Bisoprololfumaraat Niche Generics

Treatment of hypertension.

Treatment of chronic stable angina pectoris.

Treatment of stable chronic heart failure with reduced systolic ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides.

Treatment of Hypertension

Treatment of stable chronic angina

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides

Bisoprololfumaraat Niche Generics is indicated in the management of hypertension. It may be used alone or in combination with other antihypertensive agents.

Posology

Treatment of hypertension and chronic stable angina pectoris

Adults

The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.

Patients with renal or hepatic impairment

In patients with severe renal impairment (creatinine clearance < 20 ml/min) and in patients with severe hepatic function disorders the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.

Elderly

No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.

Paediatric population

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

Discontinuation of treatment

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

Treatment of stable chronic heart failure

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocking agent, 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.

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Close monitoring of vital signs (heart rate, blood pressure) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may occur within the first day after initiating the therapy.

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.

Special populations

Hepatic or renal impairment:

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

Elderly

No dosage adjustment is normally required.

Paediatric population

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

Method of administration

For oral use.

Bisoprololfumaraat Niche Generics tablets should be taken in the morning and can be taken with food. They should be swallowed with liquid and should not be chewed.

Method of administration:

For oral use.

Bisoprololfumaraat Niche Generics fumarate tablet should be taken in morning and can be taken with food in morning. They should be swallowed in liquid and should not be chewed.

Posology

Treatment of hypertension and chronic stable angina pectoris

Adults

The dosage should be individually adjusted. It is recommended to start with 5 mg per day. The usual dose is 10 mg once daily with a maximum recommended dose of 20 mg per day.

Patients with renal impairment

In patients with severe renal impairment (creatinine clearance < 20 ml/min) the dose should not exceed 10 mg once daily. This dosage may eventually be divided into halves.

Patients with severe liver impairment

No dosage adjustment is required, however careful monitoring is advised.

Elderly

No dosage adjustment is normally required. It is recommended to start with the lowest possible dose.

Paediatric population

There is no experience with Bisoprololfumaraat Niche Generics in children, therefore its use cannot be recommended for children.

Discontinuation of treatment

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

Treatment of stable chronic heart failure

Adults

Standard treatment of CHF consists of an ACE inhibitor (or an angiotensin receptor blocker in case of intolerance to ACE inhibitors), a beta-blocker, diuretics, and when appropriate cardiac glycosides. Patients should be stable (without acute failure) when Bisoprololfumaraat Niche Generics treatment is initiated.

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

Transient worsening of heart failure, hypotension, or bradycardia may occur during the titration period and thereafter.

Titration phase

The treatment of stable chronic heart failure with Bisoprololfumaraat Niche Generics requires a titration phase

The treatment with Bisoprololfumaraat Niche Generics 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) and symptoms of worsening heart failure is recommended during the titration phase. Symptoms may already occur within the first day after initiating the therapy.

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 Bisoprololfumaraat Niche Generics or to consider discontinuation.

The reintroduction and/or uptitration of Bisoprololfumaraat Niche Generics 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 Bisoprololfumaraat Niche Generics is generally a long-term treatment.

Special population

Renal or hepatic impairment

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

Elderly

No dosage adjustment is normally required.

Paediatric population

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

The dose of Bisoprololfumaraat Niche Generics must be individualized to the needs of the patient. The usual starting dose is 5 mg once daily. In some patients, 2.5 mg may be an appropriate starting dose (see Bronchospastic Disease in WARNINGS). If the antihypertensive effect of 5 mg is inadequate, the dose may be increased to 10 mg and then, if necessary, to 20 mg once daily.

Patients With Renal Or Hepatic Impairment

In patients with hepatic impairment (hepatitis or cirrhosis) or renal dysfunction (creatinine clearance less than 40 mL/min), the initial daily dose should be 2.5 mg and caution should be used in dose-titration. Since limited data suggest that bisoprolol fumarate is not dialyzable, drug replacement is not necessary in patients undergoing dialysis.

Geriatric Patients

It is not necessary to adjust the dose in the elderly, unless there is also significant renal or hepatic dysfunction (see above and Geriatric Use in PRECAUTIONS).

Pediatric Patients

There is no pediatric experience with Bisoprololfumaraat Niche Generics.

