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Drug Interactions between clopidogrel and esomeprazole

This report displays the potential drug interactions for the following 2 drugs:

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Major

clopidogrel esomeprazole

Applies to: clopidogrel and esomeprazole

GENERALLY AVOID: Coadministration with proton pump inhibitors (PPIs) may reduce the cardioprotective effects of clopidogrel. The proposed mechanism is PPI inhibition of the CYP450 2C19-mediated metabolic bioactivation of clopidogrel. This is consistent with studies that reported decreased effectiveness of clopidogrel and poorer clinical outcome in patients who have common genetic polymorphisms of CYP450 2C19 resulting in reduced or absent enzyme activity. In a population-based nested case-control study among patients aged 66 years or older who started clopidogrel after treatment of acute myocardial infarction, concomitant use of PPIs was associated with a significantly increased short-term risk of reinfarction. No association was found with more distant exposure to PPIs or with current exposure to H2-receptor antagonists. In a stratified analysis of the type of PPIs used, pantoprazole was not associated with recurrent myocardial infarction among patients receiving clopidogrel. However, the number of patients receiving pantoprazole in the study was relatively small. Compared with no treatment, the other proton pump inhibitors (lansoprazole, omeprazole, rabeprazole) were collectively associated with a 40% increase in the risk of recurrent myocardial infarction within 90 days of initial hospital discharge. In the Clopidogrel Medco Outcomes Study, a retrospective analysis of 16,690 patients taking clopidogrel for a full year following coronary stenting revealed that patients who also took a PPI (esomeprazole, lansoprazole, omeprazole, or pantoprazole) for an average of nine months experienced a 50% increase in the combined risk of hospitalization for heart attack, stroke, unstable angina, or repeat revascularization. Specifically, use of a PPI was associated with a 70% increase in the risk of heart attack or unstable angina, a 48% increase in the risk of stroke or stroke-like symptoms, and a 35% increase in the need for a repeat coronary procedure. The event rates for the individual PPIs are esomeprazole 24.9%, lansoprazole 24.3%, omeprazole 25.1%, and pantoprazole 29.2%, compared to 17.9% for the no-PPI control group. In a study of 105 consecutive high-risk coronary angioplasty patients receiving aspirin and clopidogrel, PPI users had a significantly lower antiplatelet response to clopidogrel than nonusers as measured by the VASP (vasodilator-stimulated phosphoprotein) phosphorylation assay, which provides an index of platelet reactivity to clopidogrel. No significant differences in antiplatelet response were found for users of statins, ACE inhibitors, angiotensin II receptor antagonists, and beta-blockers compared to nonusers. A subsequent study conducted by the same investigators reported similar results when omeprazole (20 mg/day) or placebo was given for seven days to 140 coronary artery stent patients receiving aspirin and clopidogrel. In contrast, a study of 300 consecutive patients with coronary artery disease undergoing PCI found that esomeprazole or pantoprazole use did not impair the response to clopidogrel as measured by VASP assay or ADP-induced platelet aggregometry. More recent studies have also found no significant effect of dexlansoprazole, lansoprazole, or pantoprazole on the pharmacokinetics or pharmacodynamics of clopidogrel, and that increasing gastric pH did not influence platelet inhibition by clopidogrel.

MANAGEMENT: Until further data are available, empiric use of proton pump inhibitors should preferably be avoided in patients treated with clopidogrel. PPIs should only be considered in high-risk patients such as those receiving dual antiplatelet therapy, those with a history of gastrointestinal bleeding or ulcers, and those receiving concomitant anticoagulant therapy, and then only after thorough assessment of risks versus benefits. If a PPI is required, dexlansoprazole, lansoprazole, or pantoprazole may be safer alternatives. Otherwise, H2-receptor antagonists or antacids should be prescribed whenever possible.

