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|genericName=Clopidogrel
|genericName=Clopidogrel
|aOrAn=a
|aOrAn=a
|drugClass=Platelet Aggregation Inhibitor and P2Y12 Platelet Inhibitor
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|indication=[[acute coronary syndrome]] ([[ACS]]), recent [[MI]], recent [[stroke]], or established [[peripheral arterial disease]]
|hasBlackBoxWarning=Yes
|hasBlackBoxWarning=Yes
Line 172: Line 171:
* SSRIs and SNRIs
* SSRIs and SNRIs
:* Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
:* Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.
|FDAPregCat=B
|useInPregnancyFDA=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, clopidogrel should be used during pregnancy only if clearly needed.
|useInNursing=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.
|useInPed=Safety and effectiveness in pediatric populations have not been established.
Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.
|useInGeri=Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older.
The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.
|useInRenalImpair=Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].
|useInHepaticImpair=No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
|alcohol=Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
}}
}}

Revision as of 02:51, 7 May 2014

Clopidogrel
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2],Sheng Shi, M.D. [3]

Disclaimer

WikiDoc MAKES NO GUARANTEE OF VALIDITY. WikiDoc is not a professional health care provider, nor is it a suitable replacement for a licensed healthcare provider. WikiDoc is intended to be an educational tool, not a tool for any form of healthcare delivery. The educational content on WikiDoc drug pages is based upon the FDA package insert, National Library of Medicine content and practice guidelines / consensus statements. WikiDoc does not promote the administration of any medication or device that is not consistent with its labeling. Please read our full disclaimer here.

Black Box Warning

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
See full prescribing information for complete Boxed Warning.
* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
  • Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
  • Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
  • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)

Overview

Clopidogrel is a {{{drugClass}}} that is FDA approved for the {{{indicationType}}} of acute coronary syndrome (ACS), recent MI, recent stroke, or established peripheral arterial disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include non-major bleeding.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Acute Coronary Syndrome

  • For patients with non-ST-elevation ACS
  • Initial loading dosage: 300 mg PO
  • Maitaining dosage: 75 mg PO qd
  • In combination with: Aspirin 75-300 mg PO qd
  • For patients with STEMI
  • Recommended dosage: 75 mg PO qd (With or without the loading dosage)
  • In combination with: Aspirin 75-300 mg PO qd

Recent MI, Recent Stroke, or Established Peripheral Arterial Disease

  • Dosing information
  • 75 mg PO qd

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

Prophylaxis of Thrombosis in PCI treated patients

  • Dosing Information

Non–Guideline-Supported Use

Prophylaxis of ThrombosisAtrial in patient with Atrial Fibrillation

  • Dosing Information

Prophylaxis of Thrombosis in patient with Chronical Heart failure

  • Dosing information

Stasis ulcer

  • Dosing information
  • Recommended dosage: 75 mg/day for 2-4 weeks[3]

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Condition 1

  • Dosing Information
(Dosage)

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

Condition 1

  • Developed by: (Organization)
  • Class of Recommendation: (Class) (Link)
  • Strength of Evidence: (Category A/B/C) (Link)
  • Dosing Information/Recommendation
  • (Dosage)

Non–Guideline-Supported Use

Prophylaxis of Arterial thrombosis

  • Dosing Information
  • Recommended dosage: 0.2 mg/kg/day[4]

Contraindications

  • Active Bleeding
  • Clopidogrel tablets are contraindicated in patients with hypersensitivity (e.g., anaphylaxis) to clopidogrel or any component of the product [see Adverse Reactions (6.2)].

Warnings

WARNING: DIMINISHED EFFECTIVENESS IN POOR METABOLIZERS
See full prescribing information for complete Boxed Warning.
* Effectiveness of clopidogrel depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. (5.1)
  • Poor metabolizers treated with clopidogrel at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. (12.5)
  • Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy. (12.5)
  • Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers. (2.3, 5.1)
  • Diminished Antiplatelet Activity Due to Impaired CYP2C19 Function
  • Clopidogrel is a prodrug. Inhibition of platelet aggregation by clopidogrel is achieved through 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.

