DRUG PROFILE

5
IUPAC Name

Drug Profile Nebivolol Hydrochloride

Molecular Structure

Alpha,alpha'-[Iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H1-benzopyran-2-methanol hydrochloride.
C22H25F2NO4.HCl 441.90

Molecular Formula Molecular Weight Melting Range Bioavailability pKa Log P Plasma protein binding Plasma half life Stability Solubility

220-222C Approximately 12% 14.12 3.20 98% 10 hours. Stable molecule soluble in

methanol,

dimethylsulfoxide,

and

N,N-

dimethylformamide, sparingly soluble in ethanol, propylene glycol, and polyethylene glycol, and very slightly soluble in Description Category Standards hexane, dichloromethane, and methylbenzene White to almost white powder Antihypertensive Contains 98.0 - 102.0 % of (C15H25NO3)2C4H6O4, calculated on the dried basis

5.1 Pharmacology38,39,40,41,42

Nebivolol is a selective 1-receptor antagonist. Activation of 1-receptors by epinephrine increases the heart rate and the blood pressure, and the heart consumes more oxygen. Nebivolol blocks these receptors which reverses the effects of epinephrine, lowering the heart rate and blood pressure. In addition, beta blockers prevent the release of renin, which BBDNITM, LUCKNOW Page 17

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is a hormone produced by the kidneys which leads to constriction of blood vessels. At high enough concentrations, this drug may also bind beta 2 receptors.

5.2 Pharmacokinetics
Absorption
Absorption of nebivolol is similar to an oral solution. Mean peak plasma nebivolol concentrations occur approximately 1.5 to 4 hours post-dosing in EMs and PMs. Food does not alter the pharmacokinetics of nebivolol. Under fed conditions, nebivolol glucuronides are slightly reduced. Nebivolol may be administered without regard to meals. Nebivolol is predominantly metabolized via direct glucuronidation of parent and to a lesser extent via N-dealkylation and oxidation via cytochrome P450 2D6. Its stereospecific metabolites contribute to the pharmacologic activity. Nebivolol is metabolized by a number of routes, including glucuronidation and hydroxylation by CYP2D6. The active isomer (d-nebivolol) has an effective half-life of about 12 hours in CYP2D6 extensive metabolizers (most people), and 19 hours in poor metabolizers and exposure to d-nebivolol is substantially increased in poor metabolizers. This has less importance than usual, however, because the metabolites, including the hydroxyl metabolite and glucuronides (the predominant circulating metabolites), contribute to -blocking activity. Plasma levels of dnebivolol increase in proportion to dose in EMs and PMs for doses up to 20mg. Exposure to l-nebivolol is higher than to d-nebivolol but l-nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1000-fold higher than lnebivolol. For the same dose, PMs attain a 5-fold higher Cmax and 10-fold higher AUC of d-nebivolol than do EMs. d-Nebivolol accumulates about 1.5-fold with repeated once-daily dosing in EMs

Elimination
After a single oral administration of 14C-nebivolol, 38% of the dose was recovered BBDNITM, LUCKNOW Page 18

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in urine and 44% in feces for EMs and 67% in urine and 13% in feces for PMs. Essentially all nebivolol was excreted as multiple oxidative metabolites or their corresponding glucuronide conjugates.

5.3 Therapeutic Uses

Vasodilator action
Nebivolol is unique as a beta-blocker. Unlike carvedilol, it has a nitric oxide (NO)potentiating, vasodilatory effect. 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. However, recent studies question the clinical relevance of this property to Nebivolol's efficacy.

Antihypertensive effect
Nebivolol lowers blood pressure (BP) by reducing peripheral vascular resistance, and significantly increases stroke volume with preservation of cardiac output] 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. Management of hypertension (alone or in combination with other classes of antihypertensive agents). One of several preferred initial therapies in hypertensive patients with heart failure, postmyocardial infarction, high CHD risk, and/or diabetes mellitus. Can be used as monotherapy for initial management of uncomplicated hypertension;

Dose and Dosage Regimen

General

Individualize dosage according to patient response.

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If long-term therapy is discontinued, reduce dosage gradually over a period of about 12 weeks.(See Abrupt Withdrawal of Therapy under Cautions.) 1-Adrenergic blocking selectivity diminishes as dosage is increased beyond 10 mg.

Administration
Oral Administration Administer orally once daily without regard to meals. Frequent administration (i.e., daily divided doses) unlikely to be more beneficial than oncedaily administration.

Dosage
Available as nebivolol hydrochloride; dosage expressed in terms of nebivolol. Adults

Hypertension
Oral Initially, 5 mg once daily. Increase at 2-week intervals (up to 40 mg daily) in patients whose BP is uncontrolled with the initial dosage.

Prescribing Limits
Adults

Hypertension
Oral

Maximum 40 mg daily.

Special Populations
Hepatic Impairment Initially, 2.5 mg once daily in patients with moderate hepatic impairment (Child-Pugh class B). Increase dosage carefully, if necessary. BBDNITM, LUCKNOW Page 20

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Contraindicated in patients with severe hepatic impairment (Child-Pugh class C). Renal Impairment Initially, 2.5 mg once daily in patients with severe renal impairment (Clcr <30 mL/minute). Increase dosage carefully, if necessary. Geriatric Patients Dosage adjustment not required. CYP2D6 Metabolizers No dosage adjustment required in poor metabolizers of CYP2D6 substrates

Dosage Forms and Strengths

Available as tablets for oral administration containing nebivolol hydrochloride equivalent to 2.5, 5, 10, and 20 mg of nebivolol.

Contraindications
1 2 3 4 5 6
7

Severe bradycardia. Heart block greater than first degree. Cardiogenic shock. Decompensated cardiac failure. Sick sinus syndrome (unless a functioning permanent pacemaker is present). Severe hepatic impairment (Child-Pugh class C). Known hypersensitivity to nebivolol or any ingredient in the formulation.

Warnings/Precautions

Adverse-Reactions

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General The most common adverse events leading to discontinuation of nebivolol in clinical trials were headache (0.4%), nausea (0.2%), and bradycardia (0.2%). Cardiovascular Cardiovascular side effects have included bradycardia, chest pain, and peripheral edema. Nervous system Nervous system side effects have included headache, dizziness, paraesthesias, asthenia, insomnia, and fatigue. Gastrointestinal Gastrointestinal side effects have included nausea, diarrhea, and abdominal pain. Respiratory Respiratory side effects have included dyspnea. Dermatologic Dermatologic side effects have included rash. Metabolic Metabolic side effects have included hypercholesterolemia and hyperuricemia

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