Plavix (clopidogrel bisulfate) is a thienopyridine class inhibitor of P2Y12 ADP platelet receptors.

Chemically it is methyl (+)- (S)-α- (2-chlorophenyl)-6,7-dihydrothieno[3,2-c]pyridine-5 (4H)-

acetate sulfate (1:1). The empirical formula of clopidogrel bisulfate is C16H16ClNO2S•H2SO4 and
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 either 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 or pink, oblong, debossed film-coated tablets containing 391.5 mg of
clopidogrel bisulfate which is the molar equivalent of 300 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.

Acute Coronary Syndrome (ACS)

 For patients with non-ST-segment elevation ACS [unstable angina (UA)/non-ST-

elevation myocardial infarction (NSTEMI)], including patients who are to be managed
medically and those who are to be managed with coronary revascularization, Plavix has
been shown to decrease the rate of a combined endpoint of cardiovascular death,
myocardial infarction (MI), or stroke as well as the rate of a combined endpoint of
cardiovascular death, MI, stroke, or refractory ischemia.
 For patients with ST-elevation myocardial infarction (STEMI), Plavix has been shown to
reduce the rate of death from any cause and the rate of a combined endpoint of death, re-
infarction, or stroke. The benefit for patients who undergo primary percutaneous
coronary intervention is unknown.

The optimal duration of Plavix therapy in ACS is unknown.

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

For patients with a history of recent myocardial infarction (MI), recent stroke, or established
peripheral arterial disease, Plavix has been shown to reduce the rate of a combined endpoint of
new ischemic stroke (fatal or not), new MI (fatal or not), and other vascular death.

DOSAGE AND ADMINISTRATION

Acute Coronary Syndrome

Plavix can be administered with or without food [see CLINICAL PHARMACOLOGY]

 For patients with non-ST-elevation ACS (UA/NSTEMI), initiate Plavix with a single 300 mg oral
loading dose and then continue at 75 mg once daily. Initiate aspirin (75-325 mg once daily) and
continue in combination with Plavix [see Clinical Studies].
 For patients with STEMI, the recommended dose of Plavix is 75 mg once daily orally,
administered in combination with aspirin (75-325 mg once daily), with or without thrombolytics.
Plavix may be initiated with or without a loading dose [see Clinical Studies].

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

The recommended daily dose of Plavix is 75 mg once daily orally, with or without food [see
CLINICAL PHARMACOLOGY].

CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizer status is associated with diminished antiplatelet response to

clopidogrel. Although a higher dose regimen in poor metabolizers increases antiplatelet response
[see CLINICAL PHARMACOLOGY], an appropriate dose regimen for this patient population
has not been established.

Use with Proton Pump Inhibitors (PPI)

Omeprazole, a moderate CYP2C19 inhibitor, reduces the pharmacological activity of Plavix.

Avoid using omeprazole concomitantly or 12 hours apart with Plavix. Consider using another
acid-reducing agent with less CYP2C19 inhibitory activity. A higher dose regimen of
clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an
appropriate dose regimen has not been established [see WARNINGS AND PRECAUTIONS,
DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].

HOW SUPPLIED

Dosage Forms And Strengths

 75 mg tablets: Pink, round, biconvex, film-coated tablets debossed with "75" on one side and
"1171" on the other
  300 mg tablets: Pink, oblong, film-coated tablets debossed with "300" on one side and "1332"
on the other

Plavix (clopidogrel bisulfate) 75 mg tablets are available as pink, round, biconvex, film-coated
tablets debossed with "75" on one side and "1171" on the other. Tablets are provided as follows:

he following serious adverse reactions are discussed below and elsewhere in the labeling:

 Bleeding [see WARNINGS AND PRECAUTIONS]

 Thrombotic thrombocytopenic purpura [see WARNINGS AND PRECAUTIONS]

Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions and durations of follow up,
adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to
rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Plavix has been evaluated for safety in more than 54,000 patients, including over 21,000 patients
treated for 1 year or more. The clinically important adverse reactions observed in trials
comparing Plavix plus aspirin to placebo plus aspirin and trials comparing Plavix alone to aspirin
alone are discussed below.

Bleeding

CURE

In CURE, Plavix use with aspirin was associated with an increase in major bleeding (primarily
gastrointestinal and at puncture sites) compared to placebo with aspirin (see Table 1). The
incidence of intracranial hemorrhage (0.1%) and fatal bleeding (0.2%) were the same in both
groups. Other bleeding events that were reported more frequently in the clopidogrel group were
epistaxis, hematuria, and bruise.

