Kowa Pharmaceuticals America, Inc. Enters into Co-Promotion Agreement with Allergan for BYSTOLIC® (nebivolol) in the United States

“Kowa has a long history of successfully co-promoting products within the cardiometabolic space, and this new partnership with Allergan aligns closely with our focus and expertise in the area of cardiometabolic diseases,” said Ben Stakely, Chairman, CEO and President of Kowa Pharmaceuticals America, Inc. “We remain committed to patients and healthcare professionals, and to providing therapies that help address serious and chronic conditions including high cholesterol and high blood pressure. Adding BYSTOLIC to our product portfolio expands our offering and will enhance our ability to support patients suffering from these diseases, which represent a significant public health issue.”

Under the terms of the co-promotion agreement, Kowa will deploy its approximately 300 cardiometabolic sales specialists to promote BYSTOLIC to cardiologists and select primary care healthcare providers, starting in February. Allergan will continue to promote BYSTOLIC to primary care healthcare providers.

The financial terms of this non-exclusive co-promotion agreement were not disclosed.

About High Cholesterol

High cholesterol is defined as total cholesterol ≥240 mg/dL based on guidelines from the National Institutes of Health (NIH). When cholesterol levels rise, thick, hard buildup can occur in the artery wall, narrowing arteries and slowing down or even blocking blood flow to the heart and brain. High cholesterol is a major risk for stroke and heart disease, the leading causes of death in the United States.¹ It can be lowered through a healthy diet, exercise, and by taking a medication (like a statin) as recommended by a physician.

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 LIVALO

LIVALO is an HMG-CoA reductase inhibitor (statin).

INDICATIONS AND USAGE

Drug therapy should be one component of multiple-risk-factor intervention in individuals who require modifications of their lipid profile. Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol only when the response to diet and other nonpharmacological measures has been inadequate.

PRIMARY HYPERLIPIDEMIA AND MIXED DYSLIPIDEMIA

LIVALO (pitavastatin) is indicated as an adjunctive therapy to diet to reduce elevated total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (Apo B), triglycerides (TG), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hyperlipidemia or mixed dyslipidemia.

LIMITATIONS OF USE

• Doses of LIVALO greater than 4 mg once daily were associated with an increased risk for severe myopathy in premarketing clinical studies. Do not exceed 4-mg, once-daily dosing of LIVALO
• The effect of LIVALO on cardiovascular morbidity and mortality has not been determined
• LIVALO has not been studied in Fredrickson Type I, III, and V dyslipidemias

Important Safety Information for LIVALO^® (pitavastatin) tablets

CONTRAINDICATIONS

LIVALO is contraindicated in patients with a known hypersensitivity to product components, in patients with active liver disease (which may include unexplained persistent elevations in hepatic transaminase levels), in women who are pregnant or may become pregnant, in nursing mothers, or in co-administration with cyclosporine.

WARNINGS AND PRECAUTIONS

Skeletal Muscle Effects

Cases of myopathy and rhabdomyolysis with acute renal failure secondary to myoglobinuria have been reported with HMG-CoA reductase inhibitors, including LIVALO. These risks can occur at any dose level, but increase in a dose-dependent manner.

• LIVALO should be prescribed with caution in patients with predisposing factors for myopathy.
• The risk of skeletal muscle effects (e.g., myopathy and rhabdomyolysis) increases in a dose-dependent manner with advanced age (≥65 years), renal impairment, inadequately treated hypothyroidism, and in combination use with fibrates or lipid-modifying doses of niacin (≥1 g/day).
• LIVALO should be administered with caution in patients with impaired renal function, in elderly patients, or when used concomitantly with fibrates or lipid-modifying doses of niacin.
• Concomitant administration of LIVALO with gemfibrozil should be avoided.
• LIVALO therapy should be discontinued if markedly elevated CK levels occur or myopathy is diagnosed or suspected. LIVALO therapy should also be temporarily withheld in any patient with an acute, serious condition suggestive of myopathy or predisposing to the development of renal failure secondary to rhabdomyolysis (e.g., sepsis; hypotension; dehydration; major surgery; trauma; severe metabolic, endocrine, and electrolyte disorders; or uncontrolled seizures).
• Advise patients to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever, and to discontinue LIVALO if these signs or symptoms appear.
• Cases of myopathy, including rhabdomyolysis, have been reported with HMG-CoA reductase inhibitors coadministered with colchicine, and caution should be exercised when prescribing LIVALO with colchicine.
• There have been rare reports of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, associated with statin use. IMNM is characterized by: proximal muscle weakness and elevated serum creatine kinase, which persist despite discontinuation of statin treatment; muscle biopsy showing necrotizing myopathy without significant inflammation; improvement with immunosuppressive agents. IMNM has not been reported with LIVALO therapy.
• Advise patients to promptly report if muscle signs and symptoms persist after discontinuing LIVALO as this may be a sign of IMNM requiring immediate medical attention.

Liver Enzyme Abnormalities

Increases in serum transaminases have been reported with HMG-CoA reductase inhibitors, including LIVALO.

• It is recommended that liver enzyme tests be performed before the initiation of LIVALO and if signs or symptoms of liver injury occur.
• There have been rare postmarketing reports of fatal and non-fatal hepatic failure in patients taking statins, including pitavastatin. If serious liver injury with clinical symptoms and/or hyperbilirubinemia or jaundice occurs during treatment with LIVALO, promptly interrupt therapy. If an alternate etiology is not found do not restart LIVALO.
• Advise patients to promptly report any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice.
• LIVALO should be used with caution in patients who consume substantial quantities of alcohol and/or have a history of chronic liver disease.

