Nebivolol (Bystolic) Drug Information
Indications
Nebivolol is FDA-approved for the treatment of hypertension to lower blood pressure and reduce cardiovascular risk. 1
Not a first-line agent for hypertension: The 2024 ESC guidelines recommend ACE inhibitors, ARBs, dihydropyridine calcium channel blockers, and thiazide/thiazide-like diuretics as first-line therapy, either alone or in combination. 2
Preferred role in resistant hypertension: When blood pressure remains uncontrolled on maximally tolerated triple-combination therapy (RAS blocker + CCB + diuretic), nebivolol is recommended as a vasodilating beta-blocker option if spironolactone is not tolerated or if beta-blockers are not already indicated. 2
Compelling indications for beta-blocker use: Nebivolol should be added at any step of hypertension treatment when patients have angina pectoris, post-myocardial infarction, systolic heart failure, or need heart rate control. 2
Off-label use in heart failure: The American College of Cardiology and European Society of Cardiology recognize nebivolol as effective for coronary artery disease and heart failure with reduced ejection fraction, with proven mortality reduction particularly in elderly patients (≥70 years) from the SENIORS trial. 3
Dosing Regimen
Start nebivolol at 5 mg once daily for most patients, with or without food, and titrate up to 40 mg daily at 2-week intervals if needed for blood pressure control. 1
Standard Dosing
- Initial dose: 5 mg once daily 1
- Titration: Increase at 2-week intervals if further blood pressure reduction needed 1
- Maximum dose: 40 mg once daily 1
- More frequent dosing is unlikely to provide additional benefit 1
Dose Adjustments
Severe renal impairment (CrCl <30 mL/min):
Moderate hepatic impairment (Child-Pugh Class B):
Elderly patients:
- No dose adjustment necessary 1
CYP2D6 poor metabolizers:
- No dose adjustment necessary despite 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol 1
Contraindications
Nebivolol is contraindicated in patients with severe hepatic impairment, as it has not been studied in this population and d-nebivolol exposure increases 10-fold in moderate hepatic impairment. 1
Additional Standard Beta-Blocker Contraindications (General Medical Knowledge):
- Severe bradycardia
- Heart block greater than first degree (without pacemaker)
- Cardiogenic shock
- Decompensated heart failure
- Sick sinus syndrome (without pacemaker)
Adverse Effects
Nebivolol is well tolerated with an adverse event profile similar to placebo, and notably better than traditional beta-blockers regarding sexual dysfunction and metabolic effects. 4, 5
Most Common Adverse Events:
- Headache (2-24%) 6
- Fatigue (4-79%) 6
- Dizziness (2-5%) 6
- Paresthesias (7-13%) 6
- Bradycardia (6-11%) 6
- Rhinitis (1-7%) 6
Key Tolerability Advantages:
- No orthostatic hypotension reported in multiple studies 4
- No impotence or decreased libido (unlike atenolol or enalapril) 4
- Neutral metabolic effects: Does not worsen glucose tolerance or insulin sensitivity, even when combined with hydrochlorothiazide 2, 7
- Superior in metabolic syndrome: Recommended for patients with diabetes risk, as traditional beta-blockers increase diabetes risk by 15-29% 7
Drug Interactions
Fluoxetine (CYP2D6 inhibitor) causes an 8-fold increase in d-nebivolol AUC and 3-fold increase in Cmax—monitor blood pressure closely and reduce nebivolol dose when co-administered with CYP2D6 inhibitors. 1
Significant Interactions:
CYP2D6 inhibitors:
- Fluoxetine: 8-fold increase in AUC, 3-fold increase in Cmax 1
- Other CYP2D6 inhibitors (paroxetine, quinidine, bupropion) expected to have similar effects 1
- Action: Monitor blood pressure and adjust nebivolol dose accordingly 1
Cimetidine:
- Causes 23% increase in d-nebivolol plasma levels 1
Sildenafil:
- Nebivolol decreases sildenafil AUC and Cmax by 21-23% 1
- Combined vital sign effects are approximately additive 1
