Published: February 2010

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Clopidogrel and omeprazole - interaction now confirmed

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Prescriber Update 31(1): 2
February 2010

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 (C_max) and exposure to (Area Under the Curve, AUC_0-24) 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

	Ratio estimate clopidogrel + omeprazole vs clopidogrel alone (90%CI)
	Clopidogrel and omeprazole at the same time	Clopidogrel and omeprazole 12 hours apart
Cmax	0.58 (0.53-0.65)	0.44 (0.40-0.49)
AUC0-24	0.60 (0.56-0.65)	0.53 (0.50-0.57)

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.

References

1. Medsafe. 2009. Clopidogrel and proton pump inhibitors - possible interaction. Prescriber Update 30(3): 18.
2. Ho PM, Maddox TM, Wang L et al. 2009. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome JAMA 301(9): 937-44.
3. Juurlink DN, Gomes T, Ko DT et al. 2009. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel CMAJ 180:713-8.
   http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA/ Plavix Label Information dated 12 November 2009.