Plavix (clopidogrel bisulfate) drug information: dosage, side effects, drug interactions and user re Mechanism of Action
Clopidogrel can be an inhibitor of platelet activation and aggregation through
the irreversible binding of their active metabolite to your P2Y12 class of ADP
receptors on platelets.
Pharmacodynamics
Clopidogrel has to be metabolized by CYP450 enzymes to generate the active metabolite
that inhibits platelet aggregation. The active metabolite of clopidogrel selectively
inhibits the binding of adenosine diphosphate (ADP) to the platelet P2Y12 receptor
and also the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex,
thereby inhibiting platelet aggregation. This process is irreversible. Consequently,
platelets confronted with clopidogrel's active metabolite suffer with the remainder
in their lifespan (about About a week). Platelet aggregation induced by agonists
other than ADP is additionally inhibited by blocking the amplification of platelet activation
by released ADP.
Dose-dependent inhibition of platelet aggregation is so visible 120 minutes after
single oral doses of Plavix. Repeated doses of 75 mg Plavix daily inhibit
ADP-induced platelet aggregation within the first day, and inhibition reaches steady
state between Day 3 and Day 7. At steady state, the typical inhibition level
observed having a dose of 75 mg Plavix per day was between 40% and 60%. Platelet
aggregation and bleeding time gradually resume baseline values after treatment
is discontinued, generally in about 5 days.
Geriatric Patients
Elderly ( ≥ 75 years) and young healthy subjects had similar effects on platelet
aggregation.
Renally-Impaired Patients
After repeated doses of 75 mg Plavix on a daily basis, patients with severe renal impairment
(creatinine clearance from 5 to fifteen mL/min) and moderate renal impairment (creatinine
clearance from 30 to 60 mL/min) showed low (25%) inhibition of ADP-induced platelet
aggregation.
Hepatically-Impaired Patients
After repeated doses of 75 mg Plavix every day for Ten days in patients with severe
hepatic impairment, inhibition of ADP-induced platelet aggregation was similar
to this affecting healthy subjects.
Gender
In a small study comparing women and men, less inhibition of ADP-induced platelet
aggregation was noticed in women.
Pharmacokinetics
Clopidogrel is often a prodrug and is also metabolized to a pharmacologically active metabolite
and inactive metabolites.
Absorption
After single and repeated oral doses of 75 mg on a daily basis, clopidogrel is rapidly
absorbed. Absorption are at least 50%, dependant on urinary excretion of clopidogrel
metabolites.
Effect of Food
Plavix is usually administered with or without food. In a very study in healthy male
subjects when Plavix 75 mg on a daily basis was presented with having a standard breakfast, mean
inhibition of ADP-induced platelet aggregation was reduced by less than 9%. The active metabolite AUC0-24 was unchanged in the presence of food, while there
was obviously a 57% decline in active metabolite Cmax. Similar effects were observed
when a Plavix 300 mg loading dose was administered with a high-fat breakfast.
Metabolism
Clopidogrel is extensively metabolized by two main metabolic pathways: one
mediated by esterases and ultimately causing hydrolysis into an inactive carboxylic
acid derivative (85% of circulating metabolites) and something mediated by multiple
cytochrome P450 enzymes. Cytochromes first oxidize clopidogrel into a 2-oxo-clopidogrel
intermediate metabolite. Subsequent metabolism in the 2-oxo-clopidogrel intermediate
metabolite results in formation from the active metabolite, a thiol derivative
of clopidogrel. This metabolic pathway is mediated by CYP2C19, CYP3A, CYP2B6
and CYP1A2. The active thiol metabolite binds rapidly and irreversibly to platelet
receptors, thus inhibiting platelet aggregation for the lifespan with the platelet.
The Cmax in the active metabolite is doubly high after having a single 300 mg
clopidogrel loading dose since it is after four times 75 mg maintenance dose. Cmax occurs approximately 30 to 1 hour after dosing. From the 75 to 300 mg
dose range, the pharmacokinetics of the active metabolite deviates from dose
proportionality: raising the dose by way of a factor of 4 ends in 2. 0- and
2. 7-fold increases in Cmax and AUC, respectively.
Elimination
Following a verbal dose of 14C-labeled clopidogrel in humans, approximately
50% of total radioactivity was excreted in urine and approximately 46% in feces
above the 5 days post-dosing. After having a single, oral dose of 75 mg, clopidogrel
features a half-life of around Six hours. The half-life in the active metabolite
is approximately Half an hour.
Pharmacogenomics
CYP2C19 is active in the formation of the active metabolite and the
2-oxo-clopidogrel intermediate metabolite. Clopidogrel active metabolite pharmacokinetics
and antiplatelet effects, as measured by ex vivo platelet aggregation assays,
differ based on CYP2C19 genotype. Genetic variants of other CYP450 enzymes
also can modify the formation of clopidogrel's active metabolite.
