Consumer medicine information

Nebilet

Nebivolol

BRAND INFORMATION

Brand name

Nebilet

Active ingredient

Nebivolol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Nebilet.

SUMMARY CMI

NEBILET®

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I taking NEBILET?

NEBILET contains the active ingredient nebivolol hydrochloride. NEBILET is used to treat high blood pressure (essential hypertension) or chronic heart failure. It is usually used in combination with other medicines. For more information, see Section 1. Why am I taking NEBILET? in the full CMI.

2. What should I know before I take NEBILET?

Do not take NEBILET if you have ever had an allergic reaction to NEBILET or any of the ingredients listed at the end of the CMI. Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I take NEBILET? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with NEBILET and affect how it works. A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I take NEBILET?

  • Follow all directions given to you by your doctor. They will determine your dose. Take your medicine at about the same time each day. Swallow the tablets whole with a full glass of water. Do not crush or chew the tablets. This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

More instructions can be found in Section 4. How do I take NEBILET? in the full CMI.

5. What should I know while taking NEBILET?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are taking NEBILET
  • Keep all of your doctor's appointments so that your progress can be checked
  • Tell your doctor if you believe that NEBILET is not helping your condition
  • If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly
Things you should not do
  • Do not stop taking this medicine suddenly or lower the dosage without checking with your doctor
  • Do not take NEBILET to treat any other complaints unless your doctor tells you to
  • Do not give your medicine to anyone else, even if they have the same condition as you
Driving or using machines
  • Be careful driving or operating machinery until you know how NEBILET affects you as this medicine may cause dizziness, light-headedness, or drowsiness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol
  • If you drink alcohol, symptoms such as dizziness or light-headedness may be worse
Looking after your medicine
  • Keep your tablets in the pack until it is time to take them
  • Keep your tablets in a cool dry place where the temperature stays below 25°C for NEBILET 1.25 mg tablet and below 30°C for NEBILET 5 mg and 10 mg tablets

For more information, see Section 5. What should I know while taking NEBILET? in the full CMI.

6. Are there any side effects?

The most common side effects of NEBILET are headache, tiredness, nausea or vomiting, stomach upset, wind, diarrhoea, constipation, and coldness or numbness in the hands or feet. Call your doctor straight away or go straight to the Emergency Department at your nearest hospital if you experience swelling of the face, lips, tongue or throat that may cause difficulty swallowing or breathing; chest tightness, shortness of breath or difficulty breathing; swelling of the feet and ankles; or chest pain or changes in heart rate.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

NEBILET®

Active ingredient(s): nebivolol hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about taking NEBILET. Keep this leaflet with the medicines. You may need to read it again.

You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using NEBILET.

Where to find information in this leaflet:

1. Why am I taking NEBILET?
2. What should I know before I take NEBILET?
3. What if I am taking other medicines?
4. How do I take NEBILET?
5. What should I know while taking NEBILET?
6. Are there any side effects?
7. Product details

1. Why am I taking NEBILET?

NEBILET contains the active ingredient nebivolol hydrochloride. NEBILET belongs to a group of medicines called beta-blockers.

NEBILET is used to treat high blood pressure (essential hypertension) or chronic heart failure. It is usually used in combination with other medicines.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed it for another reason.

High Blood Pressure (Hypertension):

NEBILET can be used to treat high blood pressure. It works by blocking the transmission of messages to the beta receptors in the heart which slows down the activity of the heart. It also relaxes the blood vessels and reduces the resistance that the heart has to pump against. The blood pressure lowering effects occur after 1 to 2 weeks, although it may take up to 4 weeks for the full effect to occur.

Chronic Heart Failure:

NEBILET can also be used to treat chronic heart failure, in addition to other medicines. It slows down the heart rate and makes it beat more regularly. It also reduces the pressure the heart has to pump against and therefore reduces the amount of work that the heart has to do. This improves the symptoms of chronic heart failure, and reduces the likelihood of you being hospitalised and/or dying from your heart condition.

2. What should I know before I take NEBILET?

Warnings

Do not take NEBILET if:

  • you are allergic to nebivolol hydrochloride, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine
  • you have liver problems
  • you have acute heart failure or cardiogenic shock, a serious heart condition causing low blood pressure
  • you have a history of slow heart rate or uneven heart beating
  • you have certain other heart conditions
  • you have asthma, bronchitis or other lung disease with tightening of the airways
  • you have untreated phaeochromocytoma, a rare tumour of the adrenal gland
  • you have metabolic acidosis, where there is too much acid in the blood
  • you have hypotension, low blood pressure
  • you have a severe blood vessel disorder causing poor circulation in the arms and legs.

Check with your doctor if you:

  • have any other medical conditions, such as:
    - low blood pressure or poor circulation
    - a slow heartbeat, lower than 60 beats per minute
    - asthma or breathing difficulties
    - angina, chest pain or any other heart problems, or your heart failure has just occurred or worsened recently
    - diabetes
    - a history of psoriasis, a skin disease with thickened patches of red skin, often with silvery scales
    - a severe blood vessel disorder causing poor circulation in the arms and legs
    - thyroid disorders
    - liver problems
    - kidney problems
    - phaeochromocytoma, a rare tumour of the adrenal gland
    - a lactose intolerance
  • or if you take any medicines for any other condition

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Do not take this medicine if you are pregnant.

It may affect your developing baby if you take it during pregnancy.

Check with your doctor if you are pregnant or intend to become pregnant.

Do not breastfeed if you are taking this medicine.

The active ingredient in NEBILET passes into breast milk and there is a possibility that your baby may be affected.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Children under the age of 18 years

Do not give NEBILET to a child under the age of 18 years.

Safety and effectiveness in children younger than 18 years have not been established.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with NEBILET and affect how it works.

