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DEXILANT (dexlansoprazole) Product Information Updated Regarding Coadministration with Plavix (clopidogrel bisulfate)

November 17, 2011

No dose adjustment of clopidogrel necessary when administered with approved dose of DEXILANT

DEERFIELD, Ill., November 17, 2011 - Today, Takeda Pharmaceuticals North America, Inc., (Takeda) announced the DEXILANT (dexlansoprazole) product labeling now includes information from a study in healthy subjects demonstrating that DEXILANT had no clinically important effect on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition. No dose adjustment of clopidogrel is necessary when administered with an approved dose of DEXILANT. DEXILANT is a proton pump inhibitor (PPI) indicated for the treatment of gastroesophageal reflux disease (GERD). GERD affects nearly 19 million Americans.

Clopidogrel is an antiplatelet drug that is indicated for the reduction of atherothrombotic events in patients with acute coronary syndromes, recent myocardial infarction, recent stroke or established peripheral arterial disease. Studies have suggested that, to varying degrees, PPIs inhibit the enzyme (CYP2C19), which metabolizes clopidogrel to its active form. Since 2009 the U.S. Food and Drug Administration (FDA) has issued multiple communications stating that the concomitant use of clopidogrel and omeprazole be avoided.

"An estimated 25 million prescriptions were dispensed for clopidogrel last year, and given the high prevalence of gastroesophageal reflux disease, it is likely that some of these same patients may also be taking a PPI for their GERD," said David A. Johnson, M.D., FACG, FASGE, professor of Medicine, chief of Gastroenterology, Eastern Virginia School of Medicine, Norfolk, VA. "The study findings are important because as health care providers we have a responsibility to find appropriate treatment regimens for these patients without potentially reducing the intended anti-platelet effects of Plavix."

About the DEXILANT and Clopidogrel Study
Takeda conducted a randomized, open-label, two-period, crossover study to evaluate the effect of DEXILANT on the pharmacokinetics and pharmacodynamics of clopidogrel in healthy subjects. The study showed that the area under the curve (AUC) of the active metabolite of clopidogrel was reduced by approximately 9 percent (mean AUC ratio was 91 percent, with 90 percent CI of 86-97 percent) when DEXILANT was coadministered compared to administration of clopidogrel alone.

Pharmacodynamic parameters were also measured and demonstrated that the change in inhibition of platelet aggregation (induced by 5 mcM ADP) was related to the change in the exposure to clopidogrel active metabolite. The clinical significance of this finding is not clear. These results were presented at the American College of Cardiology (ACC) 2011 60th Annual Scientific Session in April 2011.

Takeda worked with the FDA to determine the appropriate information to be included in the revised DEXILANT product labeling. This information can be found in the labeling's Drug Interactions and Clinical Pharmacology sections. The Drug Interactions section specifically states that no dose adjustment of Plavix is necessary when administered with an approved dose of DEXILANT.

"We are pleased to add this information into the DEXILANT labeling enabling us to provide a clearer understanding for health care prescribers about the co-administration of DEXILANT and Plavix," said Gilles Delecoeuillerie, M.D., Ph.D., executive medical director, Medical & Scientific Affairs, Gastroenterology and Internal Medicine, Takeda. "Takeda conducted this study to further understand how DEXILANT may interact with clopidogrel and to ensure that patients with GERD, who are treated with both medications, have the most up to date coadministration information."

About DEXILANT (dexlansoprazole) 30 mg and 60 mg delayed release capsules
DEXILANT is a PPI, which decreases acid production by turning off many of the acid pumps in the stomach, thus helping to protect the esophagus from acidic reflux so that esophageal inflammation can heal. DEXILANT combines an enantiomer of lansoprazole with a Dual Delayed Release (DDR) formulation designed to provide two separate releases of medication. DEXILANT is indicated for healing all grades of erosive esophagitis (EE) for up to 8 weeks, maintaining healing of EE and relief of heartburn for up to 6 months, and treating heartburn associated with symptomatic non-erosive GERD for 4 weeks.

Important Safety Information
DEXILANT is contraindicated in patients with known hypersensitivity to any component of the formulation. Hypersensitivity and anaphylaxis have been reported with DEXILANT use. Symptomatic response with DEXILANT does not preclude the presence of gastric malignancy. Long-term and multiple daily dose PPI therapy may be associated with an increased risk for osteoporosis-related fractures of the hip, wrist, or spine. Patients should use the lowest dose and shortest duration of PPI therapy appropriate to the condition being treated. Hypomagnesemia has been reported rarely with prolonged treatment with PPIs.

Most commonly reported adverse reactions were diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). Do not co-administer atazanavir with DEXILANT because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients taking concomitant warfarin may require monitoring for increases in international normalized ratio (INR) and prothrombin time. Increases in INR and prothrombin time may lead to abnormal bleeding and even death. Concomitant tacrolimus use may increase tacrolimus whole blood concentrations.

Please see accompanying full prescribing information and visit the DEXILANT Website at www.DEXILANT.com.

Takeda Pharmaceuticals North America, Inc. and Takeda Global Research & Development Center, Inc.
Based in Deerfield, Ill., Takeda Pharmaceuticals North America, Inc. and Takeda Global Research & Development Center, Inc. are subsidiaries of Takeda Pharmaceutical Company Limited, the largest pharmaceutical company in Japan. The respective companies currently market oral diabetes, insomnia, rheumatology and gastroenterology treatments and seek to bring innovative products to patients through a pipeline that includes compounds in development for diabetes, cardiovascular disease, gastroenterology, neurology and other conditions. To learn more about these Takeda companies, visit www.tpna.com.

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Jocelyn Gerst
Takeda Pharmaceuticals North America, Inc.
[email protected]

Carrie Rose
[email protected]