Study results announced at the American College of Cardiology (ACC) 2011

New Orleans, La., April 5, 2011 — Takeda Pharmaceuticals North America, Inc. (Takeda) announced the presentation of new study results, which evaluated the potential inhibitory effects of certain proton pump inhibitors (PPIs) on Plavix (clopidogrel bisulfate). The results showed that in healthy subjects, clopidogrel’s active metabolite and inhibition of platelet function were reduced less by the co-administration of clopidogrel with dexlansoprazole or lansoprazole, rather than esomeprazole. The randomized, open-label, two-period, crossover study was designed to assess the effects of selected PPIs, a class of drugs used to treat gastroesophageal reflux disease, on the pharmacokinetics (PK) and pharmacodynamics (PD) of clopidogrel. Clopidogrel is a platelet-inhibiting 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. The results were presented at the American College of Cardiology (ACC) 2011 60th Annual Scientific Session in New Orleans.

Studies have shown that PPIs may inhibit a liver enzyme (CYP2C19) important for the metabolism of clopidogrel. With CYP2C19 inhibition, clopidogrel may have reduced antiplatelet effects, potentially reducing its effectiveness. Because PPIs differ in their degree of inhibition of CYP2C19, using omeprazole as a positive control, this study evaluated the effect of several PPIs (dexlansoprazole, lansoprazole and esomeprazole) on the steady-state PK and PD of clopidogrel in healthy subjects.

“We conducted this study to look at the effect of select PPIs on Plavix and add to the growing body of evidence on the potential interaction between these drugs,” said lead investigator Alan D. Michelson, M.D., Professor of Pediatrics at Harvard Medical School and Director of the Center for Platelet Research Studies at Children’s Hospital Boston. “We found that in healthy subjects the co-administration of Plavix with dexlansoprazole or lansoprazole reduced the antiplatelet effect of Plavix less than the co-administration of Plavix with esomeprazole.”

The study showed that, while all PPIs decreased clopidogrel active metabolite peak plasma concentration, the area under the curve (AUC) decreased with treatment with esomeprazole, but not with dexlansoprazole or lansoprazole. The effect of PPI co-administration on clopidogrel’s ability to inhibit platelet function varied among PPIs, with significant reductions in platelet reactivity index (PRI) for esomeprazole, but not for dexlansoprazole or lansoprazole. Esomeprazole reduced maximal platelet aggregation (MPA) and platelet response unit (PRU) more than dexlansoprazole or lansoprazole.

“Because there are many patients taking both a PPI and Plavix, it is important to gain a better understanding of how these medications interact with each other,” said Gilles Delecoeuillerie, M.D., executive medical director, Medical & Scientific Affairs, Gastroenterology and Internal Medicine, Takeda. “This was the first prospective randomized study to comparatively assess the effects of certain PPIs, including dexlansoprazole, on the pharmacokinetic and pharmacodynamic characteristics of clopidogrel. Its results offer health care providers further information regarding the potential interaction between clopidogrel and several PPIs.”

About This Study

In this study, healthy adult subjects (n=160; 40 per PPI) were randomized to one of four PPIs (60 mg of dexlansoprazole, 30 mg of lansoprazole, 40 mg of esomeprazole, or 80 mg of omeprazole as a positive control to maximize potential interaction and demonstrate assay sensitivity). Subjects received either clopidogrel alone followed by a washout period and then clopidogrel with a PPI, or clopidogrel with a PPI followed by a washout period and then clopidogrel alone. Clopidogrel 75 mg with or without a PPI was given daily for 9 days, and PK and PD data were collected on day 9 of each 10-day period. PK endpoints were maximum plasma concentration (Cmax) and the area under the plasma concentration curve (AUC) for the active metabolite of clopidogrel, and PD endpoints were platelet reactivity index (PRI), maximal platelet aggregation (MPA) and platelet response units (PRU).

About DEXILANT (dexlansoprazole) 30 mg and 60 mg delayed release capsules

DEXILANT is a proton pump inhibitor (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, taken once daily, is approved in adults for the healing of all grades of erosive esophagitis (EE) for up to eight weeks, maintaining healing of EE for up to six months, and treating heartburn associated with symptomatic non-erosive gastroesophageal reflux disease (GERD) for four 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. The most commonly reported treatment-emergent adverse reactions include diarrhea (4.8%), abdominal pain (4.0%), nausea (2.9%), upper respiratory tract infection (1.9%), vomiting (1.6%), and flatulence (1.6%). DEXILANT must not be co-administered with atazanavir because atazanavir systemic concentrations may be substantially decreased. DEXILANT may interfere with the 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 click here for full prescribing information and visit the DEXILANT Web site at www.DEXILANT.com.

Uses of PREVACID (lansoprazole) 15 mg and 30 mg Delayed Release Capsules

In adults, the indications for PREVACID include the treatment of heartburn and other symptoms associated with GERD (up to eight weeks), short-term treatment (up to eight weeks) for healing and symptom relief of all grades of erosive esophagitis (EE), and to maintain healing of EE (controlled studies did not extend beyond 12 months).

Important Safety Information

PREVACID is contraindicated in patients with known hypersensitivity to any component of the formulation. Symptomatic response to therapy 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.

Most commonly reported adverse reactions for PREVACID were diarrhea (3.8%), abdominal

pain (2.1%), nausea (1.3%) and constipation (1%).

Do not co-administer atazanavir with PREVACID because atazanavir systemic concentrations may be substantially decreased. PREVACID may interfere with absorption of drugs for which gastric pH is important for bioavailability (e.g., ampicillin esters, digoxin, iron salts, ketoconazole). Patients treated with PREVACID and warfarin concomitantly may need to be monitored 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. Titration of theophylline dosage may be required when concomitant PREVACID use is started or stopped.

Please click here for full prescribing information for PREVACID.

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.

The American College of Cardiology

The American College of Cardiology is transforming cardiovascular care and improving heart health through continuous quality improvement, patient-centered care, payment innovation and professionalism. The College is a 39,000-member nonprofit medical society comprised of physicians, surgeons, nurses, physician assistants, pharmacists and practice managers, and bestows credentials upon cardiovascular specialists who meet its stringent qualifications. The College is a leader in the formulation of health policy, standards and guidelines, and is a staunch supporter of cardiovascular research. The ACC provides professional education and operates national registries for the measurement and improvement of quality care. More information about the association is available online at http://www.cardiosource.org/ACC.

Source: Takeda Pharmaceuticals