Lokren, 20 mg 56 pcs.

A selective beta₁-adrenoblocker. Betaxolol is characterized by three pharmacological properties: cardioselective beta₁-adrenoblocking action; absence of partial agonist activity (absence of intrinsic sympathomimetic activity); weak membrane stabilizing action (similar to that of quinidine or local anesthetic agents) in concentrations greater than therapeutic.

It should be noted that the selective effect of betaxolol on β₁-adrenoreceptors is not absolute, so when used in high doses betaxolol may affect β₂-adrenoreceptors located mainly in the smooth muscle of bronchi and vessels (but the effect of betaxolol on β₂-adrenoreceptors is much weaker than that of non-selective beta-adrenoblockers).

When using betaxolol its blocking β₁-adrenoreceptor activity is manifested by the following pharmacodynamic effects:

• reduction of HR at rest and during exercise (due to blockade of β-adrenoreceptors in the sinus node, which, combined with betaxololol’s lack of intrinsic sympathomimetic activity, results in deceleration of sinus node automatism);
• decreased cardiac output at rest and during exercise due to competitive antagonism with catecholamines in peripheral (especially cardiac) adrenergic nerve endings;
• reduction of systolic and diastolic BP at rest and at exercise (the mechanism of antihypertensive action is described below);
• reduction of orthostatic tachycardia reflex.

As a result of these effects, there is a reduction in the load on the heart at rest and during physical activity.

The mechanism of antihypertensive action of beta-adrenoblockers is not fully established.

The following mechanisms of antihypertensive action are suspected in beta-adrenoblockers:

• reduction of cardiac output;
• elimination of peripheral arterial spasm (through central action, resulting in reduction of sympathetic impulse to the periphery, to the vessels, and through inhibition of renin activity).

The antihypertensive effect of betaxolol does not decrease with long-term administration. With a single daily dose of betaxolol (5 to 40 mg), the antihypertensive effect is the same after 3-4 hours (time of reaching C_max of betaxolol in blood) and after 24 hours (before taking the next dose). When taking 5 mg and 10 mg betaxolol its antihypertensive effects are, respectively, 50% and 80% of the antihypertensive effect when taking 20 mg betaxolol.

Thus, there is a dose-dependent antihypertensive effect in the 5-20 mg dose range, with little increase in antihypertensive effect when the dose is increased from 10 mg to 20 mg. Increasing the dose from 20 mg to 40 mg does little to change the antihypertensive effect of betaxolol. The maximum antihypertensive effect of each betaxolol dose is achieved after 1-2 weeks.

In contrast to the antihypertensive effect of betaxololol, the HR reduction effect does not increase with increasing dose (from 10 mg to 40 mg).

Betaxololol is also able to slow down AV node conduction.

Indications

Active ingredient

Composition

1 coated tablet contains: Betaxolol hydrochloride 20 mg,

lactose monohydrate – 100 mg,

microcrystalline cellulose – 113 mg,

sodium carboxymethyl starch (type A) – 4 mg,

silicon dioxide colloid – 1.6 mg,

magnesium stearate – 1.4 mg.

Shell composition:

Hypromellose – 3.9 mg,

Macrogol 400 – 0.43 mg,

Titanium dioxide (E171) – 0.67 mg.

How to take, the dosage

The drug is taken orally with plenty of fluid. The tablet should not be chewed.

The starting dose of Lokren® for both indications of use is usually 10 mg (1/2 tablet 20 mg). If target BP values are not achieved within 7-14 days of treatment, the dose is doubled to 20 mg/day.

Doses of Lokren® exceeding 20 mg are not usually used (because there is no statistically significant increase in the antihypertensive effect of the drug with a dose higher than 20 mg).

The maximum daily dose of Lokren® is 40 mg.

In patients with renal insufficiency, it is recommended to adjust the dose depending on the functional state of the patient’s kidneys. In CKD over 20 ml/min the dose adjustment is not required. However, at the beginning of treatment, it is recommended to carry out clinical monitoring until equilibrium concentration of the drug in blood is reached, (which is reached on average by 4-7 days of treatment). In patients with severe renal insufficiency (CKR less than 20 ml/min), the recommended initial dose of this medicine is 5 mg/day (regardless of the frequency and days of hemodialysis procedures for patients on hemodialysis), which may be increased twofold every 1-2 weeks in case of insufficient effectiveness. The maximum daily dose is 20 mg.

In patients with hepatic insufficiency, dosage adjustment is usually not required. However, closer clinical monitoring of the patient is recommended at the beginning of therapy.

Interaction

Contraindicated combinations

With floktafenin

In case of shock or arterial hypotension due to floktafenin, beta-adrenoblockers cause a decrease in compensatory cardiovascular responses.