Endocrine Function

Increases in HbA1c and fasting serum glucose levels have been reported with HMG-CoA reductase inhibitors, including LIVALO.

ADVERSE REACTIONS

In short-term controlled studies, the most frequent adverse reactions reported by ≥2% of patients treated with LIVALO 1 mg, 2 mg, and 4 mg, respectively, and at a rate ≥ placebo were back pain (3.9%, 1.8%, 1.4% vs 2.9%), constipation (3.6%, 1.5%, 2.2% vs 1.9%), diarrhea (2.6%, 1.5%, 1.9% vs 1.9%), myalgia (1.9%, 2.8%, 3.1% vs 1.4%), and pain in extremity (2.3%, 0.6%, 0.9% vs 1.9%). This is not a complete listing of all reported adverse events.

For additional information, please see the full Prescribing Information at https://www.livalorx.com/.

© Kowa Pharmaceuticals America, Inc. (2016) - LIV-RA-0101 PI V-11-2016

About BYSTOLIC^®

Indication

• BYSTOLIC is indicated for the treatment of hypertension, to lower blood pressure. BYSTOLIC 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. There are no controlled trials demonstrating risk reduction with BYSTOLIC, but at least one pharmacologically similar drug has 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.

Important Safety Information

Contraindications

• BYSTOLIC is contraindicated in patients with severe bradycardia, heart block greater than first degree, cardiogenic shock, decompensated cardiac failure, sick sinus syndrome (unless a permanent pacemaker is in place), severe hepatic impairment (Child-Pugh >B), and in patients who are hypersensitive to any component of this product.

Warnings and Precautions

• Do not abruptly discontinue BYSTOLIC therapy in patients with coronary artery disease. Severe exacerbation of angina, myocardial infarction, and ventricular arrhythmias have been reported 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. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other beta blockers, when discontinuation of BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity. Taper BYSTOLIC over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, restart BYSTOLIC promptly, at least temporarily.
• BYSTOLIC was not studied in patients with angina pectoris or who had a recent MI.
• In general, patients with bronchospastic diseases should not receive beta blockers.
• Because beta blocker withdrawal has been associated with an increased risk of MI and chest pain, patients already on beta blockers should generally continue treatment throughout the perioperative period if undergoing major surgery. If BYSTOLIC is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene are used. If beta-blocking therapy is withdrawn prior to major surgery, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

The beta-blocking effects of BYSTOLIC can be reversed by beta agonists, eg, dobutamine or isoproterenol. However, such patients may be subject to protracted severe hypotension. Additionally, difficulty in restarting and maintaining the heartbeat has been reported with beta blockers.

• Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. 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 in these patients may be followed by an exacerbation of symptoms 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 the ECG and blood pressure of patients treated concomitantly with these agents.
• When BYSTOLIC is co-administered with an inhibitor or an inducer of CYP2D6, monitor patients closely and adjust the nebivolol dose according to blood pressure response. The dose of BYSTOLIC may need to be reduced. When BYSTOLIC is administered with fluoxetine, significant increases in d-nebivolol may be observed (ie, an 8-fold increase in AUC and a 3-fold increase in C_max for d-nebivolol).
• Renal clearance of nebivolol is decreased in patients with severe renal impairment. In patients with severe renal impairment (ClCr less than 30 mL/min) the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients receiving dialysis.
• Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. BYSTOLIC has not been studied in patients with severe hepatic impairment and therefore it is not recommended in that population.
• Patients with a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge and may be unresponsive to the usual doses of epinephrine while taking beta blockers.
• In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.

Adverse Reactions

• The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%).

Drug Interactions

• Use caution when BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc).
• Do not use BYSTOLIC with other beta blockers.
• Both digitalis glycosides and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia.
• BYSTOLIC can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium antagonists (particularly of the phenylalkylamine [verapamil] and benzothiazepine [diltiazem] classes), or antiarrhythmic agents, such as disopyramide.

Use in Specific Populations

• BYSTOLIC is not recommended during nursing.
• In a placebo-controlled trial of 2128 patients (1067 BYSTOLIC, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens consider discontinuation of BYSTOLIC.

Please see full Prescribing Information at https://www.bystolichcp.com/.

Kowa Company, Ltd. and Kowa Pharmaceuticals America, Inc.

Kowa Company, Ltd. (Kowa) is a privately held, multinational company headquartered in Nagoya, Japan. Established in 1894, Kowa is actively engaged in various business fields including the trading of textiles, machinery, and construction materials, in addition to the manufacturing and sales of medicines, medical equipment, and energy saving products. Kowa’s pharmaceutical division is focused on research and development for cardiovascular therapeutics (dyslipidemia, type 2 diabetes and atherosclerosis), ophthalmology and anti-inflammatory agents. The company’s flagship product, LIVALO^® (pitavastatin), is approved in 46 countries around the world.

Kowa Pharmaceuticals America, Inc., headquartered in Montgomery, AL, is focused primarily in the area of cardiometabolic diseases. Established in September 2008, Kowa Pharmaceuticals America focuses its efforts on the successful commercialization of its current and near-term portfolio of pharmaceutical products, and business development activities. For more information about Kowa Pharmaceuticals America, visit https://www.kowapharma.com/.

LIVALO is a registered trademark of the Kowa group of companies.

¹ Centers for Disease Control and Prevention, National Center for Health Statistics. Underlying Cause of Death 1999-2013 on CDC WONDER Online Database, released 2015. Data are from the Multiple Cause of Death Files, 1999-2013, as compiled from data provided by the 57 vital statistics jurisdictions through the Vital Statistics Cooperative Program: http://wonder.cdc.gov/ucd-icd10.html. Accessed on Feb 3, 2015

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