Berotec® [Fenoterol]

Pharmacological properties

Berotec n is an effective bronchodilator for use in acute attacks of BA and in other conditions with reversible narrowing of the airways, such as obstructive bronchitis with or without pulmonary emphysema. after oral administration, Berotec n begins to act for several minutes with a duration of action of up to 8 hours

After inhalation of fenoterol hydrobromide in obstructive pulmonary diseases, bronchodilation occurs within a few minutes. The action of the bronchodilator lasts 3-5 hours.

Pharmacodynamics In clinical studies lasting up to 3 months in adults with AD, COPD and children with AD, it was found that the tetrafluoroethane and freon-containing forms of the Berotec N aerosol inhaler have the same therapeutic efficacy.

Fenoterol hydrobromide - a sympathomimetic agent, selectively stimulates β in a therapeutic dose₂-adrenoreceptors; when used in higher doses, stimulates β₁-adrenoreceptors (for example, when it is taken with tocolysis). The binding of the drug to β₂-adrenoreceptors leads to the activation of adenylate cyclase by stimulation of the Gs protein. With an increase in the concentration of cAMP, protein kinase A is activated, which ensures phosphorylation of target proteins in smooth muscle cells. This, in turn, leads to phosphorylation of the kinase of myosin light chains, inhibition of phosphoinositide hydrolysis and the opening of large calcium-dependent potassium channels. There is evidence that large potassium channels can be activated directly by the Gs protein.

Fenoterol relaxes the smooth muscles of the bronchi and blood vessels and prevents the development of bronchospasm due to exposure to histamine, methacholine, cold air and allergens (immediate hypersensitivity reactions). Immediately after use, fenoterol blocks the release of inflammatory mediators and bronchial obstruction from mast cells. In addition, after the use of phenoterol in higher doses, an increase in mucociliary clearance is noted.

With a high concentration of the drug in blood plasma, which is most often achieved with oral or intravenous administration, a decrease in the contractile activity of the myometrium is noted. When using the drug in high doses, metabolic effects such as lipolysis, glycogenolysis, hyperglycemia and hypokalemia have been identified; the latter is caused by increased absorption of ion K⁺primarily skeletal muscle. β-adrenergic effect of the drug on cardiac activity - increased heart rate and heart rate due to the vascular effect of phenoterol, stimulation of β₂-adrenoreceptors, and when used in doses exceeding therapeutic ones, by stimulation of cardiac β₁-adrenoreceptors.

As with other β-adrenergic agents, Q – Tc lengthening has been reported. For metered-dose inhalers with fenoterol, these were particular events at doses exceeding the recommended ones. However, the systemic exposure after administration with nebulizers (UDV, r-rum for inhalation) can be higher than at the recommended doses used manually (MDI) without special devices. The clinical significance of this has not been established. The most frequently detected effect of β-adrenoreceptor agonists is tremor. In contrast to the action on the smooth muscles of the bronchi, the systemic effect of β-agonists on skeletal muscles causes the development of tolerance.

In clinical studies, high therapeutic efficacy of fenoterol in bronchospastic conditions has been established. Fenoterol eliminates bronchospasm caused by various stimulants (for example, cold air), as well as immediate bronchospastic reactions in contact with an allergen.

Pharmacokinetics The pharmacokinetics of phenoterol was studied after iv, inhalation and oral administration.The therapeutic effect of Berotec N is achieved by local effects on the respiratory tract. Thus, the concentration of the drug in blood plasma does not necessarily correlate with the bronchodilator effect.

Although the composition with tetrafluoroethane (HFA) and the composition with freon (CFC) lead to different systemic exposures of phenoterol, these two combinations can be considered therapeutically equivalent.

Suction. After inhalation, depending on the method of inhalation and the system used, about 10-30% of the active substance that is released from the aerosol preparation reaches the lower respiratory tract. The rest settles in the upper part of the respiratory tract and oral cavity and is then swallowed. The absolute bioavailability of phenoterol from dosed aerosol Berotec N after inhalation is 18.7%.

