Loxren

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOCRENÒ (LOKRENÒ)

Composition:

Active substance: betaxolol;

1 tablet contains betaxolol hydrochloride 20 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, sodium starch glycolate (type A), colloidal anhydrous silicon dioxide, magnesium stearate;

coating: hypromellose, titanium dioxide (E 171), polyethylene glycol.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: white, biconvex, round, film-coated tablets, with a score line on one side and engraving on the other.

Pharmacotherapeutic group. Selective beta-adrenoreceptor blockers.

ATC code: C07AB05.

Pharmacological Properties

Pharmacodynamics

Betaxolol selectively blocks beta-1 adrenoceptors. Betaxolol has a potent, long-lasting beta-adrenergic blocking effect. The effect becomes apparent within 24 hours after administration of 20 mg of betaxolol.

After administration of therapeutic doses of betaxolol, a pronounced reduction in arterial pressure, heart rate, and cardiac output is observed.

Betaxolol does not exhibit sympathomimetic activity or significant membrane-stabilizing properties.

Betaxolol does not cause a reduction in sodium excretion.

Betaxolol reduces plasma renin activity.

The effect of betaxolol on blood lipids, typical for beta-blockers, is negligible.

Antihypertensive effect

Administration of 20 mg of betaxolol over 24 hours results in a reduction of arterial pressure similar to that observed with atenolol (100 mg/day) or propranolol (160–320 mg/day).

Anti-anginal and anti-ischemic effects

The anti-anginal and anti-ischemic effects of betaxolol (20 mg as a single daily dose) are comparable to those of other beta-blockers such as propranolol (160 mg divided into multiple doses) or atenolol (100 mg as a single daily dose). When administered once daily at a dose of 20 mg, the effect persists for 24 hours.

Tolerability

The incidence of adverse reactions and treatment discontinuation with betaxolol is similar to that observed with other beta-blockers.

A study involving 4,685 patients did not reveal significant changes in the following parameters:

• renal function (plasma creatinine and potassium levels),
• glycaemia,
• lipid metabolism (cholesterol, triglycerides, HDL-cholesterol).

Pharmacokinetics

Due to the low first-pass hepatic effect, oral bioavailability is approximately 80%.

Betaxolol is approximately 50% bound to plasma proteins. It is lipophilic and distributes into extracellular tissues. The volume of distribution is approximately 6 L/kg.

85–90% of the administered dose of betaxolol is metabolized in the liver. Only one metabolite (2–3% of the administered dose), formed by aliphatic hydroxylation of the molecule, exhibits intrinsic beta-blocking activity. These cases are selective and correspond to approximately 50% of the beta-blocking activity of the administered dose of betaxolol.

10–15% of the administered dose is excreted unchanged by the kidneys. Metabolites are primarily eliminated via the kidneys. 73–83% of the dose is excreted in urine, and only 1–3% via the intestine.

Peak plasma concentrations are reached 2–4 hours after oral administration of 20 mg, reaching levels of 30–60 ng/mL. Intra- and inter-individual variations in peak plasma levels or at steady state are very low. The plasma elimination half-life (16–20 hours) allows for once-daily dosing. In elderly patients and patients with renal insufficiency on dialysis, the plasma elimination half-life is prolonged (24–30 hours). In such patients, the dose should be halved.

No significant changes in pharmacokinetic parameters have been observed in cases of hepatic insufficiency.

Preclinical safety data

Results from chronic toxicity studies in rats and dogs are available. Betaxolol was shown to be relatively well tolerated, with no unexpected abnormalities observed.

Mutagenicity tests in vivo and in vitro do not indicate a mutagenic potential for betaxolol.

Carcinogenicity studies conducted in both mice and rats also do not indicate a carcinogenic potential.

Clinical characteristics.

Indications.

Treatment of arterial hypertension.

Prevention of exertional angina attacks.

Contraindications.

Hypersensitivity to betaxolol or to any other component of the medicinal product.

Heart failure not controlled by treatment.

Cardiogenic shock.

Second- and third-degree atrioventricular block in patients without a pacemaker.

Sinoatrial node dysfunction (including sinoatrial block).

Prinzmetal's angina (monotherapy with the drug is contraindicated in isolated/typical form of this disease).

Bradycardia (heart rate < 45–50 beats/min).

Arterial hypotension (systolic pressure < 90 mm Hg).

Metabolic acidosis.

Severe forms of Raynaud’s syndrome and other peripheral arterial diseases.

Concomitant use of MAO inhibitors (except MAO-B inhibitors).

Severe forms of bronchial asthma and chronic obstructive pulmonary disease.

