Instructions for Berodual H aerosol metered metal can 10 ml 200 doses
Composition
active ingredients: ipratropium bromide, fenoterol hydrobromide;
1 dose contains ipratropium bromide 21 mcg, equivalent to ipratropium bromide anhydrous 20 mcg; fenoterol hydrobromide 50 mcg;
excipients: propellant: 1,1,1,2-tetrafluoroethane (HFA 134a), anhydrous citric acid, purified water, anhydrous ethanol.
Dosage form
Metered aerosol.
Main physicochemical properties: transparent, colorless or slightly yellowish or slightly brownish liquid, free from suspended particles.
Pharmacotherapeutic group
Drugs for the treatment of obstructive airway diseases. Adrenergic agents in combination with anticholinergic agents. Fenoterol and ipratropium bromide. ATX code R03A L01.
Pharmacological properties
Pharmacodynamics.
Berodual H contains two active bronchodilator ingredients: ipratropium bromide, which has an anticholinergic effect, and fenoterol hydrobromide, which is a beta-adrenomimetic.
Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. It inhibits vagal reflexes by antagonistic interaction with acetylcholine, a mediator that provides impulse transmission of the vagus nerve. Anticholinergic agents prevent the increase in intracellular Ca++ concentration that occurs as a result of the interaction of acetylcholine with muscarinic receptors of smooth muscle. The release of Ca++ is facilitated by a second mediator system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol). Bronchodilation after inhalation of ipratropium bromide is due mainly to the local, specific action of the drug, which is not systemic.
Fenoterol hydrobromide is a direct sympathomimetic that selectively stimulates beta2-adrenoceptors in the therapeutic range. At higher doses, beta1-adrenoceptors are stimulated. Through the activating Gs protein, binding of beta2-adrenoceptors leads to activation of adenylate cyclase. When the level of cyclic AMP increases, protein kinase A is activated and the corresponding proteins are phosphorylated in smooth muscle cells. In turn, this leads to phosphorylation of myosin light chain kinase, blocking phosphoinositide hydrolysis and opening of large calcium-dependent potassium channels.
Fenoterol hydrobromide causes relaxation of bronchial and vascular smooth muscle and protects against bronchoconstrictor stimulants such as histamine, methacholine, cold air and allergens (immediate-type reactions). After a single dose, fenoterol blocks the release of bronchoconstrictor and pro-inflammatory mediators from stem cells. Further, after taking fenoterol at a dose of 0.6 mcg, an improvement in mucociliary clearance was noted.
At higher plasma concentrations of fenoterol, which are more often achieved with oral administration or even intravenous administration, a decrease in the ability of the uterus to contract has been noted. Also, when using high doses, metabolic effects of the drug are possible: lipolysis, glycogenolysis, hyperglycemia and hypokalemia, the latter caused by increased K + uptake, especially in skeletal muscle. Beta-adrenergic effects of fenoterol on the heart, including an increase in heart rate and heart rate, are associated with the vascular effects of fenoterol, stimulation of beta2-adrenergic receptors of the heart, and at supratherapeutic doses - stimulation of beta1-adrenergic receptors. As with other beta-adrenergic agents, QTc prolongation is observed. For fenoterol in the form of a metered aerosol, these indicators are discrete and are observed at doses higher than recommended. However, the systemic exposure to fenoterol after administration by nebulizer (solution for inhalation) may be higher than when using the recommended doses of metered-dose aerosol. The clinical significance has not been established. The most common undesirable effect observed with beta-agonists is tremor. In contrast to the effects on bronchial smooth muscle, the systemic effects of beta-agonists on skeletal muscle are a cause for the development of tolerance.
When two active bronchodilators are used simultaneously, bronchial dilation occurs through the implementation of two different pharmacological mechanisms. Thus, the two active substances have a combined antispasmodic effect on bronchial muscles, which makes them widely used in diseases of the bronchopulmonary apparatus associated with impaired airway patency. For an effective combined effect, a very small amount of beta-mimetic is required, which should provide the possibility of individual dose selection and reduce the number of side effects.
Pharmacokinetics.
The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is manifested by local effects on the respiratory tract. Therefore, the pharmacokinetics of bronchodilation are not related to the pharmacokinetics of the active ingredients of the drug.