Bisoprolol is contraindicated in patients with:

-

- acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

- cardiogenic shock

- second or third degree AV block

- sick sinus syndrome

- sinoatrial block

- symptomatic bradycardia

- symptomatic hypotension

- severe bronchial asthma

- severe forms of peripheral arterial occlusive disease or severe forms of Raynaud's syndrome

- untreated phaeochromocytoma

- metabolic acidosis

Bisoprololfumaraat Niche Generics is contraindicated in chronic heart failure patients with:

- acute heart failure or during episodes of heart failure decompensation requiring i.v. inotropic therapy

- cardiogenic shock

- second or third degree AV block (without a pacemaker)

- sick sinus syndrome

- sinoatrial block

- Symptomatic bradycardia

- Symptomatic hypotension

- severe bronchial asthma or severe chronic obstructive pulmonary disease

- late stages of peripheral arterial occlusive disease and Raynaud's syndrome

- untreated phaeochromocytoma

- metabolic acidosis

Bisoprololfumaraat Niche Generics is contraindicated in patients with cardiogenic shock, overt cardiac failure, second or third degree AV block, and marked sinus bradycardia.

Special warnings

Applies only to chronic heart failure:

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase

Applies to all indications:

Especially in patients with ischaemic heart disease the cessation of therapy with bisoprolol must not be done abruptly unless clearly indicated, because this may lead to transitional worsening of heart condition.

Tablet contains lactose (anhydrous) - patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine

5 mg and 7.5 mg tablet only:

Tablet contains tartrazine (E102) - may cause allergic reactions.

10 mg tablet only:

Tablet contains sunset yellow (E110) - may cause allergic reactions.

Precautions

Applies only to hypertension or angina pectoris:

Bisoprolol must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Applies only to chronic heart failure:

The initiation and cessation of treatment with bisoprolol necessitates regular monitoring. For the posology and method of administration please.

There is no therapeutic experience of bisoprolol treatment in heart failure in patients with the following diseases and conditions:

- insulin dependent diabetes mellitus (type I)

- severely impaired renal function

- severely impaired hepatic function

- restrictive cardiomyopathy

- congenital heart disease

- haemodynamically significant organic valvular disease

- myocardial infarction within 3 months

Applies to all indications:

Bisoprolol must be used with caution in:

- bronchospasm (bronchial asthma, obstructive airways diseases)

- diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations, sweating) can be masked

- strict fasting

- ongoing desensitisation therapy. As with other beta-blockers, bisoprolol may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Epinephrine treatment may not always yield the expected therapeutic effect.

- first degree AV block

- Prinzmetal's angina

- peripheral arterial occlusive disease. Aggravation of symptoms may occur especially when starting therapy

- general anaesthesia.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. bisoprolol) after a careful balancing of benefits against risks.

The symptoms of thyrotoxicosis may be masked under treatment with bisoprolol.

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

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance of beta-blockade be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of reflex tachycardia, and decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

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 obstructive airways diseases, the treatment with bisoprolol should be started at the lowest possible dose and patients should be carefully monitored for new symptoms (e.g. dyspnoea, exercise intolerance, cough). In bronchial asthma or other chronic obstructive pulmonary diseases, which may cause symptoms, concomitant bronchodilating therapy is recommended. Occasionally an increase of the airway resistance may occur in patients with asthma, therefore the dose of beta2-stimulants may have to be increased.

Special warnings:

Applies only to chronic heart failure:

The treatment of stable chronic heart failure with Bisoprololfumaraat Niche Generics has to be initiated with special titration phase.

Applies to all indications:

Especially in patients with ischemic heart disease the cessation of therapy with Bisoprololfumaraat Niche Generics must not be done abruptly unless clearly indicated, because this may lead to transition worsening of heart condition.

Precautions:

Applies only to hypertension or angina pectoris:

Bisoprololfumaraat Niche Generics must be used with caution in patients with hypertension or angina pectoris and accompanying heart failure.

Applies only to chronic heart failure:

The initiation of treatment with Bisoprololfumaraat Niche Generics necessitates regular monitoring. For posology and method of administration please.

