Consumer medicine information

Bispro

Bisoprolol fumarate

BRAND INFORMATION

Brand name

Bispro

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Bispro.

What is in this leaflet

This leaflet answers some common questions about Bispro.

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 Bispro against the benefits they expect it will have for you.

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

Keep this leaflet with your medicine. You may need to read it again.

What Bispro is used for

Bispro 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.

Bispro 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. Bispro also slows your heart rate, which in turn increases the efficiency of your heart.

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

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

Your doctor may have prescribed Bispro for another reason.

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

Bispro is available only with a doctor's prescription.

There is no evidence that Bispro is addictive.

Before you take Bispro

When you must not take it

Do not take Bispro if you have an allergy to any medicine containing bisoprolol or any of the ingredients listed at the end of this leaflet.

Some of the symptoms of an allergic reaction may include:

  • shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin.

Do not take Bispro 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 Bispro 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 Bispro 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.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

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

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

  • asthma, difficulty breathing or other lung problems
  • 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.

Tell your doctor if you are pregnant or plan to become pregnant. Bispro may affect your developing baby if you take it during pregnancy. Your doctor will discuss the risks and benefits of taking Bispro during pregnancy.

Tell your doctor if you are breastfeeding or wish to breastfeed. Like most beta-blocker medicines, Bispro is not recommended while you are breastfeeding. Your doctor will discuss the risks and benefits of taking Bispro when breastfeeding.

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

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you get without a prescription from a pharmacy, supermarket or health food shop. Some medicines and Bispro may interfere with each other.

Do not take the following medicines with Bispro without special advice from your doctor:

  • certain anti-arrhythmic medicines such as disopyramide, lidocaine (lignocaine), phenytoin or flecainide (used to treat irregular or abnormal heartbeat)
  • certain calcium antagonists such as diltiazem or verapamil (medicines 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 Bispro.

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 (epinephrine), 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 Bispro 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 Bispro.

How to take Bispro

Follow all directions given to you by your doctor or pharmacist carefully. They may differ from the information contained in this leaflet.

If you do not understand the instructions on the pack, ask your doctor or pharmacist for help.

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 Bispro and during dose increase.

How to take it

Swallow the tablets whole with a full glass of water.

Do not chew the tablets.

When to take it

Take Bispro in the morning, with or without food.

If you forget to take it

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. This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

How long to take it for

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

Continue taking Bispro for as long as your doctor tells you. It is very important that you do not stop taking Bispro 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 Bispro. 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 Bispro

Things you must do

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

Tell any other doctors, dentists and pharmacists who treat you that you are taking Bispro.

If you become pregnant while taking Bispro, tell your doctor.

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

If you are being treated for diabetes, make sure you check your blood sugar level regularly and report any changes to your doctor. Bispro 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 heart beat. Bispro may make hypoglycaemia last longer. Your dose of diabetic medicines, including insulin, may need to change.

If you are about to have any medical tests, tell your doctor that you are taking Bispro. It may interfere with the results of some tests.

Keep all of your doctor's appointments so that your progress can be checked. Your doctor may check your eyes, thyroid, lipid and blood glucose levels from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Bispro to treat any other complaints unless your doctor tells you to.

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

Do not stop taking Bispro or lower the dosage without checking with your doctor. If you stop taking it suddenly, your condition may worsen or other heart complications may occur.

If you have to stop treatment, your doctor will usually advise you to reduce the dose gradually.

Things to be careful of

Be careful driving or operating machinery until you know how Bispro affects you. Bispro may cause tiredness, dizziness or lightheadedness in some people, especially after the first dose. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

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.

Things that would be helpful for your heart failure:

  • 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 Bispro. This medicine helps most people with heart failure, but it may have unwanted side effects in a few 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 the following list of side effects. You may not experience any of them.

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

Tell your doctor or pharmacist 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 or 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
  • fainting.

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 or pharmacist if you notice anything that is making you feel unwell.

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

After taking Bispro

Storage

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.

Bispro 2.5 mg should be stored below 25°C.

Bispro 5 mg and 10 mg should be stored below 30°C.

