Nebivolol - A Comprehensive Review of Its Uses, Dosage, Side Effects, Precautions, and Contraindications

Overview:

Nebivolol is a beta-blocker agent used to treat high blood pressure. The medication is Food and Drug Administration (FDA) approved to treat hypertension and patients with vascular disease. Nebivolol works by relaxing the blood vessels and slowing down the heart's activity by blocking messages sent to the heart. Nebivolol, unlike other beta-blockers, does not constrict peripheral vessels and is associated with improved heart function. The medication was first used for medical use in 1997 and was granted FDA approval on 17 December 2007.

How Does Nebivolol Work?

Nebivolol is a highly selective beta-1-adrenergic receptor antagonist that decreases vascular resistance and increases stroke volume and cardiac output. It inhibits aldosterone secretion and the release of renin. The decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. Nebivolol-1 is also responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, causing increased nitric oxide levels. This leads to decreased peripheral vascular resistance with increased stroke volume and cardiac output.

Uses:

Nebivolol is indicated for the following:

• It helps to lower blood pressure and prevent strokes, heart attacks, and kidney problems.

• The medication treats angina, arrhythmias, anxiety, hyperthyroidism, and migraine prophylaxis and prevents essential tremors.

Limitations:

Beta-blockers like Nebivolol are not recommended as initial therapy in treating essential hypertension.

Dosage Recommendation:

1. Route of Administration - Oral.

2. Dosage Strengths -

• 2.5 mg.

• 5 mg.

• 10 mg.

• 20 mg.

3. Dosage Forms-

• 2.5 mg - White, triangular tablet imprinted with "J" and "8".

• 5 mg - Light orange, triangular tablet imprinted with "J" and "9".

• 10 mg - White, circular, biconvex tablet with "G" and "N" on either side of the break line and plain on another side.

• 20 mg - Light blue, round tablet with "NL" and "20".

The recommended starting dose for most patients is 5 mg once daily.

Special Considerations:

• Pregnancy - Nebivolol should be avoided during pregnancy, especially during the third trimester, as it can increase the risk of certain problems such as low blood pressure, abnormal heart rhythm, and slow breathing in the newborn.

• Lactation - It is not known if Nebivolol passes into breast milk. The drug can cause serious side effects such as decreased heart rate and hypoglycemia and should be avoided while breastfeeding.

• Pediatric Patients - Nebivolol has not been studied in children. It should not be used on people younger than 18 years of age.

• Geriatric Patients - The beta-1-selective vasodilator is well tolerated and effectively reduces mortality and morbidity in people above 70 years of age, regardless of the initial ejection fraction.

• Renal Impairment - Renal clearance of Nebivolol is decreased in severe renal impairment. However, dose adjustment is not necessary.

• Hepatic Impairment - Patients with liver impairment have a greater risk for adverse effects due to decreased drug clearance. No dose adjustment is necessary. The drug is contraindicated for severe hepatic impairment.

Warnings and Contraindications:

Contraindications:

Nebivolol is contraindicated in the following cases:

• Premenopausal Women - The use of Nebivolol in menopausal women with hypertension have shown decreased rate and severity of vasomotion reactions and a positive effect on the menopausal syndrome.

• Pregnancy - Studies have shown that Nebivolol can cause birth defects, stillbirths, or preterm birth and should not be used unless necessary.

• Hypersensitivity - Nebivolol is contraindicated in people who have allergic reactions to the drug or its constituents.

• Bradyarrhythmias - Nebivolol is contraindicated in patients with sinus bradyarrhythmia or heart block greater than the first degree. The use of the drug is likely to exacerbate the condition.

Warnings and Precautions:

• Cholesterol Levels - Patients receiving are more likely to experience an elevation in serum cholesterol than patients receiving Tamoxifen.

• Congestive Heart Failure - Patients with overt congestive heart failure may experience worsening heart failure when given Nebivolol therapy.

• Diabetes - Using Nebivolol may mask the symptoms of hypoglycemia, such as tremors, tachycardia, and blood pressure changes. Therefore the drug should be administered cautiously in patients predisposed to spontaneous hypoglycemia.

• Ischemic Heart Disease - Abrupt withdrawal of Nebivolol therapy in patients with coronary heart disease has reported exacerbation of angina, myocardial infarction, and ventricular arrhythmias. Cessation of the drug should be gradual, with incrementally reduced dosages over a week.

• Serum Lipid Profile - Nebivolol increases serum VLDL (very low-density- lipoprotein), LDL (low-density lipoprotein), and triglycerides and requires dose adjustment.

