Bisoprolol

Registered South African indications:

• Hypertension
• Angina pectoris
• Stable chronic heart failure with reduced systolic ventricular function

Contraindications

South African manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Pregnancy (for the indication of hypertension and angina pectoris)
• Breastfeeding (for the indication of hypertension and angina pectoris)
• Uncontrolled cardiac failure
• Acute heart failure or during episodes of heart failure decompensation requiring IV inotropic therapy
• Cardiogenic shock
• Atrioventricular (AV) block of second or third degree (without a pacemaker)
• Sick sinus syndrome
• Sinoatrial block
• Bradycardia with <60 beats/min before the start of therapy
  - <50 beats/min (for the indication of hypertension and angina pectoris)
• Hypotension with systolic blood pressure <100mmHg
  - <90mmHg (for the indication of hypertension and angina pectoris)
• Severe bronchial asthma
• Severe chronic obstructive pulmonary disease
• Advanced peripheral arterial occlusive disease
• Raynaud's syndrome
• Untreated phaeochromocytoma
• Metabolic acidosis

International manufacturer recommendations

• Hypersensitivity to the active ingredient or any of its excipients
• Acute heart failure or during episodes of heart failure decompensation requiring IV inotropic therapy
• Cardiogenic shock
• Atrioventricular (AV) block of second or third degree
• Sick sinus syndrome
• Sino-atrial block
• Symptomatic bradycardia
• Symptomatic hypotension
• Severe forms of peripheral arterial occlusive disease
• Severe forms of Raynaud's syndrome
• Severe bronchial asthma
• Severe chronic obstructive pulmonary disease
• Untreated phaeochromocytoma
• Metabolic acidosis

Cautions

South African manufacturer recommendations

• Pregnancy (for the indication of stable chronic heart failure with reduced systolic ventricular function)
• Breastfeeding (for the indication of stable chronic heart failure with reduced systolic ventricular function)
• Severe renal impairment
• Severe hepatic impairment
• Elderly
  - >80 years
• Dose reduction in perioperative period
• Bronchospasm
  - Bronchial asthma
  - Obstructive airways diseases
• Diabetes mellitus with large fluctuations in blood glucose values
• Strict fasting
• Ongoing desensitisation therapy
• AV block of first degree
• Prinzmetal’s angina
• Peripheral arterial occlusive disease
• Psoriasis or a history thereof
• Hyperthyroidism
• Thyrotoxicosis
• Abrupt withdrawal
• Concomitant therapy in heart failure in patients with the following diseases and conditions
  - NYHA class II heart failure
  - Insulin dependent diabetes mellitus (type I)
  - Renal impairment (serum creatinine ≥300µmol/l)
  - Hepatic impairment
  - >80 years
  - Restrictive cardiomyopathy
  - Congenital heart disease
  - Haemodynamically significant organic valvular disease
  - Myocardial infarction <3 months
• When transferring a patient from clonidine
  - See additional prescribing points
• General and regional anaesthesia
  - Coadministration with inhalation anaesthetics

International manufacturer recommendations

• Pregnancy
• Breastfeeding
• Severe renal impairment
• Severe hepatic impairment
• Elderly
• Bronchospasm
  - Bronchial asthma
  - Chronic obstructive pulmonary disease
• Abrupt withdrawal
• Hypertension or angina in the presence of cardiac failure
• Prinzmetal's angina
• AV block of first degree
• Peripheral arterial occlusive disease
• Diabetes mellitus
  - With large fluctuations in blood glucose values
• Strict fasting
• Ongoing desensitisation therapy
• Psoriasis or a history thereof
• Thyrotoxicosis
• Concomitant therapy in heart failure in patients with the following diseases and conditions
  - Insulin dependent diabetes mellitus (type I)
  - Severe renal impairment
  - Severe hepatic impairment
  - Restrictive cardiomyopathy
  - Congenital heart disease
  - Haemodynamically significant organic valvular disease
  - Myocardial infarction <3 months
• General anaesthesia
• When transferring a patient from clonidine
  - See additional prescribing points
• Galactose intolerance
• Total lactase deficiency
• Glucose-galactose malabsorption

Forms avail. in SA and covered in this monograph: tab

Dosages below include:

• South African manufacturer recommendations
• International manufacturer recommendations

South African manufacturer recommendations

Hypertension - mild to moderate
Angina pectoris

• Oral (tab): Initial: 5mg, dly; Maintenance: 10-20mg, dly; Max: 20mg/24hrs

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In all cases the dosage should be adjusted individually, in particular according to the pulse rate and therapeutic success

