General

Nebivolol is a β-adrenergic receptor blocking agent. In extensive metabolizers (most of the population) and at doses less than or equal to 10 mg, nebivolol is preferentially β1 selective. In poor metabolizers and at higher doses, nebivolol inhibits both β1 and β2 - adrenergic receptors. Nebivolol lacks intrinsic sympathomimetic and membrane stabilizing activity at therapeutically relevant concentrations. At clinically relevant doses, BYSTOLIC does not demonstrate &alpha_1- adrenergic receptor blockade activity. Various metabolites, including glucuronides, contribute to (β-blocking activity.

Pharmacodynamics

The mechanism of action of the antihypertensive response of BYSTOLIC has not been definitively established. Possible factors that may be involved include: (1) decreased heart rate, (2) decreased myocardial contractility, (3) diminution of tonic sympathetic outflow to the periphery from cerebral vasomotor centers, (4) suppression of renin activity and (5) vasodilation and decreased peripheral vascular resistance.

Pharmacokinetics

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 (β-blocking activity.

Plasma levels of d-nebivolol 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 I- nebivolol contributes little to the drug's activity as d-nebivolol's beta receptor affinity is > 1000-fold higher than l-nebivolol. 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.

Absorption and Distribution

Absorption of BYSTOLIC is similar to an oral solution. The absolute bioavailability has not been determined.

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. BYSTOLIC may be administered without regard to meals.

The in vitro human plasma protein binding of nebivolol is approximately 98%, mostly to albumin, and is independent of nebivolol concentrations.

Metabolism and Excretion

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 (see Drug Interactions).

After a single oral administration of ¹⁴C-nebivolol, 38% of the dose was recovered 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.

Drug-Interactions

Drugs that inhibit CYP2D6 can be expected to increase plasma levels of nebivolol. When BYSTOLIC is co-administered with an inhibitor or an inducer of this enzyme, patients should be closely monitored and the nebivolol dose adjusted according to blood pressure response. In vitro studies have demonstrated that at therapeutically relevant concentrations, d- and l-nebivolol do not inhibit any cytochrome P450 pathways.

Digoxin: Concomitant administration of BYSTOLIC (10 mg once daily) and digoxin (0.25 mg once daily) for 10 days in 14 healthy adult individuals resulted in no significant changes in the pharmacokinetics of digoxin or nebivolol (see PRECAUTION: DRUG INTERACTIONS).

Warfarin: Administration of BYSTOLIC (10 mg once daily for 10 days) led to no significant changes in the pharmacokinetics of nebivolol or R- or S-warfarin following a single 10 mg dose of warfarin. Similarly, nebivolol has no significant effects on the anticoagulant activity of warfarin, as assessed by Prothrombin time and INR profiles from 0 to 144 hours after a single 10 mg warfarin dose in 12 healthy adult volunteers.

Bookmark this page: