Betac

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BETAC (BETAC)

Composition:

Active substance: betaxolol;

1 tablet contains 10 mg or 20 mg of betaxolol hydrochloride;

Excipients:

10 mg dosage: microcrystalline cellulose; lactose monohydrate; sodium starch glycolate; colloidal silicon dioxide, anhydrous; magnesium stearate; polyvinyl alcohol; titanium dioxide (E 171); purified talc; lecithin; xanthan gum;

20 mg dosage: lactose monohydrate; microcrystalline cellulose; sodium starch glycolate (Type A); magnesium stearate; colloidal silicon dioxide, anhydrous; film coating: purified talc, Opadry white OY-B-28920 (xanthan gum, lecithin, purified talc; polyvinyl alcohol; titanium dioxide (E 171)).

Pharmaceutical form. Film-coated tablets.

Main physicochemical characteristics:

10 mg tablets – white or almost white, round, biconvex, film-coated tablets with a core diameter of approximately 7.0 mm;

20 mg tablets – white or almost white, round, biconvex, film-coated tablets with a break line, with a core diameter of approximately 9.5 mm.

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. Following administration of therapeutic doses of betaxolol, a pronounced reduction in arterial pressure, heart rate, and stroke volume is observed. Betaxolol does not exhibit sympathomimetic activity or significant membrane-stabilizing properties. Betaxolol does not cause a reduction in natriuresis. 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 comparable to that achieved with atenolol (100 mg/day) or propranolol (160–320 mg/day).

Anti-anginal and anti-ischemic effect. The anti-anginal and anti-ischemic effect of betaxolol (20 mg as a single dose) is comparable to that of other beta-blockers such as propranolol (160 mg, divided into several doses) or atenolol (100 mg as a single dose). When 20 mg of betaxolol is taken once daily, the effect persists for 24 hours.

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

A study involving 4,685 patients showed no 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. Betaxolol is lipophilic and distributes into extracellular tissue. The volume of distribution is approximately 6 L/kg. 85–90% of the administered dose is metabolized in the liver. Only one metabolite (2–3% of the administered dose), formed via aliphatic hydroxylation of the molecule, exhibits intrinsic beta-blocking activity. This metabolite is approximately 50% as potent as 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. Only 1–3% is excreted via the intestine. Peak plasma levels are reached within 2–4 hours after oral administration of 20 mg, ranging from 30 to 60 ng/mL. Intraindividual and interindividual variations in peak plasma levels or at steady state are minimal. The elimination half-life from plasma (16–20 hours) allows for once-daily dosing. In elderly patients and in patients with renal insufficiency on dialysis, the plasma half-life is prolonged (24–30 hours). In these cases, the dose should be halved. No significant changes in pharmacokinetic parameters are observed in patients with hepatic impairment.

Preclinical safety data. Chronic toxicity studies in rats and dogs are available. Betaxolol was shown to be relatively well tolerated, with no unexpected abnormalities observed. In vivo and in vitro mutagenicity tests do not indicate a mutagenic potential of 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- or third-degree atrioventricular block in patients without a pacemaker.

Sinus node dysfunction (including sinoatrial block).

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

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

Arterial hypotension (systolic blood pressure < 90 mm Hg).

Metabolic acidosis.

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

Concomitant use of MAO inhibitors (exception: MAO-B inhibitors).

Severe forms of bronchial asthma and chronic obstructive pulmonary disease.

Untreated pheochromocytoma.

The drug is contraindicated for use in combination with floctafennine and sultopride (see section "Interaction with other medicinal products and other forms of interaction").

Intravenous administration of calcium channel blockers of the verapamil or diltiazem type or other antiarrhythmics (such as disopyramide or amiodarone) is contraindicated in patients receiving betaxolol. Exception: treatment under intensive care conditions where close and continuous patient monitoring is ensured (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Contraindicated combinations:

Floctafennine. In cases of floctafennine-induced shock or arterial hypotension, beta-blockers reduce cardiovascular compensatory responses.

