Nebivolol

1 INDICATIONS AND USAGE Nebivolol is a beta-adrenergic blocking agent indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions.( 1.1 ) 1.1 Hypertension Nebivolol tablets are indicated for the treatment of hypertension, to lower blood pressure [ see Clinical Studies ( 14.1 ) ]. Nebivolol may be used alone or in combination with other antihypertensive agents [ see Drug Interactions ( 7 )]. 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 class to which this drug principally belongs. There are no controlled trials demonstrating risk reduction with nebivolol. 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. For specific advice on goals and management, see published guidelines, such as those of the National High Blood Pressure Education Program's Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC). Numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. The largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. Elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmHg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. Relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. Some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). These considerations may guide selection of therapy.

2 DOSAGE AND ADMINISTRATION Can be taken with and without food. Individualize to the needs of the patient and monitor during up-titration. ( 2 ) Hypertension: Most patients start at 5 mg once daily. Dose can be increased at 2-week intervals up to 40 mg. ( 2.1 ) 2.1 Hypertension The dose of nebivolol tablets must be individualized to the needs of the patient. For most patients, the recommended starting dose is 5 mg once daily, with or without food, as monotherapy or in combination with other agents. For patients requiring further reduction in blood pressure, the dose can be increased at 2-week intervals up to 40 mg. A more frequent dosing regimen is unlikely to be beneficial. 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. Nebivolol tablets have not been studied in patients receiving dialysis [ see Clinical Pharmacology ( 12.4 ) ]. Hepatic Impairment In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily; titrate up slowly if needed. Nebivolol tablets have not been studied in patients with severe hepatic impairment and Therefore it is not recommended in that population [ see Clinical Pharmacology ( 12.4 ) ]. 2.2 Subpopulations Geriatric Patients It is not necessary to adjust the dose in the elderly [ see use in Specific Populations ( 8.5 ) ]. CYP2D6 Polymorphism No dose adjustments are necessary for patients who are CYP2D6 poor metabolizers. The clinical effect and safety profile observed in poor metabolizers were similar to those of extensive metabolizers [ see Clinical Pharmacology ( 12.3 ) ].

3 DOSAGE FORMS & STRENGTHS Nebivolol is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol. Nebivolol tablets are white to off white, round, biconvex, unscored tablet debossed with "C50" (for 2.5 mg), "C51"(for 5 mg), "C52"(for 10 mg), "C53"(for 20 mg) on one side and plain on the other side. Tablets: 2.5, 5, 10, 20 mg ( 3 )

4 CONTRAINDICATIONS Nebivolol Tablets 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) Patients who are hypersensitive to any component of this product. Severe bradycardia ( 4 ) Heart block greater than first degree ( 4 ) Patients with cardiogenic shock ( 4 ) Decompensated cardiac failure ( 4 ) Sick sinus syndrome (unless a permanent pacemaker is in place) ( 4 ) Patients with severe hepatic impairment (Child-Pugh >B) ( 4 ) Hypersensitive to any component of this product ( 4 )

5 WARNINGS AND PRECAUTIONS Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue. ( 5.1 ) Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor (5.5) 5.1 Abrupt Cessation of Therapy Do not abruptly discontinue nebivolol therapy 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. Caution patients without overt coronary artery disease against interruption or abrupt discontinuation of therapy. As with other β-blockers, when discontinuation of nebivolol is planned, carefully observe and advise patients to minimize physical activity.Taper nebivolol over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, re-start nebivolol promptly, at least temporarily. 5.2 Angina and Acute Myocardial Infarction Nebivolol was not studied in patients with angina pectoris or who had a recent MI. 5.3 Bronchospastic Diseases In general, patients with bronchospastic diseases should not receive β-blockers. 5.4 Anesthesia and Major Surgery 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 nebivolol is to be continued perioperatively, monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used. If β-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 β-blocking effects of nebivolol can be reversed by β-agonists, e.g., 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 β-blockers. 5.5 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. 5.6 Thyrotoxicosis β-blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of β-blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm. 5.7 Peripheral Vascular Disease β-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. 5.8 Non-dihydropyridine Calcium Channel Blockers 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 the ECG and blood pressure in patients treated concomitantly with these agents. 5.9 Use with CYP2D6 Inhibitors Nebivolol exposure increases with inhibition of CYP2D6 [ see Drug Interactions ( 7 ) ]. The dose of nebivolol may need to be reduced. 5.10 Impaired Renal Function Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol has not been studied in patients receiving dialysis [ see Clinical Pharmacology ( 12.4 ) and Dosage and Administration ( 2.1 ) ]. 5.11 Impaired Hepatic Function Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. Nebivolol has not been studied in patients with severe hepatic impairment [ see Clinical Pharmacology ( 12.4 ) and Dosage and Administration ( 2.1 ) ]. 5.12 Risk of Anaphylactic Reactions 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 In patients with known or suspected Pheochromocytoma, initiate an α-blocker prior to the use of any β-blocker.

