THERAPEUTIC INDICATIONS

Clopidogrel is indicated for the secondary prevention of atherothrombotic events in: • Patients suffering from myocardial infarction (from a few day until less than 35 days), ischemic stroke (from 7 days until less than 6 months) or established peripheral arterial disease. • Patients suffering from acute coronary syndrome: Non-ST segment elevation acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction), including patient 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: - Adults patients with moderate to high-risk TIA (ABCD2 score ≥4) or minor IS (NIHSS ≤3) within 24 hours of either TIA or IS event.For further information please refer to section “Pharmacodynamic properties”.

POSOLOGY AND METHOD OF ADMINISTRATION

Adults and elderly: This 300 mg tablet of clopidogrel is intended for use as a loading dose 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 loading dose and then 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 section 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 section “Pharmacodynamic properties”). 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 (75-100 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. Paediatric population: The safety and efficacy of clopidogrel in children and adolescents under 18 years old have not yet been established. Renal impairment: Therapeutic experience is limited in patients with renal impairment. Hepatic impairment: therapeutic experience with moderate hepatic disease who may have bleeding diatheses (see section “Special warnings and precaution for use”). Method of Administration: For oral use. It may be given with or without food.

CONTRA-INDICATIONS

Hypersensitivity to the active substance 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 haematologycal disorders: Due to the risk of bleeding and haematological adverse reactions, blood cell count determination and/or other appropriate testing should be considered whenever clinical symptoms suggestive of bleeding arise. As with other antiplatelet agents, clopidogrel should be used with caution in patients 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 nonsteroidal 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.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 characterized by thrombocytopenia and microangiopathic hemolytic anemia associated with either neurological findings, renal dysfunction or fever. Acquired hemophilia: acquired hemophilia has been reported following use of clopidogrel. Recent ischemic 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 “Therapeutic indication”). Recent minor IS or moderate to high-risk TIA in patients for whom intervention is indicated or planned: No data to support the use of dual antiplatelet in patient treated with carotid endarterectomy or intravascular thrombectomy is indicated, or in patients planned for thrombolysis or anticoagulant therapy. Dual antiplatelet is not recommended in these situation.

Cytochrome P450 2C19 (CYP2C19) : In patients who are poor CYP2C19 metabolisers, clopidogrel at recommended doses has a smaller effect on platelet function. Since clopidogrel is metabolized 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 use of medicinal products that induce the activity of CYP2C19 would be expected to result in increased drug levels of the active metabolite of clopidogreland might potentiate the bleeding risk. Caution is required in patients treated concomitantly with clopidogrel and CYP2C8 substrate medicinal product (see “Interaction with other medicinal products and other forms of interaction”).. Cross-reactions among thienopyridines: 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. Renal impairment: Therapeutic experience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients (see section “Posology and method of administration”).

Hepatic impairment : Experience is limited in patients with moderate hepatic disease who may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population. Excipients: Plavix contains lactose. Patients with rare hereditary problems of galactose, intolerance, total lactase deficiencies or glucose galactose malabsorption should not take this medicinal product. This medicinal product contains hydrogenated castor oil which may cause stomach upset and diarrhoea.

DRUG INTERACTIONS

Medicinal products associated with bleeding risk: There is an increased risk of bleeding due to the potential additive effect of medicinal products associated with bleeding risk. Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleedings (see “Special warnings and precautions for use”). Although the administration of clopidogrel 75 mg/day did not modify the pharmacokinetics of S-warfarin or International Normalised Ratio (INR) in patients receiving long term warfarin therapy, coadministration of clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis. Glycoprotein IIb/IIIa inhibitors: clopidogrel should be used with caution in patients who receive concomitant glycoprotein IIb/IIIa inhibitors (see “Special warnings and precautions for use”). Acetylsalicylic acid (ASA): ASA did not modify the clopidogrel- mediated inhibition of ADP- induced platelet aggregation, but clopidogrel potentiated the effect of ASA on collagen-induced platelet aggregation. However, concomitant administration of 500 mg of ASA twice a day for one day did not significantly increase the prolongation of bleeding time induced by clopidogrel intake. Heparin: in a clinical study conducted in healthy subjects, clopidogrel did not necessitate modification of the heparin dose or alter the effect of heparin on coagulation A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution (see “Special warnings and precautions for use”). Thrombolytics: The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparins are co-administered with ASA (see “Undesirable effects”). NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution (see “Special warnings and precautions for use”). SSRIs: SSRIs affect platelet activation and increase the risk of bleeding and should be undertaken with caution. Other concomitant therapy: Inducers of CYP2C19: Clopidogrel is partly metabolised by CYP2C19, use of medicinal products that induce the activity of this enzyme would be expected to result in increased drug levels of the active metabolite of clopidogrel. Rifampicin strongly induces CYP2C19, resulting in both an increased level of clopidogrel active metabolite and platelet inhibition, which in particular might potentiate the risk of bleeding. As a precaution, concomitant use of strong or moderate CYP2C19 inhibitors should be discouraged (see “Special warnings and precautions for use” and “Pharmacokinetic properties”). Inhibitors of CYP2C19: 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. Medicinal products that are strong or moderate CYP2C19 inhibitors include, for example, omeprazole and esomeprazole, fluvoxamine, fluoxetine, moclebemide, voriconazole, fluconazole, ticlopidine, , , carbamazepine, .. Proton Pump Inhibitors: Omeprazole 80 mg once daily administered either at the same time as clopidogrel or with 12 hours between the administrations of the two drugs decreased the exposure of the active metabolite by 45 % (loading dose) and 40 % (maintenance dose). Esomeprazole is expected to give a similar interaction with clopidogrel. Clopidogrel can be administered with pantoprazole. Other medicinal products: No clinically significant pharmacodynamic interactions were observed when clopidogrel was co-administered with atenolol, nifedipine, or both atenolol and nifedipine. Pharmacodynamic activity of clopidogrel was not significantly influenced by the coadministration of phenobarbital, cimetidine, or oestrogen. The pharmacokinetics of digoxin or theophylline were not modified by the co-administration of clopidogrel. Antacids did not modify the extent of clopidogrel absorption. Phenytoin and tolbutamide which are metabolized by CYP2C9 can be safely coadministered with clopidogrel.

