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BYSTOLIC—Effective as initial combination therapy with an ACEI

At week 6 of a 3-month dose titration study

BYSTOLIC as initial combination therapy with an ACEI (lisinopril) provided significant BP reductions in patients with diastolic stage II hypertension8

1.4_Combination_Therapy_ACEI_MobileChange From Baseline (mm Hg)0*P<0.0001 vs placebo ITT LOCF at week 6PlaceboBYSTOLIC 5 or 20 mg/lisinopril 10 or 40 mg(n=93)(n=189)164.7SBP Reductions From Baseline in Mean Sitting DBP and SBP at Trough at 6 Weeks2,8104.3DBP-8.0-9.9-17.2*-19.2*-20Baseline: 164.3 mm HgSBP105.0DBP-4-2-6-8-10-12-14-16-18Start BYSTOLIC with an ACEI in appropriate patients for significant BP reductions

Study Design: Results from a U.S. phase IV, 3-month, multicenter, randomized, double-blind, parallel-group, placebo- and active-controlled study of BYSTOLIC plus lisinopril as initial combination therapy for the treatment of diastolic stage II hypertension in patients <65 years of age. Inclusion criteria for baseline diastolic and systolic blood pressure were: sitting DBP ≥100 mm Hg and sitting SBP <180 mm Hg. All patients were randomized to one of four treatment groups and were initiated on a starting dose of either: combination BYSTOLIC 5 mg/lisinopril 10 mg (N=190), BYSTOLIC 5 mg monotherapy (N=189), lisinopril 10 mg monotherapy (N=190), or placebo (N=95). Results from monotherapy treatment arms are not shown. At week 2, patients not achieving treatment goal (BP <140/90 mm Hg, <130/80 mm Hg for patients with diabetes) on combination therapy were uptitrated to BYSTOLIC 20 mg, lisinopril 40 mg. Primary endpoint was change from baseline in trough seated DBP at week 6. Mean values at baseline: sitting DBP at trough, 10.4 mm Hg; sitting SBP at trough, 163.8 mm Hg (N=664).

  • At week 6 of a 3-month initial combination therapy study, adverse events occurring in ≥1% of patients taking BYSTOLIC plus lisinopril and more frequently than in patients taking placebo were upper respiratory tract infection (3.7% for BYSTOLIC plus lisinopril vs 3.2% for placebo), bradycardia (2.1% vs 0%), nasopharyngitis (2.1% vs 1.1%), constipation (1.6% vs 1.1%), cough (1.6% vs 1.1%), fatigue (1.6% vs 1.1%), oropharyngeal pain (1.6% vs 1.1%), decreased hemoglobin (1.1% vs 0%), hematuria (1.1% vs 0%), and sinus bradycardia (1.1% vs 0%)2

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The first and only beta blocker (BB) + angiotensin II receptor blocker (ARB) fixed-dose combination therapy with significant blood pressure reductions.

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  • When pregnancy is detected, discontinue BYVALSON as soon as possible.
  • Drugs that act directly on the renin-angiotensin system can cause injury and death to the developing fetus.


BYSTOLIC and BYVALSON 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), and patients who are hypersensitive to any component of this product. Do not co-administer aliskiren with BYVALSON in patients with diabetes.

Warnings and Precautions

Use of drugs that act on the renin-angiotensin system during the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and death. When pregnancy is detected, discontinue BYVALSON as soon as possible.

In patients with an activated renin-angiotensin-aldosterone system, symptomatic hypotension may occur in patients receiving BYVALSON. Correct these conditions prior to administration of BYVALSON, or start the treatment under close medical supervision. If excessive hypotension occurs, the patient should be placed in the supine position and, if necessary, given an intravenous infusion of normal saline. A transient hypotensive response is not a contraindication to further treatment, which usually can be continued without difficulty once the blood pressure has stabilized.

Do not abruptly discontinue BYSTOLIC or BYVALSON 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 beta blockers. Myocardial infarction and ventricular arrhythmias may occur with or without preceding exacerbation of the angina pectoris. As with other beta-blocker therapies, when discontinuation of BYSTOLIC or BYVALSON is planned, carefully observe and advise patients to minimize physical activity. Taper nebivolol using monotherapy over 1 to 2 weeks when possible. If the angina worsens re-start nebivolol promptly, at least temporarily.

