Consumer medicine information

APO-Bisoprolol

Bisoprolol fumarate

BRAND INFORMATION

Brand name

APO-Bisoprolol

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using APO-Bisoprolol.

SUMMARY CMI

APO-BISOPROLOL

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 using Bisoprolol fumarate?

APO-BISOPROLOL tablets contains the active ingredient bisoprolol fumarate. It is used to treat heart failure. It is usually used in combination with other medicines.

For more information, see Section 1. Why am I using bisoprolol fumarate? in the full CMI.

2. What should I know before I use Bisoprolol fumarate?

Do not use if you have ever had an allergic reaction to bisoprolol fumarate 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 use bisoprolol fumarate? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with bisoprolol fumarate 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 use Bisoprolol fumarate?

  • The usual starting dose is 1.25 mg once daily for one week. If well tolerated, your doctor will gradually increase your dose over the next ten weeks. The usual maintenance therapy is 10 mg once daily.
  • Follow the instructions provided and use bisoprolol fumarate until your doctor tells you to stop. They may differ from the information contained in this leaflet.

More instructions can be found in Section 4. How do I use Bisoprolol fumarate? in the full CMI.

5. What should I know while using Bisoprolol fumarate?

Things you should do
  • Before starting any new medicine, tell your doctor or pharmacist that you are taking APO-BISOPROLOL.
  • If you become pregnant while taking it, tell your doctor immediately.
  • If you are going to have surgery, including dental surgery, tell your doctor or dentist that you are taking APO-BISOPROLOL.
Things you should not do
  • Do not stop taking APO-BISOPROLOL or lower the dose without checking with your doctor.
  • Stopping treatment suddenly may cause your condition to worsen or other heart complications may occur.
Driving or using machines
  • Be careful driving or operating machinery until you know how APO-BISOPROLOL affects you.
  • This medicine may cause tiredness, dizziness or light-headedness in some people, especially after the first dose. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Be careful getting up from a sitting or lying position. Dizziness, light-headedness or fainting may occur, especially when you get up 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.
  • Keep your tablets in the blister pack until it is time to take them.

For more information, see Section 5. What should I know while using bisoprolol fumarate? in the full CMI.

6. Are there any side effects?

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

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

APO-BISOPROLOL

Active ingredient(s): bisoprolol fumarate

Consumer Medicine Information (CMI)

This leaflet provides important information about using bisoprolol fumarate tablets. 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 bisoprolol fumarate.

Where to find information in this leaflet:

1. Why am I using bisoprolol fumarate?
2. What should I know before I use APO-BISOPROLOL?
3. What if I am taking other medicines?
4. How do I use Bisoprolol fumarate?
5. What should I know while using APO-BISOPROLOL?
6. Are there any side effects?
7. Product details

1. Why am I using Bisoprolol fumarate?

The name of your medicine is APO-Bisoprolol tablets. It contains the active ingredient, bisoprolol fumarate. It is used to treat heart failure. It is usually used in combination with other medicines.

Heart failure occurs when the heart muscle is weak and unable to pump enough blood to supply the body's needs. Heart failure may start off with no symptoms, but as the condition progresses patients may feel short of breath and notice swelling of the feet and ankles due to fluid build-up.

Bisoprolol fumarate belongs to a group of medicines called beta-blockers. These medicines work by affecting the body's response to some nerve impulses, especially in the heart. As a result, it decreases the heart's need for blood and oxygen and therefore reduces the amount of work the heart must do. Bisoprolol fumarate also slows your heart rate, which in turn increases the efficiency of your heart.

Bisoprolol fumarate can help to reduce the number of heart failure episodes needing hospital admission and the risk of sudden death.

Your doctor may have prescribed this medicine for another reason.

Ask your doctor if you have any questions about why bisoprolol fumarate has been prescribed for you.

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

There is no evidence that bisoprolol fumarate is addictive.

Use in children

Bisoprolol fumarate is not recommended for use in children, as the safety and efficacy in children has not been established.

2. What should I know before I use APO-BISOPROLOL?

Warnings

Do not use bisoprolol fumarate if:

  • you are allergic to bisoprolol fumarate, or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include skin rash, itching or hives, swelling of the face, lips or tongue which may cause difficulty in swallowing or breathing, wheezing or shortness of breath.

Do not take APO-BISOPROLOL if you have any of the following heart problems:

  • severe heart failure that is not controlled medically
  • worsening heart failure requiring injection of medicines into a vein
  • cardiogenic shock, a serious heart condition causing low blood pressure and circulatory failure
  • certain heart conditions where the electrical activity controlling your heart rate does not work properly, causing a very slow heart rate or uneven heart beating
  • low blood pressure.

Do not take this medicine if you have any of the following medical conditions:

  • severe asthma or severe chronic obstructive lung disease
  • severe blood circulation problems in your limbs (such as Raynaud's syndrome), which may cause your fingers and toes to tingle or turn pale or blue
  • untreated phaeochromocytoma, a rare tumour of the adrenal gland
  • metabolic acidosis, a condition when there is too much acid in the blood.

