Bystolic (as nebivolol HCl) 10 MG Oral Tablet

Brand Name: Bystolic
  • Substance Name(s):



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 BYSTOLIC is co-administered with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc.) [see Clinical Pharmacology ( )].

12.5 7.2 Hypotensive Agents Do not use BYSTOLIC with other β-blockers.

Closely monitor patients receiving catecholamine-depleting drugs, such as reserpine or guanethidine, because the added β-blocking action of BYSTOLIC may produce excessive reduction of sympathetic activity.

In patients who are receiving BYSTOLIC and clonidine, discontinue BYSTOLIC 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 BYSTOLIC 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.



In clinical trials and worldwide postmarketing experience there were reports of BYSTOLIC overdose.

The most common signs and symptoms associated with BYSTOLIC overdosage are bradycardia and hypotension.

Other important adverse reactions reported with BYSTOLIC 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 BYSTOLIC worldwide involved a patient who ingested up to 500 mg of BYSTOLIC 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 BYSTOLIC, when clinically warranted: 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.

Bradycardia: Administer IV fluids and vasopressors.

Intravenous glucagon may be useful.

Hypotension: Monitor and treat with isoproterenol infusion.

Under some circumstances, transthoracic or transvenous pacemaker placement may be necessary.

Heart Block (second or third degree): Initiate therapy with digitalis glycoside and diuretics.

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

Congestive Heart Failure: Administer bronchodilator therapy such as a short acting inhaled β -agonist and/or aminophylline.

Bronchospasm: 2 Administer IV glucose.

Repeated doses of IV glucose or possibly glucagon may be required.

Hypoglycemia: Supportive measures should continue until clinical stability is achieved.

The half-life of low doses of nebivolol is 12-19 hours.

Call the National Poison Control Center (800-222-1222) for the most current information on β-blocker overdose treatment.



The chemical name for the active ingredient in BYSTOLIC (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 H F NO •HCl) with the following structural formula: 22 25 2 4 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.

BYSTOLIC as tablets for oral administration contains nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol base.

In addition, BYSTOLIC contains the following inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, D&C Red #27 Lake, FD&C Blue #2 Lake, FD&C Yellow #6 Lake, hypromellose, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, polysorbate 80, and sodium lauryl sulfate.

Structural Formula



14.1 Hypertension The antihypertensive effectiveness of BYSTOLIC as monotherapy has been demonstrated in three randomized, double-blind, multi-center, placebo-controlled trials at doses ranging from 1.25 to 40 mg for 12 weeks (Studies 1, 2, and 3).

A fourth placebo-controlled trial demonstrated additional antihypertensive effects of BYSTOLIC at doses ranging from 5 to 20 mg when administered concomitantly with up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) in patients with inadequate blood pressure control.

The three monotherapy trials included a total of 2016 patients (1811 BYSTOLIC, 205 placebo) with mild to moderate hypertension who had baseline diastolic blood pressures (DBP) of 95 to 109 mmHg.

Patients received either BYSTOLIC or placebo once daily for twelve weeks.

Two of these monotherapy trials (Studies 1 and 2) studied 1716 patients in the general hypertensive population with a mean age of 54 years, 55% males, 26% non-Caucasians, 7% diabetics and 6% genotyped as PMs.

The third monotherapy trial (Study 3) studied 300 Black patients with a mean age of 51 years, 45% males, 14% diabetics, and 3% as PMs.

Placebo-subtracted blood pressure reductions by dose for each study are presented in .

Most studies showed increasing response to doses above 5 mg.

Table 2 Table 2.

Placebo-Subtracted Least-Square Mean Reductions in Trough Sitting Systolic/Diastolic Blood Pressure (SiSBP/SiDBP mmHg) by Dose in Studies with Once Daily BYSTOLIC * p<0.05 based on pair-wise comparison vs.

placebo Study enrolled only African Americans.

¶ Study on top of one or two other antihypertensive medications.

^ Nebivolol dose (mg) 1.25 2.5 5.0 10 20 30-40 Study 1 -6.6*/-5.1* -8.5*/-5.6* -8.1*/-5.5* -9.2*/-6.3* -8.7*/-6.9* -11.7*/-8.3* Study 2 -3.8/-3.2* -3.1/-3.9* -6.3*/-4.5* Study 3 ¶ -1.5/-2.9 -2.6/-4.9* -6.0*/-6.1* -7.2*/-6.1* -6.8*/-5.5* Study 4 ^ -5.7*/-3.3* -3.7*/-3.5* -6.2*/-4.6* Study 4 enrolled 669 patients with a mean age of 54 years, 55% males, 54% Caucasians, 29% Blacks, 15% Hispanics, 1% Asians, 14% diabetics, and 5% PMs.

