Lodoz. 10 mg. 6.25 mg. 30 tablets
Lodoz. 10 mg. / 6.25 mg. 30 tablets
Qualitative and quantitative composition
Bisoprolol hemifumarate 10.00 mg Hydrochlorothiazide 6.25 mg
For excipients, see section 6.1
3 . Pharmaceutical Form
Yellow , round, biconvex , imprinted heart of the upper side of the lower die 5 .
4 . clinical data
- Good to moderate essential hypertension
4.2 Posology and method of administration
Individual therapy LODOZ is available in the following concentrations:
LODOZ 2.5/6.25 mg, film-coated tablets LODOZ 5/6.25 mg, film-coated tablets LODOZ 10/6.25 mg, film-coated tablets
The usual starting dose is one tablet daily bisoprolol 2.5 mg / hydrochlorothiazide 6.25 mg.Ako antihypertensive effect of this dose is inadequate, the dose may be increased to one tablet daily bisoprolol 5 mg / hydrochlorothiazide 6.25 mg and if the answer is still not adequate , one tablet once daily bisoprolol 10 mg / hydrochlorothiazide 6.25 mg.
LODOZ must be taken in the morning , maybe with food. The film-coated tablets should be swallowed with some liquid and not chewed .
No dose adjustment is required in patients with mild to moderate hepatic impairment or mild to moderate renal impairment (creatinine clearance > 30mL/min)
There is no pediatric experience with LODOZ, so its use in children can not be recommended.
Bisoprolol is contraindicated in any of the following conditions :
- Severe bronchial asthma or severe chronic obstructive pulmonary disease ;
- Heart failure , therapy with nekotrolirana ;
- Cardiogenic shock;
- Syndrome Sick sinus (including sinoatrial block) ;
- AV block of second or third degree (without a pacemaker implanted ) ;
- Severe bradycardia (heart rate <50 beats / min) ;
- Angina of Prinzmetal ( vasospastic angina and pure monotherapy)
- Pheochromocytomas (except after previous treatment with alpha- receptor blocker ) ;
- Severe forms of Raynaud's syndrome and severe peripheral arterial disease;
- Hypotension ;
- Hypersensitivity to Bisoprolol;
- Concomitant use of floctafenine ( see 4.5) ;
- Concomitant use of sultopride ( see 4.5) ;
Hydrochlorothiazide is contraindicated in any of the following conditions :
- Svrahuvstvitelnost to sulfate ( one) amides
- Severe renal impairment (creatinine clearance <30mL/min)
- Severe hepatic impairment
Hydrochlorothiazide should not be combined with lithium or non- anti-arrhythmic drugs that may induce torsade-de-pointes ( see 4.5) .
This medicine should not be taken by nursing mothers .
4.4 Special warnings and precautions for use
Never stopped suddenly Bisoprolol in patients with coronary artery disease (angina pectoris). Abrupt discontinuation of therapy may cause serious cardiac arrhythmias, myocardial infarction or sudden death.
In patients with liver disease, thiazide diuretics and similar drugs can precipitate hepatic encephalopathy. If this happens , diuretic therapy should be discontinued immediately .
Discontinuation of therapy
Treatment should not be stopped or interrupted abruptly , especially in patients with ischemic heart disease , but rather to reduce to approximately one or two weeks, and , if necessary , at the same time with adequate replacement therapy to deterioration predotvati simptomi.Astma of anginal and chronic obstructive pulmonary disease
Beta-blockers can be used only in mild forms of asthma or chronic obstructive pulmonary disease , using ( B- selective adrenoceptor blocking agent and a low initial dose . Recommend testing pulmonary function before starting terapiyata.Pri asthmatic / bronchospasm which may occur during the treatment, can be controlled by (B2 agonists.
Patients with compensated heart failure , who require a beta-blocker therapy , may be applied Bisoprolol, using a much lower dose , which is increased gradually under close medical supervision .
The dose should be reduced if the heart rate drops below 50-55 beats / min . and patient experiences symptoms related to bradycardia.
AVBlok first degree
As a negative dromotropic effect , beta blockers should be used with caution in patients with AV block first degree .
Beta- blockers may increase the frequency and duration of vasospastic episodes in patients with angina of Prinzmetal. Cardioselective blocker may be applied or mixed with minor clinical manifestations of angina Prinzmetal, if at the same time using a vasodilator .
Peripheral arterial disease
Beta-blockers can worsen the symptoms of peripheral artirialno disease ( Raynaud's syndrome or chronic obliterative arteritis or arterial disease of the lower limbs). In these patients it is preferable to prescribe a cardioselective beta- blocker with a partial agonistic activity and can be used with caution .
