Nebivolol: uses, appearance and warnings

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 tablets 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 tablets. 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.

Nebivolol is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of nebivolol. Nebivolol tablets 2.5 mg are light blue colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘78’ on the other side. Nebivolol tablets 5 mg are beige colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘79’ on the other side. Nebivolol tablets 10 mg are pink colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘80’ on the other side. Nebivolol tablets 20 mg are light blue colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘85’ on the other side. Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg ( 3 )

Nebivolol is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of nebivolol. Nebivolol Tablets 2.5 mg are light blue colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘78’ on the other side. They are supplied as follows: Bottles of 30 NDC 59651-137-30 Bottles of 90 NDC 59651-137-90 Nebivolol Tablets 5 mg are beige colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘79’ on the other side. They are supplied as follows: Bottles of 30 NDC 59651-138-30 Bottles of 90 NDC 59651-138-90 Nebivolol Tablets 10 mg are pink colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘80’ on the other side. They are supplied as follows: Bottles of 30 NDC 59651-139-30 Bottles of 90 NDC 59651-139-90 Nebivolol Tablets 20 mg are light blue colored, round shaped, biconvex uncoated tablets debossed with ‘L’ on one side and ‘85’ on the other side. They are supplied as follows: Bottles of 30 NDC 59651-140-30 Bottles of 90 NDC 59651-140-90 Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Nebivolol tablets are 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 )

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 anytime 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. Nebivolol Tablets, 5 mg contain FD&C Yellow No. 6 as a color additive.

Most common adverse reactions ( 6.1 ): Headache, fatigue To report SUSPECTED ADVERSE REACTIONS, Contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Nebivolol has 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. …

CYP2D6 enzyme inhibitors may increase nebivolol levels. ( 7.1 ) Reserpine or clonidine may produce excessive reduction of sympathetic activity. ( 7.2 ) Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. ( 7.3 ) Verapamil- or diltiazem-type calcium channel blockers may cause excessive reductions in heart rate, blood pressure, and cardiac contractility. ( 7.4 ) 7.1 CYP2D6 Inhibitors Use caution when nebivolol is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology (12.5) ] . 7.2 Hypotensive Agents Do not use nebivolol with other β-blockers. …