Локрен®

General characteristics. Structure:

Contains in one tablet:
active ingredient: a betaksolola a hydrochloride - 20,00 mg;
excipients: lactoses monohydrate — 100,00 mg, cellulose microcrystallic - 113,00 mg, sodium carboxymethylstarch (type A) - 4,00 mg, silicon dioxide colloid - 1,60 mg, magnesium stearate - 1,40 mg;
Cover: a gipromelloza - 3,90 mg, titanium dioxide (Е 171) - 0,67 mg, a macrogoal-400 - 0,43 mg.

Description
 Round biconvex tablets, film coated white color, with risky on one party and KE 20 engraving on other party.

Pharmacological properties:

Pharmacodynamics. Betaksolol is characterized by the following three pharmacological properties:
• cardioselective beta1-adrenoceptor blocking action;
• lack of partial agonistic activity (lack of internal sympathomimetic activity);
• weak membrane stabilizing action (similar to effect of quinidine or local anesthetics) in the concentration exceeding therapeutic.

It should be noted that the selection impact of a betaksolol on beta1-adrenergic receptors is not absolute, so at its use in high doses impact of a betaksolol on the beta2-adrenergic receptors located, mainly, in smooth muscles of bronchial tubes and vessels (however impact of a betaksolol on beta2-adrenoceptors is much weaker than that at non-selective beta adrenoblockers) is possible, At use of a betaksolol its activity blocking beta1-adrenergic receptors is shown by the following pharmakodinamichesky effects:
• reduction of the heart rate (HR) at rest and at an exercise stress (due to blockade of beta adrenoceptors in a sinus node that in combination with absence at a betaksolol of internal sympathomimetic activity leads to delay of automatism of a sinus node);
• decrease in cordial emission at rest and at an exercise stress at the expense of competitive antagonism with catecholamines in peripheral (especially cardial) adrenergic nerve terminations;
• decrease in systolic and diastolic arterial pressure at rest and at an exercise stress (the mechanism of anti-hypertensive action is described below);
• reduction of a reflex of orthostatic tachycardia.

These effects are resulted by reduction of load of heart at rest and at an exercise stress.
The mechanism of anti-hypertensive effect of beta adrenoblockers is completely not installed.
At beta adrenoblockers the following mechanisms of anti-hypertensive action are assumed:
• decrease in cordial emission;
• elimination of a spasm of peripheral arteries (due to the central action leading to decrease in a sympathetic impulsation on the periphery to vessels, and at the expense of inhibition of activity of a renin).

Anti-hypertensive action of a betaksolol at its long reception does not decrease. At reception of a betaksolol single within a day (from 5 to 40 mg) anti-hypertensive action is identical in 3-4 hours (time of achievement of the maximum concentration of a betaksolol in blood) and in 24 hours (before reception of the next dose). At reception of 5 mg and 10 mg of a betaksolol its anti-hypertensive action makes, respectively, 50% and 80% of anti-hypertensive action at reception of 20 mg of a betaksolol.
Thus, in the range of doses of 5-20 mg the dozozavisimost of anti-hypertensive effect is observed, and at increase in a dose from 10 mg to 20 mg the gain of anti-hypertensive effect is insignificant. Increase in a dose from 20 mg to 40 mg changes anti-hypertensive action of a betaksolol a little. The maximum anti-hypertensive effect of each dose of a betaksolol is reached in 1-2 weeks.
Unlike anti-hypertensive action of a betaksolol the effect of reduction of ChSS at increase in its dose (from 10 mg to 40 mg) does not increase.
Besides, бетаксолол it is capable to slow down conductivity of an atrioventricular node.

Pharmacokinetics. Absorption
 Betaksolol quickly and completely (100%) is absorbed from digestive tract.
Betaksolol has insignificant effect of "primary passing" through a liver and high bioavailability - about 85%. The maximum concentration of a betaksolol in a blood plasma are reached in 2-4 hours. Distinctions of its plasma concentration at different patients or at one patient at prolonged use have insignificant distinctions that is connected with high bioavailability of a betaksolol.
Distribution
 Betaksolol contacts proteins of a blood plasma approximately for 50%.
Permeability through a blood-brain and placental barrier - low. Secretion with breast milk - insignificant.
Distribution volume - about 6 l/kg.
Metabolism
 In an organism бетаксолол generally turns into inactive metabolites. Solubility in fats moderate.
Removal
 10-15% in not changed look are removed by kidneys in the form of metabolites (more than 80%). The elimination half-life (T1/2) of a betaksolol makes 15-20 hours. T1/2 at an abnormal liver function is extended for 33%, but the clearance does not change; at a renal failure of T1/2 doubles (decrease in doses is necessary).
Is not removed at a hemodialysis.