  • those used to treat irregular or abnormal heartbeat (e.g. quinidine, flecainide, disopyramide, lignocaine, mexiletine, amiodarone)
  • those used to treat high blood pressure (e.g. clonidine, guanfacine, moxonidine, methyldopa, amlodipine, felodipine, nifedipine, nicardipine, nimodipine, reserpine, guanethidine)
  • calcium channel blockers for high blood pressure or heart problems (e.g. verapamil, diltiazem)
  • insulin and tablets used to treat diabetes
  • those used to treat depression and anxiety (e.g. paroxetine, fluoxetine, phenothiazine, thioridazine, sedatives, antipsychotics)
  • those used to treat excessive stomach acid (e.g. cimetidine). You should take NEBILET during a meal, and the antacid between meals.
  • digoxin, a medicine used to treat heart failure
  • other beta-blocker medicines (including beta-blocker eye drops) used to treat asthma, blocked nose or certain eye disorders such as glaucoma or dilation of the pupil
  • anaesthetics
  • baclofen, an antispasmodic drug
  • amifostine, a protective medicine used during cancer treatment.

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect NEBILET.

4. How do I take NEBILET?

How much to take

  • High Blood Pressure (Hypertension):
    For the treatment of high blood pressure, the usual starting dose is one 5 mg tablet once daily. Your doctor may start you on a lower dose of NEBILET.
  • Chronic Heart Failure:
    For the treatment of chronic heart failure, your doctor will start you on a low dose of NEBILET, and gradually increase the dose depending on how you respond to this medicine.
    The usual starting dose is one 1.25 mg tablet once daily. Your doctor will gradually increase your dose stepwise over a number of weeks, one tablet at a time until you reach the best dose for you.
    The highest dose you should take is 10 mg once daily.
    When you take NEBILET for the first time, and whenever your doctor increases your dose, you should be observed by a doctor for at least 2 hours until the effect of the medicine on you is known.
  • Follow the instructions provided and take NEBILET until your doctor tells you to stop.

When to take NEBILET

  • NEBILET should be taken at about the same time each day
  • Taking it at the same time each day will have the best effect. It will also help you remember when to take it.
  • It does not matter if you take NEBILET before or after food or with food.
  • If you need to take an antacid, take it at least 2 hours before or 2 hours after your dose of NEBILET.

How to take NEBILET

  • Swallow the tablets whole with a full glass of water.
  • Do not crush or chew the tablets.

If you forget to take NEBILET

NEBILET should be taken regularly at the same time each day. If you miss your dose at the usual time, follow the instructions below.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Otherwise, take it as soon as you remember, and then go back to taking NEBILET as you would normally.

Repeated skipping of doses should be avoided.

Do not take a double dose to make up for the dose you missed.

  • If you are not sure what to do, ask your doctor or pharmacist.
  • If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much NEBILET

If you think that you have taken too much NEBILET, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26 in Australia, or 0800 764 766 in New Zealand), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Symptoms of an overdose may include feeling faint or fainting, and shortness of breath. Your blood pressure may drop too far and your heart rate might slow down too much. In extreme cases, serious heart and lung problems may occur.

5. What should I know while taking NEBILET?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking NEBILET.

Remind any doctor, dentist or pharmacist you visit that you are taking NEBILET.

If you are going to have surgery, tell the surgeon, anaesthetist or dentist that you are taking this medicine.

NEBILET may affect other medicines used during surgery. Your surgeon and anaesthetist should know well ahead of the date of your surgery so they can allow for your condition and medications.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may check your eyes, thyroid, lipid and blood glucose levels.

If you have any medical test, tell your doctor that you are taking NEBILET.

This medicine may affect the results of some tests.

Tell your doctor if you believe that NEBILET is not helping your condition.

Your doctor may need to change the dose.

Tell your doctor if, for any reason, you have not taken your medicine exactly as prescribed.

Your doctor may think it is not working effectively and change your treatment unnecessarily.

If you are being treated for diabetes, make sure you check your blood sugar level regularly and report any changes to your doctor.

NEBILET may change how well your diabetes is controlled. It may also cover up some of the symptoms of low blood sugar, called hypoglycaemia, such as fast heartbeat. NEBILET may make hypoglycaemia last longer. Your dose of diabetic medicines, including insulin, may need to change.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

You may feel light-headed or dizzy when you begin to take NEBILET. This is because your blood pressure has fallen suddenly. Standing up slowly, especially when you get up from bed or from sitting, will help your body adjust to the change in position and blood pressure. If this problem continues or gets worse, tell your doctor.

Make sure you drink enough water during exercise and in hot weather when you are taking NEBILET, especially if you sweat a lot.

If you do not drink enough water while taking this medicine you may feel faint or light-headed. This is because your blood pressure is dropping too much.

If you continue to feel unwell, talk to your doctor.

Call your doctor straight away if you:

  • If you become pregnant while taking this medicine.

Things you should not do

  • Do not stop taking your medicine or lower the dosage without checking with your doctor.
  • This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well. Continue taking NEBILET for as long as your doctor tells you.
  • If you stop taking it suddenly, your condition may worsen or you may have unwanted side effects. If possible, your doctor will gradually reduce the amount you take each day before stopping the medicine completely.
  • Do not take NEBILET to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how NEBILET affects you.

NEBILET may cause dizziness, light-headedness, or drowsiness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Alcohol may worsen symptoms such as dizziness or light-headedness.

Be careful getting up from a lying or sitting position.

You may feel dizzy or light-headed if you get up too quickly. Getting up slowly may help.

Looking after your medicine

Keep your tablets in a cool dry place where the temperature stays below 25°C for NEBILET 1.25 mg tablet and below 30°C for NEBILET 5 mg and 10 mg tablets.

Keep your tablets in the pack until it is time to take them.

If you take the tablets out of the pack they may not keep well.

Follow the instructions in the carton on how to take care of your medicine properly.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink, or
  • in the car or on window sills.

Heat and dampness can destroy some medicines.

Keep it where young children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

Do not take this medicine after the expiry date or if the packaging is torn or shows signs of tampering or the tablets do not look quite right.

If the medicine has expired or is damaged, or if your doctor tells you to stop taking this medicine, take it to any pharmacy for safe disposal.

