BISOPROLOL 10 MG TABLETS, SOLOC 10 MG TABLETS - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Soloc 10mg tablets.

Bisoprolol 10mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains bisoprolol as 10mg bisoprolol fumarate and refer to section 6.1 for the inactive ingredients.

Film-coated Tablets.

4.1

Management of hypertension.

Management of angina pectoris.

Treatment of stable chronic heart failure with reduced systolic left ventricular function in addition to ACE inhibitors, and diuretics, and optionally cardiac glycosides (for additional information see section 5.1)

4.2 Posology and method of administration

Route of administration: Oral

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

They should be swallowed with liquid and should not be chewed.

Treatment of hypertension or angina pectoris

Adults: Usual dose 10mg once daily.

This dose may be decreased or increased according to the patient’s blood pressure and tolerance. In some patients, 5mg per day may be adequate.

The maximum recommended dose is 20mg once daily.

Renal or liver impairment:-

In patients with severe renal impairment (creatinine clearance <20 ml/min) and in patients with severe liver function disorders, it is recommended that a daily dose of 10mg bisoprolol hemifumarate is not exceeded.

Treatment of stable chronic heart failure

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.

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 bisoprolol requires a titration phase.

Treatment with bisoprolol should be started with a gradual up titration 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 bisoprolol or to consider discontinuation.

The reintroduction and/or uptitration of bisoprolol should always be considered when the patient becomes stable again.

If discontinuation is considered, gradual dose decrease is recommended, since abrupt withdrawal may lead to acute deterioration of the patients

condition.

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

Renal or liver insufficiency

There is no information regarding pharmacokinetics of bisoprolol in patients with chronic heart failure and with impaired liver or renal function. Up-titration of the dose in these populations should therefore be made with additional caution.

No dosage adjustment is normally required, but 5mg per day may be adequate in some patients as for other adults.

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

4.3 Contraindications

As with other ß1-adrenoceptor antagonists, bisoprolol should not be used in cases of:

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

Cardiogenic shock

Sinoatrial block

Second or third degree atrio-ventricular block (without a pacemaker)

Marked bradycardia (less than 60 beats/min)-Symptomatic bradycardia,

Extreme hypotension (systolic blood pressure <100mmHg) -Symptomatic hypotension

Severe bronchial asthma or severe chronic obstructive pulmonary disease

Sick sinus syndrome

Severe forms of peripheral arterial occlusive disease and Raynaud's syndrome

Untreated pheochromocytoma (see section 4.4)

Metabolic acidosis

Bisoprolol is contra-indicated in patients with hypersensitivity to bisoprolol or to any of the excipients (see section 6.1).

4.4 Special warnings and precautions for use

The treatment of stable chronic heart failure with bisoprolol has to be initiated with a special titration phase (see section 4.2)

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 (see section 4.2).

The initiation of treatment of stable chronic heart failure with bisoprolol necessitates regular monitoring. For the dosage and method of administration see section 4.2.

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 liver function

restrictive cardiomyopathy

congenital heart disease

haemodynamically significant organic valvular disease

myocardial infarction within 3 months

Bisoprolol must be used with caution in

diabetes mellitus showing 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, 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

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.

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.

For patients with severe renal impairment and patients with severe liver function disorders please refer to section 4.2.

Combination of bisoprolol with calcium antagonists of the verapamil or diltiazem type or with centrally acting antihypertensive drugs is generally not recommended, for details please refer to section 4.5.

Drug Withdrawal

Patients receiving bisoprolol should be warned not to interrupt or discontinue therapy without consulting their physician. Abrupt withdrawal should be avoided in patients receiving bisoprolol for the treatment of hypertension. When bisoprolol is discontinued in patients with coronary disease or suspected thyrotoxicosis, the patient should be observed carefully; patients with coronary artery disease should be advised to temporarily limit their physical activity. If exacerbation of angina occurs or acute coronary insufficiency develops after bisoprolol therapy is interrupted or discontinued, treatment with the drug should be re-instituted, at least temporarily.

4.5 Interaction with other medicinal products and other forms of interaction Combinations not recommended

4.6 Fertility, Pregnancy and lactationPregnancy:

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, ß-adrenoceptor blockers reduce placental perfusion, which has been associated with growth retardation, intrauterine death, abortion or early labour. Adverse effects (e.g. hypoglycaemia and bradycardia) may occur in the foetus and newborn infant. If treatment with ß-adrenoceptor blockers is necessary, ß1-selective adrenoceptor blockers are preferable.