The CYP2C19*1 allele corresponds to completely functional metabolism even though the CYP2C19*2
and *3 alleles are nonfunctional. CYP2C19*2 and *3 are the cause of most
of reduced function alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles linked to absent or reduced metabolism are more uncommon,
and will include, but aren't limited by, CYP2C19*4, *5, *6, *7, and *8. Someone
with poor metabolizer status will possess two loss-of-function alleles as defined
above. Published frequencies for poor CYP2C19 metabolizer genotypes are approximately
2% for whites, 4% for blacks and 14% for Chinese. Tests are around to determine
a patient's CYP2C19 genotype.
A crossover study in 40 healthy subjects, 10 each inside four CYP2C19 metabolizer
groups, evaluated pharmacokinetic and antiplatelet responses using 300 mg followed
by 75 mg daily and 600 mg followed by 150 mg every day, each to get a total of
5 days. Decreased active metabolite exposure and diminished inhibition of platelet
aggregation were witnessed in poor people metabolizers in comparison to the other
groups. When poor metabolizers received the 600 mg/150 mg regimen, active metabolite
exposure and antiplatelet response were over using the 300 mg/75 mg regimen
(see Table 4). The ideal dose regimen with this patient population
hasn't been established in clinical outcome trials.
Table 4: Active Metabolite Pharmacokinetics and Antiplatelet
Responses by CYP2C19 Metabolizer Status
Dose
Ultra rapid
(n=10)
Extensive
(n=10)
Intermediate
(n=10)
Poor
(n=10)
Cmax (ng/mL)
300 mg (24 h)
24 (10)
32 (21)
23 (11)
11 (4)
600 mg (24 h)
36 (13)
44 (27)
39 (23)
17 (6)
75 mg (Day 5)
12 (6)
13 (7)
12 (5)
4 (1)
150 mg (Day 5)
16 (9)
19 (5)
18 (7)
7 (2)
IPA (%)*
300 mg (24 h)
40 (21)
39 (28)
37 (21)
24 (26)
600 mg (24 h)
51 (28)
49 (23)
56 (22)
32 (25)
75 mg (Day 5)
56 (13)
58 (19)
60 (18)
37 (23)
150 mg (Day 5)
68 (18)
73 (9)
74 (14)
61 (14)
VASP-PRI (%)
300 mg (24 h)
73 (12)
68 (16)
78 (12)
91 (12)
600 mg (24 h)
51 (20)
48 (20)
56 (26)
85 (14)
75 mg (Day 5)
40 (9)
39 (14)
50 (16)
83 (13)
150 mg (Day 5)
20 (10)
24 (10)
29 (11)
61 (18)
Values are mean (SD)
* Inhibition of platelet aggregation with 5mcM ADP; larger value indicates
greater platelet inhibition
Vasodilator-stimulated phosphoprotein - platelet reactivity index;
smaller value indicates greater platelet inhibition
Some published studies report that intermediate metabolizers have decreased
active metabolite exposure and diminished antiplatelet effects.
The relationship between CYP2C19 genotype and Plavix treatment outcome was
evaluated in retrospective analyses of Plavix-treated subjects in CHARISMA (n=2428)
and TRITON-TIMI 38 (n=1477), plus in several published cohort studies. In TRITON-TIMI
38 and the majority in the cohort studies, the combined gang of patients with
either intermediate or poor metabolizer status were built with a higher rate of cardiovascular
events (death, myocardial infarction, and stroke) or stent thrombosis compared
to extensive metabolizers. In CHARISMA and something cohort study, the elevated event
rate was observed only in poor metabolizers.
Scientific studies
Acute Coronary Syndrome
CURE
The CURE study included 12,562 patients with ACS without ST-elevation (UA or
NSTEMI) and presenting within A day of oncoming of the most up-to-date episode of
chest pain or symptoms in keeping with ischemia. Patients was required to have
either ECG changes suitable for new ischemia (without ST-elevation) or elevated
cardiac enzymes or troponin I or T to at least 2 times the top of limit of normal. The affected person population was largely Caucasian (82%) and included 38% women, and
52% patients ≥ 65 years of age.
Patients were randomized to get Plavix (300-mg loading dose and then
75 mg once daily) or placebo, and were treated for approximately 12 months. Patients
also received aspirin (75-325 mg once daily) along with standard therapies such
as heparin. The utilization of GPIIb/IIIa inhibitors was not permitted for 3 days
before randomization.
The amount of patients exceptional primary outcome (CV death, MI, or stroke)
was 582 (9 buy betnovate. 3%) within the Plavix-treated group and 719 (11. 4%) in the placebo-treated
group, a 20% relative risk reduction (95% CI of 10%-28%; p < 0. 001) for the
Plavix-treated group (see Table 5) buy cheap combivent online.