BYSTOLIC, 5 mg to 20 mg, administered once daily concomitantly with stable doses of up to two other antihypertensive agents (ACE inhibitors, angiotensin II receptor antagonists, and thiazide diuretics) resulted in significant additional antihypertensive effects over placebo compared to baseline blood pressure.

Effectiveness was similar in subgroups analyzed by age and sex.

Effectiveness was established in Blacks, but as monotherapy the magnitude of effect was somewhat less than in Caucasians.

The blood pressure lowering effect of BYSTOLIC was seen within two weeks of treatment and was maintained over the 24-hour dosing interval.

There are no trials of BYSTOLIC demonstrating reductions in cardiovascular risk in patients with hypertension, but at least one pharmacologically similar drug has demonstrated such benefits.





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.



BYSTOLIC is available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

BYSTOLIC tablets are triangular-shaped, biconvex, unscored, differentiated by color and are engraved with “ ” on one side and the number of mg (2 ½, 5, 10, or 20) on the other side.

FL Tablets: 2.5, 5, 10, 20 mg ( ) 3


12.1 Mechanism of Action The mechanism of action of the antihypertensive response of BYSTOLIC 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.



BYSTOLIC 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 BYSTOLIC is indicated for the treatment of hypertension, to lower blood pressure .

BYSTOLIC may be used alone or in combination with other antihypertensive agents .

[see Clinical Studies ( )] 14.1 [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 BYSTOLIC.

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.


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


8.1 Pregnancy Teratogenic Effects: Category C.

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.

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).


8.3 Nursing Mothers Studies in rats have shown that nebivolol or its metabolites cross the placental barrier and are excreted in breast milk.

It is not known whether this drug is excreted in human milk.

Because of the potential for β-blockers to produce serious adverse reactions in nursing infants, especially bradycardia, BYSTOLIC is not recommended during nursing.



WARNINGS AND PRECAUTIONS Acute exacerbation of coronary artery disease upon cessation of therapy: Do not abruptly discontinue ( ) 5.1 Diabetes: Monitor glucose as β-blockers may mask symptoms of hypoglycemia ( ) 5.5 5.1 Abrupt Cessation of Therapy Do not abruptly discontinue BYSTOLIC 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 BYSTOLIC is planned, carefully observe and advise patients to minimize physical activity.

Taper BYSTOLIC over 1 to 2 weeks when possible.

If the angina worsens or acute coronary insufficiency develops, re-start BYSTOLIC promptly, at least temporarily.

5.2 Angina and Acute Myocardial Infarction BYSTOLIC 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 BYSTOLIC 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 BYSTOLIC 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 Diabetes and Hypoglycemia β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

Nonselective β-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels.

It is not known whether nebivolol has these effects.

Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

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 .

The dose of BYSTOLIC may need to be reduced.

[see Drug Interactions ( )] 7 5.10 Impaired Renal Function Renal clearance of nebivolol is decreased in patients with severe renal impairment.

BYSTOLIC has not been studied in patients receiving dialysis .

[see Clinical Pharmacology ( ) and Dosage and Administration ( )] 12.4 2.1 5.11 Impaired Hepatic Function Metabolism of nebivolol is decreased in patients with moderate hepatic impairment.

BYSTOLIC has not been studied in patients with severe hepatic impairment .

[see Clinical Pharmacology ( ) and Dosage and Administration ( )] 12.4 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.


17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling ( ).

Patient Information Patient Advice Advise patients to take BYSTOLIC regularly and continuously, as directed.

BYSTOLIC can be taken with or without food.

If a dose is missed, take the next scheduled dose only (without doubling it).

Do not interrupt or discontinue BYSTOLIC without consulting the physician.

Patients should know how they react to this medicine before they operate automobiles, use machinery, or engage in other tasks requiring alertness.

Advise patients to consult a physician if any difficulty in breathing occurs, or if they develop signs or symptoms of worsening congestive heart failure such as weight gain or increasing shortness of breath, or excessive bradycardia.

Caution patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, that β-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia.

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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 BYSTOLIC 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.

BYSTOLIC has 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.

BYSTOLIC has 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 ( )].