Clopidogrel y la interaccion de sus metabolitos activos con IBP y otros

FDA: Avoid Coadministration of Clopidogrel and Omeprazole,
Esomeprazole

SILVER SPRING, November 2009 -- The US Food and Drug
Administration (FDA) has new data showing that the proton pump
inhibitor (PPI) omeprazole (Prilosec/Prilosec OTC) reduces the
anti-blood clotting effect of clopidogrel (Plavix) by almost half
when these 2 medicines are taken by the same patient. Patients at
risk for heart attacks or strokes who use clopidogrel to prevent
blood clots will not get the full effect of this medicine if they
are also taking omeprazole; therefore, the FDA recommends that the
coadministration of omeprazole and clopidogrel be avoided.

The new recommendations, updated from a January 2009 Early
Communication, are based on study results from the manufacturers of
clopidogrel. The studies confirm that coadministration of
omeprazole with clopidogrel results in decreased levels of
clopidogrel’s active metabolite, reducing clopidogrel’s
anticlotting effect.

Omeprazole inhibits the drug-metabolising enzyme (CYP2C19), which
is responsible for the conversion of clopidogrel into its active
metabolite. The new studies compared the amount of clopidogrel’s
active metabolite in the blood and its effect on platelets in
patients who took clopidogrel plus omeprazole versus those who took
clopidogrel alone. A reduction in active metabolite levels of about
45% was found in those who received clopidogrel with omeprazole
compared with those taking clopidogrel alone. The effect of
clopidogrel on platelets was reduced by as much as 47% in patients
receiving clopidogrel and omeprazole together. These reductions
were seen whether the drugs were given at the same time or 12 hours
apart.

Since the level of inhibition among other PPIs varies, it is
unknown to what amount other PPIs may interfere with clopidogrel.
However, esomeprazole (Nexium), a PPI that is a component of
omeprazole, inhibits CYP2C19 and should also be avoided in
combination with clopidogrel.

Other stomach acid-reducing drugs, such as ranitidine (Zantac),
famotidine (Pepcid), nizatidine (Axid), or antacids, are not
expected to interfere with the anticlotting activity of clopidogrel
because they do not inhibit CYP2C19 activity. However, cimetidine
(Tagamet/Tagamet HB) does inhibit CYP2C19 activity and should not
be used.
In addition to cimetidine, other drugs that are potent inhibitors
of the CYP2C19 enzyme would be expected to have a similar effect
and should be avoided in combination with clopidogrel. These
include fluconazole (Diflucan), ketoconazole (Nizoral),
voriconazole (VFEND), etravirine (Intelence), felbamate (Felbatol),
fluoxetine (Prozac, Sarafem, Symbyax), fluvoxamine (Luvox), and
ticlopidine (Ticlid).

Sanofi-aventis and Bristol-Myers Squibb, the makers of Plavix
(clopidogrel), are updating this drug’s label with the details of
the studies and are conducting follow-up studies to further explore
drug interactions with clopidogrel.

Until further information is available, FDA recommends the
following:
• The concomitant use of omeprazole and clopidogrel should be
avoided because of the effect on clopidogrel’s active metabolite
levels and anticlotting activity. Patients at risk for heart
attacks or strokes, who are given clopidogrel to prevent blood
clots, may not get the full protective anticlotting effect if they
also take prescription omeprazole or the OTC form.
• Separating the dose of clopidogrel and omeprazole in time will
not reduce this drug interaction.
• Other drugs that should be avoided in combination with
clopidogrel because they may have a similar interaction include
esomeprazole, cimetidine, fluconazole, ketoconazole, voriconazole,
etravirine, felbamate, fluoxetine, fluvoxamine, and ticlopidine.
• At this time the FDA does not have sufficient information about
drug interactions between clopidogrel and PPIs other than
omeprazole and esomeprazole to make specific recommendations about
their coadministration. Healthcare professionals and patients
should consider all treatment options carefully before beginning
therapy.
• There is no evidence that other drugs that reduce stomach acid,
such as most H2 blockers ranitidine (Zantac), famotidine (Pepcid),
nizatidine (Axid), except cimetidine (Tagamet and Tagamet HB - a
CYP2C19 inhibitor), or antacids interfere with the anticlotting
activity of clopidogrel. Ranitidine and famotidine are available by
prescription and OTC to relieve and prevent heartburn and antacids
are available OTC to relieve heartburn.
• Talk with your patients about the OTC medicines they take. Be
aware that patients may be taking nonprescription forms of
omeprazole and cimetidine.
The FDA will continue to investigate other drug interactions with
clopidogrel. The FDA plans on presenting this issue at the next
meeting of the FDA’s Drug Safety Oversight Board in November. The
Agency will communicate any further recommendations or conclusions
once additional information is available.