Interaction between clopidogrel and proton pump inhibitors (PPI )

• interaction between clopidogrel and PPIs
  • concomitant use of a proton pump inhibitor (PPI) with clopidogrel should be avoided unless considered essential. This is due to concerns that PPIs may reduce the effectiveness of clopidogrel
    • in the UK, the MHRA has issued the following advice:
      • the need for PPI therapy in patients who are also taking clopidogrel should be reviewed at their next appointment: avoid concomitant use of these medicines unless considered essential
      • prescribe PPIs in line with their licensed indications, where possible
      • check whether patients who are taking clopidogrel are buying over-the-counter omeprazole and consider whether another gastrointestinal (GI) therapy would be more suitable
    • for patients who need to continue taking clopidogrel and also require gastroprotection, there is currently insufficient evidence to recommend H2-receptor antagonists (H2RAs) or other GI therapies as alternatives to PPIs (1)
• in light of the most recent evidence, the previous advice on the concomitant use of clopidogrel with proton pump inhibitors has now been modified. Use of either omeprazole or esomeprazole with clopidogrel should be discouraged. The current evidence does not support extending this advice to other PPIs (2)
• product information for clopidogrel has been recently updated on the basis of pharmacokinetic, pharmacodynamic, and some clinical outcome data, which demonstrated that omeprazole competitively inhibits the CYP2C19 isoenzyme (which metabolises clopidogrel to its active metabolite); reduces the ability of clopidogrel to inhibit platelet aggregation; and reduces the beneficial effect of clopidogrel in patients
  • although evidence for a similar effect on clopidogrel metabolism with the other PPIs was relatively sparse, a precautionary approach for the whole class was adopted in light of the findings of some clinical outcome studies suggesting an attenuation of the cardioprotective effect of clopidogrel by PPIs other than omeprazole
  • in May 2009, the EU Committee for Medicinal products for Human Use (CHMP) concluded that concomitant use of any PPIs with clopidogrel should be avoided unless considered essential
    • available evidence for an interaction between clopidogrel and PPIs is therefore not completely consistent. Nevertheless, pharmacokinetic, pharmacodynamic, and some clinical outcome data suggest a significant interaction for omeprazole, and there is also some evidence in relation to esomeprazole
      
      
  • Advice for healthcare professionals:
    
    
    • concomitant use of clopidogrel and omeprazole or esomeprazole is to be discouraged unless considered essential
      
      
    • doctors should check whether patients who are taking clopidogrel are also buying over-the-counter omeprazole and consider whether other gastrointestinal therapies would be more suitable
      
      
    • pharmacists should check whether patients buying omeprazole are also taking clopidogrel
      
      
    • consider PPIs other than omeprazole or esomeprazole in patients who are taking clopidogrel. Other gastrointestinal therapy such as H2 blockers (except cimetidine) or antacids may be more suitable in some patients
      
      
    • discourage concomitant use of other known CYP2C19-inhibiting medicines with clopidogrel because these are expected to have a similar effect to omeprazole and esomeprazole (CYP2C19 inhibitors include fluvoxamine, fluoxetine, moclobemide, voriconazole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine, oxcarbazepine, and chloramphenicol)

Notes:

• a study of data of the use of prasugrel and clopidogrel in in the PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials revealed that PPIs were not significantly associated with an increased risk of the patient-oriented outcomes of CV death, myocardial infarction (MI) or stroke, after adjusting for potential confounders (3) - study findings were consistent, regardless of the individual PPI used, or the use of an H2-receptor antagonist

Reference:

• 1. MeReC Monthly No.17 August 2009.
• 2. MHRA: April 2010 Drug Safety Update
• 3.O'Donoghue ML et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009;374:989-97