Proton Pump Inhibitors

Avoid concomitant use of clopidogrel with omeprazole or esomeprazole because both significantly reduce the antiplatelet activity of clopidogrel [see Drug Interactions (7.1) andDosage and Administration (2.4)].

  • General Risk of Bleeding
  • Thienopyridines, including clopidogrel, increase the risk of bleeding. If a patient is to undergo surgery and an antiplatelet effect is not desired, discontinue clopidogrel 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% clopidogrel + aspirin; 5.3% placebo + aspirin). In patients who remained on therapy within five days of CABG, the major bleeding rate was 9.6% for clopidogrel + aspirin, and 6.3% for placebo + aspirin.
  • Thienopyridines inhibit platelet aggregation for the lifetime of the platelet (7 to 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 Clopidogrel
  • Avoid lapses in therapy, and if clopidogrel must be temporarily discontinued, restart as soon as possible. Premature discontinuation of clopidogrel may increase the risk of cardiovascular events.
  • In patients with recent TIA or stroke who are at high risk for recurrent ischemic events, the combination of aspirin and clopidogrel has not been shown to be more effective than clopidogrel alone, but the combination has been shown to increase major bleeding.
  • TTP, sometimes fatal, has been reported following use of clopidogrel, 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 (6.2)].

Adverse Reactions

Clinical Trials 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. Clopidogrel bisulfate 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 clopidogrel plus aspirin to placebo plus aspirin and trials comparing clopidogrel bisulfate alone to aspirin alone are discussed below.

Bleeding

  • CURE
  • In CURE, clopidogrel bisulfate 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.

The overall incidence of bleeding is described in Table 1. Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

  • COMMIT
  • In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin (see Table 2).
  • Ninety-two percent (92%) of the patients in the CURE study received heparin or low molecular weight heparin (LMWH), and the rate of bleeding in these patients was similar to the overall results.

COMMIT In COMMIT, similar rates of major bleeding were observed in the clopidogrel bisulfate and placebo groups, both of which also received aspirin (see Table 2).

  • CAPRIE (Clopidogrel bisulfate vs. Aspirin)
  • In CAPRIE, gastrointestinal hemorrhage occurred at a rate of 2.0% in those taking clopidogrel bisulfate vs. 2.7% in those taking aspirin; bleeding requiring hospitalization occurred in 0.7% and 1.1%, respectively. The incidence of intracranial hemorrhage was 0.4% for clopidogrel bisulfate compared to 0.5% for aspirin.

Other bleeding events that were reported more frequently in the clopidogrel bisulfate group were epistaxis and hematoma.

  • Other Adverse Events
  • In CURE and CHARISMA, which compared clopidogrel bisulfate plus aspirin to aspirin alone, there was no difference in the rate of adverse events (other than bleeding) between clopidogrel bisulfate and placebo.
  • In CAPRIE, which compared clopidogrel bisulfate to aspirin, pruritus was more frequently reported in those taking clopidogrel bisulfate. No other difference in the rate of adverse events (other than bleeding) was reported.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of clopidogrel. Because these reactions are reported voluntarily from a population of an unknown size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and lymphatic system disorders: Agranulocytosis, aplastic anemia/pancytopenia, thrombotic thrombocytopenic purpura (TTP), acquired hemophilia A

Drug Interactions

  • CYP2C19 Inhibitors
  • Clopidogrel is metabolized to its active metabolite in part by CYP2C19. Concomitant use of certain 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 (5.1) and Dosage and Administration (2.4)].

Proton Pump Inhibitors (PPI) Avoid concomitant use of clopidogrel with omeprazole or esomeprazole. In clinical studies, omeprazole was shown to reduce the antiplatelet activity of clopidogrel when given concomitantly or 12 hours apart. A higher dose regimen of clopidogrel concomitantly administered with omeprazole increases antiplatelet response; an appropriate dose regimen has not been established. A similar reduction in antiplatelet activity was observed with esomeprazole when given concomitantly with clopidogrel. Consider using another acid-reducing agent with minimal or no CYP2C19 inhibitory effect on the formation of clopidogrel active metabolite. Dexlansoprazole, lansoprazole and pantoprazole had less effect on the antiplatelet activity of clopidogrel than did omeprazole or esomeprazole [see Dosage and Administration (2.4), WarningsandPrecautions (5.1) and Clinical Pharmacology (12.3)].

