Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/30
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Plavix (Tablet, Film Coated)
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| dailymed-instance:dosage |
Recent MI, Recent Stroke, or Established Peripheral Arterial
Disease: The recommended
daily dose of PLAVIX is 75 mg once daily.<br/>Acute Coronary Syndrome: For patients with
non-ST-segment elevation acute coronary syndrome (unstable angina/non-Q-wave
MI), PLAVIX should be initiated with a single 300-mg loading dose
and then continued at 75 mg once daily. Aspirin (75 mg-325 mg once
daily) should be initiated and continued in combination with PLAVIX.
In CURE, most patients with Acute Coronary Syndrome also received
heparin acutely . For patients
with ST-segment elevation acute myocardial infarction, the recommended
dose of PLAVIX is 75 mg once daily, administered in combination with
aspirin, with or without thrombolytics. PLAVIX may be initiated with
or without a loading dose . PLAVIX
can be administered with or without food. No dosage adjustment is necessary for elderly patients or patients
with renal disease. (See Clinical Pharmacology: Special Populations.)
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| dailymed-instance:descripti... |
PLAVIX (clopidogrel bisulfate)
is an inhibitor of ADP-induced platelet aggregation acting by direct
inhibition of adenosine diphosphate (ADP) binding to its receptor
and of the subsequent ADP-mediated activation of the glycoprotein
GPIIb/IIIa complex. Chemically it is methyl (+)-(S)-��-(2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1). The empirical
formula of clopidogrel bisulfate is CHClNOS���HSOand its molecular weight
is 419.9. The structural
formula is as follows: Clopidogrel bisulfate is a white to off-white powder. It is practically
insoluble in water at neutral pH but freely soluble at pH 1. 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��. PLAVIX for oral administration is provided as pink, round, biconvex,
debossed film-coated tablets containing 97.875 mg of clopidogrel bisulfate
which is the molar equivalent of 75 mg of clopidogrel base. 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. The tablets are polished with Carnauba
wax.
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| dailymed-instance:clinicalP... |
Mechanism of Action: Clopidogrel is an
inhibitor of platelet aggregation. 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 them can reduce the event rate.<br/>Pharmacodynamic Properties: Clopidogrel selectively
inhibits the binding of adenosine diphosphate (ADP) to its platelet
receptor and the subsequent ADP-mediated activation of the glycoprotein
GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation
of clopidogrel is necessary to produce inhibition of platelet aggregation,
but an active metabolite responsible for the activity of the drug
has not been isolated. Clopidogrel also inhibits platelet aggregation
induced by agonists other than ADP by blocking the amplification of
platelet activation by released ADP. Clopidogrel does not inhibit
phosphodiesterase activity. Clopidogrel acts by irreversibly modifying the platelet ADP receptor.
Consequently, platelets exposed to clopidogrel are affected for the
remainder of their lifespan. Dose dependent inhibition of platelet aggregation can be seen 2 hours
after single oral doses of PLAVIX. Repeated doses of 75 mg PLAVIX
per day inhibit ADP-induced platelet aggregation on the first day,
and inhibition reaches steady state between Day 3 and Day 7. At steady
state, the average inhibition level observed with a dose of 75 mg
PLAVIX per day was between 40% and 60%. Platelet aggregation and
bleeding time gradually return to baseline values after treatment
is discontinued, generally in about 5 days.<br/>Pharmacokinetics and Metabolism: After repeated 75-mg
oral doses of clopidogrel (base), plasma concentrations of the parent
compound, which has no platelet inhibiting effect, are very low and
are generally below the quantification limit (0.00025 mg/L) beyond
2 hours after dosing. Clopidogrel is extensively metabolized by the
liver. The main circulating metabolite is the carboxylic acid derivative,
and it too has no effect on platelet aggregation. It represents about
85% of the circulating drug-related compounds in plasma. Following an oral dose
ofC-labeled clopidogrel in humans, approximately 50%
was excreted in the urine and approximately 46% in the feces in the
5 days after dosing. The elimination half-life of the main circulating
metabolite was 8 hours after single and repeated administration.
