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.
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
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
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.
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
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.
• 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
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
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
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
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