CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack

Main information

  • Trade name:
  • CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack
    Australia
  • Language:
  • English

Status

  • Source:
  • Dept. of Health,Therapeutic Goods Administration - Australia
  • Authorization status:
  • Registered
  • Authorization number:
  • 182121
  • Last update:
  • 22-05-2019

Public Assessment Report

Public Summary

Summary for ARTG Entry:

182121

CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack

ARTG entry for

Medicine Registered

Sponsor

Apotex Pty Ltd

Postal Address

PO Box 280,NORTH RYDE BC, NSW, 1670

Australia

ARTG Start Date

13/12/2011

Product category

Medicine

Status

Active

Approval area

Drug Safety Evaluation Branch

Conditions

Conditions applicable to all therapeutic goods as specified in the document "Standard Conditions Applying to Registered or Listed Therapeutic Goods

Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Conditions applicable to the relevant category and class of therapeutic goods as specified in the document "Standard Conditions Applying to Registered

or Listed Therapeutic Goods Under Section 28 of the Therapeutic Goods Act 1989" effective 1 July 1995.

Products

1. CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack

Product Type

Single Medicine Product

Effective date

1/07/2014

Warnings

See Product Information and Consumer Medicine Information for this product

Standard Indications

Specific Indications

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

Additional Product information

Container information

Type

Material

Life Time

Temperature

Closure

Conditions

Blister Pack

PVC/PVDC/Al

36 Months

Store below 25

degrees Celsius

Not recorded

Store in Original

Container

Protect from Light

Pack Size/Poison information

Pack Size

Poison Schedule

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

(S4) Prescription Only Medicine

Components

1. CHEMMART BISOPROLOL bisoprolol fumarate 1.25mg tablet blister pack

Dosage Form

Tablet

Route of Administration

Oral

Visual Identification

A white to off white, round, biconvex tablet, debossed '1.25' and plain on

the other side

Active Ingredients

Bisoprolol fumarate

1.25 mg

© Commonwealth of Australia.This work is copyright.You are not permitted to re-transmit, distribute or commercialise the material without obtaining prior

written approval from the Commonwealth.Further details can be found at http://www.tga.gov.au/about/website-copyright.htm.

Public Summary

Page 1 of

Produced at 29.11.2017 at 07:13:18 AEDT

This is not an ARTG Certificate document.

The onus is on the reader to verify the current accuracy of the information on the document subsequent to the date shown.

Visit www.tga.gov.au for contact information

Summary of Product characteristics: dosage, interactions, side effects

AUSTRALIAN PRODUCT INFORMATION

CHEMMART

BISOPROLOL (BISOPROLOL FUMARATE) TABLETS

1

NAME OF THE MEDICINE

Bisoprolol fumarate

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1.25 mg, 2.5 mg, 3.75 mg, 5 mg or 10 mg of Bisoprolol fumarate.

For the full list of excipients see section 6.1 List of Excipients

3

PHARMACEUTICAL FORM

1.25 mg tablets:

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

2.5 mg tablets:

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

3.75 mg tablets:

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

5 mg tablets:

A white to off white, round, biconvex tablet, debossed ‘5’ on the left of a break line and plain

on the other side.

10 mg tablets:

A white to off white, round, biconvex tablet, debossed ‘10’ on the left of a break line and plain

on the other side.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Treatment of stable chronic moderate to severe heart failure in addition to ACE inhibitors, and

diuretics, and optionally cardiac glycosides.

4.2

DOSE AND METHOD OF ADMINISTRATION

Chemmart Bisoprolol tablets are intended for oral administration.

Dosage

Treatment of chronic heart failure consists of an ACE inhibitor (or angiotensin receptor blocker

in case of intolerance to ACE inhibitors), a β-blocker, diuretics, and when appropriate cardiac

glycosides.

Patients should be stable (without acute failure) when bisoprolol treatment is initiated.

It is recommended that the treating physician should be experienced in the management of

chronic heart failure.

Titration Phase:

The treatment of stable chronic heart failure with bisoprolol requires a titration phase. The

treatment with bisoprolol is to be started with a gradual uptitration according to the following

steps:

1.25 mg once daily for 1 week, if well tolerated increase to

2.5 mg once daily for a further week, if well tolerated increase to

3.75 mg once daily for a further week, if well tolerated increase to

5 mg once daily for the 4 following weeks, if well tolerated increase to

7.5 mg once daily for the 4 following weeks, if well tolerated increase to

10 mg once daily for the maintenance therapy.