Covalent binding to platelets accounted for 2% of radiolabel with
a half-life of 11 days.<br/>Effect of Food:: Administration
of PLAVIX (clopidogrel bisulfate) with meals did not significantly
modify the bioavailability of clopidogrel as assessed by the pharmacokinetics
of the main circulating metabolite.<br/>Absorption and Distribution:: Clopidogrel
is rapidly absorbed after oral administration of repeated doses of
75 mg clopidogrel (base), with peak plasma levels (3 mg/L) of the main circulating
metabolite occurring approximately 1 hour after dosing. The pharmacokinetics
of the main circulating metabolite are linear (plasma concentrations
increased in proportion to dose) in the dose range of 50 to 150 mg
of clopidogrel. Absorption is at least 50% based on urinary excretion
of clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98%
and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100��g/mL.<br/>Metabolism and Elimination:: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its
carboxylic acid derivative. In plasma and urine, the glucuronide
of the carboxylic acid derivative is also observed.<br/>Special Populations:<br/>Geriatric Patients:: Plasma concentrations
of the main circulating metabolite are significantly higher in elderly
(���75 years) compared to young healthy volunteers but these
higher plasma levels were not associated with differences in platelet
aggregation and bleeding time. No dosage adjustment is needed for
the elderly.<br/>Renally Impaired Patients:: After repeated
doses of 75 mg PLAVIX per day, plasma levels of the main circulating
metabolite were lower in patients with severe renal impairment (creatinine
clearance from 5 to 15 mL/min) compared to subjects with moderate
renal impairment (creatinine clearance 30 to 60 mL/min) or healthy
subjects. Although inhibition of ADP-induced platelet aggregation
was lower (25%) than that observed in healthy volunteers, the prolongation
of bleeding time was similar to healthy volunteers receiving 75 mg
of PLAVIX per day.<br/>Gender:: No significant
difference was observed in the plasma levels of the main circulating
metabolite between males and females. In a small study comparing
men and women, less inhibition of ADP-induced platelet aggregation
was observed in women, but there was no difference in prolongation
of bleeding time. Inthe large, controlled clinical study (Clopidogrel
vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence
of clinical outcome events, other adverse clinical events, and abnormal
clinical laboratory parameters was similar in men and women.<br/>Race:: Pharmacokinetic
differences due to race have not been studied.
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The use of PLAVIX is contraindicated
in the following conditions:
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PLAVIX (clopidogrel bisulfate)
is available as a pink, round, biconvex, film-coated tablet debossed
with "75" on one side and "1171" on the other. Tablets are provided
as follows: NDC 63653-1171-6
bottles of 30 NDC 63653-1171-1
bottles of 90 NDC 63653-1171-5
bottles of 500 NDC
63653-1171-3 blisters of 100<br/>Storage: Store at 25��C (77��F); excursions permitted to 15�����30��C
(59�����86��F) [See USP Controlled Room Temperature].
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| dailymed-instance:inactiveI... |
dailymed-ingredient:Carnauba_wax,
dailymed-ingredient:ferric_oxide,
dailymed-ingredient:hydrogenated_castor_oil,
dailymed-ingredient:hydroxypropylcellulose,
dailymed-ingredient:hypromellose_2910,
dailymed-ingredient:lactose_monohydrate,
dailymed-ingredient:mannitol,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol_6000,
dailymed-ingredient:titianium_dioxide,
dailymed-ingredient:triacetin
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| dailymed-instance:precautio... |
General: PLAVIX prolongs
the bleeding time and therefore should be used with caution in patients
who may be at risk of increased bleeding from trauma, surgery, or
other pathological conditions (particularly gastrointestinal and intraocular).
