Consumer medicine information

AURO-BISOPROLOL

Bisoprolol fumarate

BRAND INFORMATION

Brand name

Auro-Bisoprolol Tablets

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using AURO-BISOPROLOL.

What is in this leaflet

This leaflet answers some common questions about AURO-BISOPROLOL.

It does not contain all of the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have benefits and risks. Your doctor has weighed the risks of you taking AURO-BISOPROLOL against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, talk to your doctor or pharmacist.

Keep this leaflet with your medicine.

You may need to read it again.

What AURO-BISOPROLOL used for

AURO-BISOPROLOL 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.

AURO-BISOPROLOL 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 has to do. AURO-BISOPROLOL also slows your heart rate, which in turn increases the efficiency of your heart.

AURO-BISOPROLOL can help to reduce the number of heart failure episodes needing hospital admission and also the risk of sudden death.

Your doctor may have prescribed AURO-BISOPROLOL for another reason. Ask your doctor if you have any questions about why AURO-BISOPROLOL has been prescribed for you.

AURO-BISOPROLOL is not recommended for use in children, as the safety and efficacy in children have not been established.

AURO-BISOPROLOL is available only with a doctor's prescription.

There is no evidence that AURO-BISOPROLOL is addictive.

Before you take AURO-BISOPROLOL

When you must not take AURO-BISOPROLOL

Do not take AURO-BISOPROLOL if you are allergic to medicines containing bisoprolol 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 AURO-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 AURO-BISOPROLOL 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.

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.

Before you start to take AURO-BISOPROLOL

Tell your doctor if you are allergic to any other medicines, foods, dyes or preservatives.

Tell your doctor if you are pregnant or plan to become pregnant.

AURO-BISOPROLOL may affect your developing baby if you take it during pregnancy. Your doctor will discuss the risks and benefits of taking AURO-BISOPROLOL during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed.

Like most beta-blocker medicines, AURO-BISOPROLOL is not recommended while you are breastfeeding. Your doctor will discuss the risks and benefits of taking AURO-BISOPROLOL when breastfeeding.

Tell your doctor if you have or have had any of the following medical conditions:

  • 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.

Your doctor may want to take special care if you have any of these conditions.

Tell your doctor if you are going to have anaesthesia (for example for surgery).

AURO-BISOPROLOL 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 AURO-BISOPROLOL.

Taking other medicines

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

Some medicines and AURO-BISOPROLOL may interfere with each other.

Do not take the following medicines with AURO-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 AURO-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 AURO-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 AURO-BISOPROLOL.

How to take AURO-BISOPROLOL

How much to take

The usual starting dose is 1.25 mg once daily for a week. If well tolerated, your doctor will gradually increase your dose over the next ten weeks. The usual dose for maintenance therapy is 10 mg once daily.

If your conditions gets worse or you no longer tolerate the drug, it may be necessary to reduce the dose again or to interrupt treatment. In some patients a maintenance dose lower than 10 mg may be sufficient. Your doctor will tell you what to do.

Your doctor will monitor your blood pressure, heart rate and other vital signs carefully after you start treatment with AURO-BISOPROLOL and during dose increase.

Follow all directions given to you by your doctor and pharmacist carefully.

How to take AURO-BISOPROLOL

Swallow the tablets with a glass of water.

Do not crush or chew the tablets.

If you crush or chew AURO-BISOPROLOL, they will not work as well.

When to take AURO-BISOPROLOL

Take AURO-BISOPROLOL in the morning, with or without food.

If you forget to take AURO-BISOPROLOL

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 the missed dose as soon as you remember, and then go back to taking your tablets as you would normally.

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.

How long to take AURO-BISOPROLOL for

To properly control your condition, AURO-BISOPROLOL must be taken every day, usually as a long term treatment.

Keep taking AURO-BISOPROLOL for as long as your doctor recommends.

It is very important that you do not stop taking AURO-BISOPROLOL suddenly.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think you or anyone else may have taken too much AURO-BISOPROLOL. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

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.

While you are taking AURO-BISOPROLOL

Things you must do

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

Tell all the doctors, dentists, and pharmacists who are treating you that you are taking AURO-BISOPROLOL.

If you become pregnant while taking AURO-BISOPROLOL, tell your doctor.

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

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

AURO-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. AURO-BISOPROLOL may make hypoglycaemia last longer. Your dose of diabetic medicines, including insulin, may need to change.

If you are to have any medical tests, tell your doctor that you are taking AURO-BISOPROLOL.

AURO-BISOPROLOL 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.

Things you must not do

Do not stop taking AURO-BISOPROLOL, or lower the dose, without checking with the doctor.