CYP2C8 substrate medicinal products: Clopidogrel has been shown to increase repaglinide exposure in healthy volunteers. In vitro studies have shown the increase in repaglinide exposure is due to inhibition of CYP2C8 by the glucuronide metabolite of clopidogrel. Due to the risk of increased plasma concentrations, concomitant administration of clopidogrel and drugs primarily cleared by CYP2C8 metabolism (e.g., repaglinide, paclitaxel) should be undertaken with caution..

As with other oral P2Y12 inhibitors, co-administration of opioid agonists has the potential to delay and reduce the absorption of clopidogrel because of slowed gastric emptying. Consider the use of a parenteral antiplatelet agent in acute coronary syndrome patients requiring co-administration of morphine or other opioid agonists.

PREGNANCY AND LACTATION : Pregnancy: No clinical data on exposure to clopidogrel during pregnancy, therefore it is preferable not to use clopidogrel during pregnancy. 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”). Breastfeeding: 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 Plavix. Fertility: Clopidogrel was not shown to alter fertility in animal studies.

EFFECTS ON THE ABILITY TO DRIVE AND USE MACHINES: Clopidogrel has no or negligible influence on the ability to drive and use machines.

UNDESIRABLE EFFECTS

Clopidogrel has been evaluated for safety in clinical studies, including patients treated for 1 year or more. Overall, clopidogrel 75 mg/day was comparable to ASA 325 mg/day in CAPRIE regardless of age, gender, and race. Bleeding is the most common reaction reported both in clinical studies as well as in post-marketing, mostly reported during the first month of treatment. The overall incidence of any bleeding was 9.3%. The incidence of severe cases was similar for clopidogrel and ASA. There was no excess in major bleeds with clopidogrel plus ASA within 7 days after coronary bypass graft surgery in patients who stopped therapy more than five days prior to surgery. In patients who remained on therapy within five days of bypass graft surgery, the event rate was 9.6% for clopidogrel plus ASA, and 6.3% for placebo plus ASA. There was an overall similar increase in bleeding in the clopidogrel plus ASA group vs. the placebo plus ASA group. This was consistent across subgroups of patients defined by baseline characteristics, and type of fibrinolytic or heparin therapy. The overall rate of noncerebral major bleeding or cerebral bleeding was low and similar in both groups. In another study, the rate of major bleeding was greater in the clopidogrel + ASA group than in the placebo + ASA group (6.7% versus 4.3%). Major bleeding was mostly of extracranial origin in both groups (5.3% in the clopidogrel + ASA group; 3.5% in the placebo +ASA group), mainly from the gastrointestinal tract (3.5% vs. 1.8%). There was an excess of intracranial bleeding in the clopidogrel + ASA treatment group compared to the placebo + ASA group (1.4% versus 0.8%, respectively). There was no statistically significant difference in the rates of fatal bleeding (1.1% in the clopidogrel + ASA group and 0.7% in the placebo +ASA group) and haemorrhagic stroke (0.8% and 0.6%, respectively) between groups.

Vascular disorders : Common: Haematoma. Respiratory, thoracic and mediastinal disorders: Common: Epistaxis. Gastrointestinal disorders: Common: Gastrointestinal haemorrhage, diarrhoea, abdominal pain, dyspepsia. Skin and subcutaneous tissue disorders: Common: Bruising. Reproductive systems and breast disorders: General disorders and administration site conditions: Common: Bleeding at puncture site. Investigations: Common: Bleeding time prolonged, neutrophil count decreased, platelet count decreased. For uncommon, rare and very rare side effects see full prescribing information

OVERDOSAGE

Overdose following clopidogrel administration may lead to prolonged bleeding time and subsequent bleeding complications. Appropriate therapy should be considered if bleedings are observed. No antidote to the pharmacological activity of clopidogrel has been found. If prompt correction of prolonged bleeding time is required, platelet transfusion may reserve the effects of clopidogrel.

PHARMACODYNAMIC PROPERTIES

ATC code: B01AC04

Based on approval 03 Jan 2022 (CCDS V27 dan V28)

Revision on date: 19 January 2022

This information is intended for Health Care Professional only. See local product information for full details information

PLAVIX