Questions about Atrial Fibrillation? Get answers from our expert.

Clopidogrel (Systemic)


VA CLASSIFICATION
Primary: BL117

Commonly used brand name(s): Plavix.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).



Category:


Antithrombotic—

platelet aggregation inhibitor—

Indications

Accepted

Myocardial infarction (prophylaxis) or
Stroke, thromboembolic (prophylaxis) or
Vascular death (prophylaxis)—Clopidogrel is indicated for reducing the risk of atherosclerotic events (myocardial infarction, stroke, and vascular death) in patients with atherosclerosis documented by recent myocardial infarction, recent stroke, or established peripheral arterial disease {01}.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    419.9 {01}

Solubility
    Practically insoluble in water at neutral pH, but freely soluble at pH 1; freely soluble in methanol, sparingly soluble in methylene chloride, and practically insoluble in ethyl ether {01}.

Mechanism of action/Effect:

Clopidogrel is an inhibitor of platelet aggregation; doses of 75 mg per day inhibit platelet aggregation by 40 to 60% at steady state, which occurs within 3 to 7 days {01}.

Clopidogrel inhibits adenosine diphosphate (ADP) binding to its platelet receptor and subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thus inhibiting platelet aggregation. Because clopidogrel irreversibly modifies the ADP receptor, platelets are affected for the remainder of their lifespan. An active metabolite, not yet isolated, is responsible for the medication's activity. Platelet aggregation induced by agonists other than ADP is also inhibited by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity. {01}

Absorption:

Rapid, at least 50% {01}. Bioavailability has not been found to be affected by food {01}.

Protein binding:

Very high, for clopidogrel and its main circulating metabolite (98% and 94%, respectively) {01}. Binding is nonsaturable in vitro up to a concentration of 100 micrograms per mL {01}.

Biotransformation:

Hepatic, extensive and rapid, by hydrolysis to the main circulating metabolite, a carboxylic acid derivative, which accounts for approximately 85% of the circulating drug-related compounds {01}. A glucuronic acid derivative of the carboxylic acid derivative has also been found in plasma and urine {01}. Neither the parent compound nor the carboxylic acid derivative has a platelet inhibiting effect {01}.

Half-life:


Elimination:

Carboxylic acid derivative: 8 hours (after single and multiple doses) {01}.

Note: Covalent binding to platelets has accounted for 2% of radiolabeled clopidogrel with a half-life of 11 days {01}.



Onset of action:


Dose-dependent inhibition of platelet aggregation:

After a single oral dose: 2 hours {01}.

After repeated doses of 75 mg: On the first day {01}.


Time to peak concentration:

Plasma—Approximately 1 hour for the carboxylic acid derivative {01}.

Peak plasma concentration

Approximately 3 mg per liter (carboxylic acid derivative) after repeated doses of 75 mg {01}. Pharmacokinetics of the main circulating metabolite are linear (increased in proportion to dose) in a dose range of 50 to 150 mg {01}.

Time to peak effect:

Steady-state inhibition of platelet aggregation with repeated doses of 75 mg per day usually occurs between day 3 and day 7 {01}.

Duration of action:

Platelet aggregation and bleeding time gradually return to baseline levels within about 5 days after treatment is withdrawn {01}.

Elimination:
    Renal, approximately 50%, five days after dosing with radiolabeled clopidogrel {01}.
    Fecal, approximately 46%, five days after dosing with radiolabeled clopidogrel {01}

Pharmacogenetics

No significant differences in clopidogrel pharmacokinetics or pharmacodynamics were observed between male and female subjects {01}.

Pharmacokinetic differences in different race populations have not been studied {01}.


Precautions to Consider

Tumorigenicity

Studies in mice and rats for 78 and 104 weeks, respectively, at doses of up to 77 mg per kg of body weight (mg/kg) per day (producing plasma exposures more than 25 times those in humans at the recommended daily dose of 75 mg) found no evidence of tumorigenicity {01}.

Mutagenicity

Clopidogrel was not found to be 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) or in one in vivo test (micronucleus test by oral route in mice) {01}.

Pregnancy/Reproduction
Fertility—
Studies in rats and rabbits at doses of up to 500 and 300 mg/kg per day (65 and 78 times the recommended daily human dose on a mg per square meter of body surface area [mg/m 2] basis), respectively, found no evidence of impaired fertility. Studies in male and female rats at oral doses of up to 400 mg/kg per day (52 times the recommended human dose on a mg/m 2 basis) also found no evidence of impaired fertility. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done {01}.