Stopping AURO-BISOPROLOL 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 use AURO-BISOPROLOL to treat any other conditions unless your doctor tells you to.

Do not give AURO-BISOPROLOL to anyone else, even if they have the same condition as you.

Things to be careful of

Be careful driving or operating machinery until you know how AURO-BISOPROLOL affects you.

AURO-BISOPROLOL may cause tiredness, dizziness or lightheadedness 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.

Be careful getting up from a sitting or lying position.

Dizziness, lightheadedness 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.

Side Effects

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

AURO-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 treatment 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.

Tell your doctor if you notice any of the following and they worry you:

  • 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

Tell your doctor as soon as possible if you notice any of the following:

  • muscular weakness or cramps
  • dizziness ot lightheadedness (sometimes with fainting), especially on standing up, which may be due to low blood pressure
  • a very slow heart beat
  • hallucinations
  • depression
  • irritation or redness of the eye
  • skin reactions such as rash, flush, itching, worsening of psoriasis
  • difficulty hearing.

The above list includes serious side effects that may require medical attention.

Tell your doctor immediately or go to Accident and Emergency at the nearest hospital if you notice any of the following:

  • swelling of the face, lips, tongue 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 heart beating.

The above list includes very serious side effects. You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed above may also occur in some patients.

After taking AURO-BISOPROLOL

Storage

Keep AURO-BISOPROLOL where children cannot reach it.

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

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

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

Keep your tablets in a cool dry place.

AURO-BISOPROLOL should be stored below 25 degrees C.

Do not store AURO-BISOPROLOL or any other medicine in the bathroom or near a sink.

Do not leave AURO-BISOPROLOL in the car or on window sills.

Heat and dampness can destroy some medicines.

Disposal

If your doctor tells you to stop taking AURO-BISOPROLOL, or your tablets have passed their expiry date, ask your pharmacist what to do with any that are left over.

Product Description

What AURO-BISOPROLOL looks like

AURO-BISOPROLOL 1.25, 2.5, 3.75, 5, 7.5 & 10 (1.25, 2.5, 3.75, 5, 7.5 & 10 mg bisoprolol fumarate) are presented in pack size of 28, 30 & 100 tablets in blister.

  • AURO-BISOPROLOL 1.25 (AUST R 175928)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ on one side and ‘1’ on the other side.
  • AURO-BISOPROLOL 2.5 (AUST R 175929)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘2’ on the other side.
  • AURO-BISOPROLOL 3.75 (AUST R 175918)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘3’ on the other side.
  • AURO-BISOPROLOL 5 (AUST R 175925)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘5’ on the other side.
  • AURO-BISOPROLOL 7.5 (AUST R 175920)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘7’ on the other side.
  • AURO-BISOPROLOL 10 (AUST R 175915)
    White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘10’ on the other side.

Ingredients

Active Ingredient:
Bisoprolol fumarate

Each tablet may contain either 1.25 mg, 2.5 mg, 3.75 mg, 5 mg, 7.5 mg & 10 mg of bisoprolol fumarate.

Other Ingredients:

  • microcrystalline cellulose
  • calcium hydrogen phosphate
  • colloidal anhydrous silica
  • crospovidone
  • magnesium stearate
  • Opadry white 03B28796 (PI-ARTG No. 11377).

Please read this leaflet carefully before you start taking AURO-BISOPROLOL. You may wish to keep it to read again.

Name and Address of the Sponsor

Aurobindo Pharma Australia Pty Ltd
Unit 3, North Rydelink
277-283 Lane Cove Road
Macquarie Park
NSW 2113
Australia

Date of Approval
23 September 2011

BRAND INFORMATION

Brand name

Auro-Bisoprolol Tablets

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

Name of the medicine

Bisoprolol fumarate.

Excipients.

Microcrystalline cellulose, calcium hydrogen phosphate, colloidal anhydrous silica, crospovidone, magnesium stearate and opadry white 03B28796 (PI-ARTG No. 11377).

Description

Chemical name: (RS)-1-[4-[[2-(1-methylethoxy)ethoxy] methyl]phenoxy]-3-[(1-methylethyl) amino]propan-2-ol fumarate. Molecular Formula: C40H66N2O12. Molecular Weight: 767. CAS Registry Number: [104344-23-2].
Bisoprolol fumarate is a white or almost white powder. It is very soluble in water, freely soluble in methanol.
Auro-Bisoprolol is available as tablets containing 1.25, 2.5, 3.75, 5, 7.5 and 10 mg of bisoprolol fumarate.
Auro-Bisoprolol tablets contain the following inactive ingredients: Microcrystalline cellulose, calcium hydrogen phosphate, colloidal anhydrous silica, crospovidone, magnesium stearate and opadry white 03B28796 (PI-ARTG No. 11377).

