Concor

The Different Beta Blocker

Bisoprolol is associated with a dose dependent HR reduction 1

Bisoprolol showed dose dependent reduction in the heart rate by 5.1, 7.1 and 10.2 beats/min,
respectively versus 0.9 under placebo. 1

Progressive reduction in HR with increasing dose 1

12

Bisoprolol is associated with

Heart Rate (beats/minute)

10

8 a dose dependent HR
6
reduction over 24 hours in
4
patients with mild to
2

0
moderate Hypertension1
5 mg 10 mg 20 mg Placebo
Reduction in HR

The response rate was significant with bisoprolol (47–70%) when compared placebo (18%). 1

Adapted from: Davidov ME, et al. Clin Cardiol. 1994;17:263-8.

Reference:
1. Davidov ME, et al. Bisoprolol, a Once-A-Day Beta-Blocking Agent or Patients with Mild to Moderate Hypertension. Clin Cardiol. 1994;17:263-8.
Bisoprolol effectively reduces BP and is associated
with a HR reduction1,2
Antihypertensive effect of bisoprolol (5mg)
vs. losartan (50 mg) shows that the heart
HR Reduction
rate was reduced only in the bisoprolol
group.2 87 86

The reduction in heart rate was seen due to 85

reduction of BP (target of <130/80
83
mmHg) in 30 patients (86%) with
bisoprolol vs. 28 patients (80%) in the 81 80
losartan group.2
79
A significant difference (p < 0.01) was
observed between the two treatment groups 77
in favor of bisoprolol for DBP.2 Bisoprolol Losartan

Adapted from: Parrinello G , et al. 2009.

Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011.
2. Adapted From: Parrinello G , et al. Clin Drug Invest 2009;29(9):591-600.
Concor is associated with a better HR control vs
metoprolol SR over 24 hours in hypertensive patients1

• Bisoprolol significantly lowered the 24-h mean

ambulatory, mean daytime and mean nighttime HR
over 24 hours in hypertensive patients. 1

• The overall adverse event rate was similar between

the bisoprolol treated and metoprolol treated groups. 1

• The Yang T, et al., study concluded that bisoprolol

provides better dynamic HR reduction and non-
inferior dynamic BP reduction vs. metoprolol CR/ZOK
in patients with mild-to-moderate hypertension.1

Reference:
1. Yang T, et al. Comparison of bisoprolol to a metoprolol CR/ZOK tablet for control of heart rate and blood pressure in mild-to-moderate hypertensive patients: the CREATIVE study. Hypertens Res. 2017
Jan;40(1):79-86.
BETA 1
SELECTIVITY
Beta1-blockade may be particularly beneficial in
hypertensive patients with central obesity/type 2
diabetes*/insulin resistance1
Increased
Central Insulin Release of
sympathetic
obesity or resistance leptin by
outflow and
diabetes high insulin adipocytes
norepinephrine
levels +
release
Insulin release

Selective β1-
blockade
Damage to the
reduces Renin release
Risk of
cardiac myocytes and
ventricular
and coronary angiotensin II
arrhythmias &
arteries production
vasoconstriction

*Bisoprolol must be used with caution in patients with: Diabetes mellitus showing large fluctuations in blood glucose values. Symptoms of hypoglycemia can be masked.2

Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011.
2. Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).
Bisoprolol is a third generation β-blocker with a
remarkably high β1-selectivity1
Bisoprolol was found to have the highest selectivity for the β1 receptor, displaying a β2/ β1 ratio of
19.6 (a 19.6-fold higher affinity for the β1 receptor than for the β2 receptor)
25

19.6
20

19.6 fold
15 ẞ1-than ẞ2-receptors

10
7.5
6 5.7
5

0.6 0.3
0
Concor Betaxolol Metaprolol Atenolol Carvedilol Propranolol

Adapted from: Smith C, et al. 1999.