Always check the ingredients to make sure you can use this medicine.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

Check with your doctor if you:

  • have any other medical conditions, listed above.
  • take any medicines for any other condition
  • are allergic to any other medicines, foods, dyes or preservatives
  • asthma, difficulty breathing or other lung problems
  • certain heart diseases (such as disturbances in heart rhythm or Prinzmetal angina)
  • diabetes
  • any allergic conditions
  • psoriasis, a skin disease with thickened patches of red skin, often with silvery scales
  • thyroid disorder
  • any blood vessel disorder causing poor circulation in the arms and legs
  • kidney problems
  • liver problems
  • phaeochromocytoma, a rare tumour of the adrenal gland
  • currently following a strict fasting diet.
  • are going to have anaesthesia (for example, for surgery)

Your doctor may want to take special care if you have any of these conditions. Bisoprolol fumarate may influence how your body reacts to this situation.

If you have not told your doctor about any of the above, tell them before you start taking APO-BISOPROLOL

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

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

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

Bisoprolol fumarate may affect your developing baby if you take it during pregnancy. Your doctor can discuss with you the risks and benefits of taking bisoprolol fumarate during pregnancy.

Like most beta-blocker medicines bisoprolol fumarate is not recommended while you are breastfeeding. Your doctor can discuss with you the risks and benefits of taking bisoprolol fumarate when breastfeeding.

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 and APO-BISOPROLOL may interfere with each other.

Do not take the following medicines with APO-BISOPROLOL without special advice from your doctor:

  • certain anti-arrhythmic medicines such as disopyramide, lidocaine, phenytoin or flecainide (used to treat irregular or abnormal heartbeat)
  • certain calcium antagonists such as diltiazem or verapamil (used to treat high blood pressure and angina)
  • certain medicines used to treat high blood pressure such as clonidine, methyldopa or moxonidine.

However, do not stop taking these medicines without checking with your doctor.

Check with your doctor before taking the following medicines with APO-BISOPROLOL.

Your doctor may need to check your condition more frequently:

  • anti-arrhythmic medicines such as amiodarone (used to treat irregular or abnormal heartbeat)
  • calcium antagonists such as felodipine or amlodipine (used to treat high blood pressure and angina)
  • certain medicines used to treat arthritis, pain or inflammation, such as ibuprofen or diclofenac
  • eye drops for glaucoma treatment
  • insulin and oral drugs for diabetes
  • anaesthetic agents used in surgery
  • digoxin, a medicine used to treat heart failure
  • ergot derivatives, medicines commonly used to treat migraines
  • rifampicin, a medicine used to treat tuberculosis
  • tricyclic antidepressants
  • barbiturates, medicines used to treat epilepsy
  • phenothiazines, medicines used to treat some mental conditions
  • mefloquine, a medicine used to treat malaria
  • adrenaline, a medicine used to treat allergic reactions
  • certain medicines used to treat depression called monoamine oxidase inhibitors, such as phenelzine or tranylcypromine.

These medicines may be affected by APO-BISOPROLOL or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking APO-BISOPROLOL.

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

4. How do I use Bisoprolol fumarate?

How much to take

  • The usual starting dose is 1.25 mg once daily for one week. If well tolerated, your doctor will gradually increase your dose over the next ten weeks. The usual maintenance therapy is 10 mg once daily.
    If your condition gets worse or you no longer tolerate the drug, it may be necessary to reduce the dose again or interrupt treatment. In some patients a maintenance dose lower than 10 mg may be sufficient. Your doctor will tell you what to do.
  • Follow the instructions provided and use bisoprolol fumarate until your doctor tells you to stop. They may differ from the information contained in this leaflet.

How to take it

  • Swallow the tablets whole with a full glass of water.
  • Do not crush or chew the tablets.
  • If you crush or chew the tablets, they will not work as well.

When to take Bisoprolol fumarate tablets

  • Take Bisoprolol fumarate tablets in the morning, with or without food.

How long to take it for

  • To properly control your condition, APO-BISOPROLOL must be taken every day, usually as a long-term treatment.
  • Keep taking it for as long as your doctor recommends.
  • It is very important that you do not stop taking APO-BISOPROLOL suddenly.

If you forget to use Bisoprolol fumarate tablets

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

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

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 use too much Bisoprolol fumarate (Overdose)

If you think that you have used too much bisoprolol fumarate, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), or
  • contact your doctor, or
  • go to the Emergency Department at your nearest hospital.

You may need urgent medical attention.

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

Symptoms of an overdose may include slowed heart rate, difficulty breathing, marked drop in blood pressure, severe heart failure, or a decrease in blood sugar.

5. What should I know while using APO-BISOPROLOL?

Things you should do

Before starting any new medicine, tell your doctor or pharmacist that you are taking APO-BISOPROLOL.

If you become pregnant while taking it, tell your doctor immediately.

If you are going to have surgery, including dental surgery, tell your doctor or dentist that you are taking APO-BISOPROLOL.

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

APO-BISOPROLOL 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.

Bisoprolol fumarate may make hypoglycaemia last longer. Your dose of diabetic medicines, including insulin, may need to change.

