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| Pronunciation | /kləˈpɪdəɡrɛl,kloʊ-/[1] |
| Trade names | Plavix, Iscover, others[2] |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a601040 |
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| Routes of administration | By mouth |
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| Pharmacokinetic data | |
| Bioavailability | >50% |
| Protein binding | 94–98% |
| Metabolism | Liver |
| Onset of action | 2 hours[9] |
| Eliminationhalf-life | 7–8 hours (inactive metabolite) |
| Duration of action | 5 days[9] |
| Excretion | 50%Kidney 46%bile duct |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.127.841 |
| Chemical and physical data | |
| Formula | C16H16ClNO2S |
| Molar mass | 321.82 g·mol−1 |
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Clopidogrel, sold under the brand namePlavix and other names, is anantiplatelet medication used to reduce the risk ofheart disease andstroke in those at high risk.[9] It is also used together withaspirin inheart attacks and following the placement of acoronary artery stent (dual antiplatelet therapy).[9] It is takenby mouth.[9] Its effect starts about two hours after intake and lasts for five days.[9]
Common side effects include headache,nausea, easy bruising, itching, andheartburn.[9] More severe side effects includebleeding andthrombotic thrombocytopenic purpura.[9] While there is no evidence of harm from use duringpregnancy, such use has not been well studied.[3] Clopidogrel is in thethienopyridine-class of antiplatelets.[9] It works by irreversibly inhibiting a receptor calledP2Y12 onplatelets.[9]
Clopidogrel was patented in 1982, and approved for medical use in 1997.[5][10] It is on theWorld Health Organization's List of Essential Medicines.[11] In 2023, it was the 41st most commonly prescribed medication in the United States, with more than 15 million prescriptions.[12][13] It is available as ageneric medication.[9]
Clopidogrel is used to prevent heart attack and stroke in people who are at high risk of these events, including those with a history of myocardial infarction and other forms ofacute coronary syndrome, stroke, and those withperipheral artery disease.
Treatment with clopidogrel or a related drug is recommended by theAmerican Heart Association and theAmerican College of Cardiology for people who:
It is also used, along withacetylsalicylic acid (ASA, aspirin), for the prevention ofthrombosis after placement of acoronary stent[17] or as an alternative antiplatelet drug for people intolerant to aspirin.[18] It is available as a fixed-dose combination with aspirin.[19]
A meta-analysis found clopidogrel's benefit as an antiplatelet drug in reducing cardiovascular death, myocardial infarction, and stroke to be 25% benefit in smokers, with little (8%) benefit in non-smokers.[20]
Consensus-based therapeutic guidelines also recommend the use of clopidogrel rather than aspirin (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 theproton-pump inhibitor (PPI)esomeprazole had a lower incidence of recurrent ulcer bleeding than those receiving clopidogrel.[21] However, prophylaxis with proton-pump inhibitors along with clopidogrel following acute coronary syndrome may increase adverse cardiac outcomes, possibly due to inhibition ofCYP2C19, which is required for the conversion of clopidogrel to its active form.[22][23][24] TheEuropean Medicines Agency has issued a public statement on a possible interaction between clopidogrel and proton-pump inhibitors.[25] 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.[26]
Seriousadverse drug reactions associated with clopidogrel therapy include:
In the CURE trial, people with acute coronary syndrome withoutST elevation were treated with aspirin plus either clopidogrel or placebo and followed for up to one year. The following rates of major bleed were seen:[5]
The CAPRIE trial compared clopidogrel monotherapy to aspirin monotherapy for 1.6 years in people who had recently experienced a stroke or heart attack. In this trial the following rates of bleeding were observed.[5]
In CAPRIE, itching was the only adverse effect seen more frequently with clopidogrel than aspirin. In CURE, there was no difference in the rate of non-bleeding adverse events.[5]
Rashes and itching were uncommon in studies (between 0.1 and 1% of people); serioushypersensitivity reactions are rare.[29]
Clopidogrel generally has a low potential to interact with other pharmaceutical drugs. Combination with other drugs that affect blood clotting, such asaspirin,heparins andthrombolytics, showed no relevant interactions.Naproxen did increase the likelihood ofoccultgastrointestinal bleeding, as might be the case with othernonsteroidal anti-inflammatory drugs. As clopidogrel is metabolized by the liver enzymeCYP2C19, in cellular models it has been theorized that it might increase blood plasma levels of other drugs that are metabolized by this enzyme, such asphenytoin andtolbutamide. Clinical studies showed that this mechanism is irrelevant for practical purposes.[29]
In November 2009, the USFood and Drug Administration (FDA) announced that clopidogrel should be used with caution in people using theproton-pump inhibitorsomeprazole oresomeprazole,[30][31][32] butpantoprazole appears to be safe.[33] The newer antiplatelet agentprasugrel has minimal interaction with (es)omeprazole, hence might be a better antiplatelet agent (if no other contraindications are present) in people who are on these proton-pump inhibitors.[34]
Clopidogrel is aprodrug which is metabolized by theliver into its active form. The active form specifically and irreversibly inhibits theP2Y12 subtype ofADP receptor, which is important in activation of platelets and eventual cross-linking by the proteinfibrin.[35]
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.[medical citation needed]
Clopidogrel is aprodrug, which is activated in two steps, first by the enzymesCYP2C19,CYP1A2, andCYP2B6, then by CYP2C19,CYP2C9, CYP2B6, andCYP3A.[35] The thiophene ring is converted to athiolactone. This thiolactone is then oxidized by a cytochrome P450 into a thiolactone S-oxide, that is unstable and opens in water to a sulfenic acid. In presence of cell reductants (glutathione or ascorbic acid or enzymatically) the sulfenic acid is reduced to the active thiol metabolite.[37].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 originalS configuration at C7,[36] 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 theR-configuration of the C4 group is critical for P2Y12 and platelet-inhibitory activity.[medical 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.[38][39][40]
Following an oral dose of14C-labeled clopidogrel in humans, about 50% was excreted in the urine and 46% in the feces in the five days after dosing.[9]
Clopidogrel and the main circulating metabolite bind reversiblyin vitro to human plasma proteins (98% and 94%, respectively). The binding is not saturablein vitro up to a concentration of 110 μg/mL.
In 2010, the USFood and Drug Administration (FDA) added a boxed warning, later updated, to Plavix, alerting that the drug can be less effective in people unable to metabolize the drug to convert it to its active form.[41]
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.[9]
The USFood and Drug Administration (FDA) added aboxed warning on clopidogrel in 2010 about CYP2C19-poor metabolizers.[41] People 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.[5][42]
A published review showed that some mutations ofCYP2C19,CYP3A4,CYP2C9,CYP2B6, andCYP1A2 genes could affect the clinical efficacy and safety of clopidogrel treatment. For instance, patients carrying the mutationsCYP2C19*2,CYP2C19*3,CYP2C9*2,CYP2C9*3, andCYP2B6*5 alleles may not respond to clopidogrel due to poor platelet inhibition efficacy revealed among them.[43]
The active metabolite of clopidogrel specifically and irreversibly inhibits theP2Y12 subtype ofADP receptor, which is important in activation of platelets and eventual cross-linking by the proteinfibrin.[35] 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.[44][full citation needed]
Plavix is marketed worldwide in nearly 110 countries, with sales ofUS$6.6billion in 2009.[45] It was the second-top-selling drug in the world in 2007[46] and was still growing by over 20% in 2007. US sales wereUS$4.9 billion in 2008.[47]
Before the expiry of its patent, clopidogrel was the second best-selling drug in the world. In 2010, it grossed overUS$9 billion in global sales.[48]