With sultopride

Disorders of cardiac automatism (marked bradycardia) due to additional reduction of heart rate.

Unrecommended combinations

With amiodarone

Disorders of contractility, automaticity and conduction (inhibition of sympathetic compensatory mechanisms).

With slow calcium channel blockers (bepridil, diltiazem and verapamil)

Disorders of automatism (severe bradycardia, sinus node arrest), AV conduction disorders, heart failure (synergistic / mutually reinforcing/ effects).

This combination should only be used under close clinical and ECG monitoring, especially in elderly patients or at the start of treatment.

With cardiac glycosides

The risk of developing or worsening bradycardia, AV blockade, cardiac arrest.

With MAO inhibitors

The concomitant use with MAO inhibitors is not recommended because of the significant increase in the antihypertensive effect of betaxololol; a treatment break of at least 14 days between taking MAO inhibitors and betaxololol.

With iodine-containing contrast agents

If shock or a sharp decrease in BP develops with iodine-containing contrast agents, beta-adrenoblockers reduce compensatory cardiovascular responses. If possible, beta-adrenoblocker treatment should be discontinued before radiographic examination with iodine-containing contrast agents.

Combinations to be used with caution

With inhaled halogen-containing anesthetics

Beta-adrenoblockers have a cardiodepressant effect (inhibition of β-adrenoreceptors may be reduced by administration of beta-adrenoceptors). As a rule, treatment with beta-adrenoblockers is not discontinued and abrupt withdrawal of beta-adrenoblockers should be avoided in any case. The anesthesiologist should be informed about the beta-adrenoblocker.

With drugs that can cause ventricular arrhythmias, including pirouette-type ventricular tachycardia: Class IA (quinidine, hydroquinidine and disopyramide) and Class III (amiodarone, dofetilide, ibutilide) antiarrhythmic agents, sotalol, some phenothiazine neuroleptics (chlorpromazine, cyamemazine, levomepromazine, thioridazine), benzamides (amisulpride, sulpiride, thiapride), butyrophenones (droperidol, haloperidol), other neuroleptics (pimozide) and other drugs (cisapride, difemanil, IV erythromycin, halofantrine, misolastin, moxifloxacin, pentamidine, IV spiramycin and IV vincamine

An increased risk of ventricular rhythm abnormalities, particularly pirouette-type ventricular tachycardia. Clinical and ECG monitoring is required.

With propafenone

Disorders of contractility, automaticity and conduction (suppression of sympathetic compensatory mechanisms). Clinical and ECG monitoring is required.

With baclofen

Augment the antihypertensive effects of betaxololol. BP should be monitored and the dose of betaxololol should be adjusted if necessary.

With insulin and oral hypoglycemic agents, sulfonylurea derivatives

All beta-adrenoblockers may mask certain symptoms of hypoglycemia, such as palpitations and tachycardia. The patient should be cautioned to increase regular blood glucose monitoring, including active self-monitoring by the patient, especially at the beginning of treatment.

With cholinesterase inhibitors (ambenonium, donepezil, galantamine, neostigmine, pyridostigmine, rivastigmine, tacrine)

Risk of increased bradycardia (additive effect). Regular clinical monitoring is required.

With centrally acting hypotensive agents (clonidine, apraclonidine, alpha-methyldopa, guanfacine, moxonidine, rilmenidine)

Increased risk of bradycardia, AV conduction disorders. Significant increase in BP if central hypotensive agent is abruptly withdrawn. Abrupt withdrawal of the hypotensive agent should be avoided and clinical monitoring should be performed.

With lidocaine 10% solution (IV as an antiarrhythmic agent)

Lidocaine plasma concentration increases with possible increase in unwanted neurological symptoms and cardiovascular effects (decreased lidocaine metabolism in the liver). Clinical and ECG monitoring and possibly monitoring of plasma concentrations of lidocaine during treatment with beta-adrenoblockers and after its discontinuation are recommended. Adjustment of lidocaine dose if necessary.

Combinations to be considered

With NSAIDs (drugs with systemic action), including selective COX-2 inhibitors

With COX-2 inhibitors/p>

Decrease the antihypertensive effect of betaxolol (inhibition of prostaglandin synthesis by NSAIDs and water and sodium retention by pyrazolone derivatives).

With slow calcium channel blockers from the group of dihydropyridines

Mutual enhancement of the antihypertensive effect of slow calcium channel blockers and betaxololol, development of heart failure in patients with latent heart failure or uncontrolled heart failure. Treatment with beta-adrenoblockers may minimize reflex activation of the sympathetic nervous system in response to vasodilation under the influence of slow calcium channel blockers from the group of dihydropyridines.