Pharmacology

Pharmacodynamics.

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 β1-selectivity is not absolute and at doses greater than the maximum recommended of 10 mg, bisoprolol may also inhibit β2-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 iv 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 iv 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. Epinephrine and 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 SA and 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.

Pharmacokinetics.

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.

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 non-stereoselective while the metabolism by CYP2D6 is stereoselective (R/S =1.50).

Elimination.

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.

Clinical Trials

In total 2647 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; PTCA or 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%).

Indications

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

Contraindications

Bisoprolol is contra-indicated in patients with:
acute heart failure, episodes of heart failure decompensation requiring i.v. inotropic therapy, cardiogenic shock;
second or third degree AV block (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 Precautions);
metabolic acidosis; and,
hypersensitivity to bisoprolol or to any of the excipients.

Precautions

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).

Use in pregnancy.

(Category C)
Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/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 foetus 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 foetus 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 foetus.
Administration of bisoprolol at oral doses of ≥50 mg/kg/day to pregnant rats or ≥12.5 mg/kg/day to pregnant rabbits caused embryofoetal toxicity, resorptions and abortions. The no-effect dose for embryofoetal 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.
Australian categorisation definition of Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.

Use in lactation.

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 ca 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.

Paediatric use.

The safety and efficacy in children have not been established.

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 Pharmacology, Pharmacokinetics).

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.
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: insulin dependent diabetes mellitus (type 1); severely impaired renal function; severely impaired liver function; restrictive cardiomyopathy; congenital heart disease; haemodynamically significant organic valvular disease; 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 Interactions with Other Medicines).

General anaesthesia.

β-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance β-blockade be continued peri-operatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other drugs, 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. Modern 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 peri-operative 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 A-V conduction disorder of moderate degree may become aggravated (possibly leading to A-V block). Bisoprolol should be administered with caution to patients with first degree A-V block (see 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 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. If this treatment is essential, it should only be undertaken in a Coronary or Intensive Care Unit.

Peripheral circulation.

β-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 Contraindications).

Bronchial asthma and chronic obstructive lung disease.

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 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 non-selective β-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.

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 non-selective β-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.

Renal disease.

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.

Liver disease.

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.

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.

Effects on ability to drive or use machinery.

Bisoprolol may cause dizziness or fatigue (see Adverse 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.

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 atrio-ventricular 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 atrio-ventricular 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 atrio-ventricular conduction time may be potentiated.

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

Topical β-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

Parasympathomimetic drugs.

Concomitant use may increase atrio-ventricular 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.

β-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance β-blockade be continued peri-operatively. The anaesthetist must be made aware of β-blockade because of the potential for interactions with other drugs, 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 Precautions, General anaesthesia).

Digitalis glycosides.

Reduction of heart rate, increase of atrio-ventricular conduction time.

Non-steroidal 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.

Adverse Effects

Clinical trial 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). 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.

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.

Dosage and Administration

Treatment of CHF consists of an ACE inhibitor (or an 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.

Renal or hepatic impairment.

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

Elderly.

No dosage adjustment is required.

Children.

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

Overdosage

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 i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm.

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

Hypoglycaemia.

Administer i.v. glucose.
Limited data suggest that bisoprolol is hardly dialyzable.
For information on the management of overdose, contact the Poisons Information Centre on 131 126 (Australia).

Presentation

Auro-Bisoprolol 1.25, 2.5, 3.75, 5, 7.5 and 10 (1.25, 2.5, 3.75, 5, 7.5 and 10 mg bisoprolol fumarate) are presented in pack size of 28, 30 and 100 tablets in PA/Alu/PVC-Paper/Polyester/Aluminium blister pack.

Auro-Bisoprolol 1.25 (AUST R 175928).

White, circular, biconvex, film-coated tablets debossed with ‘P’ on one side and ‘1’ on the other side.

Auro-Bisoprolol 2.5 (AUST R 175929).

White, circular, biconvex, film-coated tablets debossed with ‘P and break line’ on one side and ‘2’ on the other side.

Auro-Bisoprolol 3.75 (AUST R 175918).

White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘3’ on the other side.

Auro-Bisoprolol 5 (AUST R 175925).

White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘5’ on the other side.

Auro-Bisoprolol 7.5 (AUST R 175920).

White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘7’ on the other side.

Auro-Bisoprolol 10 (AUST R 175915).

White, circular, biconvex, film-coated tablets debossed with ‘P’ and break line’ on one side and ‘10’ on the other side.

Storage

Store below 25°C.

Poison Schedule

S4.