Call your doctor straight away if:

  • You are to have any medical tests, tell your doctor that you are taking APO-BISOPROLOL. It may affect the results of some tests.
  • Visit your doctor regularly so they can check on your progress. Your doctor may check your eyes, thyroid, lipid and blood glucose levels.
  • 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

Remind any doctor, dentist or pharmacist you visit that you are using bisoprolol fumarate tablets.

Things you should not do

  • Do not stop taking APO-BISOPROLOL or lower the dose without checking with your doctor.
  • Stopping treatment suddenly may cause your condition to worsen or other heart complications may occur.
  • If you have to stop treatment, your doctor will usually advise you to reduce the dose gradually.
  • Do not take APO-BISOPROLOL to treat any other conditions 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 APO-BISOPROLOL affects you.
This medicine may cause tiredness, dizziness or light-headedness in some people, especially after the first dose. If any of these occur, do not drive, operate machinery or do anything else that could be dangerous.

Drinking alcohol

Tell your doctor if you drink alcohol.

Be careful getting up from a sitting or lying position. Dizziness, light-headedness or fainting may occur, especially when you get up quickly. Getting up slowly may help.

Suggestions to help manage your condition:

  • Physical activity - regular exercise when symptoms are absent or mild helps improve heart function. Before starting any exercise, ask your doctor for advice.
  • Weight reduction - your doctor may suggest losing some weight to help lessen the amount of work your heart has to do.
  • Diet - eat a healthy, low fat diet which includes plenty of fresh fruit and vegetables, bread, cereals and fish. Also, try to eat less fat and sugar.
  • Salt restriction - too much salt can make your heart failure worse. Try to avoid using salt in cooking and at the table.

Looking after your medicine

  • Keep your tablets in a cool dry place where the temperature stays below 25°C.
  • Keep your tablets in the blister pack until it is time to take them.
  • If you take tablets out of the blister pack, they may not keep well.
  • Heat and dampness can destroy some medicines

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.

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

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking APO-BISOPROLOL.

APO-BISOPROLOL helps most people with heart failure, but it may have unwanted side effects in some people.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by this list of possible side effects.

You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

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
  • tiredness, feeling weak
  • dizziness
  • headache
  • sleep disturbances, nightmares
  • nausea, vomiting
  • diarrhoea, constipation
  • feeling of coldness or numbness in hands or feet
  • allergic runny nose
  • hair loss
  • sexual problems, including erectile dysfunction.
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
  • muscular weakness or cramps
  • dizziness or light-headedness (sometimes with fainting), especially on standing up, which may be due to low blood pressure
  • a very slow heartbeat
  • hallucinations
  • depression
  • irritation or redness of the eye
  • skin reactions such as rash, flush, itching, worsening of psoriasis
  • difficulty hearing
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.

Very Serious side effects

Very Serious side effectsWhat to do
  • swelling of the face, lips, tongue, or throat which may cause difficulty breathing or swallowing
  • signs of worsening heart failure such as shortness of breath, sometimes with tiredness or weakness, swelling of the feet or legs due to fluid build up
  • chest tightness, wheezing, rattly breathing
  • yellowing of the skin or eyes, dark coloured urine, itching, generally feeling unwell
  • irregular heartbeat.
The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.		Tell your doctor immediately, or go to Accident and Emergency at the nearest hospital

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.

What Bisoprolol fumarate contains

Active ingredient
(main ingredient)		Each 1.25 mg, 2.5 mg, 3.75 mg, 5 mg or 10 mg of bisoprolol fumarate as the active ingredient.
Other ingredients
(inactive ingredients)
  • colloidal anhydrous silica
  • microcrystalline cellulose
  • croscarmellose sodium
  • sodium starch glycollate (type A)
  • magnesium stearate

This medicine is gluten-free, lactose-free, sucrose-free, tartrazine-free and free of other azo dyes.

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

What Bisoprolol fumarate looks like

APO-BISOPROLOL comes in three strengths of tablets:

  • 1.25 mg; A white to off white, round, biconvex tablet, debossed '1.25' and plain on the other side. AUST R 182108.
  • 2.5 mg: A white to off white, round, biconvex tablet, debossed '2' bisect '5' and plain on the other side. AUST R 182106.
  • 3.75 mg: A white to off white, round, biconvex tablet, debossed '3.75' and plain on the other side. AUST R 182117.
  • 5 mg: A white to off white, round, biconvex tablet, debossed '5' on the left of a break line and plain on the other side. AUST R 182114.
  • 10 mg: A white to off white, round, biconvex tablet, debossed '10' on the left of a break line and plain on the other side. AUST R 182123.

Blister packs of 7, 10, 28, 30, 42, 56 and 100 tablets

Who distributes Bisoprolol fumarate

Arrotex Pharmaceuticals Pty Ltd
15-17 Chapel Street
Cremorne VIC 3121
Australia

This leaflet was prepared in September 2024

Published by MIMS November 2024

BRAND INFORMATION

Brand name

APO-Bisoprolol

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

1 Name of Medicine

Bisoprolol fumarate.

2 Qualitative and Quantitative Composition

Each tablet contains 1.25 mg, 2.5 mg, 3.75 mg, 5 mg or 10 mg of bisoprolol fumarate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

1.25 mg tablets.