The maximum recommended dose is 10 mg once daily.

Close monitoring of vital signs (heart rate, blood pressure), conduction disturbances and

symptoms of worsening heart failure is recommended during the titration phase. Symptoms

may already occur within the first day after initiating the therapy. Transient worsening of heart

failure, hypotension, or bradycardia may occur during titration period and thereafter.

Treatment modification:

If the maximum recommended dose is not well tolerated, gradual dose reduction may be

considered. In case of transient worsening of heart failure, hypotension, or bradycardia,

reconsideration of the dosage of the concomitant medication is recommended. It may also be

necessary to temporarily lower the dose of bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the

patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt

withdrawal may lead to acute deterioration of the patients condition.

Treatment of stable chronic heart failure with bisoprolol is generally a long term treatment.

Administration:

Bisoprolol tablets should be taken in the morning and can be taken with food. They should be

swallowed with liquid and should not be chewed.

Special population:

Use in patients with hepatic or renal impairment:

There is no information regarding the pharmacokinetics of bisoprolol in patients with chronic

heart failure and with impaired liver or renal function. Uptitration of the dose in these

populations should therefore be made with additional caution.

Use in the Elderly

No dosage adjustment is required.

Infants and Children

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

for children.

4.3

CONTRAINDICATIONS

Bisoprolol is contra-indicated in patients with:

acute heart failure, episodes of heart failure decompensation requiring intravenous

inotropic therapy, cardiogenic shock;

AV block of second or third degree (without a pacemaker);

sick sinus syndrome or sinoatrial block;

bradycardia with less than 60 beats/min before the start of therapy;

hypotension (systolic blood pressure less than 100 mm Hg);

severe bronchial asthma or severe chronic obstructive pulmonary disease;

late stages of peripheral arterial occlusive disease;

Raynaud's syndrome;

untreated phaeochromocytoma (see section 4.4 Special warnings and precautions

for use);

metabolic acidosis;

hypersensitivity to bisoprolol or to any of the excipients.

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Use with caution in the following circumstances

The initiation of treatment with bisoprolol necessitates regular monitoring.

There is no therapeutic experience of bisoprolol treatment of heart failure in patients with the

following diseases and conditions: insulin dependent diabetes mellitus (type 1), impaired renal

function (serum creatinine ≥ 300 μmol/l), impaired liver function, patients older than 80 years,

restrictive cardiomyopathy, congenital heart disease, haemodynamically significant organic

valvular disease and myocardial infarction within 3 months.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type, with

Class I antiarrhythmic drugs and with centrally acting antihypertensive drugs is generally not

recommended (see section 4.5 Interactions with other medicines and other forms of

interactions)

General anaesthetics: Beta-blockade reduces the incidence of arrhythmias and myocardial

ischaemia during induction and intubation, and the 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

medicines, resulting in severe bradyarrhythmias, attenuation of the reflex tachycardia and

hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and

regional sympathetic blockade, and the increased propensity for vagal-induced bradycardia.

Incidents of protracted severe hypotension or difficulty restoring normal cardiac rhythm during

anaesthesia have been reported. Modem inhalational anaesthetic agents are generally well

tolerated, although older agents (ether, cyclopropane, methoxyflurane, trichlorethylene) were

sometimes associated with severe circulatory depression in the presence of β-blockade. If it is

thought necessary to withdraw β-blocker therapy before surgery, this should be done gradually

and completed about 48 hours before anaesthesia.

Abrupt withdrawal: The cessation of therapy with bisoprolol should not be done abruptly unless

clearly indicated. Care should be taken if β-blockers have to be discontinued abruptly in

patients, particularly in patients with coronary artery disease. Severe exacerbation of angina

and precipitation of myocardial infarction and ventricular arrhythmias have occurred following

abrupt discontinuation of β-blockade in patients with ischaemic heart disease. Therefore, it is

recommended that the dosage be reduced gradually over a period of about 8-14 days during

which time the patient's progress should be assessed. Bisoprolol should be temporarily

reinstituted if the angina worsens markedly or if acute coronary insufficiency develops. If the

drug must be withdrawn abruptly, close observation is required. In the 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 AV conduction disorder of moderate degree

may become aggravated (possibly leading to AV block). Bisoprolol should be administered

with caution to patients with first degree AV block (see section 4.3 Contraindications).

