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American Journal of Medicine Publishes Hypertension Study Comparing the Fixed-Dose Combination of Azilsartan Medoxomil and Chlorthalidone versus Azilsartan Medoxomil Co-administered with Hydrochlorothiazide
Date:9/5/2012

DEERFIELD, Ill., Sept. 5, 2012 /PRNewswire/ -- Results of a 10-week, phase 3 study published online in the American Journal of Medicine found the clinic systolic blood pressure (SBP) reductions of a fixed-dose combination of azilsartan medoxomil and chlorthalidone were significantly greater at six and ten weeks than those of azilsartan medoxomil co-administered with hydrochlorothiazide. Data also showed that more patients achieved their target blood pressure levels at the end of six and 10 weeks (secondary endpoints) when taking the azilsartan medoxomil and chlorthalidone fixed-dose combination.

"Hypertension management can be complex, and the use of combination therapy with a diuretic is a common treatment approach," said study co-author William C. Cushman, M.D., professor of preventive medicine at the University of Tennessee College of Medicine in Memphis, Tenn. "While hydrochlorothiazide is more commonly used in clinical practice, this study provides further support for the use of chlorthalidone in fixed-dose combination for patients with hypertension."

About the Study
The 10-week, randomized, double-blind, titrate-to-target study compared blood pressure reductions of the fixed-dose combination of azilsartan medoxomil and chlorthalidone to azilsartan medoxomil co-administered with hydrochlorothiazide among 609 patients with stage 2 hypertension. The average age of patients in the study was 56.4 years and the average baseline clinic blood pressure was 164.6/95.4 mm Hg. After two weeks of treatment with azilsartan medoxomil (40 mg) alone, patients received 12.5 mg of either diuretic for four weeks (up to week 6) and were then titrated to 25 mg for another four weeks (up to week 10) if they had not achieved their target blood pressure; otherwise, patients continued their initial dose.

Primary endpoint data showed that at week 6, the clinic SBP reductions of the fixed-dose combination of azilsartan medoxomil and chlorthalidone were -35.1 mm Hg. These data were statistically significantly (P<0.001) greater than those of azilsartan medoxomil and hydrochlorothiazide (-29.5 mm Hg) with a mean difference of -5.6 mm Hg. At the end of 10 weeks, greater clinic SBP reductions were maintained in patients taking the fixed-dose combination of azilsartan medoxomil and chlorthalidone (-37.8 mm Hg) versus those taking azilsartan medoxomil and hydrochlorothiazide (-32.8 mm Hg) with a mean difference of -5.0 mm Hg.

Additionally, secondary endpoint data showed that a greater proportion of patients taking the fixed-dose combination of azilsartan medoxomil and chlorthalidone achieved their target blood pressure versus those taking azilsartan medoxomil and hydrochlorothiazide at the end of both six weeks (64.1 percent vs. 45.9 percent) and 10 weeks (71.5 percent vs. 62.3 percent).

Adverse events leading to permanent drug discontinuation occurred in 9.3 percent of patients taking the fixed-dose combination of azilsartan medoxomil and chlorthalidone and 7.3 percent of patients taking azilsartan medoxomil co-administered with hydrochlorothiazide. The most common adverse events accounting for study drug discontinuation were dizziness (1.0 percent versus 1.7 percent) and increased serum creatinine (4.0 percent versus 2.0 percent) in the fixed-dose combination of azilsartan medoxomil and chlorthalidone and azilsartan medoxomil and hydrochlorothiazide groups, respectively. The most common adverse events (greater or equal to five percent in either group) were increased blood creatinine, dizziness and headache. Serum potassium levels below 3.4 mmol/L were observed in 1.7 percent and 0.3 percent of patients in the fixed-dose combination of azilsartan medoxomil and chlorthalidone and azilsartan medoxomil and hydrochlorothiazide groups, respectively.

Edarbyclor (azilsartan medoxomil and chlorthalidone) was approved by the U.S. Food and Drug Administration in December 2011 for the treatment of hypertension to lower blood pressure in adults. It is the first and only hypertension medication to combine an angiotensin II receptor blocker (ARB) with the diuretic chlorthalidone in a once-daily, single tablet.

About Hypertension
Hypertension, or high blood pressure, is a chronic medical condition in which blood pressure is elevated to levels of 140 mm Hg or greater systolic and/or 90 mm Hg or greater diastolic. Hypertension impacts approximately 76 million Americans, or nearly one in three adults. It is estimated that nearly one billion people are affected by hypertension worldwide, and this figure is predicted to increase to 1.5 billion by 2025. Hypertension typically has no symptoms. Adults of all ages and backgrounds can develop hypertension; however, the risk of developing the condition increases with age, with more than half of people over age 60 affected in the U.S.

Elevated systolic or diastolic pressure increases cardiovascular risk, and lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and heart attacks. The absolute risk increase per mm Hg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit.

Hypertension is also costly to the nation's health care system. The American Heart Association recently estimated that direct and indirect expenses associated with hypertension cost the nation more than $73 billion in 2009.