Do not store Bispro or any other medicine in the bathroom or near a sink. Do not leave it in the car or on a window sill. Heat and dampness can destroy some medicines.

Keep it 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.

Disposal

If your doctor tells you to stop taking Bispro, or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

Product description

What it looks like

Bispro comes in 3 strengths of tablets:

  • Bispro 2.5 mg - white, heart-shaped, film-coated tablet with a dividing score on both sides.
  • Bispro 5 mg - yellowish white, heart-shaped, film-coated tablet with a dividing score on both sides.
  • Bispro 10 mg - pale orange - light orange, heart-shaped, film-coated tablet with a dividing score on both sides.

Bispro 2.5 mg, 5 mg and 10 mg come in packs of 28 tablets.

Ingredients

The active ingredient in Bispro is bisoprolol fumarate.

Each Bispro 2.5 mg tablet contains 2.5 mg of bisoprolol fumarate.

The tablets also contain:

  • colloidal anhydrous silica
  • magnesium stearate
  • crospovidone
  • starch - maize
  • microcrystalline cellulose
  • calcium hydrogen phosphate anhydrous
  • dimeticone 100
  • macrogol 400
  • titanium dioxide
  • hypromellose.

Each Bispro 5 mg and 10 mg tablet contains 5 mg and 10 mg of bisoprolol fumarate respectively.

These tablets also contain:

  • colloidal anhydrous silica
  • magnesium stearate
  • crospovidone
  • starch - maize
  • microcrystalline cellulose
  • calcium hydrogen phosphate anhydrous
  • dimeticone 100
  • macrogol 400
  • titanium dioxide
  • hypromellose
  • iron oxide yellow (CI 77492).

Bispro 10 mg tablets also contain:

  • iron oxide red (CI 77491).

This medicine does not contain gluten.

Supplier

Bispro is supplied by:

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

Australian registration numbers:

Bispro 2.5 mg - Aust R 130178

Bispro 5 mg - Aust R 130180

Bispro 10 mg - Aust R 130182

This leaflet was prepared on 7 April 2020.

Bispro_cmi\Apr20/00

Published by MIMS May 2020

BRAND INFORMATION

Brand name

Bispro

Active ingredient

Bisoprolol fumarate

Schedule

S4

 

1 Name of Medicine

Active ingredient: Bisoprolol fumarate.

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. With the underlying manufacturing conditions no polymorphic forms were observed.

Chemical structure.

Chemical name: (RS)-1-[4-[[2-(1- methylethoxy)ethoxy] methyl]phenoxy]- 3-[(1-methylethyl)amino] propan-2-ol fumarate.
Structural formula:
Molecular formula: C40H66N2O12.
Molecular weight: 767.

CAS number.

CAS: 104344-23-2.

2 Qualitative and Quantitative Composition

Each Bispro 1.25 mg (Starter pack) tablet contains 1.25 mg of bisoprolol fumarate.
Each Bispro 2.5 mg tablet contains 2.5 mg of bisoprolol fumarate.
Each Bispro 3.75 mg, 5 mg, 7.5 mg and 10 mg tablet contains the specified quantity of bisoprolol fumarate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Dosage form.

Film coated tablets.

Visual description.

Bispro 1.25 mg (Starter pack): White, round film-coated tablets.
Bispro 2.5 mg: White, heart-shaped, scored and film-coated tablets.
Bispro 3.75 mg: Off-white, heart-shaped, scored and film-coated tablets.
Bispro 5 mg: Yellowish white, hear-shaped, scored and film-coated tablets.
Bispro 7.5 mg: Pale yellow, heart-shaped, scored and film-coated tablets.
Bispro 10 mg: Pale orange-light orange, heart-shaped, scored and film-coated tablets.
*Marketed in Australia.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanims 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 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 i.v. 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 i.v. 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 S-A and A-V nodal conduction, and prolonged the refractory periods of the S-A and A-V 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 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%).

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.

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.

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.

4.3 Contraindications

Bisoprolol is contraindicated 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 Section 4.4 Special Warnings and Precautions for Use);
metabolic acidosis, and;
hypersensitivity to bisoprolol or to any of the excipients.

4.4 Special Warnings and Precautions for Use

Identified precautions.