Effects on the heart rate: If the patient develops increasing bradycardia (heart rate less than

50 to 55 beats/ minute), the dosage of bisoprolol should be gradually reduced or treatment

gradually withdrawn (see section 4.3 Contraindications).

Prinzmetal angina: There is a risk of exacerbating coronary artery spasm if patients with

Prinzmetal or variant angina are treated with a β-blocker. If this treatment is essential, it should

only be undertaken in a Coronary or Intensive Care Unit.

Peripheral circulation: Beta-blockade may impair the peripheral circulation and exacerbate the

symptoms

peripheral

vascular

disease.

intensification

complaints

occur,

particularly at initiation of therapy (see section 4.3 Contraindications).

Bronchial asthma and chronic obstructive lung disease: Although cardioselective (β1) beta-

blockers may have less effect on lung function than non-selective beta-blockers, as with all

beta-blockers, these should be avoided in patients with obstructive airway diseases, unless

there are compelling clinical reasons for their use. Where such reasons exist bisoprolol may

be used with caution. In patients with bronchial asthma or other chronic obstructive airway

diseases, which may cause symptoms, bronchodilating therapy should be given concomitantly.

Occasionally an increase of the airway resistance may occur in patients with asthma, therefore

the dose of β

-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

beta-blockers but they are less likely with a β

-selective agent like bisoprolol. Nevertheless

diabetic patients receiving bisoprolol should be monitored to ensure that diabetes control is

maintained.

Other metabolic effects. Beta-adrenoceptors are involved in the regulation of lipid as well as

carbohydrate metabolism. Some beta-blockers affect the lipid profile adversely although the

long-term clinical significance of this change is unknown and the effect is more apparent with

non-selective beta-blockers while it appears to be less for drugs with β1-adrenoceptor-

selectivity and for those with intrinsic sympathomimetic activity.

Thyrotoxicosis: Under treatment with bisoprolol the symptoms of thyrotoxicosis may be

masked.

Phaeochromocytoma:

patients

with

phaeochromocytoma

bisoprolol

must

administered until after alpha-receptor blockade.

Allergic conditions: As with other β-blockers, bisoprolol may increase both the sensitivity

towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not

always give the expected therapeutic effect.

Psoriasis: Patients with psoriasis, or with a history of psoriasis, should only be given β-blockers

after carefully balancing the benefits against the risks.

Effects on the eye and skin: Various rashes and conjunctival xeroses have been reported with

β-blocking agents. Cross reactions may occur between β-blockers, therefore substitutions

within the group may not necessarily preclude occurrence of symptoms.

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

Use in hepatic impairment

Caution is advised in patients with CHF and impaired hepatic function since there is no

information regarding pharmacokinetics in these patients. Renal function should be monitored

in patients with severe liver disease. Renal impairment may develop in patients with liver

disease during bisoprolol treatment, leading to a need for dose reduction.

Use in renal impairment

No dosage adjustment is required in patients with impairment of the kidney due to excretion

equally by both liver and kidney. Nevertheless, caution is advised since there is no information

regarding pharmacokinetics in CHF patients.

Use in the elderly

Based on age alone no dosage adjustments are required; however, caution is advised in

patients greater than 80 years old since data in this age group is limited (see section 5.2

Pharmacokinetic properties).

Paediatric use

The safety and efficacy in children have not been established.

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

more

than

factor

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

cardiac

output,

vasodilation).

Abrupt

withdrawal,

particularly

prior

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) 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: Beta-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

medicines, resulting in severe bradyarrhythmias, attenuation of the reflex tachycardia and

hypotension, the decreased reflex ability to compensate for blood loss, hypovolaemia and

regional sympathetic blockade, and the increased propensity for vagal-induced bradycardia

(see section 4.4 Special warnings and precautions for use – General Anaesthesia).

Digitalis glycosides: Reduction of heart rate, increase of atrioventricular 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.

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).