Sultopride. Excessive bradycardia may occur due to additive effects of betaxolol and sultopride.

Not recommended combinations:

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

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

Patients who need to discontinue clonidine after concomitant oral administration of clonidine and betaxolol must be closely monitored for arterial hypertension. Excessive increase in blood pressure may occur after abrupt withdrawal of clonidine in patients concurrently taking Betak. Therefore, clonidine may only be discontinued if betaxolol has been stopped several days earlier. After this, the dose of clonidine may 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 betaxolol 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 beta-mimetics during the procedure). Generally, Betak should not be discontinued before procedures under general anesthesia or before use of peripheral muscle relaxants. However, the anesthesiologist must be informed about betaxolol treatment. If discontinuation of treatment is necessary, a 48-hour pause should be made to ensure that sensitivity to catecholamines has been restored. Discontinuation 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 betaxolol.

Calcium channel blockers of the diltiazem type (bepridil, diltiazem, verapamil, and mibefradil). Cases of impaired automaticity (excessive bradycardia, sinus arrest), impaired atrioventricular conduction, and heart failure (due to synergistic effect) have been reported. These 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: quinidine, hydroquinidine, and disopyramide). Impairment of myocardial contractility, automaticity, and conduction may occur when used concomitantly with betaxolol due to suppression of sympathetic compensatory mechanisms. Clinical and electrocardiographic monitoring is required.

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

Insulin and antidiabetic agents (see section "Special precautions for use"). Their effect 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-blockers, reduced hepatic metabolism of lidocaine is observed, leading to increased plasma lidocaine levels. An associated increase in adverse neurological and cardiac reactions cannot be excluded. Therefore, the lidocaine dose should be adjusted. Clinical and ECG monitoring, as well as monitoring of plasma lidocaine levels, should be performed during and after discontinuation of beta-blocker therapy.

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

When using combinations, the following should be considered:

Non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs (e.g., indomethacin) may reduce the antihypertensive effect of betaxolol (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 betaxolol and calcium channel blockers of the nifedipine type (dihydropyridines) may lead to relatively abrupt reduction in blood pressure and, in isolated cases, to development of heart failure due to additive negative inotropic effects. In addition, sympathetic reflex responses to severe hemodynamic events may be reduced.

Neuroleptics. Concomitant use of Betak and neuroleptics may lead to relatively abrupt reduction in blood pressure and, in isolated cases, to development of heart failure.

Other antihypertensives, vasodilators, diuretics, tricyclic antidepressants, barbiturates, and phenothiazines. Concomitant use of Betak and these medicinal products may lead to significant reduction in blood pressure.

Antacids. When used concomitantly with antacids (e.g., aluminum hydroxide), Betak should be taken 2 hours after the antacid.

Ergot alkaloids (non-hydrogenated). Concomitant use of non-hydrogenated ergot alkaloids may enhance their vasoconstrictive effects (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 betaxolol, there is an increased risk of bradycardia due to additive bradycardia-inducing effects.

Sympathomimetics. Effects of beta-blockers may be attenuated when used concomitantly.

Adrenaline (epinephrine). Concomitant use of adrenaline may lead to a significant increase in blood pressure. 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.

Precautionary measures during use.

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

Bronchial asthma and chronic obstructive pulmonary disease. Beta-adrenergic blockers should be prescribed only to patients with mild forms of these diseases, selecting a selective beta-blocker and administering it at a low initial dose. Assessment of lung function is recommended prior to initiating treatment.

Heart failure. In patients with heart failure controlled by therapy, betaxolol may be used if necessary under close medical supervision, starting with very low doses that are gradually increased.

Bradycardia. The dose should be reduced if the resting heart rate is below 50–55 beats per minute and the patient exhibits symptoms of bradycardia.

First-degree atrioventricular block. Due to the negative dromotropic effect of beta-blockers, Betac should be prescribed cautiously to patients with first-degree atrioventricular block.