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No benefit was shown by increasing to the max dose of 20mg once daily for angina pectoris

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Stable chronic heart failure with reduced systolic ventricular function - moderate to severe (Additional agents required)
- With an ejection fraction ≤35% based on echocardiography

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

• Oral (tab): Initial: Week 1: 1.25mg, dly; Titrate by 1.25mg at intervals of 1 week; Up to 5mg; Then: 5mg, dly for 4 weeks; May be increased to 10mg if well tolerated; Maintenance: 10mg, dly; Max: 10mg/24hrs

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Uptitration of dosages should only be carried out if the current dose is well tolerated

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For stable chronic heart failure, after initiation of treatment with 1,25mg, the patients should be observed over a period of approximately 4 hours (especially with regards to blood pressure, heart rate, conduction disturbances, and signs of worsening of heart failure)

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

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The film-coated tablets are to be swallowed whole in some liquid in the morning before, during or after breakfast. The duration of treatment is not limited. It depends upon the nature and severity of the disease

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Bisoprolol therapy should not be stopped abruptly, particularly not in patients with coronary heart disease, as this may lead to acute deterioration of the patient’s state of health. If discontinuation of therapy becomes necessary, the dose should be gradually reduced (e.g. halving of the dose at weekly intervals)

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See additional prescribing points

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International manufacturer recommendations

Hypertension
Angina pectoris

• Oral (tab): Initial: 5mg, dly; Maintenance: 10-20mg, dly; Max: 20mg/24hrs

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The dosage should be individually adjusted, in particular according to the pulse rate and therapeutic success

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Treatment must not be stopped abruptly. The dosage should be diminished slowly by a weekly halving of the dose

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Stable chronic heart failure with reduced systolic left ventricular function (Additional agents required)

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

• Oral (tab): Initial: Week 1: 1.25mg, dly; Titrate by 1.25mg at intervals of 1 week; Up to 5mg; Then: 5mg, dly for 4 weeks; Titrate by 2.5mg at intervals of 4 weeks; Up to 10mg if well tolerated; Maintenance: 10mg, dly; Max: 10mg/24hrs

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

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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

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

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The treatment with bisoprolol must not be stopped abruptly since this might lead to a transitory worsening of condition. Especially in patients with ischaemic heart disease, treatment must not be discontinued suddenly. Gradual reduction of the daily dose is recommended

Not established for use in children

Pregnancy

South African manufacturer recommendations

• For the indication of hypertension and angina pectoris: Contraindicated
• For the indication of stable chronic heart failure with reduced systolic ventricular function: Caution; positive evidence of risk
• Not to be used during pregnancy
• Administration to pregnant mothers shortly before giving birth or during labour may result in the newborn infant being born hypotonic, collapsed or hypoglycaemic
• Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/ or the foetus/newborn
• Bisoprolol reduces placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour
• Adverse effects (e.g. hypoglycaemia, hypotonia, bradycardia and cardiovascular collapse) may occur in the foetus and newborn infant

International manufacturer recommendations

• Caution; positive evidence of risk
• Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-adrenoceptor blocking agents 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 beta-adrenoceptor blocking agents is necessary, beta-selective adrenoceptor blocking agents are preferable
• Bisoprolol is not recommended during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, the uteroplacental blood flow and 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

Breastfeeding

South African manufacturer recommendations

• For the indication of hypertension and angina pectoris: Contraindicated 
• For the indication of stable chronic heart failure with reduced systolic ventricular function: Caution; not recommended 
• It is not known whether bisoprolol is excreted in human milk. Therefore, mothers on treatment with bisoprolol should not breastfeed their infants
• Not to be used during breastfeeding

International manufacturer recommendations

• Caution; not recommended
• It is not known whether bisoprolol is excreted in human milk. Therefore, breastfeeding is not recommended during administration of bisoprolol

Fertility

• No information available

Renal Impairment

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: CrCl<30ml/min: Caution; dose adjustment recommended 
  Daily dose of 10mg should not be exceeded in patients with severe renal function disorders
  There is only limited experience with the use of bisoprolol in dialysis patients. There are no indications of the necessity to alter the dose regimen