Untreated pheochromocytoma.

The drug is contraindicated for use in combination with flecainide and sulpiride (see section “Interaction with other medicinal products and other types of interactions”).

Intravenous administration of calcium channel blockers of the verapamil type or diltiazem, or other antiarrhythmics (such as disopyramide or amiodarone), is contraindicated in patients receiving Lokren®. Exception is treatment under intensive care conditions, where close and continuous patient monitoring is ensured (see section “Interaction with other medicinal products and other types of interactions”).

Interaction with other medicinal products and other types of interactions.

Contraindicated combinations

Flecainide

In cases of flecainide-induced shock or arterial hypotension, beta-blockers cause a reduction in cardiovascular compensatory responses.

Sulpiride

Excessive bradycardia may occur due to the additive effect of betaxolol and sulpiride.

Not recommended combinations

Amiodarone. Concurrent use with betaxolol leads to enhanced impairment of myocardial automaticity, contractility, and conduction (due to suppression of sympathetic compensatory mechanisms).

Reserpine, alpha-methyldopa, clonidine, guanfacine, and cardiac glycosides. Concurrent use of Lokren® and these medicinal products may lead to severe bradycardia and/or slowed cardiac conduction.

Patients who need to discontinue clonidine after concomitant oral use of clonidine and Lokren® must be closely monitored for arterial hypertension. Excessive increase in blood pressure may occur after abrupt withdrawal of clonidine in patients concurrently taking Lokren®. Therefore, clonidine may be discontinued only if Lokren® has been stopped several days earlier. In this case, the dose of clonidine should be gradually reduced.

Fingolimod

Concomitant use of fingolimod with beta-blockers may enhance bradycardic effects and is therefore not recommended. If concomitant use is considered necessary, appropriate monitoring is recommended, i.e., at least overnight.

Verapamil and calcium channel blockers

Betaxolol should not be used concomitantly with calcium channel blockers of the verapamil type or within several days after therapy with verapamil-type calcium channel blockers (and vice versa).

Combinations requiring precautions when used concomitantly

Anesthetics

Concomitant use of Lokren® and anesthetics may cause pronounced reduction in blood pressure. The negative inotropic effects of anesthetics and betaxolol may be additive (beta-blockade may be counteracted by a beta-mimetic during medical intervention).

In general, therapy with Lokren® should not be discontinued before procedures under general anesthesia or before use of peripheral muscle relaxants. However, the anesthesiologist must be informed about treatment with Lokren®.

If discontinuation of therapy is necessary, a 48-hour break in betaxolol intake should be made to ensure that sensitivity to catecholamines has been restored. Discontinuation of betaxolol should be gradual and timely (see section “Special precautions for use”).

Peripheral muscle relaxants (e.g., succinylcholine, tubocurarine)

Neuromuscular blockade by peripheral muscle relaxants may be enhanced or prolonged due to beta-receptor inhibition mediated by Lokren®.

Calcium channel blockers of the diltiazem type (bepridil, diltiazem, verapamil, and mibefradil). Cases of impaired automaticity (excessive bradycardia, sinus arrest), impaired atrioventricular conduction, and development of heart failure (due to synergistic effect) have been reported. These drugs should be used concomitantly only under strict clinical and ECG monitoring, especially at the beginning of treatment.

Diltiazem. Increased risk of depression has been reported with concomitant use of beta-adrenoblockers and diltiazem (see section “Adverse reactions”).

Antiarrhythmic drugs (propafenone and class IA drugs: quinidine, hydroquinidine, and disopyramide). Impairment of myocardial contractility, automaticity, and conduction may occur with concomitant use of Lokren® due to suppression of sympathetic compensatory mechanisms.

Clinical and electrocardiographic monitoring is required.

Baclofen

Antihypertensive effect is potentiated when used concomitantly with Lokren®. Blood pressure must be carefully monitored and the dose of Lokren® adjusted if necessary.

Insulin and antidiabetic agents (see section “Special precautions for use”)

The effect of insulin and antidiabetic agents may be enhanced or prolonged. Beta-blockers may mask some symptoms of hypoglycemia, such as palpitations and tachycardia. Therefore, intensified blood glucose monitoring is required, especially at the beginning of treatment.

Lidocaine

Interaction with lidocaine has been described for propranolol, metoprolol, and nadolol. In combination with beta-receptor blockers, reduced hepatic metabolism of lidocaine and subsequent increase in plasma lidocaine levels have been observed. This may enhance neurological and cardiac adverse reactions. Therefore, the dose of lidocaine should be adjusted. Clinical and ECG monitoring, as well as monitoring of plasma lidocaine levels, should be performed during and after discontinuation of beta-receptor blocker therapy.