For Patients

Hypertension

Elevated blood pressure is a serious medical condition that significantly increases the risks to the heart, brain, and kidneys. Blood pressure is the force exerted by the circulating blood against the walls of the arteries (major blood vessels) in the body. Hypertension is when blood pressure is too high.

Why Is Nebivolol Prescribed for Hypertension?

Nebivolol is a beta-blocker that affects the response to the nerve impulses, such as epinephrine, in certain body parts, like the heart. This results in a slow heartbeat and a decrease in blood pressure. Lowering the blood pressure increases blood and oxygen flow to the heart and allows the heart to pump with less force.

Facts One Should Know About Nebivolol:

• Nebivolol is available in tablet form with dosage strengths of 2.5 mg, 5 mg,10 mg, and 20 mg. Taking an initial dose of 5 mg orally once a day is recommended. The maximum recommended dose is 40 mg per day.

• Treatment with Nebivolol can often be long-term. The medication should not be stopped suddenly, as it can worsen the condition and may cause chest pain, heart attack, or irregular heartbeat. The dosage of Nebivolol should be gradually decreased over one to two weeks.

How Should One Take Nebivolol?

• Nebivolol is available as a tablet to be taken by mouth.

• It is usually taken with or without food.

• The drug should be taken at the same time each day.

• Nebivolol is usually started on a low dose of 5 mg and is gradually increased, but not more than once every two weeks.

• Nebivolol helps to control blood pressure but does not cure it.

• It may take more than two weeks to show the full benefits of the drug, as seen in a blood pressure reading.

• Do not stop the medicine suddenly without talking to the doctor.

• Nebivolol is used for long-term treatment and requires regular blood pressure monitoring to ensure the medication works.

What Should the Patient Discuss With His Doctor Before Beginning Nebivolol Therapy?

• Allergies - Inform the physician if one has ever had an allergic reaction to Nebivolol or other ingredients in the formulation.

• Medical History - The patient must always inform the treating doctor of his illnesses, such as diabetes, bronchospastic diseases, myocardial infarction, and impaired renal or hepatic function.

• Drug History - Always give the treating doctor a complete list of the prescription and non-prescription medications that one may be taking, including any herbal supplements, nutritional supplements, and vitamins.

• Pregnancy - If one is pregnant or planning to get pregnant any time soon, it is important to inform the doctor. The use of Nebivolol may harm the fetus and the mother. Using Nebivolol during the third trimester of pregnancy may increase the risk of hypotension and low blood sugar level. If one gets pregnant while on Nebivolol, inform your doctor as soon as you find out.

• Lactation - The doctor must know if one is breastfeeding. The possibility of Nebivolol passing into the breastmilk is unknown. It is best to avoid it during nursing as beta-blockers have the potential to produce serious adverse reactions.

• Dental Treatment - It is important to brief the dental doctor about medicines (Nebivolol) before your dental procedures, as certain anesthetics may increase the risk of side effects.

Safety:

Nebivolol is a safe and FDA-approved medication for the long-term treatment of hypertension. The doctor may advise you to measure your blood pressure daily at home or between office hours to check the drug's effectiveness. When visiting a doctor, he will do routine blood tests to check the functioning of your liver and kidneys.

Effectiveness:

The antihypertensive efficacy of Nebivolol is well-established for long-term treatment.

Nebivolol is very effective when used alone in patients with isolated systolic hypertension. Studies have found a great reduction in blood pressure after six months of treatment. Nebivolol has a greater degree of selectivity for beta-adrenergic receptors than other agents in this class. It has a unique vasodilating effect, which is advantageous for a hypertensive population with diabetes and other vascular diseases. The drug also has better tolerability than other agents in this class.

Side Effects With Nebivolol:

The common side effects that occur with the use of Nebivolol are as follows:

• Dizziness.

• Tiredness.

• Slow heart rate.

• Headache.

• Diarrhea.

• Nausea.

• Stomach pain.

The serious side effects may include,

• Chest pain.

• Very slow heart rate.

• Severe dizziness.

• Fainting.

• Lightheadedness.

• Extreme tiredness.

• Swelling in the hands, arms, feet, ankles, or legs.

• Trouble breathing.

• Rapid weight gain.

• Cold feeling in hands and feet.

Can One Stop Taking Nebivolol Without the Medical Consent?

• You should never stop taking Nebivolol without first talking to your doctor. Consult your physician or visit the emergency room if you experience any side effects that require immediate attention.

• Do not skip the dose or stop taking Nebivolol suddenly. This can worsen the condition or cause serious problems, including heart attacks. The doctor will instruct you on how to gradually taper the dose.