There is no therapeutic experience of Bisoprololfumaraat Niche Generics treatment of heart failure in patients with the following diseases and conditions:

- insulin dependent diabetes mellitus (type I)

- severely impaired renal function

- severely impaired hepatic function

- restrictive cardiomyopathy

- congenital heart disease

- haemodynamically significant organic valvular disease

- myocardial infarction within 3 months

Applies to all indications:

Bisoprololfumaraat Niche Generics must be used with caution in:

- bronchospasm (bronchial asthma, obstructive airways diseases).

In bronchial asthma or other chronic obstructive lung diseases, which may cause symptoms, bronchodilating therapy is recommended to 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.

- diabetes mellitus with large fluctuations in blood glucose values; symptoms of hypoglycaemia (e.g. tachycardia, palpitations or sweating) can be masked.

- strict fasting

- ongoing desensitisation therapy

As with other beta-blockers, Bisoprololfumaraat Niche Generics may increase both the sensitivity towards allergens and the severity of anaphylactic reactions. Adrenaline treatment does not always give the expected therapeutic effect.

- first degree AV block

- Prinzmetal's angina

- peripheral arterial occlusive disease (intensification of complaints might happen especially during the start of therapy)

- general anaesthesia

In patients undergoing general anaesthesia beta-blockade reduces the incidence of arrhythmias and myocardial ischemia during induction and intubation, and the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthesist must be aware of beta-blockade because of the potential for interactions with other drugs, resulting in bradyarrhythmias, attenuation of the reflex tachycardia and the decreased reflex ability to compensate for blood loss. If it is thought necessary to withdraw beta-blocker therapy before surgery, this should be done gradually and completed about 48 hours before anaesthesia.

Patients with psoriasis or with a history of psoriasis should only be given beta-blockers (e.g. Bisoprololfumaraat Niche Generics) after carefully balancing the benefits against the risks.

In patients with phaeochromocytoma Bisoprololfumaraat Niche Generics must not be administered until after alpha-receptor blockade.

Under treatment with Bisoprololfumaraat Niche Generics the symptoms of a thyreotoxicosis may be masked.

WARNINGS

Cardiac Failure

Sympathetic stimulation is a vital component supporting circulatory function in the setting of congestive heart failure, and beta-blockade may result in further depression of myocardial contractility and precipitate more severe failure. In general, beta-blocking agents should be avoided in patients with overt congestive failure. However, in some patients with compensated cardiac failure it may be necessary to utilize them. In such a situation, they must be used cautiously.

In Patients Without A History Of Cardiac Failure

Continued depression of the myocardium with beta-blockers can, in some patients, precipitate cardiac failure. At the first signs or symptoms of heart failure, discontinuation of Bisoprololfumaraat Niche Generics should be considered. In some cases, beta-blocker therapy can be continued while heart failure is treated with other drugs.

Abrupt Cessation Of Therapy

Exacerbation of angina pectoris, and, in some instances, myocardial infarction or ventricular arrhythmia, have been observed in patients with coronary artery disease following abrupt cessation of therapy with beta-blockers. Such patients should, therefore, be cautioned against interruption or discontinuation of therapy without the physician's advice. Even in patients without overt coronary artery disease, it may be advisable to taper therapy with Bisoprololfumaraat Niche Generics over approximately one week with the patient under careful observation. If withdrawal symptoms occur, Bisoprololfumaraat Niche Generics therapy should be reinstituted, at least temporarily.

Peripheral Vascular Disease

Beta-blockers can precipitate or aggravate symptoms of arterial insufficiency in patients with peripheral vascular disease. Caution should be exercised in such individuals.

Bronchospastic Disease

PATIENTS WITH BRONCHOSPASTIC DISEASE SHOULD, IN GENERAL, NOT RECEIVE BETA-BLOCKERS. Because of its relative beta₁-selectivity, however, Bisoprololfumaraat Niche Generics may be used with caution in patients with bronchospastic disease who do not respond to, or who cannot tolerate other antihypertensive treatment. Since beta₁-selectivity is not absolute, the lowest possible dose of Bisoprololfumaraat Niche Generics should be used, with therapy starting at 2.5 mg. A beta₂ agonist (bronchodilator) should be made available.

