Clopidogrel (INN) is an oral, thienopyridine-class antiplatelet agent used to inhibit

blood clots in coronary artery disease, peripheral vascular disease, and

cerebrovascular disease. It is marketed by Bristol-Myers Squibb and Sanofi under
the trade name Plavix. The drug works by irreversibly inhibiting a receptor called
P2Y12, an adenosine diphosphate (ADP) chemoreceptor on platelet cell membranes.
Adverse effects include hemorrhage, severe neutropenia, and thrombotic
thrombocytopenic purpura.

Before the expiry of its patent, clopidogrel was the second-most prescribed drug in
the world. In 2010, it grossed over US$9 billion in global sales.[1]

Medical use[edit]
Clopidogrel is used to prevent myocardial infarction (heart attack) and stroke in people who are at
high risk in certain people at elevated risk of these events, including those with unstable
angina, myocardial infarction (heart attack) with or without ST elevation, and those with
established peripheral artery disease, recent heart attack, or ischemic stroke.
Treatment with clopidogrel or a related drug is recommended by the American Heart Association and
the American College of Cardiology for people who

Present for treatment with a heart attack with ST-elevation,[2] including

A loading dose given in advance of percutaneous coronary intervention, followed by a

full year of treatment for those receiving a vascular stent

A loading dose given in advance of fibrinolytic therapy, continued for at least 14 days

Present for treatment of a heart attack or unstable angina without ST-elevation . [3]

Including a loading dose and maintenance therapy in those receiving PCI and unable to
tolerate aspirin therapy

Maintenance therapy for up to 12 months in those at medium to high risk for which a
non-invasive treatment strategy is chosen

In those with stable ischemic heart disease,[4] treatment with clopidogrel is described a a
"reasonable" option for monotherapy in those who cannot tolerate aspirin, as is
treatment with clopidogrel in combination with aspirin in certain high risk patients.

It is also used, along with aspirin (ASA), for the prevention of thrombosis after placement of
an intracoronary stent[5] or as an alternative antiplatelet drug for people intolerant to aspirin. [6]

Clopidogrel's benefit is primarily in those who smoke cigarettes, with only slight benefit in
those who do not.[7]
International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI
and stent,[clarification needed] for clopidogrel in addition to ASA. Consensus-based therapeutic
guidelines also recommend the use of clopidogrel rather than ASA for antiplatelet therapy in
people with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by
ASA can exacerbate this condition. In people with healed ASA-induced ulcers, however,
those receiving ASA plus the proton pump inhibitor esomeprazole had a lower incidence of
recurrent ulcer bleeding than those receiving clopidogrel.[8] However, prophylaxis with proton
pump inhibitors along with clopidogrel following acute coronary syndrome may increase
adverse cardiac outcomes, possibly due to inhibition of CYP2C19, which is required for the
conversion of clopidogrel to its active form.[9][10][11] The European Medicines Agency has
issued a public statement on a possible interaction between clopidogrel and proton pump
inhibitors.[12] However, several cardiologists have voiced concern that the studies on which
these warnings are based have many limitations and that it is not certain whether an
interaction between clopidogrel and proton pump inhibitors is real. [13]

Non-ST elevation myocardial infarction (NSTEMI) [edit]

P2Y12 inhibitors such as clopidogrel or ticagrelor do not change the risk of death when
given to people who have had a non-ST elevation myocardial infarction (NSTEMI). They do
however increase the risk of bleeding and decrease the risk of further cardiovascular
problems. Thus their routine use is of questionable value

Adverse effects[edit]
Serious adverse drug reactions associated with clopidogrel therapy include:

Severe neutropenia (low white blood cells) (incidence: one in 2,000)

Thrombotic thrombocytopenic purpura (incidence: four per million patients treated)[15][16]

Hemorrhage - the annual incidence of hemorrhage may be increased by the

coadministration of aspirin.[17]

Gastrointestinal hemorrhage (incidence: 2.0% annually)

Cerebral hemorrhage (incidence: 0.1 to 0.4% annually)