International manufacturer recommendations

• Mild to moderate: CrCl≥20ml/min: No dose adjustment recommended 
• Severe: CrCl<20ml/min: Caution; dose adjustment recommended 
  Initial: 1.25-2.5mg, dly; Titrate cautiously; Max: 10mg, dly
  Experience with the use of bisoprolol in renal dialysis patients is limited. However, there is no evidence that the dosage regime needs to be altered
  There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired renal function. Uptitration of the dose in these populations should therefore be made with additional caution

Hepatic Impairment

South African manufacturer recommendations

• Mild to moderate: No dose adjustment recommended 
• Severe: Caution; dose adjustment recommended 
  Daily dose of 10mg should not be exceeded in patients with severe hepatic function disorders

International manufacturer recommendations

• Mild to moderate: No dose adjustment recommended
• Severe: Caution; dose adjustment recommended 
  Initial: 2.5mg dly; Titrate cautiously; Max: 10mg, dly
  There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired hepatic function. Uptitration of the dose in these populations should therefore be made with additional caution

Elderly

South African manufacturer recommendations

• Caution; no dose adjustment recommended 
  There is no therapeutic experience of bisoprolol treatment in heart failure in patients >80 years

International manufacturer recommendations

• Caution; no dose adjustment recommended
  Initiate at lower end of dosage range

Porphyria Information

• Probably not porphyrinogenic (PNP)

Drugs in Sport

• Prohibited - In certain sports
  
  Prohibited - In  and out of competition:
  Archery (WA)
  Shooting (ISSF) (IPC)
  
  Prohibited - In competition:
  Automobile (FIA)
  Billiards (all disciplines) (WCBS)
  Darts (WDF)
  Golf (IGF)
  Skiing / Snowboarding (FIS) in ski jumping, freestyle aerials/halfpipe and snowboard halfpipe/big air
  Underwater sports (CMAS) in constant-weight apnoea with or without fins, dynamic apnoea with and without fins, free immersion apnoea, Jump Blue apnoea, spearfishing, static apnoea, target shooting and variable weight apnoea

Central Nervous System Disorders

• Sleep disorders
• Depression
• Nightmares
• Hallucinations
• Dizziness
• Headache
• Syncope
• Fatigue

Cardiovascular Disorders

• Chest pain
• Bradycardia
• Worsening of pre-existing heart failure
• Atrioventricular conduction disturbances
• Feeling of coldness or numbness in the extremities
• Hypotension
• Orthostatic hypotension

Respiratory Disorders

• Bronchospasm
• Allergic rhinitis

Gastrointestinal Disorders

• Nausea and vomiting
• Diarrhoea
• Constipation

Hepatobiliary Disorders

• Hepatitis
• Increased liver enzymes

Genitourinary Disorders

• Potency disorders

Endocrine and Metabolic Disorders

• Increased triglycerides

Musculoskeletal Disorders

• Muscle weakness
• Muscle cramps

Skin and Subcutaneous Tissue Disorders

• Hypersensitivity reactions
• Worsening psoriasis 
• Psoriasis-like rash
• Alopecia

Sensory Disorders

• Reduced tear flow 
• Conjunctivitis
• Hearing disorders

• Calcium channel blockers
• Class I antiarrhythmics
• Class III antiarrhythmics
• Centrally-acting antihypertensives
• Agents that lower blood pressure
• Topical beta blocking agents
• Parasympathomimetics
• Antidiabetic agents
• Anaesthetic agents
• Digoxin
• Non-steroidal anti-inflammatory drugs
• Sympathomimetics
• Mefloquine
• Monoamine oxidase inhibitors
• Ergotamine derivatives
• Rifampicin

• ECG
• Heart rate

Specific cases may require

• Blood glucose

Phaeochromocytoma

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

Considerations for patients undergoing surgery

• If bisoprolol is to be withdrawn prior to surgery, at least 48 hours should be allowed to elapse between the last dose and anaesthesia. If treatment is to be continued during surgery, care should be taken when using anaesthetic agents. Vagal dominance, if it occurs, may be corrected with atropine (1-2mg IV)
• In the perioperative period it is generally unwise to reduce the dosage to which the patient is accustomed, as there may be danger of aggravation of angina pectoris or of hypertension. A patient’s normal tachycardiac response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard

Treatment in stable chronic heart failure with reduced systolic ventricular function