Major Surgery

Chronically administered beta-blocking therapy should not be routinely withdrawn prior to major surgery; however, the impaired ability of the heart to respond to reflex adrenergic stimuli may augment the risks of general anesthesia and surgical procedures.

Diabetes And Hypoglycemia

Beta-blockers may mask some of the manifestations of hypoglycemia, particularly tachycardia. Nonselective beta-blockers may potentiate insulin-induced hypoglycemia and delay recovery of serum glucose levels. Because of its beta₁-selectivity, this is less likely with Bisoprololfumaraat Niche Generics. However, patients subject to spontaneous hypoglycemia, or diabetic patients receiving insulin or oral hypoglycemic agents, should be cautioned about these possibilities and bisoprolol fumarate should be used with caution.

Thyrotoxicosis

Beta-adrenergic blockade may mask clinical signs of hyperthyroidism, such as tachycardia. Abrupt withdrawal of beta-blockade may be followed by an exacerbation of the symptoms of hyperthyroidism or may precipitate thyroid storm.

PRECAUTIONS

Impaired Renal Or Hepatic Function

Use caution in adjusting the dose of Bisoprololfumaraat Niche Generics in patients with renal or hepatic impairment (see CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).

Risk Of Anaphylactic Reaction

While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge, either accidental, diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of epinephrine used to treat allergic reactions.

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Long-term studies were conducted with oral bisoprolol fumarate administered in the feed of mice (20 and 24 months) and rats (26 months). No evidence of carcinogenic potential was seen in mice dosed up to 250 mg/kg/day or rats dosed up to 125 mg/kg/day. On a body weight basis, these doses are 625 and 312 times, respectively, the maximum recommended human dose (MRHD) of 20 mg, (or 0.4 mg/kg/day based on a 50 kg individual); on a body surface area basis, these doses are 59 times (mice) and 64 times (rats) the MRHD. The mutagenic potential of bisoprolol fumarate was evaluated in the microbial mutagenicity (Ames) test, the point mutation and chromosome aberration assays in Chinese hamster V79 cells, the unscheduled DNA synthesis test, the micronucleus test in mice, and the cytogenetics assay in rats. There was no evidence of mutagenic potential in these in vitro and in vivo assays.

Reproduction studies in rats did not show any impairment of fertility at doses up to 150 mg/kg/day of bisoprolol fumarate, or 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively.

Pregnancy Category C

In rats, bisoprolol fumarate was not teratogenic at doses up to 150 mg/kg/day which is 375 and 77 times the MRHD on the basis of body weight and body surface area, respectively. Bisoprolol fumarate was fetotoxic (increased late resorptions) at 50 mg/kg/day and maternotoxic (decreased food intake and body weight gain) at 150 mg/kg/day. The fetotoxicity in rats occurred at 125 times the MRHD on a body weight basis and 26 times the MRHD on the basis of body surface area. The maternotoxicity occurred at 375 times the MRHD on a body weight basis and 77 times the MRHD on the basis of body surface area. In rabbits, bisoprolol fumarate was not teratogenic at doses up to 12.5 mg/kg/day, which is 31 and 12 times the MRHD based on body weight and body surface area, respectively, but was embryolethal (increased early resorptions) at 12.5 mg/kg/day.

There are no adequate and well-controlled studies in pregnant women. Bisoprololfumaraat Niche Generics (bisoprolol fumarate) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Small amounts of bisoprolol fumarate (< 2% of the dose) have been detected in the milk of lactating rats. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk caution should be exercised when bisoprolol fumarate is administered to nursing women.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Bisoprololfumaraat Niche Generics has been used in elderly patients with hypertension. Response rates and mean decreases in systolic and diastolic blood pressure were similar to the decreases in younger patients in the U.S. clinical studies. Although no dose response study was conducted in elderly patients, there was a tendency for older patients to be maintained on higher doses of bisoprolol fumarate.

Observed reductions in heart rate were slightly greater in the elderly than in the young and tended to increase with increasing dose. In general, no disparity in adverse experience reports or dropouts for safety reasons was observed between older and younger patients. Dose adjustment based on age is not necessary.

In a study of coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patient's response to treatment, the ability to drive a vehicle or to use machines may be impaired. This should be considered particularly at the start of treatment and upon change of medication or in conjunction with alcohol.

