Nebivolol

RECENT MAJOR CHANGES Warnings and Precautions, Hypoglycemia (5.5) 6/2023

1. INDICATIONS AND USAGE Nebivolol tablets are 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.

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 AND STRENGTHS Nebivolol Tablets are available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol. Nebivolol Tablets, 2.5 mg are light blue colored mottled, triangular shape, biconvex uncoated tablets debossed with “I 7” on one side and plain on the other side. Nebivolol Tablets, 5 mg are beige colored mottled, triangular shape, biconvex uncoated tablets debossed with “I 8” on one side and plain on the other side Nebivolol Tablets, 10 mg are pinkish purple colored mottled, triangular shape, biconvex uncoated tablets debossed with “I 9” on one side and plain on the other side. Nebivolol Tablets, 20 mg are light blue colored mottled, triangular shape, biconvex uncoated tablets debossed with “I 10” on one side and plain on the other side Tablets: 2.5, 5, 10, 20 mg ( 3 )

4. CONTRAINDICATIONS 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 )

6 ADVERSE REACTIONS Most common adverse reactions ( 6.1 ): • Headache, fatigue To report SUSPECTED ADVERSE REACTIONS, Contact Macleods Pharma USA, Inc., at 1-888-943-3210 or 1-855-926-3384o r 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 6545 patients, including 5038 patients treated for hypertension and the remaining 1507 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 1900 patients treated for at least 6 months, and approximately 1300 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 1597 hypertensive patients treated with either 5 mg, 10 mg, or 20-40 mg of nebivolol tablets 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 – Preferred Term Placebo (n = 205) (%) Nebivolol 5 mg (n = 459) (%) Nebivolol 10 mg (n = 461) (%) Nebivolol 20-40 mg (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 4300 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 tablets 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 …

7. DRUG INTERACTIONS • 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 tablets are co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology ( 12.5 )] . 7.2 Hypotensive Agents Do not use nebivolol tablets with other β-blockers. Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of nebivolol tablets may produce excessive reduction of sympathetic activity. In patients who are receiving nebivolol tablets and clonidine, discontinue nebivolol tablets for several days before the gradual tapering of clonidine. 7.3 Digitalis Glycosides Both digitalis glycosides and β-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. 7.4 Calcium Channel Blockers Nebivolol tablets 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.

8 USE IN SPECIFIC POPULATIONS • Lactation: Breastfeeding is not recommended. ( 8.2 ) 8.1 Pregnancy Risk Summary Available data regarding use of nebivolol tablets in pregnant women are insufficient to determine whether there are drug-associated risks of adverse developmental outcomes. There are risks to the mother and fetus associated with poorly controlled hypertension in pregnancy.The use of beta blockers during the third trimester of pregnancy may increase the risk of hypotension, bradycardia, hypoglycemia, and respiratory depression in the neonate [see Clinical Considerations] . Oral administration of nebivolol to pregnant rats during organogenesis resulted in embryofetal and perinatal lethality at doses approximately equivalent to the maximum recommended human dose (MRHD). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Hypertension in pregnancy increases the maternal risk for pre-eclampsia, gestational diabetes, premature delivery, and delivery complications (e.g., need for cesarean section, and post-partum hemorrhage). Hypertension increases the fetal risk for intrauterine growth restriction and intrauterine death. Pregnant women with hypertension should be carefully monitored and managed accordingly. Fetal/Neonatal adverse reactions Neonates of women with hypertension, who are treated with beta-blockers during the third trimester of pregnancy, may be at increased risk for hypotension, bradycardia, hypoglycemia, and respiratory depression. Observe newborns for symptoms of hypotension, bradycardia, hypoglycemia and respiratory depression and manage accordingly. Data Animal Data Nebivolol was shown to increase embryo-fetal and perinatal lethality in rats at approximately 1.2 times the MRHD or 40 mg/day on a mg/m 2 basis. Decreased pup body weights occurred at 1.25 and 2.5 mg/kg in rats, when exposed during the perinatal period (late gestation, parturition and lactation). At 5 mg/kg and higher doses (1.2 times the MRHD), prolonged gestation, dystocia and reduced maternal care were produced with corresponding increases in late fetal deaths and stillbirths and decreased birth weight, live litter size and pup survival. These events occurred only when nebivolol was given during the perinatal period (late gestation, parturition and lactation). Insufficient numbers of pups survived at 5 mg/kg to evaluate the offspring for reproductive performance. In studies in which pregnant rats were given nebivolol during organogenesis, reduced fetal body weights were observed at maternally toxic doses of 20 and 40 mg/kg/day (5 and 10 times the MRHD), and small reversible delays in sternal and thoracic ossification associated with the reduced fetal body weights and a small increase in resorption occurred at 40 mg/kg/day (10 times the MRHD). No adverse effects on embryo-fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses as high as 20 mg/kg/day (10 times the MRHD). 8.2 Lactation Risk Summary There is no information regarding the presence of nebivolol in human milk, the effects on the breastfed infant, or the effects on milk production. Nebivolol is present in rat milk [see Data] . Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, nebivolol tablets is not recommended during nursing. Data In lactating rats, maximum milk levels of unchanged nebivolol were observed at 4 hours after single and repeat doses of 2.5 mg/kg/day. The daily dose (mg/kg body weight) ingested by a rat pup is 0.3% of the dam dose for unchanged nebivolol. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have …

12.1 Mechanism of Action The mechanism of action of the antihypertensive response of nebivolol tablets has not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, (4) suppression of renin activity and (5) vasodilation and decreased peripheral vascular resistance.

11. DESCRIPTION The chemical name for the active ingredient in nebivolol tablets (nebivolol) tablets is (1RS,1’RS)-1,1’-[(2RS,2’SR)-bis(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)]- 2,2’-iminodiethanol hydrochloride. Nebivolol is a racemate composed of d-Nebivolol and l-Nebivolol with the stereochemical designations of [SRRR]-nebivolol and [RSSS]-nebivolol, respectively. Nebivolol’s molecular formula is (C 22 H 25 F 2 NO 4 •HCl) with the following structural formula: Nebivolol hydrochloride is a white to almost white powder that is soluble in methanol, dimethylsulfoxide, and N,N-dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in hexane, dichloromethane, and methylbenzene. Nebivolol tablets for oral administration contain nebivolol hydrochloride equivalent to 2.5 mg, 5 mg, 10 mg, and 20 mg of nebivolol base. In addition, nebivolol tablets contain the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 80, pregelatinized starch, sodium lauryl sulfate, D&C Red No. 27 Aluminum Lake (10 mg), FD&C Blue No. 2 Aluminum Lake (2.5 mg and 20 mg), and FD&C Yellow No. 6 Aluminum Lake (5 mg). chemical structure 1 chemical structure 2

10 OVERDOSAGE In clinical trials and worldwide postmarketing experience there were reports of Nebivolol Tablets overdose. The most common signs and symptoms associated with Nebivolol Tablets overdosage are bradycardia and hypotension. Other important adverse reactions reported with Nebivolol Tablets overdose include cardiac failure, dizziness, hypoglycemia, fatigue and vomiting. Other adverse reactions associated with β-blocker overdose include bronchospasm and heart block. The largest known ingestion of Nebivolol Tablets worldwide involved a patient who ingested up to 500 mg of Nebivolol Tablets along with several 100 mg tablets of acetylsalicylic acid in a suicide attempt. The patient experienced hyperhydrosis, pallor, depressed level of consciousness, hypokinesia, hypotension, sinus bradycardia, hypoglycemia, hypokalemia, respiratory failure and vomiting. The patient recovered. Because of extensive drug binding to plasma proteins, hemodialysis is not expected to enhance nebivolol clearance. If overdose occurs, provide general supportive and specific symptomatic treatment. Based on expected pharmacologic actions and recommendations for other β-blockers, consider the following general measures, including stopping Nebivolol Tablets, when clinically warranted: Bradycardia: Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Hypotension: Administer IV fluids and vasopressors. Intravenous glucagon may be useful. Heart Block (second or third degree): Monitor and treat with isoproterenol infusion. Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary. Congestive Heart Failure: Initiate therapy with digitalis glycoside and diuretics. In certain cases, consider the use of inotropic and vasodilating agents. Bronchospasm: Administer bronchodilator therapy such as a short acting inhaled β 2 -agonist and/or aminophylline. Hypoglycemia: Administer IV glucose. Repeated doses of IV glucose or possibly glucagon may be required. Supportive measures should continue until clinical stability is achieved. The half-life of low doses of nebivolol is 12 to 19 hours. Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.

16 HOW SUPPLIED/STORAGE AND HANDLING 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 supplied in the following strengths and package configurations: Nebivolol tablets, 2.5 mg are white to off-white, triangular biconvex tablets debossed with ‘J’ on one side and ‘8’ on other side. Bottle of 30 tablets NDC 31722-585-30 Bottle of 100 tablets NDC 31722-585-01 Blister card of 10 Unit dose tablets (PVC/PVdC) NDC 31722-585-31 Blister pack of 120 (12 x 10) Unit dose tablets (PVC/PVdC) NDC 31722-585-32 Blister card of 10 Unit dose tablets (Alu-Alu) NDC 31722-585-33 Blister pack of 150 (15 x 10) Unit dose tablets (Alu-Alu) NDC 31722-585-34 Nebivolol tablets, 5 mg are light orange, triangular biconvex tablets debossed with ‘J’ on one side and ‘9’ on other side. Bottle of 30 tablets NDC 31722-586-30 Bottle of 90 tablets NDC 31722-586-90 Bottle of 100 tablets NDC 31722-586-01 Blister card of 10 Unit dose tablets (PVC/PVdC) NDC 31722-586-31 Blister pack of 100 (10 x 10) Unit dose tablets (PVC/PVdC) NDC 31722-586-32 Blister card of 7 Unit dose tablets (Alu-Alu) NDC 31722-586-33 Blister pack of 126 (18 x 7) Unit dose tablets (Alu-Alu) NDC 31722-586-34 Nebivolol tablets, 10 mg are light peach color, triangular shaped biconvex tablets debossed with ‘J’ on one side and ‘10’ on other side. Bottle of 30 tablets NDC 31722-587-30 Bottle of 90 tablets NDC 31722-587-90 Bottle of 100 tablets NDC 31722-587-01 Blister card of 10 Unit dose tablets (PVC/PVdC) NDC 31722-587-31 Blister pack of 100 (10 x 10) Unit dose tablets (PVC/PVdC) NDC 31722-587-32 Blister card of 7 Unit dose tablets (Alu-Alu) NDC 31722-587-33 Blister pack of 126 (18 x 7) Unit dose tablets (Alu-Alu) NDC 31722-587-34 Nebivolol tablets, 20 mg are white to off-white, triangular biconvex tablets debossed with ‘J’ on one side and ‘11’ on other side. Bottle of 30 tablets NDC 31722-588-30 Bottle of 90 tablets NDC 31722-588-90 Bottle of 100 tablets NDC 31722-588-01 Blister card of 10 Unit dose tablets (PVC/PVdC) NDC 31722-588-31 Blister pack of 100 (10 x 10) Unit dose tablets (PVC/PVdC) NDC 31722-588-32 Blister card of 7 Unit dose tablets (Alu-Alu) NDC 31722-588-33 Blister pack of 126 (18 x 7) Unit dose tablets (Alu-Alu) NDC 31722-588-34 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.