  • Coadministration of clopidogrel and NSAIDs increases the risk of gastrointestinal bleeding.
  • 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 clopidogrel with warfarin increases the risk of bleeding because of independent effects on hemostasis.
  • However, at high concentrations in vitro, clopidogrel inhibits CYP2C9.
  • SSRIs and SNRIs
  • Since selective serotonin reuptake inhibitors (SSRIs) and serotonin norepinephrine reuptake inhibitors (SNRIs) affect platelet activation, the concomitant administration of SSRIs and SNRIs with clopidogrel may increase the risk of bleeding.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): 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, clopidogrel should be used during pregnancy only if clearly needed.
Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Clopidogrel in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Clopidogrel during labor and delivery.

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 pediatric populations have not been established. Additional information describing a clinical study in which efficacy was not demonstrated in neonates and infants is approved in the package insert for Bristol-Myers Squibb’s clopidogrel tablets. However, due to Bristol-Myers Squibb’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Geriatic Use

Of the total number of subjects in the CAPRIE and CURE controlled clinical studies, approximately 50% of patients treated with clopidogrel were 65 years of age and older, and 15% were 75 years and older. In COMMIT, approximately 58% of the patients treated with clopidogrel were 60 years and older, 26% of whom were 70 years and older. The observed risk of bleeding events with clopidogrel plus aspirin versus placebo plus aspirin by age category is provided in Table 1 and Table 2 for the CURE and COMMIT trials, respectively [see Adverse Reactions (6.1)]. No dosage adjustment is necessary in elderly patients.

Gender

There is no FDA guidance on the use of Clopidogrel with respect to specific gender populations.

Race

There is no FDA guidance on the use of Clopidogrel with respect to specific racial populations.

Renal Impairment

Experience is limited in patients with severe and moderate renal impairment [see Clinical Pharmacology (12.2)].

Hepatic Impairment

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.2)].

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Clopidogrel in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Clopidogrel in patients who are immunocompromised.

Administration and Monitoring

Administration

There is limited information regarding Clopidogrel Administration in the drug label.

Monitoring

There is limited information regarding Clopidogrel Monitoring in the drug label.

IV Compatibility

There is limited information regarding the compatibility of Clopidogrel and IV administrations.

Overdosage

There is limited information regarding Clopidogrel overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.

Pharmacology

There is limited information regarding Clopidogrel Pharmacology in the drug label.

Mechanism of Action

There is limited information regarding Clopidogrel Mechanism of Action in the drug label.

Structure

There is limited information regarding Clopidogrel Structure in the drug label.

Pharmacodynamics

There is limited information regarding Clopidogrel Pharmacodynamics in the drug label.

Pharmacokinetics

There is limited information regarding Clopidogrel Pharmacokinetics in the drug label.

Nonclinical Toxicology

There is limited information regarding Clopidogrel Nonclinical Toxicology in the drug label.

Clinical Studies

There is limited information regarding Clopidogrel Clinical Studies in the drug label.

How Supplied

There is limited information regarding Clopidogrel How Supplied in the drug label.

Storage

There is limited information regarding Clopidogrel Storage in the drug label.

Images

Drug Images

{{#ask: Page Name::Clopidogrel |?Pill Name |?Drug Name |?Pill Ingred |?Pill Imprint |?Pill Dosage |?Pill Color |?Pill Shape |?Pill Size (mm) |?Pill Scoring |?NDC |?Drug Author |format=template |template=DrugPageImages |mainlabel=- |sort=Pill Name }}

Package and Label Display Panel

{{#ask: Label Page::Clopidogrel |?Label Name |format=template |template=DrugLabelImages |mainlabel=- |sort=Label Page }}

Patient Counseling Information

There is limited information regarding Clopidogrel Patient Counseling Information in the drug label.