6. Are there any side effects?

All medicines can have side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
General body-related:
  • headache, tiredness
  • coldness or numbness in the hands or feet
  • changes to the colour of fingers and toes in response to cold or stress
  • feeling of light-headedness or dizziness when getting out of bed or standing up
Stomach and bowel-related:
  • nausea
  • vomiting
  • stomach upset
  • wind
  • diarrhoea
  • constipation
Mind-related:
  • disturbed sleep or nightmares
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Allergic reaction-related:
  • swelling of the face, lips, tongue or throat that may cause difficulty swallowing or breathing
  • rashes, itching or hives on the skin
General body-related:
  • chest tightness, shortness of breath or difficulty breathing
  • low blood pressure
  • swelling of the hands, feet or ankles
  • severe light-headedness, dizziness or fainting
  • tingling or "pins and needles"
Heart-related:
  • slow heartbeat
  • chest pain
  • changes in heart rate
Mind-related:
  • abnormal thinking, depression or hallucinations
Sex-related:
  • impotence
Skin-related:
  • skin rashes and itching
  • worsening of psoriasis
Eye-related:
  • dry eyes
  • problems with eye sight
Muscle-related:
  • an increase in a cramp-like pain in one or both legs that develops on walking
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription.

This medicine is not addictive.

What NEBILET contains

Active ingredient
(main ingredient)		Each tablet contains 1.25 mg, 5 mg or 10 mg of nebivolol (as nebivolol hydrochloride).
Other ingredients
(inactive ingredients)		Each tablet also contains the following inactive ingredients:
  • lactose monohydrate
  • maize starch
  • croscarmellose sodium
  • hypromellose
  • polysorbate 80
  • microcrystalline cellulose
  • colloidal anhydrous silica
  • magnesium stearate

Do not take this medicine if you are allergic to any of these ingredients.

If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking NEBILET.

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

What NEBILET looks like

NEBILET tablets are almost white, round and biconvex.

NEBILET 1.25 mg tablet has a score on one side. The score is for identification purposes only and not to divide the tablet into equal doses (AUST R 148873).

NEBILET 5 mg tablet is cross-scored (AUST R 148874).

NEBILET 10 mg tablet is embossed with the number "10" on one side (AUST R 148875).

NEBILET 1.25 mg/5 mg composite starter titration pack contains 42 tablets of 1.25 mg and 14 tablets of 5 mg (AUST R 148895).

Each pack contains 28 tablets, as 2 blister packs each with 14 tablets.

Each starter pack contains either 4 or 7 tablets, as 1 blister pack each with 4 or 7 tablets.

Not all pack sizes may be marketed.

Who distributes NEBILET

A. Menarini Australia Pty Ltd
Level 8, 67 Albert Ave, Chatswood NSW 2067
Medical Information: 1800 644 542
® = Registered Trademark

This leaflet was prepared in April 2023.

For the most up to date version of this leaflet, please go to www.menarini.com.au/cmi

[vA10-0]

Published by MIMS June 2023

BRAND INFORMATION

Brand name

Nebilet

Active ingredient

Nebivolol

Schedule

S4

 

1 Name of Medicine

Nebivolol hydrochloride.

2 Qualitative and Quantitative Composition

Nebilet tablets contain 1.25 mg, 5 mg or 10 mg of nebivolol present as the hydrochloride salt.

Excipient with known effect.

Contains sugars as lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Nebilet 1.25 mg tablets: almost white, round, slightly biconvex tablets 3.1 mm high with a diameter of 9 mm and a single score on one side; the score line on the 1.25 mg tablet is for identification purposes only and is not intended for dividing doses.
Nebilet 5 mg tablets: almost white, round, cross-scored tablets.
Nebilet 10 mg tablets: almost white, round, slightly biconvex with embossment "10" on one side.

4 Clinical Particulars

4.1 Therapeutic Indications

Nebilet is indicated: to treat essential hypertension; to treat stable chronic heart failure as an adjunct to standard therapies in patients 70 years or older.

4.2 Dose and Method of Administration

The dose of Nebilet should always be adjusted to the individual requirements of the patient (see Section 5.2 Pharmacokinetic Properties).

Hypertension.

The dose is one 5 mg tablet daily, preferably at the same time of the day. Tablets may be taken with or without meals.
The blood pressure lowering effect becomes evident after 2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.

Combination with other antihypertensive agents.

Nebilet may be used as monotherapy or in combination with hydrochlorothiazide (12.5-25 mg).

Patients with renal insufficiency.

In patients with renal insufficiency, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg.

Patients with hepatic insufficiency.

Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebilet in these patients is contraindicated.

Elderly.

In patients over 65 years, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. However, in view of the limited experience in patients above 75 years, caution must be exercised and these patients monitored closely.

Paediatric.

No studies have been conducted in children and adolescents aged below 18 years. Therefore, use in children and adolescents is not recommended.

Chronic heart failure (CHF).

The treatment of stable chronic heart failure has to be initiated with a gradual up titration of dosage until the optimal individual maintenance dose is reached.
Patients should have stable chronic heart failure without acute failure during the past six weeks. It is recommended that the treating physician should be experienced in the management of chronic heart failure.
For those patients receiving cardiovascular drug therapy including diuretics and/or digoxin and/or ACE inhibitors and/or angiotensin II antagonists, dosing of these drugs should be stabilised during the past two weeks prior to initiation of Nebilet treatment.
The initial up titration should be done according to the following steps at 1-2 weekly intervals based on patient tolerability:
1.25 mg nebivolol, to be increased to 2.5 mg nebivolol once daily, then to 5 mg once daily and then to 10 mg once daily.
The maximum recommended dose is 10 mg nebivolol once daily.
Initiation of therapy and every dose increase should be done under the supervision of an experienced physician over a period of at least 2 hours to ensure that the clinical status (especially as regards blood pressure, heart rate, conduction disturbances, signs of worsening of heart failure) remains stable.
Occurrence of adverse events may prevent patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step and reintroduced as appropriate.
In cases of worsening of heart failure or intolerance in the titration phase, it is recommended first to reduce the dose of nebivolol, or, if necessary to stop it immediately. Immediate cessation should be considered especially in cases of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block.
Treatment of stable chronic heart failure with Nebilet is generally a long-term treatment. The treatment with Nebilet is not recommended to be stopped abruptly since this might lead to a transitory worsening of heart failure. If discontinuation is necessary, the dose should be gradually decreased by dividing into halves weekly.
Nebilet tablets can be given with or without meals, but a consistent approach is recommended.

