Omeprazole

Clopidogrel (Plavix®) and Proton Pump Inhibitors (PPIs): Ongoing Safety Review -
January 2009

The U.S. Food and Drug Administration (FDA) is communicating important information
regarding an ongoing safety review of clopidogrel and its effectiveness when used with
proton pump inhibitors (PPIs).

Clopidogrel is a prodrug requiring hepatic conversion via CYP3A4 and/or CYP2C19 to its
active metabolite. Impaired clopidogrel conversion to its active metabolite may be due to
either CYP450 polymorphisms or drug-drug interactions resulting in suboptimal antiplatelet
activity.

A PPI is often prescribed with the combination of aspirin and clopidogrel to prevent
gastrointestinal bleeding. A number of PPIs are available and include esomeprazole,
lansoprazole, omeprazole, pantoprazole, and rabeprazole. Several studies have reported
greater clinical event rates (eg, myocardial infarction, death) or greater platelet reactivity
associated with concurrent use of clopidogrel and a PPI (Ho, 2008; Pezella, 2008; Gilard,
2006). Similarly, a prospective, randomized, double-blind trial demonstrated a reduction in
antiplatelet activity when omeprazole and clopidogrel are used concurrently (Gilard, 2008).
Another controlled trial with the PPI lansoprazole also found evidence of a possible
interaction resulting in less antiplatelet activity (Small, 2008). This interaction is thought to
result from competitive inhibition of the CYP2C19-mediated activation of clopidogrel by
omeprazole and other PPIs, which are all metabolized to at least some degree by CYP2C19.
In contrast, one study with esomeprazole and pantoprazole did not find evidence of reduced
antiplatelet activity when administered with clopidogrel (Siller-Matula, 2009), highlighting
the need for additional studies to determine the degree to which individual PPIs may differ in
their potential for interacting with clopidogrel.

The manufacturer of Plavix® has agreed to conduct further studies to better understand the
effect of other drugs (including PPIs) and genetic factors on the effectiveness of clopidogrel.
The FDA is recommending that healthcare providers continue to prescribe clopidogrel while
reevaluating the need for prescription or over-the-counter (OTC) PPIs in patients taking
clopidogrel. Patients should continue taking clopidogrel as directed. If taking a PPI with
clopidogrel, patients should consult with their healthcare provider.

Use: Labeled Indications

Short-term (4-8 weeks) treatment of active duodenal ulcer disease or active benign gastric
ulcer; treatment of heartburn and other symptoms associated with gastroesophageal reflux
disease (GERD); short-term (4-8 weeks) treatment of endoscopically-diagnosed erosive
esophagitis; maintenance healing of erosive esophagitis; long-term treatment of pathological
hypersecretory conditions; as part of a multidrug regimen for H. pylori eradication to reduce
the risk of duodenal ulcer recurrence

OTC labeling: Short-term treatment of frequent, uncomplicated heartburn occurring ≥2

days/week

Use: Unlabeled/Investigational

Healing NSAID-induced ulcers; prevention of NSAID-induced ulcer; stress-ulcer prophylaxis

in the critically-ill

Dosing: Adults

Active duodenal ulcer: Oral: 20 mg/day for 4-8 weeks

Gastric ulcers: Oral: 40 mg/day for 4-8 weeks

Symptomatic GERD (without esophageal lesions): Oral: 20 mg/day for up to 4 weeks

Erosive esophagitis: Oral: 20 mg/day for 4-8 weeks; maintenance of healing: 20 mg/day for
up to 12 months total therapy (including treatment period of 4-8 weeks)

Peptic ulcer disease:Helicobacter pylori eradication: Oral: Dose varies with regimen: 40
mg/day as single dose or in 2 divided doses; requires combination therapy with
antibiotics for 10-14 days; may require an additional 14-18 days of Prilosec® 20
mg/day (monotherapy) after combination treatment complete if ulcer is present

Pathological hypersecretory conditions: Oral: Initial: 60 mg once daily; doses up to 120

mg 3 times/day have been administered; administer daily doses >80 mg in divided doses

Stress-ulcer prophylaxis (ICU patients; unlabeled use): Oral: 40 mg once daily;

periodically evaluate patient for continued need.

Frequent heartburn (OTC labeling): Oral: 20 mg/day for 14 days; treatment may be
repeated after 4 months if needed

Dosing: Elderly

Refer to adult dosing.

Dosing: Pediatric

GERD or other acid-related disorders: Oral: Children 1-16 years:

5 kg to <10 kg: 5 mg once daily

 10 kg to <20 kg: 10 mg once daily

≥20 kg: 20 mg once daily

Adverse Reactions

1% to 10%:

Central nervous system: Headache (3% to 7%), dizziness (2%)

Dermatologic: Rash (2%)

Gastrointestinal: Diarrhea (3% to 4%), abdominal pain (2% to 5%), nausea (2% to 4%),
vomiting (2% to 3%), flatulence (≤3%), acid regurgitation (2%), constipation
(1% to 2%), taste perversion

Neuromuscular & skeletal: Back pain (1%), weakness (1%)

Respiratory: Upper respiratory infection (2%), cough (1%)