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Bleeding and Haematological Disorders: Due to the risk of bleeding and haematological undesirable effects, blood cell count determination and/or other appropriate testing should be promptly considered whenever clinical symptoms suggestive of bleeding arise during the course of treatment (see Adverse Reactions).
As with other antiplatelet agents, clopidogrel should be used with caution in patients who may be at risk of increased bleeding from trauma, surgery or other pathological conditions and in patients receiving treatment with ASA, heparin, glycoprotein IIb/IIIa inhibitors, NSAIDs or selective serotonin reuptake inhibitors (SSRIs). Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the 1st weeks of treatment and/or after invasive cardiac procedures or surgery. Because of the increased risk of bleeding, the concomitant administration of warfarin with clopidogrel should be undertaken with caution. (See Interactions.)
If a patient is to undergo elective surgery and antiplatelet effect is not necessary, clopidogrel should be discontinued 7 days prior to surgery.
Clopidogrel prolongs bleeding time and should be used with caution in patients who have lesions with a propensity to bleed (particularly gastrointestinal and intraocular). Drugs that might induce gastrointestinal lesions (eg, ASA and NSAIDs) should be used with caution in patients taking clopidogrel.
Patients should be informed that it might take longer than usual to stop bleeding when they are taking clopidogrel (alone or in combination with ASA), and that any unusual bleeding (site or duration) should be reported to the physician. Patients should inform the physician and dentist that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Recent Ischaemic Stroke: In patients with recent transient ischaemic attack or stroke who are at high risk of recurrent ischaemic events, the combination of ASA and clopidogrel has been shown to increase major bleeding. Therefore, such addition should be undertaken with caution outside of clinical situations where the combination has proven to be beneficial.
In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (<7 days).
Thrombotic Thrombocytopenic Purpura (TTP): Thrombotic thrombocytopenic purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic hemolytic anemia associated with neurological findings, renal dysfunction or fever. Thrombotic thrombocytopenic purpura is a potentially fatal condition requiring prompt treatment including plasmapheresis (plasma exchange).
Acquired Haemophilia: Acquired haemophilia has been reported following use of clopidogrel. In cases of confirmed isolated activated partial thromboplastin Time (aPTT) prolongation with or without bleeding, acquired haemophilia should be considered. Patients with a confirmed diagnosis of acquired haemophilia should be managed and treated by specialists and clopidogrel should be discontinued.
Cytochrome P-450 2C19 (CYP2C19): Pharmacogenetics: In patients who are CYP2C19 poor metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function. Poor metabolisers with acute coronary syndrome or undergoing percutaneous coronary intervention treated with clopidogrel at recommended doses may exhibit higher CV event rates than do patients with normal CYP2C19 function (see Pharmacology: Pharmacokinetics: Pharmacogenetics under Actions). Tests are available to identify a patient's CYP2C19 genotype; these tests can be used as an aid in determining therapeutic strategy. Consider the use of higher clopidogrel doses in patients who are known CYP2C19 poor metabolisers (see Pharmacogenetics under Dosage & Administration).
Cross-Reactivity Among Thienopyridines: Patients should be evaluated for history of hypersensitivity to another thienopyridine (eg, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see Adverse Reactions). Thienopyridines may cause mild to severe allergic reactions eg, rash, angioedema or haematological reactions eg, thrombocytopaenia and neutropaenia. Patients who had developed a previous allergic reaction and/or haematological reaction to one thienopyridine may have an increased risk of developing the same or another reaction to another thienopyridine. Monitoring for cross-reactivity is advised.
Renal Impairment: Therapeutic experience with clopidogrel is limited in patients with severe renal impairment. Therefore, clopidogrel should be used with caution in these population.
Hepatic Impairment: Experience is limited in patients with severe hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Excipients: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take Plavix.
Effects on the Ability to Drive or Operate Machinery: Clopidogrel has no or negligible influence on the ability to drive and use machines.
Use in Pregnancy: As no clinical data on exposed pregnancies are available, Plavix should not be used during pregnancy, unless, in the opinion of the physician, there is a clear need. Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonic/foetal development, parturition or postnatal development (see Pharmacology: Toxicology under Actions).
Use in Children: The safety and effectiveness in pediatric populations and adolescents have not been established (see Pharmacology: Pharmacodynamics under Actions).
