Bronhoterol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRONHOTEROL

Composition:

Active substance: fenoterol;

One dose contains fenoterol hydrobromide 100 mcg;

Excipients: norflurane; citric acid, monohydrate; ethanol 96%.

Pharmaceutical form. Metered-dose aerosol.

Main physicochemical properties: clear, colorless or light yellow, or light brown solution with the smell of ethanol.

Pharmacotherapeutic group. Drugs used in obstructive diseases of the respiratory tract. Selective beta-2-adrenoreceptor agonists.

ATC code R03AC04.

Pharmacological properties.

Pharmacodynamics.

Bronchoterol is an effective bronchodilator for use in acute asthma attacks and in other conditions with reversible airway narrowing, such as obstructive bronchitis with or without pulmonary emphysema. After oral administration, Bronchoterol begins to act within a few minutes, with duration of action up to 8 hours.

After inhalation of phenoterol hydrobromide in obstructive lung diseases, bronchodilation occurs within a few minutes. The bronchodilator effect lasts 3–5 hours.

When higher doses are used, the drug stimulates beta-1-adrenoceptors (e.g., when administered for tocolysis).

Bronchoterol relaxes smooth muscle of the bronchi and blood vessels. The relaxation effect is dose-dependent. It is believed to be enhanced via influence on the adenylate cyclase system, whereby binding of beta-agonists to their receptors (stimulated by a guanosine-binding protein) leads to activation of adenylate cyclase. As a result, phosphorylation of protein (protein kinase A) increases intracellular cAMP levels, leading to relaxation of smooth muscle. At high doses, Bronchoterol also affects skeletal muscles (tremor). In addition, Bronchoterol inhibits the release of mediators from mast cells. Following administration of Bronchoterol at a dose of 0.6 mg, improvement in mucociliary clearance has been observed.

Bronchoterol has positive inotropic and chronotropic (direct and/or reflex) effects on the heart. When high doses are used, metabolic effects such as lipolysis, glycogenolysis, hyperglycemia, and hypokalemia are observed; the latter is caused by increased uptake of K+ ions, primarily by skeletal muscle. As with other beta-adrenergic agents, prolongation of the QTc interval has been reported. For metered dose inhalers containing phenoterol, such events were isolated and occurred at doses higher than recommended. Clinical significance has not been established.

Due to the high concentration of beta-2 receptors in the myometrium, phenoterol may relax uterine muscle. This effect is often observed during pregnancy. The tocolytic dose of phenoterol is much higher than the bronchospasmolytic dose. Therefore, the risk of adverse effects is high.

Pharmacokinetics.

The pharmacokinetics of phenoterol have been studied after intravenous, inhalation, and oral administration. The therapeutic effect of Bronchoterol is achieved via local action on the respiratory tract. Thus, the plasma concentration of the drug does not necessarily correlate with the bronchodilator effect.

Absorption. After inhalation, depending on the inhalation technique and delivery system used, approximately 10–30% of the active substance released from the aerosol formulation reaches the lower respiratory tract. The remainder deposits in the upper respiratory tract and oral cavity and is subsequently swallowed. The absolute bioavailability of Bronchoterol from the metered aerosol after inhalation is 18.7%.

Absorption after inhalation follows a biphasic pattern and amounts to 13% of the dose. 30% of the dose of phenoterol hydrobromide is rapidly absorbed with a half-life of 11 minutes, and 70% is slowly absorbed with a half-life of 120 minutes.

After oral administration, approximately 60% of the dose of phenoterol hydrobromide is absorbed. The absorbed amount undergoes extensive first-pass metabolism, resulting in oral bioavailability reduced to approximately 1.5%. Thus, the contribution of the dose of active ingredient swallowed by the patient to the plasma concentration after inhalation is negligible. Maximum plasma concentration is reached approximately within 60–120 minutes.