Absorption from the lungs takes place in a two-phase way. 30% of the phenoterol hydrobromide dose is rapidly absorbed with T_½ 11 min, and 70% is slowly absorbed with T_½ 120 minutes

C_max in blood plasma, 45.3 pg / ml was observed 15 minutes after taking a single dose of 100 μg of fenoterol using a metered dose inhaler with freon in patients with AD. However, studies in healthy volunteers with more frequent blood sampling for pharmacokinetic studies suggest that C_max in plasma was reached earlier: between 2 and 3.5 minutes after taking the dose. C_max in a blood plasma after inhalation of a single dose of 200 μg of fenoterol using a metered dose inhaler with tetrafluoroethane was lower and was noted later compared to inhalation using a metered dose inhaler with freon (CFC-MDI: C_max= 165 pg / ml, T_max= 3.5 minutes; HFA-MDI: C_max= 66.9 pg / ml, T_max= 15 min). After oral administration, approximately 60% of the phenoterol hydrobromide dose is absorbed. The amount of absorbed drug undergoes an intensive one-stage metabolism, which leads to the fact that the bioavailability when administered orally decreases to approximately 1.5%. Thus, the effect of a portion of the active ingredient that the patient swallowed on plasma concentration after inhalation is negligible. With the systematic administration of phenoterol hydrobromide, its elimination occurs according to a three-chamber model with T_½α = 0.42 min, T_½β= 14.3 min, T_½γ= 3.2 hours. The metabolic transformation of phenoterol hydrobromide in humans occurs almost entirely by sulfation, mainly in the intestinal wall.

In the non-metabolized state of fenoterol, hydrobromide can pass through the placenta and pass into breast milk. Regarding the effect of phenoterol hydrobromide on the metabolic state in diabetes mellitus, data are insufficient.

Distribution. Fenoterol is widely distributed in the body. The volume of distribution upon reaching the equilibrium state after iv administration is 1.9–2.7 l / kg body weight. The distribution of phenoterol in blood plasma after iv administration is adequately described by a three-chamber pharmacokinetic model with T_½: T_α= 0.42 min, T_β= 14.3 min and T_γ= 3.2 hours. Plasma protein binding is from 40 to 55%.

Metabolism. In humans, fenoterol is extensively metabolized by conjugation to glucuronides and sulfates. After oral administration, fenoterol is metabolized mainly by sulfonation. Such metabolic inactivation of the starting compound begins already in the intestinal wall.

Excretion. After iv administration, the main part (about 85%) of the average total clearance of 1.1–1.8 l / min is provided by biotransformation, including excretion with bile. Renal clearance of fenoterol (0.27 L / min) corresponds to approximately 15% of the average total clearance of a systemically available dose. Given the portion of the drug associated with plasma proteins, the value of renal clearance allows, in addition to glomerular filtration, to suggest tubular secretion of fenoterol.

Within 48 hours after oral and iv administration, the total radioactivity excreted in the urine is about 39 and 65% of the dose, respectively, and the total radioactivity excreted in the feces is 40.2 and 14.8% of the dose, respectively. After oral administration, 0.38% of the dose is excreted in the urine as the starting compound, whereas after iv administration, 15% of the compound is excreted unchanged. After inhalation from a metered dose inhaler, 2% of the dose is excreted through the kidneys unchanged.

Indications

Symptomatic treatment of acute asthmatic attacks and other conditions with reversible narrowing of the airways, such as chronic obstructive bronchitis. for patients with asthma attacks and steroid-sensitive hobble, concomitant anti-inflammatory therapy should be considered; prevention of ba induced by physical activity.

Application

Treatment of BA attacks and other conditions with reversible bronchial obstruction

In most cases, inhalation of 1 dose is enough to stop an attack of AD; if after 5 minutes the effect is insufficient, inhalation can be repeated, but not more than 8 inhalations per day.

If the attack is not eliminated in two doses and there is a need for further inhalation, the patient should immediately seek medical help.

Prevention of AD induced by physical activity: 1-2 doses per inhalation before physical activity, but not more than 8 doses per day.