Indications to use:

• Arterial hypertension (in monotherapy and structure of a combination therapy).
• Prevention of attacks of an angina of exertion (in monotherapy and structure of a combination therapy).

Route of administration and doses:

Drug is accepted inside and is washed down with enough liquid. It is not necessary to chew a tablet.
The initial dose of the drug Lokren® for both indications to use of drug makes usually 10 mg (1/2 tablets of 20 mg). If within 7-14 days of treatment target values of arterial pressure are not reached, then the dose doubles to 20 mg a day.
Usually the drug Lokren® doses exceeding 20 mg are not used (because at increase in a dose more than 20 mg are not observed statistically reliable increase in anti-hypertensive effect of drug).
The maximum daily dose of the drug Lokren® - 40 mg.
Patients with a renal failure
 Dose adjustment depending on a functional condition of kidneys of the patient is recommended.
At clearance of creatinine more than 20 ml/min. of dose adjustment are not required. However, in an initiation of treatment, it is recommended to make clinical observation before achievement of equilibrium concentration of drug in blood that is reached on average by 4-7 day of treatment).
At the expressed renal failure (clearance of creatinine less than 20 ml/min.) the recommended initial dose of drug makes 5 mg/days (regardless of frequency and days of holding a procedure of a hemodialysis at the patients who are on a hemodialysis) which at insufficient efficiency can increase twice each 1-2 weeks.
The maximum daily dose makes 20 mg.
Patients with a liver failure
 With a liver failure of dose adjustment usually it is not required from patients. However, at the beginning of therapy, more careful clinical observation of the patient is recommended.

Side effects:

The side effects provided below are given according to the following gradation of frequency of their emergence: very often (> 1/10), it is frequent (> 1/100, <1/10); not often (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000) (including separate messages).
Disturbances from skin and hypodermic fabrics
 Seldom: various skin reactions, including skin rash, an itch, a small tortoiseshell, psoriazopodobny rashes or an aggravation of a course of psoriasis (see the section "With Care").
Disturbances from a nervous system
 Often: dizziness, headache.
Very seldom: paresthesia.
Disturbances from an organ of sight
 Seldom: xerophthalmus.
Very seldom: vision disorders.
Disturbances of mentality
 Often: adynamy, sleeplessness.
Seldom: depression.
Very rare: hallucinations, confusion of consciousness, nightmares.
Disturbances from digestive tract
 Often: gastralgia, diarrhea, nausea, vomiting.
Disturbances from a metabolism and food
 Very seldom: hypoglycemia, hyperglycemia.
Disturbances from heart
 Often: bradycardia, perhaps heavy.
Seldom: development (or aggravation) symptoms of heart failure (puffiness of anklebones, feet, shins), the expressed lowering of arterial pressure, delay of atrioventricular conductivity.
Disturbances from vessels
 Often: decrease in skin temperature of upper and lower extremities.
Seldom: manifestations of a vasomotor spasm: Reynaud's syndrome, strengthening of disturbances of peripheric circulation, including "the alternating lameness", increase of attacks of stenocardia.
Disturbances from respiratory system, bodies of a thorax and a mediastinum
 Seldom: bronchospasm.
Disturbances from generative organs and a mammary gland
 Often: impotence.
Laboratory and tool data
 Seldom: the emergence of antinuclear antibodies which only in exceptional cases is combined with clinical manifestations of the volchanochnopodobny syndrome passing after the treatment termination; decrease in intraocular pressure (because of a possibility of its decrease under the influence of beta adrenoblockers).
Influence on a fruit
 Pre-natal growth inhibition, hypoglycemia, bradycardia.
Others
 Syndrome of "cancellation" (strengthening or increase of attacks of stenocardia, increase in the ABP, see the section "Special Instructions").