Patients with renal insufficiency.

No dose adjustment is required in mild to moderate renal insufficiency since up titration to the maximum tolerated dose is individually adjusted. There is no experience in patients with severe renal insufficiency (serum creatinine ≥ 250 micromol/L). Therefore, the use of Nebilet in these patients is not recommended.

Patients with hepatic insufficiency.

Data in patients with hepatic insufficiency are limited. Therefore the use of Nebilet in these patients is contraindicated.

Elderly.

No dose adjustment is required since up titration to the maximum tolerated dose is individually adjusted.

Paediatric.

No studies have been conducted in children and adolescents aged below 18 years. Therefore, use in children and adolescents is not recommended.

4.3 Contraindications

Hypersensitivity to the nebivolol hydrochloride or to any of the excipients.
Liver insufficiency or liver function impairment.
Acute heart failure, cardiogenic shock or episodes of heart failure decompensation requiring i.v. inotropic therapy.
Sick sinus syndrome, including sinoatrial block.
Second and third degree heart block (without a pacemaker).
History of bronchospasm (e.g. including that in chronic obstructive pulmonary disease) and/or asthma (see Section 4.4 Special Warnings and Precautions for Use, Respiratory).
Untreated phaeochromocytoma.
Metabolic acidosis.
Bradycardia (heart rate < 60 bpm prior to starting therapy).
Hypotension (systolic blood pressure < 100 mmHg).
Severe peripheral circulatory disturbances.

4.4 Special Warnings and Precautions for Use

The following warnings and precautions apply to β-adrenergic antagonists in general.

Abrupt withdrawal.

The cessation of therapy with Nebilet should not be done abruptly unless clearly indicated. Care should be taken if β-blockers have to be discontinued abruptly in patients with coronary artery disease. Severe exacerbation of angina and precipitation of myocardial infarction and ventricular arrhythmias have occurred following abrupt discontinuation of β-blockade in patients with ischaemic heart disease. Therefore, it is recommended that the dosage be reduced gradually over a period of about 1-2 weeks during which time the patient's progress should be assessed. Nebivolol should be temporarily reinstituted if the angina worsens markedly or if acute coronary insufficiency develops. If the drug must be withdrawn abruptly, close observation is required. In the perioperative period, β-blockers should not be withdrawn unless indicated.

Anaesthesia.

Prior to surgery the anaesthetist should be informed that the patient is receiving nebivolol because of the potential for interactions of β-blockers with other drugs, resulting in severe bradyarrhythmias and hypotension, decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and decreased propensity for vagal induced bradycardia. Continuation of β-blockade reduces the risk of arrhythmias during induction and intubation. If β-blockade is interrupted in preparation for surgery, the β-adrenergic antagonist should be discontinued at least 24 hours beforehand.
Caution should be observed with certain anaesthetics that cause myocardial depression (see Section 4.4 Special Warnings and Precautions for Use; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). The patient can be protected against vagal reactions by intravenous administration of atropine.

Cardiovascular.

In general, β-adrenergic antagonists should not be used in patients with untreated congestive heart failure, unless their condition has been stabilised (see Section 4.3 Contraindications).
β-adrenergic antagonists may induce bradycardia: if the pulse rate drops below 50-55 bpm at rest and/or the patient experiences symptoms that are suggestive of bradycardia, the dosage should be reduced or treatment gradually withdrawn (see Section 4.3 Contraindications).
β-adrenergic antagonists should be used with caution:
in patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), as aggravation of these disorders may occur (see Section 4.3 Contraindications);
in patients with first degree heart block, because of the negative effect of β-blockers on conduction time;
in patients with Prinzmetal's or variant angina due to unopposed α-receptor mediated coronary artery vasoconstriction: β-adrenergic antagonists may increase the number and duration of anginal attacks.
Combination of Nebilet with calcium channel antagonists of the verapamil and diltiazem type, with class I antiarrhythmic drugs, and with centrally acting antihypertensive drugs is generally not recommended (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Metabolic/ endocrinological.

Nebilet does not affect glucose levels in diabetic patients. Care should be taken in diabetic patients however, as nebivolol may mask certain symptoms of hypoglycaemia (tachycardia, palpitations). In patients with insulin or non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment. Such effects on the glucose metabolism may occur with nonselective β-blockers but they are less likely with a β1-selective agent like nebivolol.
β-adrenergic blocking agents may mask tachycardic symptoms in hyperthyroidism. Abrupt withdrawal may intensify symptoms.

Other metabolic effects.

β-adrenoceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some β-blockers affect the lipid profile adversely although the long-term clinical significance of this change is unknown and the effect is more apparent with nonselective β-blockers while it appears to be less for drugs with β1-adrenoceptor selectivity and for those with intrinsic sympathomimetic activity.

Respiratory.

In patients with chronic obstructive pulmonary disorders, β-adrenergic antagonists should be used with caution as airway constriction may be aggravated. Patients with a history of bronchospasm (e.g. including that in chronic obstructive pulmonary disease) and/or asthma are contraindicated (see Section 4.3 Contraindications).

Phaeochromocytoma.

In patients with phaeochromocytoma, an α-blocker should be administered prior to use of any β-blocker.

Effects on the eye and skin.

Various skin rashes and conjunctival xerosis have been reported with β-blocking agents. Cross reactions may occur between β-blockers, therefore substitutions within the group may not necessarily preclude occurrence of symptoms.
Oculomucocutaneous syndrome whose signs include conjunctivitis sicca and psoriasiform rashes, and sclerosing serositis has occurred with the chronic use of one β-adrenergic blocking agent (practolol). This syndrome has not been observed in association with nebivolol. However, physicians should be alert to the possibility of such reactions and discontinue treatment in the event that they occur.

Other.

Patients with a history of psoriasis should take β-adrenergic antagonists only after careful consideration.
β-adrenergic antagonists may increase the sensitivity to allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect.
The initiation of chronic heart failure treatment with Nebilet necessitates regular monitoring (see Section 4.2 Dose and Method of Administration). Treatment discontinuation should not be done abruptly unless clearly indicated.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose/ galactose malabsorption should not take this medicinal product.

Use in hepatic impairment.