• Remember that you must continue taking Nebivolol, regardless of how well you respond to it, unless your doctor explicitly mentions otherwise. The drug is usually meant for long-term use and should not be stopped even if you respond well.

Dietary Restrictions to Consider When Taking Nebivolol:

You may continue to follow your regular diet unless your doctor asks you to change it. No dietary restrictions are needed. The drug may be taken with or without food.

• Caffeine-Containing Foods - Avoid taking caffeine-containing food items and beverages such as tea, coffee, and chocolates while taking Nebivolol. Caffeine can decrease the effectiveness of the drug.

• High Potassium Foods - You should limit the consumption of high potassium-containing foods such as bananas, papaya, tomatoes, and avocado.

How Should You Store Nebivolol?

• Store Nebivolol at room temperature in a closed container, away from heat, moisture, and direct light.

• Nebivolol tablets should be stored in the original packaging or container with a tightly closed lid.

• Keep this drug far from the reach of children and pets.

How Should You Dispose of Nebivolol?

• Nebivolol should not be disposed of by flushing or throwing it out with regular garbage.

• You may dispose of Nebivolol through your local medicine take-back program, which you can access or learn more about through your local pharmacist.

• If you do not have access to a medicine take-back program, ask your local pharmacist about other drug disposal options.

Overdose:

• If you overdose, contact your doctor immediately, and do not take another tablet until your doctor tells you to do so.

• If you experience severe side effects like seizures or breathing difficulty, a bystander or family member should take you to the emergency room or contact local poison control services.

For Doctors

Indications:

Nebivolol is indicated for the following purposes:

• It helps to treat hypertension. Controlled blood pressure can help reduce strokes, heart attacks, and kidney problems.

• The drug helps to manage medical conditions such as high blood pressure, angina, arrhythmias, anxiety, hyperthyroidism, and migraine prophylaxis and prevents essential tremors.

• It effectively lowers the heart rate and blood pressure and reduces strain on the heart.

Pharmacology of Nebivolol:

Description:

Nebivolol is a racemate composed of d-Nebivolol and 1-Nebivolol with the molecular formula C22 H 25 F 2 NO 4 HCl.

Components -

1. Active Ingredients

• Nebivolol hydrochloride.

2. Inactive Ingredients

• Lactose.

• Silica colloidal hydrated.

• Magnesium stearate.

• Croscarmellose sodium.

• Polyethylene glycol.

Clinical Pharmacology:

Mechanism of Action

Nebivolol is a highly selective beta-1-adrenergic receptor antagonist that decreases vascular resistance and increases stroke volume and cardiac output. It inhibits aldosterone secretion and the release of renin. The decreased aldosterone leads to decreased blood volume, and decreased renin leads to reduced vasoconstriction. Nebivolol-1 is also responsible for beta-3 adrenergic receptor agonist activity that stimulates endothelial nitric oxide synthase, causing increased nitric oxide levels. This leads to decreased peripheral vascular resistance with increased stroke volume and cardiac output.

Pharmacodynamics:

Single And Repeated Doses - Reduces heart rate and blood pressure at rest and during exercise in hypertensive patients.

Therapeutic Dose - Nebivolol is devoid of alpha-adrenergic antagonism.

Nebivolol has a long duration of action, and its effects can be seen 48 hours after stopping the medication.

Pharmacokinetics:

• Mean Cmax- Ranges from 12% to 96%.

• Median Tmax- 1.5 to 4 hours. The absorption is not affected by food.

[Cmax- Maximum concentration achieved by a drug in the blood, cerebrospinal fluid, or target organ after administration of a dose]

[Tmax- Time taken for a drug to reach maximum concentration after administration of a dose]

Pharmacokinetic Changes- The dose is to be adjusted to individual requirements due to variations in the rate of metabolism.

A. Distribution

• Steady-state Plasma Levels- The concentration of unchanged Nebivolol is 23 times higher in poor metabolizers than in extensive metabolizers. When unchanged and active metabolites are considered, the difference in plasma level is 1.3 to 1.4 fold.

• Time to Approach Steady-state Levels- It is reached within 24 hours for Nebivolol and within a few days for the hydroxy-metabolites.

• Binding to Plasma Proteins- 98.1% for d-Nebivolol and 97.1% for l-Nebivolol.

B. Metabolism

• Metabolic Processes- Glucuronidation and CYP2D6 mediated hydroxylation, N-dealkylation, and oxidation.

• Active Metabolites - Aromatic hydroxyl and acyclic oxide metabolites.

• Inactive Metabolites - N-dealkylated and glucuronides.

