Berodual solution for ing. fl. 20 ml

Pharmacological properties

Pharmacodynamics. beroduat contains 2 active broncholitic ingredients: an ipratropiya the bromide having anticholinergic effect and Fenoterolum hydrobromide which is β-adrenomimetiky.

Ipratropiya's

bromide — quarternary ammonium connection with anticholinergic (parasympatolytic) properties. It inhibits vagal reflexes as the antagonist of acetylcholine — the mediator providing transfer of an impulse of vagus nerve. Anticholinergics prevent increase in intracellular concentration of Sa of ⁺⁺ which results from interaction of acetylcholine with muskarinovy receptors of unstriated muscles. Release of Ca ⁺⁺ is promoted by the second system of mediators which consists of IP3 (inositol triphosphate) and DAG (diacylglycerol).

Bronchiectasia after inhalation introduction an ipratropiya of bromide is caused by mainly local specific, but not systemic action of medicine.

Fenoterolum hydrobromide — a direct sympathomimetic which selectively stimulates in therapeutic doses β ₂ - adrenoceptors. At application in high doses there is a stimulation β ₁ - adrenoceptors. Binding β ₂ - receptors activates adenylatecyclase by means of the stimulating G _s - a protein. At increase in the tsAMF level there is an activation of a protein kinase And yes phosphorylations of the corresponding proteins in cells of unstriated muscles. It, in turn, leads to phosphorylation of a kinase of a light chain of myosin, blocking of hydrolysis of a fosfoinozitid and opening of big kaltsiyzavisimy potassium channels.

Fenoterolum hydrobromide causes a relaxation of unstriated muscles of bronchial tubes and vessels and protects from such stimulators of a bronkhokonstriktion as a histamine, metasincaline, cold air and allergens (reactions of immediate type). After single introduction Fenoterolum blocks release of bronkhokonstriktorny and pro-inflammatory mediators from stem cells. After administration of Fenoterolum in a dose of 0.6 mg note improvement of mukotsiliarny clearance.

At high concentration of Fenoterolum in blood plasma which is more often reached at oral or, even more often, at in in medicine introduction, note decrease in a sokratitelnost of a uterus. Also at application in high doses perhaps metabolic effect of medicine: the lipolysis, a glycogenolysis, a hyperglycemia and a hypopotassemia, the last causes increase in capture To ⁺ , especially in skeletal muscles. β-adrenergic influence of Fenoterolum on heart, including acceleration of heartbeat and ChSS, is connected with influence of Fenoterolum on vessels, stimulation β ₂ - heart adrenoceptors, and at application in supraterapevtichesky doses — stimulation β ₁ - adrenoceptors. As well as at application of other β-adrenergic means, reveal lengthening of an interval of Q-Tc. For Fenoterolum in the form of the dosed aerosol these indicators are discrete and are noted at doses which exceed recommended. However system influence after use of Fenoterolum by means of the nebulizer (solution for inhalations) can be higher, than at application of the recommended doses of the dosed aerosol. The clinical importance is not established. A tremor — the most frequent by-effect against the background of intake of agonists β ₂ - adrenoceptors. Unlike influence on bronchial unstriated muscles, system effects of agonists β ₂ - adrenoceptors on skeletal muscles is led to emergence of tolerance.

At simultaneous use of two active bronchodilators the bronchiectasia is done by implementation of two different pharmacological mechanisms. Thus, two active agents provide the combined spasmolytic action on bronchial muscles that gives the chance of broad therapeutic use of medicine at treatment of bronchopulmonary diseases which are connected with violation of passability of airways. The effective combined action requires very insignificant quantity of a β-adrenergic component that allows to select the medicament dosing mode individually for each patient and as much as possible to reduce amount of side effects.