Data in patients with hepatic insufficiency or impaired liver function are limited. Therefore the use of Nebilet in these patients is contraindicated.

Use in renal impairment.

Hypertension.

In patients with renal insufficiency, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. Nebilet has not been studied in patients receiving dialysis.

Chronic heart failure.

No dose adjustment is required in mild to moderate renal insufficiency since up titration to the maximum tolerated dose is individually adjusted. There is no experience in patients with severe renal insufficiency (serum creatinine ≥ 250 micromole/L). Therefore, the use of Nebilet in these patients is not recommended.

Use in the elderly.

Hypertension.

In patients over 65 years, the recommended starting dose is 2.5 mg daily. If needed, the daily dose may be increased to 5 mg. However, in view of the limited experience in patients above 75 years, caution must be exercised and these patients monitored closely.

Chronic heart failure.

The SENIORS study was restricted to patients ≥ 70 years of age. The efficacy and safety of Nebilet in patients with stable heart failure under 70 years of age has not been established. The SENIORS study enrolled patients with all NYHA functional classes. However data is limited in chronic heart failure patients with NYHA Class I and IV functional status.
No dose adjustment is required since up titration to the maximum tolerated dose is individually adjusted.

Paediatric use.

No studies have been conducted in children and adolescents aged below 18 years. Therefore, use in children and adolescents is not recommended.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Pharmacodynamic interactions.

Combinations not recommended.

Class I antiarrhythmics (quinidine, flecainide, disopyramide, lignocaine, mexiletine).

Effect on atrioventricular conduction time may be potentiated and negative inotropic effect increased (see Section 4.4 Special Warnings and Precautions for Use).

Calcium channel antagonists of verapamil/ diltiazem type.

Negative influence on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients with β-blocker treatment may lead to profound hypotension and atrioventricular block (see Section 4.4 Special Warnings and Precautions for Use).

Centrally acting antihypertensives (clonidine, guanfacine, moxonidine, methyldopa).

Concomitant use of centrally acting antihypertensive drugs may worsen heart failure by a decrease in the central sympathetic tonus (reduction of heart rate and cardiac output, vasodilation) (see Section 4.4 Special Warnings and Precautions for Use). Abrupt withdrawal, particularly if prior to β-blocker discontinuation, may increase risk of "rebound hypertension".

Other β-blockers.

Other β-blockers, including eye drops, may have additive effects. Patients receiving this combination should be kept under close surveillance.
Combinations to be used with caution.

Class III antiarrhythmic drugs (amiodarone).

Effect on atrioventricular conduction time may be potentiated.

Anaesthetics, volatile halogenated.

Concomitant use of β-adrenergic antagonists and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension (see Section 4.4 Special Warnings and Precautions for Use). As a general rule, avoid sudden withdrawal of β-blocker treatment. The anaesthesiologist should be informed when the patient is receiving Nebilet.

Insulin and oral antidiabetic drugs.

Although nebivolol does not affect glucose levels, concomitant use may mask certain symptoms of hypoglycaemia (palpitations, tachycardia).

Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, nifedipine, nimodipine).

Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded. Coadministration of nebivolol and nicardipine results in a slight mutual elevation of drug levels.

Catecholamine depleting agents.

Patients receiving catecholamine depleting drugs, such as reserpine or guanethidine, should be closely monitored, because the added β-blocking action of nebivolol may produce excessive reduction of sympathetic activity.

Baclofen (antispastic agent), amifostine (antineoplastic adjunct).

Concomitant use with antihypertensives, such as nebivolol, is likely to increase the fall in blood pressure, therefore the dosage of the antihypertensive medication should be adjusted accordingly.
Combinations requiring careful consideration.

Digitalis glycosides.

Concomitant use may increase atrioventricular conduction time. Clinical trials with nebivolol have not shown any clinical evidence of an interaction. Nebivolol does not influence the kinetics of digoxin.

Antipsychotics, sedatives, antidepressants (tricyclics and phenothiazines).

Concomitant use may enhance the hypotensive effect of the β-blockers (additive effect).

Nonsteroidal anti-inflammatory drugs (NSAID).

No effect on the blood pressure lowering effect of nebivolol.

Sympathomimetic agents.

Concomitant use may counteract the effect of β-adrenergic antagonists. β-adrenergic blockers may lead to unopposed α-adrenergic activity of sympathomimetic agents with both α and β-adrenergic effects (risk of hypertension, severe bradycardia and heart block).

Pharmacokinetic interactions.

As nebivolol metabolism involves the CYP2D6 isoenzyme, coadministration with substances inhibiting this enzyme, especially paroxetine, fluoxetine, thioridazine and quinidine may lead to increased plasma levels of nebivolol associated with an increased risk of excessive bradycardia and adverse events.
Coadministration of 400 mg cimetidine bd for 3 days increased the mean peak plasma nebivolol concentration by about 21-23% compared to placebo.
Coadministration of ranitidine did not affect the pharmacokinetics of nebivolol. Provided Nebilet is taken with the meal, and an antacid between meals, the two treatments can be coprescribed.
Coadministration of alcohol, frusemide or hydrochlorothiazide did not affect the pharmacokinetics of nebivolol. Nebivolol does not affect the pharmacokinetics and pharmacodynamics of warfarin.
The effects of sildenafil and other antihypertensive drugs on nebivolol pharmacokinetics have not been evaluated.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

A randomised, double blind, single centre, clinical trial in 30 subjects monitored the hormone levels of patients given nebivolol 5 mg and d-nebivolol 2.5 mg in a cross over fashion for 4 weeks each. Alterations in testosterone levels differed between men and women. Whilst nebivolol and d-nebivolol resulted in an increase in testosterone in males; the converse is seen in women, with administration resulting in a decrease in testosterone plasma concentration. Plasma progesterone concentrations are seen to decrease with administration of nebivolol or d-nebivolol in both male and female patients. All other hormone parameters tested, including ACTH, aldosterone, cortisol, LH, FSH and estradiol demonstrated no significant within or between treatment differences.
Adverse effects on male and female reproduction organs in rats and mice were observed. Nebivolol decreased fertility in rats at a dose of 160 mg/kg/day (145 times anticipated clinical exposure at the MRHD; mg/m2). Whether fertility of males or females or both was affected could not be determined but a no-effect level of 40 mg/kg/day (36 times MRDH; mg/m2) was achieved.
(Category C)
Nebivolol has pharmacological effects that may cause harmful effects in pregnancy and/or the fetus/ newborn. β-adrenoceptor blockers reduce placental perfusion, which may induce growth retardation, intrauterine death or immature/ premature deliveries. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If treatment with β-adrenoceptor blockers is necessary, β1-selective adrenoceptor blockers are preferable.
Reduced fetal bodyweights and associated small delays in ossification were observed following nebivolol administration to pregnant rats during organogenesis at maternally toxic doses of 20 and 40 mg/kg/day (18 and 36 times the maximum recommended human dose (MRHD); mg/m2), while a small increase in resorption occurred at 40 mg/kg/day. No adverse effects on embryo/ fetal viability, sex, weight or morphology were observed in studies in which nebivolol was given to pregnant rabbits at doses up to 10 mg/kg/day (23 times the MRHD; mg/m2).
Peri/ postnatal exposure of rats to nebivolol (late gestation, parturition and lactation) decreased pup bodyweights at 2.5 mg/kg, with 5 mg/kg and higher doses (> 5 times the MRHD; mg/m2) causing prolonged gestation and dystocia along with corresponding increases in late fetal deaths and stillbirths, and decreases in birth weight, live litter size and pup survival. The no observable adverse effect level for nebivolol for the F1 generation was 1.25 mg/kg/day (similar to MRHD, mg/m2).
Nebivolol should not be used during pregnancy unless clearly necessary. If treatment with nebivolol is considered necessary, the uteroplacental blood flow and the fetal growth should be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia and bradycardia are generally to be expected within the first 3 days.
 Animal studies have shown that nebivolol and or its metabolites cross the placental barrier and are excreted in breast milk. The dose of nebivolol, in mg/kg bodyweight, ingested by a suckling pup was 0.3% of the dose of the dam. Peri/ postnatal studies in rats have shown adverse effects following maternal nebivolol treatment through to weaning (see Use in pregnancy). Most β-blockers, particularly lipophilic compounds like nebivolol and its active metabolites, pass into breast milk to varying degrees. Therefore, mothers receiving nebivolol should not breastfeed.

4.7 Effects on Ability to Drive and Use Machines

No studies on the effects of Nebilet on the ability to drive and use machines have been performed. Pharmacodynamic studies have shown that Nebilet 5 mg does not affect psychomotor function. When driving vehicles or operating machines it should be taken into account that dizziness and fatigue may occasionally occur with Nebilet treatment (see Section 4.8 Adverse Effects (Undesirable Effects)).

4.8 Adverse Effects (Undesirable Effects)

Clinical trial data.

Hypertension.

A summary of the adverse events reported in ≥ 1% of Nebilet patients or placebo patients in therapeutic dose (5 mg) hypertension clinical trials, are provided in Table 1.
Other adverse events reported during US clinical trials with an incidence of at least 1% include: hypercholesterolaemia, hyperuricaemia, increase in BUN, uric acid, triglycerides and a decrease in HDL cholesterol and platelet count. These adverse events were in most cases observed at a similar frequency in placebo treated patients in controlled studies.

Chronic heart failure.

Data on adverse reactions in CHF patients are available from one placebo controlled clinical trial, SENIORS, involving 1067 patients taking Nebilet and 1061 patients taking placebo. In this study, a total of 449 Nebilet patients (42.1%) reported at least possibly causally related adverse reactions compared to 334 placebo patients (31.5%). The most commonly reported adverse reactions in Nebilet patients were bradycardia and dizziness, both occurring in approximately 11% of patients. The corresponding frequencies among placebo patients were approximately 2% and 7%, respectively.
Adverse events occurring in at least 5% of patients in either the Nebilet or placebo groups are listed in Table 2. The higher incidence of some adverse events compared to placebo (e.g. bradycardia) reflects the pharmacology of the drug and is therefore not unexpected. As is common for other β-blockers, the majority of these adverse events were reported during the up titration phase and so it is recommended dosage is increased gradually (see Section 4.2 Dose and Method of Administration).
In the SENIORS study, 165 (15.5%) of Nebilet patients and 136 (12.8%) of placebo patients experienced at least one adverse event that led to permanent treatment discontinuation. The higher discontinuation rate due to adverse events in the Nebilet group, in particular due to bradycardia, is not unexpected given the pharmacology of the drug.

Post-marketing experience.

A summary of postmarketing and hypertension clinical trial adverse reactions are summarised below.
The following definitions of frequency are used: very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon ≥ 1/1000 to < 1/100; rare ≥ 1/10,000 to < 1/1000; very rare ≤ 1/10,000.

Psychiatric disorders.

Uncommon: nightmares, depression.

Nervous system disorders.

Common: headache, dizziness, paraesthesia. Very rare: syncope.

Eye disorders.

Uncommon: impaired vision.

Cardiac disorders.

Uncommon: bradycardia, heart failure, slowed AV conduction/ AV block.

Vascular disorders.

Uncommon: hypotension, (increase of) intermittent claudication.

Respiratory, thoracic and mediastinal disorders.

Common: dyspnoea. Uncommon: bronchospasm.

Gastrointestinal disorders.

Common: constipation, nausea, diarrhoea. Uncommon: dyspepsia, flatulence, vomiting.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, rash erythematous. Very rare: psoriasis aggravated.

Reproductive system and breast disorders.

Uncommon: impotence.

General disorders and administration site conditions.

Common: tiredness, oedema.
There have also been occasional reports of hypersensitivity, angioneurotic oedema and urticaria during post-marketing use of nebivolol.

Events identified from spontaneous reports of nebivolol received worldwide.

The following adverse events have been identified from spontaneous reports of nebivolol received worldwide and have not been listed elsewhere. Because these events were reported voluntarily from a population of uncertain size, it is not possible to estimate their frequency or establish a causal relationship to nebivolol exposure: abnormal hepatic function (including increased AST, ALT and bilirubin), acute pulmonary oedema, acute renal failure, myocardial infarction, Raynaud's phenomenon, thrombocytopenia and various rashes and skin disorders.
The following adverse reactions have also been reported with some β-adrenergic antagonists: hallucinations, psychoses, confusion, cold/ cyanotic extremities, Raynaud phenomenon, dry eyes, and oculo-mucocutaneous toxicity of the practolol type.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

No data are available on overdose with Nebilet.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Symptoms.