Prinzmetal's angina. In patients suffering from 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 or secondary forms of the disease provided a vasodilator is concurrently administered.

Peripheral arterial disease. Beta-adrenergic blockers may worsen the condition of patients with peripheral arterial disease (Raynaud’s disease or Raynaud’s syndrome, arteritis, or chronic occlusive arterial disease of the lower limbs). Use of betaxolol is contraindicated in patients with advanced stages of peripheral arterial disease (see section "Contraindications").

Phaeochromocytoma. When beta-adrenergic blockers are used to treat hypertension requiring appropriate management, careful monitoring of blood pressure is necessary. 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 according to serum creatinine concentration or creatinine clearance (see section "Administration and dosage").

Hypoglycemia. There is an increased susceptibility to 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 signs of hypoglycemia such as tachycardia, palpitations, and sweating may be masked (see sections "Interaction with other medicinal products" and "Adverse reactions").

Psoriasis. Prescribing the drug requires careful assessment of the necessity of its use, as there have been reports of worsening psoriasis during beta-adrenergic blocker therapy (see section "Adverse reactions").

Allergic reactions. Beta-receptor blockers may increase sensitivity to allergens (particularly iodine-containing contrast agents and floctafenine) (see sections "Interaction with other medicinal products and other types of interactions") and may exacerbate 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 or in patients undergoing therapy to reduce sensitivity or immune responsiveness to allergens (desensitization therapy; caution: excessive anaphylactic reactions). The response to adrenaline in usual doses may be diminished.

Anesthesia. In patients undergoing general anesthesia, beta-receptor blockers reduce the incidence of arrhythmias and myocardial ischemia during induction of anesthesia, intubation, and the postoperative period. The risk of hypertensive crisis is also reduced if beta-blocker therapy is continued. It is currently recommended not to discontinue ongoing beta-blocker therapy prior to 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 increased risk of hypotension.

If discontinuation of treatment and withdrawal of the drug is necessary, a 48-hour interval is considered sufficient for restoration of 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 preoperatively, considering the risk associated with abrupt withdrawal of beta-adrenergic blockers;
• in emergency situations or when discontinuation of treatment is not feasible, the patient should be protected from the consequences of excessive vagal stimulation by appropriate premedication with atropine (atropine administration may be repeated if necessary);
• anesthetics with minimal myocardial depressant effect should be used. The risk of anaphylactic reactions must be considered.

Ophthalmology. Beta-adrenergic receptor blockade reduces intraocular pressure and may alter 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 agents.

Thyrotoxicosis. Beta-blockers may mask cardiovascular symptoms of thyrotoxicosis.

Elderly patients. Treatment of elderly patients should begin with a low dose and under close supervision.

Athletes. Use of Betac may result in a positive test in anti-doping controls. Abuse of the drug as a doping agent may be hazardous to health.

Excipients.

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

Sodium. This medicinal product contains less than 1 mmol 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. Animal studies have not shown any teratogenic effects of the drug. There are no reports of teratogenic effects in humans. Beta-adrenergic blockers may reduce placental perfusion, potentially leading to intrauterine fetal death, miscarriage, or premature delivery. Additionally, adverse effects (mainly hypoglycemia and bradycardia) may occur in the fetus.

Betaxolol should be used during pregnancy only if strictly indicated and after careful assessment of the benefit-risk ratio.

Neonatal period. The effect of the beta-blocker may persist for several days after birth in newborns whose mothers received the drug during pregnancy and may cause bradycardia, respiratory distress, and hypoglycemia; however, this residual effect is usually without clinical consequences. Nevertheless, high doses of beta-blockers may lead to heart failure due to suppression of cardiovascular compensatory mechanisms. In case of neonatal heart failure, 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). Use of betaxolol during pregnancy is not recommended except when the benefit outweighs the potential risks. If treatment continues until delivery, close 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 should be discontinued during treatment with Betac, as the risk of hypoglycemia or bradycardia in newborns has not been studied. For these reasons and as a precautionary measure, breastfeeding is not recommended throughout the entire treatment period.