Use in pregnancy

Category C

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or

the fetus/newborn. In general, β-adrenoceptor blockers reduce placental perfusion, which has

been associated with growth retardation, intrauterine death, abortion or early labour. Adverse

effects (e.g. hypoglycaemia and bradycardia) may occur in the fetus and newborn infant. If

treatment with β-adrenoceptor blockers is necessary, β

-selective adrenoceptor blockers are

preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with

bisoprolol is considered necessary, the uteroplacental blood flow and the fetal growth should

be monitored. In case of harmful effects on pregnancy or the fetus alternative treatment should

be considered. The newborn infant must be closely monitored. Symptoms of hypoglycaemia

and bradycardia are generally to be expected within the first 3 days.

Studies in rats have shown that bisoprolol and/or its metabolites cross the placenta and

distribute to the fetus.

Administration of bisoprolol at oral doses of ≥50 mg/kg/day to pregnant rats or ≥12.5 mg/kg/day

to pregnant rabbits caused embryofetal toxicity, resorptions and abortions. The no-effect dose

embryofetal

toxicity

mortality

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.

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 birth weight and retarded physical

development. The no-effect dose (50 mg/kg) for these effects was associated with an AUC

about 14 times greater than that expected in humans.

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol

exposure in infants. Therefore, breastfeeding is not recommended during administration of

bisoprolol.

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

Bisoprolol may cause dizziness or fatigue (see section 4.8 Adverse effects (Undesirable

effects)) and, therefore, may adversely affect the patient's ability to drive or use machinery. In

a study with coronary heart disease patients bisoprolol did not impair driving performance.

However, due to individual variations in reactions to the drug, the ability to drive a vehicle or

operate machinery may be impaired. This should be considered particularly at the start of

treatment and upon change of medication, as well as in conjunction with alcohol.

4.8

ADVERSE EFFECTS (UNDESIRABLE EFFECTS)

Clinical trials data

The table below 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.

Preferred Term WHO

Placebo (n = 1321)

Bisoprolol (n = 1328)

Patients with

AE

% Patients with

AE

Patients with

AE

% Patients with

AE

Cardiac failure

22.8

18.4

Dyspnoea

13.8

Dizziness

13.3

Cardiomyopathy

10.6

Bradycardia

15.2

Hypotension

11.4

Tachycardia

10.9

Fatigue

Viral infection

Pneumonia

Hypertension

Bronchitis

Arrhythmia

Coughing

Dyspepsia

Peripheral oedema

Chest pain

Headache

Purine metabolism

disorder

Carbohydrate

metabolism disturbed

Ischaemia

Exertional dyspnoea

Conduction disorder

Upper resp. tract

infection

Asthenia

Oedema

Left cardiac failure

Pain in limbs

Cerebrovascular

disorder

Weight changes

Arthralgia

Syncope

Insomnia

Body pain

Epigastric pain not

food-related

Abdominal pain

Cholesterol changes

Depression

Respiratory distress

Constipation

Palpitation

Hepatomegaly

Stridor

Vein disorder

Preferred Term WHO

Placebo (n = 1321)

Bisoprolol (n = 1328)

Patients with

AE

% Patients with

AE

Patients with

AE

% Patients with

AE

Urinary tract infection

Respiratory tract

oedema

Fever

Myalgia

Potassium levels

altered

Anxiety

Gastritis

Arthropathy

Blood lipids changes

Fractures

Malaise

Pruritus

Respiratory tract

hemorrhage

AE = Adverse Events

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.

Rare: syncope.

General disorders:

Common: asthenia, fatigue.

Hepatobiliary disorders:

Rare: hepatitis.

Reproductive system and breast disorders:

Rare: potency disorders.

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Reporting suspected adverse effects

Reporting suspected adverse reactions after registration of the medicinal product is important.

It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare

professionals

asked

report

suspected

adverse

reactions

www.tga.gov.au/reporting-problems

contact

Apotex

Medical

Information

Enquiries/Adverse Drug Reaction Reporting on 1800 195 055.

4.9

OVERDOSE

most

common

signs

expected

with

overdosage

β-blocker

bradycardia,

hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited

experience with overdose of bisoprolol, only a few cases of overdose with bisoprolol have been

reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide

interindividual variation in sensitivity to one single high dose of bisoprolol and patients with

heart failure are probably very sensitive.

In general, if overdose occurs, discontinuation of bisoprolol treatment and supportive and

symptomatic treatment is recommended.

