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From Clinical Drug Investigation

Comparison of the Effects of Nebivolol and Bisoprolol on Systematic Vascular Resistance in Patients With Essential Hypertension
S.E. Brett, P. Forte, P.J. Chowienczyk, N. Benjamin and J.M. Ritter Authors and Disclosures Posted: 10/04/2002; Clin Drug Invest. 2002;22(6) 2002 Adis Data Information BV Pharmacist :Rating 0) ( Votes Rate This :Article
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....processing Abstract and Introduction Patients and Methods Results Discussion Conclusion References
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.Experience the fastest, most comprehensive, FREE medical app used by physicians Available for iPhone, iPod touch, iPad, Android, and BlackBerry Learn more Abstract and Introduction
Abstract

Objective: To compare the haemodynamic effects of nebivolol, a highly selective antagonist of 1-adrenergic receptors with additional actions caused via the L-

arginine/nitric oxide pathway, with those of bisoprolol, another selective

.adrenergic receptor antagonist Patients and Methods: The study had a double-blind, randomised, crossover design, and was performed in an outpatient setting. Study participants comprised 15 patients (11 men, four women, aged 29 to 69 years) with uncomplicated mild essential hypertension. Patients were randomised to receive nebivolol (5mg orally daily) or bisoprolol (10mg orally daily) for 2 weeks, followed by a 2-week washout and 2 weeks of the other treatment. Measurements (by mercury sphygmomanometer and bioimpedance) were made at the end of each baseline and each active treatment .period Results: Mean heart rate fell during active treatment (from 65 2 to 53 3 beats/min during bisoprolol, p < 0.05, and from 64 3 to 59 3 beats/min during nebivolol). Systolic/diastolic blood pressure fell during active treatments to a similar extent with each treatment (bisoprolol: 143 3/90 2mm Hg to 127 3/80 2mm Hg; nebivolol: 144 4/92 2mm Hg to 131 4/83 3mm Hg; each p < 0.01). In contrast, the systemic vascular resistance index fell during nebivolol (from 2854 201 to 2646 186 dyn sec cm-5 m2, p < 0.05), but did not change

significantly during bisoprolol treatment (baseline 2848 177, with treatment 2787 .(159 dyn sec cm-5 m2

Conclusion: The fall in systemic vascular resistance index during nebivolol (but not bisoprolol) treatment can be explained on the basis of a systemic vasodilator action of .nebivolol. The clinical importance of this action requires further investigation
Introduction

Nebivolol, the most selective antagonist of

-adrenoreceptors clinically available,

has additional haemodynamic effects attributable to systemic vasodilatation. The vasorelaxant effect of nebivolol in the dog coronary artery is endothelium-dependent, [1] and when administered into the brachial artery of healthy normotensive or hypertensive human subjects in high doses, it increases forearm blood flow.[2,3] This contrasts with propranolol or atenolol, which produce no change in forearm blood flow even at high doses.[2,4] The vasodilator effects of nebivolol are mediated via the endothelial L-arginine/nitric oxide (NO) pathway.[1-3,5] There is a disparity between the high potency of nebivolol when administered long term by mouth and the relatively large doses that are required to increase forearm blood flow when administered short term via the brachial artery. The present study addresses the question of whether nebivolol reduces systemic vascular resistance when administered long term by mouth .at the licensed dose (5mg daily) to patients with essential hypertension

 Next: Patients and Methods Section 1 of 5

Abstract and Introduction Patients and Methods Results Discussion Conclusion [ CLOSE WINDOW ] References Gao YS, Nagao T, Bond RA, et al. Nebivolol induces endothelium-dependent.1 relaxation of canine coronary arteries. J Cardiovasc Pharmacol 1991; 17: 9649 Cockcroft JR, Chowienczyk PJ, Brett SE, et al. Nebivolol vasodilates human.2 forearm vasculature: evidence for an L-arginine/NO dependent mechanism. J Pharmacol Exp Ther 1995; 274: 1067-71

Dawes M, Brett SE, Chowienczyk PJ, et al. The vasodilator action of.3 nebivolol in forearm vasculature of subjects with essential hypertension. Br J Clin Pharmacol 1999; 48: 460-3 Robinson BF, Wilson AG. Effect on forearm arteries and veins of attenuation.4 of the cardiac response to leg exercise. Clin Sci 1968; 35: 143-52 Broeders MAW, Doevendans PA, Bekkers B, et al. Nebivolol: a third.5 generation -blocker that augments vascular nitric oxide release.

Endothelial

2-adrenergic receptor-mediated nitric oxide production.