• Bisoprolol is indicated for the treatment of stable chronic moderate to severe heart failure with reduced systolic ventricular function (ejection fraction ≤35%, based on echocardiography) in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides
• The patients should have stable chronic heart failure without acute failure during the previous six weeks and an unchanged basic therapy during the previous two weeks
• They should be treated at optimal dose with an ACE inhibitor (or other vasodilator in case of intolerance to ACE inhibitors) and a diuretic, and optionally cardiac glycosides, prior to the administration of bisoprolol
• Occurrence of adverse events may prevent all patients being treated with the maximum recommended dose. If necessary, the dose reached can also be decreased step by step
• The treatment may be interrupted if necessary and reintroduced as appropriate. During the titration phase, in case of worsening of the heart failure or intolerance, it is recommended first to reduce the dose of bisoprolol, or to stop immediately if necessary (in case of severe hypotension, worsening of heart failure with acute pulmonary oedema, cardiogenic shock, symptomatic bradycardia or AV block)

Transferring a patient from clonidine

South African manufacturer recommendations

• Caution should be exercised when transferring a patient from clonidine
• The withdrawal of clonidine may result in the release of large amounts of catecholamines, which may give rise to a hypertensive crisis
• If beta-blockers are administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If a beta-blocker and clonidine are given concurrently, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker, as severe rebound hypertension may occur

International manufacturer recommendations

• Concomitant use of centrally acting antihypertensive agents such as clonidine 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 beta-blocking agent discontinuation, may increase the risk of “rebound hypertension”

Bronchial asthma and chronic obstructive pulmonary disease

South African manufacturer recommendations

• In bronchial asthma or other chronic obstructive lung 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
• 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

International manufacturer recommendations

• In patients with obstructive airways diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully monitored for new symptoms
• In bronchial asthma or other chronic obstructive lung 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 beta₂-stimulants may have to be increased

Bisoprolol is a beta-blocker which acts preferentially on beta1-adrenergic receptors in the heart. It has negative inotropic effects resulting in reduction in heart rate, myocardial contractility, impulse conduction rate and adrenergic-induced renin release. As with other beta-blockers, the mode of action of bisprolol in the treatment of hypertension is unclear.

Film-coated tablet 2.5mg

• Emcor (Merck) clone

Tablet 2.5mg

• Cardicor (Merck) originator
• Presicard 2.5 (Accord Healthcare)

Film-coated tablet 5mg

• Adco-Bisocor (Adcock Ingram)
• Betacor 5 (Merck) clone
• Bisoprolol Unichem 5 mg (Unichem)
• Emcor (Merck) clone
• Mylan Bisoprolol 5 mg (Mylan)

Tablet 5mg

• Bilocor (Pharma Dynamics)
• Bisbeta 5 mg (Aurobindo)
• Bislo 5 (Unichem)
• Bisohexal 10 (Sandoz)
• Bisoprolol Unicorn (Unicorn)
• Bisoprolol Zydus (Zydus)
• Bisozyd fct (Zydus)
• Cardicor (Merck) originator
• Concor  (Merck) originator
• Presicard 5 (Accord Healthcare)
• Retocar 5 mg (Novagen)
• Ziapro 5 mg (Pharmacare)

Film-coated tablet 10mg

• Adco-Bisocor (Adcock Ingram)
• Bisoprolol Unichem 10 mg (Unichem)
• Emcor (Merck) clone
• Mylan Bisoprolol 10 mg (Mylan)

Tablet 10mg

• Betacor (Merck) clone
• Bilocor (Pharma Dynamics)
• Bisbeta 10 mg (Aurobindo)
• Bislo 10 (Unichem)
• Bisohexal 10 (Sandoz)
• Bisoprolol Unicorn (Unicorn)
• Bisoprolol Zydus (Zydus)
• Bisozyd fct (Zydus)
• Cardicor (Merck) originator
• Concor  (Merck) originator
• Presicard 10 (Accord Healthcare)
• Retocar 10 mg (Novagen)
• Ziapro 10 mg (Pharmacare)

COMBINATION PREPARATIONS

Bisoprolol/ Hydrochlorothiazide

Tablet 2.5mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisozyd Co (Zydus)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)

Tablet 5mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisoprolol Co Unicorn (Pharma Dynamics)
• Bisozyd Co (Zydus)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)

Tablet 10mg/6.25mg

• Bilocor Co (Pharma Dynamics)
• Bisoprolol Co Unicorn (Pharma Dynamics)
• Bisozyd Co (Zydus)
• Ziabeta (Merck)
• Ziak (Merck)
• Zirinak Co (Ranbaxy)