Use of nonsteroidal anti-inflammatory drugs is discouraged in those taking

clopidogrel due to increased risk of digestive tract hemorrhage

Bleeding in the postoperative period is especially problematic for patients after heart
surgery, where clopidogrel is associated with a more than double the take-back for bleeding
rate, as well as other complications. The take-back for bleeding occurs when chest
tube clogging occurs in the setting of ongoing bleeding in early postoperative period. Often,
if chest tube clogging can be avoided, and the chest tubes drain, the patient can be given
platelets until the platelet defect is corrected and the bleeding ceases. But, if the bleeding
continues, and the chest tubes occlude, then the patient will become hemodynamically
unstable and may require an emergency take-back to the operating room. This affects
outcomes and costs of care.[citation needed]
Most studies researching clopidogrel do not compare patients on clopidogrel to patients

taking placebo; rather, clopidogrel use is compared to aspirin use. Thus, attributing side effects
directly to clopidogrel is difficult. Other side effects may include:

Other gastrointestinal side effects

Upper GI discomfort (27% vs 29% in patients taking aspirin alone)

Gastric or duodenal ulcer, gastritis

Diarrhea (4.5% of patients in the CAPRIE trial) [18]

Rash (6% overall, 0.33% severe)[19]

Respiratory (infrequent)

Upper respiratory infections, rhinitis, shortness of breath, cough

Cardiovascular

chest pain

edema (generalized swelling)

Thrombocytopenia (reduction of platelets, 0.2% severe cases as compared to 0.1%

under aspirin)

Interactions[edit]
Clopidogrel interacts
with: phenytoin (Dilantin), tamoxifen (Nolvadex), tolbutamide (Orinase), torsemide (Demadex), fluvas
tatin (Lescol), a blood thinner such
as warfarin(Coumadin), heparin, ardeparin (Normiflo), dalteparin (Fragmin), danaparoid (Orgaran), e
noxaparin (Lovenox),
or tinzaparin (Innohep), anistreplase (Eminase), dipyridamole(Persantine), streptokinase (Kabikinase
, Streptase), ticlopidine (Ticlid), and urokinase (Abbokinase).

In November 2009, the FDA announced that clopidogrel should be used with caution in patients
using the proton pump inhibitors omeprazole or esomeprazole,[20][21] butpantoprazole appears to be
safe.[22] The newer antiplatelet agent prasugrel has minimal interaction with (es)omeprazole, hence
might be a better antiplatelet agent (if no other contraindications are present) in patients who are on
these proton pump inhibitors.[23]

Pharmacology[edit]
Clopidogrel is a prodrug, which requires CYP2C19 for its activation.[24] It acts on the ADP receptor
on platelet cell membranes. The drug specifically and irreversibly inhibits theP2Y12 subtype of ADP
receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin.
[25]

Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the

onset of action is slow, so a loading dose of either 600 or 300 mg is administered when a rapid effect
is needed.[26]

Pharmacokinetics and metabolism[edit]

Clopidogrel (top left) being activated: The first step is an oxidation mediated (mainly) by CYP2C19, unlike the
activation of the related drug prasugrel. The two structures at the bottom are tautomers of each other; and the final
step is a hydrolysis. The active metabolite (top right) hasZ configuration at the double bond C3C16 and
possiblyR configuration at the newly asymmetric C4.[27]

After repeated oral doses of 75 mg of clopidogrel (base), plasma concentrations of the parent
compound, which has no platelet-inhibiting effect, are very low and, in general, are below the
quantification limit (0.258 g/l) beyond two hours after dosing.[citation needed]
Clopidogrel is activated in the liver by cytochrome P450 enzymes, including CYP2C19. Due to
opening of the thiophene ring, the chemical structure of the active metabolite has three sites that are
stereochemically relevant, making a total of eight possible isomers. These are: a stereocentre at C4
(attached to the SH thiol group), a double bond at C3C16, and the original stereocentre at C7.
Only one of the eight structures is an active antiplatelet drug. This has the following
configuration: Z configuration at the C3C16 double bond, the original S configuration at C7,[27] and,

although the stereocentre at C4 cannot be directly determined, as the thiol group is too reactive,
work with the active metabolite of the related drug prasugrel suggests the R-configuration of the C4
group is critical for P2Y12 and platelet-inhibitory activity.[citation needed]
The active metabolite has an elimination half-life of about 0.5 to 1.0 h, and acts by forming a
disulfide bridge with the platelet ADP receptor. Patients with a variant allele of CYP2C19 are 1.5 to
3.5 times more likely to die or have complications than patients with the high-functioning allele. [28][29][30]
Following an oral dose of 14C-labeled clopidogrel in humans, about 50% was excreted in the urine
and 46% in the feces in the five days after dosing.

Effect of food: Administration of clopidogrel bisulfate with meals did not significantly modify
the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating
metabolite.