Circulation 2000; 102: 677-84 Petrie JC, O'Brien ET, Littler WA, et al. Recommendations on blood pressure.6 measurement. BMJ 1986; 293: 611-5 Ng NWK, Walley T, Breckenridge AM. Comparison and reproducibility of.7 transthoracic bioimpedance and dual beam Doppler ultrasound. Br J Clin Pharmacol 1991; 32: 275-82 Janssens WJ, Xhonneux R, Janssen PAJ. Animal pharmacology of nebivolol..8 Drug Invest 1991; 3 (1 Suppl): 13-24 Goldstein M, Vincent J-L, De Smet J-M, et al. Administration of nebivolol.9 after coronary artery bypass in patients with altered left ventricular function. J Cardiovasc Pharmacol 1993; 22: 253-8 De Cree J, Geukens H, Franken P, et al. Non invasive cardiac hemodynamics.10 of nebivolol in men. Acta Antwerpiensia 1989; 6: 2-21 Jennings G, Esler M, Dart A, et al. Effects of nebivolol on haemodynamics,.11 cardiac dimension and function, cardiovascular reflexes and bichemical measure of sympathetic activity in normal human subjects. Drug Invest 1991; 3: 51-9 Bowman AJ, Chen CP, Ford GA. Nitric oxide mediated venodilator effects of.12 nebivolol. Br J Clin Pharmacol 1994; 38: 199-204 Kubli S, Feihl F, Waeber B. Beta-blockade with nebivolol enhances the.13 acetylcholine-induced cutaneous vasodilation. Clin Pharmacol Ther 2001; 69: 238-44 Tzemos N, Lim PO, McDonald T. Nebivolol reverses endothelial dysfunction.14 in essential hypertension. Circulation 2001; 104: 511-4 De Cree J, Franken PH, Vandevivere J, et al. Haemodynamic effects of.15 nebivolol in men: comparison of radionuclide angiocardiography with systolic time intervals. Angiology 1988; 39: 526-34 Duprez D, Lefebvre R, De Backer T, et al. Influence of nebivolol on.16 cardiovascular haemodynamics during postural changes and isometric exercise. Drug Invest 1991; 3 Suppl. 1: 144-5 Uhlir O, Dvorak I, Gregor P, et al. Nebivolol in the treatment of cardiac.17 failure: a double blind controlled clinical trial. J Card Fail 1997; 3 (4): 271-6 Rousseau MF, Chapelle F, Van Eyll C, et al. Medium-term effects of beta-.18 blockade on left ventricular mechanics: a double blind, placebo-controlled

comparison of nebivolol and atenolol in patients with ischemic left ventricular dys-function. J Card Fail 1996; 2: 15-23 Wisenbaugh T, Katz I, Davis J, et al. Long term (3-month) effect of a new.19 beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Cardiol 1993, 1100 Burkat F, Pfisterer M, Sheinmann E. Effects of bisoprolol in relation to.20 metoprolol and bufuralol on left ventricular hemodynamics at rest and during exercise in chronic ischemic heart disease. J Cardivasc Pharmacol 1986; 8: 578-84 [ CLOSE WINDOW ] Table I. Table I. Summary of patient characteristics. Values are (given as mean ( standard deviation (Gender (male/female (Smoking (yes/no (Total cholesterol (mmol/L (LDL-cholesterol (mmol/L (HDL-cholesterol (mmol/L (Triglycerides (mmol/L (Glucose (mmol/L (DBP (mm Hg 11/4 6/9 (1.2) 5.2 (1.1) 3.1 (0.5) 1.4 (0.6) 1.5 (0.5) 4.7 (5.0) 93

(BMI (kg/m2 (4.4) 26.7

(SBP (mm Hg (13.6) 145 BMI = body mass index; DBP = diastolic blood pressure; HDL = high-density .lipoprotein; LDL = low-density lipoprotein; SBP = systolic blood pressure [ CLOSE WINDOW ] Table II. Table II. Summary of haemodynamic data. Values are (presented as mean ( standard error Bisoprolol washout (HR (min
-1

Nebivolol washout (2.8) 64 (2.2) 92 treatment (2.8) 59 **(2.6) 83

treatment *(2.6) 53 **(1.8) 80

(2.0) 65 (1.8) 90

(SBP (mm Hg (DBP (mm Hg (CI (L min-1 m2

(3.3) 143 **(3.2) 127

(4.0) 144 **(3.5) 131

(0.2) 3.1 (SVRI (dyn sec cm m

-5 2

*(0.2) 2.8

(0.1) 3.1

(0.1) 3.0

(177) 2848 (159) 2787 (201) 2854 *(186) 2646 CI = cardiac index; DBP = diastolic blood pressure; HR = heart rate; SBP = systolic blood pressure; SVRI = systemic vascular resistance index. * p < 0.05, ** p < 0.01 .versus washout

[CLOSE WINDOW]

Authors and Disclosures

S.E. Brett, Department of Clinical Pharmacology, Centre for Cardiovascular Biology and Medicine, St Thomas's Hospital, London, UK; P. Forte, Department of Clinical Pharmacology, St Bartholomew's Hospital, London, UK; P.J. Chowienczyk, Department of Clinical Pharmacology, Centre for Cardiovascular Biology and Medicine, St Thomas's Hospital, London, UK; N. Benjamin, Department of Clinical Pharmacology, St Bartholomew's Hospital, London, UK; and J.M. Ritter, Department of Clinical Pharmacology, Centre for Cardiovascular Biology and Medicine, St Thomas's Hospital, London, UK

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Patients and Methods

The study was a double-blind, randomised, crossover, single-centre investigation comparing nebivolol with bisoprolol in 15 patients with essential hypertension. Study participants were screened and, after giving written informed consent, antihypertensive medication was discontinued if relevant. Research ethics committee .approval was obtained from the St Thomas' hospital local research ethics committee Eighteen patients aged between 18 and 70 years were screened to provide 15 evaluable subjects. Eligible patients with essential hypertension were recruited sequentially from the Guy's and St Thomas' Trust hypertension clinic. Patient recruitment included those who had received antihypertensive treatment for at least 6 months, or those who were newly diagnosed on the basis of three or more readings (using mercury sphygmomanometry on separate visits) >159mm Hg (systolic) and/or >89mm Hg (diastolic) or a mean ambulatory diastolic pressure (Spacelabs) from 8.00am to 8.00pm of >89mm Hg. Patients were excluded if they had any of the following: evidence of secondary hypertension (based on history, physical examination, biochemical and imaging investigations as clinically indicated); a history of accelerated or malignant hypertension; history of stroke or transient ischaemic attack; ischaemic heart disease (including angina pectoris or previous

myocardial infarction); a clinically significant abnormality of renal (serum creatinine >135 mol/L) or hepatic function; evidence of other serious disease [including type 1 diabetes mellitus (insulin-dependent diabetes mellitus) and heart failure]; a .contraindication to -blockade

The protocol specified withdrawal in the event of a serious adverse event. Study participants could also withdraw whenever they wished, without giving a reason. History, physical examination, laboratory tests and written informed consent were performed at a screening visit. After a washout period of at least 2 weeks, patients came to the Department of Clinical Pharmacology to start the study. Haemodynamic measurements were performed four times on each subject: at baseline; at the end of 2 weeks' treatment with bisoprolol (10mg orally daily) or nebivolol (5mg orally daily); after 2 weeks' washout during which no tablets (active or placebo) were given; and after 2 weeks' treatment with nebivolol or bisoprolol. Two-week washout and treatment periods were considered sufficient in relation to the elimination half-life of bisoprolol (10 to 12 hours), which lacks active metabolites, and of nebivolol (approximately 10 hours; elimination half-life of metabolites approximately 24 .hours). All randomised patients completed the trial Patients attended the research laboratory in the morning on each occasion, and rested in a quiet, temperature-controlled (23 to 25C) environment for at least 30 minutes before measurements were made. Blood pressure was measured (with the patient resting supine and the upper arm at heart level) by a single trained observer (who was blind to the active treatment) using a mercury sphygmomanometer according to British Hypertension Society guidelines.[6] Mean arterial pressure was calculated as diastolic pressure plus one-third of the pulse pressure. Cardiac output was estimated using a non-invasive bioimpedance method (BoMed NCCOM3 monitor, California, USA), which has been previously validated.[7] This had less intra-subject than between-subject variation. We therefore used a crossover rather than a parallel group design. Cardiac output was normalised for body surface area and expressed as cardiac index in L min-1 m-2. The systemic vascular resistance index was calculated

by dividing mean arterial pressure by cardiac index and expressed in dyn

sec

cm-5

m2. Five measurements were made and the mean of the last three

measurements used for subsequent analysis. At each visit, any adverse event was recorded and graded for severity; venous blood was taken for routine haematology and biochemistry; urine was tested by dipstick, and an electrocardiogram was .performed
Statistical Analysis

Data were summarised as mean standard error, and statistical analysis was by repeated measures analysis of variance (SUPERANOVATM). A p-value < 0.05 was .considered to be statistically significant

Results
Patient characteristics are summarised in Table I , and haemodynamic data in Table II . As expected, mean heart rate declined from the relevant baseline during treatment both with nebivolol and with bisoprolol, although the reduction was significant only in the case of bisoprolol. Both drugs reduced systolic blood pressure (by 16 and 13mm Hg for bisoprolol and nebivolol, respectively, each p < 0.01) and diastolic blood pressure (by 10 and 9mm Hg for bisoprolol and nebivolol, respectively, each p < 0.01). There was no significant difference between bisoprolol and nebivolol with regard to effects on heart rate, or systolic or diastolic blood pressure. In contrast, there was a small but consistent reduction in systemic vascular resistance index during treatment with nebivolol of 208 62 dyn sec cm-5 m2 (approximately

7%, p < 0.05), but no significant change during treatment with bisoprolol (61 102 dyn sec cm-5 m2). The difference between nebivolol and bisoprolol was

approximately 5% (p < 0.05) [figure 1]. There was a small reduction in cardiac index during treatment with bisoprolol (0.3 L min-1 m-2, p <0.05) but no significant

change during treatment with nebivolol (figure 2). There were no adverse events, and no clinically relevant changes in blood chemistry or haematology. Furthermore, there .were no clinically relevant electrocardiographic changes, except for bradycardia
.Figure 1

Systemic vascular resistance index (SVRI) before and during treatment with nebivolol and bisoprolol in patients with mild essential .hypertension. * p < 0.05 versus bisoprolol
Enlarge) (Image [ CLOSE WINDOW ]

.Figure 1
Systemic vascular resistance index (SVRI) before and during treatment with nebivolol and bisoprolol in patients with mild essential hypertension. * .p < 0.05 versus bisoprolol .Figure 2

Cardiac index (CI) before and during treatment with bisoprolol and nebivolol in patients with mild essential hypertension. * p < 0.05 versus .washout
Enlarge) (Image

Discussion
The effects of oral nebivolol (5mg) on blood pressure and heart rate did not differ significantly from those of bisoprolol (10mg), although the mean changes during nebivolol administration were smaller than those during bisoprolol treatment. The study was not powered to detect blood pressure differences of the order of those observed. Differences of this magnitude, if real, could be clinically relevant in highrisk patients. The objective of the present study was, however, to investigate a .possible effect of nebivolol on systemic vascular resistance In contrast to the lack of significant effects on heart rate or blood pressure, there were significant differences between nebivolol and bisoprolol concerning effects on systemic vascular resistance and cardiac index. Systemic vascular resistance index

was reduced by nebivolol (by a mean of approximately 7% from baseline, p < 0.05), but did not change significantly during treatment with bisoprolol (mean change from baseline 0.6%). This confirms and extends previous work that has demonstrated that nebivolol has vasodilating activity in animal tissue[1] and in vivo, both in experimental mammals and in anaesthetised humans.[8,9] In healthy volunteers[2] and in hypertensive patients,[3] brachial artery infusion of nebivolol increased forearm blood flow, assessed by venous occlusion plethysmography. In the same experimental conditions, atenolol infusion does not modify forearm blood flow. A decrease in peripheral vascular resistance during oral treatment with nebivolol has also been described.[10,11] It is believed that the vasodilator effect of nebivolol is mediated via the endothelial Larginine/NO pathway, since co-infusion of L-NMMA, an inhibitor of NO synthase, antagonises the vasodilation and this can be prevented by excess L-arginine.[2,12] Oral nebivolol, but not atenolol, enhances vasodilation induced in the skin by acetylcholine iontophoresis[13] and increases the forearm blood flow response to brachial artery administered acetylcholine in hypertensive patients.[14] These observations suggest that nebivolol improves endothelial function and stimulates vascular NO production or release. Since NO protects against atherosclerosis, this may have implications in terms of clinical outcome as well as tolerability; considerations that are unfortunately .beyond the scope of the present investigation In our study, the cardiac index decreased during bisoprolol treatment (mean 7.8% reduction from baseline, p < 0.01), but was not significantly modified by nebivolol (mean 0.6% reduction from baseline). This observation is consistent with previous studies that reported that nebivolol does not reduce stroke volume or ejection fraction (both in healthy individuals and in patients with hypertension or heart failure),[15-19] [ and that bisoprolol reduces stroke volume and cardiac output.[20

Conclusion
In conclusion, the fall in systemic vascular resistance during nebivolol (but not bisoprolol) treatment can be explained on the basis of a systemic vasodilator action of nebivolol. This could contribute to the previously reported good tolerability of nebivolol. The clinical implications of this vasodilator action require further .investigation Nebivolol is a 1 receptor blocker with nitric oxide-potentiating vasodilatory effect used in treatment of hypertension and, in Europe, also for left ventricular failure.[1] It is highly cardioselective under certain circumstances[1] but has less evidence of [ survival benefit than other beta-blockers[2

Contents
[hide] Pharmacology and biochemistry 1 1 Selectivity 1.1 Vasodilator action 1.2 Antihypertensive effect 1.3 Pharmacology of side-effects 1.4

FDA warning letter about advertising claims 1.5 Contraindications 2 Adverse drug reactions 3 History 4 References 5 External links 6

edit] Pharmacology and biochemistry]

edit] 1 Selectivity]
Beta blockers help patients with cardiovascular disease by blocking 1 receptors, while many of the side-effects of these medications are caused by their blockade of 2 receptors.[3] For this reason, beta blockers that selectively block 1 receptors (termed cardioselective or 1-selective beta blockers) produce fewer adverse effects (for instance, bronchoconstriction) than those drugs that non-selectively block both 1 and 2 receptors. Nebilovol has been marketed by Micro Labs under the brand name Nebilong; by Forest Laboratories under the name Bystolic; and by Menarini under the names Hypoloc, Lobivon, Nebilet, Nebilox, Nobiten, and Temerit. Micro Labs further ventured into providing a combination with diuretic (hyrdochlorthiazide) marketed under the trade name Nebilong-H. In a laboratory experiment conducted on biopsied heart tissue, nebivolol proved to be the most 1-selective of the -blockers tested, being approximately 3.5 times more 1-selective than bisoprolol.[4] However, the drug's receptor selectivity in humans is more complex and depends on the drug dose and the genetic profile of the patient taking the medication.[5] The drug is highly cardioselective at 5 mg.[6] However, at doses above 10 mg, nebivolol loses its cardioselectivity and blocks both 1 and 2 receptors.[5] (While the recommended starting dose of nebivolol is 5 mg, sufficient control of blood pressure may require doses up to 40 mg).[5] Furthermore, nebivolol is also not cardioselective when taken by patients with a genetic makeup that makes them "poor metabolizers" of nebivolol (and other drugs).[5] As many as 1 in 10 Whites and even more Blacks are poor CYP2D6 metabolizers and therefore would likely not benefit from nebivolol's [ cardioselectivity.[citation needed

edit] Vasodilator action]

Nebivolol is unique as a beta-blocker.[7] Unlike carvedilol, it has a nitric oxide (NO)potentiating, vasodilatory effect.[8][9] Along with labetalol and carvedilol, it is one of three beta blockers to cause dilation of blood vessels in addition to effects on the heart.[9] However, recent studies question the clinical relevance of this property to [ Nebivolol's efficacy.[2

edit] Antihypertensive effect]

Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output.[10] The net hemodynamic effect of nebivolol is the result of a balance between the depressant effects of beta-blockade and an action that maintains cardiac output.[11] Antihypertensive responses were significantly higher with nebivolol than with placebo in trials enrolling patient groups considered representative of the US hypertensive population, in Black patients, and in those receiving concurrent [ treatment with other antihypertensive drugs.[12

edit] Pharmacology of side-effects]

Several studies have suggested that nebivolol has reduced typical beta-blocker-related side effects, such as fatigue, clinical depression, bradycardia, or impotence.[13][14][15] :However, according to the FDA

[16]

edit] FDA warning letter about advertising claims]

In late August 2008, the FDA issued a Warning Letter to Forest Laboratories citing exaggerated and misleading claims in their sales force's promotional materials, in [ particular over claims of superiority and novelty of action. [16

edit] Contraindications]
This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. (Unsourced material may be challenged and removed. (April 2011 Hepatic insufficiency Children Pregnancy Lactation

edit] Adverse drug reactions]

This section does not cite any references or sources. Please help improve this section by adding citations to reliable sources. (Unsourced material may be challenged and removed. (April 2011 Headache Parasthesia Dizziness

edit] History]
Mylan Laboratories licensed the U.S. and Canadian rights to nebivolol from Janssen Pharmaceutica N.V. in 2001. Nebivolol is already registered and successfully marketed in more than 50 other countries, including the US. It is marketed under the brand name Nebilet. Nebivolol is manufactured by Forest Laboratories, Inc. In India, Nebivolol is available as Nebilong 5 mg (Micro Labs) Nebicard-5 (Torrent), Nubeta (Nicholas Piramal) and Nodon (Cadila Pharmaceuticals). In Greece and Italy, Nebivolol is marketed under the name Lobivon from Menarini pharmaceutical. In middle east is marketed under the name Nebilet . In the US, it is marketed under the .brand name Bystolic from Mylan Laboratories and Forest Laboratories

edit] References]