There is no evidence that the pharmacokinetics of the combination of both ingredients differ from the pharmacokinetics of the monosubstances.
Fenoterol hydrobromide. The ingested portion of the drug is mainly metabolized to sulfate conjugates. Absolute bioavailability after oral administration is low (approximately 1.5%).
After intravenous administration, the fractions of free fenoterol and conjugated fenoterol reach 15% and 27% of the administered dose in the daily urine, respectively. After inhalation using a metered-dose aerosol BERODUAL N, approximately 1% of the inhaled dose is excreted in the daily urine as free fenoterol. Accordingly, it was found that the total systemic bioavailability of inhaled doses of fenoterol hydrobromide is 7%.
Kinetic parameters characterizing the disposition of fenoterol were calculated based on the plasma concentration of fenoterol after intravenous administration. After intravenous administration, the plasma concentration-time relationship can be described by a three-compartment model with a terminal half-life of approximately 3 hours. According to this three-compartment model, the expected volume of distribution of fenoterol at steady state (Vdss) is approximately 189 l (≈ 2.7 l/kg).
Approximately 40% of the drug is bound to plasma proteins. Preclinical studies in animals have shown that fenoterol and its metabolites cross the blood-brain barrier. The total clearance of fenoterol is 1.8 l/min, and the renal clearance is 0.27 l/min.
In an excretion balance study, total renal clearance (2 days) of the radioactive drug (including parent compound and all metabolites) was 65% of the dose after intravenous administration, and total radioactivity in feces was 14.8% of the dose. After oral administration, total radioactivity in urine was approximately 39% of the dose, and total radioactivity in feces was 40.2% of the dose over 48 hours.
Ipratropium bromide. The cumulative renal excretion (0-24 hours) of ipratropium (parent compound) was approximately 46% of the dose after intravenous administration, less than 1% after oral administration and approximately 3-13% after inhalation administration using the BERODUAL N metered dose inhaler. Based on these data, it can be stated that the total systemic bioavailability after oral and inhalation administration of ipratropium bromide is estimated to be 2% and 7-28%, respectively. Therefore, the portion of the ipratropium bromide dose that is ingested will not significantly affect the systemic exposure.
The kinetic parameters characterizing the disposition of ipratropium are calculated based on its concentration after intravenous administration. A rapid biphasic decline in plasma concentrations is observed. The apparent volume of distribution at steady state (Vdss) is approximately 176 L (≈ 2.4 L/kg). The drug is minimally bound to plasma proteins (less than 20%). Preclinical animal studies indicate that the quaternary amine ipratropium does not cross the blood-brain barrier.
The terminal elimination half-life is approximately 1.6 hours. Total clearance of ipratropium is 2.3 l/min, renal clearance is 0.9 l/min. After intravenous administration, approximately 60% of the dose is metabolized, probably mainly in the liver by oxidation.
In an excretion balance study, the total renal clearance (6 days) of the radiopharmaceutical (including the parent compound and all metabolites) was 72.1% of the dose after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. The total radioactivity in the feces was 6.3% of the dose after intravenous administration, 88.5% after oral administration and 69.4% after inhalation. The main route of elimination of the radiopharmaceutical after intravenous administration is the kidney. The elimination half-life of the radiopharmaceutical (parent compound and all metabolites) is 3.6 hours. Binding of the major urinary metabolites to muscarinic receptors is negligible and the metabolites should be considered ineffective.
Indication
Prevention and symptomatic treatment of chronic obstructive airways diseases: allergic and non-allergic (endogenous) bronchial asthma, exercise-induced asthma, and chronic obstructive bronchitis with or without emphysema; preparation for "lung opening" and support of aerosol therapy with corticosteroids, mucolytics, saline, cromoglycic acid, and antibiotics.
With long-term therapy, concomitant anti-inflammatory therapy should be prescribed.
Contraindication
Hypersensitivity to fenoterol hydrobromide or to atropine-like substances or to any of the excipients of this drug.
Hypertrophic obstructive cardiomyopathy and tachyarrhythmia.
Interaction with other medicinal products and other types of interactions
Chronic concomitant use of BERODUAL with other anticholinergic drugs has not been studied and is therefore not recommended.
