SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Bisoprolol Fumarate / Hydrochlorothiazide 2.5 mg / 6.25 mg Film-Coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Film-coated tablet.

Yellow, film-coated, round tablet, debossed with "2.5" on one side of the tablet and "BH" on the other side of the tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Mild to moderate essential hypertension.

4.2.    Posology and method of administration

Other strengths of this medicinal product or other products are available.

The usual starting dose is one bisoprolol 2.5 mg / hydrochlorothiazide 6.25 mg tablet once daily.

If the antihypertensive effect of this dosage is inadequate, the dose will be increased to one bisoprolol 5 mg / hydrochlorothiazide 6.25 mg tablet once daily and, if response is still inadequate, to one bisoprolol 10 mg / hydrochlorothiazide 6.25 mg tablet once daily.

If discontinuation is necessary, gradual discontinuation of bisoprolol treatment is recommended, since abrupt withdrawal of bisoprolol may lead to an acute deterioration of the patient's condition, in particular in patients with ischaemic heart disease.

The tablets should be swallowed in the morning, and can be taken with food. They should be swallowed with some liquid and not be chewed.

Renal and hepatic impairment

No dose adjustment is necessary in patients with mild to moderate hepatic impairment or mild to moderate renal impairment (creatinine clearance > 30 ml/min).

Elderly patients

No dose adjustment is normally required (see section 4.4).

Paediatric patients

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

4.3 Contraindications

This medicinal product is contraindicated in patients with hypersensitivity to bisoprolol, hydrochlorothiazide, other thiazides, sulphonamides or any of the excipients (see section 6.1).

Bisoprolol/HCTZ is contra-indicated in patients with:

- hypersensitivity to bisoprolol, hydrochlorothiazide, other thiazides, sulphonamides, or any of the excipients

•    acute heart failure or during episodes of heart failure decompensation requiring intravenous inotropic therapy

•    cardiogenic shock

•    second or third degree AV block

•    sick sinus syndrome

•    sinoatrial block

•    symptomatic bradycardia

•    severe bronchial asthma or severe chronic obstructive pulmonary disease

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

•    untreated phaeochromocytoma

•    severe renal impairment (creatinine clearance 30 ml/min)

•    severe hepatic impairment

•    metabolic acidosis

•    refractory hypokalaemia

4.4 Special warnings and precautions for use

Warnings

Treatment with bisoprolol must not be withdrawn abruptly unless clearly indicated, since abrupt withdrawal of bisoprolol may lead to an acute deterioration of the patient's condition in particular in patients with ischaemic heart disease.

Bisoprolol must be used with caution in patients with

Liver disease

Liver disease, thiazide diuretics and related products may trigger hepatic encephalopathy. Should this happen, diuretic therapy must be stopped immediately.

Lactating women

This medicinal product should not be taken by lactating women (see section 4.6).

Asthma and chronic obstructive pulmonary disease

Beta-blockers may be used only in mild forms of asthma or COPD, using a beta₁-selective adrenoceptor blocking agent and a low starting dose. Pulmonary function testing is recommended before the start of therapy. Concomitant bronchodilating therapy is recommended in symptomatic patients. Occasionally, an increase in airway resistance may occur in patients with asthma or COPD, therefore the dose of beta₂-stimulants may have to be increased.

Cardiac failure

Patients with compensated cardiac failure who require beta-blocker therapy may be administered bisoprolol using a very low starting dose, to be increased gradually with close medical monitoring.

First degree atrioventricular block

Having negative dromotropic activity, beta-blockers should be used cautiously in patients with first degree atrioventricular block.

Prinzmetal ’s angina

Beta-blockers may increase the frequency and length of vasospastic episodes in patient with Prinzmetal’s angina. A beta₁-selective beta-blocker may be used in minor or mixed clinical presentations of Prinzmetal’s angina if a vasodilator is used concurrently.

Peripheral arterial occlusive disease

Beta-blockers may aggravate symptoms of peripheral arterial occlusive disease (PAOD) or Raynaud's syndrome. Such patients should preferably be prescribed a beta₁-selective beta-blocker.

Phaeochromocytoma

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

Blood pressure should be closely monitored.