If a patient is to undergo elective surgery and an antiplatelet effect
is not desired, PLAVIX should be discontinued 5 days prior to surgery. Due to the risk of bleeding
and undesirable hematological effects, blood cell count determination
and/or other appropriate testing should be promptly considered, whenever
such suspected clinical symptoms arise during the course of treatment
. In patients
with recent TIA or stroke who are at high risk of recurrent ischemic
events, the combination of aspirin and PLAVIX has not been shown to
be more effective than PLAVIX alone, but the combination has been
shown to increase major bleeding.<br/>GI Bleeding:: In CAPRIE,
PLAVIX was associated with a rate of gastrointestinal bleeding of
2.0%, vs. 2.7% on aspirin. In CURE, the incidence of major gastrointestinal
bleeding was 1.3% vs 0.7% (PLAVIX + aspirin vs. placebo + aspirin,
respectively). PLAVIX should be used with caution in patients who
have lesions with a propensity to bleed (such as ulcers). Drugs that
might induce such lesions should be used with caution in patients
taking PLAVIX.<br/>Use in Hepatically Impaired Patients:: Experience
is limited in patients with severe hepatic disease, who may have bleeding
diatheses. PLAVIX should be used with caution in this population.<br/>Use in Renally-impaired Patients:: Experience
is limited in patients with severe renal impairment. PLAVIX should
be used with caution in this population.<br/>Information For Patients: Patients should
be told that it may take them longer than usual to stop bleeding,
that they may bruise and/or bleed more easily when they take PLAVIX
or PLAVIX combined with aspirin, and that they should report any unusual
bleeding to their physician. Patients should inform physicians and
dentists that they are taking PLAVIX and/or any other product known
to affect bleeding before any surgery is scheduled and before any
new drug is taken.<br/>Drug Interactions: Study of specific
drug interactions yielded the following results:<br/>Aspirin:: Aspirin
did not modify the clopidogrel-mediated inhibition of ADP-induced
platelet aggregation. Concomitant administration of 500 mg of aspirin
twice a day for 1 day did not significantly increase the prolongation
of bleeding time induced by PLAVIX. PLAVIX potentiated the effect
of aspirin on collagen-induced platelet aggregation. PLAVIX and aspirin
have been administered together for up to one year.<br/>Heparin:: In a study
in healthy volunteers, PLAVIX did not necessitate modification of
the heparin dose or alter the effect of heparin on coagulation. Coadministration
of heparin had no effect on inhibition of platelet aggregation induced
by PLAVIX.<br/>Nonsteroidal Anti-Inflammatory Drugs (NSAIDs):: In healthy
volunteers receiving naproxen, concomitant administration of PLAVIX
was associated with increased occult gastrointestinal blood loss.
NSAIDs and PLAVIX should be coadministered with caution.<br/>Warfarin:: Because
of the increased risk of bleeding, the concomitant administration
of warfarin with PLAVIX should be undertaken with caution.<br/>Other Concomitant Therapy:: No clinically
significant pharmacodynamic interactions were observed when PLAVIX
was coadministered with atenolol, nifedipine, or both atenolol
and nifedipine. The pharmacodynamic activity of PLAVIX was also not
significantly influenced by the coadministration of phenobarbital, cimetidine or estrogen. The pharmacokinetics of digoxin or theophylline were not modified
by the coadministration of PLAVIX (clopidogrel bisulfate). At high concentrations in vitro, clopidogrel inhibits P(2C9). Accordingly, PLAVIX may interfere with the metabolism
of phenytoin, tamoxifen, tolbutamide, warfarin,
torsemide, fluvastatin, and many non-steroidal anti-inflammatory agents, but there are no
data with which to predict the magnitude of these interactions. Caution
should be used when any of these drugs is coadministered with PLAVIX. In addition to
the above specific interaction studies, patients entered into clinical
trials with PLAVIX received a variety of concomitant medications including diuretics, beta-blocking agents, angiotensin converting
enzyme inhibitors, calcium antagonists, cholesterol lowering agents,
coronary vasodilators, antidiabetic agents (including insulin), thrombolytics,
heparins (unfractionated and LMWH), GPIIb/IIIa antagonists, antiepileptic agents and hormone replacement therapy without evidence
of clinically significant adverse interactions. There are no data on the concomitant use of oral anticoagulants,
non study oral anti-platelet drugs and chronic NSAIDs with clopidogrel.<br/>Drug/Laboratory Test Interactions: None known.<br/>Carcinogenesis, Mutagenesis, Impairment Of Fertility: There was no evidence
of tumorigenicity when clopidogrel was administered for 78 weeks to
mice and 104 weeks to rats at dosages up to 77 mg/kg per day, which
afforded plasma exposures>25 times that in humans at the recommended
daily dose of 75 mg. Clopidogrel was not genotoxic in four in vitro tests (Ames test, DNA-repair test in rat hepatocytes,
gene mutation assay in Chinese hamster fibroblasts, and metaphase
chromosome analysis of human lymphocytes) and in one in vivo test (micronucleus test by oral
route in mice). 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/mbasis).<br/>Pregnancy: Pregnancy Category
B. Reproduction studies performed in rats and rabbits at doses up
to 500 and 300 mg/kg/day (respectively, 65 and 78 times the recommended
daily human dose on a mg/mbasis), revealed no evidence
of impaired fertility or fetotoxicity due to clopidogrel. There are,
however, no adequate and well-controlled studies in pregnant women.
