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FDA Approves Byvalson

Allergan Announces FDA Approval of Byvalson (nebivolol and valsartan) for Hypertension

DUBLIN, June 6, 2016 /PRNewswire/ -- Allergan plc (NYSE: AGN), a leading global pharmaceutical company, today announced the approval of Byvalson (nebivolol and valsartan) 5 mg/ 80 mg tablets, by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension to lower blood pressure. Byvalson is the first and only fixed-dose combination (FDC) of a beta blocker (BB) and angiotensin II receptor blocker (ARB) available in the U.S.

"Achieving blood pressure control is critical to reducing the risk of serious and life-threatening cardiovascular events. There remains a need for new therapies, as observed by the nearly half of patients in the U.S. who remain uncontrolled," said David Nicholson, Chief R&D Officer at Allergan. "We are pleased with the FDA approval of Byvalson, which will provide physicians a new fixed dose combination therapy treatment option for patients affected by hypertension."

Hypertension represents a significant public health problem with high prevalence in the U.S. Hypertension often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke, heart failure, and myocardial infarction. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the beta-blocker class to which nebivolol principally belongs and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Byvalson.

"The majority of patients with hypertension require two or more medications to achieve their blood pressure goals," said William B White, MD Professor of Medicine and Chief of the Division of Hypertension and Clinical Pharmacology, Calhoun Cardiology Center at UConn Health in Farmington and immediate past president of the American Society of Hypertension. "Nebivolol and valsartan are used widely in the management of hypertension and are effective drugs. The new fixed-dose combination Byvalson, that includes these 2 therapies, offers reduction of blood pressure through multiple mechanisms of action."

The FDA approval of Byvalson was based on a Phase 3, double-blind, placebo-controlled, dose-escalating, 8-week efficacy and safety study, published in The Lancet, which randomized approximately 4,100 patients with Stage 1 or 2 hypertension. In this pivotal efficacy and safety study, treatment with the FDC of nebivolol and valsartan for 4 weeks demonstrated statistically significant reductions from baseline in diastolic and systolic blood pressure versus either nebivolol alone or valsartan alone. The overall rate of adverse events was similar across treatment groups and placebo during this 4 week period.

Allergan expects Byvalson to be available in the 2nd half of 2016.

About Byvalson

Byvalson (nebivolol/valsartan) 5 mg/ 80 mg tablet is a fixed-dose combination that combines two FDA approved, once daily, blood pressure lowering agents with different mechanisms of action.

Nebivolol (marketed in the U.S. as Bystolic) is a beta-adrenergic receptor blocking agent that is preferentially beta-1 selective up to and including the 10 mg dose and in extensive metabolizers. While nebivolol's mechanism of action has not been definitively established, possible factors include vasodilation and decreased peripheral vascular resistance (PVR), reduced heart rate and myocardial contractility, suppression of renin, and reduced sympathetic activity.

Valsartan is an angiotensin II receptor blocker (ARB) that blocks the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland, thereby blocking its vasoconstrictor and aldosterone-secreting effects.

As of 2015 data, the worldwide exposure of each component drug has been ~50 million patient-years for nebivolol and ~200 million patient-years for valsartan.

INDICATIONS AND USAGE

Byvalson is indicated for the treatment of hypertension, to lower blood pressure.­­ Byvalson may be used alone or in combination with other antihypertensive agents. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes, including the beta-blocker class to which nebivolol principally belongs and the ARB class to which valsartan principally belongs. There are no controlled trials demonstrating risk reduction with Byvalson.

IMPORTANT SAFETY INFORMATION

WARNING: FETAL TOXICITY

When pregnancy is detected, discontinue Byvalson as soon as possible. Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.

Contraindications

Byvalson is contraindicated in the following conditions: severe bradycardia, heart block greater than first degree, patients with cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), patients with severe hepatic impairment (Child-Pugh >B), and patients who are hypersensitive to any component of this product. Do not co-administer aliskiren with Byvalson in patients with diabetes.