Distribution. Bronchoterol is widely distributed throughout the body. The volume of distribution at steady state (Vss) after intravenous administration is 1.9–2.7 L/kg. Distribution of Bronchoterol in plasma after intravenous administration is adequately described by a three-compartment pharmacokinetic model with half-lives of tα = 0.42 minutes, tβ = 14.3 minutes, and tγ = 3.2 hours. Plasma protein binding ranges from 40 to 55%.

Biological transformation. In humans, Bronchoterol undergoes extensive metabolism via conjugation to glucuronides and sulfates. After oral intake, Bronchoterol is metabolized predominantly by sulfonation. This metabolic inactivation of the parent compound begins in the intestinal wall.

After intravenous administration, biotransformation, including biliary excretion, accounts for the majority (approximately 85%) of the mean total clearance, which equals 1.1–1.8 L/min. Renal clearance of Bronchoterol (0.27 L/min) accounts for approximately 15% of the mean total clearance of the systemically available dose. Considering the fraction of drug bound to plasma proteins, the magnitude of renal clearance suggests, in addition to glomerular filtration, tubular secretion of Bronchoterol.

Within 48 hours after oral and intravenous administration, the total urinary excretion of radioactivity amounts to approximately 39% and 65% of the dose, respectively, while total fecal excretion of radioactivity equals 40.2% and 14.8% of the dose, respectively. After oral administration, 0.38% of the dose is excreted in urine as unchanged compound, whereas after intravenous administration, 15% of the compound is excreted unchanged. After inhalation from a metered dose inhaler, 2% of the dose is excreted unchanged by the kidneys within 24 hours.

Unmetabolized Bronchoterol can cross the placental barrier. Sympathomimetic effects may occur in the fetus. After prolonged infusion, fetal blood levels of Bronchoterol have been observed to reach up to 50% of maternal concentrations. Bronchoterol is eliminated much more slowly in preterm infants than in adults.

Bronchoterol passes into breast milk.

Data on effects in diabetic patients are insufficient.

There may be minor effects in infants or newborns up to 20 months of age.

Clinical characteristics.

Indications.

• Symptomatic treatment of acute asthma attacks.
• Prevention of exercise-induced asthma.
• Symptomatic treatment of bronchial asthma of allergic and non-allergic origin and/or other conditions with reversible airway obstruction, such as chronic obstructive bronchitis with or without emphysema.

Long-term therapy should always be accompanied by concomitant anti-inflammatory treatment.

Contraindications.

• Hypersensitivity to fenoterol hydrobromide or to any of the excipients of the metered aerosol (see section "Composition").
• Hypertrophic obstructive cardiomyopathy.
• Tachyarrhythmia.

Interaction with other medicinal products and other forms of interactions.

Concomitant use with other beta-2-adrenergic agents, methylxanthines (e.g., theophylline), anticholinergic agents, and corticosteroids may enhance the effect of the drug. If the drug is used concomitantly with other beta-2-adrenergic agents, methylxanthines (e.g., theophylline), or systemic-acting anticholinergic agents (agents containing pirenzepine), an increased risk of adverse effects (such as tachycardia, arrhythmia) may occur.

Hypokalemia induced by beta-2 agonists may be exacerbated by concomitant therapy with xanthine derivatives, corticosteroids, and diuretics. This should be taken into account, particularly in patients with severe airway obstruction. In such cases, electrolyte levels should be monitored, especially if diuretics and digoxin glycosides are used concomitantly.

Concomitant use of the drug and beta-blockers results in mutual reduction of effects and increases the risk of beta-blocker-induced severe bronchospasm in patients with bronchial asthma.

Treatment with the drug may also reduce the hypoglycemic effect of antidiabetic medicinal products. However, this is expected only at high doses, typically used for systemic administration (tablets or injections/infusions).

There is an increased risk of severe cardiac arrhythmias and decreased arterial blood pressure in patients using fenoterol preparations when inhaling halogenated anesthetics such as halothane, methoxyflurane, or enflurane (see note).

Concomitant use of the drug with monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants may enhance the cardiovascular effects of Bronhoterol.

