LODOZ - PACKAGE LEAFLET - LEAFLETS

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Lodoz - Package Leaflet

Indications Contraindications Precautions for use Interactions Warnings Dosage and method of use Overdose Unwanted Effects Shelf Life

Active ingredients: Bisoprolol (Bisoprolol fumarate), Hydrochlorothiazide

Lodoz 2.5 mg / 6.25 mg, film-coated tablet
Lodoz 5 mg / 6.25 mg, film-coated tablet
Lodoz 10 mg / 6.25 mg, film-coated tablet

Why is Lodoz used? What is it for?

Lodoz contains the active substances bisoprolol and hydrochlorothiazide:

Bisoprolol belongs to a group of medicines called beta blockers and is used to lower blood pressure.
Hydrochlorothiazide belongs to a group of medicines called diuretics thiazides. It helps lower blood pressure by increasing urine production.

Lodoz is indicated for the treatment of mild and moderate high blood pressure.

Contraindications When Lodoz should not be used

Do not take Lodoz if any of the following conditions are present:

allergy (hypersensitivity) to bisoprolol, hydrochlorothiazide, other thiazides, sulfonamides or to any of the excipients (see section "What Lodoz contains")
severe asthma or some forms of severe chronic bronchial diseases
heart failure not controlled with therapy or cardiogenic shock (a severe acute heart disease causing low blood pressure and circulatory failure)
some heart arrhythmias, particularly slow heartbeat which causes problems, conduction disturbances and a disorder called sick sinus syndrome.
pheochromocytoma (tumor of the adrenal gland that secretes substances that induce severe high blood pressure) untreated
severe circulation problems in the limbs (such as Raynaud's syndrome, which can cause tingling or pale or bluish discoloration of the fingers or toes)
increased blood acidity (metabolic acidosis) as a result of severe illness
severe liver or kidney problems
low blood levels of potassium with failure to respond to treatment

Precautions for use What you need to know before taking Lodoz

Never stop treatment suddenly, especially if you suffer from certain heart conditions (ischemic heart disease, for example angina pectoris).

Before taking Lodoz tell your doctor if you have any of the following conditions:

any heart disease such as heart failure, arrhythmias or Prinzmetal's angina
circulation problems in the less severe limbs (particularly due to Raynaud's syndrome)
liver or kidney problems
pheochromocytoma (tumor of the adrenal gland)
less severe chronic bronchial diseases (asthma or chronic obstructive airway disease)
diabetes
thyroid disorders
psoriasis
tight fasting
history of penicillin allergy.

Also, tell your doctor:

if you have suffered from gout, as Lodoz may increase the risk of gout attacks
if you will be subjected to anesthesia (for example, for a "surgical operation) since Lodoz can influence the body's reaction in this circumstance
if you plan to undergo desensitization therapy, as Lodoz may increase the chances of allergic reactions, or these reactions may be more severe
if you are breastfeeding or intend to breastfeed
if you intend to expose yourself to sunlight or artificial (UV) light, as some patients have developed a rash after exposure. If so, you must protect your skin during treatment with Lodoz.
if you experience acute decrease in vision or eye pain within hours or weeks of starting treatment with the medicine. If left untreated, acute narrow-angle glaucoma (a disorder affecting the eye) can lead to permanent loss of vision , then tell your doctor right away.

Additional tests

Hydrochlorothiazide acts on the balance of salt and water levels in the body. The doctor may deem it appropriate to carry out sporadic checks of these values. This becomes particularly important in the presence of additional conditions that could worsen in the event of an alteration in the "balance of" electrolyte: Your doctor will also check sporadic blood levels of fat, uric acid or glucose.

Concomitant use of this medicine is not recommended with lithium, used to treat some psychiatric disorders, or with medicines used to treat high blood pressure, angina pectoris or irregular heartbeat (such as verapamil, diltiazem or bepridil) ( see section 'Taking other medicines')

For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.

Interactions Which drugs or foods can modify the effect of Lodoz

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines.

Only take Lodoz together with one of the following medicines as directed by your doctor, as the combination with such medicines is generally not recommended (see the above section 'Take special care with Lodoz'):

Some medicines used to treat high blood pressure, angina pectoris or irregular heartbeat (such as verapamil, diltiazem or bepridil), which can increase the risk of heart arrhythmias.
Lithium, used to treat some psychiatric disorders.

Warnings It is important to know that:

Pregnancy, breastfeeding and fertility

The use of this medicine is not recommended during pregnancy

The use of this medicine is not recommended during breastfeeding.

Driving and using machines

Lodoz does not generally affect the ability to drive or use machines. However, the individual response can affect the ability to concentrate and react. In such circumstances, do not drive or use machines.

Dose, Method and Time of Administration How to use Lodoz: Posology

Always take this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist.

The starting dose is usually 1 tablet of Lodoz 2.5 mg / 6.25 mg per day.