Interaction with other medicines:

Contraindicated combinations
With floktafeniny
 In case of shock or the arterial hypotension caused floktafeniny beta adrenoblockers cause reduction of compensatory cardiovascular reactions.
With sultopridy
 Disturbances of automatism of heart (the expressed bradycardia) owing to additional reduction of ChSS.
Not recommended combinations
With Amiodaronum
 Disturbances of contractility, automatism and conductivity (oppression of sympathetic compensatory mechanisms).
With blockers of "slow" calcium channels (bepridit, diltiazem and verapamil)
Automatism disturbances (the expressed bradycardia, stop of a sinus node), disturbances of atrioventricular conductivity, heart failure [the synergetic (mutually amplifying) effects].
Such combination can be applied only under careful clinical and electrocardiographic observation, especially at elderly patients or in an initiation of treatment.
With cardiac glycosides
 Risk of development or aggravation of bradycardia, atrioventricular block, cardiac standstill.
With MAO inhibitors
 Simultaneous use with MAO inhibitors owing to considerable strengthening of anti-hypertensive action of a betaksolol is not recommended, having rummaged in treatment between reception of MAO inhibitors and a betaksolola has to make not less than 14 days.
With iodinated contrast agents
 In case of development of shock or a sharp lowering of arterial pressure at administration of iodinated contrast mediums, beta adrenoblockers reduce compensatory cardiovascular reactions. If it is possible, then before carrying out a radiographic research using iodinated contrast means it is necessary to cancel treatment by beta adrenoblocker.
Combinations which should be applied with care
With inhalation anesthetics of a galogensoderzhashchicha
 Beta adrenoblockers possess cardiodepressive action (the inhibition of beta adrenergic receptors can be reduced at introduction of beta adrenostimulyator). As a rule, treatment by beta adrenoblockers does not stop and anyway it is necessary to avoid sharp cancellation of beta adrenoblockers. The anesthesiologist needs to be informed of beta adrenoblocker reception.
With the drugs capable to cause ventricular disturbances of a heart rhythm, including ventricular tachycardia like "pirouette": antiarrhytmic means of the class IA (quinidine, hydroquinidine and Disopyramidum) and a class III (Amiodaronum, дофетилид, ибутилид), соталол, some neuroleptics from group of a fenotiazin (Chlorpromazinum, циамемазин, levomepromazinum, thioridazine), benzamides (амисульприд, Sulpiridum, тиаприд), phenyl propyl ketones (Droperidolum, a haloperidol), other neuroleptics (Pimozidum) and other drugs (цизаприд, difemanit, the erythromycin entered intravenously, галофантрин, мизоластин, moxifloxacin, the pentamidine entered intravenously Spheromycinum and Vincaminum entered intravenously
 Increase in risk of ventricular disturbances of a rhythm, in particular ventricular tachycardia like "pirouette".
Clinical and electrocardiographic control is required.
With propafenony
 Disturbances of contractility, automatism and conductivity (suppression of sympathetic compensatory mechanisms).
Clinical and electrocardiographic control is required.
With Baclofenum
 Strengthening of anti-hypertensive action of a betaksolol.
Control of the ABP and dose adjustment of a betaksolol in case of need is necessary.
With insulin and hypoglycemic means for intake, derivatives
sulphonylurea (see the sections "With Care", "Side effect", "Special Instructions").
All beta adrenoblockers can mask certain symptoms of a hypoglycemia, such as heart consciousness and tachycardia.
The patient has to be warned about need of strengthening of regular control of concentration of glucose for blood, including active self-checking by the patient, especially in an initiation of treatment.
With cholinesterase inhibitors (амбеномиум, donepezil, Galantaminum, неостигмин, pyridostigmine, ривастигмин, такрин)
Risk of strengthening of bradycardia (additive action).
Regular clinical control is required.
With antihypertensives of the central action (clonidine, апраклонидип, alpha Methyldopum, гуанфацин, моксонидин, рилменидин)
The increased risk of development of bradycardia, disturbance of atrioventricular conductivity.
Substantial increase of the ABP at sharp cancellation of an antihypertensive of the central action. It is necessary to avoid sharp cancellation of an antihypertensive and to carry out clinical control.
With lidocaine, 10% solution, (intravenously as antiarrhytmic means)
Increase in concentration of lidocaine in a blood plasma with possible increase in undesirable neurologic symptoms and effects from cardiovascular system (decrease in metabolism of lidocaine in a liver).
Clinical and electrocardiographic observation and, perhaps, control of concentration of lidocaine in a blood plasma is recommended during treatment by beta adrenoblockers and after its termination. If necessary - lidocaine dose adjustment.
Combinations which should be taken into account
With non-steroidal anti-inflammatory drugs (NPVP) (drugs with systemic action), including the selection inhibitors of cyclooxygenase-2 (TsOG-2)
Decrease in anti-hypertensive effect of a betaksolol (oppression of synthesis of NPVP prostaglandins and delay of water and sodium pyrazolon derivatives).
With blockers of "slow" calcium channels from group of dihydropyridines
 Mutual strengthening of anti-hypertensive action of blockers of "slow" calcium channels and a betaksolol, development of heart failure in patients with latentnoprotekayushchy heart failure or uncontrollable heart failure. Treatment by beta adrenoblockers can minimize reflex activation of a sympathetic nervous system in response to a vazodilatation under the influence of blockers of "slow" calcium channels from group of dihydropyridines.
With tricyclic antidepressants (like Imipraminum), neuroleptics
 Strengthening of anti-hypertensive effect of a betaksolol and risk of orthostatic hypotension (additive action).
With meflokhiny
 Risk of bradycardia (additive action).
With Dipiridamolum (intravenous administration)
Strengthening of anti-hypertensive effect of a betaksolol.
With alpha adrenoblockers, including applied in urology (альфузозин, доксазозин, Prazozinum, тамсулозин, теразозин.)
Strengthening of anti-hypertensive effect of a betaksolol. The increased risk of orthostatic hypotension.
With amifostiny
 Strengthening of anti-hypertensive effect of a betaksolol.
With the allergens used for an immunotherapy or extracts of allergens for skin tests
 The increased risk of emergence of heavy system allergic reactions or an anaphylaxis at the patients receiving бетаксолол.
With Phenytoinum (intravenous administration)
Increase in expressiveness of cardiodepressive action and probability of decrease in the ABP.
With xanthines
 Betaksolol reduces clearance of xanthines (except Diphyllinum) and increases their concentration in a blood plasma, especially at patients with initially increased clearance of theophylline (for example, under the influence of smoking).
With estrogen
 Easing of anti-hypertensive effect of a betaksolol (delay of sodium and water).
With glucocorticosteroids and tetrakozaktidy
 Easing of anti-hypertensive effect of a betaksolol (delay of sodium and water).
With diuretics
 Perhaps excessive lowering of arterial pressure.
With not depolarizing muscle relaxants
 Betaksolol extends action of not depolarizing muscle relaxants.
With coumarins
 Strengthening of anticoagulating effect of coumarins.
With alcohol (ethanol), sedative and somnolent medicines
 Strengthening of oppression of the central nervous system.
With not hydrogenated ergot alkaloids
 Not hydrogenated alkaloids of an ergot increase risk of development of disturbances of peripheric circulation at reception of a betaksolol.