Pharmacokinetics. The therapeutic effect of a combination an ipratropiya of bromide and Fenoterolum of hydrobromide is shown by local impact on airways. Therefore the pharmacokinetics of a bronkhodilatation is not connected with pharmacokinetics of active ingredients of medicine.

about 10-39% of a dose of medicine in general settle

After inhalation in lungs depending on a form of release, a technique of inhalation and the device, and the others remain on an inhaler tip, in a mouth and the top part of airways (stomatopharynx).

do not have

confirmations that the pharmacokinetics of both ingredients in a combination differs from pharmacokinetics of each substance separately.

Fenoterolum hydrobromide. That part which is swallowed, metabolized to sulphatic conjugates. The absolute bioavailability after oral administration is low (about 1.5%).

Later in/in introductions free Fenoterolum and the conjugated Fenoterolum reach 15 and 27% of the entered dose in daily urine. After inhalation by means of the dosed Berodual aerosol about 1% of the inhalated dose is removed in the form of free Fenoterolum in daily urine. According to it it is established that the general system bioavailability of the inhalated doses of Fenoterolum of hydrobromide is 7%.

Kinetic parameters characterizing Fenoterolum disposition calculated

concerning concentration of Fenoterolum in blood plasma later in/in introductions. Later in/in introductions the indicators of AUC can be described on three-chambered model where terminal T _½ makes about 3 h. On this three-chambered model the expected volume of distribution of Fenoterolum in a stable state (Vdss) is about 189 l (≈2.7 l/kg).

About 40% of medicine contact proteins of blood plasma. Preclinical trials on animals showed that Fenoterolum and its metabolites pass through GEB. The general clearance of Fenoterolum is 1.8 l/min, and kidney — 0.27 l/min.

In a research of balance of excretion the general kidney clearance (2 days) of radioactive medicine (including maternal connection and all metabolites) was 65% of a dose later in/in introductions, and the general level of radioactivity in Calais — 14.8% of a dose. After oral administration the general level of radioactivity in urine was about 39% of a dose, and the general level of radioactivity in Calais — 40.2% of a dose during 48 h

Ipratropiya's

bromide. Cumulative kidney excretion (0–24 h) an ipratropiya (maternal connection) was about 46% of a dose later in/in introductions, 1% — after intake and about 3-13% — after inhalation application by means of the dosed inhaler Berodual. Proceeding from these data, the general system bioavailability after oral and inhalation administration the ipratropiya of bromide makes, by calculations, 2 and 7–28% respectively. Considering it, a part of a dose a bromide ipratropiya which is swallowed, considerably will not affect system influence.

Kinetic parameters characterizing a disposition an ipratropiya are calculated by

on the basis of its concentration after introduction. Note fast two-phase decrease in concentration of medicine in blood plasma. The seeming distribution volume in a stable state (Vdss) is about 176 l (≈2.4 l/kg). Drug in the minimum degree (20%) contacts proteins of blood plasma. Preclinical trials on animals show that quarternary amine of ipratropiya does not pass through GEB.

T _½ a final eliminative phase is made by about 1.6 h. The general clearance an ipratropiya — 2.3 l/min, kidney clearance — 0.9 l/min. Later in/in applications about 60% of a dose are metabolized probably mainly in a liver by oxidation.

In a research of balance of excretion the general kidney clearance (6 days) of radioactive medicine (including maternal connection and all metabolites) was 72.1% of a dose later in/in introductions, 9.3% — after intake and 3.2% — after inhalation application. The general level of radioactivity in Calais was 6.3% of a dose later in/in introductions, 88.5% — after intake and 69.4% — after inhalation application. Later in/in introductions the main way of removal of radioactive medicine are kidneys. T _½ at elimination of radioactive medicine (maternal connection and all metabolites) makes 3.6 h. Linking of the main metabolites of urine with muskarinovy receptors is insignificant, and metabolites should be considered inefficient.

Indication

Prevention and symptomatic treatment of chronic obstructive violations of passability of airways: allergic and not allergic (endogenous) oh; asthma caused by physical activity and chronic obstructive bronchitis with emphysema and without it.

needs to appoint by

At long therapy the accompanying anti-inflammatory therapy.

Use

Only for inhalation by means of the nebulizer.