Studies in rats and rabbits at doses of up to 500 and 300 mg/kg per day (65 and 78 times the recommended daily human dose on a mg/m 2 basis), respectively, found no evidence of fetotoxicity.

Consideration of risk-benefit is recommended before using clopidogrel during pregnancy {01}.

FDA Pregnancy Category B {01}.

Breast-feeding

It is not known whether clopidogrel is distributed into human breast milk. Clopidogrel and/or its metabolites are distributed into the milk of lactating rats. Consideration of risk-benefit is recommended in making decisions about using clopidogrel in breast-feeding women or continuing breast-feeding in women taking clopidogrel. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of clopidogrel have not been performed in the pediatric population. Safety and efficacy have not been established {01}.


Geriatrics


Plasma concentrations of the main circulating metabolite have been found to be significantly higher in elderly individuals (³ 75 years of age) than in young healthy volunteers, but these higher concentrations have not been found to be associated with differences in platelet aggregation and bleeding time. No dosage adjustment is recommended for elderly patients. {01}


Dental

Because of the risk of increased surgical blood loss, it is recommended that clopidogrel be discontinued 7 days prior to elective dental surgery if an antiplatelet effect is not desired {01}.

Surgical

Because of the risk of increased surgical blood loss, it is recommended that clopidogrel be discontinued 7 days prior to elective surgery if an antiplatelet effect is not desired {01}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

» Aspirin or
» Nonsteroidal anti-inflammatory drugs (NSAIDs)    (concurrent use of clopidogrel with these agents may increase the risk of gastrointestinal bleeding {01})

    (aspirin has not been found to modify the clopidogrel-mediated inhibiton of ADP-induced platelet aggregation, nor has it been found to increase the prolongation of bleeding time induced by clopidogrel; however, clopidogrel potentiated the effect of aspirin on collagen-induced platelet aggregation {01})


Fluvastatin or
Nonsteroidal anti-inflammatory drugs (NSAIDs) or
Phenytoin or
Tamoxifen or
Tolbutamide or
Torsemide or
Warfarin    (because clopidogrel inhibits hepatic cytochrome P450 enzyme activity at high concentrations in vitro , a possibility exists that it could interfere with the metabolism of these medications; caution is recommended {01})


Heparin or
Warfarin    (safety of concurrent use has not been established; caution is recommended {01})



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Bilirubin, serum concentrations and
Hepatic enzymes, serum values    (may be increased {01})


Cholesterol, total    (serum concentrations may be increased {01})


Neutrophil count and
Platelet count    (may be decreased {01})


Nonprotein nitrogen (NPN)    (serum concentrations may be increased {01})


Uric acid    (serum concentrations may be increased {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Bleeding, active{01} , such as:
Intracranial hemorrhage{01}
Peptic ulcer{01}    (risk of severe bleeding)


Risk-benefit should be considered when the following medical problems exist
» Any condition in which there is a significant risk of bleeding{01} , such as:
Gastrointestinal ulceration{01}
Surgery{01}
Trauma{01}
Hepatic function impairment    (caution is recommended {01}; experience is limited in patients with severe hepatic function impairment, who may have bleeding diatheses {01})


Sensitivity to clopidogrel{01}


Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent (³ 5%)
    
Chest pain{01} —incidence 8.3%
    
pain, generalized{01} —incidence 6.4%
    
purpura{01} (red or purple spots on skin, varying in size from pinpoint to large bruises)—incidence 5.3%
    
upper respiratory infection{01} (cough; runny nose; sneezing; sore throat)—incidence 8.7%

Incidence less frequent (1 to < 5%)
    
Atrial fibrillation{01}
or palpitations{01} (irregular heartbeat)
    
bronchitis{01} (cough; shortness of breath)—incidence 3.7%
    
dyspnea{01} (shortness of breath)—incidence 4.5%
    
edema{01} (swelling of feet or lower legs)—incidence 4.1%
    
epistaxis{01} (nosebleed)—incidence 2.9%
    
gastrointestinal hemorrhage{01} (vomiting of blood or material that looks like coffee grounds)—incidence 2%
    
gout{01} (joint pain)
    
hypertension{01} —incidence 4.3%
    
syncope{01} (fainting)
    
urinary tract infection{01} (frequent urination; painful or difficult urination)

Note: Incidence of gastrointestinal hemorrhage is increased in patients receiving aspirin {01}. Approximately 0.7% of patients receiving clopidogrel have experienced gastrointestinal hemorrhage severe enough to require hospitalization {01}.