About Edarbyclor
Azilsartan medoxomil and chlorthalidone (currently marketed as Edarbyclor) is a fixed-dose combination therapy in a single tablet for the treatment of hypertension. Azilsartan medoxomil is an angiotensin II receptor blocker that blocks the action of angiotensin II, a hormone that naturally exists in the body. Chlorthalidone is a diuretic that reduces the amount of salt and water in the body by increasing the flow of urine. Edarbyclor is indicated for the treatment of hypertension to lower blood pressure in adults and may be used in patients not adequately controlled with monotherapy and as an initial therapy if a patient is likely to need multiple drugs to help achieve blood pressure goals. The recommended starting dose in adults is 40/12.5 mg taken orally once daily. The maximum recommended dose is 40/25 mg.

Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and heart attacks. There are no controlled trials demonstrating risk reduction with Edarbyclor, but trials with chlorthalidone and at least one pharmacologically similar drug to azilsartan medoxomil have demonstrated such benefits. For example, ALLHAT and SHEP were landmark clinical trials that have shown that long-term use of chlorthalidone at doses of 12.5 mg to 25 mg was associated with reductions in risk of serious cardiovascular events, such as heart attack and stroke.

Important Safety Information
WARNING: FETAL TOXICITY See full Prescribing Information for complete boxed warning.
When pregnancy is detected, discontinue Edarbyclor as soon as possible.
Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Edarbyclor is contraindicated in patients with anuria.

Fetal Toxicity: Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue Edarbyclor as soon as possible. Thiazides cross the placental barrier and appear in cord blood and may be associated with adverse reactions, including fetal or neonatal jaundice and thrombocytopenia.

In patients with an activated renin-angiotensin-aldosterone system (RAAS), such as volume- and/or salt-depleted patients, Edarbyclor can cause excessive hypotension. Correct volume or salt depletion prior to administration of Edarbyclor.

Monitor for worsening renal function in patients with renal impairment. In patients whose renal function may depend on the activity of the renin-angiotensin system, treatment with ACE inhibitors and ARBs has been associated with oliguria or progressive azotemia and rarely with acute renal failure and death. In patients with renal artery stenosis, Edarbyclor may cause renal failure. In patients with renal disease, chlorthalidone may precipitate azotemia. Consider withholding or discontinuing Edarbyclor if progressive renal impairment becomes evident.

Hypokalemia is a dose-dependent adverse reaction that may develop with chlorthalidone. Coadministration of digitalis may exacerbate the adverse effects of hypokalemia. Edarbyclor attenuates chlorthalidone-associated hypokalemia.

Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving chlorthalidone or other thiazide diuretics.

Adverse Reactions (AEs): AEs that occurred at an incidence of ≥2% of Edarbyclor -treated patients and greater than azilsartan medoxomil or chlorthalidone were dizziness (8.9%) and fatigue (2.0%).

Incidence of consecutive elevations of creatinine (≥50% from baseline and >ULN) was 2% and were typically transient, or nonprogressive and reversible, and associated with large blood pressure reductions.

Drug Interactions: Renal clearance of lithium is reduced by diuretics, such as chlorthalidone, increasing the risk of lithium toxicity. Monitor renal function periodically in patients receiving Edarbyclor and NSAIDs who are also elderly, volume-depleted (including those on diuretics), or who have compromised renal function due to potential reversible deterioration of renal function. NSAIDs may interfere with antihypertensive effect.

For further information, please click here for complete Edarbyclor Prescribing Information.

Indications and Usage
Edarbyclor is an angiotensin II receptor blocker (ARB) and a thiazide-like diuretic combination product indicated for the treatment of hypertension to lower blood pressure. Edarbyclor may be used if a patient is not adequately controlled on monotherapy or as initial therapy if multiple drugs are needed to help achieve blood pressure goals. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. There are no controlled trials demonstrating risk reduction with Edarbyclor, but trials with chlorthalidone and at least one pharmacologically similar drug to azilsartan medoxomil have demonstrated such benefits. 

Control of high blood pressure should be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. Many patients will require more than one drug to achieve blood pressure goals. Edarbyclor may be used with other antihypertensive agents.

Takeda Pharmaceuticals U.S.A., Inc. and Takeda Global Research & Development Center, Inc.
Based in Deerfield, Ill., Takeda Pharmaceuticals U.S.A., 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, gastroenterology, and cardiovascular treatments and seek to bring innovative products to patients through a pipeline that includes compounds in development for metabolic and cardiovascular disease, gastroenterology, neurology and other conditions. To learn more about these Takeda companies, visit www.tpna.com.

Contacts:
Jocelyn Gerst
Corporate Communications
Takeda Pharmaceuticals U.S.A., Inc.
224-554-5542
jocelyn.gerst@takeda.com

Jaimee Lumm
GolinHarris
312-729-4276
jlumm@golinharris.com


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SOURCE Takeda Pharmaceuticals U.S.A., Inc.
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