Treatment should be begun and carried out by

under observation of the doctor, for example in the conditions of a hospital.

to

Treatment in house conditions after consultation with the experienced doctor can be recommended to patients to whom application in low doses of β-agonists of fast action, such as Berodual of N, the aerosol dosed was insufficient for simplification of a state. Treatment of the house also can be recommended to patients who need use of the nebulizer for other reasons (for example because of problems with use of aerosols). Or because of need of receiving high doses for the patients familiar with instructions for use of the nebulizer. Therapy always should be begun with the minimum recommended dose.

Dose should be selected individually depending on weight of a sharp episode. Use should be stopped when reduction of expressiveness of symptoms is reached.

Solution for inhalations is intended to

only for inhalation by means of the corresponding nebulizer, and it cannot be accepted orally.

For application needs to part the recommended dose with physiological solution (0.9%) up to the final volume of 3-4 ml. Divorced solution, ready to application, should be inhaled, sufficient reduction of expressiveness of symptoms will not be reached yet.

Divorced solution, ready to application, has to be freshly cooked every time before use. Solution, ready to application, has to be used right after preparation; any residues of the diluted solution need to be destroyed. Patients have to follow instructions of the producer of the nebulizer.

recommends to inhale

through a mouthpiece the sprayed solution intended for application by means of the nebulizer. In the absence of a mouthpiece it is necessary to use a mask which densely adjoins to the person. Patients with predisposition to development of glaucoma have to care for protection of eyes especially carefully.

Solution Berodual can be applied to inhalations by means of various models of nebulizers. The general dose and a dose which reaches lungs depends on the used nebulizer and can be higher, than at use of Berodual aerosol of N, depending on efficiency of the device.

Recommended dosing modes

Adults and children are aged more senior than 12 years. Urgent treatment of bad attacks of a bronchospasm. Depending on weight of an ostory attack apply 1.0-2.5 ml of Berodual after dilution by physiological solution up to the volume of 3-4 ml.

can apply

In exclusively hard cases to 4 ml of Berodual after dilution by physiological solution up to the volume of 3-4 ml.

For prevention of asthma caused by physical activity, or expected allergic contact are applied by 0.1-0.2 ml of Berodual, divorced 2–3 ml of physiological solution if it is possible, in 10–15 min. prior to an incident.

Children at the age of 6–12 years. Urgent treatment of bad attacks OH. Depending on weight of a bad attack and age of the patient apply 0.5-2.0 ml of Berodual after dilution by physiological solution up to the volume of 3-4 ml.

For prevention of asthma caused by physical activity, or expected allergic contact are applied by 0.1-0.2 ml of Berodual, divorced 2–3 ml of physiological solution if it is possible, in 10–15 min. prior to an incident.

Children under 6 years (with the body weight of 22 kg). Considering that information on use of medicine for this age group is limited, it is recommended to use medicament in such dose only on condition of medical observation of a condition of the patient: 0.1 ml/kg of body weight (at most up to 0.5 ml) on 1 dose after dilution by physiological solution up to the volume of 3-4 ml.

Berodual cannot dissolve Solution for inhalations with the distilled water. Berodual is suitable for the accompanying inhalations with the medicine Lazolvan, solution for inhalations and oral administration.

Contraindication

Hypersensitivity to Fenoterolum to hydrobromide, atropinopodobny substances or other components of medicine, a hypertrophic subaortic stenosis, a tachyarrhythmia.

Side effects

can explain the Majority of the side below-mentioned effects to

with anticholinergic and β-adrenergic properties of a berodual. side reactions on medicine are revealed on the basis of the data obtained during clinical trials and pharmacovigilance during use of medicine after its registration.

Frequency of cases according to the Convention MedDRA: very frequent (≥1/10); frequent (≥1/100, 1/10); infrequent (≥1/1000, 1/100); single (≥1/10,000, 1/1000); very rare (1/10,000); it is unknown (it is impossible to determine by the available data).

from the immune system: single — anaphylactic reactions *, hypersensitivity *; it is unknown — purple.