A white to off white, round, biconvex tablet, debossed '1.25' and plain on the other side.

2.5 mg tablets.

A white to off white, round, biconvex tablet, debossed '2' bisect '5' and plain on the other side.

3.75 mg tablets.

A white to off white, round, biconvex tablet, debossed '3.75' and plain on the other side.

5 mg tablets.

A white to off white, round, biconvex tablet, debossed '5' on the left of a break line and plain on the other side.

10 mg tablets.

A white to off white, round, biconvex tablet, debossed '10' on the left of a break line and plain on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of stable chronic moderate to severe heart failure in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides.

4.2 Dose and Method of Administration

APO-Bisoprolol tablets are intended for oral administration.

Dosage.

Treatment of chronic heart failure consists of an ACE inhibitor (or angiotensin receptor blocker in case of intolerance to ACE inhibitors), a β-blocker, diuretics, and when appropriate cardiac glycosides.
Patients should be stable (without acute failure) when bisoprolol treatment is initiated.
It is recommended that the treating physician should be experienced in the management of chronic heart failure.

Titration phase.

The treatment of stable chronic heart failure with bisoprolol requires a titration phase. The treatment with bisoprolol is to be started with a gradual uptitration according to the following steps:
1.25 mg once daily for 1 week, if well tolerated increase to;
2.5 mg once daily for a further week, if well tolerated increase to;
3.75 mg once daily for a further week, if well tolerated increase to;
5 mg once daily for the 4 following weeks, if well tolerated increase to;
7.5 mg once daily for the 4 following weeks, if well tolerated increase to;
10 mg once daily for the maintenance therapy.
The maximum recommended dose is 10 mg once daily.
Close monitoring of vital signs (heart rate, blood pressure), conduction disturbances and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy. Transient worsening of heart failure, hypotension, or bradycardia may occur during titration period and thereafter.

Treatment modification.

If the maximum recommended dose is not well tolerated, gradual dose reduction may be considered. In case of transient worsening of heart failure, hypotension, or bradycardia, reconsideration of the dosage of the concomitant medication is recommended. It may also be necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.
The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.
If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patient's condition.
Treatment of stable chronic heart failure with bisoprolol is generally a long-term treatment.

Administration.

Bisoprolol tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.

Special population.

Use in patients with hepatic or renal impairment.

There is no information regarding the pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or renal function. Uptitration of the dose in these populations should therefore be made with additional caution.

Use in the elderly.

No dosage adjustment is required.

Infants and children.

There is no paediatric experience with bisoprolol, therefore its use cannot be recommended for children.

4.3 Contraindications

Bisoprolol is contraindicated in patients with:
acute heart failure, episodes of heart failure decompensation requiring intravenous inotropic therapy, cardiogenic shock;
AV block of second or third degree (without a pacemaker);
sick sinus syndrome or sinoatrial block;
bradycardia with less than 60 beats/min before the start of therapy;
hypotension (systolic blood pressure less than 100 mmHg);
severe bronchial asthma or severe chronic obstructive pulmonary disease;
late stages of peripheral arterial occlusive disease;
Raynaud's syndrome;
untreated phaeochromocytoma (see Section 4.4 Special Warnings and Precautions for Use);
metabolic acidosis;
hypersensitivity to bisoprolol or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Use with caution in the following circumstances.

The initiation of treatment with bisoprolol necessitates regular monitoring.
There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the following diseases and conditions: NYHA class II heart failure, insulin dependent diabetes mellitus (type 1), impaired renal function (serum creatinine ≥ 300 micromol/L), impaired liver function, patients older than 80 years, restrictive cardiomyopathy, congenital heart disease, haemodynamically significant organic valvular disease and myocardial infarction within 3 months.
Combination of bisoprolol with calcium antagonists of the verapamil or 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).

General anaesthetics.

Beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the postoperative period. It is currently recommended that maintenance β-blockade be continued perioperatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other medicines, resulting in severe bradyarrhythmias, attenuation of the reflex tachycardia and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal induced bradycardia. Incidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during anaesthesia have been reported. Modem inhalational anaesthetic agents are generally well tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were sometimes associated with severe circulatory depression in the presence of β-blockade. If it is thought necessary to withdraw β-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

Abrupt withdrawal.

The cessation of therapy with bisoprolol should not be done abruptly unless clearly indicated. Care should be taken if β-blockers have to be discontinued abruptly in patients, particularly 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 8-14 days during which time the patient's progress should be assessed. Bisoprolol 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.

Cardiac failure.

There is inadequate evidence of efficacy and safety of bisoprolol treatment in heart failure in patients with NYHA class II heart failure.

Conduction disorders.

Very rarely, a pre-existing AV conduction disorder of moderate degree may become aggravated (possibly leading to AV block). Bisoprolol should be administered with caution to patients with first degree AV block (see Section 4.3 Contraindications).

Effects on the heart rate.

If the patient develops increasing bradycardia (heart rate less than 50 to 55 beats/minute), the dosage of bisoprolol should be gradually reduced or treatment gradually withdrawn (see Section 4.3 Contraindications).

Prinzmetal angina.

