Clopidogrel

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 names	Plavix
AHFS/Drugs.com	Monograph
MedlinePlus	a601040
[[Regulation of therapeutic goods |Template:Engvar data]]	US FDA: Plavix
Pregnancy category	AU: B1 US: B (No risk in non-human studies)
Routes of administration	Oral
ATC code	B01AC04 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	>50%
Protein binding	94–98%
Metabolism	Hepatic
Elimination half-life	7–8 hours (inactive metabolite)
Excretion	50% renal 46% biliary
Identifiers
IUPAC name (+)-(S)-methyl 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]pyridin-5(4H)-yl)acetate
CAS Number	113665-84-2 Y
PubChem CID	60606
DrugBank	DB00758 Y
ChemSpider	54632 Y
UNII	A74586SNO7
KEGG	D07729 Y
ChEBI	CHEBI:37941 Y
ChEMBL	ChEMBL1771 Y
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C16H16ClNO2S
Molar mass	321.82 g/mol
3D model (JSmol)	Interactive image
SMILES COC(=O)[C@H](c1ccccc1Cl)N2CCc3c(ccs3)C2
InChI InChI=1S/C16H16ClNO2S/c1-20-16(19)15(12-4-2-3-5-13(12)17)18-8-6-14-11(10-18)7-9-21-14/h2-5,7,9,15H,6,8,10H2,1H3/t15-/m0/s1 Y Key:GKTWGGQPFAXNFI-HNNXBMFYSA-N Y
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Jesus Rosario Hernandez, M.D. [2]

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:

• Prevention of vascular ischemic events in people with symptomatic atherosclerosis
• Acute coronary syndrome without ST-segment elevation (NSTEMI)
• ST elevation MI (STEMI)

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

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

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. 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. The European Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton pump inhibitors. 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.

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)
• Hemorrhage - The annual incidence of hemorrhage may be increased by the co-administration of aspirin.
  • 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)
  • Rash (6% overall, 0.33% severe)
  • 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. 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.

Pharmacology

Clopidogrel is a prodrug, which requires CYP2C19 for its activation. 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. 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.

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.

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. 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.

Marketing and Litigation

A box of Plavix

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

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. The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011. The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire on May 17, 2012. The FDA approved generic versions of Plavix on May 17, 2012.

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.

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.

External Links

• Plavix official website Bristol-Myers Squibb/Sanofi
• Plavix prescribing information Bristol-Myers Squibb/Sanofi
• Plavix, Aspirin and Stents : Patients' Forum : Angioplasty.Org
• Drug promises end to migraine misery
• U.S. National Library of Medicine: Drug Information Portal - Clopidogrel
• Krka official website