Elderly

No dose adjustment is normally required. However, elderly patients should be closely monitored (see paragraph 'Fluid and electrolyte balance').

Diabetics

Diabetic patients should be aware of the risk of hypoglycaemic episodes and of the increased need for careful home glucose monitoringin the initial phase of therapy.

The warning signs of hypoglycaemia, particularly tachycardia, palpitations and sweating, may be masked.

Psoriasis

There have been reports of beta-blockers being associated with worsening of psoriasis, thus patients with psoriasis should receive bisoprolol only if clearly needed.

Hypersensitivity reactions

In patients at risk of severe anaphylactic reaction to whatever allergen, particularly when using iodine-containing contrast materials (see section 4.5) or during specific immunotherapy (desensitisation), beta-blockers may aggravate the anaphylactic reaction and cause unresponsiveness to the usual doses of epinephrine used to treat hypersensitivity reactions.

General anaesthesia

In patients undergoing general anaesthesia, beta-blockade reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation, and in the post-operative period. It is currently recommended that maintenance beta-blockade be continued peri-operatively. The anaesthetist must be aware of beta-blockade because of the potential for interactions with other agents, 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.

Thyrotoxicosis

Beta-blockers may mask the cardiovascular signs of hyperthyroidism.

Competitive athletes

Competitive athletes should be aware that this medicinal product contains an agent that may give a positive reaction in doping tests.

Strict fasting

This medicinal product must be used with caution in patients under strict fasting.

Combination with verapamil, diltiazem or bepridil

Such combinations require a close clinical and electrocardiographical monitoring, notably in the elderly and at the beginning of the treatment (see section 4.5).

Fluid and electrolyte balance

During long-term therapy with bisoprolol/hydrochlorothiazide, periodic monitoring of serum electrolytes (especially potassium, sodium, calcium), creatinine and urea, serum lipids (cholesterol and triglycerides), uric acid as well as blood glucose is recommended.

Long-term, continuous administration of hydrochlorothiazide may lead to fluid and electrolyte disturbances, in particular hypokalaemia and hyponatraemia, also to hypomagnesaemia and hypochloraemia, and hypercalcaemia.

Plasma sodium

Plasma sodium should be determined before and periodically during therapy. Any diuretic therapy may give rise to hyponatraemia, with serious consequences in some cases.

As hyponatraemia may initially be asymptomatic, periodic monitoring is indispensable and should be more frequent in high-risk populations, i.e. the elderly and patients with cirrhosis of the liver.

Plasma potassium

Potassium loss resulting in hypokalaemia is the greatest risk associated with thiazide diuretics and related drugs.

The risk of hypokalaemia (< 3.5 mmol/L) should be anticipated in certain high-risk populations, i.e. the elderly and/or malnourished and/or taking multiple drugs, and patients with coronary artery disease or heart failure, where hypokalaemia increases the cardiotoxicity of digitalis glycosides and the risk of cardiac arrhythmia.

Also at risk are patients with long QT syndrome, either congenital or iatrogenic. Hypokalaemia (as well as bradycardia) facilitates the development of severe arrhythmias, particularly torsades de pointes, which may be fatal.

More frequent plasma potassium monitoring is indicated in all of the above populations, starting within the week after initiation of therapy.

Plasma calcium

Thiazide diuretics and related drugs may reduce urinary calcium excretion, resulting in mild, transient hypercalcaemia. Significant hypercalcaemia may be related to undiagnosed hyperparathyroidism.

Therapy must be interrupted before performin parathyroid function tests.

Combination with lithium

Due to the diuretic, this combination should be avoided (see section 4.5).

Blood glucose

In diabetics, blood glucose must be monitored, especially in the presence of hypokalaemia.

Uric acid

In patients with hyperuricaemia, the risk for attacks of gout may be increased. Dosage should be adjusted as a function of uric acid plasma concentrations.

Kidney function and diuretics

Full benefit from thiazide diuretics can be derived only if kidney function is normal or almost normal (serum creatinine levels < 25 mg/L, or 220 pmol/L in adults).

Serum creatinine needs to be corrected for age, weight and gender, using Cockroft’s formula, for instance:

* Cl_Cr = (140 - age) x weight/0.814 x serum creatinine

Where age is indicated in years, weight in kg, and serum creatinine in micromol/L.

The above formula gives ClCr for elderly male subjects, and needs to be corrected for elderly female subjects by multiplying by 0.85.

Hypovolaemia secondary to diuretic-induced water and sodium loss at the start of therapy reduces glomerular filtration, which may result in blood urea nitrogen and serum creatinine increases.

This transient functional renal impairment is non-relevant in patients with normal kidney function but may worsen pre-existing renal insufficiency.

Combination with other antihypertensive drugs

It is advisable to reduce the dosage when this medicinal product is combined with another antihypertensive, at least in the initial phase of therapy.

Photosensitivity

If photosensitivity reactions occur, it is recommended to protect exposed areas to the sun or to artificial UVA light. In severe cases it may be necessary to stop the treatment.

Competitive athletes

Competitive athletes should be aware that this medicinal product contains an agent that may give a positive reaction in doping tests.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations not recommended

Lithium: Bisoprolol / hydrochlorothiazide may intensify the cardiotoxic and neurotoxic effect of lithium through a reduction of lithium excretion.

Calcium antagonists of the verapamil type and the diltiazem type: Negative effect on contractility and atrio-ventricular conduction. Intravenous administration of verapamil in patients on B-blocker treatment may lead to profound hypotension and atrioventricular block.

Centrally-acting antihypertensive agents: Concomitant use of centrally-acting antihypertensive agents may lead to a further reduction in heart rate and cardiac output and to vasodilatation. Abrupt withdrawal, may increase the risk of 'rebound hypertension'.

Combinations to be used with caution

Calcium antagonists of the dihydropyridine type: Concomitant use may increase the risk of hypotension, and an increase in the risk of a further deterioration of the ventricular pump function in patients with heart failure cannot be excluded.

Concomitant use with other antihypertensive agents or with other medicinal products with blood pressure lowering potential may increase the risk of hypotension.

ACE inhibitors, Angiotensin II antagonists: Risk of significant fall in blood pressure and/or acute renal failure during initiation of ACE inhibitor therapy in patients with preexisting sodium depletion (particularly in patients with renal artery stenosis).

If prior diuretic therapy has produced sodium depletion, either stop the diuretic 3 days before starting ACE inhibitor therapy, or initiate ACE inhibitor therapy at a low dose.

Class-I antiarrhythmic agents: Effect on atrio-ventricular conduction time may be potentiated and negative inotropic effect increased.

Class-III antiarrhythmic agents: Effect on atrio-ventricular conduction time may be potentiated.

Antiarrhythmic agents that may induce torsade de pointes: Hypokalaemia may facilitate the occurrence of torsades de pointes.

Nonantiarrhythmic agents that may induce torsade de pointes: Hypokalaemia may facilitate the occurrence of torsades de pointes.

Parasympathomimetic agents: Concomitant use may increase atrio-ventricular conduction time and the risk of bradycardia.

Topical beta-blockers (e.g. eye drops for glaucoma treatment) may add to the systemic effects of bisoprolol.

Insulin and oral antidiabetic agents: Increase of blood sugar lowering effect. Blockade of beta-adrenoceptors may mask symptoms of hypoglycaemia.

Anaesthetic agents: Attenuation of the reflex tachycardia and increase of the risk of hypotension.

Digitalis glycosides: Increase of atrio-ventricular conduction time, reduction in heart rate. If hypokalaemia and/or hypomagnesaemia develop during treatment with Bisoprolol / hydrochlorothiazide the myocardium may show increased sensitivity to cardiac glycosides, leading to an enhanced effect and adverse effects of the glycosides.

Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs may reduce the hypotensive effect.

In patients developing hypovolaemia the concomitant administration of NSAIDs can trigger acute renal failure.

Beta-sympathomimetics: Combination with bisoprolol may reduce the effect of both agents.

Sympathomimetics that activate both beta- and alpha-adrenoceptors: Combination with bisoprolol may lead to blood pressure increase. Such interactions are considered to be more likely with nonselective beta-blockers.

Potassium-wasting medicinal products may result in increased potassium losses.