Since hypokalemia may develop during treatment with high doses, electrolyte levels should be monitored. This is particularly important when diuretics and digoxin glycosides are used concomitantly.

Note. If inhalation anesthesia with halogenated anesthetics is planned, it should be taken into account that Bronhoterol must be discontinued at least 6 hours before the start of anesthesia.

Special precautions for use

Bronhoterol should be used with caution, particularly when administering the highest recommended dose, and only after careful assessment of risk versus benefit in the following cases: severe heart disease, especially recent myocardial infarction and coronary heart disease; concomitant use of cardiac glycosides; severe and untreated arterial hypertension; aneurysm; hyperthyroidism; poorly controlled diabetes mellitus; and phaeochromocytoma.

This is particularly relevant when using the highest recommended doses.

Paradoxical bronchospasm

Like other inhaled medicinal products, Bronhoterol may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, Bronhoterol must be discontinued immediately and alternative therapy initiated.

Cardiovascular effects

Cardiovascular effects may occur with the use of sympathomimetic agents, including Bronhoterol. There is some evidence of myocardial ischemia associated with beta-agonists from post-marketing data and isolated publications. Patients with significant underlying heart disease (e.g., ischemic heart disease, arrhythmias, or severe heart failure) receiving Bronhoterol should be warned to seek medical attention if they experience chest pain or other symptoms suggestive of worsening cardiac disease.

Careful evaluation of symptoms such as dyspnea and chest pain is necessary, as these may have either respiratory or cardiac origin.

Hypokalemia

Severe hypokalemia may occur during therapy with beta-2-agonists. Particular caution is required in severe asthma, as hypokalemia may be potentiated by concomitant administration of xanthine derivatives, glucocorticosteroids, and diuretics. In addition, hypoxia as a symptom of bronchial asthma may intensify the effects of hypokalemia on cardiac rhythm. In patients taking digoxin, hypokalemia may increase susceptibility to arrhythmias. Monitoring of serum potassium levels is recommended in such conditions.

Progressive acute dyspnea

In case of acute dyspnea that rapidly worsens, patients should seek immediate medical attention.

Patients on regular anti-inflammatory therapy should be advised to continue using anti-inflammatory medications even when symptoms improve and they do not require Bronhoterol.

If a previously effective dosing regimen no longer provides the same symptomatic relief, the patient should consult a physician as soon as possible, as this may indicate worsening asthma control and requires reassessment of asthma therapy.

Excessive use of short-acting beta-agonists may mask progression of the underlying disease and lead to worsening asthma control, increasing the risk of severe asthma exacerbations and death.

Patients using fenoterol more than twice a week on an as-needed basis (excluding prophylactic use before physical exertion) should be re-evaluated for appropriate treatment adjustment, as these patients belong to a high-risk group for excessive fenoterol use.

Concomitant use with sympathomimetic or anticholinergic bronchodilators

Other sympathomimetic bronchodilators should be used concomitantly with Bronhoterol only under medical supervision (see section "Interaction with other medicinal products and other forms of interaction"). Anticholinergic bronchodilators may be used together with Bronhoterol.

As an increase in blood glucose levels may occur, glucose levels should be monitored in patients with diabetes.

Due to lack of pharmacokinetic data on fenoterol in patients with hepatic or renal impairment, the drug should be used with caution in these patient groups.

The medicinal product contains 96% ethanol (alcohol; less than 100 mg per dose).

Use of Bronhoterol may result in positive doping test results.

Use during pregnancy or breastfeeding

Pregnancy. Bronhoterol crosses the placental barrier.

The drug may be used during pregnancy only after careful assessment of benefits versus risks, particularly during the first trimester. Although the active substance does not show tocolytic effects with inhaled administration, the possibility of such an effect cannot be completely ruled out.

Breastfeeding. It is unknown whether Bronhoterol has a negative effect on the infant. Since Bronhoterol passes into breast milk, use of the drug during breastfeeding is recommended only after careful assessment of benefit versus risk.