Contraindications:

• Hypersensitivity to a betaksolol and excipients of drug.
• Severe forms of bronchial asthma and chronic obstructive pulmonary disease.
• The acute heart failure, chronic heart failure in a decompensation stage which is not compensated as a result of treatment by diuretics, inotropic means, APF inhibitors, other vazodilatator.
• Cardiogenic shock.
• An atrioventricular block of II and III degrees (without the established artificial pacemaker).
• Printsmetal's stenocardia (monotherapy is contraindicated).
• A sick sinus syndrome (including sinuatrial blockade).
• The expressed bradycardia (ChSS less than 45-50 beats/min.).
• Severe forms of a Raynaud's disease and obliterating diseases of peripheral arteries.
• A pheochromocytoma without concomitant use of alpha adrenoblockers.
• Arterial hypotension (systolic arterial pressure <100 mm of mercury.).
• Anaphylactic reactions in the anamnesis.
• Metabolic acidosis.
• At simultaneous use with floktafeniny (see the section "Interaction with Other Medicines").
• At simultaneous use with sultopridy (see the section "Interaction with Other Medicines").
• At a concomitant use of inhibitors of a monoaminooxidase (MAO).
• A cardiomegaly (without symptoms of heart failure).
• Age up to 18 years (efficiency and safety are not established).
• Deficit of lactase, a lactose intolerance, glyukozo-galaktozny malabsorption (in connection with presence at composition of drug of lactose).

With care
• At bronchial asthma and a chronic obstructive pulmonary disease of a medium-weight current (to begin treatment with small doses and it is desirable under control of indicators of function of external respiration; thanks to beta1-selectivity of a betaksolol at emergence of an attack of bronchial asthma against the background of its reception stopping of an attack of a beta2-adrenomimetikama is possible).