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);
severely impaired renal function;
severely impaired liver function;
patients older than 80 years;
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 Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

General anaesthesia.

β-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 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 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 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 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.

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 Section 4.3 Contraindications).

Bronchial asthma and chronic obstructive lung disease.

Although cardioselective (beta1) 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 airways 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 non-insulin dependent diabetes, especially labile diabetes, or with a history of spontaneous hypoglycaemia, β-blockade may result in the loss of diabetic control and delayed recovery from hypoglycaemia. The dose of insulin or oral hypoglycaemic agent may need adjustment. Such effects on the glucose metabolism may occur with nonselective β-blockers but they are less likely with a β1-selective agent like 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 nonselective 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.

Allergic conditions.

As with other β-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline (epinephrine) 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.

Strict fasting.

Bisoprolol must be used with caution in patient undergoing strict fasting.

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 for 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.

β-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 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 Section 4.4 Special Warnings and Precautions for Use, General anaesthesia).

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 (epinephrine)).

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 (epinephrine) 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 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 foetal 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.
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.

4.8 Adverse Effects (Undesirable 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.

Postmarketing 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 pre-existing heart failure. Uncommon: A-V 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 (pruritus, flush, rash and angioedema). Very rare: alopecia, β-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.

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. Frequency not known: syncope.

General disorders.

Common: asthenia, fatigue.

Hepatobiliary disorders.

Rare: hepatitis.

Reproductive system and breast disorders.

Rare: erectile dysfunction.

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 http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

Dosage (dose and interval).

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.

Method of 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.

Use in 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.

Use in renal 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.

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.

4.9 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.

A-V 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 Poison Information Centre on 131126 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Each Bispro 1.25 mg (Starter pack) tablet contains 1.25 mg of bisoprolol fumarate. The tablets also contain the following inactive ingredients: silica - colloidal anhydrous, magnesium stearate, crospovidone, starch - pregelatinised maize, starch - maize, cellulose - microcrystalline, calcium hydrogen phosphate, dimeticone 100, purified talc, macrogol 400, titanium dioxide and hypromellose.
Each Bispro 2.5 mg tablet contains 2.5 mg of bisoprolol fumarate. The tablets also contain the following inactive ingredients: silica - colloidal anhydrous, magnesium stearate, crospovidone, starch - maize, cellulose - microcrystalline, calcium hydrogen phosphate, dimeticone 100, macrogol 400, titanium dioxide and hypromellose.
Each Bispro 3.75 mg, 5 mg, 7.5 mg and 10 mg tablet contains the specified quantity of bisoprolol fumarate. The tablets also contain the following inactive ingredients: silica - colloidal anhydrous, magnesium stearate, crospovidone, starch - maize, cellulose - microcrystalline, calcium hydrogen phosphate, dimeticone 100, macrogol 400, titanium dioxide, iron oxide yellow (CI 77492) and hypromellose. Bispro 10 mg tablets also contain iron oxide red (CI 77491).

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

Bispro 1.25 mg (starter pack).

Store below 25°C.

Bispro 2.5 mg.

Store below 25°C.

Bispro 3.75 mg.

Store below 25°C.

Bispro 5 mg.

Store below 30°C.

Bispro 7.5 mg.

Store below 30°C.

Bispro 10 mg.

Store below 30°C.
*Marketed in Australia.

6.5 Nature and Contents of Container

Bispro 1.25 mg (Starter pack).

Available in blister packs of 7, 10*, 28, 30, 42, 56 and 100 tablets.

Bispro 2.5 mg.

Available in blister packs of 7, 10, 28*, 30, 42, 56 and 100 tablets.

Bispro 3.75 mg.

Available in blister packs of 7, 10, 28, 30, 42, 56 and 100 tablets.

Bispro 5 mg.

Available in blister packs of 7, 10, 28*, 30, 42, 56 and 100 tablets.

Bispro 7.5 mg.

Available in blister packs of 10, 28, 30, 42, 56 and 100 tablets.

Bispro 10 mg.

Available in blister packs of 10, 28*, 30, 42, 56 and 100 tablets.
*Marketed in Australia.

6.6 Special Precautions for Disposal

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

Summary Table of Changes