Fertility. There are no clinical data on the effect of fenoterol hydrobromide on fertility. Preclinical studies have shown no adverse effects of fenoterol hydrobromide on fertility.

Ability to affect reaction speed when driving or operating machinery

No studies have been conducted on the effect of fenoterol hydrobromide on the ability to drive a vehicle or operate machinery. However, patients should be warned about the possible occurrence of adverse effects such as dizziness during treatment with Bronhoterol. If such effects occur, patients should avoid potentially hazardous activities such as driving or operating machinery.

Method of Administration and Dosage

The dose should be adjusted according to the nature and severity of the disease.

For adults and children aged 6 years and older, the following dosage regimens are recommended.

To relieve an acute attack of bronchial asthma or an episode of dyspnea, the recommended dose is 100 mcg of fenoterol hydrobromide (1 inhalation).

Generally, 1 inhalation is sufficient during an acute episode of dyspnea to achieve rapid relief of breathing. If there is no significant improvement in breathing within 5 minutes after administration, a second inhalation may be administered. If no effect is observed after 2 inhalations, additional inhalations may be required. In such cases, the patient must seek immediate medical attention (see section "Special Precautions").

If long-term treatment with beta-2-sympathomimetics is indicated, the recommended dose is 1–2 inhalations of Bronchoterol 3–4 times daily. In general, the timing and dose of each administration of Bronchoterol should be determined based on the frequency and severity of dyspnea (according to symptoms). Treatment should be accompanied by anti-inflammatory therapy, especially in bronchial asthma. There should be an interval of at least 3 hours between inhalations. The total daily dose must not exceed 8 inhalations, and the maximum single dose must not exceed 4 inhalations, since higher doses do not provide additional therapeutic benefits overall but may cause severe adverse effects.

For specific prophylaxis of exercise-induced asthma or when exposure to an allergen is expected, 1–2 inhalations of Bronchoterol should be administered, if possible, 10–15 minutes before the anticipated event.

For children aged 4–6 years, unless otherwise prescribed, the following dosage regimens are recommended.

To relieve an acute attack of bronchial asthma or an episode of dyspnea, the recommended dose is 100 mcg of fenoterol hydrobromide (1 inhalation).

For long-term treatment or prevention of attacks, 100 mcg (1 inhalation) of fenoterol hydrobromide should be administered 4 times daily. The timing and dose of each administration of Bronchoterol should be determined based on the frequency and severity of dyspnea (according to symptoms). Treatment must be accompanied by anti-inflammatory therapy, especially in bronchial asthma. There should be an interval of at least 3 hours between inhalations. The total daily dose must not exceed 4 inhalations, and the maximum single dose must not exceed 2 inhalations, since higher doses do not provide additional therapeutic benefits overall but may cause severe adverse effects.

For specific prophylaxis of exercise-induced asthma or when exposure to an allergen is expected, 100 mcg (1 inhalation) of fenoterol hydrobromide should be administered, if possible, 10–15 minutes before the anticipated event.

This medicinal form is not suitable for use in children under 4 years of age.

WARNINGS. In the absence of significant improvement or if the condition worsens despite prescribed treatment, the patient should consult a physician to review the treatment plan, consider combining with other medications (anti-inflammatory agents such as corticosteroids, or bronchodilators such as theophylline), or adjust the dosage. Sudden and progressive worsening of asthma symptoms may be life-threatening. In such cases, immediate medical assistance is required. The use of doses significantly exceeding the recommended ones is dangerous.

There have been reports of several cases of increased risk of serious complications of the underlying disease, as well as fatal outcomes, with long-term treatment of bronchial asthma using excessively high doses of inhaled beta-2-sympathomimetics without adequate anti-inflammatory therapy. The causal relationship has not been fully established. However, adequate anti-inflammatory therapy plays a vital role.

Special Precautions in Therapy. Treatment of bronchial asthma should be stepwise and adjusted according to disease severity. Response to treatment should be monitored regularly.