Precautions with Alcohol

Alcohol-Clopidogrel interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Clopidogrel Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Clopidogrel Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. ↑ ACTIVE Investigators. Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M et al. (2009) Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J Med 360 (20):2066-78. DOI:10.1056/NEJMoa0901301 PMID: 19336502
  2. ↑ Massie BM, Collins JF, Ammon SE, Armstrong PW, Cleland JG, Ezekowitz M et al. (2009) Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial. Circulation 119 (12):1616-24. DOI:10.1161/CIRCULATIONAHA.108.801753 PMID: 19289640
  3. ↑ Bick RL, Scott RG (2001) Stasis ulcers refractory to therapy--accelerated healing by treatment with clopidogrel +/- dalteparin: a preliminary report. Clin Appl Thromb Hemost 7 (1):21-4. PMID: 11190899
  4. ↑ Li JS, Yow E, Berezny KY, Bokesch PM, Takahashi M, Graham TP et al. (2008) Dosing of clopidogrel for platelet inhibition in infants and young children: primary results of the Platelet Inhibition in Children On Clopidogrel (PICOLO) trial. Circulation 117 (4):553-9. DOI:10.1161/CIRCULATIONAHA.107.715821 PMID: 18195173
Clopidogrel
PLAVIX® FDA Package Insert
Indications and Usage
Dosage and Administration
Dosage Forms and Strengths
Contraindications
Warnings and Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Overdosage
Description
Clinical Pharmacology
Nonclinical Toxicology
Clinical Studies
How Supplied/Storage and Handling
Patient Counseling Information
Labels and Packages
Clinical Trials on Clopidogrel
ClinicalTrials.gov
Clopidogrel
File:S-Clopidogrel structure.svg
Clinical data
Trade namesPlavix
AHFS/Drugs.comMonograph
MedlinePlusa601040
[[Regulation of therapeutic goods |Template:Engvar data]]
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration		Oral
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
Pharmacokinetic data
Bioavailability>50%
Protein binding94–98%
MetabolismHepatic
Elimination half-life7–8 hours (inactive metabolite)
Excretion50% renal
46% biliary
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
E number{{#property:P628}}
ECHA InfoCard{{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value).
Chemical and physical data
FormulaC16H16ClNO2S
Molar mass321.82 g/mol
3D model (JSmol)
  (verify)

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [5]

For patient information about Clopidogrel, click here.

Synonyms / Brand Names: PLAVIX®

Overview

Clopidogrel 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 (TTP).

Category

Antiplatelets

FDA Package Insert

PLAVIX (clopidogrel bisulfate) tablet, film coated

Indications and Usage | Dosage and Administration | Dosage Forms and Strengths | Contraindications | Warnings and Precautions | Adverse Reactions | Drug Interactions | Use in Specific Populations | Overdosage | Description | Clinical Pharmacology | Nonclinical Toxicology | Clinical Studies | How Supplied/Storage and Handling | Patient Counseling Information | Labels and Packages

Medical Use

Clopidogrel is indicated for:[1]

It is also used, along with acetylsalicylic acid (ASA), for the prevention of thrombosis after placement of intracoronary stent[1] or as an alternative antiplatelet drug for people intolerant to ASA.[2]

Its benefit is primarily in those who smoke cigarettes, with only slight benefit in those who do not.[3]

International guidelines granted the highest grade of recommendation for NSTE-ACS, PCI and stent, for clopidogrel in addition to ASA. Consensus-based therapeutic guidelines also recommend the use of clopidogrel rather than ASA for antiplatelet therapy in patients with a history of gastric ulceration, as inhibition of the synthesis of prostaglandins by ASA can exacerbate this condition. A study has shown that, in patients with healed ASA-induced ulcers, however, patients receiving ASA plus the proton pump inhibitor esomeprazole had a lower incidence of recurrent ulcer bleeding than patients receiving clopidogrel.[4] However, a more recent study suggested that 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.[5][6][7] The European Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors.[8] 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 there really is an interaction between clopidogrel and proton pump inhibitors.[9]

