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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, nonsteroidal anti-inflammatory drugs including Cox-2 inhibitors, heparin, glycoprotein IIb/IIIa inhibitors or thrombolytics. Patients should be followed carefully for any signs of bleeding including occult bleeding, especially during the first weeks of treatment and/or after invasive cardiac procedures or surgery. The concomitant administration of clopidogrel with warfarin is not recommended since it may increase the intensity of bleedings (see Interactions).
If a patient is to undergo elective surgery and an 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).
Patients should be told that it may take longer than usual to stop bleeding when they take clopidogrel (alone or in combination with ASA), and that they should report any unusual bleeding (site or duration) to their physician. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.
Thrombotic thrombocytopaenic purpura (TTP) has been reported very rarely following the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopaenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a condition requiring prompt treatment including plasmapheresis.
In view of the lack of data, in patients with acute myocardial infarction with ST-segment elevation, clopidogrel therapy should not be initiated within the first few days following myocardial infarction.
In view of a lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (<7 days).
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore, clopidogrel should be used with caution in these patients.
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pharmacogenetics: Based on literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses, and generally exhibit higher cardiovascular event rates following myocardial infarction than do patients with normal CYP2C19 function.
Since clopidogrel is metabolized to its active metabolite partly by CYP2C19, use of drugs that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel and a reduction in clinical efficacy. Concomitant use of drugs that inhibit CYP2C19 should be discouraged.
Use in pregnancy: Reproduction studies performed in rats and in rabbits revealed no evidence of impaired fertility of harm to the foetus due to clopidogrel. There are, however, no adequate and well-controlled studies in pregnant women. In view of the lack of data, clopidogrel is not recommended during pregnancy.
Use in lactation: Studies in rats have shown that clopidogrel and/or its metabolites are excreted in the milk. It is not known whether clopidogrel is excreted in human milk.
Use in children: Safety and efficacy in subjects <18 years have not been established.
