Drug Monograph
Brand Name: Bystolic (approved by FDA in December 2007)
Generic Name: Nebivolol hydrochloride
Manufacturer: Forest/Mylan
Drug Class: Antihypertensive, beta-antagonist, cardioselective
Uses:
Mechanism of Action: 2 Nebivolol is a long-acting cardioselective beta-1 adrenoceptor antagonist without membrane stabilizing or intrinsic sympathomimetic activities (ISA). The mechanism of action of the antihypertensive response of nebivolol is not fully understood. Possible mechanisms include decreased heart rate, decreased myocardial contractility, diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppression of renin activity, and vasodilation and decreased peripheral vascular resistance.
Pharmacokinetics: 1, 3
Tmax |
1.4 to 4 hours |
Vd |
695 to 2755 L |
T1/2 |
Adults: 12 to 19 hr |
Clearance |
Not available |
Protein binding |
98% (mostly to albumin), independent of concentration |
Bioavailability |
12% (extensive metabolizers) to 96% (poor metabolizers) |
Metabolism: Nebivolol is metabolized by the liver through various routes, including glucuronidation and hydroxylation by CYP 2D6. Nebivolol is a racemic mixture of d-nebivolol (active) and l-nebivolol (unactive). The predominant metabolites, namely the hydroxy metabolite and glucuronide, contribute to beta-blocking activity.
Elimination: Nebivolol elimination occurs via the kidneys. Less than 1% unchanged. Following a single oral dose of C-nebivolol, 38% was recovered in the urine and 44% in feces for extensive metabolizers (EMs) and 67% in urine and 13% in feces for poor metabolizers (PMs). For the most part nebivolol is excreted as multiple oxidative metabolites or their corresponding glucuronide conjugate.
Efficacy: 4, 5, 6
Citation: Flather MD, Shibata MC, et. al. Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). European Heart Journal. (2005) 26, 215-225.
Study Design: Prospective, multi-centre, mult-national, double-blind, placebo-controlled, parallel-group randomized trial.
Description of Study: The SENIORS study was designed to evaluate the effects of nebivolol, compared with placebo, in addition to standard therapy in clinically stable elderly patients (> 70 years) with chronic heart failure, with or without impairment of left ventricular systolic function. The mean maintenance dose of nebivolol was 7.7 mg and of placebo 8.5 mg. The primary outcome measure was all cause mortality and cardiovascular hospital admissions (time to first event). The proportion of patients who suffered death or cardiovascular hospital admission in the nebivolol group was 31.1% compared with 35.3% in the placebo group [hazard ratio (HR) 0.86, 95% CI 0.74–0.99; P = 0.039]. The unadjusted analysis showed an HR of 0.85 with the same CI (P = 0.034). The proportion of deaths was 15.8 and 18.1% in the nebivolol and placebo groups, respectively (HR 0.88, 95% CI 0.71–1.08; P = 0.21). The proportion of cardiovascular deaths which might be considered sudden deaths was 36% in the nebivolol group and 48% in the placebo group. Secondary outcomes included all cause mortality, composite of all cause mortality or all cause hospital admissions, cardiovascular hospital admissions, cardiovascular mortality, functional capacity by New York Heart Association (NYHA) class, and functional capacity by six minute walk test. The proportions of cardiovascular hospital admissions were 24.0 and 26.0% in the nebivolol and placebo groups, respectively (HR 0.90, 95% CI 0.76–1.06).
Limitations: The primary outcome was analyzed using the intention to treat (ITT) principle. This will cause nebivolol to appear more safe than it really is. There were 160 active centres from 10 countries, thus variability may have been a problem.
Conclusion: Patients with heart failure tend to be the elderly population. This population is more at risk of adverse events from medication, yet 68% of the nebivolol group reached maximum dose. Although this statistic may be exaggerated due to the ITT analysis, nebivolol’s therapeutic benefit seems to outweigh the risk.
Citation: Tzemos N, Lim PO, et. al. Nebivolol reverses endothelial dysfunction in essential hypertension. A randomized, double-blind, crossover study. Circulation 2001; 104: 511-514.
Study design: 2 week placebo run-in period; randomized, double-blind, crossover study.