Adverse Effects

Serious adverse drug reactions associated with clopidogrel therapy include:

  • Severe neutropenia (low white blood cells) (Incidence: 1/2,000)
  • Thrombotic thrombocytopenic purpura (TTP) (Incidence: 4/1,000,000 patients treated)[10][11]
  • Hemorrhage - The annual incidence of hemorrhage may be increased by the co-administration of aspirin.[12]
    • 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: This is especially a problem for patients after heart surgery, where clopidogrel is associated with a more than double the take-back for bleeding rate, as well as other complicatons. 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 impacts outcomes and costs of care.
  • 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)[13]
    • Rash (6% overall, 0.33% severe)[14]
    • 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

Clopidogrel interacts with the following drugs: phenytoin (Dilantin); tamoxifen (Nolvadex); tolbutamide (Orinase); torsemide (Demadex); fluvastatin (Lescol); a blood thinner such as warfarin (Coumadin), heparin, ardeparin (Normiflo), dalteparin (Fragmin), danaparoid (Orgaran), enoxaparin (Lovenox), or tinzaparin (Innohep); (Activase), 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 on proton pump inhibitors.[15][16] The newer antiplatelet agent, prasugrel has minimal interaction with proton pump inhibitors and hence might be a better antiplatelet agent (if there are no other contraindication) in patients who are on proton pump inhibitors.[17]

Pharmacology

Clopidogrel is a prodrug, which requires CYP2C19 for its activation.[18] It acts on the ADP receptor on platelet cell membranes. The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor, which is important in activation of platelets and eventual cross-linking by the protein fibrin.[19] Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel, but the onset of action is slow, so that a loading-dose of either 600 or 300 mg is administered when a rapid effect is needed.

Pharmacokinetics and Metabolism

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 µg/L) beyond two hours after dosing.

Clopidogrel is a pro-drug 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 C3—C16, 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 C3—C16 double bond, the original S configuration at C7, 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 that R-configuration of the C4 group is critical for P2Y12 and platelet-inhibitory activity.

The active metabolite has an elimination half-life of about 0.5 to 1 hour 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.[20][21][22]

Following an oral dose of 14C-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 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 (approx. 3 mg/L) of the main circulating metabolite occurring approximately 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 nonsaturable in vitro up to a concentration of 110 μg/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. Food and Drug Administration (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.[23][24]

Pharmacogenetics

CYP2C19 is an important drug-metabolizing enzyme that catalyzes the biotransformation of many clinically useful drugs including antidepressants, barbiturates, proton pump inhibitors, 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 or Plavix. 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.[23] Researchers have found that 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.[25]

Marketing and Litigation

A box of Plavix

Plavix is marketed worldwide in nearly 110 countries, with sales of US$6.6 billion in 2009.[26] It had been the second-top-selling drug in the world for a few years as of 2007[27] and was still growing by over 20% in 2007. U.S. sales were US$3.8 billion in 2008.[28]

In 2006, generic clopidogrel was briefly marketed by Apotex, a Canadian generic pharmaceutical company before a court order halted further production until resolution of a patent infringement case brought by Bristol-Myers Squibb.[29] The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011.[30] The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire on May 17, 2012.[31] The FDA approved generic versions of Plavix on May 17, 2012.[32]

In June 2009, the European Medicines Agency (EMEA) gave authorisation to six generic versions of clopidogrel bisulfate and the drug is now available in several European countries, including the United Kingdom.[33]

Generic clopidogrel is produced by several pharmaceutical companies in India and elsewhere, and often sold under its INN clopidogrel. Clopidogrel is marketed by Cipla under the trade name Clopivas, by Sun Pharmaceuticals as Clopilet, by Ranbaxy Laboratories as Ceruvin, under the name "Clavix" by Intas Pharmaceuticals and under the name "Deplatt" by Torrent Pharmaceuticals. In India, it is sold as Clopivas AP, by Cipla, Clopigrel A, by USV, Clopitab A, by Lupin by Lupin(mixed with aspirin).