CYP2C19 Inhibitors

Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of

drugs that inhibit the activity of this enzyme results in reduced plasma concentrations of the
active metabolite of clopidogrel and a reduction in platelet inhibition [see WARNINGS AND
PRECAUTIONS and DOSAGE AND ADMINISTRATION].

Proton Pump Inhibitors (PPI)

A study was conducted with Plavix (300 mg loading dose followed by 75 mg/day) administered
with a high dose (80 mg/day) of omeprazole. As shown in Table 3 below, with concomitant
dosing of omeprazole, exposure (Cmax and AUC) to the clopidogrel active metabolite and
platelet inhibition were substantially reduced. Similar reductions in exposure to the clopidogrel
active metabolite and platelet inhibition were observed when Plavix and omeprazole were
administered 12 hours apart (data not shown).

There are no adequate studies of a lower dose of omeprazole or a higher dose of Plavix in
comparison with the approved dose of Plavix.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

Coadministration of Plavix and NSAIDs increases the risk of gastrointestinal bleeding.

Warfarin (CYP2C9 Substrates)

Although the administration of clopidogrel 75 mg per day did not modify the pharmacokinetics
of S-warfarin (a CYP2C9 substrate) or INR in patients receiving long-term warfarin therapy,
coadministration of Plavix with warfarin increases the risk of bleeding because of independent
effects on hemostasis.

However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.

PRECAUTIONS

Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function

Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is due to an active

metabolite. The metabolism of clopidogrel to its active metabolite can be impaired by genetic
variations in CYP2C19 [see Boxed Warning] and by concomitant medications that interfere
with CYP2C19. Avoid concomitant use of Plavix and strong or moderate CYP2C19 inhibitors.

Omeprazole, a moderate CYP2C19 inhibitor, has been shown to reduce the pharmacological
activity of Plavix if given concomitantly or if given 12 hours apart. Consider using another acid-
reducing agent with less CYP2C19 inhibitory activity. Pantoprazole, a weak CYP2C19 inhibitor,
had less effect on the pharmacological activity of Plavix than omeprazole [see DRUG
INTERACTIONS and DOSAGE AND ADMINISTRATION].

General Risk of Bleeding

Thienopyridines, including Plavix, increase the risk of bleeding. If a patient is to undergo surgery
and an antiplatelet effect is not desired, discontinue Plavix five days prior to surgery. In patients
who stopped therapy more than five days prior to CABG the rates of major bleeding were similar
(event rate 4.4% Plavix + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy
within five days of CABG, the major bleeding rate was 9.6% for Plavix + aspirin, and 6.3% for
placebo + aspirin.

Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7-10 days), so
withholding a dose will not be useful in managing a bleeding event or the risk of bleeding
associated with an invasive procedure. Because the half-life of clopidogrel's active metabolite is
short, it may be possible to restore hemostasis by administering exogenous platelets; however,
platelet transfusions within 4 hours of the loading dose or 2 hours of the maintenance dose may
be less effective.

Discontinuation of Plavix

Avoid lapses in therapy, and if Plavix must be temporarily discontinued, restart as soon as
possible. Premature discontinuation of Plavix may increase the risk of cardiovascular events.

Patients with Recent Transient Ischcmic Attack (TIA) or Stroke

In patients with recent TIA or stroke who are at high risk for 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.

Thrombotic Thrombocytopenic Purpura (TTP)

TTP, sometimes fatal, has been reported following use of Plavix, sometimes after a short
exposure ( < 2 weeks). TTP is a serious condition that requires urgent treatment including
plasmapheresis (plasma exchange). It is characterized by thrombocytopenia, microangiopathic
hemolytic anemia (schistocytes [fragmented RBCs] seen on peripheral smear), neurological
findings, renal dysfunction, and fever [see ADVERSE REACTIONS].

Nonclinical Toxicology

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/m2 basis).

Use In Specific Populations

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, respectively, on a mg/m2
basis), 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.

