Secondary prevention of atherothrombotic events
Clopidogrel is indicated in:
- Adult patients suffering from myocardial infarction (from a few days until less than 35 days), ischaemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease.
- Adult patients suffering from acute coronary syndrome:
• Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patients undergoing a stent placement following percutaneous coronary intervention, in combination with acetylsalicylic acid (ASA).
• ST segment elevation acute myocardial infarction, in combination with ASA in medically treated patients eligible for thrombolytic therapy.
In patients with moderate to high-risk Transient Ischemic Attack (TIA) or minor Ischemic Stroke (IS)
Clopidogrel in combination with ASA is indicated in:
Adult patients with moderate to high-risk TIA (ABCD21 score ≥4) or minor IS (NIHSS2 ≤3) within 24 hours of either the TIA or IS event.
1 Age, Blood pressure, Clinical features, Duration, and Diabetes mellitus diagnosis
2 National Institutes of Health Stroke Scale
Prevention of atherothrombotic and thromboembolic events in atrial fibrillation
In adult patients with atrial fibrillation who have at least one risk factor for vascular events, are not suitable for treatment with Vitamin K antagonists (VKA) and who have a low bleeding risk, clopidogrel is indicated in combination with ASA for the prevention of atherothrombotic and thromboembolic events, including stroke.
Adults and elderly
Clopidogrel should be given as a single daily dose of 75 mg.
In patients suffering from acute coronary syndrome:
- Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction): clopidogrel treatment should be initiated with a single 300 mg or 600mg loading dose. A 600 mg loading dose may be considered in patients "<"75 years of age when percutaneous coronary intervention is intended (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE). Clopidogrel treatment should be continued at 75 mg once a day (with acetylsalicylic acid (ASA) 75 mg-325 mg daily). Since higher doses of ASA were associated with higher bleeding risk it is recommended that the dose of ASA should not be higher than 100 mg. The optimal duration of treatment has not been formally established. Clinical trial data support use up to 12 months, and the maximum benefit was seen at 3 months (see PHARMACODYNAMIC PROPERTIES).
- ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a 300 mg loading dose in combination with ASA and with or without thrombolytics. For patients over 75 years of age clopidogrel should be initiated without a loading dose. Combined therapy should be started as early as possible after symptoms start and continued for at least four weeks. The benefit of the combination of clopidogrel with ASA beyond four weeks has not been studied in this setting (see PHARMACODYNAMIC PROPERTIES).
Adult patients with moderate to high-risk TIA or minor IS
Adult patients with moderate to high-risk TIA (ABCD2 score ≥ 4) or minor IS (NIHSS ≤ 3) should be given a loading dose of clopidogrel 300 mg followed by clopidogrel 75 mg once daily and ASA (75 mg -100 mg once daily). Treatment with clopidogrel and ASA should be started within 24 hours of the event and be continued for 21 days followed by single antiplatelet therapy.
In patients with atrial fibrillation
Clopidogrel should be given as a single daily dose of 75 mg. ASA (75 - 100 mg daily) should be initiated and continued in combination with clopidogrel (see PHARMACODYNAMIC PROPERTIES).
If a dose is missed:
- Within less than 12 hours after regular scheduled time: patients should take the dose immediately and then take the next dose at the regular scheduled time.
- For more than 12 hours: patients should take the next dose at the regular scheduled time and should not double the dose.
Clopidogrel should not be used in children because of efficacy concerns.
Therapeutic experience is limited in patients with renal impairment (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Therapeutic experience is limited in patients with moderate hepatic disease who may have bleeding diatheses (see SPECIAL WARNINGS AND PRECAUTIONS FOR USE).
Method of administration
For oral use. It may be given with or without food.
Hypersensitivity to clopidogrel or to any of the excipients.
Severe hepatic impairment.