Absorption and distribution: Clopidogrel is rapidly absorbed after oral administration of

repeated doses of 75-milligram clopidogrel (base), with peak plasma levels (about 3 mg/l) of the
main circulating metabolite occurring around one 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 not saturable in vitro up to a concentration of 110 g/ml.

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.

In March 2010, the U.S. FDA added a boxed warning to Plavix alerting that the drug can be less
effective in people unable to metabolize the drug to convert it to its active form. [31][32]

Pharmacogenetics[edit]
CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many
clinically useful drugs, including antidepressants, barbiturates, proton pump inhibitors, and
antimalarial and antitumor drugs. Clopidogrel is one of the drugs metabolized by this enzyme.
Several recent landmark studies have proven the importance of 2C19 genotyping in treatment using
clopidogrel. In March 2010, the FDA put a black box warning on Plavix to make patients and
healthcare providers aware that CYP2C19-poor metabolizers, representing up to 14% of patients,
are at high risk of treatment failure and that testing is available.[31] Patients with variants in

cytochrome P-450 2C19 (CYP2C19) have lower levels of the active metabolite of clopidogrel, less
inhibition of platelets, and a 3.58-times greater risk for major adverse cardiovascular events such as
death, heart attack, and stroke; the risk was greatest in CYP2C19 poor metabolizers

Dosage forms[edit]
Clopidogrel is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly
under the trade name Plavix, as 75- and 300-mg oral tablets.

Platelet-aggregation inhibitor; thienopyridine P2Y12 platelet adenosine diphosphate

(ADP)-receptor antagonist.1

Uses for Plavix

Cardiovascular Risk Reduction Following Recent MI or Stroke or in Established

Peripheral Arterial Disease

Reduction of the risk of cardiovascular or cerebrovascular events (new MI, new ischemic stroke, and
vascular death) in patients with a history of recent MI, recent ischemic stroke, or established
peripheral arterial disease.1 2 6 8 23 1009 1010 1011
The American College of Chest Physicians (ACCP) recommends long-term antiplatelet therapy with
either aspirin or clopidogrel in patients with established CAD. 1010 Because of cost considerations,
clopidogrel generally recommended as an alternative to aspirin in those with aspirin intolerance or
contraindications (e.g., allergy).5 6 20 23 992
ACCP, the American Stroke Association (ASA), and AHA consider clopidogrel an acceptable
antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or TIAs; other
options include aspirin monotherapy, cilostazol, or the combination of aspirin and extended-release
dipyridamole.9901009
Oral anticoagulation (e.g., warfarin, dabigatran) rather than antiplatelet therapy is recommended in
patients with a history of ischemic stroke or TIA and concurrent atrial fibrillation; however, in patients
who cannot take or choose not to take oral anticoagulants (e.g., those with difficulty maintaining
stable INRs, compliance issues, dietary restrictions, cost limitations), dual antiplatelet therapy with
clopidogrel and aspirin is recommended.1009

Recommended by ACCP as an acceptable antiplatelet therapy for secondary prevention of

cardiovascular events in patients with symptomatic peripheral arterial disease, including those with
intermittent claudication and those undergoing revascularization procedures (peripheral artery
percutaneous transluminal angioplasty or peripheral artery bypass graft surgery). 1011
Recommended by ACCP as an option for long-term antiplatelet therapy in patients with symptomatic
carotid stenosis, including those who have undergone recent carotid endarterectomy.1011

Unstable Angina or Non-ST-Segment Elevation MI (NSTEMI)

Used in combination with aspirin for reduction of the risk of cardiovascular or cerebrovascular events
in patients with non-ST-segment elevation ACS, including unstable angina and
NSTEMI.1 5 18 35 992 993 994 1010 Used in patients who are managed medically or with coronary intervention
(e.g., PCI with or without coronary artery stenting, CABG).1 5 18 35 992 993 9941010
Dual-drug antiplatelet therapy with a P2Y12-receptor antagonist and aspirin is considered part of the
current standard of care in patients with ACS.991 992 993 994 1010 The American College of Cardiology
Foundation (ACCF), AHA, and other experts recommend antiplatelet therapy with a P2Y12-receptor
antagonist (clopidogrel, prasugrel, or ticagrelor) in conjunction with aspirin for treatment and
secondary prevention in patients with ACS, including those undergoing PCI. 991 992993 994 1010
Ticagrelor or clopidogrel generally is recommended in patients treated medically without stent
placement; ticagrelor, clopidogrel, or prasugrel is recommended in patients undergoing PCI with
stent placement (bare-metal or drug-eluting).992 993 994 1010
Experts generally recommend continuing treatment with a P2Y12-receptor antagonist for up to 12
months in patients managed medically without stenting and 12 months in those with coronary artery
stents (bare-metal or drug-eluting); continue aspirin therapy indefinitely. 992 993 9941010
ACCP suggests use of ticagrelor over clopidogrel in patients with ACS, regardless of whether PCI is
performed; other expert guidelines make no specific recommendations regarding P2Y12-receptor
antagonist of choice.992 993 994 1010 When selecting an appropriate antiplatelet regimen, consider individual
patient (e.g., ischemic and bleeding risk) and drug-related (e.g., adverse effects, drug interaction
potential) factors.140 141
Efficacy of pretreatment with clopidogrel prior to diagnostic cardiac catheterization is controversial;
balance potential benefit of pretreatment against increased risk of bleeding should emergency CABG
be needed.35 994
Temporarily discontinue therapy 5 days prior to CABG.1 35 40 1004