If the blood pressure lowering effect obtained with this dose is inadequate, it will be necessary to increase the dose to 1 tablet of Lodoz 5 mg / 6.25 mg per day and, if the response is still inadequate, to 1 tablet of Lodoz 10. mg / 6.25 mg per day.

Take Lodoz in the morning, with or without food. Swallow the tablet with liquid and do not chew it.

Never stop therapy suddenly (see section 'If you stop taking Lodoz "

Use in children

Experience with Lodoz in pediatric patients is limited, therefore its use is not recommended in this population.

Lodoz with food and drink

Lodoz can be taken with or without food, but it must be taken in the morning.

Overdose What to do if you have taken too much Lodoz

If you take more Lodoz than you should

If you have taken more Lodoz tablets than prescribed, consult your doctor immediately. The doctor will determine the necessary countermeasures based on the level of overdose.

Symptoms of overdose may include low blood pressure, slow heart rate, sudden heart problems, dizziness, nausea, sleepiness, sudden breathing problems, low blood glucose levels.

If you forget to take Lodoz

If you forget to take this medicine, take it as soon as possible. Then take your next dose at the usual time. However, if it is almost time for your next dose, skip the missed dose. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Lodoz

Never stop taking this medicine unless directed by your doctor. Otherwise, your condition could seriously worsen. If you have to stop treatment, your doctor will advise you to reduce the dose gradually. If you have any questions about the use of this medicine, ask your doctor or pharmacist.

Side Effects What are the side effects of Lodoz

Like all medicines, this medicine can cause side effects, although not everybody gets them. These side effects are listed below by how often they occur:

Common side effects (present in less than 1 in 10 people):

feeling cold or numb in the hands and feet
tiredness, dizziness, headache. These symptoms occur mainly at the start of treatment. The effects are generally mild and usually disappear within 1 to 2 weeks of starting treatment.
stomach or intestinal upset, such as nausea, vomiting, diarrhea or constipation.

Uncommon side effects (affecting less than 1 in 100 people):

muscle weakness, muscle cramps, feeling of weakness
slow heart rate, altered heart rate, worsening of heart failure, drop in blood pressure when standing or standing
sleep disturbances, depression, loss of appetite
respiratory problems in patients with asthma or chronic bronchial disease
increased blood levels of creatinine or urea
abdominal discomfort
increased levels of amylase (digestive enzymes)
alteration of the balance of liquids and electrolytes
increased blood levels of fat, cholesterol, uric acid or sugar; increased urine sugar levels

Rare side effects (affecting less than 1 in 1,000 people):

nightmares, hallucinations
allergic-type reactions, such as itching, sudden redness of the face or rash, even after exposure to sunlight, hives, small reddish-purple skin spots due to bleeding under the skin (purpura)
increased levels of some liver enzymes, liver inflammation, yellowing of the skin and eyes (jaundice)
erection disorders
hearing problems
allergic rhinorrhea, reduced tear secretion, visual disturbances
decreased number of white blood cells (leukocytopenia) or platelets (thrombocytopenia)
syncope

Very rare side effects (affecting less than 1 in 10,000 people):

irritation and redness of the eyes (conjunctivitis), hair loss
appearance or worsening of pre-existing scaly skin rashes (psoriasis); appearance of thick scaly patches (cutaneous lupus erythematosus)
chest pain
severe reduction in the number of white blood cells (agranulocytosis)
inflammation of the pancreas
low presence of acids in the blood (metabolic alkalosis)
allergic (anaphylactic) reactions, severe bullous reactions (Lyell's syndrome).

Side effects whose frequency is not known (frequency cannot be estimated from the available data):

interstitial lung disease
transient myopia
eye pain (possible sign of acute angle-closure glaucoma).

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at https://www.aifa.gov.it/content/segnalazioni-reazioni-avverse

By reporting side effects you can help provide more information on the safety of this medicine.

Expiry and Retention

Keep this medicine out of the sight and reach of children.
Do not use this medicine after the expiry date which is stated on the carton after EXP.
Do not store above 30 ° C.

Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.

What Lodoz contains

Lodoz 2.5 mg / 6.25 mg

The active ingredients are bisoprolol fumarate and hydrochlorothiazide. Each film-coated tablet contains 2.5 mg bisoprolol fumarate and 6.25 mg hydrochlorothiazide
The other components are

Tablet core: magnesium stereate, crospovidone, maize starch, pregelatinised maize starch, microcrystalline cellulose, anhydrous dibasic calcium phosphate. Tablet coating: polysorbate 80, yellow iron oxide (E 172), macrogol 400, titanium dioxide (E171), hypromellose.

Lodoz 5 mg / 6.25 mg

The active ingredients are bisoprolol fumarate and hydrochlorothiazide. Each film-coated tablet contains 5 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide.
The other components are

Tablet core: anhydrous colloidal silica, magnesium stearate, microcrystalline cellulose, corn starch, anhydrous dibasic calcium phosphate. Tablet coating: yellow iron oxide (E 172), red iron oxide (E 172), polysorbate 80, macrogol 400, titanium dioxide (E171), hypromellose.

Lodoz 10 mg / 6.25 mg:

The active ingredients are bisoprolol fumarate and hydrochlorothiazide. Each film-coated tablet contains 10 mg of bisoprolol fumarate and 6.25 mg of hydrochlorothiazide.
The other components are

Tablet core: anhydrous colloidal silica, magnesium stearate, microcrystalline cellulose, corn starch, anhydrous dibasic calcium phosphate. Tablet coating: polysorbate 80, macrogol 400, hypromellose, titanium dioxide (E171

Description of what Lodoz looks like and contents of the pack

Lodoz 2.5 mg / 6.25 mg: Yellow, round, biconvex film-coated tablet; heart in relief on the top, number "2.5" in relief on the bottom.

Lodoz 5 mg / 6.25 mg: Pastel pink, round, biconvex film-coated tablet; heart in relief on the top, number "5" in relief on the bottom.

Lodoz 10 mg / 6.25 mg: White, round, biconvex film-coated tablet; heart embossed on the top, number "10" embossed on the bottom. Each pack contains: 30, 50, 60, 90 or 100 tablets.

Not all pack sizes may be marketed.

Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.

Further information on Lodoz can be found in the "Summary of Characteristics" tab. 01.0 NAME OF THE MEDICINAL PRODUCT 02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION 03.0 PHARMACEUTICAL FORM 04.0 CLINICAL PARTICULARS 04.1 Therapeutic indications 04.2 Posology and method of administration 04.3 Contraindications 04.4 Special warnings and appropriate precautions for use 04.5 Interactions with other medicinal products and other forms of interaction04.6 Pregnancy and lactation04.7 Effects on the ability to drive and use machines04.8 Undesirable effects04.9 Overdose05.0 PHARMACOLOGICAL PROPERTIES05.1 Pharmacodynamic properties05.2 Pharmacokinetic properties05.3 Preclinical data of 06.0 PHARMACEUTICAL PARTICULARS 06.1 Excipients 06.2 Incompatibilities 06.3 Shelf life 06.4 Special precautions for storage 06.5 Nature of the immediate packaging and contents of the package 06.6 Instructions for use and handling 07.0 HOLDER OF THE ALL AUTHORIZATION "PLACING ON MARKETING 08.0 AUTHORIZATION NUMBER" PLACING ON MARKET09.0 DATE OF PR IMA AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION 10.0 DATE OF REVISION OF THE TEXT 11.0 FOR RADIOPharmaceuticals, FULL DATA ON INTERNAL RADIATION DOSIMETRY 12.0 FOR RADIOPharmaceuticals, ADDITIONAL DETAILED INSTRUCTIONS ON ESTEMPORAN PREPARATION AND QUALITY CONTROL

01.0 NAME OF THE MEDICINAL PRODUCT

LODOZ

02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION

Lodoz 2.5 mg / 6.25 mg, film-coated tablets:

Bisoprolol hemifumarate 2.5 mg.

Hydrochlorothiazide 6.25 mg.

Lodoz 5 mg / 6.25 mg, film-coated tablets:

Bisoprolol hemifumarate 5 mg.

Hydrochlorothiazide 6.25 mg.

Lodoz 10 mg / 6.25 mg, film-coated tablets:

Bisoprolol hemifumarate 10 mg.

Hydrochlorothiazide 6.25 mg.

For the full list of excipients, see section 6.1

03.0 PHARMACEUTICAL FORM

Lodoz 2.5 mg / 6.25 mg, film-coated tablets:

Yellow, round, biconvex film-coated tablets, engraved with a heart on the upper face and the inscription 2.5 on the lower face.

Lodoz 5 mg / 6.25 mg, film-coated tablets:

Pastel pink, round, biconvex film-coated tablets, engraved with a heart on the upper face and 5 on the lower face.

Lodoz 10 mg / 6.25 mg, film-coated tablets:

White, round, biconvex film-coated tablets, engraved with a heart on the top and 10 on the bottom.

04.0 CLINICAL INFORMATION

04.1 Therapeutic indications

Mild or moderate essential arterial hypertension.

04.2 Posology and method of administration

For individual therapy Lodoz is available in the dosages:

Lodoz 2.5 mg / 6.25 mg, film-coated tablets

Lodoz 5 mg / 6.25 mg, film-coated tablets

Lodoz 10 mg / 6.25 mg, film-coated tablets

The starting effective dose is one 2.5 mg bisoprolol tablet and 6.25 mg hydrochlorothiazide once daily.

If the antihypertensive effect of this strength is insufficient, the dose can be increased to one bisoprolol 5 mg tablet and 6.25 mg hydrochlorothiazide once daily and, if response is still insufficient, to one 10 tablet. mg bisoprolol and 6.25 mg hydrochlorothiazide once daily.

If discontinuation of therapy is necessary, a gradual reduction of bisoprolol treatment is recommended as abrupt cessation of bisoprolol administration may lead to an acute deterioration of the patient's condition, especially in patients with ischemic heart disease.

Lodoz is to be taken in the morning and can be taken with food. The coated tablets must be swallowed with liquid and must not be chewed.

No dose adjustments are required in patients with mild to moderate hepatic impairment or mild to moderate renal impairment (creatinine clearance> 30 mL / min).

Elderly: Dose adjustment is generally not required (see section 4.4).

There is no experience of use of Lodoz in pediatrics, therefore its use cannot be recommended in children.

04.3 Contraindications

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

Bisoprolol

Bisoprolol is contraindicated if any of the following conditions are present:

- Severe asthma or severe chronic obstructive pulmonary disease;

- Heart failure not controlled by therapy;

- Cardiogenic shock;

- Sinus node disease (including SA block);

- Second or third degree AV block (without implanted pacemaker);

- symptomatic bradycardia;

- Pheochromocytoma (except after initiating therapy with alpha-blockers);

- Severe forms of Raynaud's phenomenon and severe peripheral arterial occlusive diseases;

Metabolic acidosis;

Concomitant use of sultopride

Hydrochlorothiazide

Hydrochlorothiazide is contraindicated if any of the following conditions are present:

- Severe renal impairment (creatinine clearance ≤30 mL / min).

Severe hepatic impairment.

Refractory hypokalemia.

04.4 Special warnings and appropriate precautions for use

Warnings

Bisoprolol

Administration of bisoprolol should never be stopped suddenly in patients with coronary artery disease (angina pectoris), as this could lead to severe cardiac arrhythmias, myocardial infarction or sudden death.

Hydrochlorothiazide

In patients with liver disease, thiazide diuretics and similar drugs can trigger hepatic encephalopathy. In this case, diuretic therapy must be stopped immediately.

This medicinal product must not be taken by women who are breastfeeding (see section 4.6).

Precautions for use

Bisoprolol

Asthma and chronic obstructive pulmonary disease

Beta-blockers can only be used in mild forms of asthma or chronic obstructive pulmonary disease (chronic obstructive pulmonary disease) and in this case only those selective for the b1 receptors and with low initial doses should be used. A pulmonary function test is recommended before starting therapy.

In symptomatic patients, concomitant therapy with bronchodilators is recommended.

Occasionally, in patients with asthma or chronic obstructive pulmonary disease, increased airway resistance may occur and therefore the need to increase the dose of stimulant b2 may arise.

Heart failure

Patients with compensated heart failure who require beta-blocker therapy can take bisoprolol starting with a very low starting dose, which can be gradually increased under careful medical supervision.

First degree AV block

Due to their negative dromotropic activity, beta-blockers should be used with particular care in patients with first degree AV block.

Prinzmetal's angina

Beta-blockers may increase the frequency and duration of vasospasm episodes in patients with Prinzmetal's angina. In case of concomitant use of a vasodilator, a b1-selective beta-blocker can be used in the mild or mixed forms of angina of Prinzmetal.

Occlusive peripheral arterial disease

Beta-blockers can aggravate symptoms of peripheral arterial occlusive disease (PAD) or Raynaud's syndrome. Such patients should preferably be prescribed a b1-selective beta-blocker.

Pheochromocytoma

In patients with pheochromocytoma Lodoz should not be given until alpha-receptor blockade has been achieved.

Blood pressure must be carefully monitored.

Senior citizens

A dose adjustment is generally not necessary. However, older patients should be carefully monitored (see 'Fluids and electrolyte balance' section).

Diabetics

Patients with diabetes should be informed of the risk of hypoglycaemic episodes and the increased need for careful home blood glucose monitoring in the initial phase of therapy. The warning signs of a hypoglycemic state (especially tachycardia, palpitations and sweating) may be masked.

Psoriasis

Since the administration of beta-blockers has been associated with worsening of psoriasis, patients with this disease should only be treated with bisoprolol when clearly needed.

Allergic reactions

In patients at risk of severe anaphylactic reactions to any allergen, beta-blockers may aggravate a possible anaphylactic reaction and reduce responsiveness to the doses of epinephrine commonly used to treat allergic reactions, especially when using iodine-containing contrast media ( see 4.5) or during specific immunotherapy (desensitization).

General anesthesia

In patients who need to undergo general anesthesia, the beta-blocker reduces the incidence of arrhythmias and myocardial ischaemia during induction and intubation and in the postoperative phase. It is currently recommended to maintain beta-blocker therapy in phase. peri-operative. The anesthetist must be informed that the patient is being treated with beta-blockers due to a potential interaction with other drugs that may result in bradi-arrhythmias, attenuation of reflex tachycardia and reduced reflex ability to compensate a loss of blood.

If it is deemed necessary to discontinue beta-blocker therapy prior to surgery, this should be done gradually and completed approximately 48 hours prior to anesthesia.

Thyrotoxicosis

Beta-blockers may mask the cardiovascular signs of hyperthyroidism.

Competitive athletes

Competitive athletes should be advised that this medicinal product contains a drug capable of giving a positive result in doping tests.

Fast fast

Lodoz should be used with caution in patients with a strict fast.

Combination with verapamil, diltiazem or bepridil

Such combinations require close clinical and electrocardiographic monitoring, especially in older patients and at initiation of treatment (see section 4.5).

Hydrochlorothiazide

Fluids and electrolyte balance

Periodic monitoring of serum electrolytes (especially potassium, sodium, calcium), creatinine and urea, serum lipids (cholesterol and triglycerides), uric acid and also blood glucose is recommended during long-term therapy with Lodoz.

Long-term continuous administration of hydrochlorothiazide may lead to fluid and electrolyte disturbances, particularly hypokalemia and hyponatremia, and also to hypomagnesaemia, hypochloraemia and hypercalcaemia.

Plasma sodium

Plasma sodium should be determined prior to therapy and at periodic intervals during therapy. Any diuretic therapy can give rise to hyponatremia which in some cases can have serious consequences.

Since hyponatremia may initially be asymptomatic, periodic checks are required and should be more frequent in high-risk populations, for example in the elderly and in patients with liver cirrhosis.

Plasma potassium

Hypokalaemia following potassium loss is the highest risk associated with thiazide diuretics and similar drugs.

It is necessary to know how to predict the risk of hypokalemia (malnourished and / or on therapy with different drugs, and in patients suffering from coronary heart disease or heart failure, in which hypokalemia increases the cardiotoxicity of digitalis glycosides and therefore the risk of cardiac arrhythmia.

Patients with a congenital or iatrogenic long QT syndrome are also at risk. Hypokalaemia - similar to bradycardia - facilitates the development of severe arrhythmias, particularly torsades de pointes, which can prove fatal.

In the above mentioned population, more frequent plasma potassium checks are indicated, to be carried out starting from the first week of therapy.

Plasma calcium

Thiazide diuretics and similar drugs can reduce urinary excretion of calcium and thus cause mild and transient hypercalcaemia. Significant hypercalcaemia may be related to undiagnosed hyperparathyroidism. Treatment should be discontinued before performing parathyroid function tests.

Association with lithium

This association should be avoided due to the presence of diuretic (see section 4.5).

Glycemia

In diabetics it is necessary to control blood sugar, especially in the presence of hypokalemia.

Uric acid

In patients with hyperuricaemia the risk of gout attacks may increase. The dosage should be adjusted according to the plasma concentration of uric acid.

Renal function and diuretics

The full benefits of thiazide diuretics can only be realized if kidney function is normal or nearly normal (in adults: serum creatinine

Serum creatinine must be corrected in relation to age, weight and gender, for example using the Crockroft formula:

ClCr = (140 - age) ´weight / 0.814 ´ serum creatinine

Where: age is indicated in years,

weight in kg and serum creatinine in mmol / L.

The above formula is used to calculate the ClCr for male seniors and should be corrected for female seniors by multiplying by 0.85.

Hypovolemia secondary to diuretic-induced loss of water and sodium at the start of therapy reduces glomerular filtration and may therefore lead to an increase in blood urea nitrogen (BUN) and serum creatinine.

This transient impairment of renal function is not significant in patients with normal renal function but may worsen pre-existing renal insufficiency.

Association with other antihypertensive drugs

If this medicinal product is combined with another antihypertensive, it is recommended to reduce the dosage, at least in the initial phase of therapy.

Photosensitivity

In rare cases, photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If a photosensitivity reaction occurs during treatment, it is recommended that therapy be discontinued. If re-administration of the therapy is deemed necessary, it is recommended to protect the areas exposed to sunlight or artificial UVA light.

Competitive athletes

Competitive athletes should be informed that this medicinal product contains a drug capable of giving a positive result in doping tests.

04.5 Interactions with other medicinal products and other forms of interaction

1 - Interactions related to bisoprolol

Contraindications

+ Sultopride

Increased risk of ventricular arrhythmias, particularly torsades de pointes (see section 4.3).

Associations not recommended

+ Verapamil, diltiazem

Risk of bradycardia and adverse effects on cardiac contractility and atrio-ventricular conduction.

This combination can only be used under close clinical and electrocardiographic supervision, particularly in elderly patients and in the initial phase of therapy (see section 4.4).

+ Bepridil

Risk of bradycardia and adverse effects on cardiac contractility and atrio-ventricular conduction. Also, increased risk of ventricular arrhythmias and especially torsades de pointes.

This combination can only be used under close clinical and electrocardiographic supervision, particularly in elderly patients and in the initial phase of therapy (see section 4.4).