Description of Study: This study was designed to compare the effects of nebivolol and atenolol on endothelial function. Following the placebo run-in, patients were randomized to either 5 mg of nebivolol with 2.5 mg of bendrofluazide or 50 mg of atenolol with 2.5 mg of bendrofluazide for 8 weeks. At the end of the first active treatment period, patients underwent a 2 week placebo wash out period, then they were crossed over to the alternate treatment arm for another 8 weeks. Both nebivolol/bendrofluazide and atenolol/bendrofluazide treatments reduced systolic and diastolic blood pressures to the same extent at the end of the each 8-week treatment period compared with placebo (132±7/82±6 and 132±9/83±8 versus 154±8/98±9 mm Hg, respectively; P < 0.001).
Limitations: Forearm blood flow (FBF) was expressed as mean + SEM. Standard error of the mean reports smaller numbers of variance, which look better to investigators; while other values used standard deviation. Primary and secondary outcome measures are not explicitly stated so the reader must make assumptions. The manufacturer of nebivolol funded this study and provided a grant to the Hypertension Research Centre, where the authors are affiliated.
Conclusion: This study uses SEM as opposed to SD, thereby contributing to the bias of the study. There may be reader misconception as to the degree of variation in FBF with nebivolol/bendrofluazide over atenolol/bendrofluazide, because using SEM reports smaller figures. Futhermore, the manufacturer’s financial involvement introduced bias into the study, which weakens the integrity of this trial.
Citation: Van Nueten L, Taylor FR, Robertson JIS. Nebivolol vs atenolol and placebo in essential hypertension: a double-blind randomized trail. Journal of Human Hypertension (1998) 12; 135-140.
Study Design: 4 week single-blind placebo run-in, then patients were randomized to treatment drug or placebo each given once daily in a double-blind, parallel group trial.
Description of Study: The aim of this study was to establish the efficacy and safety of nebivolol in comparison to atenolol and placebo. Patients received nebivolol 5 mg, atenolol 50 mg, and placebo for one month. It can be seen that by 2 weeks, and then throughout the period of active therapy, both nebivolol and atenolol lowered both systolic and diastolic pressures significantly (P < 0.001) in comparison with placebo, but with no appreciable differences in effect between the two drugs. Both active drugs preserved the slight rise in diastolic pressure, which occurs normally on standing. The percentages of pre-defined responders were nebivolol 59%, atenolol 59% and placebo 29% (both active drugs P < 0.001 vs placebo).
Limitations: ITT analysis was performed on all randomized patients, possibly inflating tolerance. No patient in the nebivolol group had severe DBP (> 115 mm Hg), in contrast to the other groups. Non-responders were eliminated which further exaggerated results. Primary and secondary outcomes were not explicitly stated.
Conclusion: There was no real advantage of nebivolol over atenolol with regards to adverse events (With the except of fatigue). Resting heart rate was lowered similarly between nebivolol and atenolol. Both drugs lowered SBP and DBP significantly with no appreciable differences between the two drugs. Nebiviolol may prove to be a better benefit for those with hypertension and coronary artery disease due to vasodilating effects and enhancement of left ventricular function. However, based on this study neither drug has an advantage over the other concerning essential hypertension.
Contraindications: 1, 3
Precautions: 1, 3
Adverse Effects: 2, 7
Drug Interactions: 4, 8, 9, 11
Dosing/Administration: 1, 2, 4
Use in Special Circumstances: 1, 2
Conclusion: Bystolic (nebivolol) is a lipophilic beta receptor blocker of third generation with distinct beta-1 and vasodilating properties used as monotherapy or in combination with other antihypertensive medications. It is important to monitor blood pressure and heart rate while patients are receiving nebivolol. Patients with diabetes should have their blood glucose monitored while on beta-blocker therapy. Liver function tests and serum creatinine should also be measured periodically. Those patients on concomitant non-dihydropyridine calcium channel blockers need close monitoring for heart arrhythmias, using an electrocardiogram. Nebivolol has proven to be therapeutic in the adult population with a side effect profile similar to well established beta-blockers. Based on the cited studies, the safety of nebivolol has not been fully elucidated, although adverse effects are comparable to other beta-blockers. Clinically, practioners should reserve nebivolol for treatment in patients resistant to other antihypertensives until there is more safety data available. The recommendation is that this medication be stored at room temperature between 20 and 25 degrees C (68 and 77 degrees F). Protect from light.
Prepared by: Casey R. Watts, Doctor of Pharmacy Candidate.
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