Disbolism, metabolism: single — a hypopotassemia; very rare — increase in level of glucose in blood.

Mental disorders: infrequent — nervousness; single — agitation, mental changes.

Mental violations are shown by

in hyperexcitability, hyperactive behavior, sleep disorders and hallucinations. It is noted generally at children aged to 12 years.

from nervous system: infrequent — a headache, a tremor, dizziness; it is unknown — hyperactivity.

from an organ of sight: single — glaucoma *, increase in intraocular pressure *, accommodation violation *, a mydriasis *, illegibility of sight *, eye pain *, cornea hypostasis *, conjunctiva hyperaemia *, feeling of emergence of an aura before glazami*.

from a cardiovascular system: infrequent — tachycardia, the accelerated heartbeat; single — arrhythmias, fibrillation of auricles, supraventricular tachycardia *, myocardium ischemia *; it is unknown — anginal pain, ventrikulyarny premature ventricular contraction.

from a respiratory system: frequent — cough; infrequent — pharyngitis, a dysphonia; single — a bronchospasm, irritation in a throat, pharyngeal hypostasis, a laryngospasm *, a paradoxical bronchospasm * (caused by inhalation), dryness in a throat *; it is unknown — local irritation.

from digestive system: infrequent — nausea, vomiting, dryness in an oral cavity; single — stomatitis, a glossitis, violations of motility of a GIT **, diarrhea, a lock *, oral cavity hypostasis *, heartburn.

from skin and hypodermic cellulose: single — urticaria, rash, an itch, an angioedema *, petechias, gipergidroz*.

from the musculoskeletal system and connective tissue: single — muscle weakness, a muscular spasm, myalgia.

from an urinary system: single — an ischuria.

Research: infrequent — increase in systolic arterial blood pressure; single — decrease in diastolic arterial blood pressure, thrombocytopenia.

* the By-effects which are not noted during any clinical trials of the medicine Berodual. Frequency is specified on the upper bound of 95% of the confidence interval calculated from the total number of the patients who received treatment according to the Instruction of the EU for drawing up short characteristic of medicine (3/4968=0.00060 that means the "single" phenomena).

** Especially sick with a mucoviscidosis can be

more inclined to development of violations of motility of a GIT at use of inhalation anticholinergic medicines (which contain in the medicament Berodual).

As well as at other inhalation therapy, Berodual can cause symptoms of local irritation. Cough, dryness in a mouth, a headache, a tremor, pharyngitis, nausea, dizziness, a dysphonia, tachycardia, a cardiopalmus, vomiting, increase in systolic arterial blood pressure and nervousness were the most widespread side effects revealed during clinical trials.

Special instructions

in case of a sharp dispnoe (breath difficulty) which quickly progresses should see a doctor immediately.

As well as other inhalation medicines, Berodual can cause a paradoxical bronchospasm which can be life-threatening. In case of a paradoxical bronchospasm Berodual's use should be stopped and replaced with alternative therapy.

State at which Berodual it is necessary to apply only after careful assessment of risk/advantage especially if the dose is higher than recommended:

• insufficiently controlled course of diabetes;
• recently postponed myocardial infarction;
• myocarditis;
• serious organic diseases of heart or vessels (especially in the presence of tachycardia);
• hyperthyroidism;
• pheochromocytoma;
• use of cardiac glycosides;
• heavy and not treated AG;
• an aneurysm.

At use of sympathomimetic medicines, including Berodual, cardiovascular effects can reveal

. Post-marketing data and publications in literature confirm isolated cases of the ischemia of a myocardium connected with β-agonists. Patients with a basic disease — a serious illness of heart (for example an ischemic heart disease, arrhythmia or heavy heart failure) which receive Berodual, it is necessary to warn that they asked for medical care at feeling of pain in a thorax or other symptoms of deterioration in cardiac performance. It is necessary to pay attention to assessment of such symptoms as dispnoe and thorax pain as they can be respiratory or warm origin.