Worsening heart failure or fluid retention may occur during nebivolol therapy because of its beta-blocking effects. Consider diuretic therapy and treat heart failure appropriately, according to current guidelines.

In general, patients with bronchospastic diseases should not receive beta blockers.

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery, however the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures. Monitor patients closely when anesthetic agents which depress myocardial function, such as ether, cyclopropane, and trichloroethylene, are used.

Beta blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Advise patients subject to spontaneous hypoglycemia and diabetic patients receiving insulin or oral hypoglycemic agents about these possibilities.

Beta blockers may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta blockers may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate a thyroid storm.

Beta blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease.

Because of significant negative inotropic and chronotropic effects in patients treated with beta blockers and calcium channel blockers of the verapamil and diltiazem type, monitor heart rate and blood pressure in patients treated concomitantly with these agents.

Changes in renal function including acute renal failure can be caused by drugs that inhibit the renin-angiotensin system and by diuretics. Patients whose renal function may depend in part on the activity of the renin-angiotensin system may be at particular risk of developing acute renal failure on valsartan. Monitor renal function periodically in these patients. Consider withholding or discontinuing therapy in patients who develop a clinically significant decrease in renal function on valsartan.

Renal clearance of nebivolol is decreased in patients with severe renal impairment. Nebivolol has not been studied in patients receiving dialysis.

Metabolism of nebivolol is decreased in patients with moderate hepatic impairment. Nebivolol has not been studied in patients with severe hepatic impairment.

While taking beta 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.

In patients with known or suspected pheochromocytoma, initiate an alpha blocker prior to the use of any beta blocker.

In hypertensive patients, greater than 20% increases in serum potassium were observed in 4.4% of valsartan-treated patients compared to 2.9% of placebo-treated patients. Discontinuation of BYVALSON may be required.

Adverse Reactions

The most common adverse events with BYSTOLIC versus placebo (approximately ≥1% and greater than placebo) were headache, fatigue, dizziness, diarrhea, nausea, insomnia, chest pain, bradycardia, dyspnea, rash, and peripheral edema. The most common adverse events that led to discontinuation of BYSTOLIC were headache (0.4%), nausea (0.2%), and bradycardia (0.2%).

Drug Interactions


Avoid concomitant use with CYP2D6 inhibitors (quinidine, propafenone, fluoxetine, paroxetine, etc).

Do not use with other beta blockers. Monitor patients receiving catecholamine-depleting drugs (eg, reserpine or guanethidine) or clonidine as they may produce excessive reduction of sympathetic activity. Discontinue nebivolol for several days before the gradual tapering of clonidine.

Concomitant use with digitalis glycosides can increase the risk of bradycardia. Monitor for bradycardia.

Nebivolol can exacerbate the effects of myocardial depressants or inhibitors of AV conduction, such as certain calcium channel blockers (particularly of the verapamil- and diltiazem-type) or antiarrhythmic agents. Monitor for effects on heart rate and cardiac conduction.


Concomitant use with other agents that block the renin-angiotensin system, potassium-sparing diuretics, potassium supplements or salt substitutes, or other agents that may increase potassium levels may result in hyperkalemia. Monitor serum potassium.

Co-administration with NSAIDs may result in deterioration of renal function, including possible acute renal failure, and loss of antihypertensive effect. Monitor renal function.

Concomitant use with ACE inhibitors or with aliskiren is associated with increased risks of hypotension, hyperkalemia, and changes in renal function (including acute renal failure) compared to monotherapy. Monitor blood pressure, renal function and electrolytes. Avoid concomitant use with aliskiren in patients with renal impairment. Do not co-administer aliskiren with BYVALSON in patients with diabetes.

Increases in lithium concentrations and toxicity have been reported during concomitant administration with lithium. Monitor serum lithium levels.

Please see full Prescribing Information for BYSTOLIC.

Please see full Prescribing Information for BYVALSON.