Based on the expected pharmacologic actions and recommendations for other β-blockers, the

following general measures should be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or

another agent with positive chronotropic properties may be given cautiously. Under some

circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous

glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with

isoprenaline infusion or temporary pacing.

Acute

worsening

of

heart

failure:

Administer

intravenous

diuretics,

inotropic

agents,

vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, β

-sympathomimetic

drugs and/or aminophylline.

Hypoglycaemia: Administer intravenous glucose.

Limited data suggest that bisoprolol is hardly dialyzable.

For information on the management of overdose, contact the Poisons Information Centre on

131126 (Australia).

5

PHARMACOLOGICAL PROPERTIES

5.1

PHARMACODYNAMIC PROPERTIES

Mechanism of action

Bisoprolol is a β1-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and

relevant membrane stabilising activity. It only shows very low affinity to the β2-receptor of the

smooth muscles of bronchi and vessels as well as to the β2-receptors concerned with

metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the

airway resistance and β2-mediated metabolic effects. Its β1-selectivity extends beyond the

therapeutic dose range. However, its beta1-selectivity is not absolute and at doses greater

than the maximum recommended of 10 mg, bisoprolol may also inhibit beta2-adrenoreceptors.

The haemodynamic effects of bisoprolol are those that can be expected from β-adrenoceptor

blockade. Besides the negative chronotropic effect resulting in a reduction in resting and

exercise heart rate there is, as shown in acute studies with intravenous administration, a fall in

resting and exercise cardiac output with only little change in stroke volume, and a small

increase in right atrial pressure at rest or during exercise. The decrease in cardiac output

correlates with the heart rate reduction, and the observed increases in total peripheral

resistance and pulmonary arterial resistance after acute administration are considered to be

due to reflex autonomic changes resulting from the negative chronotropic and slight negative

inotropic effects.

Acute

intravenous

administration of

10 mg

bisoprolol

to hypertensive patients

reduced

glomerular filtration rate (GFR), renal blood flow (RBF) and plasma renin activity (PRA)

whereas the renal vascular resistance was reduced after short-term treatment (10 mg

bisoprolol po for 4 weeks) with no significant changes in RBF, GFR or PRA. Adrenaline

(epinephrine) and noradrenaline (norepinephrine) levels also remained unaffected after the 4-

week treatment in hypertensive patients.

Bisoprolol

shows

same

pattern

cardiac

electrophysiologic

effects

other

adrenoceptor blocking agents. It acts on those parts of the conduction system that are

influenced by the sympathetic nervous system. In electrophysiological studies it reduced heart

rate, prolonged sinoatrial (SA) and atrioventricular (AV) nodal conduction, and prolonged the

refractory periods of the SA and AV node. There was no statistically significant effect on atrial

effective refractory period in patients with a history of syncope or cardiac arrhythmias.

However, in patients with coronary artery disease, there was a small significant increase in

right atrial effective and functional refractory periods. Right ventricular effective refractory

period was temporarily prolonged during a study in patients with coronary artery disease, but

the clinical relevance of the small increase is uncertain. RR and PR intervals were increased

and QTc intervals reduced but all parameters remained within normal limits after bisoprolol.

Clinical trials

In total 2,647 ambulatory patients with chronic heart failure were included in the CIBIS II trial

in accordance with the following inclusion/exclusion criteria:

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

Exclusion criteria: Resting heart rate < 60 beats/min; supine systolic BP < 100 mmHg;

myocardial infarction or unstable angina within the preceding 3 months; percutaneous

transluminal coronary angioplasty (PTCA) or coronary artery bypass graft (CABG) within the

preceding 6 months; atrioventricular block of second degree or greater without a functioning

pacemaker, haemodynamically significant organic valvular disease; obstructive or restrictive

cardiomyopathy.

83% (n = 2202) of patients were in NYHA class III and 17% (n = 445) were in NYHA class IV.

They had stable symptomatic systolic heart failure (ejection fraction ≤ 35%, based on

echocardiography). Total mortality was reduced from 17.3% to 11.8% (absolute reduction

5.5%; relative reduction 34% [95% confidence interval 19-46%]).

A decrease in sudden death (3.6% vs. 6.3%, relative reduction 44%) and a reduced number

of heart failure episodes requiring hospital admission (12% vs 17.6%, relative reduction 36%)

was observed. Finally, a significant improvement of the functional status according to NYHA

classification

been

shown.