In a study with coronary heart disease patients Bisoprololfumaraat Niche Generics did not impair driving performance. However, due to individual variations in reactions to the drug, the ability to drive a vehicle or to operate machinery may be impaired. This should be considered particularly at start of treatment and upon change of medication as well as in conjunction with alcohol.

The following definitions apply to the frequency terminology used hereafter:

Very common (>1/10)

Common (>1/100 to <1/10)

Uncommon (>1/1,000 to <1/100)

Rare (>1/10,000 to <1/1,000)

Very rare (<1/10,000)

Not known (cannot be estimated from the available data).

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Nervous system disorders:

Common: dizziness*, headache*.

Rare: syncope.

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing disorders.

Cardiac disorders:

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: AV-conduction disturbances; worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension especially in patients with heart failure.

Uncommon: orthostatic hypotension.

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.

Hepatobiliary disorders:

Rare: hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions such as itching, flush, rash.

Very rare: alopecia, beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness, muscle cramps.

Reproductive system and breast disorders:

Rare: potency disorders.

General disorders and administration site conditions:

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with hypertension or angina pectoris).

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Paediatric population:

No data are available.

applies only to hypertension or angina pectoris:

*These symptoms especially occur at the beginning of the therapy. They are generally mild and often disappear within 1 to 2 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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)

Psychiatric disorders:

Uncommon: sleep disorders, depression.

Rare: nightmares, hallucinations.

Nervous system disorders:

Common: dizziness*, headache*

Rare: syncope

Eye disorders:

Rare: reduced tear flow (to be considered if the patient uses lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders:

Rare: hearing disorders.

Cardiac disorders:

Very common: bradycardia (in patients with chronic heart failure).

Common: worsening of pre-existing heart failure (in patients with chronic heart failure).

Uncommon: AV-conduction disturbances, worsening of pre-existing heart failure (in patients with hypertension or angina pectoris); bradycardia (in patients with hypertension or angina pectoris).

Vascular disorders:

Common: feeling of coldness or numbness in the extremities, hypotension especially in patient with heart failure.

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.

Hepatobiliary disorders:

Rare: hepatitis.

Skin and subcutaneous tissue disorders:

Rare: hypersensitivity reactions (such as itching, flush, rash).

Very rare: beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon: muscular weakness and cramps.

Reproductive system and breast disorders:

Rare: potency disorders

General disorders:

Common: asthenia (in patients with chronic heart failure), fatigue*.

Uncommon: asthenia (in patients with hypertension or angina pectoris)

Investigations:

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Applies only to hypertension or angina pectoris:

*These symptoms especially occur at the beginning of the therapy. They are generally mild and usually disappear within 1 - 2 weeks.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the national reporting system Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

Safety data are available in more than 30,000 patients or volunteers. Frequency estimates and rates of withdrawal of therapy for adverse events were derived from two U.S. placebo-controlled studies.

In Study A, doses of 5, 10, and 20 mg bisoprolol fumarate were administered for 4 weeks. In Study B, doses of 2.5, 10, and 40 mg of bisoprolol fumarate were administered for 12 weeks. A total of 273 patients were treated with 5-20 mg of bisoprolol fumarate; 132 received placebo.

Withdrawal of therapy for adverse events was 3.3% for patients receiving bisoprolol fumarate and 6.8% for patients on placebo. Withdrawals were less than 1% for either bradycardia or fatigue/lack of energy.

The following table presents adverse experiences, whether or not considered drug related, reported in at least 1% of patients in these studies, for all patients studied in placebo-controlled clinical trials (2.5- 40 mg), as well as for a subgroup that was treated with doses within the recommended dosage range (5- 20 mg). Of the adverse events listed in the table, bradycardia, diarrhea, asthenia, fatigue, and sinusitis appear to be dose related.

The following is a comprehensive list of adverse experiences reported with bisoprolol fumarate in worldwide studies, or in postmarketing experience (in italics):

Central Nervous System

Dizziness, unsteadiness, vertigo, syncope, headache, paresthesia, hypoesthesia, hyperesthesia, somnolence, sleep disturbances, anxiety/restlessness, decreased concentration/memory.

