Nebivolol + Valsartan

Approved Indications:

• Essential Hypertension:
  Indicated for the treatment of primary (essential) hypertension in adult patients whose blood pressure is not adequately controlled with Nebivolol or Valsartan monotherapy, or when combination therapy is clinically appropriate.
• Initial Combination Therapy:
  May be used as an initial treatment in patients likely to require multiple antihypertensive agents to achieve target blood pressure levels.

Clinically Accepted Off-label Uses:

• Hypertension with Left Ventricular Hypertrophy (LVH):
  Especially in patients who benefit from both beta-blockade and renin-angiotensin system inhibition.
• Hypertension in Patients with Metabolic Syndrome or Obesity:
  Nebivolol’s vasodilatory and metabolically neutral profile, combined with Valsartan’s RAAS inhibition, provides effective control with fewer metabolic side effects.
• Hypertension in Early-Stage Heart Failure with Preserved Ejection Fraction (HFpEF):
  Used cautiously in hypertensive patients with diastolic dysfunction, under cardiologist supervision.

Adults:

• Initial Dose:
  Nebivolol 5 mg + Valsartan 80 mg, orally once daily.
• Titration:
  May be increased after 2–4 weeks to Nebivolol 10 mg + Valsartan 160 mg, then to Nebivolol 10 mg + Valsartan 320 mg, based on clinical response and tolerability.
• Maximum Dose:
  Nebivolol 10 mg + Valsartan 320 mg once daily.
• Administration:
  Take at the same time each day, with or without food. Swallow whole with water.

Elderly:

• Initiate at the lowest available dose. Monitor blood pressure, heart rate, renal function, and electrolyte balance closely during dose adjustments.

Pediatric Use:

• Not recommended. Safety and efficacy have not been established in children and adolescents under 18 years of age.

Renal Impairment:

• Mild to Moderate (CrCl ≥30 mL/min): Use with caution. Monitor serum creatinine and potassium.
• Severe (CrCl <30 mL/min): Use is not recommended due to insufficient data and increased risk of adverse renal effects.

Hepatic Impairment:

• Mild Impairment: Use cautiously; start with lower doses.
• Moderate to Severe Impairment: Contraindicated, due to reduced metabolism of Nebivolol and altered pharmacokinetics of Valsartan.

Route of Administration: Oral
Frequency: Once daily
Duration: Long-term therapy, based on blood pressure targets and individual risk factors

Nebivolol + Valsartan combines two antihypertensive agents with complementary mechanisms:

• Nebivolol is a β1-selective adrenergic receptor blocker that reduces heart rate, myocardial contractility, and cardiac output. Unlike traditional beta-blockers, it enhances nitric oxide-mediated vasodilation via β3 agonist activity, contributing to reduced peripheral vascular resistance.
• Valsartan is an angiotensin II receptor blocker (ARB) that selectively inhibits the binding of angiotensin II to the AT1 receptor. This prevents vasoconstriction, aldosterone secretion, and sodium retention, leading to vasodilation and decreased blood volume.

Together, this combination provides effective dual antihypertensive action through reduction of both cardiac workload and vascular resistance, improving overall cardiovascular outcomes.

Nebivolol:

• Absorption: Rapid; peak plasma concentration within 1.5–4 hours.
• Bioavailability: ~12% in extensive metabolizers; ~96% in poor metabolizers (CYP2D6-dependent).
• Protein Binding: ~98%.
• Metabolism: Hepatically metabolized via CYP2D6, forming active hydroxylated metabolites.
• Elimination: Through urine (~38%) and feces.
• Half-life: 10–30 hours, depending on metabolic phenotype.

Valsartan:

• Absorption: Peak levels reached in 2–4 hours.
• Bioavailability: ~25%.
• Protein Binding: ~95% (mostly albumin).
• Metabolism: Minimal hepatic metabolism (not CYP-based).
• Elimination: Excreted mainly via feces (83%) and urine (13%) as unchanged drug.
• Half-life: 6–9 hours.