The simultaneous administration of the following drugs/classes of drugs may affect the effect of BERODUAL N.
other beta-adrenergic agents (all routes of administration); other anticholinergic agents (all routes of administration); xanthine derivatives (e.g. theophylline); anti-inflammatory agents (corticosteroids); monoamine oxidase inhibitors; tricyclic antidepressants; halogenated hydrocarbon anesthetics (e.g. halothane, trichloroethylene and enflurane). They may particularly potentiate the effects on the cardiovascular system.
Reducing the effect:
simultaneous administration of beta-blockers.
Other possible interactions:
Hypokalemia associated with beta-agonists may be potentiated by concomitant administration of xanthine derivatives, corticosteroids, and diuretics. This fact should be considered when treating patients with severe airway obstruction.
Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may increase the negative effect of hypokalemia on heart rhythm. In such cases, it is recommended to monitor the level of potassium in the blood.
The risk of acute glaucoma attack (see section "Special warnings and precautions for use") is increased both when sprayed ipratropium enters the eyes and in combination with beta2-agonists.
Treatment with BERODUAL H may also reduce the hypoglycaemic effect of antidiabetic medicinal products. However, this is only expected at the high doses usually used for systemic administration (tablets or injections/infusions).
If inhalation anesthetics are planned, it should be taken into account that fenoterol should be discontinued at least 6 hours before the start of anesthesia.
Application features
In case of acute dyspnea (difficulty breathing) that progresses rapidly, you should seek immediate medical attention.
As with other inhaled medicinal products, BERODUAL may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, BERODUAL should be discontinued and alternative therapy instituted.
BERODUAL N should only be used after careful consideration of the benefits, especially if the dose is higher than recommended, in the following cases:
poorly controlled diabetes mellitus; recent myocardial infarction; myocarditis; severe organic heart or vascular diseases (especially in the presence of tachycardia); hyperthyroidism; pheochromocytoma; patients taking cardiac glycosides; severe and untreated hypertension; aneurysm.
Cardiovascular effects may occur with sympathomimetic medicinal products, including BERODUAL N. There is evidence from post-marketing data and from scientific publications of isolated cases of myocardial ischemia associated with beta-agonists. Patients with underlying severe cardiac disease (e.g. coronary artery disease, arrhythmia or severe heart failure) receiving BERODUAL N should be advised to seek medical attention if they experience chest pain or other symptoms of worsening cardiac function. Attention should be paid to the evaluation of symptoms such as dyspnea and chest pain, as they may be of respiratory or cardiac origin.
Berodual N, like other anticholinergic agents, should be used with caution:
Patients with a predisposition to narrow-angle glaucoma; Patients with existing urinary tract obstruction (e.g. benign prostatic hyperplasia or intravesical obstruction); Patients with renal insufficiency; Patients with hepatic insufficiency.
There have been reports of isolated cases of complications from the organs of vision (such as mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) resulting from the contact of ipratropium bromide aerosol or its combination with beta2-agonists with the eyes.
Attention! Patients should be instructed in detail on the rules for using the Berodual N metered-dose aerosol inhaler. Care should be taken to avoid the drug getting into the eyes.
Signs of an acute attack of narrow-angle glaucoma include:
eye pain or discomfort; blurred vision; sensation of a halo; sensation of colored spots before the eyes; redness of the eye in the form of conjunctival or corneal hyperemia.
If the above symptoms appear in any combination, you should begin treatment with eye drops that help constrict the pupil and immediately seek specialized medical attention.
Patients with cystic fibrosis may be more prone to developing gastrointestinal motility disorders when taking anticholinergics. Gastrointestinal motility will recover after discontinuation of treatment.
Long-term use.
· In patients with bronchial asthma, BERODUAL N should be used only when necessary. In patients with mild forms of COPD, treatment "on demand" (symptomatic treatment) may be more appropriate than regular use, if circumstances allow.
Regular use of increased doses of a drug containing beta2-agonists, such as Berodual H, to relieve symptoms of bronchial obstruction may lead to deterioration in control of the course of the disease.
In the case of increased bronchial obstruction, simply increasing the dose of beta2-agonists, including Berodual N, over the recommended dose for a long time is not only unjustified, but also dangerous. To prevent worsening of the life-threatening course of the disease, the patient's treatment plan and adequate anti-inflammatory therapy with inhaled corticosteroids should be considered.