Autonomic Nervous System

Dry mouth.

Cardiovascular

Bradycardia, palpitations and other rhythm disturbances, cold extremities, claudication, hypotension, orthostatic hypotension, chest pain, congestive heart failure, dyspnea on exertion.

Psychiatric

Vivid dreams, insomnia, depression.

Gastrointestinal

Gastric/epigastric/abdominal pain, gastritis, dyspepsia, nausea, vomiting, diarrhea, constipation, peptic ulcer.

Musculoskeletal

Muscle/joint pain, arthralgia, back/neck pain, muscle cramps, twitching/tremor.

Skin

Rash, acne, eczema, psoriasis, skin irritation, pruritus, flushing, sweating, alopecia, dermatitis, angioedema, exfoliative dermatitis, cutaneous vasculitis.

Special Senses

Visual disturbances, ocular pain/pressure, abnormal lacrimation, tinnitus, decreased hearing, earache, taste abnormalities.

Metabolic

Gout.

Respiratory

Asthma/bronchospasm, bronchitis, coughing, dyspnea, pharyngitis, rhinitis, sinusitis, URI.

Genitourinary

Decreased libido/impotence, Peyronie's disease, cystitis, renal colic, polyuria.

Hematologic

Purpura.

General

Fatigue, asthenia, chest pain, malaise, edema, weight gain, angioedema.

In addition, a variety of adverse effects have been reported with other beta-adrenergic blocking agents and should be considered potential adverse effects of Bisoprololfumaraat Niche Generics:

Central Nervous System

Reversible mental depression progressing to catatonia, hallucinations, an acute reversible syndrome characterized by disorientation to time and place, emotional lability, slightly clouded sensorium.

Allergic

Fever, combined with aching and sore throat, laryngospasm, respiratory distress.

Hematologic

Agranulocytosis, thrombocytopenia, thrombocytopenic purpura.

Gastrointestinal

Mesenteric arterial thrombosis, ischemic colitis.

Miscellaneous

The oculomucocutaneous syndrome associated with the beta-blocker practolol has not been reported with Bisoprololfumaraat Niche Generics (bisoprolol fumarate) during investigational use or extensive foreign marketing experience.

Laboratory Abnormalities

In clinical trials, the most frequently reported laboratory change was an increase in serum triglycerides, but this was not a consistent finding.

Sporadic liver test abnormalities have been reported. In the U.S. controlled trials experience with bisoprolol fumarate treatment for 4-12 weeks, the incidence of concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 3.9%, compared to 2.5% for placebo. No patient had concomitant elevations greater than twice normal.

In the long-term, uncontrolled experience with bisoprolol fumarate treatment for 6-18 months, the incidence of one or more concomitant elevations in SGOT and SGPT from 1 to 2 times normal was 6.2%. The incidence of multiple occurrences was 1.9%. For concomitant elevations in SGOT and SGPT of greater than twice normal, the incidence was 1.5%. The incidence of multiple occurrences was 0.3%. In many cases these elevations were attributed to underlying disorders, or resolved during continued treatment with bisoprolol fumarate.

Other laboratory changes included small increases in uric acid, creatinine, BUN, serum potassium, glucose, and phosphorus and decreases in WBC and platelets. These were generally not of clinical importance and rarely resulted in discontinuation of bisoprolol fumarate.

As with other beta-blockers, ANA conversions have also been reported on bisoprolol fumarate. About 15% of patients in long-term studies converted to a positive titer, although about one-third of these patients subsequently reconverted to a negative titer while on continued therapy.

Symptoms

With overdose (e.g. daily dose of 15 mg instead of 7.5 mg) third degree AV-block, bradycardia, and dizziness have been reported.

Management

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 beta-blockers, the following general measures may 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 transvenous cardiac pacemaker insertion.

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Limited data suggest that bisoprolol is hardly dialysable.

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is limited experience with overdose of Bisoprololfumaraat Niche Generics, only a few cases of overdose with Bisoprololfumaraat Niche Generics have been reported. Bradycardia and/or hypotension were noted. All patients recovered. There is a wide inter-individual variation in sensitivity to one single high dose of Bisoprololfumaraat Niche Generics and patients with heart failure are probably very sensitive.