Reference:
1. Smith C, et al. Beta-Blocker Selectivity at Cloned Human Beta1- and Beta2-Adrenergic Receptors. Cardiovasc Drugs Ther. 1999;13(2):123-126.
Bisoprolol: β1-selectivity vs. nebivolol1
In a study by Maack C, et al (2001), bisoprolol proved to be 5x more cardio-selective
than nebivolol.1
β1 selectivity

40
40 Bisoprolol

Nebivolol
30

β1 selectivity
30 Both bisoprolol
and nebivolol
are highly β1-
20
selective*
20

10
10

0
0
GppNHp (+)
GppNHp (-)

β1 selectivity of Bisoprolol vs. nebivolol in human myocardium 1

Adapted from: Maack C, et al. 2001.

*From the available data it cannot definitely be decided which agent is more β1-selective 1-4

Reference:
1. Maack C, et al. Characterization of β1-selectivity, adrenoceptor-Gs-protein interaction and inverse agonism of nebivolol in human myocardium. Br J Pharmacol. 2001;132:1817-26
PHARMACOKINETIC
PROPERTIES
 Bisoprolol is a highly beta1-selective beta-blocker that was
chosen for clinical development because of its excellent
pharmacological and pharmacokinetic properties1-3
• The drug does not have any partial agonistic nor
membrane stabilizing activity.1

• Absolute oral bioavailability of >90%, with virtually no

first-pass effect (<10 %)2

• Terminal elimination half-life of 10-12 hours, enabling

once-daily dosing with a clearance of approximately
16 L/hour.2

• Low plasma protein binding (30%) minimizes the risk

of drug interactions and a balanced clearance via renal
and hepatic routes ensures that bisoprolol is suitable
for use in patients with renal or hepatic insufficiency. 2,3

Reference:
1. Leopold G, et al. Bisoprolol: pharmacokinetic profile. Rev Contemp. Rev Contemp Pharmacother. 1997;8:35-43.
2. Leopold G, et al. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-621.
3. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
Overview of pharmacokinetics of bisoprolol1-3

Criteria Bisoprolol

Absorption >90%

Bioavailability ~90%

Plasma protein binding 30%

Metabolism 50% (inactive)

Plasma elimination half-life 10–12 hours

Reference:
1. Leopold G, et al. Rev Contemp Pharmacother. 1997;8:35-43.
2. Leopold G, et al. J Clin Pharmacol. 1986;26:616-621.
3. Leopold G. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
Bisoprolol shows a consistent pharmacokinetic profile with a
clearance which is balanced between renal elimination (~50%)
and hepatic metabolism (~50%)1-3

• The resulting ”balanced“ clearance is that even in Bisoprolol

cases of complete failure of one of the clearance

organs, the elimination half-life of bisoprolol is in
general only up to about double that of the half-life
Excreted
in the healthy.1-3

• A dose adjustment of bisoprolol is not required for

patients with mild to moderate renal or hepatic Unchanged
Inactive metabolites
substance via the
in the liver
impairment.1-3 kidneys

Reference:
1. Leopold G, et al. Rev Contemp Pharmacother. 1997;8:35-43.
2. Leopold G, et al. J Clin Pharmacol. 1986;26:616-621.
3. Leopold G. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
 In contrast to metoprolol, bisoprolol offers a reliable
pharmacokinetic profile regardless of the patient´s
metabolic phenotype1-4
• The plasma metoprolol profile differed significantly
(p<0.05) from the bisoprolol profile regarding time to
maximum concentration, mean residence time, the ratio
of peak concentration (Cmax) to the area under the curve
(AUC) and the plateau time as estimated from the half-
value duration.1
• The average drug plasma concentration observed 24 h
after administration still accounted for 54% of the Cmax
value for the metoprolol controlled release tablet, but
only 23% with the bisoprolol normal release tablet. 1

Adapted from: Deroubaix X , et al. 1996.