Associations requiring special precautions for use

+ Centrally acting antihypertensive drugs (for example: clonidine, methyldopa, moxonidine, rilmenidine):

Concomitant use of centrally acting antihypertensive drugs and bisoprolol may further reduce central sympathetic tone and therefore may result in further reduction in cardiac rate and output and induce vasodilation / hypotension.

A "sudden discontinuation, especially if prior to discontinuation of the beta-blocker, may increase the risk of" rebound hypertension ".

Avoid any abrupt discontinuation of centrally acting antihypertensive agents.

+ Propafenone, cibenzolin, flecainide

Risk of bradycardia and adverse effects on cardiac contractility and atrio-ventricular conduction.

Clinical and electrocardiographic monitoring is required as appropriate.

+ Lidocaine

Increased plasma levels of lidocaine which may increase the likelihood of neurological and cardiac side effects, due to reduced hepatic blood flow caused by the beta-blocking agent and consequent reduced clearance of lidocaine.

Clinical, biological and electrocardiographic monitoring is required, if appropriate, with adjustment of the lidocaine dosage if necessary.

+ Antidiabetics (insulin, sulfonylureas, glinides)

All beta-blockers can mask the signs of hypoglycemia, particularly palpitations and tachycardia.

Patients with diabetes should be informed of the risk of hypoglycaemic episodes and of the increased need for careful home blood glucose monitoring, especially in the initial phase of therapy.

+ Other drugs that induce bradycardia (cholinesterase inhibitors, digitalis glycosides, mefloquine ...)

Increased risk of bradycardia.

Clinical monitoring should be performed regularly.

+ Calcium antagonists of the dihydropyridine class (for example: nifedipine, amlodipine)

Combined use may increase the risk of hypotension, and an additional risk of deterioration in ventricular pump function cannot be excluded in patients with heart failure.

+ Beta-blockers for topical use (for example: eye drops for glaucoma therapy)

They can add their effects to the systemic effects of bisoprolol.

2- Interactions related to hydrochlorothiazide

Associations not recommended

+ Lithium

Increased plasma levels of lithium with signs of overdose, similar to a low sodium diet, due to reduced urinary excretion of lithium. If this association cannot be avoided, careful monitoring of the plasma lithium concentration and, if necessary, dosage adjustments should be made.

Associations requiring special precautions for use

+ NSAIDs (systemic) and acetylsalicylic acid at anti-inflammatory dosage regimens

Acute renal failure in dehydrated patients (NSAIDs reduce glomerular blood flow by inhibiting the synthesis of prostaglandins with a vasodilator effect).

Rehydrate the patient. Check renal function at the start of therapy.

+ Potassium-sparing drugs (alone or in combination)

This association, possibly useful, does not exclude the onset of hypo or hyperkalemia, with a higher frequency than the second in the case of diabetes or renal damage. Check the plasma potassium concentration and, if necessary, perform an electrocardiographic check. treatment may need to be re-evaluated.

+ Hypokalaemic drugs (IV amphotericin, systemic corticosteroids, tetracosactide, stimulating laxatives)

Increased risk of hypokalemia.

Monitoring and, if appropriate, correction of plasma potassium. This is especially important in the case of concomitant use of digitalis glycosides. The use of non-stimulant laxatives is preferable.

+ Angiotensin converting enzyme inhibitors (ACE inhibitors)

+ Angiotensin II receptor antagonists (sartans)

Risk of markedly decreased blood pressure and / or acute renal failure upon initiation of ACE inhibitor therapy in patients with pre-existing sodium depletion (especially in patients with renal artery stenosis).

If previous diuretic therapy has resulted in sodium depletion, administration of the diuretic should be discontinued 3 days prior to initiating therapy with ACE inhibitors or sartans, reintroducing the diuretic later if necessary, or therapy with a reduced dose should be initiated. of ACE inhibitor or sartan, which is then gradually increased.

+ Carbamazepine

Risk of symptomatic hyponatremia.

Clinical and biological monitoring is required. Another class of diuretics should be used.

+ Contrast media containing iodine

Increased risk of acute renal failure in case of diuretic dehydration, especially when using high doses of iodine-containing contrast media.

Rehydrate the patient before administering iodine-containing contrast media.

+ Resins

They reduce the absorption of hydrochlorothiazide.

The intake of resins and the administration of Lodoz must be carried out after an interval of at least 2 hours.

+ Agents that lower uric acid levels

Concomitant administration of hydrochlorothiazide may attenuate their effect.

+ Calcium salts

Risk of hypercalcemia due to reduced urinary excretion.

+ Ciclosporine

Risk of hypercreatininemia without modification of cyclosporine levels, even in the absence of sodium depletion.

3- Interactions related to both bisoprolol and hydrochlorothiazide

Associations requiring special precautions for use

+ Antiarrhythmic drugs that can produce torsades de pointes (agents of subclass IA: quinidine, hydroquinidine and disopyramide and of subclass III: amiodarone, sotalol, dofetilide, ibutilide):

Greater risk of ventricular arrhythmias, especially torsades de pointes, facilitated by bradycardia and / or hypokalemia.

