NEBIVOLOL (nebivolol 10 mg) Dailymed

3. Dosage Forms And Strengths

Nebivolol tablets are available for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

Nebivolol tablets are triangular-shaped, biconvex, unscored, differentiated by color and are debossed with “S” on one side and the number (671, 672, 673, or 674) 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)

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 tablets 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 tablets is planned, carefully observe and advise patients to minimize physical activity. Taper nebivolol tablets over 1 to 2 weeks when possible. If the angina worsens or acute coronary insufficiency develops, re-start nebivolol tablets promptly, at least temporarily.

5.2 Angina and Acute Myocardial Infarction

Nebivolol tablets were 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 tablets are 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 tablets 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 tablets may need to be reduced.

5.10 Impaired Renal Function

Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol tablets have 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 tablets have 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 Solco Healthcare US, LLC at 1-866-257-2597 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 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 uls 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
Bradycardia Diarrhea Nausea Fatigue Chest pain Peripheral edema Headache Dizziness Insomnia Dyspnea Rash

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
0	0	0	1
Gastrointestinal Disorders
2	2	2	3
0	1	3	2
General Disorders
1	2	2	5
0	0	1	1
0	1	1	1
Nervous System Disorders
6	9	6	7
2	2	3	4
Psychiatric Disorders
0	1	1	1
Respiratory Disorders
0	0	1	1
Skin and subcutaneous Tissue Disorders
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 were 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 uled 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 tablets 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.

• •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 2-4% and 15-20%, 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/m² 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 are 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 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 [see Nonclinical Toxicology (13.1)].

Juvenile Animal Toxicity Data

Daily oral doses of nebivolol to juvenile rats from post-natal day 14 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.

8.5 Geriatric Use

Of the 2800 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.

8.6 Heart Failure

In a placebo-controlled trial of 2128 patients (1067 nebivolol tablets, 1061 placebo) over 70 years of age with chronic heart failure receiving a maximum dose of 10 mg per day for a median of 20 months, no worsening of heart failure was reported with nebivolol compared to placebo. However, if heart failure worsens consider discontinuation of nebivolol tablets.