In patients with pheochromocytomas LODOZ should be used only after alpha- receptor blokada.Stoynostite blood pressure should be closely monitored . Elderly vazrastStriktno account all contraindications is mandatory for the elderly . Treatment they need to start with low doses and closely monitored .
Diabetic patients should be aware of the risk of hypoglycaemic episodes and the increased need for careful monitoring of blood sugar levels at home in the initial phase of therapy. The warning signs of hypoglycemia, particularly tachycardia , palpitations and sweating can be masked.
Saoshtavano is that beta- blockers are associated with worsening of psoriasis , so these patients should use Bisoprolol, only if clearly needed.
In patients at risk of severe anaphylactic reactions to any allergen , especially when administered iodinated radiopaque materials (see 4.5) or in specific immunotherapy ( desensitization ) , beta- blockers may worsen the anaphylactic reaction and to suppress the response to usual doses of epinephrine used in the treatment of hypersensitivity reactions .
Beta-blockers are responsible for mitigating reflex tachycardia, increasing the risk of hypotension . Continued treatment with beta- blockers decrease the risk of arrhythmia , myocardial ischemia , and hypertensive episodes. The anesthetist should be informed that the patient is being treated with beta- blockers.
If interruption of treatment is considered necessary , discontinuation of beta- blocker within 48 hours is considered sufficient for the restoration of reactivity to catecholamines.
In some cases, treatment with beta- blocker can be stopped at the following conditions :
In patients with coronary artery disease is advisable to continue therapy to surgery because of the risk of suddenly stopping treatment with beta-blockers. In an emergency or when beta blockers can not be stopped , the patient should be protected from the precarious state of saotvetnatata atropine premedication , which may be repeated if necessary . Must be chosen such anesthetic agents with minimal depression of myocardial function and blood loss must be compensated .
It should be borne in mind the risk of anaphylactic shock .
Beta- blockers may mask the symptoms of hyperthyroidism cardiovascular .
Active athletes should be aware that this product contains a medicine which can give a positive reaction in doping tests.
Fluid balance and electrolytes
Sodium in plasma should be determined before and periodically during therapy. Each treatment with diuretics may enhance hyponatremia, in some cases with serious posleditsi.Tay as hyponatraemia may be in the early asymptomatic , periodic monitoring is mandatory and should be common in high - risk groups , eg . elderly or patients with hepatic cirrhosis ( see section 4.8 and 4.9).
Potassium loss leading to hypokalemia is the biggest risk associated with thiazide diuretics and related drugs.
The risk of hypokalemia (<3.5 mmol / L) to be expected in certain high risk groups , e. the elderly and / or malnourished and / or receiving a lot of medicines , patients with liver cirrhosis with edema and ascites , in patients with coronary artery disease or heart failure who hipokalimiyata increases the cardiotoxicity of digitalis glycosides and risk of heart ritmiya.Patsienti with prolonged QT interval, congenital or iatrogenic , are also a risk group . Hypokalemia (and bradycardia ) facilitating the development of severe arrhythmia, especially torsade-de-pointes, which may be fatal .
Calcium in plasma
Thiazides and related drugs can reduce the excretion of urinary calcium , leading to mild , transient hypercalcemia . Heavy hypercalcemia may be due to undiagnosed hyperparathyroidism. Therapy should be discontinued prior to testing the function of the parathyroid glands.
In diabetic patients , blood sugar levels need to be monitored , especially in the presence of hypokalemia .
In patients with hyperuricemia risk of gout attacks may be increased . The dose should be adjusted as a function of plasma uric acid.
Renal function and diuretics
Full benefit of thiazide diuretics may be obtained only if renal function is normal or nearly normal (serum creatinine <25 mg / L or 220 pmol / L in adults)
In elderly patients, the serum creatinine must be adjusted according to the age , weight and sex , using the formula IA Cockroft, such as : * SLsg = ( 140 - age) x teglo/0.814 x serum creatinine, where age is given in years , weight in kilograms , and serum creatinine pmol / LGoreposochenata formula gives CLcr for elderly male and must be corrected for the elderly female multiplied by 0.85.Hipovolemiyata secondary induced by diuretics, due to loss of water and sodium, in the beginning of therapy , reduced glomerular filtration rate , which can lead to increased serum creatinine and urea .
This functionally transient renal impairment is not relevant in patients with normal renal function but may worsen predhodstvashta renal failure.