Generic clopidogrel is produced in Slovenia (European Union) under the trade names Zyllt, Kardogrel and Clopidogrel Krka by Krka d.d., Novo Mesto.

Another Generic clopidogrel is produced for Julphar brand (Gulf Pharmaceutical industries) UAE (GCC) under name of Lavigard by EGIS Pharmaceuticals PLC, Budabest, Hungary ingredient listed as Clopidogrel.

Dosage Forms

Clopidogrel is marketed as clopidogrel bisulfate (clopidogrel hydrogen sulfate), most commonly under the trade names Plavix, as 75 mg and 300 mg oral tablets.[34]

References

  1. ↑ 1.0 1.1 Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3
  2. ↑ Michael D Randall; Karen E Neil (2004). Disease management. 2nd ed. London: Pharmaceutical Press. 159.
  3. ↑ Gagne, JJ (Sep 17, 2013). "Effect of smoking on comparative efficacy of antiplatelet agents: systematic review, meta-analysis, and indirect comparison". BMJ (Clinical research ed.). 347: f5307. PMID 24046285. Unknown parameter |coauthors= ignored (help)
  4. ↑ Chan FK (2005). "Clopidogrel versus aspirin and esomeprazole to prevent recurrent ulcer bleeding" (PDF). N. Engl. J. Med. 352 (3): 238–44. doi:10.1056/NEJMoa042087. PMID 15659723. Unknown parameter |coauthors= ignored (help)
  5. ↑ Mistry SD, Trivedi HR, Parmar DM, Dalvi PS, Jiyo C. (2011). "Impact of [[proton pump inhibitor]]s on efficacy of clopidogrel: Review of evidence". Indian Journal of Pharmacology. 43 (2): 183–6. doi:10.4103/0253-7613.77360. PMC 3081459. PMID 21572655. URL–wikilink conflict (help)
  6. ↑ Ho PM, Maddox TM, Wang L, Fihn SD, Jesse RL, Peterson ED, Rumsfeld JS. (2009). "Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome". Journal of the American Medical Association. 301 (9): 937–44. doi:10.1001/jama.2009.261. PMID 19258584.
  7. ↑ Stockl, KM (April 2010). "Risk of rehospitalization for patients using clopidogrel with a proton pump inhibitor" (PDF). Arch Intern Med. 170 (8): 704–10. doi:10.1001/archinternmed.2010.34. ISSN 1538-3679. PMID 20421557. Unknown parameter |coauthors= ignored (help)
  8. ↑ Wathion, Noël. "Public statement on possible interaction between clopidogrel and proton pump inhibitors" (PDF). Retrieved 31 March 2011.
  9. ↑ Hughes, Sue. "EMEA issues warning on possible clopidogrel-PPI interaction, but is there really a problem?". Retrieved 31 March 2011.
  10. ↑ Zakarija A (2004). "Clopidogrel-Associated TTP An Update of Pharmacovigilance Efforts Conducted by Independent Researchers, Pharmaceutical Suppliers, and the Food and Drug Administration" (PDF). Stroke. 35 (2): 533–8. doi:10.1161/01.STR.0000109253.66918.5E. PMID 14707231. Unknown parameter |coauthors= ignored (help)
  11. ↑ Plavix prescribing information. Bristol-Myers Squibb / Sanofi.
  12. ↑ Diener HC (2004). "Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial". The Lancet. 364 (9431): 331–7. doi:10.1016/S0140-6736(04)16721-4. PMID 15276392. Unknown parameter |coauthors= ignored (help)
  13. ↑ Harker LA, Boissel JP, Pilgrim AJ, Gent M (October 1999). "Comparative safety and tolerability of clopidogrel and aspirin: results from CAPRIE. CAPRIE Steering Committee and Investigators. Clopidogrel versus aspirin in patients at risk of ischaemic events". Drug Saf. 21 (4): 325–35. doi:10.2165/00002018-199921040-00007. PMID 10514023.
  14. ↑ none listed (November 1996). "A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee". The Lancet. 16 (9038): 1329–39. PMID 8918275.