Symptoms of overdose with β-blockers are: bradycardia, hypotension, bronchospasm and acute cardiac insufficiency.

Treatment.

In case of overdose or hypersensitivity, the patient should be kept under close supervision and be treated in an intensive care ward. Blood glucose levels should be checked. Artificial respiration may be required. Bradycardia or extensive vagal reactions should be treated by administering atropine. Hypotension and shock should be treated with plasma/ plasma substitutes and, if necessary, catecholamines. The β-blocking effect can be counteracted by slow intravenous administration of isoprenaline hydrochloride, starting with a dose of approximately 5 microgram/minute, or dobutamine, starting with a dose of 2.5 microgram/minute, until the required effect has been obtained. In refractory cases isoprenaline can be combined with dopamine. If this does not produce the desired effect either, intravenous administration of glucagon 50-100 microgram/kg i.v. may be considered. If required, the injection should be repeated within one hour, to be followed (if required) by an intravenous infusion of glucagon 70 microgram/kg/h. In extreme cases of treatment resistant bradycardia, a pacemaker may be inserted.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Nebivolol is a racemate of two enantiomers, d-nebivolol and l-nebivolol.
Pharmacological studies have shown that the d-enantiomer is largely responsible for the β-receptor antagonist activity while the l-enantiomer has mild vasodilating properties attributable to an interaction with the L-arginine/ nitric oxide pathway.
Nebivolol is a selective β1-receptor antagonist in extensive metabolisers and at doses less than or equal to 10 mg. Nebivolol is devoid of α1-adrenergic receptor blocking activity and lacks intrinsic sympathomimetic and membrane stabilising activity at clinically relevant doses/ concentrations. Many of nebivolol's hydroxylated and glucuronidated metabolites contribute to β-blocking activity.
Single and repeated doses of nebivolol reduce heart rate and blood pressure at rest and during exercise, both in normotensive subjects and in hypertensive patients. The antihypertensive effect is maintained during chronic treatment.
During acute and chronic treatment with nebivolol in hypertensive patients systemic vascular resistance is decreased. Despite heart rate reduction, reduction in cardiac output during rest and exercise may be limited due to an increase in stroke volume. The clinical relevance of these haemodynamic differences as compared to other β1-receptor antagonists has not been fully established.
In hypertensive patients, nebivolol increases the NO mediated vascular response to acetylcholine (ACh) which is reduced in patients with endothelial dysfunction.

Clinical trials.

Hypertension. Initial randomised, double blind, placebo controlled dose finding trials included a total of 1106 patients in 5 studies administered placebo or nebivolol. Four out of the five trials showed that 5 mg doses significantly decreased diastolic blood pressure (DBP) and systolic blood pressure (SBP) compared to placebo. The optimal antihypertensive dose was 5 mg. Four of the five dose finding trials were of 1 month duration with the fifth study of 3 months duration.
Further randomised, double blind, placebo and/or active controlled therapeutic dose trials were conducted. These trials included 1493 patients in 7 studies administered placebo, nebivolol or another active comparator. They ranged in duration from 1 to 3 months, with one study of 36 months duration. The data generated confirmed that 5 mg nebivolol significantly reduces blood pressure in hypertensive patients versus placebo. Noninferiority margins were not defined in the active controlled trials.
Combined analysis of a subset of patients from dose finding and therapeutic dose trials treated with the therapeutic dose of 5 mg of nebivolol (n = 932 patients) showed that nebivolol decreased DBP at drug trough level from 103.1 mmHg to 90.8 mmHg and SBP from 162.0 mmHg to 147.4 mmHg. The 5 mg dose adequately controls blood pressure over 24 hours, with a trough/ peak ratio of 87.9% at end point in placebo controlled trials. End of treatment response and normalised blood pressure (BP) rates for all 5 mg therapeutic dose trials are presented in Table 3.
The blood pressure lowering effect becomes evident after 2 weeks of treatment. Occasionally, the optimal effect is reached only after 4 weeks.

Long-term use.

Continued long-term antihypertensive effects of nebivolol have been demonstrated in 6 studies (5 of which were open label and uncontrolled) involving 596 patients over a duration of up to 3 years. A combined analysis showed that SBP/DBP remained decreased during long-term treatment, with SBP/DBP of 165.9/103.7 mmHg at base line (n = 596) and 140.0/85.4 mmHg at 3 years (n = 204).
Hypertension registration trials provided no data on the effects of nebivolol on cardiovascular morbidity and mortality and target organ damage.
Chronic heart failure. The efficacy of nebivolol as add-on treatment in treating chronic heart failure (CHF) was evaluated in a mortality morbidity, multinational multicentre, centrally randomised, placebo controlled trial in 2128 patients. Patients enrolled were aged ≥ 70 years (median age 75.2 years) and 37% were women. Patients had stable chronic heart failure with or without impaired left ventricular ejection fraction and were on standard therapy. Patients entered had either a documented hospital discharge diagnosis of congestive heart failure in the last 12 months or a documented LVEF < 35% in the last 6 months. Patients were evenly matched at baseline including background therapies and were mainly in NYHA class II (56.4%) or class III (38.7%) with background therapy being ACE inhibitors (82%), diuretics (86%), cardiac glycosides (39%), aldosterone antagonists (28%), antiarrhythmics (13%) and angiotensin receptor blockers (7%). Median LVEF was 33% with a range of 4-82% and 80% reached a maintenance dose ≥ 5 mg (68% on 10 mg daily). The trial was named SENIORS - Study on the Effects of Nebivolol Interventions on Outcomes and Rehospitalisation in Seniors with heart failure, and had an average follow-up period of 20 months.
The primary outcome in the SENIORS study was a combined end-point of cardiovascular hospital admission or all cause mortality (time to first event).
Treatment duration exceeded 12 months in all patients. The population of CHF patients studied is highly representative of that found in the community in terms of advanced age, gender distribution and wide range of LV ejection fraction (including 64.3% with a LVEF of ≤ 35%). See Table 4.
The study period encompassed an up titration period from between 4 and 16 weeks, with a dose escalation every 1-2 weeks. The maintenance period continued for up to 40 months, resulting in a median observation period of 20 months (in quartile range 14 to 29 months) and a median treatment exposure of 17 months. The trial concluded with a down titration phase involving halving the dose every week.
The clinical efficacy results from the SENIORS trial are summarised in Table 5. The table presents the primary composite endpoint together with those secondary outcomes that contribute to the primary result. Functional capacity as measured by changes in NYHA status or 6 minute walk test showed no differences between nebivolol and placebo.
Nebivolol, on top of standard therapy, induced a statistically and clinically significant benefit over placebo by prolonging the time to occurrence of either death from any cause or cardiovascular hospitalisation (time to first event, primary endpoint for efficacy) with a relative risk reduction of 14% and absolute risk reduction of 4.2%. This corresponds to a number needed to treat (NNT) of 28 patients to prevent one death or one cardiac hospitalisation. The benefit over placebo is evident after about 6 month's treatment and was maintained for the duration of follow-up.
The SENIORS study indicated that the effect of nebivolol was independent from age, gender or left ventricular ejection fraction of the population on study.