Iodine-containing contrast agents

In cases of shock or drop in blood pressure after administration of iodine-containing contrast agents, beta-receptor blockers reduce cardiovascular compensatory mechanisms. Therefore, if possible, beta-receptor blocker therapy should be discontinued before imaging procedures using contrast agents. If continuation of beta-receptor blocker therapy is mandatory, intensive care support must be available.

When using combinations, the following should be considered.

Nonsteroidal anti-inflammatory drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs (e.g., indomethacin) may reduce the antihypertensive effect of Lokren® (due to inhibition of vasodilatory prostaglandins by NSAIDs, fluid and sodium retention by pyrazolone-type NSAIDs).

Calcium channel blockers of the nifedipine type

Concomitant use of Lokren® and calcium channel blockers of the nifedipine type (dihydropyridines) may lead to a relatively sharp drop in blood pressure and, in isolated cases, to development of heart failure due to additive negative inotropic effects. In addition, sympathetic reflex responses to serious hemodynamic events may be reduced.

Neuroleptics

Concomitant use of Lokren® and neuroleptics may lead to a relatively sharp drop in blood pressure and, in isolated cases, to development of heart failure.

Other antihypertensives, vasodilators, diuretics, tricyclic antidepressants, barbiturates, and phenothiazines

Concomitant use of Lokren® and the above-mentioned medicinal products may lead to significant reduction in blood pressure.

Antacids

When antacids (e.g., aluminum hydroxide) are used concomitantly, Lokren® should be taken 2 hours after the antacid.

Unhydrolyzed ergot alkaloids

When unhydrolyzed ergot alkaloids are used concomitantly, their vasoconstrictive effect may be enhanced (increased risk of peripheral circulation disorders).

Corticosteroids and tetracosactide (corticotropin)

Due to sodium and fluid retention, the antihypertensive effect of betaxolol may be reduced.

Mefloquine

When used concomitantly with Lokren®, there is an increased risk of bradycardia due to additive bradycardic effects.

Sympathomimetics

The effects of beta-receptor blockers may be diminished when used concomitantly.

Adrenaline

Significant increase in blood pressure may occur when used concomitantly with adrenaline.

When beta-blockers, including betaxolol, are used in combination with other medicinal products known to induce sinus node arrest, sinus node arrest may occur (see section “Adverse reactions”).

Special precautions for use.

Precautions for use.

Discontinuation of the drug.

Treatment with LokrenÒ should not be stopped abruptly, especially in patients with ischemic heart disease. The dose should be gradually reduced over 1–2 weeks, and if necessary, replacement therapy should be initiated simultaneously to prevent worsening of angina.

Bronchial asthma and chronic obstructive pulmonary disease.

Beta-blockers may be prescribed only to patients with mild forms of these diseases, and a selective beta-blocker should be chosen and administered at a low initial dose. Lung function assessment is recommended prior to initiating treatment.

Heart failure.

In patients with heart failure controlled by therapy, LokrenÒ may be used if necessary under strict medical supervision, starting with very low doses, which should be gradually increased.

Bradycardia.

The dose should be reduced if the resting heart rate is less than 50–55 beats per minute and symptoms of bradycardia occur.

First-degree atrioventricular block.

Due to the negative dromotropic effect of beta-blockers, LokrenÒ should be prescribed with caution in patients with first-degree atrioventricular block.

Prinzmetal's angina.

In patients with Prinzmetal's angina, beta-blockers may increase the frequency and duration of attacks (see section «Contraindications»).

A cardioselective beta-1 blocker may be used in mild and secondary forms of the disease provided a vasodilator is simultaneously administered.

Peripheral arterial disease.

Beta-adrenergic blockers may worsen the condition of patients with peripheral arterial diseases (Raynaud's disease or Raynaud's syndrome, arteritis, or chronic occlusive arterial disease of the lower limbs). The use of the medicinal product Lokren® is contraindicated in patients with advanced stages of peripheral arterial disease (see section «Contraindications»).

Pheochromocytoma.

When beta-adrenergic blockers are used to treat hypertension caused by pheochromocytoma, careful monitoring of blood pressure is required. Beta-blockers should only be administered after prior alpha-blockade.

Patients with hepatic impairment.

Clinical monitoring is recommended at the beginning of treatment in patients with impaired liver function.

Patients with renal impairment.

Dosage must be adjusted in patients with renal impairment based on serum creatinine concentration or creatinine clearance (see section «Dosage and administration»).