Berodual, as well as other anticholinergics, it is necessary to apply with care at patients:

• with tendency to development of a narrow angle glaucoma;
• with obstruction of urinary tract (for example with a benign hyperplasia of a prostate or intravezikalny obstruction);
• with a renal failure;
• with a liver failure.

messages about separate cases of the complications from an organ of sight (mydriasis, increase in intraocular pressure, a narrow angle glaucoma, eye pain) resulting from hit in aerosol eyes an ipratropiya of bromide or its combination with β ₂ - agonists Are available.

Attention! Patsiyentov it is necessary to instruct in detail about rules of use of the medicine Berodual, solution for inhalations. It is necessary to be careful to avoid hit of medicine in eyes.

Signs of a bad attack of a narrow angle glaucoma include

: eye pain or discomfort; illegibility of sight; feeling of emergence of an aura; feeling of emergence of color spots before eyes; reddening of an eye in the form of conjunctival or corneal hyperaemia.

At emergence of the above-stated symptoms in any combination should begin treatment with eye drops which promote narrowing of a pupil and to ask immediately for specialized medical care.

Patients with a mucoviscidosis can be more inclined

to development of violations of motility of a GIT at use of medicine.

Prolonged use. At patients with OH Berodual it is necessary to apply only in case of need. At patients with the HOZL easy forms the treatment "on demand" (symptomatic) can be more expedient, than regular application.

Should remember

need of application or strengthening of anti-inflammatory therapy for control of inflammatory process of airways and for prevention of deterioration in control of a disease at patients with OH or with the HOZL steroidozavisimy forms.

Regular application of the raised doses of the medicine containing β ₂ - agonists, for example Beroduala, for knocking over of symptoms of bronchial obstruction can cause deterioration in control of a course of the disease.

in case of strengthening of bronchial obstruction the simple increase for a long time in a dose β ₂ - agonists, including Berodual, above recommended, not only is not justified, but also it is dangerous. For prevention of deterioration in a course of the disease, life-threatening, it is necessary to consider a question of revision of the treatment plan of the patient and adequate anti-inflammatory therapy by inhalation corticosteroids.

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It was reported about several cases of increase in risk of serious complications of a basic disease and also about lethal cases at long-term treatment of patients with OH excessively high doses inhalation β to ₂ - sympathomimetics without sufficient anti-inflammatory therapy. Relationship of cause and effect was not completely explained. However adequate anti-inflammatory therapy has the vital value.

should appoint Other sympathomimetic bronchodilators by

along with the medicine Berodual only under medical observation (see INTERACTIONS).

Because of application of high doses β ₂ - agonists potentially serious hypopotassemia (see OVERDOSE) can arise. At the low initial level of potassium it is recommended to control potassium level in blood. Increase in level of glucose in blood is possible. Therefore it is necessary to control glucose level at patients with diabetes.

Seldom or never after Berodual's reception such reactions of hypersensitivity as a small tortoiseshell, a Quincke's disease, rash, a bronchospasm, oropharyngeal hypostasis and allergic reactions can develop at once.

Drug contains preservative a benzalkoniya chloride and the stabilizer of dinatrium edetat a dihydrate. The specified components can cause a bronchospasm in patients with hyperreactive airways.

Berodual's Use can result

in positive takes of analyses of doping control samples.

Period of pregnancy and feeding by a breast. In data of preclinical trials the negative impact of Fenoterolum and an ipratropiya on pregnancy is not revealed. However it is necessary to observe usual precautionary measures in connection with use of medicines during pregnancy. It is necessary to consider the inhibiting influence of Fenoterolum on sokratitelny function of a uterus.

Use β ₂ - sympathomimetics at the end of pregnancy or in high doses can negatively influence the baby (a tremor, tachycardia, fluctuations of level of glucose in blood, a hypopotassemia).

Fenoterolum hydrobromide gets into breast milk. Data on penetration an ipratropiya in breast milk are absent. However, considering the fact that many medicines get into breast milk, it is necessary to appoint with care Berodual during feeding by a breast.