- Combination with other antihypertensive agents
It is advisable to reduce the dose when this product is combined with other antihypertensive agents, at least in the initial phase of therapy.
- Active athletes
Active athletes should be aware that this product contains a medicine which can give a positive reaction in doping tests.
4.5 Interactions with other medicaments and other forms of interaction
Contraindicated + Floctafenine
In the event of shock -induced hypotension or floctafenine , beta blockers would reduce cardiovascular compensatory reactions.
increased risk of ventricular arrhythmia, torsade de pointes especially
Combinations not recommended
Contractility disorders , automation and conductivity pulse ( suppression of compensatory sympathetic mechanisms ) . Combinations to be used with caution
Halogenated inhaled anesthetics +
Beta-blockers reduce cardiovascular compensatory responses. (During the surgical procedure, the beta blockade can be reversed by the beta - agonists) .
As a general rule, do not interrupt therapy with beta- Boqueria and never stops suddenly. The anesthetist should be informed that the patient is on beta- blocker therapy.
+ Calcium antagonists (Bepridil, Diltiazem, Verapamil) violations of automation (excessive bradycardia, sinus arrest ), SA and AV conduction abnormalities and heart failure ( synergistic effect). Such a combination can be used in strict clinical and ECG monitoring , especially in older patients and in the initial phase of treatment.
+ Antiarrhythmics (Propafenone and Class IA agents Quinidine, Disopyramide) disorders contractility , automaticity and conduction of impulses ( suppression of compensatory sympathetic mechanisms ) . Providing clinical and ECG monitoring.
+ Insulin, sulfonylurea oral antidiabetic produktiVsichki beta-blockers may mask the warning signs of hypoglycemia , particularly tachycardia and palpitations . Diabetic patients should be aware of the risk of hypoglycaemic episodes and the increased need for careful monitoring of blood sugar levels at home , especially in the initial phase of therapy.
+ Lidocaine ( lidocaine interactions are described with propanolol , metoprolol and nadolol ) Increased plasma levels of lidocaine - like increase of cardiac and neurological side effects (decreased hepatic biotransformation of lidocaine ) .
Adjust the dose of lidocaine . Clinical, ECG monitoring and , if necessary, the monitoring of plasma levels of the treating agent during or after the beta -blocker therapy .
+ Iodinated rengenokotrastni in case of shock induced by iodinated rentgenfkotrastni funds or hypotension , beta- blockers would block the compensatory cardiovascular reactions. Treatment with beta- blockers should if possible be stopped before any radoilogichno study. If therapy can not be interrupted , you must provide cardiopulmonary resuscitation immediately available equipment and personnel.
+ Cholinesterase inhibitoriRisk fatty bradycardia (additive bradycardic effects) . Regular clinical pregledi.Kombinatsii that should be taken into account
+ NSAIDNamalen antihypertensive effect (NSA1D inhibit vasodilatory prostaglandins and pyrazolone derivatives cause further loss of water and sodium).
+ Calcium antagonists of the dihydropyridine type (amlodipine, felodipine, lacidipine, nifedipine, nicardipine, nimodipine, nitrendipine) Hypotension, heart failure in patients with latent or controlled heart failure (in vitro dihydropyridines have more or less pronounced negative inotropic activity , which leads to the cumulative to the negative inotropic activity of beta-blockers ) therapy with beta -blockers may also minimize reflex sympathetic response in the event of extensive hemodynamic response.
+ MefloquineRisk of bradycardia (additive bradycardic effects) .
Combinations not recommended
+ LitiyPovisheni plasma lithium levels with signs of overdose occurring in a diet low in sodium ( reduced excretion. Lithium in the urine) . If this combination can not be avoided to carry out regular monitoring of the plasma lithium levels and to adjust if necessary .
+ Non- antiarrhythmic drugs that may cause Torsade de Pointes (astemizole, bepridil, IV erythromycin, halofantrine, pentamidine, sparfloxacin, terfenadine, vincamine) ( see for sultopride Bisoprolol contraindicated ): Torsade de Pointes ( induced hypokalemia , bradycardia and existing long QT syndrome) . In the event of hypokalemia to medicinal products that cause Torsade de Pointes.
Combinations to be used with caution
+ NSAID ( system) , high doses of salicylates
Acute renal failure in dehydrated patients (NSAID GFR decreased by inhibition of vasodilating prostaglandins ) .
Rehydration of the patient. Monitoring renal function after initiation of therapy.