Unsupervised increase in the dose of beta-2-sympathomimetics such as Bronchoterol may be dangerous for the patient.

Sudden and progressive worsening of asthma symptoms may be life-threatening.

An increased need for beta-2-sympathomimetics such as Bronchoterol is a sign of deterioration in condition. In such circumstances, the physician must review the patient's treatment plan and decide on initiating or increasing anti-inflammatory therapy or starting additional treatment with other medications.

From a medical standpoint, daily self-monitoring by the patient according to physician instructions is important for assessing disease progression and the effectiveness of bronchodilator and anti-inflammatory therapy. This may include recording the forced expiratory volume measured by a peak flow meter.

Instructions for Use of Metered Aerosol.

Proper use of the metered aerosol is essential for successful treatment. Patients should be instructed on the correct use of the metered aerosol. During inhalation, the arrow on the container should point straight upward and the mouthpiece downward, regardless of the inhalation position. Use while sitting or standing, if possible.

Before the first use of the canister, press the valve twice.

Steps to follow before each administration:

1. Remove the protective cap.
2. Breathe out fully.
3. Hold the device and place the mouthpiece in the mouth. The arrow and base of the container should be facing upward, and the mouthpiece downward.
4. Inhale as deeply as possible while simultaneously pressing firmly on the base of the container, releasing the metered dose. Hold breath for several seconds, then remove the mouthpiece and exhale.

If you cannot inhale deeply due to severe dyspnea, first spray 1 inhalation into the oral cavity: this will ease breathing and allow you to use the medication correctly.

If another inhalation is needed, repeat the steps described above (points 2–4).

1. After use, replace the protective cap.

Bronchoterol should be used in advance to prepare for "opening the lungs" and to support aerosol therapy with corticosteroids, saline solution, and sodium cromoglicate.

Duration of treatment should be determined based on the nature, severity, and progression of the disease. The physician should individually adjust the dose.

Additional Instructions. Patients should be instructed on the correct use of the metered aerosol. Children should only use the metered aerosol Bronchoterol upon a physician's recommendation and under adult supervision.

If the metered aerosol canister has not been used for more than 3 days, press the valve once before use to release an aerosol spray.

Clean the inhaler at least once a week.

It is important to keep the inhaler mouthpiece clean to ensure that the medication does not thicken and obstruct the release of the aerosol.

To clean, first remove the dust cap and detach the container from the inhaler. Rinse the inhaler with water until thickened medication and/or dirt are washed away.

After cleaning, shake the inhaler and leave it to dry in the air without using any heating device. When the mouthpiece is dry, reattach the container and dust cap.

The plastic mouthpiece is specifically designed for use with Bronchoterol metered aerosol, 100 mcg. The mouthpiece must not be used with any other metered aerosol. Bronchoterol metered aerosol must only be used with the mouthpiece supplied with the product.

The container is under pressure and must never be opened by force under any circumstances.

The container is opaque. Therefore, it is not possible to see when it is empty. The aerosol canister is designed to deliver 200 doses. When all doses have been used, it may appear that a small amount of liquid remains in the canister. However, the canister must be replaced, as it is no longer possible to deliver an accurate dose of the medication.

The amount of medication in the aerosol canister can be checked as follows: detach the plastic mouthpiece from the canister and place the canister in a container of water. The content of the aerosol canister can be assessed by observing its position in the water.

Children.

To be used in children aged 4 years and older only upon a physician's prescription and under adult supervision.

Overdose.

Symptoms. Depending on the duration of overdose, the following adverse reactions typical of beta-2-adrenergic agents may occur: flushing, mild dizziness, headache, tachycardia, rapid heartbeat, arrhythmia, hypotension, or even shock, arterial hypertension, restlessness, chest pain, excitement, possible extrasystoles, and pronounced tremor in the fingers and throughout the body. Hyperglycemia, hyperlipidemia, and hyperketonemia may develop.