References

  1. "Product Information. Prevacid (lansoprazole)." TAP Pharmaceuticals Inc PROD (2001):
  2. "Product Information. Protonix (pantoprazole)." Wyeth-Ayerst Laboratories PROD (2001):
  3. Hulot JS, Bura A, Villard E, et al. "Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects." Blood (2006):
  4. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J "Influence of omeprazol on the antiplatelet action of clopidogrel associated to aspirin." J Thromb Haemost 4 (2006): 2508-9
  5. Small DS, Farid NA, Payne CD, et al. "Effects of the proton pump inhibitor lansoprazole on the pharmacokinetics and pharmacodynamics of prasugrel and clopidogrel." J Clin Pharmacol 48 (2008): 475-84
  6. Frere C, Cuisset T, Morange PE, et al. "Effect of Cytochrome P450 Polymorphisms on Platelet Reactivity After Treatment With Clopidogrel in Acute Coronary Syndrome." Am J Cardiol 101 (2008): 1088-1093
  7. Gilard M, Arnaud B, Cornily JC, et al. "Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized, double-blind OCLA (Omeprazole CLopidogrel Aspirin) study." J Am Coll Cardiol 51 (2008): 256-60
  8. Pezalla E, Day D, Pulliadath I "Initial assessment of clinical impact of a drug interaction between clopidogrel and proton pump inhibitors." J Am Coll Cardiol 52 (2008): 1038-9
  9. Siller-Matula JM, Spiel AO, Lang IM, Kreiner G, Christ G, Jilma B "Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel." Am Heart J 157 (2009): 148.e1-5
  10. Freedman JE, Hylek EM "Clopidogrel, genetics, and drug responsiveness." N Engl J Med 360 (2009): 411-3
  11. "Product Information. Kapidex (dexlansoprazole)." Takeda Pharmaceuticals America (2009):
  12. Juurlink DN, Gomes T, Ko DT, et al. "A population-based study of the drug interaction between proton pump inhibitors and clopidogrel." CMAJ 180 (2009): 713-8
  13. Li XQ, Andersson TB, Ahlstrom M, Weidolf L "Comparison of inhibitory effects of the proton pump-inhibiting drugs omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole on human cytochrome P450 activities." Drug Metab Dispos 32 (2004): 821-7
  14. Collet JP, Hulot JS, Pena A, et al. "Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study." Lancet 373 (2009): 309-17
  15. Mega JL, Close SL, Wiviott SD, et al. "Cytochrome p-450 polymorphisms and response to clopidogrel." N Engl J Med 360 (2009): 354-62
  16. Lau WC, Gurbel PA "The drug-drug interaction between proton pump inhibitors and clopidogrel." CMAJ 180 (2009): 699-700
  17. Moayyedi P, Sadowski DC "Proton pump inhibitors and clopidogrel -- hazardous drug interaction or hazardous interpretation of data?" Can J Gastroenterol 23 (2009): 251-2
  18. Simon T, Verstuyft C, Mary-Krause M, et al. "Genetic determinants of response to clopidogrel and cardiovascular events." N Engl J Med 360 (2009): 363-75
  19. Varenhorst C, Janes S, Erlinge D, et al. "Genetic variation of CYP2C19 affects both pharmacokinetic and pharmacodynamic responses to clopidogrel but not prasugrel in aspirin-treated patients with coronary artery disease." Eur Heart J 30 (2009): 1744-52
  20. de Aquino Lima JP, Brophy JM "The potential interaction between clopidogrel and proton pump inhibitors: a systematic review." BMC Med 8 (2010): 81
  21. EMA. European Medicines Agency "Interaction between clopidogrel and proton-pump inhibitors. http://www.ema.europa.eu/ema/index.jsp?curl=documents/document_library/Public_statement/2010/03/WC500076346.sjsp&jsenabled=true" (2011):
  22. "Product Information. Dexilant (dexlansoprazole)." Takeda Pharmaceuticals America (2011):
View all 22 references

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Drug and food interactions

Moderate

esomeprazole food

Applies to: esomeprazole

ADJUST DOSING INTERVAL: Food may interfere with the absorption of esomeprazole. The manufacturer reports that the area under the concentration-time curve for esomeprazole following a single 40 mg dose was 33% to 53% lower when administered after food intake as opposed to during fasting conditions.

MANAGEMENT: Esomeprazole should be taken at least one hour before meals. When administered to patients receiving continuous enteral nutrition, some experts recommend that the tube feeding should be interrupted for at least 1 hour before and 1 hour after the dose of esomeprazole is given.

References

  1. "Product Information. Nexium (esomeprazole)." Astra-Zeneca Pharmaceuticals PROD (2001):
  2. Wohlt PD, Zheng L, Gunderson S, Balzar SA, Johnson BD, Fish JT "Recommendations for the use of medications with continuous enteral nutrition." Am J Health Syst Pharm 66 (2009): 1438-67

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Therapeutic duplication warnings

No warnings were found for your selected drugs.

Therapeutic duplication warnings are only returned when drugs within the same group exceed the recommended therapeutic duplication maximum.


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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.
Major Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown No interaction information available.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.