Pharmacology Update

Nebivolol Tablets (Bystolic™)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved another beta-adrenergic blocker. Nebivolol is a selective b1 adrenergic receptor antagonist, and seems to possess additional pharmacologic action that is related to the L-arginine/nitric oxide pathway.1 It is licensed from Mylan Laboratories, Inc. and marketed by Forest Pharmaceuticals Inc as Bystolic.

Indications

Nebivolol is indicated for the treatment of hypertension as monotherapy or in combination with other antihypertensive agents.2

Dosage

The recommended initial dose is 5 mg once daily. If further blood pressure reduction is required, the dose may be increased at 2-week intervals up to 40 mg daily. Patients with severe renal impairment (creatinine clearance less than 30 mL/min) or moderate hepatic impairment should be initiated at 2.5 mg daily and titration should be done with caution. Nebivolol may be taken without regard to meals.2

Nebivolol is available as 2.5 mg, 5 mg, and 10 mg tablets.

Potential Advantages

Nebivolol does not appear to negatively affect lipid or carbohydrate metabolism. It does appear to benefit endothelial function and may reduce systemic oxidative stress.1,3 Compared to atenolol, nebivolol was less likely to negatively affect insulin sensitivity and erectile dysfunction.4,5

Potential Disadvantages

Nebivolol is metabolized by CYP2D6 therefore drugs that inhibit or induce this enzyme would be expected to affect its plasma level. In patients who are poor metabolizers, b1 selectivity is reduced. As monotherapy, nebivolol was somewhat less effective in African Americans compared to Caucasians.2

Comments

Nebivolol is a selective b1 adrenergic receptor inhibitor at lower doses (5 mg to 10 mg) and inhibitor both b1 and b2 receptors at higher doses or in patients that are poor metabolizers.2 Nebivolol is a racemic mixture and both enantiomers appear to contribute to its pharmacologic effect. The d-nebivolol is a selective b1 adrenergic blocker and l-nebivolol cause vasodilation via the L-arginine-nitric oxide pathway. The efficacy as monotherapy was demonstrated in three placebo controlled randomized studies in patients with mild to moderate hypertension with baseline diastolic blood pressure of 95 to 109 mm Hg (n = 2016). Patients were randomized to doses of nebivolol ranging from 1.25 mg to 40 mg or placebo for 12 weeks.2,6 At the recommended starting dose of 5 mg the least square placebo-subtracted reduction of sitting trough blood pressure ranged from -3.3 to -5.5 for diastolic blood pressure (SiDBP) and -2.6 to -8.1 for systolic blood pressure (SiSBP). All the differences in SiDBP were statistically different at p < 0.05. A dose dependent trend was generally observed. Blood pressure reduction was seen within 2 weeks and was maintained over 24 hours.2 Nebivolol is effective as monotherapy in African American patients but may be less effective in magnitude of effect compared to Caucasian.2,7 In a number of comparative studies, nebivolol (5 mg daily) was similar to atenolol (50 mg to 100 mg daily), bisoprolol (5 mg daily), and metoprolol (100 mg twice daily) as well as to other classes of antihypertensives.8 Nebivolol has shown benefit (all cause mortality or cardiovascular hospitalization) compared to placebo in heart failure9 but it is currently not FDA approved for this use. Nebivolol is well tolerated with the most common adverse effects (2-7%) including headache, fatigue, dizziness, diarrhea, and nausea.2 The monthly cost of nebivolol is $45, which is about 3 times that of generic atenolol.

Clinical Implications

Nebivolol is the newest b-adrenergic blocker and is the 19th drug in this class approved in the US. Beta-blockers in general, and atenolol in particular, have fallen out of favor as first line therapy as they may be less effective in reducing strokes compared to other classes of antihypertensives.10 Whether nebivolol's additional vasodilatory effect make it unique within this class remains to be established.

References

1. Rosei EA, Rizzoni D. Drugs. 2007;67(8):1097-1107.

2. Bystolic Product Information. Forest Pharmaceutical Inc. December 2007.

3. Tzemos N, et al. Circulation. 2001;104(5):511-514.

4. Poirier L, et al. J Hypertens. 2001;19(8):1429-1435.

5. Boydak B, et al. Clin Drug Investig. 2005;25(6):409-416.

6. Weiss RJ, et al. J Clin Hypertens. 2007;9:667-676.

7. Saunders E, et al. J Clin Hypertens. (Greenwich) 2007;9(11):866-875.

8. Moen MD, Wagstaff AJ. Drugs. 2006;66(10):1389-1409.

9. Fisher MD, et al. Eur Heart J. 2005;26(3):215-225.

10. Lindholm LH, et al. Lancet. 2005;366(9446):1684-1689.