6 ADVERSE REACTIONS Most common adverse reactions ( 6.1 ): Headache, fatigue To report SUSPECTED ADVERSE REACTIONS, contact Modavar Pharmaceuticals LLC at 1-800-688-4697, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies Experience Nebivolol tablets have been evaluated for safety in patients with hypertension and in patients with heart failure. The observed adverse reaction profile was consistent with the pharmacology of the drug and the health status of the patients in the clinical trials. Adverse reactions reported for each of these patient populations are provided below. Excluded are adverse reactions considered too general to be informative and those not reasonably associated with the use of the drug because they were associated with the condition being treated or are very common in the treated population. The data described below reflect worldwide clinical trial exposure to nebivolol tablets in 6,545 patients, including 5,038 patients treated for hypertension and the remaining 1,507 subjects treated for other cardiovascular diseases. Doses ranged from 0.5 mg to 40 mg. Patients received nebivolol tablets for up to 24 months, with over 1,900 patients treated for at least 6 months, and approximately 1,300 patients for more than one year. HYPERTENSION : In placebo-controlled clinical trials comparing nebivolol tablets with placebo, discontinuation of therapy due to adverse reactions was reported in 2.8% of patients treated with nebivolol and 2.2% of patients given placebo. The most common adverse reactions that led to discontinuation of nebivolol tablets were headache (0.4%), nausea (0.2%) and bradycardia (0.2%). Table 1 lists treatment-emergent adverse reactions that were reported in three 12-week, placebo- controlled monotherapy trials involving 1,597 hypertensive patients treated with either 5 mg, 10 mg, or 20 to 40 mg of nebivolol and 205 patients given placebo and for which the rate of occurrence was at least 1% of patients treated with nebivolol and greater than the rate for those treated with placebo in at least one dose group. Table 1. Treatment-Emergent Adverse Reactions with an Incidence (over 6 weeks) ≥ 1% in Nebivolol Tablets-Treated Patients and at a Higher Frequency than Placebo-Treated Patients System Organ Class – Placebo Nebivolol Nebivolol Nebivolol Preferred Term 5 mg 10 mg 20 to 40 mg (n = 205) (n = 459) (n = 461) (n = 677) (%) (%) (%) (%) Cardiac Disorders Bradycardia 0 0 0 1 Gastrointestinal Disorders Diarrhea 2 2 2 3 Nausea 0 1 3 2 General Disorders Fatigue 1 2 2 5 Chest pain 0 0 1 1 Peripheral edema 0 1 1 1 Nervous System Disorders Headache 6 9 6 7 Dizziness 2 2 3 4 Psychiatric Disorders Insomnia 0 1 1 1 Respiratory Disorders Dyspnea 0 0 1 1 Skin and subcutaneous Tissue Disorders Rash 0 0 1 1 Listed below are other reported adverse reactions with an incidence of at least 1% in the more than 4,300 patients treated with nebivolol tablets in controlled or open-label trials except for those already appearing in Table 1 , terms too general to be informative, minor symptoms, or adverse reactions unlikely to be attributable to drug because they are common in the population. These adverse reactions were in most cases observed at a similar frequency in placebo-treated patients in the controlled studies. Body as a Whole : asthenia. Gastrointestinal System Disorders : abdominal pain Metabolic and Nutritional Disorders : hypercholesterolemia Nervous System Disorders : paraesthesia 6.2 Laboratory Abnormalities In controlled monotherapy trials of hypertensive patients, nebivolol was associated with an increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. 6.3 Postmarketing Experience The following adverse reactions have been identified from spontaneous reports of nebivolol tablets received worldwide and have not been listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or potential causal connection to nebivolol tablets. Adverse reactions common in the population have generally been omitted. Because these adverse reactions were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to nebivolol exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary edema, acute renal failure, atrioventricular block (both second and third degree), bronchospasm, erectile dysfunction, hypersensitivity (including urticaria, allergic vasculitis and rare reports of angioedema), hypotension, myocardial infarction, pruritus, psoriasis, Raynaud's phenomenon, peripheral ischemia/claudication, somnolence, syncope, thrombocytopenia, various rashes and skin disorders, vertigo, and vomiting.

16 HOW SUPPLIED/STORAGE AND HANDLING Nebivolol is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 10 mg of nebivolol. Nebivolol tablets are white to off white ,round, biconvex, unscored tablet debossed with "C52"(for 10 mg) on one side and plain on the other side. NDC: 72162-2414-3: 30 Tablets in a BOTTLE NDC: 72162-2414-9: 90 Tablets in a BOTTLE Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight,light-resistant containerasdefinedintheUSPusing a child-resistant closure. Repackaged/Relabeled by: Bryant Ranch Prepack, Inc. Burbank, CA 91504