Nebivolol + Hydrochlorothiazide

Approved Indications:

• Essential Hypertension: Indicated for the treatment of high blood pressure in patients whose blood pressure is not adequately controlled with monotherapy of either Nebivolol or Hydrochlorothiazide.
• Combination Antihypertensive Therapy: Used in patients who require a beta-blocker and a thiazide diuretic to achieve blood pressure goals.

Clinically Accepted Off-label Uses:

• Hypertension in Metabolic Syndrome or Obese Patients: Where Nebivolol’s vasodilatory and metabolically neutral profile is preferred.
• Adjunct in Early Heart Failure with Hypertension: Carefully selected patients with early left ventricular dysfunction and coexisting hypertension.

রেজিস্টার্ড চিকিৎসকের নির্দেশনা অনুযায়ী ঔষধ সেবন করুন।

Adults:

• Initial Dose:
  One tablet of Nebivolol 5 mg + Hydrochlorothiazide 12.5 mg, once daily, orally.
• Titration:
  If blood pressure is not adequately controlled, the dose may be increased to Nebivolol 10 mg + Hydrochlorothiazide 25 mg once daily.
• Administration:
  Administer at the same time each day, with or without food.

Elderly (≥65 years):

• Start at the lowest dose (5 mg/12.5 mg). Titrate cautiously based on response. Monitor renal function and blood pressure closely.

Pediatric Use:

• Not recommended. Safety and effectiveness have not been established in individuals under 18 years.

Renal Impairment:

• Mild to Moderate (CrCl ≥30 mL/min): Use with caution. Monitor electrolytes and renal function regularly.
• Severe (CrCl <30 mL/min): Use is not recommended due to the increased risk of fluid and electrolyte disturbances.

Hepatic Impairment:

• Mild Impairment: Use with caution.
• Moderate to Severe Impairment: Contraindicated due to impaired metabolism of Nebivolol.

রেজিস্টার্ড চিকিৎসকের নির্দেশনা অনুযায়ী ঔষধ সেবন করুন।

This fixed-dose combination combines two antihypertensive agents:

• Nebivolol is a β1-selective adrenergic blocker that decreases heart rate, myocardial contractility, and cardiac output. It also uniquely stimulates endothelial nitric oxide (NO) production, leading to vasodilation and further reduction in blood pressure.
• Hydrochlorothiazide is a thiazide diuretic that inhibits sodium and chloride reabsorption in the distal convoluted tubule, reducing plasma volume and peripheral resistance.

Together, they synergistically reduce blood pressure through complementary actions: decreased cardiac output and reduced vascular volume.

Nebivolol:

• Absorption: Rapid oral absorption; peak plasma concentration within 1.5–4 hours.
• Bioavailability: 12% in extensive metabolizers; nearly 96% in poor metabolizers.
• Distribution: Highly protein-bound (~98%).
• Metabolism: Hepatically metabolized, primarily via CYP2D6, into active metabolites.
• Elimination: Via urine (38%) and feces.
• Half-life: 10–30 hours depending on CYP2D6 status.

Hydrochlorothiazide:

• Absorption: Peak levels in 1.5–2 hours after oral administration.
• Bioavailability: ~65–75%.
• Metabolism: Not metabolized.
• Elimination: Excreted unchanged in urine.
• Half-life: 6–15 hours, prolonged in renal impairment.

Pregnancy:

• FDA Category: Not assigned (per updated labeling).
• Nebivolol: May reduce uteroplacental blood flow and cause fetal bradycardia.
• Hydrochlorothiazide: May cause fetal electrolyte imbalance, jaundice, or thrombocytopenia.
  Recommendation: Avoid, especially during the second and third trimesters.

Lactation:

• Nebivolol: Small amounts may be present in breast milk; potential effects on infant heart rate.
• Hydrochlorothiazide: Excreted into breast milk; may suppress lactation or cause electrolyte imbalance in infants.
• Recommendation: Avoid use during breastfeeding unless clearly needed and supervised.

• Primary Class: Antihypertensive Combination
• Subclasses:
• Nebivolol: β1-selective Beta-blocker with Vasodilatory Effect
• Hydrochlorothiazide: Thiazide Diuretic

• Hypersensitivity to Nebivolol, Hydrochlorothiazide, or any component of the formulation
• Severe hepatic impairment
• Severe renal impairment (CrCl <30 mL/min)
• Anuria
• Second- or third-degree atrioventricular (AV) block
• Severe bradycardia (<50 bpm)
• Cardiogenic shock or decompensated heart failure
• Sinus node dysfunction without a pacemaker
• Electrolyte imbalances: significant hypokalemia, hyponatremia

• Bradycardia & Heart Block: Monitor heart rate regularly.
• Hypotension: Avoid abrupt dose increases; assess volume status before initiation.
• Electrolyte Imbalances: Monitor sodium, potassium, and magnesium periodically.
• Renal Impairment: Monitor renal function during treatment, especially in the elderly.
• Hyperuricemia: Hydrochlorothiazide may raise uric acid levels and provoke gout.
• Diabetes Mellitus: May mask hypoglycemia and alter glucose tolerance.
• Photosensitivity: Hydrochlorothiazide may cause increased sensitivity to sunlight.
• Tapering: Avoid abrupt discontinuation to prevent rebound hypertension or angina.

Common Adverse Effects:

• Cardiovascular: Bradycardia, orthostatic hypotension, palpitations
• Neurological: Fatigue, dizziness, headache
• Gastrointestinal: Nausea, constipation
• Metabolic: Hypokalemia, hyperuricemia
• General: Cold extremities, weakness

Less Common:

• Erectile dysfunction
• Sleep disturbances
• Muscle cramps
• Dry mouth

Rare but Serious Effects:

• Severe hypotension or syncope
• Acute kidney injury
• Stevens-Johnson syndrome (rare, HCTZ-related)
• Bronchospasm (especially in asthmatics)
• Arrhythmias from electrolyte imbalance

Timing of Onset: Most side effects occur within 1–2 weeks of therapy initiation or dose change.

Major Drug Interactions:

• Other Antihypertensives: Additive blood pressure lowering effects
• CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): May increase Nebivolol levels
• Digoxin: Increased risk of bradycardia
• NSAIDs: May reduce antihypertensive efficacy and increase nephrotoxicity risk
• Lithium: Hydrochlorothiazide may reduce renal clearance of lithium, increasing toxicity risk
• Insulin or Antidiabetics: Beta-blockers may mask hypoglycemia symptoms

Food Interactions:

• May be taken with or without food.

Alcohol:

• May enhance hypotensive effect. Use with caution.

• 2023 ACC/AHA Guidelines: Support early use of combination therapy in stage 2 hypertension.
• Clinical Preference: Nebivolol is increasingly favored for its favorable metabolic profile and vasodilatory action.
• Regulatory Status: No new safety alerts issued by FDA or EMA as of 2024.

• Storage Temperature: Below 25°C (77°F)
• Humidity: Store in a dry place
• Light Protection: Keep in the original blister or container; protect from light
• Handling: Do not split or crush tablets unless scored and approved
• Refrigeration/Reconstitution: Not required