ST-Segment Elevation MI (STEMI)

Used in combination with aspirin for reduction of the rate of ischemic cardiovascular and
cerebrovascular events in patients with STEMI.1 31 36 134
Experts recommend treatment for 1428 days in addition to aspirin, with or without reperfusion
therapy (i.e., thrombolytic therapy, primary PCI), in patients with suspected STEMI.68
In patients in whom CABG is planned, withhold clopidogrel for 5 days prior to surgery. 1004
In patients with STEMI in whom PCI is planned, experts recommend a loading dose of a P2Y12receptor antagonist (e.g., clopidogrel, prasugrel, ticagrelor) before or at the time of PCI in conjunction
with aspirin therapy.994
Continue therapy for 12 months after stent implantation (bare-metal or drug-eluting), unless risk of
bleeding outweighs anticipated net benefit; continue aspirin therapy indefinitely. 992 993 994(See Risks of
Premature Discontinuance of Therapy under Cautions.)
The addition of warfarin to antiplatelet therapy is recommended in STEMI patients who have
indications for anticoagulation (e.g., atrial fibrillation, left ventricular dysfunction, cerebral emboli,
extensive wall-motion abnormality, mechanical heart valves).993 1007 1010
Triple antithrombotic therapy with clopidogrel, low-dose aspirin, and warfarin (target INR 23) is
suggested by ACCP in patients with anterior MI and left ventricular thrombus (or at high risk for such
thrombi) undergoing stent implantation; recommended duration of triple antithrombotic therapy is
dependent on whether patient has a bare-metal or drug-eluting stent. 1010
Suggested by the American Diabetes Association (ADA) as alternative to aspirin for primary
prevention of MI in aspirin-allergic patients with type 1 or type 2 diabetes mellitus who are at high
risk for cardiovascular events (i.e., family history of CHD, smoking, hypertension, obesity,
albuminuria, elevated blood cholesterol or triglyceride concentrations). 95

Chronic Stable Angina

May be used as an alternative to aspirin in patients with symptomatic chronic stable angina who
cannot tolerate aspirin.96

Embolism Associated with Atrial Fibrillation and/or Valvular Heart

Disease
Has been used in combination with aspirin as an alternative to warfarin for prevention of stroke and
systemic embolism in patients with atrial fibrillation.995 997 1007

In patients with atrial fibrillation at increased risk of stroke who cannot or choose not to take oral
anticoagulants for reasons other than concerns about major bleeding (e.g., those with difficulty
maintaining stable INRs, compliance issues, dietary restrictions, cost limitations), combination
therapy with clopidogrel and aspirin rather than aspirin alone is recommended. 998 1007
In patients with atrial fibrillation and mitral stenosis who cannot or choose not to take warfarin
therapy for reasons other than concerns about major bleeding, ACCP recommends combination
therapy with clopidogrel and aspirin rather than aspirin alone. 1007

Plavix Dosage and Administration

General
Timing of Treatment in Relation to PCI or CABG

In patients with ACS in whom PCI is planned, experts recommend administration of a loading
dose of clopidogrel as early as possible before or at the time of the procedure. 134 994

Temporarily discontinue therapy 5 days prior to CABG and resume as soon as possible
after procedure.1 35 40 134 1004

Administration
Administer orally without regard to meals.1 6 8

Dosage
Available as clopidogrel bisulfate; dosage expressed in terms of clopidogrel. 1
Pharmacogenomic factors can influence response to clopidogrel; although a higher dosage or
administration of additional loading doses may increase the antiplatelet response in patients who are
poor metabolizers, manufacturer states that an appropriate dosage of the drug in such patients has
not been determined.1 121 123 130 (See Reduced Efficacy Associated with Impaired CYP2C19 Function
under Cautions.)