Hypoglycemia.

There is an increased risk of hypoglycemia, for example, during prolonged fasting or intense physical exertion.

Patients with diabetes mellitus.

Patients with diabetes should be warned about the need for frequent blood glucose monitoring, as symptoms of hypoglycemia such as tachycardia, palpitations, and sweating may be masked (see sections «Interaction with other medicinal products and other forms of interaction» and «Adverse reactions»).

Psoriasis.

Prescribing the drug requires careful assessment of the necessity of its use, as there are reports of worsening of psoriasis during beta-blocker therapy (see section «Adverse reactions»).

Allergic reactions.

Beta-receptor blockers may increase sensitivity to allergens, including iodine-containing contrast agents and pholcodine (see section «Interaction with other medicinal products and other forms of interaction»), and may also increase the severity of anaphylactic reactions, i.e., acute systemic allergic reactions. Therefore, they should not be used unless strictly indicated in patients with a history of severe hypersensitivity reactions and in patients undergoing therapy to reduce or eliminate sensitivity to allergic reactions (desensitization therapy; caution is required in cases of excessive anaphylactic reactions).

The response to adrenaline at usual doses may be reduced.

Anesthesia.

In patients undergoing general anesthesia, beta-receptor blockers reduce the incidence of arrhythmias and myocardial ischemia during induction of anesthesia, intubation, and in the postoperative period. The risk of hypertensive crisis is also reduced when beta-blocker therapy is continued.

Currently, it is recommended not to discontinue existing beta-blocker therapy during surgical procedures. The anesthesiologist must be informed that the patient is receiving beta-blocker treatment, as this may lead to potential interactions with other drugs, bradyarrhythmias, blunted reflex tachycardia, impaired reflex counter-regulation in case of blood loss, and an increased risk of hypotension.

If discontinuation of treatment and withdrawal of the drug is necessary, a 48-hour period is considered sufficient to restore sensitivity to catecholamines.

Beta-adrenergic blocker therapy should not be discontinued:

• in patients with coronary insufficiency, for whom it is desirable to continue the drug before surgery due to the risk associated with abrupt withdrawal of beta-adrenergic blockers;
• in emergency situations or when discontinuation of treatment is impossible, the patient should be protected from the consequences of excessive vagal stimulation by appropriate premedication with atropine (atropine may be repeated if necessary).

Anesthetics with minimal myocardial depression should be used.

The risk of developing anaphylactic reactions should be considered.

Ophthalmology.

Beta-adrenergic receptor blockade leads to a reduction in intraocular pressure and may alter the results of glaucoma screening tests. The ophthalmologist should be informed that the patient is taking betaxolol. Patients receiving beta-blockers both systemically and as eye drops should be monitored due to the potential additive effect of these drugs.

Thyrotoxicosis.

Beta-blockers may mask cardiovascular symptoms of thyrotoxicosis.

Elderly patients.

Treatment of elderly patients should be initiated with a low dose and under close supervision.

Athletes.

The use of the medicinal product Lokren® may result in a positive reaction in anti-doping control tests. Misuse of Lokren® as a doping agent may be hazardous to health.

Excipients.

Lactose.

The product contains lactose. It is not recommended for use in patients with rare hereditary forms of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption syndrome.

Sodium.

This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., it is practically sodium-free. Caution should be exercised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding.

Teratogenicity.

No teratogenic effects of the drug were observed in animal studies. There are no reports of teratogenic effects in humans to date. Beta-adrenergic blockers may reduce placental perfusion, which may lead to intrauterine fetal death, miscarriage, or premature delivery. In addition, adverse effects (mainly hypoglycemia and bradycardia) may occur in the fetus.

Betaxolol should be used during pregnancy only under strict indications and after careful assessment of the benefit-risk ratio.

Neonatal period.

The effect of beta-blockers persists for several days after birth in newborns whose mothers received treatment with this medicinal product and may cause bradycardia, respiratory distress, and hypoglycemia, although this residual effect is usually without clinical consequences. However, high doses of beta-blockers may lead to heart failure due to suppression of cardiovascular compensatory responses. If neonatal heart failure occurs, hospitalization in an intensive care unit is required (see section «Overdose»), and plasma expanders should be avoided (due to the risk of acute pulmonary edema).

The use of betaxolol during pregnancy is not recommended, except in cases where the benefit of using the drug outweighs the possible risks. If treatment continues until delivery, careful monitoring of the newborn in specialized conditions is recommended (monitoring of heart rate and blood glucose levels during the first 3–5 days of life).

