NEBCAR

The chemical name for the active ingredient in 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 as tablets for oral administration contains nebivolol hydrochloride equivalent to 2.5, 5, 10, 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, pregelatinized starch (maize), polysorbate and sodium lauryl sulfate.

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 Hypertension Nebivolol tablets are indicated for the treatment of hypertension, to lower blood pressure.

Nebivolol 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.

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.

Nebivolol is a β-adrenergic receptor blocking agent.

In extensive metabolizers (most of the population) and at doses less than or equal to 10 mg, nebivolol is preferentially β 1 selective.

In poor metabolizers and at higher doses, nebivolol inhibits both β 1 and β 2.

• adrenergic receptors.

Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations.

At clinically relevant doses, nebivolol does not demonstrate α 1 -adrenergic receptor blockade activity.

Various metabolites, including glucuronides, contribute to β-blocking activity. 12.1 Mechanism of Action The mechanism of action of the antihypertensive response of nebivolol has not been definitively established.

Possible factors that may be involved include: decreased heart rate, decreased myocardial contractility, diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppression of renin activity and vasodilation and decreased peripheral vascular resistance. 12.3 Pharmacokinetics Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6.

The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers.

This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to β-blocking activity.

Plasma levels of d–nebivolol increase in proportion to dose in EMs and PMs for doses up to 20mg.

Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1,000-fold higher than l-nebivolol.

For the same dose, PMs attain a 5-fold higher C max and 10-fold higher AUC of d-nebivolol than do EMs. d.

• Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs.

Absorption of nebivolol tablets are similar to an oral solution.

The absolute bioavailability has not been determined.

Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs.

Food does not alter the pharmacokinetics of nebivolol.

Under fed conditions, nebivolol glucuronides are slightly reduced.

Nebivolol may be administered without regard to meals.

The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6.

Its stereospecific metabolites contribute to the pharmacologic activity.

After a single oral administration of 14C-nebivolol, 38% of the dose was recovered in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs.

Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates. 12.4 Pharmacokinetics in Special Populations Hepatic Disease d-Nebivolol peak plasma concentration increased 3-fold, exposure (AUC) increased 10-fold, and the apparent clearance decreased by 86% in patients with moderate hepatic impairment (Child-Pugh Class B).

No formal studies have been performed in patients with severe hepatic impairment and nebivolol should be contraindicated for these patients.

The apparent clearance of nebivolol was unchanged following a single 5 mg dose of nebivolol tablets in patients with mild renal impairment (ClCr to 80 mL/min, n=7), and it was reduced negligibly in patients with moderate (ClCr to 50 mL/min, n=9), but clearance was reduced by 53% in patients with severe renal impairment (ClCr <30 mL/min, n=5).

No studies have been conducted in patients on dialysis. 12.5 Drug-Drug Interactions Drugs that inhibit CYP2D6 can be expected to increase plasma levels of nebivolol.

When nebivolol is co-administered with an inhibitor or an inducer of this enzyme, monitor patients closely and adjust the nebivolol dose according to blood pressure response.

In vitro studies have demonstrated that at therapeutically relevant concentrations, d.

• and l-nebivolol do not inhibit any cytochrome P450 pathways.

Concomitant administration of nebivolol (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol.

Administration of nebivolol (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R.

• or S-warfarin following a single 10 mg dose of warfarin.

Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers.

No pharmacokinetic interactions were observed in healthy adults between nebivolol (10 mg daily for 10 days) and furosemide (40 mg single dose), hydrochlorothiazide (25 mg once daily for 10 days), or spironolactone (25 mg once daily for 10 days).

Concomitant administration of nebivolol (10 mg once daily) and ramipril (5 mg once daily) for 10 days in 15 healthy adult volunteers produced no pharmacokinetic interactions.

Concomitant administration of nebivolol tablets (10 mg single dose) and losartan (50 mg single dose) in 20 healthy adult volunteers did not result in pharmacokinetic interactions.