Adults
Cardiovascular Risk Reduction Following Recent MI or Stroke or in
Established Peripheral Arterial Disease
Oral
75 mg once daily.1 2 3 5 6 8 23

Acute Coronary Syndromes

Unstable Angina or NSTEMI
Oral
Manufacturer recommends 300-mg initial loading dose promptly at diagnosis, then 75 mg once daily
given concomitantly with aspirin.1 18 20 22
Patients undergoing PCI: Some experts suggest a 600-mg loading dose, administered as early as
possible prior to or at time of the procedure, then 75 mg once daily. 146 993 994 No apparent benefit with
higher loading doses (e.g., 900 mg).147 994
Manufacturer states that optimal duration of therapy unknown;1 other experts recommend
administering clopidogrel for up to 12 months in patients being managed medically and for 12
months in those undergoing PCI with coronary artery stent placement; continue aspirin
indefinitely.992 993 994 1010
In patients receiving a bare-metal stent for a non-ACS indication, administer clopidogrel for up to 12
months unless patient has an increased risk of bleeding; in this situation, give clopidogrel with aspirin
for a minimum of 2 weeks.994

STEMI
Oral
Manufacturer recommends 75 mg once daily with or without a loading dose in combination with
aspirin.1
Patients undergoing PCI: Some experts recommend a 600-mg loading dose, administered as early
as possible prior to or at time of the procedure, then 75 mg once daily. 146 994 No apparent benefit with
higher loading doses (e.g., 900 mg).147 994

Manufacturer states that optimal duration of therapy unknown.1 Some experts generally recommend
dual antiplatelet therapy (e.g., clopidogrel and aspirin) for 12 months following ACS, and possibly
longer in those undergoing PCI with stent placement.992 994 1010

Special Populations
Hepatic Impairment
No dosage adjustment necessary.1

Geriatric Patients

Cautions for Plavix

Contraindications

Active pathological bleeding (e.g., peptic ulcer, intracranial hemorrhage). 1 6

Known hypersensitivity to clopidogrel or any ingredient in the formulation. 1

Warnings/Precautions
Warnings
Risks of Premature Discontinuance of Therapy
In general, because of the increased risk of cardiovascular events, do not prematurely discontinue
treatment with a thienopyridine derivative (e.g., clopidogrel). 1 45 Stent thrombosis with potentially fatal
sequelae, particularly with drug-eluting stents (DES), associated with premature discontinuance of
therapy with a thienopyridine derivative and aspirin.43 44 45 46 47 48 49 54 (See Unstable Angina or Non-STSegment Elevation MI [NSTEMI] under Uses.)
Before implantation of a DES, carefully assess patients for likelihood of compliance with prolonged
dual-drug antiplatelet therapy.45 59 1004 Consider avoiding use of a DES in patients who are not expected
to comply.45 59 (See Advice to Patients.) In patients who are likely to require invasive or surgical
procedures 12 months after DES implantation, consider implantation of a bare-metal stent or use of
balloon angioplasty with provisional stent implantation instead.45 1004
Advise patients to never stop taking dual-drug antiplatelet therapy without first consulting with their
cardiologist, even if instructed to do so by another health-care professional. 1 45

Clinicians performing invasive procedures must understand the consequences of premature

discontinuance of thienopyridine derivative therapy in patients with DES.45 If issues about a patients
antiplatelet therapy are unclear (e.g., concern about periprocedural bleeding), such professionals
should contact the patients cardiologist.45 Defer elective procedures with substantial bleeding risk
until completion of dual-drug antiplatelet therapy.45 If an invasive procedure is required, temporarily
discontinue clopidogrel 5 days prior to the procedure.1 For non-elective procedures that mandate
discontinuance of thienopyridine-derivative therapy, continue aspirin therapy if at all
possible.45 Restart clopidogrel therapy as soon as possible after the procedure.1 45