Clinical and electrocardiographic monitoring is required.

+ Non-antiarrhythmic drugs that can produce torsades de pointes (for example: astemizole, bepridil, cisapride, diphemanyl, iv erythromycin, halofantrine, lumefantrine, methadone, moxifloxacin, pentamidine, sotalol, iv spiramycin, sparfloxacin, some antipsycin, terfenadin pimozide, haloperidol, benzamides):

Greater risk of ventricular arrhythmias, especially torsades de pointes, facilitated by bradycardia and / or hypokalemia.

Clinical and electrocardiographic monitoring is required.

+ Digitalis glycosides

The presence of hydrochlorothiazide causes a risk of hypokalemia which can facilitate the toxic effects of digitalis glycosides. The presence of bisoprolol causes a risk of bradycardia and a negative effect on atrioventricular conduction.

Clinical follow-up is required at regular intervals. Monitoring of plasma potassium levels and, if appropriate, electrocardiography should be performed.

Associations that need to be considered

+ Other antihypertensive agents, tricyclics, phenothiazines, baclofen, amifostine.

Concomitant use of these blood pressure lowering drugs as a major or undesirable effect increases the risk of hypotension.

+ NSAIDs

Reduced antihypertensive effect, due to the inhibition of the vasodilator effect of prostaglandins (pyrazole derivatives also induce sodium retention).

+ Corticosteroids, tetracosactide

Reduced antihypertensive effect due to sodium retention.

04.6 Pregnancy and lactation

Pregnancy

Since this product contains a thiazide diuretic, its use during pregnancy is contraindicated.

Bisoprolol

Studies conducted on animals have not shown the onset of teratogenic effects.

To date, the results of well-controlled prospective studies conducted with beta-blockers have shown no defects in infants. In infants born to mothers treated with beta-blockers, beta-blocker activity persists for several days after delivery and can lead to bradycardia, difficulty breathing and hypoglycaemia. In many cases, this has no clinical consequences. However, insufficiency may occur. cardiac needing treatment in intensive care, avoiding the use of plasma expander given the risk of acute pulmonary edema

Hydrochlorothiazide

Diuretics may increase the risk of fetoplacental ischaemia with the consequent risk of fetal hypotrophy. Rare cases of severe neonatal thrombocytopenia have been reported.

Feeding time

It is not known whether bisoprolol is excreted in human milk. Thiazide diuretics are excreted in breast milk. Therefore this product should not be taken by breastfeeding women (see section 4.4).

Bisoprolol

The risk of hypoglycaemia and bradycardia in nursing infants has not yet been evaluated.

Hydrochlorothiazide

Thiazide diuretics can cause:

- Decrease or even suppression of milk secretion,

- Biological adverse events (hypokalaemia)

-Hemolysis (G6PD deficiency) and hypersensitivity due to the sulfonamide structure.

04.7 Effects on ability to drive and use machines

Depending on the patient's individual response to treatment with Lodoz, the ability to drive and use machines may be impaired. This must be carefully considered at the start of treatment and also in the case of alcohol intake.

04.8 Undesirable effects

Common (≥1% e

Disorders of the blood and lymphatic system

Rare: leukopenia, thrombocytopenia

Very rare: agranulocytosis

Metabolism and nutrition disorders

Uncommon: loss of appetite, hyperglycemia, hyperuricaemia, fluid and electrolyte homeostasis disorders (particularly hypokalemia and hyponatremia, plus hypomagnesaemia and hypochloraemia and also hypercalcemia)

Very rare: metabolic alkalosis

Psychiatric disorders

Uncommon: depression, sleep disturbances

Rare: nightmares, hallucinations

Nervous system disorders

Uncommon: dizziness *, headache *

Eye disorders

Rare: reduced lacrimation (to be considered in patients using contact lenses), visual disturbances.

Very rare: conjunctivitis

Ear and labyrinth disorders

Rare: hearing disorders

Cardiac pathologies

Uncommon: bradycardia, AV conduction disturbances, worsening of pre-existing heart failure

Vascular pathologies

Common: feeling of cold or numbness in the extremities

Uncommon: orthostatic hypotension

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm in patients with bronchial asthma or a history of disease

obstructive airway.

Rare: allergic rhinitis

Gastrointestinal disorders

Common: gastrointestinal disturbances such as nausea, vomiting, diarrhea, constipation

Uncommon: abdominal discomfort

Very rare: pancreatitis

Hepatobiliary disorders

Rare: hepatitis, jaundice

Skin and subcutaneous tissue disorders

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

Very rare: anaphylactic reactions, toxic epidermal necrolysis (Lyell's syndrome), alopecia, cutaneous lupus erythematosus. Beta-blockers can cause or worsen psoriasis or induce a psoriasis-like rash.