There is a risk of exacerbating coronary artery spasm if patients with Prinzmetal or variant angina are treated with a β-blocker. Cases of coronary vasospasm have been observed. If this treatment is essential, it should only be undertaken in a coronary or intensive care unit.

Peripheral circulation.

Beta-blockade may impair the peripheral circulation and exacerbate the symptoms of peripheral vascular disease. An intensification of complaints may occur, particularly at initiation of therapy (see Section 4.3 Contraindications).

Bronchial asthma and chronic obstructive lung disease.

Although cardioselective (β1) beta-blockers may have less effect on lung function than non-selective beta-blockers, as with all beta-blockers, these should be avoided in patients with obstructive airway diseases, unless there are compelling clinical reasons for their use. Where such reasons exist bisoprolol may be used with caution. In patients with bronchial asthma or other chronic obstructive airway diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of β2-stimulants may have to be increased. Bisoprolol is contraindicated in patients with severe bronchial asthma or severe chronic obstructive lung disease.

Diabetes.

Bisoprolol should be used with caution in patients with diabetes mellitus, especially those who are receiving insulin or oral hypoglycaemic agents. Diabetic patients should be warned that β-blockers affect glucose metabolism and may mask some important premonitory signs of acute hypoglycaemia, such as tachycardia.
In patients with insulin or noninsulin 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 beta-blockers but they are less likely with a β1-selective agent like bisoprolol. Nevertheless diabetic patients receiving bisoprolol should be monitored to ensure that diabetes control is maintained.

Other metabolic effects.

Beta-adrenoceptors are involved in the regulation of lipid as well as carbohydrate metabolism. Some beta-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 beta-blockers while it appears to be less for drugs with β1-adrenoceptor-selectivity and for those with intrinsic sympathomimetic activity.

Thyrotoxicosis.

Under treatment with bisoprolol the symptoms of thyrotoxicosis may be masked.

Phaeochromocytoma.

In patients with phaeochromocytoma bisoprolol must not be administered until after alpha-receptor blockade.

Allergic conditions.

As with other β-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect.

Psoriasis.

Patients with psoriasis, or with a history of psoriasis, should only be given β-blockers after carefully balancing the benefits against the risks.

Effects on the eye and skin.

Various rashes and conjunctival xeroses 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.

Fasting.

Bisoprolol should be used with caution in patients under strict fasting conditions.

Use in hepatic impairment.

Caution is advised in patients with CHF and impaired hepatic function since there is no information regarding pharmacokinetics in these patients. Renal function should be monitored in patients with severe liver disease. Renal impairment may develop in patients with liver disease during bisoprolol treatment, leading to a need for dose reduction.

Use in renal impairment.

No dosage adjustment is required in patients with impairment of the kidney due to excretion equally by both liver and kidney. Nevertheless, caution is advised since there is no information regarding pharmacokinetics in CHF patients.

Use in the elderly.

Based on age alone no dosage adjustments are required; however, caution is advised in patients greater than 80 years old since data in this age group is limited (see Section 5.2 Pharmacokinetic Properties).

Paediatric use.

The safety and efficacy in children have not been established.
There is no paediatric experience with bisoprolol; therefore, its use cannot be recommended in children.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

General.

The clearance of bisoprolol is 'balanced' between renal elimination of the unchanged drug and hepatic metabolism, renal clearance accounting for at least 50% of the dose. The remainder is subject to metabolism primarily by CYP3A4, with a minor contribution from CYP2D6. Bisoprolol plasma concentrations are expected to increase during concurrent administration of CYP3A4 inhibitors by not more than a factor of 2, and decrease during concurrent administration of CYP3A4 inducers. Due to the minor role of CYP2D6 in bisoprolol metabolism, CYP2D6 inhibitors and genetic differences in CYP2D6 activity do not significantly alter bisoprolol plasma concentrations. Bisoprolol may increase the plasma concentrations of other drugs metabolised by CYP3A4 and possibly those metabolised by CYP2D6.

Combinations not recommended.

Calcium antagonists of the verapamil type and to a lesser extent of the diltiazem type.

Negative influence on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients on β-blocker treatment may lead to profound hypotension and atrioventricular block.

Class I antiarrhythmic drugs (e.g. quinidine, disopyramide; lidocaine, phenytoin; flecainide, propafenone).

Effect on atrioventricular conduction time may be potentiated and negative inotropic effect increased.

Centrally acting antihypertensive drugs such as clonidine and others (e.g. methyldopa, moxonidine, rilmenidine).

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). Abrupt withdrawal, particularly if prior to β-blocker discontinuation, may increase risk of rebound hypertension.

Combinations to be used with caution.

Calcium antagonists of the dihydropyridine type such as felodipine and amlodipine.

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.

Class-III antiarrhythmic drugs (e.g. amiodarone).

Effect on atrioventricular conduction time may be potentiated.

Topical β-blockers (e.g. eye drops for glaucoma treatment).

May add to the systemic effects of bisoprolol.

Parasympathomimetic drugs.

Concomitant use may increase atrioventricular conduction time and the risk of bradycardia.

Insulin and oral antidiabetic drugs.

Intensification of blood sugar lowering effect. Blockade of β-adrenoreceptors may mask symptoms of hypoglycaemia.