Reduced Efficacy Associated with Impaired CYP2C19 Function

Possible reduced efficacy of clopidogrel (i.e., increased risk of cardiovascular events) due to genetic
polymorphism of CYP2C19 or concurrent use of drugs (e.g., omeprazole, esomeprazole) that inhibit
CYP2C19.1 72 76 78 79 80 81 82 83 84 85 86 100 101 121 350 351 352 356 Consider use of other antiplatelet agents (e.g., prasugrel,
ticagrelor) or alternative dosing strategies for clopidogrel in patients identified as potential poor
metabolizers of CYP2C19.1 121 123 140 143 (See Boxed Warning.)
Specific variant alleles of CYP2C19 (e.g., CYP2C19*2, CYP2C19*3) associated with reduced
metabolism of and diminished antiplatelet response to clopidogrel; data on clinical outcomes are
conflicting, but higher rates of major adverse cardiovascular events (e.g., death, MI, stroke, stent
thrombosis) reported in patients receiving recommended dosages of clopidogrel who possess such
alleles.1 76 78 79 80 82 83 88 89 90 92 104 117 118 121 (See Actions.)
Genetic tests are available to identify patients with variant CYP2C19 genotypes.1 20 121 122 143 145While such
tests are appropriate for any patient currently receiving or considering treatment with clopidogrel, the
need for pharmacogenetic testing should be determined individually. 121 122 123 143Genetic variants of other
CYP isoenzymes (e.g., CYP2C19*17, CYP2B6) also may affect response to clopidogrel. 1 78 123 131
Concurrent use of clopidogrel with omeprazole or esomeprazole (potent CYP2C19 inhibitors) also
shown to reduce antiplatelet effects of clopidogrel.1 72 79 84 88 89 98 100 101 102 103 109 350 351 352 (See Proton-Pump
Inhibitors under Interactions.) Clinical importance not fully elucidated, but reduced effectiveness in
preventing cardiovascular events possible.1 73 74 81 89 91 92 98 100 101 102 103 115Concomitant use of other drugs that
inhibit CYP2C19 also may decrease response to clopidogrel. 1 100 101 (See Drugs Affecting or
Metabolized by Hepatic Microsomal Enzymes under Interactions.) Avoid concomitant therapy with
known inhibitors of CYP2C19 activity.1 20 101

Thrombotic Thrombocytopenic Purpura (TTP)

Rarely reported, sometimes after short exposure (<2 weeks) to the drug. 1 11 12 Potentially fatal;
requires urgent treatment, including plasmapheresis.1

General Precautions
Bleeding
Increased risk of bleeding.1 136 138
Temporarily discontinue clopidogrel 5 days prior to elective surgery (e.g., CABG) if antiplatelet
effect is undesirable.1 23 35 43 68 1004
May restore hemostasis with exogenous administration of platelets; however, platelet transfusions
within 4 hours of a loading dose or within 2 hours of a maintenance dose may have reduced
effectiveness.1
Bleeding is unlikely to be resolved or prevented by withholding a dose of clopidogrel because of the
drugs prolonged inhibitory effects on platelet function. 1
American College of Cardiology Foundation/American College of Gastroenterology/American Heart
Association (ACCF/ACG/AHA) recommends prophylactic proton-pump inhibitor therapy to reduce
risk of ulcer complications and GI bleeding in patients with additional GI risk factors receiving
clopidogrel and aspirin.81 87 89 136 However, consider possibility of reduced antiplatelet effects when
clopidogrel is used concomitantly with certain proton-pump inhibitors (e.g., omeprazole,
esomeprazole).1 76 100 101 350 351 352 356 (See Proton-Pump Inhibitors under Interactions.)

Specific Populations
Pregnancy
Category B.1

Lactation
Distributed into milk in rats; not known whether distributed into human milk.1 Discontinue nursing or
the drug.1

Pediatric Use
Manufacturer states that safety and efficacy not established in patients <21 years of age. 1 20
In neonates and infants up to 24 months of age with systemic to pulmonary artery shunts or other
cardiac conditions predisposing to thrombosis, clopidogrel 0.2 mg/kg daily for 14 weeks achieved

similar inhibition of platelet aggregation as a 75-mg daily dosage in adults; no serious hemorrhagic
events reported.97

Geriatric Use
In patients 75 years of age, no difference in platelet aggregation observed compared with younger
healthy individuals.1 In a clinical trial, geriatric patients were at greater risk for thrombotic events and
major bleeding than younger patients.1

Hepatic Impairment
Inhibition of ADP-induced platelet aggregation in patients with severe hepatic impairment appears to
be similar to that observed in healthy individuals.1

Renal Impairment
Experience limited in patients with moderate or severe renal impairment. 1
Inhibition of ADP-induced platelet aggregation is decreased in patients with moderate (Cl cr 3060
mL/minute) or severe (Clcr 515 mL/minute) renal impairment.1