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
SPECIAL WARNINGS AND PRECAUTIONS FOR USE
Bleeding and haematological disorders
Due to the risk of bleeding and haematological adverse reactions, 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 or non-steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors, or selective serotonin reuptake inhibitors (SSRIs), or CYP2C19 strong inducers or other medicinal products associated with bleeding risk such as pentoxifylline (see INTERACTIONS). 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 oral anticoagulants is not recommended since it may increase the intensity of bleedings (see INTERACTIONS).
If a patient is to undergo elective surgery and antiplatelet effect is temporarily not desirable, clopidogrel should be discontinued 7 days prior to surgery. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicinal product is taken. 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 might 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.
The use of clopidogrel 600 mg loading dose is not recommended in patients with non-ST segment elevation acute coronary syndrome and ≥ 75 years of age due to increased bleeding risk in this population.
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 haemolytic anaemia associated with either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.
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.
Recent ischaemic stroke
Initiation of therapy
- In acute minor IS or moderate to high-risk TIA patients, dual antiplatelet therapy (clopidogrel and ASA) should be started no later than 24 hours after the event onset.
- There is no data regarding the benefit-risk of short term dual antiplatelet therapy in acute minor IS or moderate to high-risk TIA patients, with a history of (non-traumatic) intracranial hemorrhage.
- In non-minor IS patients, clopidogrel monotherapy should be started only after the first 7 days of the event.
Non-minor IS patients (NIHSS >4)
In view of the lack of data, use of dual antiplatelet therapy is not recommended (see INDICATIONS).
Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned
There is no data to support the use of dual antiplatelet therapy in patients for whom treatment with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy. Dual antiplatelet therapy is not recommended in these situations.
Cytochrome P450 2C19 (CYP2C19)
Pharmacogenetics: In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses forms less of the active metabolite of clopidogrel and has a smaller effect on platelet function.
Since clopidogrel is metabolised to its active metabolite partly by CYP2C19, use of medicinal products that inhibit the activity of this enzyme would be expected to result in reduced drug levels of the active metabolite of clopidogrel. The clinical relevance of this interaction is uncertain. As a precaution concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see INTERACTIONS for a list of CYP2C19 inhibitors, see also PHARMACOKINETIC PROPERTIES).
Use of medicinal products 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 concomitant use of strong CYP2C19 inducers should be discouraged (see INTERACTIONS).
Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal products (see INTERACTIONS).
Cross-reactions among thienopyridines
Patients should be evaluated for history of hypersensitivity to thienopyridines (such as clopidogrel, ticlopidine, prasugrel) since cross-reactivity among thienopyridines has been reported (see ADVERSE REACTIONS). Thienopyridines may cause mild to severe allergic reactions such as rash, angioedema, or haematological cross-reactions such as 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 signs of hypersensitivity in patients with a known allergy to thienopyridines is advised.
Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore, clopidogrel should be used with caution in these patients (see POSOLOGY AND MODE OF ADMINISTRATION).
Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population (see POSOLOGY AND MODE OF ADMINISTRATION).
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactose deficiency or glucose-galactose malabsorption should not take this medicinal product.
PREGNANT AND BREAST-FEEDING WOMEN
As no clinical data on exposure to clopidogrel during pregnancy are available, it is preferable not to use clopidogrel during pregnancy as a precautionary measure.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see PRECLINICAL SAFETY DATA).
It is unknown whether clopidogrel is excreted in human breast milk. Animal studies have shown excretion of clopidogrel in breast milk. As a precautionary measure, breast-feeding should not be continued during treatment with clopidogrel.
Clopidogrel was not shown to alter fertility in animal studies.
EFFECTS ON ABILITY TO DRIVE AND USE MACHINES
Clopidogrel has no or negligible influence on the ability to drive and use machines.
Box of 3 blisters of 10 film-coated tablets (Alu/Alu blister).
Box of 10 blisters of 10 film-coated tablets (Alu/Alu blister).
STORAGE CONDITION: Keep in dry place at a temperature not exceeding 30ºC.
SHELF LIFE: 24 months from manufacturing date.
SPECIFICATION: Current BP.