General anaesthetics.

Beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the postoperative period. It is currently recommended that maintenance β-blockade be continued perioperatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other medicines, resulting in severe bradyarrhythmias, attenuation of the reflex tachycardia and hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and regional sympathetic blockade, and the increased propensity for vagal induced bradycardia (see Section 4.4 Special Warnings and Precautions for Use, General anaesthetics).

Digitalis glycosides.

Reduction of heart rate, increase of atrioventricular conduction time.

Nonsteroidal anti-inflammatory drugs (NSAIDs).

NSAIDs may reduce the hypotensive effect of bisoprolol.

β-Sympathomimetic agents (e.g. isoprenaline, dobutamine).

Combination with bisoprolol may reduce the effect of both agents.

Sympathomimetics that activate both β and α-adrenoceptors (e.g. noradrenaline, adrenaline).

Combination with bisoprolol may unmask the α-adrenoceptor-mediated vasoconstrictor effects of these agents leading to blood pressure increase and exacerbated intermittent claudication. Such interactions are considered to be more likely with nonselective β-blockers. Higher doses of adrenaline may be necessary for treatment of allergic reactions.
Concomitant use with antihypertensive agents as well as with other drugs with blood pressure lowering potential (e.g. tricyclic antidepressants, barbiturates, phenothiazines) may increase the risk of hypotension.

Combinations to be considered.

Mefloquine.

Increased risk of bradycardia.

Monoamine oxidase inhibitors (except MAO-B inhibitors).

Enhanced hypotensive effect of the β-blockers but also risk for hypertensive crisis.

Ergotamine derivatives.

Exacerbation of peripheral circulatory disturbances.

Rifampicin.

Slight reduction of the half-life of bisoprolol is possible due to the induction of hepatic drug metabolising enzymes. Normally no dosage adjustment is necessary.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No effect on fertility was observed in male or female rats treated with bisoprolol at oral doses up to 150 mg/kg/day (associated with bisoprolol plasma concentrations (AUC) about 50 times those expected in humans after daily doses of 10 mg bisoprolol).
(Category C)
Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the fetus/ newborn. In general, β-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. 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.
Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol 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.
Studies in rats have shown that bisoprolol and/or its metabolites cross the placenta and distribute to the fetus.
Administration of bisoprolol at oral doses of ≥ 50 mg/kg/day to pregnant rats or ≥ 12.5 mg/kg/day to pregnant rabbits caused embryofetal toxicity, resorptions and abortions. The no effect dose for embryofetal toxicity and mortality was 40 mg/kg/day (associated with plasma drug concentrations (AUC) 11 times that expected in humans after 10 mg/kg/day bisoprolol) for rats and 10 mg/kg/day for rabbits (associated with AUC lower than that expected in humans after 10 mg/kg/day doses). No evidence for teratogenic effects of bisoprolol was observed at any dose in rats or rabbits.
 Bisoprolol and/or its metabolites have been found in the milk of lactating rats.
Treatment of rats with bisoprolol at oral doses of 150 mg/kg/day from late gestation and during the lactation period was associated with decreased offspring birthweight and retarded physical development. The no effect dose (50 mg/kg) for these effects was associated with an AUC about 14 times greater than that expected in humans.
There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects on Ability to Drive and Use Machines

Bisoprolol may cause dizziness or fatigue (see Section 4.8 Adverse Effects (Undesirable Effects)) and, therefore, may adversely affect the patient's ability to drive or use machinery. In a study with coronary heart disease patients bisoprolol did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or operate machinery may be impaired. This should be considered particularly at the start of treatment and upon change of medication, as well as in conjunction with alcohol.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials data.

Table 1 shows incidences of adverse events reported from both the placebo and the bisoprolol cohort of the CIBIS II trial. Regardless of causal relationship all adverse events are included. Each patient is only counted once for each adverse event occurring in at least 1% of the study population.

Post-marketing data.

The following definitions apply to the frequency terminology used hereafter: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000).

Investigations.

Rare: increased triglycerides, increased liver enzymes (ALT, AST).

Cardiac disorders.

Very common: bradycardia. Common: worsening of heart failure. Uncommon: AV conduction disturbances.

Nervous system disorders.

Common: dizziness, headache.

Eye disorders.

Rare: reduced tear flow (to be considered if the patient uses lenses). Very rare: conjunctivitis.

Ear and labyrinth disorders.

Rare: hearing disorders.

Respiratory, thoracic and mediastinal disorders.

Uncommon: bronchospasm in patients with bronchial asthma or a history of obstructive airways disease. Rare: allergic rhinitis.

Gastrointestinal disorders.

Common: gastrointestinal complaints such as nausea, vomiting, diarrhoea, constipation.

Skin and subcutaneous tissue disorders.

Rare: hypersensitivity reactions (itching, flush, rash, and angioedema). Very rare: β-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders.

Uncommon: muscular weakness and cramps.

Vascular disorders.

Common: feeling of coldness or numbness in the extremities, hypotension. Uncommon: orthostatic hypotension. Rare: syncope.

General disorders.

Common: asthenia, fatigue.