Reference:
1. Adapted from: Deroubaix X , et al. Comparative bioavailability of a metoprolol controlled release formulation and a bisoprolol normal release tablet after single oral dose administration in healthy
volunteers. Int J Clin Pharmacol Ther. 1996;34:61-70.
2. Leopold G, et al. Bisoprolol: pharmacokinetic profile. Rev Contemp. Rev Contemp Pharmacother. 1997;8:35-43.
3. Leopold G, et al. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-621.
4. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
 CONCOR®
SAFETY AND TOLERABILITY PROFILE
 Bisoprolol: Beta1-selectivity results in minimal effects on lung
function in coronary patients with chronic obstructive lung*
disease1,2
• After 24 hours, the significant reduction in HR from Reduction in patients with COPD and angina.
baseline was still evident with bisoprolol (p<0.01), but 100
not with atenolol, indicating sustained beta1-blockade. 2 91.25

Reduction in BP (%)
90
80
• Bisoprolol is contra-indicated in patients with severe 68.54
bronchial asthma.3 70 P<0.01

60

β1-selective Lower risk of 50

Non-selective
β-blockers1 bronchoconstriction In
patients with COPD
β-blockers1 40
30 23.13
20
10
*Although cardio selective (beta1) beta-blockers may have less
effect on lung function than nonselective beta-blockers, as with 0
all beta-blockers, these should be avoided in patients with Category 1
obstructive airways diseases, unless there are compelling clinical
reasons for their use.3 Placebo Atenolol Bisoprolol

Adapted from: Dorow P, et al. 1986.

Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011.
2. Adapted from: Dorow P, et al. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Eur J Clin Pharmacol.
1986;31:143–7.
3. Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).
Bisoprolol results in minimal effects on lung*
function1,2
Significant increase in AWR with atenolol vs. placebo
• Bisoprolol did not increase the airways resistance when (p < 0.05) and bisoprolol (p < 0.05)2
compared to atenolol and placebo, suggesting that risk
of bronchoconstriction decreases with increasing β 1- AWR (n=11)

selectivity.2 1.5
1.18

• Bisoprolol proved to have minimal effects on lung 1

function, even in patients with COPD and suitable for P<0.05

hypertension therapy.2 0.5

-0.35
• Bisoprolol is contra-indicated in patients with severe 0

bronchial asthma.3 -0.25

-0.5

n.s.p>0.05 P<0.05
-1

Placebo Bisoprolol Atenolol

*Although cardio selective (beta1) beta-blockers may have less effect on lung function
than nonselective
Adapted beta-blockers,
from: Dorow as with all beta-blockers, these should be avoided in
P, et al. 1986.
patients with obstructive airways diseases, unless there are compelling clinical reasons for
their use.3
 Bisoprolol has minimal effects on glucose*1-3
Course of the blood glucose before and after 12, 24, and 36 months of treatment 3

Adapted from: Giesecke HG. and Bushner-Moil D. 1990.

*Bisoprolol must be used with caution in patients with: Diabetes mellitus showing large fluctuations in blood glucose values. Symptoms of hypoglycemia can
be masked.4
Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011. Doc ID.
2. Janka HU, et al. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–9.
3. Adapted from: Giesecke HG and Bushner-Moil D. Three Years of Experience with Bisoprolol in the Treatment of Mild to Moderate Hypertension. J Cardiovasc Pharmacol 1990;16(Suppl 5): S175-8.
4. Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).

17
Bisoprolol has minimal effects on lipids1-3
Course of the triglycerides before and after 12, 24, and 36 months of treatment 3

Adapted from: Giesecke HG. and Bushner-Moil D. 1990.

*Bisoprolol may cause undesirable side effects in rare conditions like increased triglycerides, increased liver enzymes (ALAT, ASAT). 4

Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011. Doc ID.
2. Janka HU, et al. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–9.
3. Adapted from: Giesecke HG and Bushner-Moil D. Three Years of Experience with Bisoprolol in the Treatment of Mild to Moderate Hypertension. J Cardiovasc Pharmacol 1990;16(Suppl 5): S175-8.
4. Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).

18
 Bisoprolol has minimal effects on lipids1-3
Course of the cholesterol before and after 12, 24, and 36 months of treatment 3

Adapted from: Giesecke HG. and Bushner-Moil D. 1990.

Reference:
1. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011. Doc ID.
2. Janka HU, et al. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–9.
3. Adapted from: Giesecke HG and Bushner-Moil D. Three Years of Experience with Bisoprolol in the Treatment of Mild to Moderate Hypertension. J Cardiovasc Pharmacol 1990;16(Suppl 5): S175-8.