+ Potassium-depleting drugs (IV) amphotericin B (systematic ) gluco- and mineralocorticoids , tetracosactide (cosyntropin), stimulant laxatives : Increased risk of hypokalaemia (additive effect). Monitoring and , if necessary, adjusting the plasma potassium . This is particularly important when using concomitant digitalis . Use of stimulant laxatives .
Digitalis + glikozidiHipokaleimiya , facilitating the toxic effects of cardiac glycosides . Monitoring of plasma potassium and , if appropriate, the ECG .
+ Potassium- sparing diuretics (amiloride, potassium canreonate, spironolactone, triamterene): While for some patients is a valid and useful , this combination does not exclude hypokalaemia . Particularly in patients with renal failure and / or diabetes , hypokalemia may be izklyuchi.Monitorirane plasma potassium levels and , if appropriate, the ECG, if necessary, re- reflection treatment.
+ ACE inhibitors: The risk of a significant drop in blood pressure and / or acute renal failure during initiation of therapy with ACE inhibitors in patients with preexisting sodium deprivation ( particularly in patients with renal artery stenosis) . Upon hypertension if previous therapy diuretics may have caused a shortage of sodium, to stop the diuretic 3 days prior to initiation of treatment with an ACE inhibitor , and later , if required , to re-apply the kaliuretic diuretic or to start therapy with a reduced dose of an ACE inhibitor , which then increase postepenno.Pri congenital heart failure can then reduce the dose applied parallel potassium- losing diuretic therapy be started at a very low dose of ACE inhibitor. In any case, monitoring of renal function ( serum creatinine ) during the first few weeks of treatment with an ACE inhibitor.
+ Anti-arrhythmic drugs , which can cause ; Torsade de Pointes Class I A means (Quinidine, Hydroquinidine, Disopyramide, Amiodarone, Bretylium, Sotalol): Torsade de Pointes ( facilitated by hypokalemia, bradycardia and pre-existing long QT syndrome) . Pretvratyavane and , if necessary, correction of hypokalemia . Monitoring of the QT interval. In the case of Torsade de Pointes not be applied antiarrhythmics ( electricity rate ) .
+ Metformin MetforminIndutsiranata of lactic acidosis is unlocked by renal dysfunction , owing to the use of diuretics , especially loop diuretitsi.Da not used Metformin, if the serum creatinine levels exceed 15 mg / L ( 135 mmoI / L) in men and 12 mg / L ( 110 pmol / L) in women .
+ Iodinated radiopaque sredstvaV case of dehydration caused by diuretics , increased risk of acute Renal failure , especially when using high doses of iodinated radiopaque sredstva.Rehidrirane the patient prior to administration of the iodine -containing material.Kombinatsii which must be Given its + calcium (salts ) Risk of hypercalcemia due to reduced calcium excretion in the urine
+ CyclosporinRisk of increase in serum creatinine , no change in serum levels of the cyclosporin , even in the absence of loss of water and sodium.
Combined produktKombinatsii requiring precautions for use
+ BaclofenPovishen antihypertensive effect . Monitoring of the blood pressure and adapting the dose of medicinal product antihepertenzivniya if neobhodimo.Kombinatsii which must be taken into account
+ Tricyclic antidepressants type of Imipramine , antipsychotics increase the antihypertensive effect and increased risk of orthostatic hypotension ( additive effect)
+ Corticosteroids , tetracosactide ( system) Decreased antihypertensive effect ( corticosteroid - induced water retention and sodium)
4.6 Pregnancy and lactation
This medicine contains a thiazide diuretic. Therefore, the use during pregnancy is not recommended.
BisoprololOpitite not indicate nikakakav teratogenic . Until now , the results of well-controlled , prospective studies with some beta -blockers showed no birth defects in the newborn. Infants born to mothers treated with beta -blockers , beta- blockade activity is a few days after birth and may induce bradycardia , respiratory distress and hypoglycaemia. However, it may occur heart failure requiring emergency measures , avoiding plasma infusion (risk of acute pulmonary edema) .
Diuretics can lead to fetal - placental ischemia with accompanying risk of fetal hypotrophy . Have been reports of rare cases of severe thrombocytopenia in neonates.
It is not known whether Bisoprolol is excreted in breast milk. Thiazides are excreted in breast milk , so this product should not be taken by nursing mothers (see 4.3)
The risk of hypoglycemia and bradycardia in infants has not been evaluated .
Thiazide diuretics may cause :
- Reduce , even stop breast milk
- Adverse biological effects ( hypokalemia )
- Haemolysis (G6PD defect ) and hypersensitivity due to the properties of the sulfonamide
4.7 Effects on ability to drive and use machines
Due to the risk othipotoniya and dizziness treatment Lodoz may affect the ability to drive and use machines.
