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Because many drugs are excreted in human milk and because of the
potential for serious adverse reactions in nursing infants, a
decision should be made whether to discontinue nursing or to
discontinue the drug, taking into account the importance of the
drug to the nursing woman. In patients receiving aspirin, the
corresponding rates were 2. The incidence of intracranial
hemorrhage was 0. The incidence of intracranial hemorrhage (0.
The patients were followed for 30 days. A total of 99. The number
of patients who reached the primary endpoint was 262 (15. This
benefit is not known to pertain to patients who receive primary
angioplasty.
The active thiol metabolite which has been
isolated in vitro, binds rapidly and irreversibly to platelet
receptors, thus inhibiting platelet aggregation. After a single,
oral dose of 75 mg, clopidogrel has a plavix drug
contraindications of approximately 6 hours. The elimination
halflife of the inactive acid metabolite was 8 hours after single
and repeated administration. Covalent binding to platelets
accounted for 2% of radiolabel with a halflife of 11 days.
A variety of drugs that inhibit platelet function have been shown
to decrease morbid events in people with established
cardiovascular atherosclerotic disease as evidenced by stroke or
transient ischemic attacks, myocardial infarction, unstable angina
or the need for vascular bypass or angioplasty. This indicates
that platelets participate in the initiation and/or evolution of
these events and that inhibiting platelet function can reduce the
event rate. This action is irreversible. Consequently, platelets
exposed to clopidogrel's active metabolite are affected for the
remainder of their lifespan (about 7 to 10 days).
Major*
noncerebral or cerebral bleeding 134 (0. The median duration of
therapy was 20 months, with a maximum of 3 years. Other adverse
experiences of potential importance occurring in 1% to 2.
Platelet, bleeding and clotting disorders: hemarthrosis,
hematuria, hemoptysis, hemorrhage intracranial, hemorrhage
retroperitoneal, hemorrhage of operative wound, ocular hemorrhage,
pulmonary hemorrhage, purpura allergic, thrombocytopenia.
Platelet aggregation and bleeding time gradually return to
baseline values after treatment is discontinued, generally in
about 5 days. Mean peak plasma levels of unchanged clopidogrel
(approximately 2. Cytochromes first oxidize clopidogrel to a
2oxoclopidogrel intermediate metabolite. Subsequent metabolism of
the 2oxoclopidogrel intermediate metabolite results in formation
of the active metabolite, a thiol derivative of clopidogrel.
It is not clear whether this difference is real or a chance
occurrence. In the metaanalyses of studies of aspirin vs. There
was a suggestion of heterogeneity in these studies too, with the
effect strongest in patients with a history of myocardial
infarction, weaker in patients with a history of stroke, and not
discernible in patients with a history of peripheral vascular
disease. Patients also received aspirin (75325 mg once daily) and
other standard therapies such as heparin.
It also
dissolves freely in methanol, dissolves sparingly in methylene
chloride, and is practically insoluble in ethyl ether. It has a
specific optical rotation of about +56. Each tablet contains
hydrogenated castor oil, hydroxypropylcellulose, mannitol,
microcrystalline cellulose and polyethylene glycol 6000 as
inactive ingredients. The pink film coating contains ferric oxide,
hypromellose 2910, lactose monohydrate, titanium dioxide and
triacetin.
Genetic determinants of response to
clopidogrel and cardiovascular events. No dosage adjustment is
needed for the elderly. The mean bleeding time prolongation was
also similar in the two groups. Patients received randomized
treatment for an average of 1.
The individual components
do not represent a breakdown of the primary and coprimary
outcomes, but rather the total number of subjects experiencing an
event during the course of the study. Primary outcome 582 (9. The
coprimary endpoints were death from any cause and the first
occurrence of reinfarction, stroke or death. Such subgroup
analyses should be interpreted very cautiously.
This was
consistent across subgroups of patients defined by baseline
characteristics, and type of fibrinolytics or heparin therapy. The
incidence of fatal bleeding (0. The relative rate of major
noncerebral or cerebral bleeding was independent of age. Event
rates for placebo + aspirin by age were: 60 years = 0.
Life threatening and other major bleeding. Major bleeding 3. There
was no excess in major bleeds within seven days after coronary
bypass graft surgery in patients who stopped therapy more than
five days prior to surgery (event rate 4. In patients who remained
on therapy within five days of bypass graft surgery, the event
rate was 9.
In plasma and urine, the glucuronide of the
carboxylic acid derivative is also observed. Lower active
metabolite exposure results in less platelet inhibition or higher
residual platelet reactivity. To date, diminished antiplatelet
responses to clopidogrel have been described for intermediate and
poor metabolizers in 21 reported studies involving 4,520 subjects.
The relative difference in antiplatelet response between genotype
groups varies across studies depending on the method used to
evaluate response, but is typically greater than 30%.
Deaths not easily attributable to nonvascular causes were all
classified as vascular. The overall risk reduction (9. Similar
results were obtained when allcause mortality and allcause strokes
were counted instead of vascular mortality and ischemic strokes
(risk reduction 6. The event curves separated early and continued
to diverge over the 3year followup period.
A single oral
dose of clopidogrel at 1500 or 2000 mg/kg was lethal to mice and
to rats and at 3000 mg/kg to baboons. The optimal dose regimen for
poor metabolizers has yet to be determined. All rights reserved.
Active pathological bleeding such as peptic ulcer or intracranial
hemorrhage. Clopidogrel was found to have no effect on fertility
of male and female rats at oral doses up to 400 mg/kg per day (52
times the recommended human dose on a mg/m2 basis). There are,
however, no adequate and wellcontrolled studies in pregnant women.
It is not known whether this drug is excreted in human milk.
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