Byvalson - Drug Monograph

Introduction

Byvalson (nebivolol/valsartan) is a fixed-dose combination medication approved by the U.S. Food and Drug Administration (FDA) for the treatment of hypertension. It combines two antihypertensive agents with complementary mechanisms of action: nebivolol, a beta-blocker with vasodilatory properties, and valsartan, an angiotensin II receptor blocker (ARB). This combination provides synergistic blood pressure lowering effects while potentially minimizing side effects associated with higher doses of either component alone.

Mechanism of Action

Byvalson exerts its antihypertensive effects through dual mechanisms:

• Selective β1-adrenergic receptor antagonist with vasodilatory properties
• Prevents catecholamine-induced stimulation of cardiac β1-receptors
• Promotes nitric oxide-mediated vasodilation through β3-receptor agonism

• Selective angiotensin II type 1 (AT1) receptor antagonist
• Blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II
• Reduces peripheral vascular resistance without affecting heart rate

The combination results in complementary reduction of blood pressure through both sympathetic nervous system inhibition and renin-angiotensin-aldosterone system blockade.

Indications

• Treatment of hypertension
• May be used as initial therapy in patients likely to need multiple drugs to achieve blood pressure goals
• Alternative for patients inadequately controlled with monotherapy

Dosage and Administration

• Available as 5 mg/80 mg, 5 mg/160 mg, and 10 mg/160 mg (nebivolol/valsartan) tablets
• Initial dose: 5 mg/80 mg once daily
• May be titrated at 2-week intervals based on blood pressure response
• Maximum recommended dose: 10 mg/320 mg once daily

• Renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min)
• Hepatic impairment: Use with caution in moderate to severe hepatic impairment
• Geriatric patients: No dosage adjustment required
• Pediatric patients: Safety and effectiveness not established

• Administer with or without food
• Tablets should be swallowed whole with water
• Consistent timing of administration recommended

Pharmacokinetics

• Nebivolol: Absolute bioavailability ~12% in extensive metabolizers, ~96% in poor metabolizers
• Valsartan: Absolute bioavailability ~25%
• Food does not significantly affect systemic exposure

• Nebivolol: Extensive tissue distribution, protein binding ~98%
• Valsartan: Protein binding ~94-97%
• Both components cross the blood-brain barrier to a limited extent

• Nebivolol: Extensive first-pass metabolism via CYP2D6 (polymorphic)
• Valsartan: Minimal hepatic metabolism (<20%) primarily via CYP2C9
• No significant metabolic drug-drug interactions between components

• Nebivolol: Primarily fecal excretion (~67%), renal excretion (~13%)
• Valsartan: Primarily biliary excretion (~83%), renal excretion (~13%)
• Half-life: Nebivolol ~12-19 hours, Valsartan ~6 hours

Contraindications

• Hypersensitivity to any component of Byvalson or other ARBs
• Severe bradycardia
• Heart block greater than first degree
• Cardiogenic shock
• Decompensated heart failure
• Sick sinus syndrome (unless a permanent pacemaker is in place)
• Severe hepatic impairment (Child-Pugh C)
• Concomitant use with aliskiren in patients with diabetes

Warnings and Precautions

• Discontinue when pregnancy is detected due to risk of injury and death to developing fetus

• Symptomatic hypotension may occur, particularly in volume-depleted patients

• Monitor renal function in patients with renal artery stenosis

• May occur, particularly in patients with renal impairment or diabetes
• Monitor serum potassium periodically

• Gradually taper beta-blocker therapy to avoid rebound hypertension or angina

• Beta-blockers may precipitate or aggravate symptoms of arterial insufficiency

• Use with caution in patients with bronchospastic disease who do not respond to bronchodilator therapy

• Increased risk in patients with history of severe anaphylactic reactions to allergens

Drug Interactions

• Strong inhibitors (fluoxetine, paroxetine) may increase nebivolol exposure

• Additive hypotensive effects with other blood pressure medications

• Increased lithium concentrations and toxicity

• May reduce antihypertensive effectiveness and increase risk of renal impairment

• Nebivolol may increase digoxin concentrations

• Enhanced hypotensive effects, increased risk of volume depletion

• Increased risk of hyperkalemia

• Beta-blockers may mask symptoms of hypoglycemia

Adverse Effects

• Headache (6%)
• Fatigue (5%)
• Dizziness (5%)
• Diarrhea (3%)
• Nausea (2%)
• Bradycardia (2%)

• Fetal toxicity
• Hypotension
• Hyperkalemia
• Acute renal failure
• Hepatotoxicity
• Severe bradycardia and heart block
• Anaphylactic reactions
• Angioedema

Monitoring Parameters

• Blood pressure and heart rate
• Renal function (BUN, creatinine, eGFR)
• Electrolytes (potassium, sodium)
• Liver function tests
• Pregnancy test in women of childbearing potential

• Blood pressure at regular intervals
• Heart rate (watch for bradycardia)
• Renal function periodically
• Serum potassium, especially in at-risk patients
• Signs and symptoms of hypotension
• Weight monitoring for fluid retention

• Diabetic patients: Blood glucose monitoring
• Patients with heart failure: Signs of worsening heart failure
• Elderly patients: Orthostatic blood pressure measurements

Patient Education

• Take medication at the same time each day
• Do not stop taking abruptly without medical supervision
• Inform healthcare provider if you miss a dose

• Continue recommended dietary changes (low sodium, heart-healthy diet)
• Maintain regular physical activity as tolerated
• Limit alcohol consumption
• Avoid excessive potassium intake unless directed by physician

• Dizziness, lightheadedness, or fainting
• Unusual tiredness or weakness
• Swelling of face, lips, tongue, or throat
• Difficulty breathing or swallowing
• Significant weight gain or swelling
• Slow heart rate (<50 bpm)
• Signs of infection (fever, sore throat)

• Inform all healthcare providers about Byvalson use
• Use effective contraception if of childbearing potential
• Be cautious when rising quickly from sitting or lying position
• Monitor blood pressure at home if recommended
• Avoid driving or operating machinery until effects are known

References

1. FDA Prescribing Information: Byvalson (nebivolol and valsartan) tablets. Revised 2021. 2. White WB, et al. Am J Cardiovasc Drugs. 2016;16(2):129-137. 3. Neutel JM, et al. J Clin Hypertens (Greenwich). 2015;17(9):694-701. 4. Chrysant SG, et al. J Am Soc Hypertens. 2014;8(5):325-333. 5. Weber MA, et al. J Clin Hypertens (Greenwich). 2013;15(7):478-486. 6. Pool JL, et al. J Clin Hypertens (Greenwich). 2007;9(10):757-765. 7. McInnes GT. J Hum Hypertens. 2007;21 Suppl 1:S1-S19. 8. Mancia G, et al. J Hypertens. 2013;31(7):1281-1357. 9. Whelton PK, et al. J Am Coll Cardiol. 2018;71(19):e127-e248.