Hepatobiliary disorders.

Rare: hepatitis.

Reproductive system and breast disorders.

Rare: potency disorders.

Psychiatric disorders.

Uncommon: sleep disorders, depression. Rare: nightmares, hallucinations.

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 and contact Arrotex Medical Information Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9 Overdose

The most common signs expected with overdosage of a β-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide interindividual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.
In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and symptomatic treatment is recommended.
Based on the expected pharmacologic actions and recommendations for other β-blockers, the following general measures should be considered when clinically warranted.

Bradycardia.

Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension.

Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree).

Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing.

Acute worsening of heart failure.

Administer intravenous diuretics, inotropic agents, vasodilating agents.

Bronchospasm.

Administer bronchodilator therapy such as isoprenaline, β2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia.

Administer intravenous glucose.
Limited data suggest that bisoprolol is hardly dialyzable.
For information on the management of overdose, contact the Poisons Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Bisoprolol is a β1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and relevant membrane stabilising activity. It only shows very low affinity to the β2-receptor of the smooth muscles of bronchi and vessels as well as to the β2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and β2-mediated metabolic effects. Its β1-selectivity extends beyond the therapeutic dose range. However, its beta1-selectivity is not absolute and at doses greater than the maximum recommended of 10 mg, bisoprolol may also inhibit beta2-adrenoreceptors.
The haemodynamic effects of bisoprolol are those that can be expected from β-adrenoceptor blockade. Besides the negative chronotropic effect resulting in a reduction in resting and exercise heart rate there is, as shown in acute studies with intravenous administration, a fall in resting and exercise cardiac output with only little change in stroke volume, and a small increase in right atrial pressure at rest or during exercise. The decrease in cardiac output correlates with the heart rate reduction, and the observed increases in total peripheral resistance and pulmonary arterial resistance after acute administration are considered to be due to reflex autonomic changes resulting from the negative chronotropic and slight negative inotropic effects.
Acute intravenous administration of 10 mg bisoprolol to hypertensive patients reduced glomerular filtration rate (GFR), renal blood flow (RBF) and plasma renin activity (PRA) whereas the renal vascular resistance was reduced after short-term treatment (10 mg bisoprolol po for 4 weeks) with no significant changes in RBF, GFR or PRA. Adrenaline (epinephrine) and noradrenaline (norepinephrine) levels also remained unaffected after the 4 week treatment in hypertensive patients.
Bisoprolol shows the same pattern of cardiac electrophysiologic effects as other β-adrenoceptor blocking agents. It acts on those parts of the conduction system that are influenced by the sympathetic nervous system. In electrophysiological studies it reduced heart rate, prolonged sinoatrial (SA) and atrioventricular (AV) nodal conduction, and prolonged the refractory periods of the SA and AV node. There was no statistically significant effect on atrial effective refractory period in patients with a history of syncope or cardiac arrhythmias. However, in patients with coronary artery disease, there was a small significant increase in right atrial effective and functional refractory periods. Right ventricular effective refractory period was temporarily prolonged during a study in patients with coronary artery disease, but the clinical relevance of the small increase is uncertain. RR and PR intervals were increased and QTc intervals reduced but all parameters remained within normal limits after bisoprolol.

Clinical trials.

In total 2,647 ambulatory patients with chronic heart failure were included in the CIBIS II trial in accordance with the following inclusion/ exclusion criteria.

Inclusion criteria.

CHF of at least three months duration (stable for at least 6 weeks).

Exclusion criteria.

Resting heart rate < 60 beats/min; supine systolic BP < 100 mmHg; myocardial infarction or unstable angina within the preceding 3 months; percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within the preceding 6 months; atrioventricular block of second degree or greater without a functioning pacemaker, haemodynamically significant organic valvular disease; obstructive or restrictive cardiomyopathy.
83% (n = 2202) of patients were in NYHA class III and 17% (n = 445) were in NYHA class IV. They had stable symptomatic systolic heart failure (ejection fraction ≤ 35%, based on echocardiography). Total mortality was reduced from 17.3% to 11.8% (absolute reduction 5.5%; relative reduction 34% [95% confidence interval 19-46%]).
A decrease in sudden death (3.6% vs. 6.3%, relative reduction 44%) and a reduced number of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%) was observed. Finally, a significant improvement of the functional status according to NYHA classification has been shown. During the initiation and titration of bisoprolol hospital admissions due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation (4.97%) were observed, but they were not more frequent than in the placebo group (0%, 0.3% and 6.74%).

5.2 Pharmacokinetic Properties

Absorption.

Bisoprolol is almost completely (> 90%) absorbed from the gastrointestinal tract and, because of its small first pass metabolism of about 10%-15%, has an absolute bioavailability of about 85-90% after oral administration. The bioavailability is not affected by food. The drug shows linear kinetics and the plasma concentrations are proportional to the administered dose over the dose range 5 to 20 mg. Peak plasma concentrations occur within 2-3 hours.
Following oral administration of bisoprolol fumarate 10 mg to healthy subjects under fasting conditions, a mean peak plasma concentration (Cmax) of bisoprolol of approximately 31.86 nanogram/mL was achieved within approximately 2 hours (Tmax).

