Clopidogrel
From Ganfyd
rINN: Clopidogrel
Other Names
clopidogrel hydrogen sulphate, Plavix®, clopidogrel besilate, Grepid®,
Pharmacological Information
Pharmacology Images
Web information on Clopidogrel
Metabolism & Interactions
Pro-drug metabolised to active unstable compound by cytochrome P450 CYP3A4.
Mechanism of Action
Selectively blocks ADP-induced platelet aggregation at a specific platelet adenosine 5'-diphosphate (ADP) receptor P2Y(12)
Other Issues for Clopidogrel
All drugs that inhibit CYP2C19 might decrease its effectiveness. To date this has been shown for every PPI on the market although initial studies had been interpreted by many that this was drug specific. Although genotyping for CYP2C19 seems attractive there is no proof of benefit from so doing.
Relevant Clinical Literature
UK Guidance
Regulatory Literature
Other Literature
Please read pharmacological data limitations
Other Wikis
Medpedia on Clopidogrel (Less technical, good quality control)
Wikipedia on Clopidogrel (Less technical, ? quality control)
Contents |
Introduction
A blockbuster.
Clinical Use
Indications
Some products only have manufacturing authorization for particular indications
- Prevention of atherothrombotic events in:
- Acute coronary syndrome:
- In combination with aspirin in:
- NSTEMI
- Stent placement following percutaneous coronary intervention
- STEMI after thrombolytic therapy.
- NSTEMI
Advantages
- Alternative to aspirin
- Combined with aspirin gives extra antiplatelet action
Disadvantages
- Relative cost to aspirin
- Short half life
- Same rate of serious bleeds after a year despite no COX 1 activity
- Drug interactions
Evidence
- Midlands Therapeutics Review and Advisory Committee Clopidogrel (acute coronary syndrome) reports that clopidogrel, in combination with aspirin for the prevention of atherothrombotic events in patients with ACS should be initiated in secondary care. It is appropriate for continued prescribing, in primary care, for up to 12 months.
- Midlands Therapeutics Review and Advisory Committee Clopidogrel (atherothrombotic events) [1]
- London’s Medicine Information Service Does aspirin added to clopidogrel further reduce the risk of recurrent ischaemic vascular events in high-risk patients after transient ischaemic attack or ischaemic stroke?
- WeMeReC Prescribing clopidogrel. Their summary states that a reasonable place for use of clopidogrel is where aspirin is indicated for secondary prevention of atherothrombotic events but where there is a clear allergy or a serious gastro-intestinal adverse reaction to aspirin. Although they also point out that clopidogrel can also be associated with such events. They also comment on the controversy over the appropriate place and duration of treatment when combining clopidogrel with aspirin for acute coronary syndrome. They state that trial evidence suggests that treatment of high-risk cases for three months gives the best balance risk and benefit, but use for up to 12 months is licensed.
- Northern and Yorkshire Drug and Therapeutic Centre review [2].
- MeReC Prescribing antiplatelet drugs in primary care discuss clopidogrel. They state that there is no robust evidence that clopidogrel has a lower risk of GI side effects. They also report that clopidogrel can be considered as an alternative to aspirin for the secondary prevention of CV events in people where aspirin is contraindicated or there is a genuine aspirin intolerance. However, it points out that there are very few people who are genuinely intolerant of aspirin. In people experiencing dyspepsia while taking aspirin they should have their dose reduced to 75mg daily and be co-prescribed a PPI, before switching to clopidogrel.
- NICE, Clopidogrel and modified release dipyridamole in the prevention of occlusive vascular events Technology Appraisal.
- NICE, Clopidogrel in the treatment of non-ST-segment-elevation acute coronary syndrome Technology Appraisal.
- Scottish Medicines Consortium Summary of Recommendation.
- The NLH Q&A Service has answered numerous questions on this topic.
Interactions
The following drugs (according to FDA) should not be co-administered because of strong evidence of metabolic negation of effect: omeprazole, esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine. The EMEA initially extended this advice to include all proton pump inhibitors but in March 2010 limited it to omeprazole and esomeprazole.
Pharmacology
There is evidence that clopidogrel resistance can be related to CYP2C19[1][2][3] and CYP3A4 genotype[4] and can be modified by drugs. This is not important with statins but the other common inhibitors of CYP3A4 have not been studied.[5]. However poorer cardiovascular outcomes have now been shown for all[6] proton pump inhibitors if given at the same time as clopidogrel, possibly because all of these affect CYP2C19 metabolism.[7] Further the risk of poorer cardiovascular outcomes does not imply that prospective genotyping for loss of function CYP2C19 will be resource effective because alternative strategies to standard dose clopidrogel in such higher risk patients have yet to be defined[8].
References
- ↑ Collet JP, Hulot JS, Pena A, Villard E, Esteve JB, Silvain J, Payot L, Brugier D, Cayla G, Beygui F, Bensimon G, Funck-Brentano C, Montalescot G. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. 2008 Dec 22.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, Steg PG, Ferrières J, Danchin N, Becquemont L. Genetic Determinants of Response to Clopidogrel and Cardiovascular Events. The New England journal of medicine. 2008 Dec 22.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Mega JL, Close SL, Wiviott SD, Shen L, Hockett RD, Brandt JT, Walker JR, Antman EM, Macias W, Braunwald E, Sabatine MS. Cytochrome P-450 Polymorphisms and Response to Clopidogrel. The New England journal of medicine. 2008 Dec 22.(Epub ahead of print) (Link to article – subscription may be required.)
- ↑ Lau WC, Gurbel PA, Watkins PB, Neer CJ, Hopp AS, Carville DG, et al. Contribution of hepatic cytochrome P450 3A4 metabolic activity to the phenomenon of clopidogrel resistance. Circulation 2004;109:166-71. (Direct link – subscription may be required.)
- ↑ Neubauer H, Mugge A. Thienopyridines and statins: assessing a potential drug-drug interaction.Curr Pharm Des. 2006;12(10):1271-80.
- ↑ MHRA Drug Safety Update July 2009:2;12
- ↑ Sanofi-aventis/Bristol-Myers Squibb Pharmaceuticals Limited Direct Healthcare Professional Communication on potential interaction of proton pump inhibitors with clopidogrel-containing medicines (Plavix®) 29 July 2009
- ↑ Storey RF. Clopidogrel in acute coronary syndrome: to genotype or not? Lancet. 2008 Dec 22.(Epub ahead of print) (Link to article – subscription may be required.)