Gastrointestinal reactions, including nausea and vomiting, may occur, especially after oral overdose.

With Bronchoterol overdose, increased translocation of potassium into the intracellular space may occur, leading to hypokalemia, hyperglycemia, hyperlipidemia, and hyperketonemia. Metabolic acidosis and hypokalemia have been observed when Bronchoterol was used in doses higher than recommended according to approved indications for Bronchoterol.

Treatment. Administration of Bronchoterol should be discontinued. Monitoring of acid-base balance and electrolytes should be considered. Treatment of beta-sympathomimetic overdose is symptomatic. The effects of Bronchoterol may be counteracted by beta-receptor blockers. However, possible exacerbation of bronchial obstruction must be taken into account; therefore, dose selection must be carefully considered in patients with bronchial asthma. This also applies to so-called cardioselective beta-receptor blockers.

Monitoring of cardiac function, including ECG, is recommended.

Side effects

Like all medicinal products, Bronhoterol may cause adverse reactions.

Frequency of adverse reactions:

• very common ≥ 1/10;
• common ≥ 1/100 to < 1/10;
• uncommon ≥ 1/1,000 to < 1/100;
• rare ≥ 1/10,000 to < 1/1,000;
• very rare < 1/10,000;
• not known – cannot be estimated from the available data.

Immune system disorders:

• not known – hypersensitivity (e.g. pruritus, rash, purpura, thrombocytopenia, facial swelling).

Metabolism and nutrition disorders:

• uncommon – hypokalemia (including severe hypokalemia);
• rare – hyperglycemia.

Hypokalemia is more frequently observed in patients with severe bronchial asthma who are concurrently receiving xanthine derivatives (e.g. theophylline), corticosteroids and/or diuretics. In addition, hypoxia may influence the effect of hypokalemia on heart rhythm. In such cases, monitoring of serum potassium levels is recommended.

Increased blood levels of insulin, free fatty acids, glycerol, and ketone bodies have been observed.

Psychiatric disorders:

• uncommon – psychiatric disturbances, excitation;
• not known – nervousness.

Psychiatric disturbances manifest as increased excitability, hyperactive behavior, sleep disorders, and hallucinations. These have been observed primarily in children under 12 years of age.

Nervous system disorders:

• common – tremor, dizziness;
• not known – headache.

Cardiac disorders:

• uncommon – arrhythmia, anginal pain, ventricular extrasystoles;
• not known – tachycardia, palpitations, myocardial ischemia.

Respiratory, thoracic and mediastinal disorders:

• common – cough;
• uncommon – paradoxical bronchospasm;
• not known – local irritation.

If paradoxical bronchospasm occurs, treatment should be discontinued immediately.

Gastrointestinal disorders:

• common – nausea;
• uncommon – vomiting, heartburn.

Skin and subcutaneous tissue disorders:

• common – hyperhidrosis;
• uncommon – pruritus;
• not known – urticaria, skin reactions such as rash.

Musculoskeletal and connective tissue disorders:

• uncommon – muscle cramps;
• not known – muscle weakness, myalgia.

Renal and urinary disorders:

• uncommon – urinary disorders.

Investigations:

• uncommon – increased blood pressure, decreased blood pressure.

Shelf life. 2 years.

Storage conditions. Store at a temperature not exceeding 25 °C. Do not freeze. Protect from direct sunlight. Keep out of reach of children.

Packaging.

10 ml (200 doses) in a canister sealed with a metering valve, 1 canister with an inhalation nozzle and protective cap in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

"Multisprey" Limited Liability Company.

Manufacturer's address and place of business.

24, Valeriy Petrosov St., lit. "A-2", Kharkiv, Kharkiv region, 61052, Ukraine.

Marketing Authorization Holder.

"VALARTIN PHARMA" LLC.

Address of the Marketing Authorization Holder.

60, Hrushevskoho St., village Chayky, Kyiv-Sviatoshyn district, Kyiv region, 08135, Ukraine.