Common Adverse Effects

Chest pain,1 6 accidental injury,1 6 influenza-like
symptoms,1 6 pain,1 6 headache,1 6 dizziness,1 6abdominal
pain,1 6 8 dyspepsia,1 2 3 6 8 diarrhea,1 2 3 6 8 11 nausea,1 2 3 6 arthralgia,1 6 back pain,1 6purpura,1 6 upper
respiratory tract infection,1 6 rash,1 2 3 6 8 11 pruritus.1 6

Interactions for Plavix

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Appears to inhibit CYP2C9 isoenzyme in vitro at high concentrations.1 8 20
Converted to active metabolite by CYP2C19.1 72 78 80 81 82 83 (See Metabolism under Pharmacokinetics.)
Potential pharmacokinetic (decreased concentrations of active metabolite) and pharmacodynamic
(reduced antiplatelet effects) interaction with inhibitors of CYP2C19.1 72 7681 88 89 Avoid concomitant use
of drugs known to be potent inhibitors of CYP2C19.1 20 101 352 356

Proton-Pump Inhibitors

Potential for reduced systemic exposure to clopidogrels active metabolite and reduced antiplatelet
effects with certain proton-pump inhibitors (e.g., omeprazole, esomeprazole) (via inhibition of
CYP2C19 by proton-pump inhibitor).1 20 72 73 74 79 84 86 88 89 91 100 101 102 103 106 107 109 350 351 352 356(See Reduced Efficacy
Associated with Impaired CYP2C19 Function under Cautions and see Drugs Affecting or
Metabolized by Hepatic Microsomal Enzymes under Interactions.) Conflicting data on clinical
outcomes reported, but increased risk of adverse cardiovascular events
possible.1 72 73 74 81 91 98 102 103 104 105 107 108 110 111 112 113 115 119
If concomitant proton-pump inhibitor therapy is considered necessary, consider using an agent with
little or no CYP2C19-inhibitory activity.81 89 92 102 103 109 111 112 114 350 352 (See Specific Drugs under Interactions.) In
healthy individuals, dexlansoprazole, lansoprazole, or pantoprazole had less effect on clopidogrel's
antiplatelet activity than did omeprazole or esomeprazole; of these proton-pump inhibitors,
dexlansoprazole appeared to have the least potential to interact with clopidogrel. 350 351 352
Weigh risks and benefits of concomitant use of any proton-pump inhibitor in individual
patients.102103 112 119 ACCF/ACG/AHA states that use of a proton-pump inhibitor concomitantly with dual
antiplatelet therapy may provide the optimal balance of risk and benefit in patients with ACS who
have a history of upper GI bleeding.136 Risk/benefit tradeoff may favor concomitant use of dual
antiplatelet therapy and a proton-pump inhibitor in stable patients with a history of GI bleeding who
undergo coronary revascularization and receive a coronary stent. 136 ACCF/ACG/AHA states that the
risk reduction with proton-pump inhibitors is substantial in patients with risk factors for GI bleeding
(e.g., advanced age; concomitant use of warfarin, corticosteroids, or NSAIAs; H. pyloriinfection) and
may outweigh potential reduction in cardiovascular efficacy of antiplatelet treatment associated with a
drugdrug interaction.136 In patients without such risk factors for GI bleeding, risk/benefit balance may
favor use of antiplatelet therapy without a concomitant proton-pump inhibitor. 136 Alternatively, consider
concomitant therapy with antacids or H2-receptor antagonists (i.e., ranitidine, famotidine, nizatidine),
except for cimetidine (also a potent CYP2C19 inhibitor).1 81 89 92 100 103 112

Plavix Pharmacokinetics
Absorption
Bioavailability
Rapidly absorbed after oral administration;1 50% of an oral dose is absorbed.1 Peak plasma
concentrations of the active metabolite occur approximately 3060 minutes following an oral dose. 1

Onset
Following oral administration of a single dose, dose-dependent platelet aggregation inhibition can be
observed in 2 hours.1

Repeated dosage (75 mg daily) causes inhibition of ADP-induced platelet aggregation on the first
day, and steady-state inhibition (4060%) occurs in 37 days.1 2 6

Duration
After discontinuance, platelet aggregation and bleeding times gradually return to baseline in about 5
days.1 2 6

Food
In healthy men, administration with a high-fat or standard meal decreased mean inhibition of platelet
aggregation by <9%.1 Although food decreased peak plasma concentrations of the active metabolite
by 57%, systemic exposure to the active metabolite was unaffected. 1

Special Populations
Peak plasma concentrations and exposure to clopidogrels active metabolite decreased by 3050%
in patients with genetically reduced CYP2C19 function.1 (See Reduced Efficacy Associated with
Impaired CYP2C19 Function under Cautions).

