ORGACLOP Tablet

Clopidogrel is indicated in adults for the prevention of atherothrombotic events in:

- 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.

- 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.

+ ST segment elevation acute myocardial infarction, in medically treated patients eligible for thrombolytic therapy.

Dosage and administration

Posology

・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, 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).

- 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.

・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 is limited in patients with moderate hepatic disease who may have bleeding diathese.

・Method of administration

For oral use. It may be given with or without food.

・Hypersensitivity to the active substance.

・severe hepatic impairment.

・Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.

Haematoma, Epistaxis, Gastrointestinal haemorrhage, diarrhoea, abdominal pain, Dyspepsia, Bruising, Bleeding at puncture site, Bleeding time prolonged, neutrophil count decreased, Platelet count decreased, Haematuria, Rash, Pruritus, Purpura, Gastric ulcer, Duodenal ulcer, Gastritis, Vomiting, Nausea, Constipation, Flatulence, Intracranial bleeding, Headache, Paraesthesia, Dizziness.

Oral anticoagulants: the concomitant administration of clopidogrel with oral anticoagulants is not recommended since it may increase the intensity of bleeding. 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 increase the risk of bleeding because of independent effects on hemostasis.

Glycoprotein llb/lla inhibitors: Clopidogrel should be used with caution in patients who receive concomitant glycoprotein llb/llla inhibitors.

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. A pharmacodynamic interaction between clopidogrel and acetylsalicylic acid is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution. 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. Co-administration of heparin had no effect on the inhibition of platelet aggregation induced by clopidogrel. A pharmacodynamic interaction between clopidogrel and heparin is possible, leading to increased risk of bleeding. Therefore, concomitant use should be undertaken with caution.

Thrombolytics: the safety of the concomitant administration of clopidogrel, fibrin or non-fibrin specific thrombolytic agents and heparins was assessed in patients with acute myocardial infarction. The incidence of clinically significant bleeding was similar to that observed when thrombolytic agents and heparin are co-administered with ASA.

NSAIDs: in a clinical study conducted in healthy volunteers, the concomitant administration of clopidogrel and naproxen increased occult gastrointestinal blood loss. However, due to the lack of interaction studies with other NSAIDs it is presently unclear whether there is an increased risk of gastrointestinal bleeding with all NSAIDs. Consequently, NSAIDs including Cox-2 inhibitors and clopidogrel should be co-administered with caution.

Proton pump inhibitors (PPI):

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). The decrease was associated with a 39% (loading dose) and 21% (maintenance dose) reduction inhibition of platelet aggregation. Esomeprazole is expected to give a similar interaction with clopidogrel.

less pronounced reductions of metabolite exposure has been observed with pantoprazole or lansoprazole.

The plasma concentrations of the active metabolite was 20% reduced (loading dose) and 14% reduced (maintenance dose) during concomitant treatment with pantoprazole 80 mg once daily. This was associated with a reduction of the mean inhibition of platelet aggregation by 15% and 11%, respectively. These results indicate that clopidogrel can be administered with pantoprazole.

Pregnancy:

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.

Lactation:

It is unknown whether clopidogrel is expected 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.

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. 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 reveiving treatment with ASA, heparin, glycoprotein llb/llla inhibitors or non steroidal anti-inflammatory drugs (NSAIDs) including Cox-2 inhibitors. 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 anti-coagulants is not recommended since it may increase the intensity of bleedings.

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 infrom physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new medicianl 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).

Thrombotic Thrombocytopenic purpura (TTP)

Thrombotic Thrombocytopenic Purpura (TTP) has been reported very rarely floowing the use of clopidogrel, sometimes after a short exposure. It is characterised by thrombocytopenia and microangiopathic haemolytic anaemia associated with either neurological findings, renal dysfuntion or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis.

Acquired haemophilia

Acquired haemophilia has been reported following use of clopidogrel. In case 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 specilists, and clopidogrel should be discontinued.

Recent ischaemic stroke

In view of the lack of data, clopidogrel cannot be recommended during the first 7 days after acute ischaemic stroke.

Allergic cross-reactivity

Patients should be evaluated for history of hypersensitivity to another thienopyridine (such as ticlopidine, prasugrel) since allergic cross-reactivity among thienopyridines has been reported. Patients who have had previous hypersensitivity to other thienopyridines should be carefully monitored for signs of hypersensitivity to clopidogrel during treatment.

Renal impairment

Therapeutic expirience with clopidogrel is limited in patients with renal impairment. Therefore clopidogrel should be used with caution in these patients.

Hepatic impairment

Experience is limited in patients with moderate hepatic disease wo may have bleeding diatheses. Clopidogrel should therefore be used with caution in this population.