With tricyclic antidepressants (such as imipramine), neuroleptics

Augmentation of the antihypertensive effect of betaxolol and risk of orthostatic hypotension (additive effect).

With mefloquine

Risk of bradycardia (additive effect).

With dipyridamole (IV)

Augmentation of the antihypertensive effect of betaxololol.

With alpha-adrenoblockers, including those used in urology (alfuzosin, doxazosin, prazosin, tamsulosin, terazosin)

Augmentation of the antihypertensive effect of betaxololol. Increased risk of orthostatic hypotension.

With amifostine

Amplification of the antihypertensive effect of betaxololol.

With allergens used for immunotherapy or allergen extracts for skin testing

An increased risk of severe systemic allergic reactions or anaphylaxis in patients receiving betaxolol.

With phenytoin (intravenous)

An increase in the severity of cardiodepressant effects and likelihood of BP decrease.

With xanthines

Betaxolol decreases clearance of xanthines (except diphylline) and increases their plasma concentrations, especially in patients with initially increased clearance of theophylline (e.g., as a result of smoking).

With estrogens

Weakening of the antihypertensive effect of betaxololol (sodium and water retention).

With GCS and tetracosactide

Attenuation of the antihypertensive effect of betaxololol (sodium and water retention).

With diuretics

Possible excessive BP reduction.

With nondepolarizing myorelaxants

Betaxololol prolongs the effect of nondepolarizing myorelaxants.

With coumarins

Magnifies the anticoagulant effect of coumarins.

With alcohol (ethanol), sedative and hypnotic drugs

Augmentation of CNS depression.

With nonhydrogenated ergot alkaloids

Nonhydrogenated ergot alkaloids increase the risk of peripheral circulatory disturbances when taking betaxolol.

Special Instructions

The treatment with Lokren® should not be interrupted abruptly and the recommended dose should not be changed without first consulting a physician, as this may lead to a temporary worsening of heart function. Treatment should not be interrupted suddenly, especially in patients with CHD, since abrupt withdrawal may lead to severe cardiac rhythm disturbances, myocardial infarction, or cardiac arrest. The dose should be reduced gradually, i.e., over 2 weeks, and, if necessary, substitution therapy with another antianginal agent may be started at the same time to avoid the frequency of angina attacks.

In patients taking Lokren® it is necessary to monitor HR and BP (at the beginning of treatment daily, then once every 3-4 months), blood glucose concentration in diabetic patients (once every 4-5 months), kidney function in elderly patients (once every 4-5 months).

The patient should be taught how to calculate heart rate, and the patient should be instructed to see a physician if the heart rate decreases below 50 bpm.

In about 20% of patients with angina pectoris, beta-adrenoblockers are ineffective. The main reasons are severe coronary atherosclerosis with low ischemic threshold (heart rate at the time of angina attack less than 100 bpm) and increased left ventricular end-diastolic pressure, which impairs subendocardial blood flow.

If clonidine is taken concomitantly, its administration may not be discontinued until several days after withdrawal of Lokren®.

Lokren® should be discontinued before testing blood and urine catecholamine, normetanephrine, and vanillin acid concentrations; and blood antinuclear antibody titers.

Bronchial asthma and chronic obstructive pulmonary disease

Beta-adrenoblockers may only be prescribed in patients with moderate disease severity, with selection of a selective beta-adrenoblocker at a low starting dose. Respiratory function assessment is recommended before starting treatment.

Bronchodilators-beta2-adrenomimetics may be used if seizures develop during treatment.

Heart failure

In patients with therapeutically controlled heart failure, if necessary, betaxololol can be used under close medical supervision at very low initial doses with gradual increase if necessary and if good tolerability (maintenance of compensated chronic heart failure).

Bradycardia

If resting heart rate falls below 50-55 bpm, the dose of Lokren® should be reduced.

Degree I AV blockade

In view of the negative dromotropic effect of beta-adrenoblockers, the drug should be used with caution in degree I blockade.

Prinzmetal angina

Beta-adrenoblockers may increase the frequency and duration of attacks in patients with Prinzmetal angina. The use of cardioselective beta1-adrenoblockers is possible in mild Prinzmetal angina or mixed type angina, provided that treatment is combined with vasodilators.

Peripheral circulatory disorders

Beta-adreno-blockers may worsen in patients with peripheral circulatory disorders (Raynaud’s disease or Raynaud’s syndrome, arteritis, or chronic obliterative arterial disease of the lower extremities).

Pheochromocytoma

When using beta-adrenoblockers in the treatment of arterial hypertension caused by pheochromocytoma, close monitoring of BP is required. Administration of Lokren® is possible only with the use of alpha-adrenoblockers.

Elderly patients

The treatment of elderly patients should be started with a low dose and under close supervision.