5.2 Pharmacokinetic Properties

Absorption.

Both nebivolol enantiomers are rapidly absorbed after oral administration. Nebivolol can be given with or without meals, but a consistent approach is recommended.

Distribution.

Steady-state plasma levels in most subjects (fast metabolisers) are reached within 24 hours for nebivolol and within a few days for the hydroxy-metabolites.
Plasma concentrations are dose-proportional between 1 and 30 mg. The pharmacokinetics of nebivolol are not affected by age.
In plasma, both nebivolol enantiomers are predominantly bound to albumin. Plasma protein binding is 98.1% for d-nebivolol and 97.9% for l-nebivolol.

Metabolism.

Nebivolol is extensively metabolised, partly to active hydroxy-metabolites. Nebivolol is metabolised via alicyclic and aromatic hydroxylation, N-dealkylation and glucuronidation; in addition, glucuronides of the hydroxy-metabolites are formed. The metabolism of nebivolol by aromatic hydroxylation is subject to the CYP2D6 dependent genetic oxidative polymorphism. The approximate oral bioavailability of nebivolol averages 13% in fast metabolisers and is virtually complete in slow metabolisers. At steady state and at the same dose level, the peak plasma concentration of unchanged nebivolol is about 23 times higher in poor metabolisers than in extensive metabolisers. When unchanged drug plus active metabolites are considered, the difference in peak plasma concentrations is 1.3 to 1.4-fold. Because of the variation in rates of metabolism, the dose of Nebilet should always be adjusted to the individual requirements of the patient: poor metabolisers therefore may require lower doses.

Excretion.

In fast metabolisers, elimination half-lives of the nebivolol enantiomers average 10 hours. In slow metabolisers, they are 3-5 times longer. In fast metabolisers, plasma levels of l-nebivolol are slightly higher than for d-nebivolol. In slow metabolisers, this difference is larger. In fast metabolisers, elimination half-lives of the hydroxymetabolites of both enantiomers average 24 hours, and are about twice as long in slow metabolisers.
One week after administration, 38% of the dose is excreted in the urine and 48% in the faeces. Urinary excretion of unchanged nebivolol is less than 0.5% of the dose.

5.3 Preclinical Safety Data

Genotoxicity.

Nebivolol was not genotoxic or clastogenic when tested in a battery of assays (Ames, in vitro mouse lymphoma TK+/-, in vitro human peripheral lymphocyte chromosome aberration, in vivo Drosophila melanogaster sex linked recessive lethal, and in vivo bone marrow micronucleus tests).

Carcinogenicity.

In a two year study of nebivolol in mice, a statistically significant increase in the incidence of benign testicular Leydig cell tumours was observed at 40 mg/kg/day (18 times MRHD; mg/m2). Similar treatment related findings were not observed in the same study at doses up to 5 times the MRHD (mg/m2) or in a two year rat study at doses up to 10 mg/kg/day (9 times MRHD; mg/m2). There is evidence that the Leydig cell hyperplasia and tumours observed in mice are related to a species specific reduction in blood LH by nebivolol which is not observed in humans.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, maize starch, croscarmellose sodium, hypromellose, polysorbate 80, microcrystalline cellulose, colloidal anhydrous silica and magnesium stearate.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

1.25 mg tablets - store below 25°C.
5 mg and 10 mg tablets - store below 30°C.

6.5 Nature and Contents of Container

Nebilet 1.25 mg, 5 mg and 10 mg tablets: Packs contain 4, 7 or 28 tablets supplied in PVC/ aluminium foil blister strips.
Titration pack: Comprising 42 Nebilet 1.25 mg tablets and 14 Nebilet 5 mg tablets, supplied in PVC/ aluminium foil blister strips, used for the initial titration to a patient's optimal dose when treating for chronic heart failure.
Not all pack sizes may be marketed.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Nebivolol is a white to almost white powder with a solubility in water at a pH of 5.4 of 0.091 g/100 mL solution. It is a racemate mixture of the RSSS (= SSSR) enantiomer called l-nebivolol and the SRRR (= RRRS) enantiomer called d-nebivolol.

Chemical structure.


Chemical name.

(IRS, 1'RS)-1,1'-[(2RS, 2'SR)- bis(6-fluorochroman-2-yl)]-2,2'- iminodiethanol hydrochloride or (IRS, 1'RS)-1,1'-[(2RS, 2'SR)- bis(6-fluoro-3,4-dihydro- 2H-1-benzopyran-2-yl)]- 2,2'-iminodiethanol hydrochloride or [2R*[R*[R*(S*)]]]- α,α'-[iminobis(methylene)] bis[6-fluoro-3,4-dihydro- 2H-1-benzopyran-2-methanol] hydrochloride.

Molecular formula.

C22H25F2NO4.HCl.

Molecular weight.

441.90.

CAS number.

152520-56-4.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes