Berodual of N aer. doser. cylinder. 10 ml, 200 doses

Pharmacological properties

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

Ipratropiya's

bromide is quarternary ammonium connection with anticholinergic (parasympatolytic) properties. Inhibits vagal reflexes due to antagonistic interaction with acetylcholine, a mediator which provides transfer of an impulse of vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca ²⁺ resulting from interaction of acetylcholine with muskarinovy receptors of unstriated muscles. Release of Ca ²⁺ is promoted by the second system of mediators consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).

Bronchiectasia after inhalation introduction an ipratropiya of bromide is caused by mainly local, specific effect of medicine, and is not system.

Fenoterolum hydrobromide represents a direct sympathomimetic which selectively stimulates in therapeutic range β ₂ - adrenoceptors. At application of high doses there is a stimulation β ₁ - adrenoceptors. Binding β - adrenoceptors by means of the activating Gs-protein leads ₂ to adenylatecyclase activation. At increase in the tsAMF level occur activation of a protein kinase And yes phosphorylation of the corresponding proteins in smooth muscle cells. In turn, it causes phosphorylation of a kinase of a light chain of myosin, blocking of hydrolysis of a fosfoinozitid and opening of large kaltsiyzavisimy potassium channels.

Fenoterolum hydrobromide causes a relaxation of bronchial and vascular unstriated muscles and protects from stimulators of a bronkhokonstriktion, such as histamine, metasincaline, cold air, and allergens (reactions of immediate type). After single dose Fenoterolum blocks release of bronkhokonstriktorny and pro-inflammatory mediators from stem cells. Further, after intake of Fenoterolum in a dose of 0.6 mkg, improvement of mukotsiliarny clearance is noted.

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At higher concentration of Fenoterolum in blood plasma which is more often reached at oral administration or even in in introduction, noted decrease in contractility of a uterus. Also at application of high doses perhaps metabolitichesky effect of medicine: a lipolysis, a glycogenolysis, a hyperglycemia and a hypopotassemia, the last is called by increase in capture To ⁺ , especially in a skeletal muscle. β-adrenergic influences of Fenoterolum on heart, including increase in a warm rhythm and ChSS, are connected with vascular effects of Fenoterolum, stimulation β ₂ - heart adrenoceptors, and at supraterapevtichesky doses — with stimulation β ₁ - adrenoceptors. As well as at application of other β-adrenergic means, note 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 above recommended. However system influence of Fenoterolum after application 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. The undesirable effect most often noted for β-mimetik is the tremor. Unlike influence on bronchial unstriated muscles, system effects of β-mimetik are a reason for development of tolerance.

At simultaneous use of two active bronchodilators the bronchiectasia is done by implementation of two various pharmacological mechanisms. Thus, two active agents have the combined spasmolytic effect on bronchial muscles that allows to apply widely them at the diseases of the bronchopulmonary device connected with violation of passability of airways. The efficiency of the combined action requires very insignificant quantity of a β-mimetik 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 that 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

proofs that the pharmacokinetics of a combination of both ingredients differs from that monosubstances.

Fenoterolum hydrobromide. A part of medicine which is swallowed is mainly metabolized to sulphatic conjugates. Absolute bioavailability after oral administration low (about 1.5%).

Later in/in introductions the share of free Fenoterolum and the conjugated Fenoterolum reaches respectively 15 and 27% of the entered dose in daily urine. After inhalation by means of the dosed aerosol Berodual of N about 1% of the inhalated dose is removed in the form of free Fenoterolum with 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

according to concentration of Fenoterolum in blood plasma later in/in introductions. Later in/in introductions the indicators "concentration in plasma — time" can be described by means of 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 (the V _dss ) makes 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 clearance — 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 reception orally and about 3-13% after inhalation application by means of the dosed inhaler Berodual N. Opirayas on these data, it is possible to claim that the general system bioavailability after oral and inhalation administration the ipratropiya of bromide makes, by calculations, 2 and 7–28% respectively. So, 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 later in/in introductions. Fast two-phase decrease in concentration of medicine in blood plasma is recorded. The seeming distribution volume in a stable state (the V _dss ) is about 176 l (≈2.4 l/kg). Drug in the minimum volume (less than 20%) contacts proteins of blood plasma. Preclinical trials on animals indicate 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 the ipratropiya makes 2.3 l/min, kidney clearance — 0.9 l/min. Later in/in applications about 60% are metabolized, possibly mainly in a liver by oxidation.

during the 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 reception orally 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 reception orally and 69.4% — after inhalation application. In the main way of removal of radioactive medicine later in/in introductions kidneys are. 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 or without it; preparation for "opening of lungs" and support of aerosol therapy by corticosteroids, mucolytics, salt solution, kromoglitsiyevy acid and antibiotics.

needs to appoint by

At long therapy the accompanying anti-inflammatory therapy.

Use

Dose is selected depending on character and disease severity. for adults and children 6 years are aged more senior recommend the below-mentioned modes of dosing.

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For knocking over of a bad attack of a bronchospasm and an attack of short wind recommends inhalation of a dose of 100 mkg of Fenoterolum of hydrobromide and 40 mkg a bromide ipratropiya (2 inhalations). In total at a bad attack of an asthma there is enough 1 inhalation for fast simplification of breath. If in 5 min. the breath significantly does not improve after application of 1-2 inhalations, it is possible to make 1-2 more additional inhalations. If there is no effect after performing 4 inhalations, there can be a need for holding additional actions. In such cases the patient has to see a doctor immediately.

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If recognized necessary Berodual's application in N for long-term treatment, the recommended dose — 1–2 inhalations 3–4 times a day. The dosed Berodual aerosol of N should be applied to treatment of asthma only if necessary. Time and a dose of each inhalation need to be determined by symptoms. Between inhalations there has to be an interval not less than 3 h. The general daily dose should not exceed 12 inhalations as the highest dose does not add therapeutic advantages in general, but can increase the probability of potentially heavy side effects.

To prevention of the attack of asthma caused by physical activity, or expected contact with allergen are applied by 2 inhalations if it is possible in 10–15 min. prior to an incident.

Patients should be instructed about the correct use of the dosed aerosol for ensuring successful treatment (see an application Order).

application Order. The correct use of the dosed aerosol is important for ensuring successful treatment. Patsiyentov it is necessary to instruct rather correct use of the dosed aerosol. During inhalation of the shooter on a barrel specifies directly up, and a mouthpiece — from top to bottom, irrespective of position of a body for inhalation. To apply if it is possible, sitting or standing.

Before the first use of the dosed aerosol needs to remove a protective cap and to press twice the valve.

it is necessary for

Before each use of the dosed aerosol:

1. To remove a protective cap (if the barrel with the dosed aerosol was not used by more than 3 days, before application it is necessary to press 1 time the valve).

2. It is deep to exhale.

3. To clasp with lips a tip. The arrow on a barrel has to be turned up, and a mouthpiece — from top to bottom.

4. To inhale as it is possible more deeply, at the same time to press a barrel bottom before release of 1 measured dose. For several seconds to hold the breath, then to take out a tip from a mouth and to exhale slowly.

5. After use to put on a protective cap.

Patients should be instructed about the correct use of the dosed aerosol. If the barrel with the dosed aerosol was not used more than 3 days, before application it is necessary to press once the valve. It is necessary to avoid hit of medicine in eyes. At children the dosed aerosol Berodual the N should be applied only according to the recommendation of the doctor and under supervision of adults.

to Clean an inhaler not less than 1 time a week. It is important to keep an inhaler mouthpiece clean to guarantee that medicine did not thicken and nothing interferes with aerosol current. To clean an inhaler, at first remove a dustproof cap and disconnect a barrel from an inhaler. Wash an inhaler with water before full cleaning of the thickened medicine and/or dirt.

After cleaning to stir up an inhaler and to leave it to dry on air without use of any heating system. When the mouthpiece dries, to attach a barrel and a dustproof cap.

Prevention: the mouthpiece is intended especially for the dosed Berodual N. Mundshtuk aerosol it is not necessary to use with any other dosed aerosols. Berodual of N is allowed to use only with a special mouthpiece. Contents of a barrel are under pressure. Not to open a barrel using force.

Barrel opaque. Therefore it is impossible to see when it becomes empty. The aerosol barrel has to provide 200 doses. When all these doses are used, in a barrel there can be a little liquid. However this barrel needs to be replaced, otherwise it will be impossible to receive exact amount of medicine.

Presence of medicine in an aerosol barrel can be checked as follows: having stirred up a barrel, to check availability of liquid; to disconnect a plastic mouthpiece from a barrel and to place a barrel in the container with water. Contents of an aerosol barrel can be estimated by its situation in water.

Any unused product or waste have to be utilized by

.

Contraindication

Hypersensitivity to Fenoterolum to hydrobromide or atropinopodobny substances, or any excipients of this medicine.

Hypertrophic subaortic stenosis and tachyarrhythmia.

Side effects

As well as all medicines, was beroduat by N can cause side reactions. the majority of the side below-mentioned effects can be explained with anticholinergic and β-adrenergic properties of a berodual of N

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 MedDRA: very often — ≥1/10; often — ≥1/100, 1/10; infrequently — ≥1/1000, 1/100; single — ≥1/10,000, 1/1000; very seldom — 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.

Disturbance of metabolism and metabolism: single — a hypopotassemia *; very seldom — increase in level of glucose in blood.

Mental violations: infrequently — nervousness; single — excitement, mental violations.

Mental violations are shown by hyperexcitability, hyperactive behavior, sleep disorders and hallucinations. It was noted generally at children aged to 12 years.

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

from the respiratory system, bodies of a thorax and mediastinum: often — cough; infrequently — pharyngitis, a dysphonia; single — a bronchospasm, irritation of a throat, throat hypostasis, a laryngospasm *, a paradoxical bronchospasm * (caused by inhalation), dryness in a throat *; it is unknown — local irritation.

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

from skin and hypodermic fabric: single — urticaria, rashes, an itch, a Quincke's disease *, petechias, gipergidroz*.

from the musculoskeletal system and connective tissue: single — weakness of muscles, muscular spasms, myalgia.

from kidneys and an urinary system: single — an ischuria.

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

* the By-effects which are not revealed in one clinical trial. Frequency is specified according to the upper bound of 95% of the confidence interval calculated from the total number of 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 the inhalation anticholinergic medicines (which are contained in the medicament Berodual of N).

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

Berodual of N needs to be applied only after careful assessment of advantage/advantage, especially if the dose is higher recommended, in the following cases:

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

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At use of sympathomimetic medicines, including Berodual of N, cardiovascular effects can be observed. The messages received from post-marketing data and scientific publications confirm the isolated cases of 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 of N, it is necessary to warn that they asked for medical care at feeling of pain in a thorax or at other symptoms of deterioration in cardiac performance. It is necessary to pay attention to assessment of such symptoms as short wind and thorax pain as they can be respiratory or warm origin. Berodual of N, as well as other anticholinergics, it is necessary to apply with care at patients:

• with tendency to development of a narrow angle glaucoma;
• with the available 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 application of the dosed aerosol inhaler Berodual N. Neobkhodimo 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 anticholinergics. The motility of a GIT will be restored after completion of treatment.

Prolonged use. At patients with OH Berodual the N should be applied only in case of need. At patients with the HOZL easy forms the treatment on demand (symptomatic treatment) can be more expedient, than regular application if circumstances allow.

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 the HOZL steroidzavisimy forms.

Regular application of the raised doses of the medicine containing β ₂ - agonists, for example Berodual the N, 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 of N, 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.

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 OH by excessively high doses inhalation β to ₂ - sympathomimetics without sufficient anti-inflammatory therapy. Relationship of cause and effect is completely not found out. However inadequate anti-inflammatory therapy has the vital value.

Other sympathomimetic bronchodilators should apply along with Berodual N only under medical observation (see INTERACTIONS).

Because of excessive therapy β ₂ - agonists potentially serious hypopotassemia (see OVERDOSE) can arise. At the low level of potassium at the beginning 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 the N can develop such reactions of hypersensitivity as a small tortoiseshell, a Quincke's disease, rash, a bronchospasm, oropharyngeal hypostasis and anaphylactic reactions at once.

Medicine contains ethanol of 99% (alcohol; 100 mkg on a dose). Berodual's use the N can yield positive takes of analysis of doping control samples.

Use during pregnancy and feeding by a breast. Pregnancy. During preclinical trials and clinical use of Berodual of N the negative influence of Fenoterolum and an ipratropiya on pregnancy is still not revealed. However it is necessary to observe the precautionary measures connected with use of medicines during pregnancy.

Should remember

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).

Feeding by a breast. Preclinical trials showed that Fenoterolum gets into breast milk. There are no data on penetration an ipratropiya in breast milk. It is improbable, especially when using an aerosol form of medicine that ipratropiya will influence the baby substantially. It is necessary to appoint with care Berodual N during feeding by a breast.

Fertility. There are no clinical data on influence on fertility of a combination an ipratropiya of bromide and Fenoterolum of hydrobromide, and for each component separately. Preclinical trials of influence of application separately an ipratropiya of bromide and Fenoterolum of hydrobromide showed lack of undesirable impacts on fertility.

Children. Apply at children aged 6 years on doctor's orders and under supervision of adults are more senior.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Researches of effect of medicine on ability to drive the car and to work with technical means were not conducted. However patients should be warned about possibility of such undesirable effects as dizziness, a tremor, accommodation violation, a mydriasis and illegibility of sight at treatment by N. Berodual. Owing to this fact it is necessary to be careful at control of vehicles or work with the equipment. At emergence of the above-stated effects the patients should avoid potentially dangerous types of activity, for example control of vehicles or work with technical means.

Prolonged simultaneous use of a berodual of N with other anticholinergics is not studied by

Interaction

and therefore it is not recommended.

Co-administration of medicines / classes stated below of medicines can affect effect of medicine N. 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);
• MAO inhibitors;
• tricyclic antidepressants;
• halogenated carbohydrate anesthetics (for example a halothane, trikhloroetilen and enfluran). Especially they can strengthen influence on a cardiovascular system.

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

Other possible interactions. The hypopotassemia connected with application of β-adrenomimetik can be strengthened by co-administration of ksantinovy derivatives, corticosteroids and diuretics. This fact should pay special attention at treatment of patients with heavy violations of passability of airways.

Hypopotassemia can lead

to increase in risk of developing of arrhythmias at the patients receiving digoxin. Besides, the hypoxia can increase negative impact of a hypopotassemia on a warm rhythm. In similar cases it is recommended to carry out monitoring determination of level of potassium to blood.

Risk of a bad attack of glaucoma (see. Special INSTRUCTIONS) raises as at hit sprayed an ipratropiya in eyes, and in a combination with β ₂ - agonists. Also the Berodual medicament treatment of N can reduce hypoglycemic effect of antidiabetic medicines. However it is expected only at high doses which usually apply to system introduction (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 there can be side reactions typical for β2-адренергических means: 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.

violations from a GIT, including nausea and vomiting Can note

, especially after oral overdose.

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

overdose Symptoms a bromide ipratropiya (feeling of dryness in a mouth, violation of visual accommodation) are a little expressed to

because of very low system bioavailability inhaled an ipratropiya.

Therapy. Treatment Berodualy N has to be stopped. It is necessary to consider acid-base balance and electrolytic monitoring. Administration of sedatives, tranquilizers, in hard cases — the intensive care including hospitalization.

as specific antidotes can apply blockers of β-adrenoceptors to Fenoterolum, it is desirable β for ₁ - selection; however it is necessary to consider possible increase in bronchial obstruction under the influence of blockers of β-adrenoceptors and to carefully select a dose for patients with BA or HOZL because of risk of development of a sharp bronchospasm which can have a lethal outcome.

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recommended control of warm activity, namely — the ECG.

Storage conditions

At a temperature not above 25 °C. to protect from influence of direct sunshine, heat and a frost.