocular bleeding with significant loss of vision||0.05||0.03|
|Requiring 2 to 3 units of blood||1.3||0.9|
|Minor bleeding †||5.1||2.4|
In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin (see Table 2).
|Type of Bleeding||Clopidogrel bisulfate (+ aspirin) (n=22961)||Placebo (+ aspirin) (n=22891)||p-value|
|Major * noncerebral or cerebral bleeding||0.6||0.5||0.59|
|Other noncerebral bleeding (nonmajor)||3.6||3.1||0.005|
|Any noncerebral bleeding||3.9||3.4||0.004|
CAPRIE (clopidogrel bisulfate vs Aspirin)
In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate 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 clopidogrel bisulfate compared to 0.5% for aspirin.
Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.
Other Adverse Events
In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.
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