Elimination
Metabolism
Extensively metabolized via 2-step pathway: 1) esterase-mediated hydrolysis to inactive carboxylic
acid derivative 2) formation of active thiol metabolite mediated by CYP isoenzymes (e.g., 2C19, 3A4,
2B6, 1A2).1

Elimination Route
Excreted in urine (50%) and in feces (46%).1

Half-life
Clopidogrel: Approximately 6 hours following single oral dose of 75 mg. 1 1
Active metabolite: 30 minutes.1

Stability

Storage
Oral
Tablets
25C (may be exposed to 1530 C).1

Actions

Prodrug; platelet-aggregation inhibitory activity is dependent on hepatic transformation to an

active metabolite.1 2 6 8 11 72 78 80 81 82 83 Metabolism influenced by CYP2C19
polymorphism.1 78 7980 82 83 Patients with one or more variant CYP2C19 alleles (e.g., CYP2C19*2,
CYP2C19*3) are described as poor or intermediate metabolizers; lower concentrations of active
metabolite, diminished antiplatelet effects, and higher incidence of major adverse cardiovascular
events observed in such patients receiving clopidogrel. 1 78 79 80 81 82 83 90 117 118 Approximately 214% of
the population is estimated to be poor metabolizers of CYP2C19; however, there is wide
variability among different racial/ethnic populations.121 (See Reduced Efficacy Associated with
Impaired CYP2C19 Function under Cautions.)

Active metabolite binds selectively and noncompetitively to platelet surface low-affinity

platelet P2Y12 ADP-receptor binding site.1 2 4 6 11 Inhibits ADP binding to the receptor and
subsequent receptor activation of the platelet glycoprotein (GP IIb/IIIa) complex necessary for
fibrinogen-platelet binding.1 2 4

ADP receptor is irreversibly modified, so platelets exposed to clopidogrel remain affected for
the remainder of their lifespan (about 710 days).1 2 4 6 62

Also inhibits ADP-mediated release of platelet dense granule (e.g., ADP, calcium, serotonin)
and alpha granule (e.g., fibrinogen, thrombospondin) contents that augment platelet
aggregation.1 6

Advice to Patients

Importance of counseling patients about potential risks versus benefits of clopidogrel. 1

Importance of informing patients that they may bleed more easily and that a longer than
normal time will be required to stop bleeding when taking clopidogrel. 1

Before implantation of drug-eluting stent (DES), determine likelihood of patient compliance

with 12 months of aspirinclopidogrel combination therapy.45

Importance of informing patients prior to hospital discharge about risks associated with
premature discontinuance of such combination therapy.45 Importance of informing patient not to
discontinue therapy without consulting their prescribing clinician, even if instructed to do so by
another health-care professional (e.g., dentist).1 45

Importance of patient informing clinician about any unanticipated, prolonged, or excessive

bleeding, or blood in urine or stool.1 6

Importance of patient informing clinician about clopidogrel therapy before any surgery is
scheduled.1 6 Prior to scheduling an invasive procedure, patients should inform their clinicians
(including dentists) that they are currently taking clopidogrel; clinicians performing the invasive
procedure should consult with the prescribing clinician before discontinuing clopidogrel therapy. 1

Importance of patient informing clinician of existing or contemplated concomitant therapy,

including prescription and OTC drugs, particularly omeprazole (including Prilosec OTC) or
esomeprazole and drugs that affect bleeding (e.g., warfarin, NSAIAs). 1 76 100 101 102 114 352

Importance of women informing clinicians if they are or plan to become pregnant or plan to
breast-feed.1

Importance of informing patients of other important precautionary information. 1 (See

Cautions.)

Preparations
Excipients in commercially available drug preparations may have clinically important effects in some
individuals; consult specific product labeling for details.

Clopidogrel Bisulfate

Routes Dosage

Strengths

Forms

Oral

Tablets

Brand

Manufacturer

Names

75 mg (of

Plavix

clopidogrel)

300 mg (of
clopidogrel)

Sanofi-Aventis (also promoted by

Bristol-Myers Squibb)

Plavix

Sanofi-Aventis (also promoted by

Bristol-Myers Squibb)