Because animal reproduction studies are not always predictive of
a human response, PLAVIX should be used during pregnancy only if clearly
needed.<br/>Nursing Mothers: Studies in rats
have shown that clopidogrel and/or its metabolites are excreted in
the milk. It is not known whether this drug is excreted in human
milk. Because many drugs are excreted in human milk and because of
the potential for serious adverse reactions in nursing infants, a
decision should be madewhether to discontinue nursing or to discontinue
the drug, taking into account the importance of the drug to the nursing
woman.<br/>Pediatric Use: Safety and effectiveness
in the pediatric population have not been established.<br/>Geriatric Use: Of the total number
of subjects in the CAPRIE, CURE and CLARITY controlled clinical studies,
approximately 50% of patients treated with PLAVIX were 65 years of
age and older, and 15% were 75 years and older. In COMMIT, approximately
58% of the patients treated with PLAVIX were 60 years and older, 26%
of whom were 70 years and older. The observed risk of thrombotic events with clopidogrel plus aspirin
versus placebo plus aspirin by age category is provided in Figures
3 and 6 for the CURE and COMMIT trials, respectively . The observed risk of bleeding events with clopidogrel plus aspirin
versus placebo plus aspirin by age category is provided in Tables
5 and 6 for the CURE and COMMIT trials, respectively .
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Overdose following clopidogrel
administration may lead to prolonged bleeding time and subsequent
bleeding complications. 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. Symptoms of acute toxicity were vomiting (in baboons), prostration,
difficult breathing, and gastrointestinal hemorrhage in all species.<br/>Recommendations About Specific Treatment:: Based on biological
plausibility, platelet transfusion may be appropriate to reverse the
pharmacological effects of PLAVIX if quick reversal is required.
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clopidogrel bisulfate
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Plavix (Tablet, Film Coated)
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PLAVIX has been evaluated
for safety in more than 42,000 patients, including over 9,000 patients
treated for 1 year or more. The clinically important adverse events
observed in CAPRIE, CURE, CLARITY and COMMIT are discussed below. The overall tolerability of PLAVIX
in CAPRIE was similar to that of aspirin regardless of age, gender
and race, with an approximately equal incidence (13%) of patients
withdrawing from treatment because of adverse reactions Hemorrhagic: In CAPRIE patients
receiving PLAVIX, gastrointestinal hemorrhage occurred at a rate of
2.0%, and required hospitalization in 0.7%. In patients receiving
aspirin, the corresponding rates were 2.7% and 1.1%, respectively.
The incidence of intracranial hemorrhage was 0.4% for PLAVIX compared
to 0.5% for aspirin. In CURE, PLAVIX use with aspirin was associated with an increase
in bleeding compared to placebo with aspirin (see Table 5). There was an excess in major
bleeding in patients receiving PLAVIX plus aspirin compared with placebo
plus aspirin, primarily gastrointestinal and at puncture sites. The
incidence of intracranial hemorrhage (0.1%), and fatal bleeding (0.2%),
were the same in both groups. The overall incidence of bleeding is described in Table 5 for patients
receiving both PLAVIX and aspirin in CURE. Ninety-two percent (92%)
of the patients in the CURE study received heparin/LMWH, and the rate
of bleeding in these patients was similar to the overall results. 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
4.4% PLAVIX + aspirin; 5.3% placebo + aspirin). In patients who remained
on therapy within five days of bypass graft surgery, the event rate
was 9.6% for PLAVIX + aspirin, and 6.3% for placebo + aspirin. In CLARITY, the incidence of
major bleeding (defined as intracranial bleeding or bleeding associated
with a fall in hemoglobin>5 g/dL) was similar between groups (1.3%
versus 1.1% in the PLAVIX + aspirin and in the placebo + aspirin groups,
respectively). This was consistent across subgroups of patients defined
by baseline characteristics, and type of fibrinolytics or heparin
therapy. The incidence of fatal bleeding (0.8% versus 0.6% in the
PLAVIX + aspirin and in the placebo + aspirin groups, respectively)
and intracranial hemorrhage (0. 5% versus 0.7%, respectively) was
low and similar in both groups. The overall rate of noncerebral major bleeding or cerebral bleeding
in COMMIT was low and similar in both groups as shown in Table 6 below. Adverse events occurring
in���2.5% of patients on PLAVIX in the CAPRIE controlled clinical
trial are shown below regardless of relationship to PLAVIX. The median
duration of therapy was 20 months, with a maximum of 3 years. No additional clinically
relevant events to those observed in CAPRIE with a frequency���2.5%,
have been reported during the CURE and CLARITY controlled studies.