Bradycardia or serious drop in blood pressure , the following applies intravenously :
- Atropine 1-2 mg bolus
- 10 mg of Glucagon slowly intravenously , followed by infusion at doses of 1-10 mg / hour , if necessary,
- Then, if necessary - or isoproterenol (isoprenaline) 15-18 ug by slow injection , repeated as necessary , without exceeding a total dose of 300 ug, or dobutamine 2.5-10 pg / kg / min .
In case of cardiac decompensation in infants born to mothers treated with beta -blockers :
- Glucagon 0.3 mg / kg;
- Resuscitative measures;
- Isoproterenol (isoprenaline) or dobutamine: High doses and prolonged treatment , which is usually necessary require close monitoring and specialized conditions.
5 . pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Combinations of adrenoceptor blocking agent (pi- selective ) and a thiazide diuretic
ATC code: S07VV07
Clinical studies indicate that the antihypertensive effects of the two products are complementary to, and efficacy at the lowest dose , 2.5 mg/6.25 mg, in the treatment of mild to moderate hypertension is established.
Pharmacodynamic effects including hypokalemia (hydrochlorothiazide), bradycardia, asthenia and headache (Bisoprolol) are dose - dependent.
Combining the two drugs in a quarter / half of the doses used in monotherapy (2.5 mg/6.25 mg) aims to reduce these effects.
Bisoprolol is a highly selective pi- adrenoceptor blocking agent devoid of intrinsic sympathomimetic activity ( ICA) and without significant membrane stabilizing aktivnost.Kakto with other pi- receptor blockers , the mechanism of the antihypertensive activity of Bisoprolol is not fully established. However, it is shown that the drug leads to a clear reduction in plasma renin activity and decrease in heart rate.
Hydrochlorothiazide is a thiazide diuretic with antihypertensive activity . Its diuretic effect is due to inhibition of active Na + transport by the renal tubules to the blood by interfering with Na + reabsorption .
5.2 Pharmacokinetic properties
- Absorption: Tmax ranging from 1 to 4 hours
- Bioavailability was high ( 88% ) first pass hepatic extraction is very low , and the absorption is not influenced by the presence of food . The kinetics is linear for dose of 5-40 mg.
- Distribution : 30% bound to plasma proteins and the volume of distribution is high (approximately 3 L / kg)
- Metabolism : 40% of Bisoprolol dose is metabolized in the liver. Its metabolites are not active.
- Elimination: The plasma elimination half- a 11:00
Renal and hepatic clearance were comparable and approximately half the dose ( unchanged ) and the metabolites are excreted in urine. Total clearance is approximately 15 l / kg.
- Absorption : the bioavailability of Hydrochlorothiazide shows variability between people and is within 60-80 %. Tmax ranged from 1.5 to 5 hours (main ~ 4 hours).
- Distribution : The plasma protein binding is 40%.
- Elimination : Hydrochlorothiazide is not metabolized and is excreted almost entirely as nepromeno drug by glomerular filtration and active tubular secretion. The terminal elimination half-life is about 8 hours.
- Renal clearance of Hydrochlorothiazide decreases the half -life is increased in patients with renal and / or heart failure . The same is true in older patients is also observed an increase in Cmax .
- Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk
5.3 Preclinical safety data
According to conventional preclinical tests ( prolonged toxicity , mutagenicity , genotoxicity and carcinogenicity ) is not proven Bisoprolol and hydrochlorothiazide are toxic to humans. Like other beta-blockers in animal experiments found that Bisoprolol in high doses has toxic effects on maternal ( decreased food intake and weight gain ) and embryo / fetus (increased late resorptions, reduced birth weight , delay physical development by the end of the lactation period) . However , Bisoprolol, and hydrochlorothiazide is not teratogenic . No increase in toxicity when the two products are given in combination .
6 . pharmaceutical features
Silica, colloidal, anhydrous 0.5 mg
Magnesium stearate 2.0 mg
Cellulose, microcrystalline 10.0 mg
Maize-starch, fine powder 10,0 mg
Calcium hydrogen phoshate, anhydrous 131.25 mg
Film coating : OPADRY WHITE YS- 1-7003 *
* Ingredients : Polysorbate 80 VS 0.045 mg
Macrogol 400 0.360 mg
Hypromellose 2910/3 1.34438 mg
Hypromellose 2910/5 1.34438 mg
Titanium dioxide E171 1.40625 mg
6.3 Shelf life
6.4 Special precautions for storage
Store up to 25 ° C.