  15. ↑ DeNoon, Daniel J. "FDA Warns Plavix Patients of Drug Interactions", WebMD, 2009-11-19. Retrieved 2009-11-23.
  16. ↑ "Public Health Advisory: Updated Safety Information about a drug interaction between Clopidogrel Bisulfate (marketed as Plavix) and Omeprazole (marketed as Prilosec and Prilosec OTC)". Food and Drug Administration (FDA). November 17, 2009. Archived from the original on 2009-12-29. Retrieved March 13, 2010.
  17. ↑ John, Jinu (2012). "Current Oral Antiplatelets: Focus Update on Prasugrel". Journal of american board of family medicine. 25: 343–349. doi:10.3122/jabfm.2012.03.100270. Unknown parameter |coauthors= ignored (help)
  18. ↑ http://www.ncbi.nlm.nih.gov/pubmed/23046071
  19. ↑ Savi, P (July 2006). "The active metabolite of Clopidogrel disrupts P2Y12 receptor oligomers and partitions them out of lipid rafts" (PDF). Proceedings of the National Academy of Sciences of the USA. 103 (29): 11069–11074. doi:10.1073/pnas.0510446103. PMC 1635153. PMID 16835302. Unknown parameter |coauthors= ignored (help)
  20. ↑ Mega JL; Close, SL; Wiviott, SD; Shen, L; Hockett, RD; Brandt, JT; Walker, JR; Antman, EM; MacIas, W (January 2009). "Cytochrome p-450 polymorphisms and response to clopidogrel" (PDF). The New England Journal of Medicine. 360 (4): 354–62. doi:10.1056/NEJMoa0809171. PMID 19106084.
  21. ↑ Simon T; Verstuyft, C; Mary-Krause, M; Quteineh, L; Drouet, E; Méneveau, N; Steg, PG; Ferrières, J; Danchin, N (January 2009). "Genetic Determinants of Response to Clopidogrel and Cardiovascular Events" (PDF). The New England Journal of Medicine. 360 (4): 363–75. doi:10.1056/NEJMoa0808227. PMID 19106083.
  22. ↑ Collet, J; Hulot, JS; Pena, A; Villard, E; Esteve, JB; Silvain, J; Payot, L; Brugier, D; Cayla, G (January 2009). "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study". The Lancet. 373 (9660): 309–17. doi:10.1016/S0140-6736(08)61845-0. PMID 19108880.
  23. ↑ 23.0 23.1 "FDA Announces New Boxed Warning on Plavix: Alerts patients, health care professionals to potential for reduced effectiveness" (Press release). Food and Drug Administration (FDA). March 12, 2010. Retrieved March 13, 2010.
  24. ↑ "FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor metabolizers of the drug". Food and Drug Administration (FDA). March 12, 2010. Retrieved March 13, 2010.
  25. ↑ PGxNews.Org (June 2009). "FDA updates Plavix label with PGx data". PGxNews.Org. Retrieved 2009-06-13. [dead link]
  26. ↑ "New products and markets fuel growth in 2005". IMS Health. Retrieved 2009-03-02.[dead link]
  27. ↑ "Top Ten Global Products - 2007" (PDF). IMS Health. 2008-02-26. Retrieved 2009-03-02.
  28. ↑ "Details for Plavix".[verification needed]
  29. ↑ "Preliminary Injunction Against Apotex Upheld on Appeal" (Press release). Bristol-Myers Squibb. December 8, 2006. Retrieved 2010-03-14.
  30. ↑ "U.S. judge upholds Bristol, Sanofi patent on Plavix". Reuters. June 19, 2007. Retrieved 2007-09-05.
  31. ↑ "FDA Gives Plavix a 6 Month Extension-Patent Now Expires on May 17, 2012". January 26, 2011. Retrieved 2012-01-12.
  32. ↑ "FDA approves generic versions of blood thinner Plavix" (Press release). Food and Drug Administration (FDA). May 17, 2012.
  33. ↑ Generic Clopidogrel http://www.genericclopidogrel.com/generic-clopidogrel/
  34. ↑ Joint Royal Colleges Ambulance liaison committee Clinical Practise Guideines Guidelines

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