COMMIT collected only limited safety data. Other adverse experiences of potential importance occurring in 1%
to 2.5% of patients receiving PLAVIX (clopidogrel bisulfate) in the
controlled clinical trials are listed below regardless of relationship
to PLAVIX. In general, the incidence of these events was similar
to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin
(in the other clinical trials). Autonomic
Nervous System Disorders: Syncope, Palpitation. Body as a Whole-general disorders:
Asthenia, Fever, Hernia. Cardiovascular
disorders: Cardiac failure. Central and peripheral nervous system disorders: Cramps
legs, Hypoaesthesia, Neuralgia, Paraesthesia, Vertigo. Gastrointestinal system disorders:
Constipation, Vomiting. Heart rate and
rhythm disorders: Fibrillation atrial. Liver and biliary system disorders:
Hepatic enzymes increased. Metabolic
and nutritional disorders: Gout, hyperuricemia, non-protein
nitrogen (NPN) increased. Musculo-skeletal
system disorders: Arthritis, Arthrosis. Platelet, bleeding&clotting disorders: GI hemorrhage, hematoma platelets decreased. Psychiatric disorders: Anxiety, Insomnia.Red blood cell disorders:
Anemia. Respiratory system disorders: Pneumonia, Sinusitis. Skin and appendage
disorders: Eczema, Skin ulceration. Urinary system disorders: Cystitis.Vision disorders: Cataract,
Conjunctivitis. Other
potentially serious adverse events which may be of clinical interest
but were rarely reported (<1%) in patients who received PLAVIX
in the controlled clinical trials are listed below regardless of relationship
to PLAVIX. In general, the incidence of these events was similar
to that in patients receiving aspirin (in CAPRIE) or placebo + aspirin
(in the other clinical trials). Body as a whole: Allergic reaction, necrosis ischemic. Cardiovascular disorders: Edema generalized.Gastrointestinal system disorders: Peptic, gastric or duodenal ulcer, gastritis, gastric ulcer perforated,
gastritis hemorrhagic, upper GI ulcer hemorrhagic. Liver and Biliary system disorders:
Bilirubinemia, hepatitis infectious, liver fatty. Platelet, bleeding and clotting disorders: hemarthrosis, hematuria, hemoptysis, hemorrhage intracranial, hemorrhage
retroperitoneal, hemorrhageof operative wound, ocular hemorrhage,
pulmonary hemorrhage, purpura allergic, thrombocytopenia. Red blood cell disorders: Anemia aplastic,
anemia hypochromic. Reproductive disorders,
female: Menorrhagia. Respiratory
system disorders: Hemothorax. Skin and appendage disorders: Bullous eruption, rash erythematous,
rash maculopapular, urticaria. Urinary
system disorders: Abnormal renal function, acute renal
failure. White cell and reticuloendothelial
system disorders: Agranulocytosis, granulocytopenia, leukemia,
leukopenia, neutropenia.<br/>Postmarketing Experience: The following events
have been reported spontaneously from worldwide postmarketing experience:
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PLAVIX (clopidogrel bisulfate)
is indicated for the reduction of atherothrombotic events as follows:
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| dailymed-instance:name |
Plavix
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