Methyldopa: haemolysis due to the formation of antibodies to hydrochlorothiazide has been described in isolated cases.

The effect of uric-acid-lowering agents may be attenuated in concomitant administration of Bisoprolol / hydrochlorothiazide

Cholestyramine, colestipol: reduces the absorption of the hydrochlorothiazide component of Bisoprolol / hydrochlorothiazide.

Combinations to be considered

Mefloquine: increased risk of bradycardia.

Corticosteroids: Reduced antihypertensive effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

Bisoprolol

Bisoprolol has pharmacological effects that may cause harmful effects on pregnancy and/or the foetus/newborn. In general, beta-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 beta-adrenoceptor blockers is necessary, beta1-selective adrenoceptor blockers are preferable.

Hydrochlorothiazide

There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient.

Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the second and third trimester may compromise feto-placental perfusion and may cause fetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia.

Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used.

Lactation

Bisoprolol is not recommended in breastfeeding women. Hydrochlorothiazide can inhibit the milk production.

4.7 Effects on ability to drive and use machines

In general Bisoprolol has no or neglible influence on the ability to drive and use machines. Depending on the individual patient’s response to treatment with bisoprolol/hydrochlorothiazide the ability to drive and use machines may be impaired. This should be considered particularly at the start of treatment as well as in conjuction with alcohol.

4.8. Undesirable effects

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)

Blood and lymphatic system disorders Rare: leucopenia, thrombocytopenia Very rare:    agranulocytosis

Metabolism and nutrition disorders

Uncommon:    loss of appetite, hyperglycaemia, hyperuricaemia, disturbances of

fluid and electrolyte balance (in particular hypokalaemia and hyponatraemia, also hypomagnesaemia and hypochloraemia as well as hypercalcaemia)

Very rare:    metabolic alkalosis

Psychiatric disorders

Uncommon:    depression, sleep disorders

Rare: nightmares, hallucinations

Nervous system disorders Common    dizziness*, headache*

Eye disorders

Rare: reduced tear flow (to be taken into consideration in patients wearing contact lenses), visual disturbances Very rare: conjunctivitis

Ear and labyrinth disorders Rare: hearing disorders

Cardiac disorders

Uncommon:    bradycardia, atrioventricular conduction disturbances, worsening of

pre-existing heart failure

Vascular disorders

Common:    feeling of coldness or numbness in extremities

Uncommon:    orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon:    bronchospasm in patients with bronchial asthma or history of

obstructive airways disease Rare: allergic rhinitis

Gastrointestinal disorders

Common:    gastrointestinal complaints such as nausea, vomiting, diarrhoea,

constipation

Uncommon:    abdominal complaints

Very rare:    pancreatitis

Hepatobiliary disorders Rare: hepatitis, jaundice

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions such as itching, flush, rash, photodermatitis, purpura, urticaria.

Very rare:    anaphylactic reactions, toxic epidermic necrolysis (Lyell syndrome),

alopecia, cutaneous lupus erythematosus. Beta-blockers may provoke or worsen psoriasis or induce psoriasis-like rash.

Musculoskeletal and connective tissue disorders Uncommon:    muscle weakness, muscle cramps

Reproductive system and breast disorders Rare: potency disorders

General disorders Common:    fatigue*

Uncommon:    asthenia

Very rare:    chest pain

Investigations

Uncommon:    increase in amylase, reversible increase of serum creatinine and urea,

increased triglyceride and cholesterol levels, glucosuria,

Rare: increase in liver enzymes (ASAT, ALAT)

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

4.9 Overdose

Symptoms

The most common signs expected with overdose of a beta-blocker are bradycardia, hypotension, bronchospasm, acute cardiac insufficiency and hypoglycaemia. There is wide inter-individual variation in sensitivity to one single high dose of bisoprolol and patients with heart failure are probably very sensitive.

The clinical picture in acute or chronic overdose of hydrochlorothiazide is characterised by the extent of fluid and electrolyte loss. The most common signs are dizziness, nausea, somnolence, hypovolaemia, hypotension, hypokalaemia.

Management

In general, if overdose occurs, discontinuation of bisoprolol/hydrochlorothiazide and supportive and symptomatic treatment is recommended.