In 2006, generic clopidogrel was briefly marketed byApotex, aCanadian genericpharmaceutical company before a court order halted further production until resolution of a patent infringement case brought byBristol-Myers Squibb.[49] The court ruled that Bristol-Myers Squibb's patent was valid and provided protection until November 2011.[50] The FDA extended the patent protection of clopidogrel by six months, giving exclusivity that would expire in May 2012.[51] The FDA approved generic versions of clopidogrel in May 2012.[52]
Generic clopidogrel is marketed by many companies worldwide under many brand names.[2]
List of brand names |
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As of March 2017[update], brands included Aclop, Actaclo, Agregex, Agrelan, Agrelax, Agreless, Agrelex, Agreplat, Anclog, Angiclod, Anplat, Antiagrex, Antiban, Antigrel, Antiplaq, Antiplar, Aplate, Apolets, Areplex, Artepid, Asogrel, Atelit, Atelit, Ateplax, Atervix, Atheros, Athorel, Atrombin, Attera, Bidogrel, Bigrel, Borgavix, Carder, Cardogrel, Carpigrel, Ceraenade, Ceruvin, Cidorix, Clatex, Clavix, Clentel, Clentel, Clidorel, Clodel, Clodelib, Clodian, Clodil, Cloflow, Clofre, Clogan, Clogin, Clognil, Clogrel, Clogrelhexal, Clolyse, Clont, Clood, Clopacin, Clopcare, Clopeno, Clopex Agrel, Clopez, Clopi, Clopid, Clopida, Clopidep, Clopidexcel, Clopidix, Clopidogrel, Clopidogrelum, Clopidomed, Clopidorex, Clopidosyn, Clopidoteg, Clopidowel, Clopidra, Clopidrax, Clopidrol, Clopigal, Clopigamma, Clopigrel, Clopilet, Clopimed, Clopimef, Clopimet, Clopinovo, Clopione, Clopiright, Clopirite, Clopirod, Clopisan, Clopistad, Clopistad, Clopitab, Clopithan, Clopitro, ClopiVale, Clopivas, Clopivaz, Clopivid, Clopivin, Clopix, Cloplat, Clopra, Cloprez, Cloprez, Clopval, Clorel, Cloriocard, Cloroden, Clotix, Clotiz, Clotrombix, Clova, Clovas, Clovax, Clovelen, Clovex, Clovexil, Clovix, Clovvix, Copalex, Copegrel, Copidrel, Copil, Cordiax, Cordix, Corplet, Cotol, CPG, Cugrel, Curovix, Dapixol, Darxa, Dasogrel-S, Dclot, Defrozyp, Degregan, Deplat, Deplatt, Diclop, Diloxol, Dilutix, Diporel, Doglix, Dogrel, Dogrel, Dopivix, Dorel, Dorell, Duopidogrel, DuoPlavin, Eago, Egitromb, Espelio, Eurogrel, Expansia, Farcet, Flucogrel, Fluxx, Freeclo, Globel, Glopenel, Grelet, Greligen, Grelix, Grepid, Grepid, Grindokline, Heart-Free, Hemaflow, Hyvix, Idiavix, Insigrel, Iscover, Iskimil, Kafidogran, Kaldera, Kardogrel, Karum, Kerberan, Keriten, Klepisal, Klogrel, Klopide, Klopidex, Klopidogrel, Klopik, Klopis, Kogrel, Krossiler, Larvin, Lodigrel, Lodovax, Lofradyk, Lopigalel, Lopirel, Lyvelsa, Maboclop, Medigrel, Miflexin, Mistro, Mogrel, Monel, Monogrel, Moytor, Myogrel, Nabratin, Nadenel, Nefazan, Niaclop, Nivenol, Noclog, Nofardom, Nogreg, Nogrel, Noklot, Norplat, Novigrel, Oddoral, Odrel, Olfovel, Opirel, Optigrel, Panagrel, Pedovex, Pegorel, Piax, Piclokare, Pidgrel, Pidogrel, Pidogul, Pidovix, Pigrel, Pingel, Placta, Pladel, Pladex, Pladogrel, Plagerine, Plagrel, Plagril, Plagrin, Plahasan, Plamed, Planor, PlaquEx, Plasiver, Plataca, Platarex, Platec, Platel, Platelex, Platexan, Platil, Platless, Platogrix, Platrel, Plavedamol, Plavicard, Plavictonal, Plavidosa, Plavigrel, Plavihex, Plavitor, Plavix, Plavocorin, Plavogrel, Plavos, Pleyar, Plogrel, Plvix, Pravidel, Pregrel, Provic, Psygrel, Q.O.L, Ravalgen, Replet, Respekt, Revlis, Ridlor, Roclas, Rozak, Sanvix, Sarix, Sarovex, Satoxi, Shinclop, Sigmagrel, Simclovix, Sintiplex, Stazex, Stroka, Stromix, Sudroc, Synetra, Talcom, Tansix, Tessyron, Thinrin, Throimper, Thrombifree, Thrombo, Timiflo, Tingreks, Torpido, Triosal, Trogran, Troken, Trombex, Trombix, Tuxedon, Unigrel, Unplaque, Vaclo, Vasocor, Vatoud, Venicil, Vidogrel, Vivelon, Vixam, Xydrel, Zakogrel, Zillt, Zopya, Zylagren, Zyllt, and Zystol.[2] As of 2017[update], it was marketed as acombination drug withacetylsalicylic acid (aspirin) under the brand names Anclog Plus, Antiban-ASP, Asclop, Asogrel-A, Aspin-Plus, Cargrel-A, Clas, Clasprin, Clavixin Duo, Clodrel Forte, Clodrel Plus, Clofre AS, Clognil Plus, Clontas, Clopid-AS, Clopid-AS, Clopida A, Clopil-A, Clopirad-A, Clopirin, Clopitab-A, Clorel-A, Clouds, Combiplat, Coplavix, Coplavix, Cugrel-A, Dorel Plus, DuoCover, DuoCover, DuoPlavin, DuoPlavin, Ecosprin Plus, Grelet-A, Lopirel Plus, Myogrel-AP, Noclog Plus, Noklot Plus, Norplat-S, Odrel Plus, Pidogul A, Pladex-A, Plagerine-A, Plagrin Plus, Plavix Plus, Replet Plus, Stromix-A, and Thrombosprin.[2] |
Clopidogrel has been shown to be effective at decreasing platelet aggregation in cats, so its use in prevention of feline aortic thromboembolism has been advocated.[53]