Several cases of increased risk of serious complications of the underlying disease, as well as fatalities, have been reported in the long-term treatment of bronchial asthma with excessively high doses of inhaled beta2-sympathomimetics without adequate anti-inflammatory therapy. The causal relationship has not been fully elucidated. However, inadequate anti-inflammatory therapy is of vital importance.
Other sympathomimetic bronchodilators should be used concomitantly with Berodual H only under medical supervision (see section "Interaction with other medicinal products and other types of interactions").
Potentially serious hypokalaemia may occur due to excessive beta2-agonist therapy (see section 4.8). In case of low potassium levels, it is recommended to monitor blood potassium levels initially. Blood glucose levels may increase. Therefore, glucose levels should be monitored in diabetic patients.
In rare cases, hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, oropharyngeal edema and anaphylactic reactions may develop immediately after taking Berodual H.
The medicine contains ethanol 99% (alcohol; less than 100 mcg per dose).
The use of BERODUAL H may give positive results in doping tests.
Use during pregnancy or breastfeeding
Pregnancy. During preclinical studies and clinical use of Berodual N, no negative effects of fenoterol and ipratropium on pregnancy have been identified so far. However, precautions associated with the use of drugs during pregnancy should be observed.
It should be remembered about the inhibitory effect of fenoterol on the contractile function of the uterus. The use of beta2-sympathomimetics at the end of pregnancy or in high doses may adversely affect the infant (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia).
Breastfeeding. Preclinical studies have shown that fenoterol passes into breast milk. There is no data on the passage of ipratropium into breast milk. It is unlikely, especially when using the aerosol form of the drug, that ipratropium will affect the infant to a significant extent. Berodual N should be prescribed with caution during breastfeeding.
Fertility: There are no clinical data on the effects on fertility for the combination of ipratropium bromide and fenoterol hydrobromide or for each component separately. Preclinical studies of the effects of ipratropium bromide and fenoterol hydrobromide alone have shown no adverse effects on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
Studies on the effect of the drug on the ability to drive and use machines have not been conducted. However, patients should be warned about the possibility of such undesirable effects as dizziness, tremor, accommodation disorders, mydriasis and blurred vision during treatment with BERODUAL N. Therefore, caution should be exercised when driving or operating machinery. If the above effects occur, patients should avoid potentially hazardous activities, such as driving or operating machinery.
Method of administration and doses
The dose should be selected depending on the nature and severity of the disease. The following dosage regimens are recommended for adults and children aged 6 years and over.
For the relief of acute bronchospasm and dyspnea, inhalation of a dose of 100 mcg fenoterol hydrobromide and 40 mcg ipratropium bromide (2 inhalations) is recommended. In general, in an acute attack of dyspnea, 1 inhalation is sufficient for rapid relief of breathing. If breathing does not improve significantly after 1-2 inhalations within 5 minutes, 1-2 additional inhalations can be administered. If there is no effect after 4 inhalations, additional measures may be necessary. In such cases, the patient should immediately consult a doctor.
If long-term use of BERODUAL N is deemed necessary, the recommended dose is 1-2 inhalations 3-4 times a day. For the treatment of asthma, BERODUAL N metered-dose aerosol should be used only when necessary. In general, the time and dose of each inhalation should be determined by symptoms. There should be an interval of at least 3 hours between inhalations. The total daily dose should not exceed 12 inhalations, since the highest dose does not add therapeutic benefits overall, but may increase the likelihood of potentially serious undesirable effects.
Patients should be instructed on the correct use of the metered dose aerosol to ensure successful treatment (see Instructions for Use).
Application procedure.
Correct use of the metered dose inhaler is essential to ensure successful treatment. Patients should be instructed in the correct use of the metered dose inhaler. When inhaling, the arrow on the canister should point straight up and the mouthpiece should point straight down, regardless of the inhalation position. Use while sitting or standing, if possible.
Before using the metered dose aerosol for the first time, you should: remove the protective cap and press the valve twice.
Before each use of the metered dose aerosol, you should:
1. Remove the protective cap.
If the metered aerosol can has not been used for more than 3 days, press the valve once before use.
2. Exhale deeply.
3. While holding the inhaler, place your lips around the mouthpiece. The arrow on the mouthpiece should be facing up and the mouthpiece should be facing down.