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.

Atrioventricular block (second or third degree): patients should be carefully monitored and treated with isoprenaline infusion or intravenous cardiac pacemaker insertion.

Acute worsening of heart failure: administer intravenous diuretics, inotropic agents, vasodilating agents.

Bronchospasm: administer bronchodilatator therapy such as isoprenaline, beta₂-sympatthomimetic agents and/or aminophylline.

Hypoglycaemia: administer intravenous glucose.

Limited data suggest that bisoprolol is hardly dialyzable. The degree to which hydrochlorothiazide is removed by haemodialysis has not been established.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Beta blocking agents, selective, and thiazides ATC code: C07B B07

Clinical studies have shown that the antihypertensive effects of these two drugs are additive, and the efficacy of the lowest dose, 2.5 mg/6.25 mg, in the treatment of mild to moderate essential hypertension has been demonstrated.

The pharmacodynamic effects, including hypokalaemia (hydrochlorothiazide), and bradycardia, asthenia and headache (bisoprolol fumarate) are dose-related.

Combining both active ingredients at one fourth/half the doses used in singleagent therapy (2.5 mg/6.25 mg) aims to reduce those effects.

Bisoprolol fumarate is a highly selective p₁-adrenoceptor blocking agent with no intrinsic sympathomimetic activity and without significant membrane-stabilising activity.

As with other Preceptor blocking drugs, the mechanism of bisoprolol fumarate’s antihypertensive effect has not been completely established.

However, it has been shown that the drug produces a marked decrease in plasma renin and a reduction in heart rate.

Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity. Its diuretic effect is due to inhibition of active Na+ transport from the renal tubules to the blood, affecting Na+ reabsorption.

5.2. Pharmacokinetic properties

Bisoprolol

Absorption

T_max varies from 1-4 hours.

Bioavailability is high (88%); hepatic extraction is very low; and absorption is not affected by the presence of food. The kinetics are linear for doses from 5-40 mg.

Distribution

Plasma protein binding is 30%, and the volume of distribution is high (approximately 3 L/kg).

Biotransformation

40% of a bisoprolol dose is metabolised in the liver. Bisoprolol metabolites are inactive.

Elimination

The plasma elimination half-life is 11 hours.

Renal clearance and hepatic clearance are approximately comparable, and half of a dose (unchanged) as well as the metabolites are excreted in urine. The total clearance is approximately 15 L/h.

Hydrochlorothiazide

Absorption

The bioavailability of hydrochlorothiazide shows between-subject variability and ranges from 60-80%. T_max varies from 1.5-5 hours (mean value ~4 hrs).

Distribution

Plasma protein binding is 40%.

Elimination

Hydrochlorothiazide is not metabolised and is excreted almost entirely as unchanged drug by glomerular filtration and active tubular secretion. The terminal t./₂ of hydrochlorothiazide is approximately 8 hours.

The renal clearance of hydrochlorothiazide is reduced and the elimination half-life prolonged in patients with renal and/or cardiac insufficiency. The same applies to elderly subjects, who also show an increase in C_max.

Hydrochlorothiazide crosses the placental barrier and is excreted in human milk

5.3 Preclinical safety data

Bisoprolol fumarate or hydrochlorothiazide have not been found to be hazardous to humans according to the standard preclinical toxicity tests (longterm toxicity, mutagenicity, genotoxicity or carcinogenicity tests). Like other beta-blockers, bisoprolol fumarate at high doses has been found in animal experiments to cause toxic effects to the mother (decreased food intake and body weight gain), and to the embryo/foetus (increased late resorptions, reduced birth weight of the offspring, retardation of the physical development up to the end of lactation). However, bisoprolol fumarate as well as hydrochlorothiazide were not teratogenic. There was no increase in toxicity when both components were given in combination.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Core

Maize starch,

Microcrystalline cellulose,

Colloidal anhydrous silica,

Calcium hydrogen phosphate, anhydrous, Magnesium stearate.

Coating

Hypromellose,

Polysorbate 80,

Macrogol 400,

Titanium dioxide E171,

Iron oxide yellow, red and black E172

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

24 months.