Distribution.

Bisoprolol is extensively distributed. The volume of distribution is 3.5 L/kg. Binding to plasma proteins is approximately 35%; uptake into human blood cells was not observed.

Metabolism.

In humans, only oxidative metabolic pathways have been detected with no subsequent conjugation. All metabolites, being very polar, are renally eliminated. The major metabolites in human plasma and urine were found to be without pharmacological activity. In vitro data from studies in human liver microsomes show that bisoprolol is primarily metabolized via CYP3A4 (~ 95%) with CYP2D6 having only a minor role. The minor contribution of CYP2D6 to the metabolism of bisoprolol observed in vitro is consistent with the in vivo data in extensive and restricted debrisoquine metabolisers, which showed no difference between the two groups of metabolisers. Bisoprolol is a racemate consisting of the R and S enantiomers. The intrinsic clearance by human recombinant CYP3A4 appears to be nonstereoselective while the metabolism by CYP2D6 is stereoselective (R/S = 1.50).

Excretion.

The clearance of bisoprolol is 'balanced' between renal elimination of the unchanged drug (~ 50%) and hepatic metabolism (~ 50%) to metabolites which are also renally excreted. The total clearance of the drug is 15.6 ± 3.2 L/h with renal clearance being 9.6 ± 1.6 L/h. In a study with 14C-labelled bisoprolol the total urinary and fecal excretion was 90 ± 2.7% and 1.4 ± 0.1% of the dose, respectively (mean ± SEM recoveries of the total dose within 168 hours). Bisoprolol has an elimination half-life of 10-12 hours.

Renal impairment.

Since the clearance of bisoprolol is balanced between renal and hepatic mechanisms, the plasma accumulation factor of bisoprolol in patients with either complete renal or hepatic impairment should not exceed 2. In a study in patients with a mean creatinine clearance of 28 mL/min the plasma accumulation factor was less than 2, and it has been shown that as the creatinine clearance falls the AUC increases as does the t1/2 and Cmax. According to these studies in patients with renal impairment no dosage adjustment is normally required up to the maximum dose of 10 mg bisoprolol.

Hepatic impairment.

There were no clinically relevant differences in the pharmacokinetics of bisoprolol between patients with normal or impaired hepatic function. Thus, dose reduction is not required in patients with liver disease. Renal function should be monitored in patients with severe liver disease, since renal impairment may develop and require dose reduction.

Chronic cardiac failure.

In a small substudy of the CIBIS II study in patients with CHF (NYHA III) on 10 mg bisoprolol, the steady state AUC was greater, the t1/2 longer (17 ± 5 hours) and the clearance lower than in healthy volunteers, the values being similar to those observed in patients with renal impairment. Bisoprolol pharmacokinetics in patients with CHF and concomitant impaired liver and/or renal function have not been studied, however dose reduction may be required in such patients.

Elderly.

Some pharmacokinetic parameters (t1/2, AUC, Cmax) have been found to be greater in the elderly compared to those in the young which appears to be due to a reduction in renal clearance in the elderly. However, the pharmacokinetic differences between the young and the elderly are unlikely to be clinically significant, and based on age alone no dosage adjustments are required.

5.3 Preclinical Safety Data

Genotoxicity.

No evidence for genotoxic activity was observed with bisoprolol in in vitro assays of gene mutation (reverse mutation in Salmonella typhimurium, forward mutation in Chinese hamster V79 fibroblasts) or chromosomal damage (CHO cytogenetic assay). Negative findings were also obtained with bisoprolol in in vivo assays of chromosomal damage (Chinese hamster bone marrow cytogenetic assay and the mouse micronucleus test).

Carcinogenicity.

Bisoprolol showed no evidence of carcinogenic activity when administered orally (via the diet) to mice for 20-26 months at doses up to 250 mg/kg/day and to rats for 24 months at doses up to 125 mg/kg/day. These doses were associated with plasma drug concentrations (AUC) 38 times (mice) or 15-18 times (rats) greater than those expected in humans after 10 mg/day of bisoprolol.

6 Pharmaceutical Particulars

6.1 List of Excipients

Microcrystalline cellulose, colloidal anhydrous silica, croscarmellose sodium, sodium starch glycollate type A, 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

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

APO-Bisoprolol tablets.

1.25 mg tablets.

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182108).

2.5 mg tablets.

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182106).

3.75 mg tablets.

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182117).

5 mg tablets.

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182114).

10 mg tablets.

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182123).
APO and APOTEX are registered trade marks of Apotex Inc.
Not all strengths and/or pack sizes may be available.

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

Bisoprolol fumarate is a white crystalline substance with a melting range of 100-104°C. It is very soluble in water and methanol, freely soluble in ethanol, glacial acetic acid and chloroform. As the substance is present in the form of a racemate, the aqueous solution does not show optical activity.

Chemical structure.


Chemical Name: (±)-1-[[α-(2-isopropoxyethoxy)-p-tolyl] oxy]-3-isopropylamino- 2-propanol hemifumarate.
Molecular Formula: C18H31NO4.½C4H4O4.
Molecular Weight: 383.49.

CAS number.

104344-23-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes