Nebivolol

Pronunciation: ne-BIV-oh-lol
Class: Beta-adrenergic blocking agent

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Trade Names

Bystolic
- Tablets 2.5 mg
- Tablets 5 mg
- Tablets 10 mg
- Tablets 20 mg

Pharmacology

Blocks beta receptors. Factors that may be involved in mechanism of action include decreased heart rate and myocardial contractility, diminished tonic sympathetic outflow to the periphery from cerebral vasomotor centers, suppressed renin activity, and decreased peripheral vascular resistance. Lacks intrinsic sympathomimetic activity at therapeutically relevant doses.

Pharmacokinetics

Absorption

Mean C _max is approximately 1.5 to 4 h postdosing.

Distribution

Protein binding is 98%, primarily to albumin.

Metabolism

Predominantly metabolized via direct glucuronidation and, to a lesser extent, via N-dealkylation and oxidation by CYP2D6. Stereospecific metabolites contribute to the pharmacologic activity.

Elimination

In extensive metabolizers, elimination is 38% in urine and 44% in feces, while, in poor metabolizers, elimination is 67% in urine and 13% in feces.

Special Populations

Renal Function Impairment

Cl was unchanged in patients with mild renal impairment and was reduced negligibly in patients with moderate renal impairment. However, Cl was reduced by 53% in patients with severe renal impairment.

Hepatic Function Impairment

C _max increases 3-fold, AUC increases 10-fold, and apparent Cl decreases 86% in patients with moderate hepatic impairment.

Indications and Usage

Treatment of hypertension.

Contraindications

Severe bradycardia; heart block more than first degree; cardiogenic shock; decompensated cardiac failure; sick sinus syndrome (unless a permanent pacemaker is in place); severe hepatic impairment; hypersensitivity to any component of the product.

Dosage and Administration

Hypertension
Adults

PO Recommended starting dosage is 5 mg/day. The dose can be increased at 2-week intervals up to 40 mg/day.

Renal Function Impairment
Adults

PO Start with 2.5 mg/day and cautiously titrate dose upward if needed. Studies have not been conducted in patients receiving dialysis.

Hepatic Function Impairment
Adults

PO Start with 2.5 mg/day and cautiously titrate dose upward if needed. Studies have not been conducted in patients with severe hepatic impairment.

General Advice

May be given with or without food.
May be given with other antihypertensive medications.
When discontinuing nebivolol, taper over 1 to 2 wk while carefully observing the patient.

Storage/Stability

Store between 68° and 77°F. Protect from light.

Drug Interactions

Alpha-1-adrenergic blockers (eg, prazosin)

The severity and duration of hypotension following the first dose of alpha-1-adrenergic blockers may be enhanced in patients receiving nebivolol. It may be necessary to administer a smaller starting dose of alpha-1-adrenergic blockers.

Beta-agonists (eg, dobutamine, isoproterenol)

Nebivolol effects may be reversed. However, patients may be subject to protracted, severe hypotension. Avoid coadministration.

Calcium channel blockers (ie, diltiazem, nifedipine, verapamil)

The pharmacologic effects of nebivolol may be increased by certain calcium channel blockers. Therapeutic and toxic effects of nebivolol and the calcium channel blocker may be increased. Hypotension, bradycardia, cardiac failure, and life-threatening cardiac conduction abnormalities may occur. Use with caution in patients treated concomitantly with these agents and monitor ECG and BP. Adjust treatment as needed.

Cimetidine

Nebivolol plasma concentrations may be increased. Monitor BP when starting or stopping cimetidine. If an interaction is suspected, adjust the nebivolol dose as needed.

Clonidine

The severity of rebound hypertension associated with abrupt withdrawal of clonidine may be greater in patients taking nebivolol. This combination has also been reported to cause paradoxical hypertension. Avoid abrupt discontinuation of clonidine. In patients receiving clonidine and nebivolol concurrently, discontinue nebivolol for several days before gradually tapering the clonidine dose. If rebound hypertension occurs, reinstitute the clonidine or use an alpha-adrenergic blocker. If paradoxical hypertension occurs during coadministration, it may be necessary to discontinue one or both agents.

CYP2D6 inhibitors (eg, fluoxetine, paroxetine, propafenone, quinidine)

Nebivolol plasma concentrations may be elevated, increasing the pharmacologic effects and risk of adverse reactions. Use with a caution. Monitor BP. The dose of nebivolol may need to be reduced based on BP response.

Digitalis glycosides

Both digitalis glycosides and nebivolol slow AV conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. Monitor cardiac function and heart rate. If an interaction is suspected, adjust treatment as needed.

Disopyramide

Pharmacologic effects of disopyramide and nebivolol may be increased. The clearance of disopyramide may be decreased by beta-blockers; adverse reactions (eg, hypotension, sinus bradycardia) may occur. Use with caution. Carefully select patients and closely monitor CV function, especially during initiation of treatment.

Food

Under fed conditions, nebivolol glucuronides are slightly reduced. However, nebivolol may be administered without regard to meals.

Guanethidine, other beta-blockers, reserpine

Excessive sympathetic activity may occur. Closely monitor the patient during concomitant use. Do not coadminister other beta-blockers.

Hypoglycemic agents (eg, insulin, sulfonylureas)

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. It is not known whether nebivolol has these effects. Monitor blood glucose. Advise patients receiving insulin or oral hypoglycemic agents of these possibilities.

Mibefradil

Coadministration may result in additive effects, increasing the risk of CV toxicity, including lowering of heart rate and suppression of sinoatrial node activity. Avoid coadministration, especially in patients with lowered heart rates and/or sick sinus syndrome.

NSAIDs (eg, indomethacin)

The antihypertensive effect of nebivolol may be decreased. If coadministration cannot be avoided, larger dosages of nebivolol may be required. Monitor BP and adjust the nebivolol dose as needed.

Sildenafil

Sildenafil and nebivolol plasma concentrations may be reduced slightly with coadministration. The magnitude of these changes is not expected to be clinically important.

Terbinafine

Plasma concentrations and pharmacologic effects of nebivolol may be increased. Closely monitor heart rate and BP. Adjust the nebivolol dose as needed.

Adverse Reactions

Cardiovascular

Bradycardia (1%); MI, peripheral ischemia/claudication, second- and third-degree AV block, syncope (postmarketing).

CNS

Headache (9%); fatigue (5%); dizziness (4%); asthenia, paresthesia (at least 1%); insomnia (1%); somnolence, vertigo (postmarketing).

Dermatologic

Rash (1%); pruritus, psoriasis, various rashes and skin disorders (postmarketing).

GI

Diarrhea, nausea (3%); abdominal pain (at least 1%); vomiting (postmarketing).

Genitourinary

Acute renal failure, erectile dysfunction (postmarketing).

Hematologic-Lymphatic

Thrombocytopenia (postmarketing).

Hepatic

Abnormal hepatic function, including increased ALT, AST, and bilirubin (postmarketing).

Hypersensitivity

Hypersensitivity, including urticaria, allergic vasculitis, and angioedema.

Lab Tests

Decreased HDL cholesterol and platelet count, increased BUN, triglycerides, and uric acids (at least 1%).

Metabolic-Nutritional

Hypercholesterolemia (at least 1%).

Respiratory

Dyspnea (1%); acute pulmonary edema, bronchospasm (postmarketing).

Miscellaneous

Chest pain, peripheral edema (1%).

Precautions

Monitor

Closely monitor patients receiving anesthetic agents that depress myocardial function. When discontinuation of nebivolol is planned, carefully observe patients and advise them to minimize physical activity. Closely monitor patients suspected of developing thyrotoxicosis when nebivolol therapy is to be withdrawn.

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Elderly

No overall difference in efficacy or adverse reactions between older and younger patients.

Renal Function

Use with caution and adjust dose in severe renal impairment.

Hepatic Function

Use with caution and reduce dose in patients with moderate hepatic impairment.

Abrupt discontinuation

Severe exacerbation of angina, ventricular arrhythmias, and MI have occurred in patients with coronary artery disease following abrupt discontinuation of therapy.

Anaphylactic reactions

Patients receiving beta-blockers who have a history of severe anaphylactic reactions to a variety of allergens may be more reactive to repeated challenge. Such patients may be unresponsive to the usual dose of epinephrine used to treat allergic reactions.

Anesthesia and surgery

If nebivolol use is continued perioperatively, closely monitor when anesthetic agents that depress myocardial function (eg, ether) are used.

Bronchospastic disease

Avoid use.

Diabetes and hypoglycemia

Use with caution because beta-blockers may mask symptoms of hypoglycemia (eg, tachycardia) and nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels.

Peripheral vascular disease

Use with caution in patients with peripheral vascular disease because symptoms of arterial insufficiency may be precipitated.

Pheochromocytoma

In patients with known or suspected pheochromocytoma, initiate an alpha-blocker prior to the use of any beta-blocker.

Thyrotoxicosis

May mask signs of hyperthyroidism (eg, tachycardia); abrupt withdrawal may exacerbate symptoms of hyperthyroidism or potentiate thyroid storm.

Overdosage

Symptoms

Bradycardia, bronchospasm, cardiac failure, dizziness, fatigue, heart block, hypoglycemia, hypotension, vomiting.

Patient Information

Advise patients that this medicine may be taken with or without food.
Advise patients that if a dose is missed, to take the next scheduled dose only and not to double the dose.
Advise patients not to operate automobiles, use machinery, or engage in tasks requiring alertness until they know how they react to this medicine.
Instruct patients to consult health care provider if they experience difficulty in breathing, or if they develop signs or symptoms of worsening of CHF, such as weight gain or increasing shortness of breath, or excessive bradycardia.
Advise patients subject to spontaneous hypoglycemia or diabetic patients receiving insulin or oral hypoglycemic agents that some symptoms of hypoglycemia (eg, tachycardia) may be masked.
Caution patients to avoid sudden position changes to prevent orthostatic hypotension.