Bisoprolol should not be used during pregnancy unless clearly necessary. If treatment with bisoprolol is considered necessary, monitoring of the uteroplacental blood flow and the foetal growth is recommended. 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.

There are no data on the excretion of bisoprolol in human breast milk or the safety of bisoprolol exposure in infants. Therefore, breastfeeding is not recommended during administration of bisoprolol.

4.7 Effects on ability to drive and use machines

In a study of coronary heart disease patients, bisoprolol did not impair driving performance. However, depending on the individual patients response to treatment, an effect on the ability to drive a vehicle or to use machinery cannot be excluded. This needs to be considered particularly at the start of treatment, upon change of medication, or in conjunction with alcohol.

4.8 Undesirable effects

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), 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 pectoria), bradycardia (in patients with hypertension or angina

pectoria).

Vascular disorders:

Common:       feeling of coldness or numbness in the extremities,

hypotension (especially in patients 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 (itching, flush, rash).

Very rare:      beta-blockers may provoke or worsen psoriasis or induce

psoriasis-like rash, alopecia.

Musculoskeletal and connective tissue disorders:

Uncommon:    muscle weakness, muscle cramps.

Reproductive system and breast disorders:

General disorders:

Rare:

potency disorders.

Investigations

Rare:

increased triglycerides, increased liver enzymes (ALAT, ASAT)

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

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.

4.9 Overdose

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

In general, if overdose occurs, bisoprolol treatment should be stopped and supportive and symptomatic treatment is recommended. Limited data suggest that bisoprolol is hardly dialysable.

Based on the expected pharmacological actions and recommendations for other B-blockers, the following general measures should be considered when clinically warranted.

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

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

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

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

Bronchospasm: Administer bronchodilator therapy such as isoprenaline, B2– sympathomimetic drugs and/or aminophylline.

Hypoglycaemia: Administer i.v. glucose.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective

ATC Code: C07AB07

Bisoprolol is a highly pi-selective adrenoreceptor blocking agent without intrinsic sympathomimetic activity and 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.

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 towards 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 hospitalisation at study end (32.4% in 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.

Bisoprolol is also used for the treatment of hypertension and angina pectoris.

As with other P1-blocking agents, the mode of action in hypertension is not clear but it is known that bisoprolol markedly depresses plasma renin activity.

In patients with angina, the blockade of P1-receptors reduces heart action and thus reduces oxygen demand. Hence, bisoprolol is effective in eliminating or reducing the symptoms.

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.

5.2 Pharmacokinetic properties

Bisoprolol is absorbed and has a biological availability of about 90% after oral administration. The plasma protein binding of bisoprolol is about 30%. The distribution volume is 3.5l/kg. Total clearance is approximately 15l/h. The half-life in plasma of 10–12 hours gives a 24 hour effect after dosing once daily.

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. The pharmacokinetics in patients with stable chronic heart failure and with impaired liver or renal function has not been studied.

The kinetics of bisoprolol are linear and independent of age.

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.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenicity. Like other beta-blocking agents, bisoprolol caused maternal (decreased food intake and decreased body weight) and embryo/foetal toxicity (increased incidence of resorptions, reduced birth weight of the offspring, retarded physical development) at high doses but was not teratogenic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Maize Starch

Microcrystalline Cellulose

Crospovidone

Calcium Hydrogen Phosphate

Magnesium Stearate

Colloidal Silica

Film-coating:

Hypromellose

Iron Oxide (E172)

Titanium dioxide (E171)

Macrogol

Dimeticone

6.2 Incompatibilities

None stated.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVC /PVDC aluminium blister packs

Blister pack sizes 28, 30, 56, 100 & 112

Blister packs 28, 56 & 112 containing strips of 14 tablets.

Blister packs 30 & 100 containing strips of 10 tablets.

6.6 Special precautions for disposal None.

7 MARKETING AUTHORISATION HOLDER

Dalkeith Laboratories Ltd

2 Park Street

Woburn

Bedfordshire

MK17 9PG

8 MARKETING AUTHORISATION NUMBER(S)

PL 17496/0026

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

3 April 2002