Can i take omeprazole and esomeprazole together

Clopidogrel is indicated for the prevention of atherothrombotic events in patients who have had a myocardial infarction or ischaemic stroke, or who have established peripheral arterial disease. Combined with aspirin, the brand leader product (Plavix) may also be used to prevent atherothrombotic events in patients with acute coronary syndrome. Proton pump inhibitors (PPIs) are indicated for the treatment of oesophageal reflux disease, dyspepsia, or gastric ulcers, and are frequently co-prescribed with clopidogrel.

Previous advice regarding an interaction

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.

See Drug Safety Update, July 2009.

The 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.

New evidence

Since then, new evidence has become available which, although having some methodological limitations, casts some doubt on the clinical relevance of possible interactions between clopidogrel and PPIs. However, the evidence in favour of an interaction with omeprazole and esomeprazole is still a concern.

Recent (unpublished) mechanistic studies in healthy volunteers have indicated that the addition of omeprazole to clopidogrel therapy reduces the inhibition of platelet aggregation, whether the two medicines are given simultaneously or 12 hours apart.

However, post hoc analyses from the PRINCIPLE-TIMI and TRITON-TIMI trials found that use of PPIs (unspecified) reduced platelet function in patients who were randomly assigned clopidogrel, but did not affect clinical outcome.

Furthermore, the COGENT study, which randomly allocated patients to clopidogrel with or without omeprazole, found no effect of concomitant omeprazole on cardiovascular outcome (this study was terminated early after 133 days).

A retrospective study of cardiovascular and gastrointestinal outcome in patients on clopidogrel and aspirin with and without gastroprotective agents found that although PPI use was associated with an increase in adverse cardiovascular events, it was also associated with a significantly reduced incidence of upper GI bleeding.

Summary of available evidence

The 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.

It is possible that the findings of clinical studies for the different PPIs are inconsistent because there is true variation in the extent to which they interact with clopidogrel. This inconsistency may also reflect several variables including an individual’s pharmacogenetics, medication compliance, and comorbidities; the doses of clopidogrel and PPI; and the study design.

In light of the most recent evidence, the previous advice (to avoid all PPIs unless absolutely necessary for patients taking clopidogrel) is no longer considered necessary. Nevertheless, as a precaution, concomitant use of clopidogrel with omeprazole or esomeprazole should be discouraged. Information for prescribers and patients will be updated with the latest advice.

The current evidence does not support extending this advice to other PPIs. However, because it is not possible to completely exclude a possible interaction with these PPIs on the basis of available data, the potential risk of a slight reduction in efficacy of clopidogrel should be weighed against the potential gastrointestinal benefit of the PPI.

In August 2009 Medsafe advised prescribers it was reviewing a possible interaction between clopidogrel and proton pump inhibitors (PPIs).1 This review followed the publication of studies suggesting concomitant use of proton pump inhibitors can reduce the efficacy of clopidogrel.2,3

Clopidogrel inhibits platelet aggregation and is indicated for the prevention of vascular ischaemia associated with atherothrombotic events. Clopidogrel is a prodrug that is converted to its active form by drug metabolising enzymes CYP3A4 and 3A5, with contributions from CYP2C19, CYP2C9, and CYP1A2.

Proton pump inhibitors are frequently co-prescribed with clopidogrel to reduce the gastrointestinal irritation associated with clopidogrel use. Omeprazole is an inhibitor of CYP2C19.

A pharmacokinetic interaction between clopidogrel and omeprazole has now been confirmed following two pharmacokinetic/pharmacodynamic interaction studies. The results from these studies show that co-administration of clopidogrel with omeprazole results in significantly reduced exposure to the active metabolite of clopidogrel.

The first randomised crossover study involved 72 healthy subjects. In one treatment period subjects were given omeprazole (80mg/day) alone for a five day run-in period followed by clopidogrel (a single 300mg loading dose followed by a daily dose of 75 mg) and omeprazole (80mg/day) administered at the same time for a further five days. In the other treatment period subjects were given clopidogrel (300mg loading dose followed by 75mg/day) alone for five days. Subjects were crossed over to the alternate treatment period after a washout of at least 14 days.

When omeprazole was given with clopidogrel reductions of 42% and 40% were observed in maximum plasma concentration (Cmax) and exposure to (Area Under the Curve, AUC0-24) the active metabolite of clopidogrel, respectively (Table 1).

The second crossover study was identical in design except that clopidogrel and omeprazole were given 12 hours apart. Findings were similar to those in the first study indicating that administering clopidogrel and omeprazole at different times does not prevent this interaction (Table 1).

Table 1: Pharmacokinetic results

A 30% reduction in the mean inhibition of platelet aggregation was observed when omeprazole was given at the same time as clopidogrel compared to clopidogrel alone.4 Decreases in bleeding times and increases in platelet reactivity index were also observed, consistent with a reduction in anti-clotting ability.

Healthcare professionals are advised to avoid the concomitant use of clopidogrel with omeprazole and other CYP2C19 inhibitors e.g. esomeprazole, cimetidine, fluconazole, ketoconazole, viriconazole, etravirine, fluoxetine, and fluvoxamine.

Currently Medsafe does not have sufficient information about interactions between clopidogrel and PPIs other than omeprazole and esomeprazole to be able to make specific recommendations.

There is no evidence that other medicines that reduce stomach acid such as H2 receptor antagonists (except cimetidine) or antacids interfere with the anti-clotting activity of clopidogrel.

The New Zealand data sheets for clopidogrel will be updated to include information to avoid concomitant use with omeprazole and other CYP2C19 inhibitors.

Medsafe is continuing to monitor the evidence in relation to interactions between clopidogrel and PPIs other than omeprazole. Further advice will be communicated as more information becomes available.

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