Pregnancy:

• Nebivolol: May impair uteroplacental blood flow and cause fetal growth restriction or bradycardia.
• Valsartan: Contraindicated in the 2nd and 3rd trimesters due to risk of fetal renal dysfunction, oligohydramnios, skull hypoplasia, and neonatal death.
• Recommendation: Discontinue immediately upon pregnancy detection.

Lactation:

• Nebivolol: Present in small amounts in breast milk; may cause bradycardia or hypotension in the infant.
• Valsartan: Unknown excretion in human milk; potential risk cannot be excluded.
• Recommendation: Not recommended during breastfeeding. Use only if benefits outweigh potential risks.

• Primary Therapeutic Class: Antihypertensive Agent
• Subclasses:
• Nebivolol: β1-selective Beta-blocker with Vasodilatory Properties
• Valsartan: Angiotensin II Receptor Blocker (ARB)

• Hypersensitivity to Nebivolol, Valsartan, or any excipients
• Pregnancy (especially 2nd and 3rd trimesters)
• Severe hepatic impairment
• Severe renal impairment (CrCl <30 mL/min)
• Anuria
• Cardiogenic shock
• Symptomatic bradycardia
• Second or third-degree atrioventricular block (without a pacemaker)
• Decompensated heart failure
• Sinus node dysfunction (without pacemaker)

• Bradycardia & AV Block: Due to Nebivolol; monitor heart rate and ECG.
• Hypotension: May occur, especially in volume- or sodium-depleted patients.
• Hyperkalemia: Risk increased with Valsartan; monitor potassium levels regularly.
• Renal Function Impairment: Monitor serum creatinine and BUN in at-risk patients.
• Hepatic Dysfunction: Use with caution in mild cases; contraindicated if severe.
• Abrupt Discontinuation: Should be avoided; taper gradually to prevent rebound hypertension.
• Diabetes Mellitus: Nebivolol may mask signs of hypoglycemia.

Common Side Effects:

• Fatigue
• Dizziness
• Headache
• Bradycardia
• Orthostatic hypotension
• Hyperkalemia
• Elevated BUN or serum creatinine

Less Common:

• Insomnia
• Erectile dysfunction
• Nausea
• Abdominal discomfort
• Back pain
• Cough (rare; less frequent than with ACE inhibitors)

Serious (Rare):

• Angioedema (Valsartan-related)
• Acute kidney injury
• Severe hypotension or syncope
• Heart block
• Hepatic dysfunction

Timing of Onset:
Most side effects occur within 1–2 weeks of therapy initiation or dose change. Electrolyte and renal changes may take longer to manifest.

Major Drug-Drug Interactions:

• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): May increase plasma levels of Nebivolol.
• NSAIDs: May attenuate antihypertensive effects and increase renal risk.
• Potassium-sparing diuretics, potassium supplements: Increase risk of hyperkalemia with Valsartan.
• Other antihypertensives: Additive hypotensive effect.
• Lithium: Valsartan may reduce lithium clearance, increasing toxicity risk.
• Insulin or Oral Antidiabetics: Nebivolol may mask hypoglycemia symptoms.

Food Interactions:

• Food does not significantly affect absorption. May be taken with or without food.

Alcohol:

• May potentiate hypotensive effect. Caution is advised.

• 2023 ACC/AHA Hypertension Guidelines: Support earlier use of combination therapy in patients with stage 2 hypertension or high cardiovascular risk.
• Current Practice Trends: Nebivolol + ARB combinations (such as Valsartan) are favored in patients with metabolic syndrome or diabetes due to minimal adverse metabolic effects.
• Regulatory Status: No new safety alerts or changes in approved indications as of mid-2024 by FDA or EMA.

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Humidity: Protect from moisture; keep container tightly closed
• Light Protection: Store in original packaging; protect from light exposure
• Handling Instructions:
• Do not split or crush tablets unless scored
• Keep out of reach of children
• Refrigeration/Reconstitution: Not required