C. Excretion

• Recovery of Nebivolol - 85% recovered in feces and urine.

D. Elimination

After One Week Of Administration -

38% of the dose is excreted in the urine

44% is excreted in the feces.

Urinary excretion of unchanged Nebivolol is less than 0.5 % of the dose.

Mean Elimination Half-Life -

• 12 hours in extensive metabolism.

• 19 hours of poor metabolism.

Special Considerations:

• Renal Impairment - In patients with severe renal impairment, the recommended initial dose is 2.5 mg once daily. It may be titrated up slowly if needed.

• Hepatic Impairment - In patients with moderate hepatic impairment, the recommended initial dose is 2.5 mg once daily. It may be titrated up if needed.

• Age - No age-related effects have been reported in the elderly.

Drug Interactions:

• CYP2D6 Inhibitors - Co-administration with substances inhibiting CYP2D6 may lead to increased plasma levels of Nebivolol and increased risk of excessive bradycardia.

• Beta-Blockers - Combining other beta-blockers with Nebivolol can produce an excessive reduction of sympathetic activity.

• Digitalis Glycosides - Combining Digitalis glycosides and Nebivolol can increase the risk of bradycardia and slow the heart rate.

• Calcium Channel Blockers - Nebivolol can exacerbate the effects of myocardial depressants or AV (atrioventricular) conduction inhibitors, such as certain calcium antagonists, or antiarrhythmic agents, such as Disopyramide.

• Centrally Acting Hypertensives - Concomitant use of centrally acting antihypertensives such as Clonidine, Guanfacine, Methyldopa, or Nimenidine may worsen heart failure by a decrease in the central sympathetic tonus.

What Have Clinical Trials Shown With Regard to Nebivolol?

Aim of Trial 1:

To evaluate the efficacy and safety of Nebivolol in patients with untreated or poorly controlled hypertension receiving stable therapy with Lisinopril.

A double-blinded, randomized trial study in patients with heart failure once daily Nebivolol 2.5 mg or 5.0 mg with placebo on a constant background of Digitalis Plus diuretic.

Placebo Comparator - 5 mg or 20 mg once daily, oral administration.

Intervention 1 - Drug Nebivolol 5 mg, titrated to 20 mg once daily, oral administration.

All patients continued with unchanged diuretic and Digitalis dosage.

Primary Outcome - (one to four weeks) - Changes in blood pressure.

Results - Nebivolol merits as a beta-blocker to treat heart failure. The capacity of the drug to enhance endothelial nitric oxide production appears potentially good.

Aim of Trial 2:

To determine the effect of Nebivolol on mortality and cardiovascular hospital Admission in elderly patients with heart failure.

Large randomized trials have shown that beta-blockers reduce mortality and hospital admission in patients with heart failure. The study was performed to assess the effects of the beta-blocker, Nebivolol in patients over 70 years of age, regardless of ejection fraction. One thousand sixty-seven senior patients with a history of heart failure. Nebivolol was titrated from 1.25 mg once daily to 10 mg once daily in1061 placebo.

Primary Outcome - A composite of all-cause mortality or cardiovascular hospital admission ( time to the first event).

Mean Duration of Follow-up - 21 months.

Mean Maintenance Dose of Nebivolol - 7.7 mg, and the placebo - 8.5 mg.

Results - There was no significant influence of age, gender, or ejection fraction on the effect of Nebivolol on the primary outcome. Nebivolol, with its vasodilating properties, is an effective and well-tolerated treatment for heart failure in the elderly.

Patient Counseling Information:

Administration Instructions

• Take Nebivolol only as prescribed by the doctor.

• This drug may be taken with or without food.

• Swallow these tablets and do not crush, split, or chew them.

• Do not stop taking Nebivolol abruptly.

Complications or Side Effects

• Pregnancy - Studies have shown that Nebivolol can cause birth defects, stillbirths, or preterm birth and should not be used unless necessary.

• Hypersensitivity - Nebivolol is contraindicated in people who have allergic reactions to the drug or its constituents.

• Bradyarrhythmias - Nebivolol is contraindicated in patients with sinus bradyarrhythmia or heart block greater than the first degree. The use of the drug is likely to exacerbate the condition.

• Asthma - Nebivolol can make breathing more difficult, especially in patients with breathing problems such as asthma or obstructive pulmonary disease.

• Diabetes - The drug may mask the signs of low blood sugar. It is necessary to monitor the blood sugar level regularly and more closely.

• Hyperthyroidism - Nebivolol can mask the signs and symptoms of an overactive thyroid gland, such as a fast heart rate. The condition may worsen if the drug is stopped suddenly.