Fluoxetine, a CYP2D6 inhibitor, administered at 20 mg per day for 21 days prior to a single 10 mg dose of nebivolol to 10 healthy adults, led to an 8-fold increase in the AUC and 3-fold increase in Cmax for d-nebivolol.

Histamine-2 Receptor Antagonists: The pharmacokinetics of nebivolol (5 mg single dose) were not affected by the co-administration of ranitidine (150 mg twice daily).

Cimetidine (400 mg twice daily) causes a 23% increase in the plasma levels of d-nebivolol.

The pharmacokinetics of nebivolol (10 mg single dose) were not affected by repeated co-administration (4, 8, 12, 16, 22, 28, 36, and 48 hours after nebivolol administration) of activated charcoal (Actidose-Aqua®).

The co-administration of nebivolol and sildenafil decreased AUC and C max of sildenafil by and 23% respectively.

The effect on the C max and AUC for d-nebivolol was also small (< 20%).

The effect on vital signs (e.g., pulse and blood pressure) was approximately the sum of the effects of Sildenafil and nebivolol.

Utilizing population pharmacokinetic analyses, derived from hypertensive patients, the following drugs were observed not to have an effect on the pharmacokinetics of nebivolol: acetaminophen, acetylsalicylic acid, atorvastatin, esomeprazole, ibuprofen, levothyroxine sodium, metformin, sildenafil, simvastatin, or tocopherol.

No meaningful changes in the extent of in vitro binding of nebivolol to human plasma proteins were noted in the presence of high concentrations of diazepam, digoxin, diphenylhydantoin, enalapril, hydrochlorothiazide, imipramine, indomethacin, propranolol, sulfamethazine, tolbutamide, or warfarin.

Additionally, nebivolol did not significantly alter the protein binding of the following drugs:diazepam, digoxin, diphenylhydantoin, hydrochlorothiazide, imipramine, or warfarin at their therapeutic concentrations.

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.

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 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 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.

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.

In clinical trials and worldwide post marketing experience there were reports of nebivolol overdose.

The most common signs and symptoms associated with nebivolol tablets over dosage 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, 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.

Administer IV fluids and vasopressors.

Intravenous glucagon may be useful.

Block (second or third degree) : Monitor and treat with isoproterenol infusion.

Initiate therapy with digitalis glycoside and diuretics.

In certain cases, consider the use of inotropic and vasodilating agents.

Administer bronchodilator therapy such as a short acting inhaled β2-agonist and/or aminophylline.

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 to 19 hours.

Center for the most current information on β-blocker overdose treatment.

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 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) Hypersensitive to any component of this product.

Can be taken with and without food.

Individualize to the needs of the patient and monitor during up-titration.

Most patients start at 5 mg once daily.

Dose can be increased at 2-week intervals up to 40 mg. 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.

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.

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. 2.2 Subpopulations Geriatric Patients It is not necessary to adjust the dose in the elderly.

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.

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) .

Dispense in a tight,light-resistant containerasdefinedintheUSPusing a child-resistant closure.

Repackaged/Relabeled by: Bryant Ranch Prepack, Inc.

Burbank, CA 91504.

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.

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 to 4% and to 20%, respectively.

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.

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 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).

Safety and effectiveness in pediatric patients have not been established.

Pediatric studies in ages newborn to 18 years old have not been conducted because of incomplete characterization of developmental toxicity and possible adverse effects on long-term fertility.

Daily oral doses of nebivolol to juvenile rats from post-natal day to post-natal day 27 showed sudden unexplained death at exposures equal to those in human poor metabolizers given a single dose of 10 mg. No mortality was seen at half the adult human exposure.

In surviving rats, cardiomyopathy was seen at exposures greater than or equal to the human exposure.

Male rat pups exposed to twice the human exposure showed decreases in total sperm count as well as decreases in the total and percentage of motile sperm.

Of the 2,800 patients in the U.S. sponsored placebo-controlled clinical hypertension studies, 478 patients were 65 years of age or older.

No overall differences in efficacy or in the incidence of adverse events were observed between older and younger patients.