19
Safety profile and tolerability of bisoprolol1-10
Lung* function
β1-selectivity of bisoprolol results in minimal effects on
Although cardio selective (beta1) beta-blockers
lung function in patients with chronic obstructive lung
may have less effect on lung function than diseases1,2
Peripheral circulation
nonselective beta-blockers, as with all beta- Bisoprolol has minimal effect on peripheral
circulation3-6
blockers, these should be avoided in patients
Male sexual function
with obstructive airways diseases, unless there Bisoprolol has minimal effect on male sexual
function7
are compelling clinical reasons for their use.
Renal clearance and hepatic metabolism
Bisoprolol is contra-indicated in patients with Bisoprolol shows a consistent pharmacokinetic profile
with a clearance which is balanced between renal
severe bronchial asthma.11 elimination (~50%) and hepatic metabolism (~50%)8-10

Reference:
1. Dorow P et al. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Eur J Clin Pharmacol (1986) 31: 143-7.
2. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011. Doc ID.
3. Chang PC, et al. Beta-1 adrenoceptor selectivity of single oral doses of bisoprolol and atenolol. J Cardiovasc Pharmacol. 1988;12:317-22.
4. Chang PC, et al. Double-blind comparison of the beta 1-selectivity of single doses of bisoprolol and atenolol.J Cardiovasc Pharmacol. 1986;8(Suppl 11):S58-60.
5. Bailliart O, et al. Effects of bisoprolol on local vascular resistance. Eur Heart J. 1987;8(Suppl M):87-93.
6. Asmar RG, et al. Effect of bisoprolol on blood pressure and arterial hemodynamics in systemic hypertension. Am J Cardiol. 1991;68(1):61-4.
7. Prisant LM, et al. Self reported sexual dysfunction in men and women treated with bisoprolol, hydrochlorothiazide, enalapril, amlodipine), placebo or bisoprolol/hydrochlorothiazide. J Clin Hypertens
(Greenwich). 1999;1(1):22-6.
8. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
9. Leopold G, et al. Bisoprolol: pharmacokinetic profile. Rev Contemp. Rev Contemp Pharmacother. 1997;8:35-43.
10.Leopold G, et al. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
11.Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).
SUMMARY
Bisoprolol has well established safety profile1-20
β1-Selectivity:
Efficacy:
• Bisoprolol is a third generation beta-blocker with a
• Greater SBP & DBP reduction vs. atenolol1, as well remarkably high beta1-selectivity.7
as other antihypertensive agents such as
losartan, amlodipine and hydrochlorothiazide.2 Safety profile:
• Better heart rate reduction vs. metoprolol,3 • Minimal effects on blood glucose*, and lipids8-10, as well as
carvedilol and nebivolol.4 lung function**8,11, peripheral circulation12-15, and male sexual
function.16
• More effective than nifedipine SR in reducing the
total ischemic burden and risk of coronary events • Consistent pharmacokinetic profile with a balanced renal
in CHD.5 clearance and
• Reduces morbidity and mortality in CHF.6 • hepatic metabolism.17-19

*Bisoprolol must be used with caution in patients with: Diabetes mellitus showing large fluctuations in blood glucose values. Symptoms of hypoglycemia can be masked.