For the treatment of children, Berotec N metered-dose aerosol should be used only as directed by a doctor and under the supervision of adults.

Application

For successful therapy, it is necessary to use metered aerosol correctly. Before using the can for the first time, double-click the valve. Before each inhalation, the following rules must be observed:

1. Remove the protective cap.

2. Exhale completely.

3. Holding the metered aerosol with the dispenser down, cover the mouthpiece with your lips. The arrow and base of the container should be turned up.

4. Inhale as deep as possible, while firmly pressing the base of the container, this will lead to the release of a measured dose. Hold your breath for a few seconds, then take out the mouthpiece and exhale.

If you need another inhalation, repeat the above steps (paragraphs 2–4).

After application, return the protective cap to its place.

If the dosed aerosol has not been used for 3 days, press the valve 1 time.

The container is opaque. Therefore, you cannot see when it is empty. An aerosol can should provide 200 doses. When all these doses have been used, it may seem that there is still a little liquid left in the can. However, it must be replaced, since in this case it is impossible to obtain the exact amount of the drug.

The amount of medicine in the aerosol can can be checked as follows: disconnect the plastic mouthpiece from the can and place the can in a container of water. The contents of the aerosol can can be estimated by observing its position in water: with a liquid content of more than ³/₄ volume, it will sink and be at the bottom; an empty spray will float on the surface of the water; if the liquid occupies ½ of the volume, the can will float on the surface vertically, with the bottom up; accordingly, with a liquid content of about ¹/₄ volume - at an angle to the surface of the water.

Clean the inhaler at least 1 time per week. It is important to keep the mouthpiece of the inhaler clean to ensure that the drug is not thickened and does not interfere with the flow of aerosol.

To clean, first remove the dust cap and separate the container from the inhaler. Rinse the inhaler with water until the thickened product and / or dirt are washed off.

After cleaning, shake the inhaler and let it dry in air (do not dry with any heating system). When the mouthpiece dries, attach the container and dust cap.

Warning: the plastic tip is specifically designed for metered aerosol Berotec N 100 mcg and serves for accurate dosing. The tip cannot be used with other metered-dose aerosols and Berotec N cannot be used with a different tip.

The container is under pressure; it cannot be opened with the use of force or heated to a temperature above 50 ° C.

Contraindications

Hypertrophic obstructive cardiomyopathy, tachyarrhythmia. hypersensitivity to fenoterol hydrobromide or inactive ingredients of a dosed aerosol.

The period of breastfeeding.

Side effects

As with other β-adrenergic agonists, Berotec n can cause the following side effects, including severe hypokalemia. as with any other inhalation therapy, the use of Berotec n may cause symptoms of local irritation.

Immune system disorders: hypersensitivity.

From the side of metabolism and digestion: hypokalemia.

Mental disorders: increased irritability, nervousness.

From the side of the central nervous system: tremor, headache, dizziness.

From the cardiovascular system: myocardial ischemia, arrhythmia, tachycardia, palpitations.

From the respiratory system, chest and mediastinum (only for inhaled dosage forms): paradoxical bronchospasm, cough, throat irritation.

From the digestive tract: nausea, vomiting.

From the skin and subcutaneous tissues: hyperhidrosis, skin reactions: rash, itching, urticaria.

From the musculoskeletal system: muscle spasm, myalgia, muscle weakness.

Research: increased systolic blood pressure or decreased diastolic blood pressure.

special instructions

The need for simultaneous anti-inflammatory therapy in patients with BA and patients with steroid-dependent hobl should be considered.

When using a new metered-dose aerosol Berotec N for the first time, some patients may note that its taste is slightly different from the previous aerosol containing freon. Patients should be informed about this when prescribing a new metered-dose aerosol Berotec N, and also that both dosage forms of the aerosol are interchangeable and identical in their properties, and the difference in taste does not affect the effectiveness and safety of the drug.

Simultaneous use with other sympathomimetic bronchodilators should be carried out only under medical supervision. Anticholinergic bronchodilators can be used for inhalation simultaneously with Berotec N.