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 from
clopidogrel, a decision should be made whether to discontinue nursing or to discontinue the drug,
taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric Use

Of the total number of subjects in the CAPRIE and CURE 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 2 and 5 for the CURE and COMMIT trials, respectively
[see Clinical Studies]. The observed risk of bleeding events with clopidogrel plus aspirin versus
placebo plus aspirin by age category is provided in Tables 1 and 2 for the CURE and COMMIT
trials, respectively [see ADVERSE REACTIONS]. No dosage adjustment is necessary in
elderly patients.

Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see CLINICAL
PHARMACOLOGY].

CONTRAINDICATIONS

Active Bleeding

Plavix is contraindicated in patients with active pathological bleeding such as peptic ulcer or
intracranial hemorrhage.

Hypersensitivity
Plavix is contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or
any component of the product [see ADVERSE REACTIONS].

Mechanism of Action

Clopidogrel is an inhibitor of platelet activation and aggregation through the irreversible binding
of its active metabolite to the P2Y12 class of ADP receptors on platelets.

Pharmacodynamics

Clopidogrel must be metabolized by CYP450 enzymes to produce the active metabolite that
inhibits platelet aggregation. The active metabolite of clopidogrel selectively inhibits the binding
of adenosine diphosphate (ADP) to its platelet P2Y12 receptor and the subsequent ADP-mediated
activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. 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). Platelet aggregation induced by
agonists other than ADP is also inhibited by blocking the amplification of platelet activation by
released ADP.

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.

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 per day, patients with severe renal impairment (creatinine
clearance from 5 to 15 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 per day for 10 days in patients with severe hepatic
impairment, inhibition of ADP-induced platelet aggregation was similar to that observed in
healthy subjects.

Gender

In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation
was observed in women.
Pharmacokinctics

Clopidogrel is a prodrug and is metabolized to a pharmacologically active metabolite and

inactive metabolites.

Absorption

After single and repeated oral doses of 75 mg per day, clopidogrel is rapidly absorbed.
Absorption is at least 50%, based on urinary excretion of clopidogrel metabolites.

Effect of Food

Plavix can be administered with or without food. In a study in healthy male subjects when Plavix
75 mg per day was given with 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 a 57% decrease in active metabolite Cmax. Similar results
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 leading to hydrolysis into an inactive carboxylic acid derivative (85% of circulating
metabolites) and one mediated by multiple cytochrome P450 enzymes. Cytochromes first oxidize
clopidogrel to a 2-oxo-clopidogrel intermediate metabolite. Subsequent metabolism of the 2-oxo-
clopidogrel intermediate metabolite results in formation of 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 of the platelet.

The Cmax of the active metabolite is twice as high following a single 300 mg clopidogrel
loading dose as it is after four days of 75 mg maintenance dose. Cmax occurs approximately 30
to 60 minutes after dosing. In the 75 to 300 mg dose range, the pharmacokinetics of the active
metabolite deviates from dose proportionality: increasing the dose by a factor of four results in
2.0- and 2.7-fold increases in Cmax and AUC, respectively.

Elimination

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% of total

radioactivity was excreted in urine and approximately 46% in feces over the 5 days post-dosing.
After a single, oral dose of 75 mg, clopidogrel has a half-life of approximately 6 hours. The half-
life of the active metabolite is about 30 minutes.

Pharmacogcnomics

CYP2C19 is involved in the formation of both 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 according to CYP2C19 genotype.
Genetic variants of other CYP450 enzymes may also affect the formation of clopidogrel's active
metabolite.

The CYP2C19*1 allele corresponds to fully functional metabolism while the CYP2C19*2 and
*3 alleles are nonfunctional. CYP2C19*2 and *3 account for the majority of reduced function
alleles in white (85%) and Asian (99%) poor metabolizers. Other alleles associated with absent
or reduced metabolism are less frequent, and include, but are not limited to, CYP2C19*4, *5, *6,
*7, and *8. A patient 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 available to
determine a patient's CYP2C19 genotype.

A crossover study in 40 healthy subjects, 10 each in the four CYP2C19 metabolizer groups,
evaluated pharmacokinetic and antiplatelet responses using 300 mg followed by 75 mg per day
and 600 mg followed by 150 mg per day, each for a total of 5 days. Decreased active metabolite
exposure and diminished inhibition of platelet aggregation were observed in the poor
metabolizers as compared to the other groups. When poor metabolizers received the 600 mg/150
mg regimen, active metabolite exposure and antiplatelet response were greater than with the 300
mg/75 mg regimen (see Table 4). An appropriate dose regimen for this patient population has
not been established in clinical outcome trials.