During the

initiation and titration

of bisoprolol

hospital

admissions due to bradycardia (0.53%), hypotension (0.23%), and acute decompensation

(4.97%) were observed, but they were not more frequent than in the placebo-group (0%, 0.3%

and 6.74%).

5.2

PHARMACOKINETIC PROPERTIES

Absorption

Bisoprolol is almost completely (> 90%) absorbed from the gastrointestinal tract and, because

of its small first pass metabolism of about 10%-15%, has an absolute bioavailability of about

85-90% after oral administration. The bioavailability is not affected by food. The drug shows

linear kinetics and the plasma concentrations are proportional to the administered dose over

the dose range 5 to 20 mg. Peak plasma concentrations occur within 2-3 hours.

Following oral administration of bisoprolol fumarate 10 mg to healthy subjects under fasting

conditions,

mean

peak

plasma

concentration

Bisoprolol

approximately

31.86 ng/mL was achieved within approximately 2 hours (T

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).

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

C-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 t

and C

. 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 t

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 (t

, AUC, C

) have been found to be greater in the

elderly compared to those in the young which appears to be due to a reduction in renal

clearance in the elderly. However, the pharmacokinetic differences between the young and the

elderly are unlikely to be clinically significant, and based on age alone no dosage adjustments

are required.

5.3

PRECLINICAL SAFETY DATA

Genotoxicity

No evidence for genotoxic activity was observed with bisoprolol in in vitro assays of gene

mutation (reverse mutation in Salmonella typhimurium, forward mutation in Chinese hamster

V79 fibroblasts) or chromosomal damage (CHO cytogenetic assay). Negative findings were

also obtained with bisoprolol in in vivo assays of chromosomal damage (Chinese hamster bone

marrow cytogenetic assay and the mouse micronucleus test).

Carcinogenicity

Bisoprolol showed no evidence of carcinogenic activity when administered orally (via the diet)

to mice for 20-26 months at doses up to 250 mg/kg/day and to rats for 24 months at doses up

to 125 mg/kg/day. These doses were associated with plasma drug concentrations (AUC) 38

times (mice) or 15 - 18 times (rats) greater than those expected in humans after 10 mg/day of

bisoprolol.

6

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

Microcrystalline cellulose

colloidal anhydrous silica

croscarmellose sodium

sodium starch glycollate type A

magnesium stearate

6.2

INCOMPATIBILITIES

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

medicine.

6.3

SHELF LIFE

In Australia, information on the shelf life can be found on the public summary of the Australian

Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Store below 25°C. Protect from light.

6.5

NATURE AND CONTENTS OF CONTAINER

Chemmart Bisoprolol tablets

1.25 mg tablets:

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182121).

2.5 mg tablets:

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182118).

3.75 mg tablets:

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182124).

5 mg tablets:

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182125).

10 mg tablets:

Blister pack (PVC/PVDC/Al) of 7, 10, 28, 30, 42, 56 and 100 tablets (AUST R 182111).

Not all strengths and/or pack sizes may be available.

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

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

local pharmacy.

6.7

PHYSICOCHEMICAL PROPERTIES

Bisoprolol fumarate is a white crystalline substance with a melting range of 100-104°C. It is

very soluble in water and methanol, freely soluble in ethanol, glacial acetic acid and chloroform.

As the substance is present in the form of a racemate, the aqueous solution does not show

optical activity.

Chemical structure

Chemical Name:

(±)-1-[[α-(2-Isopropoxyethoxy)-p-tolyl]oxy]-3-isopropylamino-2-

propanol hemifumarate

Molecular Formula:

Molecular Weight:

383.49

CAS number

104344-23-2

7

MEDICINE SCHEDULE (POISONS STANDARD)

S4 – Prescription Only Medicine

8

SPONSOR

Apotex Pty Ltd

16 Giffnock Avenue

Macquarie Park NSW 2113

Australia

Tel: (02) 8877 8333

Web: www1.apotex.com/au

9

DATE OF FIRST APPROVAL

5 December 2011

10 DATE OF REVISION

18 April 2019

Summary table of changes

Section Changed

Summary of new information

All

Reformatted product information; minor editorial changes

4.4, 4.8

Safety related Updates