Ability to influence reaction speed when driving or operating machinery. Studies on the effect of betaxolol on the ability to drive or operate machinery have not been conducted. When driving or operating machinery, it should be borne in mind 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, adults should be given Betak at a dose of ½ tablet once daily. If necessary, the dose may be increased to 1 tablet once daily. For the treatment of moderate arterial hypertension and prevention of exertional angina attacks, the standard dose is 1 tablet once daily.

Elderly patients. Treatment of elderly patients should begin with a low dose and under close medical supervision.

Patients with hepatic or renal impairment. Dose adjustment is generally not required in patients with hepatic impairment or in cases of renal dysfunction (creatinine clearance down to 30 mL/min). However, clinical monitoring of these patients 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 tablet of Betak (10 mg betaxolol hydrochloride).

Method of Administration. Film-coated tablets are intended for oral administration. Betak should be taken whole, with sufficient amount of liquid. It can be taken independently of food. For patients undergoing dialysis, the daily dose can be administered regardless of the timing of dialysis sessions. After prolonged use, treatment with the drug should generally be discontinued gradually, especially in patients with ischemic heart disease, since abrupt discontinuation may lead to cardiac 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 the drug 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 cardiovascular and central nervous system symptoms. Overdose may lead to severe arterial hypotension, bradycardia, and even cardiac arrest, heart failure, and cardiogenic shock. Cases of sinus node arrest have also been reported. In addition, respiratory distress, bronchospasm, vomiting, impaired consciousness, and occasionally generalized seizures may occur.

Treatment measures in case of overdose. In case of overdose or critically low heart rate and/or blood pressure, treatment with the drug should be discontinued, taking into account appropriate preventive measures (see section "Special Warnings and Precautions for Use").

General measures for initial elimination of the drug should be implemented, with vital parameters monitored in intensive care conditions 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 depending on body weight and effect: dopamine, dobutamine, orciprenaline, and adrenaline;

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

In cases of 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.

Side effects

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

Metabolic and nutritional disorders: very rare – hypoglycaemia, hyperglycaemia.

Psychiatric disorders: common – asthenia, insomnia; rare – depression; very rare – hallucinations, confusion, nightmares.

Disorders of the nervous system: common – dizziness, headache; very rare – distal paraesthesia; frequency not known – lethargy.

Eye disorders: rare – dry eyes; very rare – blurred vision.

Cardiac disorders: common – bradycardia, sometimes severe; rare – heart failure, hypotension; atrioventricular conduction delay or worsening of existing atrioventricular block; frequency not known – sinus arrest in predisposed patients (e.g. elderly patients or patients with pre-existing bradycardia, sinus node dysfunction, or atrioventricular block).

Vascular disorders: common – cold extremities; rare – Raynaud's syndrome, worsening of intermittent claudication.

Respiratory, thoracic and mediastinal disorders: rare – bronchospasm.

Gastrointestinal disorders: common – stomach pain, diarrhoea, nausea and vomiting.

Skin and subcutaneous tissue disorders: rare – skin reactions, including psoriasiform eruptions or exacerbation of psoriasis (see section "Special precautions"); frequency not known – urticaria, pruritus, hyperhidrosis, alopecia.

Reproductive system and breast disorders: common – impotence.

Laboratory test abnormalities: rare – appearance of antinuclear antibodies, which only in exceptional cases was associated with clinical manifestations resembling systemic lupus erythematosus, which resolved after discontinuation of treatment.

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at temperatures not exceeding 25 °C in the original packaging, in a place inaccessible to children.

Packaging. 10 tablets of 10 mg or 20 mg in a blister. 3 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer. Medochemie Limited.

Manufacturer's address.
Konstantinoupoleos 1-10, Limassol, 3011, Cyprus / Konstantinoupoleos 1-10, Limassol, 3011, Cyprus.