**Although cardio selective (beta1) beta-blockers may have less effect on lung function than nonselective 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. Bisoprolol is contra-indicated in patients with severe bronchial asthma.20
Reference:
1. Neutel JM, et al. Application of Ambulatory Blood Pressure Monitoring in Differentiating Between Antihypertensive Agents. Am J Med. 1993 Feb;94(2):181-7.
2. Hiltunen TP, et al. Predictors of Antihypertensive Drug Responses: Initial Data from a Placebo-Controlled, Randomized, Cross-Over Study With Four Antihypertensive Drugs (The GENRES Study). Am J Hypertens. 2007 Mar;20(3):311-8.
3. Yang T, et al. Comparison of bisoprolol to a metoprolol CR/ZOK tablet for control of heart rate and blood pressure in mild-to-moderate hypertensive patients: the CREATIVE study. Hypertens Res. 2017 Jan;40(1):79-86.
4. Stoschitzky K et al. Comparing beta-blocking effects of bisoprolol, carvedilol and nebivolol. Cardiology 2006;106:199-206.
5. von Arnim T, et al. Medical treatment to reduce total ischemic burden: total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine. The TIBBS Investigators. J Am Coll Cardiol 1995;25:231–8.
6. CIBIS II Investigators and Committees. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomized trial. Lancet 1999;353:913.
7. Smith C, et al. Beta-blocker selectivity at cloned human beta1- and beta2- adrenergic receptors. Cardiovasc Drugs Ther. 1999;13(2):123-126.
8. Cruickshank JM. The Modern Role of Beta-blockers in Cardiovascular Medicine. Shelton, CT: People's Medical Publishing House-USA;2011. Doc ID.
9. Janka HU, et al. Influence of bisoprolol on blood glucose, glucosuria, and haemoglobin A1 in noninsulin-dependent diabetics. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S96–9.
10. Giesecke HG and Bushner-Moil D. Three Years of Experience with Bisoprolol in the Treatment of Mild to Moderate Hypertension. J Cardiovasc Pharmacol 1990;16(Suppl 5): S175-8.
11. Dorow P et al. Effects of single oral doses of bisoprolol and atenolol on airway function in nonasthmatic chronic obstructive lung disease and angina pectoris. Eur J Clin Pharmacol (1986) 31: 143-7.
12. Chang PC, et al. Beta-1 adrenoceptor selectivity of single oral doses of bisoprolol and atenolol. J Cardiovasc Pharmacol. 1988;12:317-22.
13. Chang PC, et al. Double-blind comparison of the beta 1-selectivity of single doses of bisoprolol and atenolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):S58-60.
14. Bailliart O, et al. Effects of bisoprolol on local vascular resistance. Eur Heart J. 1987;8(Suppl M):87-93.
15. Asmar RG, et al. Effect of bisoprolol on blood pressure and arterial hemodynamics in systemic hypertension. Am J Cardiol. 1991;68(1):61-4.
16. Prisant LM, et al. Self reported sexual dysfunction in men and women treated with bisoprolol, hydrochlorothiazide, enalapril, amlodipine), placebo or bisoprolol/hydrochlorothiazide. J Clin Hypertens (Greenwich). 1999;1(1):22-6.
17. Leopold G. Balanced pharmacokinetics and metabolism of bisoprolol. J Cardiovasc Pharmacol. 1986;8(Suppl 11):16-20.
18. Leopold G, et al. Bisoprolol: pharmacokinetic profile. Rev Contemp. Rev Contemp Pharmacother. 1997;8:35-43.
19. Leopold G, et al. Basic pharmacokinetics of bisoprolol, a new highly beta1-selective adrenoceptor antagonist. J Clin Pharmacol. 1986;26:616-21.
20. Concor®/Concor® COR. Product information (abbreviated prescribing information shortened for visual).
Abbreviated prescribing information
Concor® / Concor® COR Product information (abbreviated prescribing information shortened for visual)
Products: Concor 5, 10; Concor COR 1.25, 2.5, 3.75, 5, 7.5, 10 film-coated tablets for oral use
containing 1.25 mg,
2.5 mg, 3.75 mg, 5 mg, 7.5 mg, or 10 mg bisoprolol fumarate, respectively. Different brand
names are used for the products in some countries.
Indications: Concor: Treatment of hypertension; treatment of coronary heart disease (angina
Important Interactions: Class I antiarrhythmic drugs, Calcium antagonists of the verapamil
type and to a lesser extend of the diltiazem type, Centrally-acting antihypertensive drugs.
Pregnancy and lactation: Bisoprolol is not recommended during pregnancy and lactation.
Adverse reactions: Very common: bradycardia. Common: worsening of pre-existing heart
failure, dizziness, headache, gastrointestinal complaints such as nausea, vomiting, diarrhoea,

ed
pectoris, AP). Concor Cor: treatment of stable chronic moderate to severe heart failure in constipation; feeling of coldness or numbness in the extremities, hypotension, asthenia, fatigue.