Patients with renal insufficiency

The dose must be adjusted according to the blood creatinine concentration or CK.

Patients with diabetes mellitus

The patient should be cautioned to increase blood glucose monitoring, including active self-monitoring by the patient, at the beginning of treatment. The patient should be aware that the initial symptoms of hypoglycemia (especially tachycardia, palpitations, and sweating) may be masked by betaxolol.

Persoriasis

A careful assessment of the need for the drug is required, because there have been reports of worsening of the course of psoriasis during treatment with beta-adrenoblockers.

Allergic reactions

Beta-adrenoblockers, including Lokren®, may increase allergen sensitivity and the severity of anaphylactic reactions because of impaired adrenergic compensatory regulation by beta-adrenoblockers. Therapy of anaphylactic reactions with epinephrine (adrenaline) does not always give the expected therapeutic effect.

In patients prone to severe anaphylactic reactions, especially those associated with the use of floktafenine or during desensitization, therapy with beta-adrenoblockers may lead to further worsening of reactions and decrease the effectiveness of therapy.

General anesthesia

In general anesthesia, the risk of β-adrenoreceptor blockade (decreased HR, decreased cardiac output, lower systolic and diastolic BP) should be considered.

Beta-adrenoblockers mask reflex tachycardia and increase the risk of arterial hypotension. Continued therapy with beta-adrenoblockers reduces the risk of arrhythmias, myocardial ischemia, and hypertensive crises. The anesthesiologist should be informed that the patient is receiving treatment with beta-adrenoblockers.

If therapy with Lokren® is to be discontinued before surgical intervention, this should be done gradually and completed 48 hours before general anesthesia, because it is believed that discontinuing therapy for 48 hours allows restoration of catecholamine receptor sensitivity.

The therapy with beta-adrenoblockers may not be interrupted in some cases:

Contraindications

Side effects

Allergic reactions: skin rash, itching, urticaria.

The side effects listed below are given according to the following frequency gradations: very frequently (≥1/10); frequently (≥1/100, < 1/10); infrequently (≥1/1000, < 1/100); rarely (≥1/10 000, < 1/1000); very rarely (< 1/10 000) (including individual reports).

Dermatological reactions: rare – various skin reactions, including skin rash, pruritus, urticaria, psoriasis-like rashes or exacerbation of psoriasis.

Nervous system disorders: frequently – dizziness, headache, asthenia, insomnia; rarely – depression; very rarely – hallucinations, confusion, nightmares, paresthesia.

Overlooking organ: rarely – dry eyes, decreased intraocular pressure (due to the possibility of its reduction under the influence of beta-adrenoblockers); very rarely – visual disorders.

Digestive system disorders: frequently – gastralgia, diarrhea, nausea, vomiting.

Metabolic disorders: very rarely – hypoglycemia, hyperglycemia.

Cardiovascular system: often – bradycardia, possibly severe, decrease of skin temperature of upper and lower extremities; rarely – development (or worsening) of symptoms of heart failure (edema of ankles, feet, lower legs), marked BP reduction, slowing of AV conduction, angiospasm manifestations: Raynaud’s syndrome, increase of peripheral circulatory disorders, including intermittent claudication.including intermittent claudication, increased frequency of angina attacks.

Respiratory system disorders: rarely – bronchospasm.

The sexual organs: often – impotence.

Laboratory findings: rare – appearance of antinuclear antibodies, only in exceptional cases combined with clinical manifestations of lupus-like syndrome, which disappears after discontinuation of treatment.

Fetal effects: intrauterine growth retardation, hypoglycemia, bradycardia.

Others: withdrawal syndrome (increased or more frequent attacks of angina pectoris, increased BP).

Overdose

Symptoms: marked bradycardia, dizziness, AV-blockade, marked BP decrease, arrhythmias, ventricular extrasystoles, fainting, heart failure, difficulty in breathing, bronchospasm, cyanosis of finger nails and palms, convulsions.

Treatment: gastric lavage, administration of adsorptive agents; if bradycardia develops, atropine 1-2 mg w/v; then (if necessary) slow infusion of 25 µg isoprenaline or infusion of dobutamine 2.5-10 µg/kg/min; sometimes a temporary artificial pacemaker may be required; in cases of excessive BP decrease, intravenous infusion of plasma substitute solutions and vasopressor drugs is recommended; in bronchospasm, prescription of bronchodilators, including beta.including beta2-adrenomimetics and/or aminophylline; in case of heart failure (decompensation) in newborns whose mothers took beta-adrenoblockers during pregnancy, hospitalization in the intensive care unit is recommended, isoprenaline and dobutamine – long term and usually in high doses, supervision of a specialist.

Similarities