Musculoskeletal and connective tissue disorders

Uncommon: muscle weakness, cramps

Diseases of the reproductive system and breast

Rare: sexual potency disorders

Systemic pathologies

Common: fatigue *

Uncommon: asthenia

Very rare: chest pain

Diagnostic tests

Uncommon: increased amylase, reversible increase in serum creatinine and urea, increased cholesterol and triglyceride levels, glucosuria.

Rare: increased liver enzymes (ALT, AST)

* These symptoms usually appear at the start of therapy. They are generally minor and mostly disappear within 1-2 weeks.

04.9 Overdose

The most common symptoms of a beta-blocker overdose are bradycardia, hypotension, bronchospasm, acute heart failure and hypoglycemia.

There is "a" large inter-individual variability in sensitivity to a single high dose of bisoprolol and patients with heart failure are probably the most sensitive.

The clinical picture in the presence of acute or chronic overdose of hydrochlorothiazide is characterized by a decrease in blood volume and electrolytes.

The most common symptoms are dizziness, nausea, somnolence, hypovolaemia, hypotension, hypokalemia.

In general, in the presence of overdose, discontinuation of Lodoz and supportive and symptomatic treatment is recommended.

Bradycardia: administer atropine intravenously. If the response is inadequate, isoprenaline or another agent with positive chronotropic action should be administered with caution.

In some cases, transvenous application of a pacemaker may be necessary.

Hypotension: intravenous fluids and vasopressor substances should be administered.

AV block (second or third degree): Patients should be monitored closely and treated with isoprenaline infusion or transvenous cardiac pacemaker application.

Acute aggravation of heart failure: intravenously administer diuretics, inotropic agents, vasodilators.

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

Hypoglycemia Administer IV glucose

Limited data suggests that bisoprolol is difficult to dialyzable. The degree of removal of hydrochlorothiazide by hemodialysis has not been established.

05.0 PHARMACOLOGICAL PROPERTIES

05.1 Pharmacodynamic properties

Pharmacotherapeutic group: combination beta-blocker (b1-selective) and thiazide diuretic.

ATC code: C07BB07

Clinical studies have shown that the antihypertensive effects of these two drugs are additive and that the lower dose (2.5 mg / 6.25 mg) is effective in the treatment of mild or moderate essential hypertension.

Pharmacodynamic effects, including hypokalaemia (hydrochlorothiazide), and bradycardia, asthenia and headache (bisoprolol) are related to the administered dose.

The combination of both drugs at a quarter / half the dose used in monotherapy (2.5 mg / 6.25 mg) is intended to reduce these effects.

Bisoprolol is a potent, highly selective inhibitor of b1 receptors, with no intrinsic sympathomimetic activity and without significant membrane stabilization activity.

As with other b1-blockers, the exact mechanism of action of bisoprolol responsible for the antihypertensive effects has not yet been fully identified. However, the drug has been shown to produce 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 the inhibition of the active transport of Na + from the renal tubules to the blood (reduction of Na + reabsorption).

05.2 "Pharmacokinetic properties

Bisoprolol

- Absorption: Tmax varies from 1 to 4 hours.

- Bioavailability is high (88%), extraction due to first pass hepatic metabolism is very low and absorption is not affected by the presence of food. Kinetics are linear for doses of 5-40 mg.

Distribution: The plasma protein binding is 30% and the volume of distribution is large (approximately 3 L / kg).

- Biotransformation: 40% of the bisoprolol dose is metabolised in the liver. The metabolites of bisoprolol are inactive.

- Elimination: The plasma elimination half-life is 11 hours.

Renal and hepatic clearance are approximately comparable and half of the dose is detected in urine (unchanged form) as well as metabolites. Total clearance is approximately 15L / h

Hydrochlorothiazide

- Absorption: the bioavailability of hydrochlorothiazide shows an inter-individual variability and ranges from 60% to 80%. The Tmax varies from 1.5 to 5 hours (mean »4 hours).

- Distribution: plasma protein binding is 40%.

- Elimination: Hydrochlorothiazide is not metabolised and is excreted almost completely as unchanged drug by glomerular filtration and active tubular secretion. The final T ½ of hydrochlorothiazide is approximately 8 hours.

- In patients with renal and / or cardiac insufficiency the renal clearance of hydrochlorothiazide is reduced and the elimination half-life is prolonged. The same is true for the elderly, who show a similar increase in Cmax.

- Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk.

05.3 Preclinical safety data

Based on standard preclinical toxicity tests (long-term toxicity, mutagenicity, genotoxicity, and carcinogenicity studies), bisoprolol or hydrochlorothiazide was found not to be hazardous to humans. In animal studies, as with other beta-blockers, high dose bisoprolol caused toxicity in the mother (decreased feeding and weight gain) and in the embryo / fetus (late resorption increased, decreased birth weight of the child, delayed in physical development until the end of lactation). However bisoprolol and hydrochlorothiazide are not teratogenic.There is no increase in toxicity following the simultaneous administration of the two components.