FDA label 29967cca-83f1-410f-84e1-6989f8f7eac1

WARNING: FETAL TOXICITY When pregnancy is detected, discontinue BYVALSON as soon as possible ( 5.1 , 8.1 ). Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus. ( 5.1 , 8.1 ). WARNING: FETAL TOXICITY See full prescribing information for complete boxed warning. When pregnancy is detected, discontinue BYVALSON as soon as possible ( 5.1 , 8.1 ) Drugs, including BYVALSON, that act directly on the renin­angiotensin system can cause injury and death to the developing fetus. ( 5.1 , 8.1 )

5 WARNINGS AND PRECAUTIONS Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.3 ) Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor. ( 5.7 ) Monitor renal function and potassium in susceptible patients. ( 5.11 ) 5.1 Fetal Toxicity Valsartan 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 [see Use in Specific Populations ( 8.1 )] . 5.2 Hypotension 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. 5.3 Abrupt Cessation of Therapy Nebivolol 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 β-blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. As with other β -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. 5.4 Cardiac Failure Nebivolol Worsening heart failure or fluid retention may occur during nebivolol therapy because of its β-blocking effects. Consider diuretic therapy and treat heart failure appropriately, according to current guidelines. 5.5 Bronchospastic Diseases Nebivolol In general, patients with bronchospastic diseases should not receive β-blockers. 5.6 Anesthesia and Major Surgery Nebivolol 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. 5.7 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 5.8 Thyrotoxicosis Nebivolol β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β­blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. 5.9 Peripheral Vascular Disease Nebivolol β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.10 Non-dihydropyridine Calcium Channel Blockers Nebivolol Because of significant negative inotropic and chronotropic effects in patients treated with β-blockers and calcium channel blockers of the verapamil and diltiazem type, monitor heart rate and blood pressure in patients treated concomitantly with these agents. 5.11 Impaired Renal Function Valsartan Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin­angiotensin 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 [see Drug Interactions ( 7 )] . 5.12 Risk of Anaphylactic Reactions Nebivolol While taking β-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. 5.13 Pheochromocytoma Nebivolol In patients with known or suspected pheochromocytoma, initiate a α-blocker prior to the use of any β­blocker. 5.14 Hyperkalemia Valsartan 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.

6 ADVERSE REACTIONS The following serious adverse reactions are included in more detail in the Warnings and Precautions section of the label: Hypotension [see Warnings and Precautions ( 5.2 )] Hyperkalemia [see Warnings and Precautions ( 5.14 )] No adverse reactions were observed more frequently on BYVALSON than on placebo. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1­800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. BYVALSON BYVALSON has been evaluated for safety in patients with hypertension. A total of 1,664 patients received at least 1 dose of a fixed-dose combination of nebivolol/valsartan in an 8-week trial. A total of 807 patients received at least 1 dose of nebivolol and valsartan in an open-label safety study; of these, 621 patients completed 180 days and 476 patients completed 360 days of open-label treatment with nebivolol and valsartan. The safety of the 5 mg/ 80 mg dose of nebivolol/valsartan was evaluated during the first 4 weeks of an 8-week placebo-controlled trial. During the 4 week period, the overall incidence of adverse events on therapy with BYVALSON 5 mg/ 80 mg was similar to placebo and the individual components (nebivolol 5 mg and valsartan 80 mg). Discontinuation of therapy due to a clinical adverse event occurred in 2.0% of patients treated with BYVALSON 5 mg/ 80 mg versus 3.2% of patients given placebo and approximately 1% of patients given nebivolol 5 mg or valsartan 80 mg as monotherapy. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of either nebivolol or valsartan. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nebivolol The following adverse reactions have been reported in post-marketing experience: Cardiac: atrioventricular block (both second and third degree), myocardial infarction Central Nervous System: somnolence, syncope, vertigo Circulatory: Raynaud’s phenomenon, peripheral ischemia/claudication, thrombocytopenia Dermatologic: pruritus, psoriasis, various rashes and skin disorders Digestive: vomiting Hepatic: Abnormal hepatic function (including increased AST, ALT and bilirubin) Hypersensitivity: hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema) Renal: acute renal failure Respiratory: acute pulmonary edema, bronchospasm Sexual Dysfunction: erectile dysfunction Valsartan The following additional adverse reactions have been reported in post-marketing experience: Hypersensitivity: Angioedema. Digestive: Elevated liver enzymes, hepatitis Renal: Impaired renal function, renal failure Clinical Laboratory Tests: Hyperkalemia Dermatologic: Alopecia, bullous dermatitis Blood and Lymphatic: thrombocytopenia Vascular: Vasculitis