Home › Drugs › Nebivolol Hydrochloride

Nebivolol Hydrochloride

FDA Drug Information • Also known as: Bystolic, Nebivolol, Nebivolol Hydrochloride

Brand Names
Bystolic, Nebivolol, Nebivolol Hydrochloride
Dosage Form
TABLET
Product Type
DRUG FOR FURTHER PROCESSING

Description

11 DESCRIPTION The chemical name for the active ingredient in Nebivolol Tablets is [2S*[R*[R*[R*]]]] and [2R*[S*[S*[S*]]]]-(±) α, α'-[iminobis(metylene)] bis [6-fluoro-3,4-dihydro-2H-1-benzopyran-2-methanol] 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: SRRR - or d-nebivolol hydrochloride RSSS - or l-nebivolol hydrochloride MW: 441.9 g/mol Nebivolol hydrochloride is a white to off-white crystalline powder that is sparingly soluble in Dimethyl formamide and slightly soluble in Methanol. Nebivolol Tablets for oral administration contain nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol base. In addition, Nebivolol Tablets contain the following inactive ingredients: lactose monohydrate NF, pregelatinized starch USNF, croscarmellose sodium USNF, FD&C Blue #2 aluminium lake, D&C Red #27, FD&C Yellow #6, hydroxypropyl methyl cellulose USP, polysorbate 80 USP-NF, microcrystalline cellulose NF, colloidal silicon dioxide NF, magnesium stearate USP-NF, and sodium lauryl sulphate USNF. image-1.jpg image-2.jpg

    • What Is Nebivolol Hydrochloride Used For?

    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...

    Dosage and Administration

    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 )].

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS Most common adverse reactions (6.1):

  • Headache, fatigue To report SUSPECTED ADVERSE REACTIONS, contact Beximco Pharmaceuticals USA Inc. at 877-372-6093or 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 to 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% inNebivolol 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 to 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 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 listed elsewhere. These adverse reactions have been chosen for inclusion due to a combination of seriousness, frequency of reporting or...

    • Drug Interactions

    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 is 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.

    • Contraindications

    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 )

    • Pregnancy and Breastfeeding

    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...

    Overdosage

    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...

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 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 are triangular shaped, biconvex, unscored, differentiated by color and are engraved with (B125, B126, B127, or B128) on one side and plain on the other side. Nebivolol Tablets are supplied in the following strengths and package configurations: Nebivolol Tablets Tablet Strength Package Configuration NDC # Tablet Color Engraving 2.5 mg Bottles of 30 tablets with child-resistant closure Bottles of 90 tablets with child-resistant closure NDC 24689- 159 -01 NDC 24689- 159 -02 Light Blue engraved with ‘B125’ on one side and plain on the other side. 5 mg Bottles of 30 tablets with child-resistant closure Bottles of 90 tablets with child-resistant closure NDC 24689- 160 -01 NDC 24689- 160 -02 Beige engraved with ‘B126’ on one side and plain on the other side. 10 mg Bottles of 30 tablets with child-resistant closure Bottles of 90 tablets with child-resistant closure NDC 24689- 161 -01 NDC 24689- 161 -02 Pinkish-Purple engraved with ‘B127’ on one side and plain on the other side. 20 mg Bottles of 30 tablets with child-resistant closure Bottles of 90 tablets with child-resistant closure NDC 24689- 162 -01 NDC 24689- 162 -02 Light Blue engraved with ‘B128’ on one side and plain on the other side. Store at 20°C to 25°C (68°F 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.

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.