v
addition to ACE inhibitors, and diuretics, and, optionally cardiac glycosides; treatment of stable Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure, bradycardia,

r o
chronic heart failure (CHF). bronchospasm in patients with bronchial asthma or a history of obstructive airway disease,

p p
Posology: Treatment of hypertension or AP: the dosage is 5 mg bisoprolol fumarate once daily muscle weakness, muscle cramps, asthenia, depression, sleep disorders. Rare: increased

a
triglycerides, increased liver enzymes (ALAT, ASAT), reduced tear flow, hearing disorders,

y
which may be increased to 10 mg once daily if necessary. The max. recommended dose is 20

l l
mg once daily. Treatment of stable CHF: requires a titration phase, starting with a low dose allergic rhinitis, hypersensitivity reactions such as itching, flush, rash; hepatitis, potency

c a n
(1.25 mg once daily) and with gradual up-titration (2.5, 3.75, 5, 7.5, 10 mg once daily) disorders, nightmares, hallucinations. Very rare: conjunctivitis, alopecia; beta-blockers may

lo t io
according to tolerability It is recommended that the treating physician is experienced in the provoke or worsen psoriasis or induce psoriasis-like rash. Frequency not known: syncope.

t h a
management of CHF. The max. recommended dose for CHF is 10 mg bisoprolol fumarate once Overdose: The most common signs expected with overdose of a beta-blocker are bradycardia,

w i r m
daily. The treatment with bisoprolol must not be stopped abruptly, since this might lead to a hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is a wide

e fo
transitory worsening of condition, especially in patients with ischemic heart disease or CHF. inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with

ac i n
Special populations: In severe renal impairment (creatinine clearance <20 ml/min) or severe heart failure are probably very sensitive. If overdose occurs, discontinuation of bisoprolol

Rep l n g
liver function disorders a daily dose of 10 mg bisoprolol fumarate should not be exceeded and treatment and supportive and symptomatic treatment is recommended.

b i
dose titration in patients with CHF and these functional impairments should be made with Marketing Authorization Holder: Merck KGaA, Frankfurter Str. 250, 64293 Darmstadt,

r i
particular caution. Use in children cannot be recommended (lack of experience).

c
Germany; www.merckgroup.com

s
Contraindications: acute heart failure or during episodes of heart failure decompensation,

e
Date of product information preparation: May 2017

pr
cardiogenic shock, second or third degree AV block, sick sinus syndrome, sinoatrial block, Please refer to local prescribing information as this may vary between countries.
symptomatic bradycardia or hypotension, severe bronchial asthma, severe forms of peripheral
arterial occlusive disease or severe forms of Raynaud’s syndrome, untreated
pheochromocytoma, metabolic acidosis, hypersensitivity to bisoprolol or to any of the excipients.
Warnings and precautions for use: Cessation of therapy with bisoprolol must not be done
abruptly unless clearly indicated, transitional worsening of heart condition possible.
AP/Hypertension: To be used with caution with accompanying heart failure. CHF: To be initiated
with a special titration phase. Initiation of treatment of stable chronic heart failure with
bisoprolol necessitates regular monitoring. No therapeutic experience in CHF in patients with:
insulin-dependent diabetes mellitus (type I), restrictive cardiomyopathy, congenital heart
disease, haemodynamically significant organic valvular disease, myocardial infarction within 3
months. CHF: No therap. experience in patients with: NYHA class II heart failure, impaired renal
(serum creatinine ≥ 300 micromol/l) and liver function, older than 80 years.
All indications: Must be used with caution in: Diabetes mellitus showing large fluctuations in
blood glucose values, symptoms of hypoglycemia can be masked; strict fasting; ongoing
desensitization therapy; first degree AV block; Prinzmetal’s angina; peripheral arterial occlusive
disease. Patients with psoriasis or with a history of psoriasis should only be given beta-blockers
(e.g. bisoprolol) after a careful balancing of benefits and risks. Symptoms of thyrotoxicosis may
be masked. In patients with pheochromocytoma bisoprolol must not be administered until after
alpha-receptor blockade. In patients undergoing general anesthesia, the anesthesist must be 23