Warnings and Precautions

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. Resulting oligohydramnios can be associated with fetal lung hypoplasia and skeletal deformations. Potential neonatal adverse effects include skull hypoplasia, anuria, hypotension, renal failure, and death. When pregnancy is detected, discontinue Byvalson as soon as possible.

In patients with an activated renin-angiotensin-aldosterone system, such as volume- and/or salt-depleted patients (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur in patients receiving Byvalson. Correct these conditions prior to administration of Byvalson, or start the treatment under close medical supervision. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Do not abruptly discontinue Byvalson in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction and ventricular arrhythmias have been reported in patients with coronary artery disease following the abrupt discontinuation of therapy with beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. As with other beta-blocker therapies, when discontinuation of Byvalson is planned, carefully observe and advise patients to minimize physical activity. Taper nebivolol using monotherapy over 1 to 2 weeks when possible. If the angina worsens re-start nebivolol promptly, at least temporarily.

Worsening heart failure or fluid retention may occur during nebivolol therapy because of its beta-blocking effects. Consider diuretic therapy and treat heart failure appropriately, according to current guidelines.

In general, patients with bronchospastic diseases should not receive beta blockers.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.

Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor heart rate and blood pressure in patients treated concomitantly with these agents.

Changes in renal function, including acute renal failure, can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system (e.g. patients with renal artery stenosis, chronic kidney disease, severe congestive heart failure, or volume depletion) may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan.

While taking beta blockers, patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated accidental, diagnostic, or therapeutic challenge. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.

In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of valsartan-treated patients compared to 2.9% of placebo-treated patients. Discontinuation of Byvalson may be required.

About Hypertension

According to the U.S. Centers for Disease Control and Prevention, hypertension has been called the "silent killer" because it often has no warning signs or symptoms and has been associated with serious cardiovascular (CV) risks, such as stroke and myocardial infarction. Hypertension represents a significant public health issue with high prevalence in the United States. According to the National Institute for Health Statistics, approximately 30 percent of adults in the U.S. have hypertension. Inadequate control of hypertension is a significant public health problem, with approximately half of all patients still not achieving target goals. Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce CV morbidity and mortality, and it can be concluded that it is blood pressure reduction that is largely responsible for those benefits. In addition, approximately two-thirds of hypertensive patients will require more than one drug to achieve blood pressure goals.

About Allergan

Allergan plc (NYSE: AGN), headquartered in Dublin, Ireland, is a unique, global pharmaceutical company and a leader in a new industry model – Growth Pharma. Allergan is focused on developing, manufacturing and commercializing innovative branded pharmaceuticals, high-quality generic and over-the-counter medicines and biologic products for patients around the world.

Allergan markets a portfolio of best-in-class products that provide valuable treatments for the central nervous system, eye care, medical aesthetics, gastroenterology, women's health, urology, cardiovascular and anti-infective therapeutic categories, and operates the world's third-largest global generics business, providing patients around the globe with increased access to affordable, high-quality medicines. Allergan is an industry leader in research and development, with one of the broadest development pipelines in the pharmaceutical industry and a leading position in the submission of generic product applications globally.

With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives.

For more information, visit Allergan's website at www.allergan.com.

Allergan Forward-Looking Statement

Statements contained in this press release that refer to future events or other non-historical facts are forward-looking statements that reflect Allergan's current perspective of existing trends and information as of the date of this release. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements. Actual results may differ materially from Allergan's current expectations depending upon a number of factors affecting Allergan's business. These factors include, among others, the risks associated with acquisition transactions; the difficulty of predicting the timing or outcome of FDA approvals or actions, if any; the impact of competitive products and pricing; market acceptance of and continued demand for Allergan's products; difficulties or delays in manufacturing; and other risks and uncertainties detailed in Allergan's periodic public filings with the Securities and Exchange Commission, including but not limited to Allergan's Quarterly Report on Form 10-Q for the quarter ended March 31, 2016 (such periodic public filings having been filed under the "Actavis plc" name) and from time to time in Allergan's other investor communications. Except as expressly required by law, Allergan disclaims any intent or obligation to update these forward-looking statements.

SOURCE Allergan plc

Posted: June 2016

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