Mild to moderate essential hypertension.
(for additional information see section 5.1).

Other strengths of this medicinal product or other products are available. The usual starting dose
is one bisoprolol 5 mg / hydrochlorothiazide 12.5 mg tablet once daily. If the antihypertensive
effect of this dosage is inadequate, the dose will be increased to one bisoprolol 5 mg /
hydrochlorothiazide 12.5 mg tablet once daily and, if response is still inadequate, to one
bisoprolol 10 mg / hydrochlorothiazide 12.5 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.

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

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Treatment with bisoprolol must not be withdrawn abruptly unless clearly indicated, since abrupt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 is chaemic 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.
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 broncho dilating 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 inpatient with
Prinzmetal’s angina. A beta1-selective beta-blocker may be used in minoror 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 abeta1-selective betablocker.
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 bloodloss. 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.
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 andelectrolyte 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 increasesthe
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 perform in parathyroid function tests.

Combination with lithium
Due to the diuretic, this combination should be avoided.
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 μmol/L in adults). Serum creatinine needs to
be corrected for age, weight and gender, using Cock roft’s
formula, for instance:
* ClCr = (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.
 

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 ß-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-ventricularconduction 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 heartrate. If
hypokalaemia and/or hypomagnesaemia develop during treatment with Bisoprolol / hydrochlorothiazide the myocardium may show increased sensitivity tocardiac 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 alphaadrenoceptors:
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.
 

Pregnancy Category C
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) mayoccur 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 preeclampsia
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.

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.

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.

 

To reports any side effect(s):
• Saudi Arabia
-The National Pharmacovigilance and Drug Safety Centre (NPC)
o Fax: +966-11-205-7662
o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.
o Toll free phone: 19999
o E-mail: npc.drug@sfda.gov.sa
o Website: www.sfda.gov.sa/npc

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 ischaracterised 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.

Pharmacotherapeutic group: Beta blocking agents, selective
ATC Code: C07AB07G
Clinical studies have shown that the antihypertensive effects of these two drugs are additive, and
the efficacy of the lowest dose, 2.5 mg/12.5 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 doserelated.
Combining both active ingredients at one fourth/half the doses used in single agent
therapy (2.5 mg/12.5 mg) aims to reduce those effects.Bisoprolol fumarate is a highly selective
β1-adrenoceptor blocking agent with no intrinsic sympathomimetic activity and without
significant membrane stabilizing activity.
As with other β1-receptor blocking drugs, the mechanism of bisoprololfumarate’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. Itsdiuretic effect is due
to inhibition of active Na+ transport from the renal tubules to the blood, affecting Na+ re
absorption. T e

Bisoprolol
Absorption
Tmax 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%. Tmax 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 t½ 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 Cmax.
Hydrochlorothiazide crosses the placental barrier and is excreted in human milk

Bisoprolol fumarate or hydrochlorothiazide have not been found to be hazardous to humans
according to the standard preclinical toxicity tests (longtermtoxicity, mutagenicity, genotoxicity
or carcinogenicity tests). Like otherbeta-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

List of excipients
Maize starch
Microcrystalline Cellulose
Crospovidone
Dibasic Calcium Phosphate Dihydrate
Colloidal Silicone Dioxide
Magnesium Stearate
Purified Water
Opadry White
Propylene Glycol
Simethicone USP

Not Applicable 

2 years

Do not store above 30 °C

Immediate Container: Alu-PVC/PVDC blister.

No special requirements.