In such situations, especially when using doses exceeding the recommended, Berotec N should be used only after a careful assessment of the risk / benefit ratio:

• insufficiently controlled diabetes mellitus;
• recent myocardial infarction, severe organic lesions of the heart or blood vessels;
• hyperthyroidism, pheochromocytoma.

In case of sudden development and rapid progression of shortness of breath, the patient should immediately consult a doctor.

With prolonged use of the drug:

• symptomatic treatment is more preferable than regular use;
• it is necessary to assess the feasibility of additional or strengthening anti-inflammatory therapy (for example, inhaled GCS) to control the inflammatory process of the respiratory tract and to avoid complicating the control of the disease.

With increasing bronchial obstruction, exceeding the recommended dose of drugs containing β₂-agonists, such as Berotec N, is not only impractical, but also dangerous. Use in high doses of β₂-agonists, such as Berotec N, for a long time can lead to poor control of symptoms of bronchial obstruction.In this situation, to prevent a potentially life-threatening condition, it is necessary to revise the treatment regimen and especially the adequacy of anti-inflammatory therapy.

In therapy with β agonists₂-adrenoreceptors severe hypokalemia may occur. Particular attention is necessary in severe asthma, since in this case hypokalemia can be potentiated by the simultaneous use of xanthine derivatives, corticosteroids, and diuretics. In addition, hypoxia as a symptom of AD can enhance the negative effect of hypokalemia on heart rate.

In patients taking digoxin, hypokalemia can lead to an increased tendency to arrhythmias. In such situations, it is recommended to monitor the level of potassium in the blood serum.

When using sympathomimetic drugs, including Berotec N, cardiovascular effects are possible. There is some evidence of myocardial ischemia associated with the use of β-adrenoreceptor agonists, obtained from post-marketing data and isolated cases published in the literature.

Patients with major severe heart diseases (e.g., coronary heart disease, arrhythmias, or decompensated heart failure) who take Berotec N should be warned about the need to consult a doctor if chest pain or other symptoms of worsening heart disease occur.

Attention should be paid to assessing symptoms such as dyspnea and chest pain, as they can be of either respiratory or cardiac origin.

During pregnancy and breastfeeding. There was no negative effect when using the drug during pregnancy. However, the usual warnings should be followed when using the drug during pregnancy.

The inhibitory effect of phenoterol on uterine contractility must be taken into account. It was revealed that fenoterol passes into breast milk. The safety of the drug during breast-feeding has not been established.

Children. Apply to children from the age of 6 years as prescribed by a doctor and under the supervision of adults.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. There are no data on the effect, but the possibility of adverse reactions when using the drug should be considered.

Interactions

Β-adrenergic agonists, anticholinergics, and xanthine derivatives (such as theophylline) can enhance the effects of phenoterol. the simultaneous administration of other β-mimetics, the systematic use of anticholinergics and xanthine derivatives (e.g. theophylline) can enhance the side effect.

With the simultaneous use of β-adrenoreceptor blockers, a serious reduction in bronchodilation is potentially possible.

Β-adrenergic agonists should be used with caution in patients taking MAO inhibitors or tricyclic antidepressants, since the effect of β-adrenergic agents may be enhanced.

Inhalations of halogenated hydrocarbon anesthetics (halotane, trichlorethylene, enflurane) can increase the severity of the action of β-adrenergic drugs on the cardiovascular system.

Overdose

Symptoms the likely symptoms of an overdose are excessive β-adrenergic stimulation, including tachycardia, a feeling of palpitations, tremor, ag, arterial hypotension, increased pulse fluctuations in hell, angina pectoris, arrhythmia, and flushing.

Treatment: sedatives, tranquilizers; in severe cases, intensive care. As specific antidotes, β-adrenoreceptor blockers are used, preferably β₁-selective. The possibility of increased bronchospasm should be considered, therefore, patients with AD must carefully select the dose.

Storage conditions

At a temperature not exceeding 25 ° C.Protect from direct sunlight, heat and low temperatures. the contents of the can are under pressure. Do not open the spray can.