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Apo-Clopidogrel

Product Description / Availability of Dosage Form
APO-CLOPIDOGREL 75 mg: Each reddish-brown, round, film-coated tablet engraved with "CL" over "75' on one side and 'APO' on the other side contains clopidogrel bisulfate equivalent to 75 mg clopidogrel. Available in blister packs of 30's.

Pharmacodynamics
Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor, and the subsequent ADP-mediated activation of the GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation.

Clopidogrel also inhibits platelet aggregation induced by other agonists by blocking the amplification of platelet activation by released ADP. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan and recovery of normal platelet function occurs at a rate consistent with platelet turnover.

Repeated doses of 75 mg per day produced substantial inhibition of ADP-induced platelet aggregation from the first day; this increased progressively and reached steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg per day was between 40% and 60%. Platelet aggregation and bleeding time gradually returned to baseline values, generally within 5 days after treatment was discontinued.

Pharmacokinetics
After repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed. However, plasma concentrations of the parent compound are very low and below the quantification limit (0.00025 mg/l) beyond 2 hours. Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Clopidogrel is extensively metabolised by the liver and the main metabolite, which is inactive, is the carboxylic acid derivative, which represents about 85% of the circulating compound in plasma. Peak plasma levels of this metabolite (approx. 3mg/I after repeated 75 mg oral doses) occurred approximately 1 hour after dosing.

Clopidogrel is a prodrug. The active metabolite, a thiol derivative, is formed by oxidation of clopidogrel to 2-oxo-clopidogrel and subsequent hydrolysis. The oxidative step is regulated primarily by Cytochrome P450 isoenzymes 2B6 and 3A4 and to a lesser extent by 1A1, 1A2 and 2C19. The active thiol metabolite, which has been isolated in vitro, binds rapidly and irreversibly to platelet receptors, thus inhibiting platelet aggregation. This metabolite has not been detected in plasma.

The kinetics of the main circulating metabolite were linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel.

Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94% respectively). The binding is non-saturable in vitro over a wide concentration range.

Following an oral dose of 14C-labelled clopidogrel in man, approximately 50% was excreted in the urine and approximately 46% in the faeces in the 120-hour interval after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration.

After repeated doses of 75 mg clopidogrel per day, plasma levels of the main circulating metabolite were lower in subjects with severe renal disease (creatinine clearance from 5 to 15 ml/min) compared to subjects with moderate renal disease (creatinine clearance from 30 to 60 ml/min) and to levels observed in other studies with healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy subjects, the prolongation of bleeding was similar to that seen in healthy subjects receiving 75 mg of clopidogrel per day. In addition, clinical tolerance was good in all patients.

The pharmacokinetics and pharmacodynamics of clopidogrel were assessed in a single and multiple dose study in both healthy subjects and those with cirrhosis (Child-Pugh class A or S). Daily dosing for 10 days with clopidogrel 75 mg/day was safe and well tolerated. Clopidogrel Cmax for both single dose and steady state for cirrhotics was many fold higher than in normal subjects. However, plasma levels of the main circulating metabolite together with the effect of clopidogrel on ADP-induced platelet aggregation and bleeding time were comparable between these groups.

Indication
Clopidogrel is indicated 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 combination with acetylsalicylic acid (ASA) in medically treated patients eligible for thrombolytic therapy

Recommended Dosage and Mode of Administration
Adults and elderly: Clopidogrel should be given as a single daily dose of 75 mg with or without food.

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.

- ST segment elevation acute myocardial infarction: clopidogrel should be given as a single daily dose of 75 mg initiated with a loading dose in combination with ASA and with or without thrombolytics. For patients greater than 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

Children and adolescents: Safety and efficacy in subjects below the age of 18 have not been established.

Contraindications
Hypersensitivity to the active substance or to any of the excipients of the medicinal product.
Severe liver impairment.
Active pathological bleeding such as peptic ulcer or intracranial haemorrhage.
Breast-feeding.

Warnings and Precautions
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. 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, non-steroidal anti-inflammatory drugs including Cox-2 inhibitors, heparin or glycoprotein IIb/IIIa 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 warfarin is not recommended since it may increase the intensity of bleedings.

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).

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. Patients should inform physicians and dentists that they are taking clopidogrel before any surgery is scheduled and before any new drug is taken.

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 either neurological findings, renal dysfunction or fever. TTP is a potentially fatal condition requiring prompt treatment including plasmapheresis. In view of the lack of data, clopidogrel cannot be recommended in acute ischaemic stroke (less than 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 CYP22C19 function (intermediate or poor metabolisers) 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.

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