In general, if overdose occurs, discontinuation of Bisoprololfumaraat Niche Generics treatment and supportive and symptomatic treatment is recommended.

Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures may be considered when clinically warranted.

Bradycardia: Administer intravenous atropine. If the response is inadequate, isoprenaline or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension: Intravenous fluids and vasopressors should be administered. Intravenous glucagon may be useful.

AV block (second or third degree): Patients should be carefully monitored and treated with isoprenaline infusion or temporary pacing..

Acute worsening of heart failure: Administer i.v. diuretics, inotropic agents, vasodilating agents.

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, beta2-sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

Limited data suggest that Bisoprololfumaraat Niche Generics is hardly dialysable.

The most common signs expected with overdosage of a beta-blocker are bradycardia, hypotension, congestive heart failure, bronchospasm, and hypoglycemia. To date, a few cases of overdose (maximum: 2000 mg) with bisoprolol fumarate have been reported. Bradycardia and/or hypotension were noted. Sympathomimetic agents were given in some cases, and all patients recovered.

In general, if overdose occurs, Bisoprololfumaraat Niche Generics therapy should be stopped and supportive and symptomatic treatment should be provided. Limited data suggest that bisoprolol fumarate is not dialyzable. Based on the expected pharmacologic actions and recommendations for other beta-blockers, the following general measures should be considered when clinically warranted:

Bradycardia

Administer IV atropine. If the response is inadequate, isoproterenol or another agent with positive chronotropic properties may be given cautiously. Under some circumstances, transvenous pacemaker insertion may be necessary.

Hypotension

IV fluids and vasopressors should be administered. Intravenous glucagon may be useful.

Heart Block (Second Or Third Degree)

Patients should be carefully monitored and treated with isoproterenol infusion or transvenous cardiac pacemaker insertion, as appropriate.

Congestive Heart Failure

Initiate conventional therapy (ie, digitalis, diuretics, inotropic agents, vasodilating agents).

Bronchospasm

Administer bronchodilator therapy such as isoproterenol and/or aminophylline.

Hypoglycemia

Administer IV glucose.

Pharmacotherapeutic group: Beta blocking agents, selective, ATC code: C07 AB07

Chronic heart failure:

Mechanism of action

Bisoprolol is a potent, highly beta1-selective adrenoreceptor blocking agent lacking intrinsic sympathomimetic activity and without relevant membrane stabilising activity. It only shows low affinity to the beta2-receptor of the smooth muscles of bronchi and vessels as well as to the beta2-receptors concerned with metabolic regulation. Therefore, bisoprolol is generally not to be expected to influence the airway resistance and beta2-mediated metabolic effects. Its beta1-selectivity extends beyond the therapeutic dose range.

Clinical efficacy

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) 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% (relative reduction 34%). 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 admission 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%). The numbers of fatal and disabling strokes during the total study period were 20 in the bisoprolol group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged >65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had not been treated previously with ACE inhibitors, beta-blocking agents, or angiotensin receptor blockers. Patients were treated with a combination of bisoprolol and enalapril for 6 to 24 months after an initial 6 months treatment with either bisoprolol or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when bisoprolol was used as the initial 6 months treatment. Non inferiority of bisoprolol-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the bisoprolol-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that bisoprolol can also be used in elderly chronic heart failure patients with mild to moderate disease.

Hypertension or angina pectoris:

Mechanism of action

Antianginal mechanism: Bisoprolol by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

In acute administration in patients with coronary heart disease without chronic heart failure bisoprolol reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.

Pharmacodynamic effects

Bisoprolol is used for the treatment of hypertension and angina pectoris. As with other Beta-1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprolol reduces plasma renin activity markedly.

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Bisoprololfumaraat Niche Generics is a potent highly beta₁-selective-adrenoceptor blocking agent, lacking intrinsic stimulating and without relevant membrane stabilising activity. It only shows low affinity to the beta₂-receptor of the smooth muscles of bronchi and vessels as well as to the beta₂-receptors concerned with metabolic regulation. Therefore, Bisoprololfumaraat Niche Generics is generally not to be expected to influence the airway resistance and beta₂-mediated metabolic effects. Its beta₁-selectivity extends beyond the therapeutic dose range.