Incidence rare (< 1%)
    
Intracranial hemorrhage{01} (headache, sudden severe; weakness, sudden)—incidence 0.4%
    
neutropenia, including agranulocytosis{01} (fever, chills, sore throat, other signs of infection; ulcers, sores, or white spots in mouth)
    
peptic, gastric, or duodenal ulcer{01} (stomach pain, severe)—incidence 0.7%
    
skin reactions, severe{01} (blistering, flaking, or peeling of skin)—incidence 0.7%
    
thrombocytopenia{01} (unusual bleeding or bruising; black, tarry stools; blood in urine or stools; pinpoint red spots on skin)—usually asymptomatic



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent (³ 5%)
    
Abdominal or stomach pain —incidence 5.6%
    
arthralgia{01} (joint pain)—incidence 6.3%
    
back pain{01} —incidence 5.8%
    
dizziness{01} —incidence 6.2%
    
dyspepsia{01} (heartburn)—incidence 5.2%
    
flu-like symptoms{01} (aching muscles; fever and chills; general feeling of discomfort or illness; headache)—incidence 7.5%
    
headache{01} —incidence 7.6%

Incidence less frequent (< 5%)
    
Anxiety{01}
    
asthenia{01} (weakness)
    
constipation{01}
    
cough —incidence 3.1%
    
diarrhea{01} —incidence 4.5%
    
fatigue{01} (unusual tiredness)—incidence 3.3%
    
hypoesthesia or paresthesia{01} (numbness or tingling)
    
insomnia{01} (trouble in sleeping)
    
itching{01} —incidence 3.3%
    
leg cramps{01}
    
mental depression{01} —incidence 3.6%
    
nausea{01} —incidence 3.4%
    
rhinitis{01} (runny nose)—incidence 4.2%
    
skin rash{01} —incidence 4.2%
    
vomiting{01}





Overdose
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Clinical effects of overdose
No adverse effects have been reported after ingestion of up to fourteen 75-mg tablets; bleeding time after six 75-mg tablets was prolonged by about the same amount as with the usual therapeutic dose of one 75-mg tablet {01}.

The lethal single oral dose in mice and rats was 1500 or 2000 mg per kg of body weight (mg/kg) and in baboons was 3000 mg/kg. Symptoms of acute toxicity included vomiting (in baboons), prostration, difficult breathing, and gastrointestinal hemorrhage in all species. {01}

Treatment of overdose
If quick reversal of pharmacologic effects is required, platelet transfusions may be useful {01}.


Patient Consultation
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to clopidogrel





Dental—Risk of increased blood loss during dental procedures

Surgical
Risk of increased blood loss during surgical procedures
Other medications, especially aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)
Other medical problems, especially bleeding, including bleeding from a stomach ulcer

Proper use of this medication
Compliance with prescribed treatment regimen

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage

Precautions while using this medication
» Need to inform all health care providers of use of medicine

» Caution if any kind of surgery (including dental surgery) is required

» Notifying physician immediately if signs and symptoms of bleeding occur


Side/adverse effects
Signs of potential side effects, especially chest pain, generalized pain, purpura, upper respiratory infection, atrial fibrillation or palpitations, bronchitis, edema, epistaxis, gastrointestinal hemorrhage, gout, hypertension, syncope, urinary tract infection, intracranial hemorrhage, neutropenia, agranulocytosis, gastrointestinal ulcers, severe skin reactions, thrombocytopenia


General Dosing Information
It is recommended that clopidogrel be discontinued 7 days prior to elective surgery because of the risk of increased blood loss {01}.

Diet/Nutrition
Clopidogrel tablets may be taken with or without food {01}.


Oral Dosage Forms

CLOPIDOGREL BISULFATE TABLETS

Note: Strength and dosage are expressed in terms of base {01}.


Usual adult dose
Antithrombotic
Oral, 75 mg (base) once a day {01}.


Usual pediatric dose
Safety and efficacy have not been established {01}.

Usual geriatric dose
See Usual adult dose {01}.

Strength(s) usually available
U.S.—


75 mg (base) (Rx) [Plavix (lactose)]

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), preferably at 25 °C (77 °F) {01}.



Developed: 05/22/98



References
  1. Plavix package insert (Bristol-Myers Squibb/Sanofi—U.S.), Rev 11/97, Rec 2/98.
Hide
(web2)