Clopidogrel

CLOPIDOGREL- clopidogrel bisulfate tablet, film coated
Preferred Pharmaceuticals, 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.

1. INDICATIONS AND USAGE

1.1 Acute Coronary Syndrome (ACS)

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.

1.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

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.

2 DOSAGE AND ADMINISTRATION

2.1 Acute Coronary Syndrome

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)] .

2.2 Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

75 mg once daily orally without a loading dose [see Clinical Pharmacology (12.3) and Clinical Pharmacology (14.2)] .

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

4.1 Active Bleeding

Clopidogrel tablets are contraindicated in patients with active pathological bleeding such as peptic ulcer or intracranial hemorrhage.

4.2 Hypersensitivity

Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)] .

5 WARNINGS AND PRECAUTIONS

5.1 Diminished Antiplatelet Activity in Patients with Impaired CYP2C19 Function

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)].

5.2 General Risk of Bleeding

Thienopyridines, including clopidogrel bisulfate, increase the risk of bleeding.

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.

5.3 Discontinuation of Clopidogrel Bisulfate

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.

5.4 Thrombotic Thrombocytopenic Purpura (TTP)

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)].

5.5 Cross-Reactivity among Thienopyridines

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)].

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