Table 5: Outcome Events inside the CURE Primary Analysis
Outcome
Plavix (+aspirin)* (n=6259)
Placebo (+ aspirin)* (n=6303)
Relative Risk Reduction (%) (95% CI)
Primary outcome (Cardiovascular death, MI, stroke)
582(9. 3%)
719 (11. 4%)
20% (10. 3, 27. 9) p < 0. 001
All Individual Outcome Events:
CV death
318(5. 1%)
345 (5. 5%)
7% (-7. 7, 20. 6)
MI
324(5. 2%)
419 (6. 6%)
23% (11. 0, 33. 4)
Stroke
75(1. 2%)
87 (1. 4%)
14% (-17. 7, 36. 6)
* Other standard therapies were used as appropriate.
Anyone components will not represent an explanation in the
primary and co-primary outcomes, but alternatively the total quantity of subjects
experiencing a function during the course of the investigation.
Most on the benefit of Plavix took place the 1st 60 days, nevertheless the difference
from placebo was maintained through the course of the trial (up to Yr)
(see Figure 1).
Figure 1: Cardiovascular Death, Myocardial Infarction, and
Stroke within the CURE Study
In CURE, the application of Plavix was of the lower incidence of CV death,
MI or stroke in patient populations with different characteristics, as shown
in Figure 2. The huge benefits associated with Plavix were independent of the use
of other acute and long-term cardiovascular therapies, including heparin/LMWH,
intravenous glycoprotein IIb/IIIa (GPIIb/IIIa) inhibitors, lipid-lowering drugs,
beta-blockers, and ACE-inhibitors. The efficacy of Plavix was observed independently
from the dose of aspirin (75-325 mg once daily). The utilization of oral anticoagulants,
non-study anti-platelet drugs, and chronic NSAIDs had not been allowed in CURE.
Figure 2: Hazard Ratio for Patient Baseline Characteristics
and On-Study Concomitant Medications/Interventions with the CURE Study
The usage of Plavix in CURE was associated with a reduction in the use of thrombolytic
therapy (71 patients [1. 1%] inside the Plavix group, 126 patients [2. 0%] from the
placebo group; relative risk decrease in 43%), and GPIIb/IIIa inhibitors (369
patients [5. 9%] within the Plavix group, 454 patients [7. 2%] from the placebo group,
relative risk reduction of 18%). The utilization of Plavix in CURE wouldn't change the
volume of patients cured with CABG or PCI (without or with stenting), (2253
patients [36. 0%] in the Plavix group, 2324 patients [36. 9%] inside placebo group;
relative risk reduction of 4. 0%).
COMMIT
In patients with STEMI, the safety and efficacy of Plavix were evaluated in
the randomized, placebo-controlled, double-blind study, COMMIT. COMMIT included
45,852 patients presenting within One day of the oncoming of the signs of myocardial
infarction with supporting ECG abnormalities (i. e. , ST-elevation, ST-depression
or left bundle-branch block).
Patients were randomized to get Plavix (75 mg once daily) or placebo, in
in conjunction with aspirin (162 mg every day), for 28 days or until hospital discharge,
whichever came first.
The primary endpoints were death from any cause and the first occurrence of
re-infarction, stroke or death.
The patient population included 28% women, 58% age ≥ 60 years (26% age ≥
70 years), 55% patients who received thrombolytics, 68% who received ACE-inhibitors,
simply 3% who underwent PCI.
As shown in Table 6 and Figure 3 and Figure 4 below, Plavix significantly reduced
the relative probability of death from the cause by 7% (p=0. 029), along with the relative
chance of the mix of re-infarction, stroke or death by 9% (p=0. 002).
Table 6: Outcome Events within the COMMIT Analysis
Event
Plavix (+ aspirin) (N=22961)
Placebo (+ aspirin) (N=22891)
Odds ratio (95% CI)
p-value
Composite endpoint: Death, MI, or Stroke*
2121 (9. 2%)
2310 (10. 1%)
0. 91
(0. 86, 0. 97)
0. 002
Death
1726 (7. 5%)
1845 (8. 1%)
0. 93
(0. 87, 0. 99)
0. 029
Non-fatal MI**
270 (1. 2%)
330 (1. 4%)
0. 81
(0. 69, 0. 95)
0. 011
Non-fatal Stroke**
127 (0. 6%)
142 (0. 6%)
0. 89
(0. 70, 1. 13)
0. 33
* The difference between the composite endpoint
and also the sum of death+non-fatal MI+non-fatal stroke suggests that 9 patients
(2 clopidogrel and 7 placebo) suffered both a non-fatal stroke as well as a non-fatal
MI.