• At chronic heart failure in compensation stage, (treatment betaksololy is possible only under strict medical observation; treatment should be begun with very small doses with their gradual increase).

• At an atrioventricular block of the I degree (careful observation, including ECG control is required).

• At obliterating diseases of peripheral arteries, Reynaud's syndrome (except for a severe form, see the section "Contraindications") (strengthening of disturbances of peripheric circulation is possible).

• At Printsmetal's stenocardia (increase of attacks of stenocardia is possible; use of the selection beta1-adrenoblocker is possible only at simultaneous use of vazodilatator).

• At a treated pheochromocytoma (at treatment by the drug Lokren® of arterial hypertension against the background of a treated pheochromocytoma careful observation of indicators of arterial pressure is required).

• At patients of advanced age (it is necessary to begin treatment with small doses and under careful medical observation).

• At a renal failure (at the clearance of creatinine (CC) more than 20 ml/min. - careful observation of the patient during the first 4 days of treatment; at KK less than 20 ml/min. and/or carrying out a hemodialysis are required correction of the mode of dosing, see the section "Route of Administration and Doses").

• At a liver failure (more careful clinical observation in an initiation of treatment is required).

• At patients with a diabetes mellitus (regular control of concentration of glucose in blood, including active self-checking by the patient, in an initiation of treatment is necessary; reduction of expressiveness of harbingers of development of a hypoglycemia, such as tachycardia, heart consciousness and the increased sweating is possible).

• At psoriasis (beta adrenoblockers can make heavier the course of psoriasis).

• When performing the desensibilizing therapy.

Use during pregnancy and in the period of a lactation
Pregnancy
 In experiments on animals at a betaksolol teratogenic action was not revealed.
So far it was not reported about teratogenic effects at the person.
As a rule, beta adrenoblockers reduce a blood stream in a placenta and can influence fetation. It is necessary to trace a blood stream in a placenta and a uterus, and also to watch growth and development of future child, and in case of the undesirable phenomena concerning pregnancy and/or a fruit, to take alternative therapeutic measures.
It is necessary to inspect carefully the newborn after the delivery. In the first 3-5 days of life there can be symptoms of bradycardia, a hypoglycemia as effect of beta adrenoblockers at newborns whose mothers accepted them before childbirth remains within several days after the birth. In the neonatal and post-natal period newborns have an increased risk of cardial and respiratory complications. In case of developing of heart failure hospitalization of the newborn in the block of an intensive care is required (see the section "Overdose"). It is necessary to avoid use of plasma substitutes (risk of development of an acute fluid lungs). Also it was reported about development of bradycardia, respiratory insufficiency and a hypoglycemia. In this regard during the first 3-5 days of life careful observation of such newborns in specialized department is required (ChSS, concentration of glucose in blood).
In this regard use of the drug Lokren® at pregnancy is not recommended and it is possible only in that case when the advantage for mother exceeds potential risk for a fruit or the child.
Lactation period
 Beta adrenoblockers, including бетаксолол, are emitted with breast milk (see the section "Pharmacokinetics"). The risk of a hypoglycemia or bradycardia at babies was not studied therefore as a precautionary measure feeding by a breast during treatment needs to be stopped.

Overdose:

Symptoms
 The expressed bradycardia, dizziness, atrioventricular block, the expressed decrease in the ABP, arrhythmia, ventricular premature ventricular contraction, unconscious state, heart failure, breath difficulty, bronchospasm, cyanosis of nails of fingers and palms, spasms.
Treatment
 Gastric lavage, use of the adsorbing means.
In case of development of bradycardia it is recommended: atropine of 1-2 mg intravenously; then (in case of need) slow infusion of 25 mkg of an izoprenalin or infusion dobutamina2,5-10 mkg/kg/min.; temporary statement of an artificial pacemaker can sometimes be required.
In case of excessive decrease in the ABP it is recommended: intravenous administration of plasma substituting solutions and angiotonic drugs.
At a bronchospasm:
purpose of bronchodilators, including beta2-adrenomimetik and/or Aminophyllinum.
In case of heart failure (decompensation) at newborns whose mothers during pregnancy accepted beta adrenoblockers it is recommended:
hospitalization in intensive care unit; изопреналин and Dobutaminum: observation of the specialist is long and usually in high doses.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity of 5 years. Not to use drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 20 mg.
On 14 tablets in the blister from PVC and aluminum foil.
On 2 blisters together with the application instruction in a cardboard pack.