No Significant Interactions:
- Digoxin: No pharmacokinetic changes 1
- Warfarin: No effect on anticoagulation (PT/INR) or pharmacokinetics 1
- Diuretics (furosemide, hydrochlorothiazide, spironolactone): No interactions 1
- Ramipril: No interactions 1
- Losartan: No interactions 1
- Ranitidine: No interactions 1
- Activated charcoal: No effect on nebivolol pharmacokinetics 1
Safety Considerations
Never abruptly discontinue nebivolol—taper by reducing the dose by 50% every 3-7 days over 1-2 weeks to prevent rebound hypertension, tachycardia, and acute coronary events. 8
Critical Tapering Protocol:
- Reduce dose by 50% every 3-7 days over 1-2 weeks 8
- Example: 10 mg daily → 5 mg daily (week 1) → 2.5 mg daily (week 2) → discontinue 8
- Monitor heart rate, blood pressure, and heart failure symptoms (dyspnea, edema, weight gain) during taper 8
When to Continue Indefinitely:
- Coronary artery disease or prior myocardial infarction 8
- Heart failure (discontinuation associated with higher mortality and rehospitalization) 8
Common Pitfalls to Avoid:
- Do not discontinue for asymptomatic low blood pressure, mild blood pressure reductions, or mild renal function deterioration 8
- Do not discontinue in reactive airway disease without attempting dose reduction first—nebivolol is cardioselective and preferred in this population 8
- Never allow patients to abruptly stop on their own—patient education is essential 8
Special Populations:
Pregnancy/Lactation (General Medical Knowledge):
- Beta-blockers cross the placenta and are excreted in breast milk
- Use only if benefit outweighs risk
Diabetes:
- Nebivolol does not mask hypoglycemia symptoms as severely as non-selective beta-blockers due to beta-1 selectivity 9
Asthma/COPD:
- Nebivolol is highly beta-1 selective and does not significantly decrease airway conductance compared to atenolol or propranolol 9
- May be useful in patients who experienced erectile dysfunction with other beta-blockers due to vasodilatory properties 7
Alternative First-Line Antihypertensive Options
For initial hypertension treatment, use ACE inhibitors, ARBs, dihydropyridine calcium channel blockers, or thiazide/thiazide-like diuretics as first-line agents, preferably as low-dose combination therapy in a single pill. 2
Recommended First-Line Classes:
- ACE inhibitors (e.g., lisinopril, ramipril) 2
- ARBs (e.g., losartan, telmisartan) 2
- Dihydropyridine calcium channel blockers (e.g., amlodipine, nifedipine) 2
- Thiazide or thiazide-like diuretics (e.g., hydrochlorothiazide, chlorthalidone, indapamide) 2
Initial Treatment Strategy:
- Start with low-dose double combination therapy (preferably as single-pill combination) for most patients with confirmed hypertension 2
- Assess blood pressure control at 1 month if possible, otherwise at 1-3 months 2
- If uncontrolled, advance to low-dose triple combination (RAS blocker + CCB + diuretic) 2
- If still uncontrolled on maximally tolerated triple therapy, consider resistant hypertension and add spironolactone or vasodilating beta-blocker like nebivolol 2
Exception:
- Do not combine two RAS blockers (ACE inhibitor + ARB) 2
Unique Pharmacological Properties
Nebivolol is a highly selective beta-1 blocker with nitric oxide-mediated vasodilation, distinguishing it from traditional beta-blockers and providing advantages in central hemodynamics and metabolic effects. 3, 9
Mechanism of Action:
- Beta-1 selective adrenergic blockade 9
- Stimulates endothelial nitric oxide production via L-arginine-nitric oxide pathway 3, 10
- Leads to vasodilation and decreased peripheral vascular resistance 10
- No intrinsic sympathomimetic activity 9
Hemodynamic Advantages:
- Reduces central pulse pressure and aortic stiffness better than atenolol or metoprolol 2, 7
- Does not compromise left ventricular function 9
- May increase stroke volume 9
- Does not reduce heart inotropism during exertion 9