** Non-fatal MI and non-fatal stroke exclude patients who died (of a typical
cause).
Figure 3: Cumulative Event Rates for Death inside the COMMIT
Study *
* All treated patients received aspirin.
Figure 4: Cumulative Event Rates to the Combined Endpoint
Re-Infarction, Stroke or Death from the COMMIT Study*
* All treated patients received aspirin.
The effect of Plavix wouldn't differ significantly in several pre-specified
subgroups as shown in Figure 5. The effect has also been similar in non-prespecified
subgroups including those based on infarct location, Killip class or prior MI
history (see Figure 6). Such subgroup analyses must be interpreted
cautiously.
Figure 5: Outcomes of Adding Plavix to Aspirin for the Combined
Primary Endpoint across Baseline and Concomitant Medication Subgroups with the
COMMIT Study
* Three similar-sized prognostic index groups were based on absolute chance of
primary composite outcome for every patient calculated from baseline prognostic
variables (excluding allocated treatments) using a Cox regression model.
Figure 6: Outcomes of Adding Plavix to Aspirin from the Non-Prespecified
Subgroups within the COMMIT Study
Recent Myocardial Infarction, Recent Stroke, or Established Peripheral Arterial
Disease
CAPRIE
The CAPRIE trial was a 19,185-patient, 304-center, international, randomized,
double-blind, parallel-group study comparing Plavix (75 mg daily) to aspirin
(325 mg daily). The patients randomized had: 1) recent histories of myocardial
infarction (within 35 days); 2) recent histories of ischemic stroke (within
Six months) with at the least per week of residual neurological signs; or 3) established
peripheral arterial disease. Patients received randomized strategy for a typical
of a single. 6 years (maximum of Three years).
The trial's primary outcome was the time to first occurrence of new ischemic
stroke (fatal you aren't), new myocardial infarction (fatal or otherwise not), or some other vascular
death. Deaths not easily attributable to nonvascular causes were all classified
as vascular.
Table 7: Outcome Events inside CAPRIE Primary Analysis
Patients
Plavix
n=9599
aspirin
n=9586
Ischemic stroke (fatal or not)
438 (4. 6%)
461 (4. 8%)
MI (fatal you aren't)
275 (2. 9%)
333 (3. 5%)
Other vascular death
226 (2. 4%)
226 (2. 4%)
Total
939 (9. 8%)
1020 (10. 6%)
As shown in Table 7, Plavix was from a lower incidence of outcome
events, primarily MI. The general relative risk reduction (9. 8% vs. 10. 6%) was
8. 7%, p=0. 045. Similar results were obtained when all-cause mortality and all-cause
strokes were counted instead of vascular mortality and ischemic strokes (risk
reduction 6. 9%). In patients who survived an on-study stroke or myocardial infarction,
the incidence of subsequent events was lower in the Plavix group.
The curves showing the general event rate are shown in Figure 7. The event
curves separated early and continued to diverge above the 3-year follow-up period.
Figure 7: Fatal or Non-Fatal Vascular Events inside CAPRIE
Study
The statistical significance favoring Plavix over aspirin was marginal (p=0. 045). However, because aspirin is itself good at reducing cardiovascular events
in patients with recent myocardial infarction or stroke, the consequence of Plavix
is substantial.
The CAPRIE trial included a population that was randomized judging by
3 entry criteria. The efficacy of Plavix compared to aspirin was heterogeneous
across these randomized subgroups (p=0. 043). It is not clear whether this difference
is real or maybe a chance occurrence. However the CAPRIE trial had not been meant to
measure the relative benefit for Plavix over aspirin within the individual patient
subgroups, the main benefit got strongest in patients have been enrolled
as a consequence of peripheral vascular disease (specially those who also had a history
of myocardial infarction) and weaker in stroke patients. In patients who had been
participating in the trial around the sole basis of a recent myocardial infarction, Plavix
has not been numerically superior to aspirin.
Absence of Established Benefit of Plavix plus Aspirin in Patients with Multiple
Risk Factors or Established Vascular Disease
CHARISMA
The CHARISMA trial would be a 15,603 subject, randomized, double-blind, parallel
group study comparing Plavix (75 mg daily) to placebo for protection against ischemic
events in patients with vascular disease or multiple risks for atherosclerosis. All subjects were treated with aspirin 75-162 mg daily. The mean time period of
treatment was 23 months. Case study failed to demonstrate reverse mortgage the
occurrence of the primary endpoint, an amalgamated of CV death, MI, or stroke. A full of 534 (6. 9%) patients within the Plavix group versus 573 (7. 4%) patients
from the placebo group experienced a principal outcome event (p=0. 22). Bleeding
of the severities was more prevalent in the subjects randomized to Plavix.
Last reviewed on RxList: 6/13/2011
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