Data on influence on fertility for a combination an ipratropiya of bromide and Fenoterolum of hydrobromide are absent. Preclinical trials with individual components an ipratropiya bromide and Fenoterolum hydrobromide showed lack of undesirable impacts on fertility.

Children. Berodual apply in pediatric practice. To children under 6 years medicine is appointed only on condition of medical observation of a condition of the patient.

Ability to influence speed of response at control of vehicles and work with other mechanisms. Researches were not conducted. Patsiyentov it is necessary to warn about the probability of emergence of undesirable reactions, such as dizziness, tremor, accommodation violation, mydriasis and illegibility of sight, at Berodual's application. It is necessary to be careful at control of vehicles or work with other mechanisms. In case of any of side effects the patient should avoid potentially dangerous activity.

Prolonged accompanying use of medicine beroduat

Interaction

with other anticholinergic medicines did not study and therefore it is not recommended.

Co-administration of medicines / classes stated below of medicines can affect efficiency of application of Berodual.

Strengthening of effect and/or increase in risk of side reactions:

• other β-adrenergic means (all ways of introduction);
• other anticholinergics (all ways of introduction);
• ksantinovy derivatives (for example theophylline);
• anti-inflammatory medicaments (corticosteroids);
• monoamine oxidase inhibitors;
• tricyclic antidepressants;
• halogenated hydrocarbon anesthetics (for example a halothane, trichloroethylene and enfluran). Especially they can strengthen influence on a cardiovascular system.

Decrease in effect: co-administration of blockers of β-adrenoceptors.

Other possible interactions. The hypopotassemia at use of agonists β ₂ - adrenoceptors can amplify simultaneous therapy by ksantinovy derivatives, corticosteroids and diuretics. This fact should be considered, especially at treatment of patients with severe forms of obstruction of airways.

Hypopotassemia can increase risk of developing of arrhythmias at patients who receive digoxin. Besides, the hypoxia can strengthen influence of a hypopotassemia on a warm rhythm. In such cases it is recommended to carry out monitoring of level of potassium to blood.

Risk of a bad attack of glaucoma (see. Special INSTRUCTIONS) raises as at hit in eyes sprayed an ipratropiya, and at application in a combination with β ₂ - agonists.

Also the Berodual medicament treatment can reduce hypoglycemic effect of antidiabetic medicines. However it is expected only at high doses which are usually applied to system introduction (in the form of tablets or injections/infusions).

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If plans use of inhalation anesthetics, it is necessary to take into account that it is necessary to stop use of Fenoterolum at least for 6 h prior to the beginning of anesthesia.

Overdose

Symptoms. depending on duration of overdose such side reactions typical for β2-адренергических means can be observed: inflows, slight dizziness, a headache, tachycardia, a cardiopalmus, arrhythmia, arterial hypotension or even shock, ag, concern, thorax pain, excitement, premature ventricular contraction and a strong tremor in fingers and also in all body is possible. the hyperglycemia can develop. complaints from a GIT are possible, including nausea and vomiting, especially after oral overdose.

At use of Fenoterolum in the doses exceeding recommended according to indications for Berodual noted a metabolic acidosis and also a hypopotassemia.

overdose Symptoms a bromide ipratropiya (feeling of dryness in a mouth, violation of visual accommodation) are weak because of very low system availability an ipratropiya, applied is inhalation.

Treatment. Treatment by Berodual has to be stopped. It is necessary to consider acid-base balance and electrolytic monitoring. Administration of sedative medicines, tranquilizers, in hard cases — the intensive care including hospitalization. As specific antidote it is possible to use blockers of β-adrenoceptors, it is desirable selection blockers β for ₁ - adrenoceptors. However it is necessary to consider possible strengthening of bronchial obstruction under the influence of blockers of β-adrenoceptors and to carefully select a dose for patients with BA or HOZL in view of risk of development of a sharp bronchospasm which can be lethal. It is recommended to p to carry out by

control of warm activity, namely — the ECG.

Storage conditions

In original packing at a temperature not above 25 °C.