Clopidogrel - Warnings and Precautions
The following warnings and precautions are taken directly from the US FDA-approved drug label for Clopidogrel. This is the same information dispensing pharmacists read.
\u26a0\ufe0f Boxed Warning (Highest FDA Alert)
WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE The effectiveness of clopidogrel tablets 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 , Clinical Pharmacology ]. Clopidogrel tablets 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 ]. Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers. WARNING: DIMINISHED ANTIPLATELET EFFECT IN PATIENTS WITH TWO LOSS-OF-FUNCTION ALLELES OF THE CYP2C19 GENE See full prescribing information for complete boxed warning. • Effectiveness of clopidogrel tablets depends on conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. ( 5.1 , 12.3 ) • Tests are available to identify patients who are CYP2C19 poor metabolizers. • Consider use of another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.
5 WARNINGS AND PRECAUTIONS • CYP2C19 inhibitors: Avoid concomitant use of omeprazole or esomeprazole. • Bleeding: Clopidogrel tablets increases risk of bleeding. • Discontinuation: Premature discontinuation increases risk of cardiovascular events.
Discontinue 5 days prior to elective surgery that has a major risk of bleeding. • Thrombotic thrombocytopenic purpura (TTP) has been reported. • Cross-reactivity among thienopyridines has been reported.
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 tablets with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel tablets [see Drug Interactions ].
5.2 General Risk of Bleeding P2Y12 inhibitors (thienopyridines), including clopidogrel tablets, 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 and Clinical Pharmacology ].
Risk factors for bleeding include concomitant use of other drugs that increase the risk of bleeding (e.g., anticoagulants, antiplatelet agents, and chronic use of NSAIDs) [see Drug Interactions ( 7.4 , 7.5 , 7.6 , 7.7 )].
5.3 Discontinuation of clopidogrel tablets Discontinuation of clopidogrel tablets increases the risk of cardiovascular events.
If clopidogrel tablets 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 tablets for five days prior to such surgery.
Resume clopidogrel tablets as soon as hemostasis is achieved.
5.4 Thrombotic Thrombocytopenic Purpura (TTP) TTP, sometimes fatal, has been reported following use of clopidogrel tablets, sometimes after a short exposure (less than 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 ].
5.5 Cross-Reactivity among Thienopyridines Hypersensitivity including rash, angioedema or hematologic reaction has been reported in patients receiving clopidogrel tablets, including patients with a history of hypersensitivity or hematologic reaction to other thienopyridines [see Contraindications and Adverse Reactions ].
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