Chronic heart failure:

In total 2647 patients were included in the CIBIS II trial. 83% (n = 2202) 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% (relative reduction 34%). 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 Bisoprololfumaraat Niche Generics hospital admission 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%). The numbers of fatal and disabling strokes during the total study period were 20 in the Bisoprololfumaraat Niche Generics group and 15 in the placebo group.

The CIBIS III trial investigated 1010 patients aged >65 years with mild to moderate chronic heart failure (CHF; NYHA class II or III) and left ventricular ejection fraction ≤35%, who had not been treated previously with ACE inhibitors, beta-blockers, or angiotensin receptor blockers. Patients were treated with a combination of Bisoprololfumaraat Niche Generics and enalapril for 6 to 24 months after an initial 6 months treatment with either Bisoprololfumaraat Niche Generics or enalapril.

There was a trend toward higher frequency of chronic heart failure worsening when Bisoprololfumaraat Niche Generics was used as the initial 6 months treatment. Non inferiority of Bisoprololfumaraat Niche Generics-first versus enalapril-first treatment was not proven in the per-protocol analysis, although the two strategies for initiation of CHF treatment showed a similar rate of the primary combined endpoint death and hospitalization at study end (32.4% in the Bisoprololfumaraat Niche Generics-first group vs. 33.1 % in the enalapril-first group, per-protocol population). The study shows that Bisoprololfumaraat Niche Generics can also be used in elderly chronic heart failure patients with mild to moderate disease.

Hypertension or angina pectoris:

Bisoprololfumaraat Niche Generics is used for the treatment of hypertension and angina pectoris. As with other Beta- 1-blocking agents, the method of acting in hypertension is unclear. However, it is known that Bisoprololfumaraat Niche Generics reduces plasma renin activity markedly.

Antianginal mechanism: Bisoprololfumaraat Niche Generics by inhibiting the cardiac beta receptors inhibits the response given to sympathetic activation. That results in the decrease of heart rate and contractility this way decreasing the oxygen demand of the cardiac muscle.

In acute administration in patients with coronary heart disease without chronic heart failure Bisoprololfumaraat Niche Generics reduces the heart rate and stroke volume and thus the cardiac output and oxygen consumption. In chronic administration the initially elevated peripheral resistance decreases.

Absorption

Bisoprolol is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%.

Distribution

The plasma protein binding of bisoprolol is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

Biotransformation

50 % is metabolised by the liver to inactive metabolites which are then excreted by the kidneys.

Elimination

Bisoprolol is excreted from the body by two routes. 50% is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50% is excreted by the kidneys in an unmetabolised form. Since the elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency.

Other special population

In patients with chronic heart failure (NYHA stage III) the plasma levels of bisoprolol are higher and the half-life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half-life is 17±5 hours.

Bisoprololfumaraat Niche Generics is absorbed almost completely from the gastrointestinal tract. Together with the very small first pass effect in the liver, this results in a high bioavailability of approximately 90%. The plasma protein binding of Bisoprololfumaraat Niche Generics is about 30 %. The distribution volume is 3.5 l/kg. The total clearance is approximately 15 l/h.

The plasma elimination half-life (10-12 hours) provides 24 hours efficacy following a once daily dosage.

Bisoprololfumaraat Niche Generics is excreted from the body by two routes, 50 % is metabolised by the liver to inactive metabolites which are then excreted by the kidneys. The remaining 50 % is excreted by the kidneys in an unmetabolised form. Since elimination takes place in the kidneys and the liver to the same extent a dosage adjustment is not required for patients with impaired liver function or renal insufficiency.

In patients with chronic heart failure (NYHA stage III) the plasma levels of Bisoprololfumaraat Niche Generics are higher and the half life is prolonged compared to healthy volunteers. Maximum plasma concentration at steady state is 64±21 ng/ml at a daily dose of 10 mg and the half life is 17±5 hours.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential, toxicity to reproduction and development.

Like other beta-blockers, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity..

Like other beta-blockers, Bisoprololfumaraat Niche Generics caused maternal (decreased food intake and decreased body weight) and embryo/fetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

Not applicable.

Not applicable

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.