Breastfeeding.

Beta-adrenergic blockers pass into breast milk. Breastfeeding during treatment with LokrenÒ should be discontinued, as the risk of hypoglycemia or bradycardia in newborns has not been studied. For these reasons and as a precaution, breastfeeding is not recommended throughout the entire treatment period.

Ability to affect reaction speed when driving or operating machinery.
Studies on the effect of betaxolol on the ability to drive vehicles or operate machinery have not been conducted. When driving vehicles or operating machinery, it should be considered that dizziness or increased fatigue may occasionally occur during treatment with this drug.

Method of Administration and Dosage

Dosage

Adults

For the treatment of mild arterial hypertension, the recommended dose of Lokren® is ½ tablet coated with film, once daily.

If necessary, the dose of Lokren® may be increased to 1 coated tablet once daily.

For the treatment of moderate arterial hypertension and prevention of exertional angina attacks, the standard dose of Lokren® is 1 coated tablet once daily.

Elderly Patients

Treatment of elderly patients should be initiated with a low dose and under close monitoring.

Patients with Hepatic or Renal Impairment

Dose adjustment is generally not required in patients with hepatic impairment or renal dysfunction (creatinine clearance up to 30 mL/min). However, clinical monitoring is recommended at the beginning of treatment.

In patients with severe renal impairment (creatinine clearance below 30 mL/min) and in patients undergoing dialysis, the dose should not exceed ½ coated tablet (10 mg betaxolol hydrochloride).

Method of Administration

The coated tablets are intended for oral administration.

Lokren® tablets should be taken whole, with sufficient fluid, independent of food intake.

In patients undergoing dialysis, the daily dose may be administered regardless of the timing of dialysis.

After prolonged use, discontinuation of Lokren® therapy should generally be gradual and tapered, especially in patients with ischemic heart disease, since abrupt withdrawal may lead to myocardial ischemia with exacerbation of angina, myocardial infarction, or worsening of arterial hypertension (see section "Special Warnings and Precautions for Use").

Children. The safety and efficacy of betaxolol in children have not been established. Therefore, the use of betaxolol in children and adolescents is not recommended.

In children, the hypoglycemic effect of beta-blockers may occur more rapidly, increasing the risk of seizures in this patient population.

Overdose

Symptoms of Overdose

Depending on the degree of intoxication, the clinical picture is predominantly characterized by symptoms affecting the cardiovascular and central nervous systems. Overdose may lead to severe arterial hypotension, bradycardia, and even cardiac arrest, heart failure, and cardiogenic shock. Sinus node arrest has also been reported in cases of overdose. Additionally, respiratory distress, bronchospasm, vomiting, impaired consciousness, and occasionally generalized seizures may occur.

Therapeutic Measures in Overdose

In case of overdose or critical reduction in heart rate and/or blood pressure, treatment with Lokren® must be discontinued with appropriate precautionary measures (see section "Special Warnings and Precautions for Use").

In addition to general supportive measures upon initial discontinuation of Lokren®, vital parameters should be monitored in an intensive care setting and corrected as necessary.

As antidotes, the following may be used:

• 1–2 mg atropine intravenously as a bolus;
• 1–10 mg glucagon intravenously, followed by continuous infusion of 2–2.5 mg per hour;
• sympathomimetics according to body weight and effect: dopamine, dobutamine, orciprenaline, and epinephrine.

In case of bronchospasm, beta-2 adrenergic agonists may be administered as an aerosol (or intravenously if response is inadequate), or intravenous aminophylline.

In generalized seizures, slow intravenous administration of diazepam is recommended.

Betaxolol and its metabolites are only minimally removed by hemodialysis or peritoneal dialysis.

In neonates with cardiac decompensation whose mothers received beta-adrenergic blockers during pregnancy:

• glucagon at a dose of 0.3 mg/kg body weight;
• hospitalization in an intensive care unit;
• isoprenaline and dobutamine: prolonged administration, generally in high doses, requires specialist supervision.

Adverse reactions

The frequency of adverse reactions is classified into the following categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Adverse reactions are listed within each category in decreasing order of frequency.

Reporting of suspected adverse reactions.

Reporting of adverse reactions following the authorization of a medicinal product is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Keep out of reach of children. No special storage conditions required.

Packaging.

No. 28 (14×2): 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Sanofi Winthrop Industrie.

Manufacturer’s location and address of the site of operation.

30 Avenue Gustave Eiffel, Tours, 37100, France.

Marketing Authorization Holder.

CHEPLAPHARM Arzneimittel GmbH, Germany.