4. Inhale as deeply as possible, simultaneously pressing the bottom of the canister until 1 (one) metered dose is released. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly.
5. After use, put on the protective cap.
Patients should be instructed on the correct use of the metered-dose aerosol. If the metered-dose aerosol can has not been used for more than 3 days, the valve should be pressed once before use. Avoid getting the spray into the eyes. BERODUAL N metered-dose aerosol should be used in children only on the recommendation of a doctor and under adult supervision.
Clean your inhaler at least once a week. It is important to keep the mouthpiece of your inhaler clean to ensure that the medication does not become thick and that nothing is blocking the flow of the aerosol. To clean your inhaler, first remove the dust cap and detach the canister from the inhaler. Rinse the inhaler with water until any thick medication and/or dirt is removed.
After cleaning, shake the inhaler and let it air dry without using any heating system. When the mouthpiece is dry, attach the canister and dust cap.
WARNING: The mouthpiece is designed specifically for Berodual N metered-dose aerosol.
The mouthpiece should not be used with any other metered-dose aerosols. BERODUAL N may only be used with the mouthpiece specifically designed for it. The contents of the canister are under pressure. The canister must not be opened by force.
The canister is opaque. Therefore, you cannot see when it is empty. The aerosol canister should provide 200 doses. When all these doses are used, there may be a little liquid left in the canister. However, this canister must be replaced, otherwise it is not possible to get the exact amount of medicine.
The presence of the drug in the aerosol can can be checked as follows:
Shake the can to check for liquid;
Remove 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 its position in the water.
Any unused product or waste material should be disposed of.
Children
Use in children over 6 years of age as directed by a doctor and under adult supervision.
Overdose
Symptoms.
Depending on the duration of the overdose, the following adverse reactions typical of beta2-adrenergic agents may occur: flushing, mild dizziness, headache, tachycardia, palpitations, arrhythmia, hypotension or even shock, hypertension, restlessness, chest pain, agitation, possible extrasystole and severe tremor in the fingers and the whole body. Hyperglycemia may develop.
Gastrointestinal disturbances, including nausea and vomiting, may occur, especially after oral overdose.
When using fenoterol in doses higher than recommended for the indications for BERODUAL, metabolic acidosis and hypokalemia were observed.
Symptoms of ipratropium bromide overdose (dry mouth, impaired visual accommodation) are mild due to the very low systemic availability of inhaled ipratropium.
Therapy: Treatment with BERODUAL should be discontinued. Acid-base balance and electrolyte monitoring should be considered.
Administration of sedatives, tranquilizers, in severe cases - intensive care, including hospitalization. Beta-adrenergic blockers (preferably beta1-selective) can be used as specific antidotes for fenoterol; however, it is necessary to take into account the possible increase in bronchial obstruction under the influence of beta-blockers and carefully select the dose for patients suffering from bronchial asthma or COPD due to the risk of developing acute bronchospasm, which can be fatal.
Monitoring of cardiac activity, namely ECG, is recommended.
Adverse reactions
When using BERODUAL N, as with all medicines, side effects may occur.
Most of the undesirable effects listed below can be attributed to the anticholinergic and beta-adrenergic properties of BERODUAL N.
Adverse drug reactions were identified based on data obtained during clinical trials and pharmacovigilance during the period of use of the drug after its registration.
Frequency of occurrence according to MedDRA:
very often ≥ 1/10;
common ≥ 1/100, < 1/10;
rare ≥ 1/10,000, < 1/1,000;
rare <1/10,000;
unknown cannot be determined from the available data.
On the part of the immune system:
rare – anaphylactic reactions*, hypersensitivity*;
unknown – purpura.
Metabolic and nutritional disorders:
rare – hypokalemia*;
rare - increased blood glucose levels.
Mental disorders:
infrequently – nervousness;
isolated - agitation, mental disorders.
Psychiatric disorders are manifested by increased excitability, hyperactive behavior, sleep disorders and hallucinations. This was observed mainly in children under 12 years of age.
From the nervous system:
infrequently - headache, tremor, dizziness;
unknown - hyperactivity.
On the part of the organs of vision:
rare – glaucoma*, increased intraocular pressure*, accommodation disorder*, mydriasis*, blurred vision*, eye pain*, corneal edema*, conjunctival hyperemia*, halo sensation*.
From the side of the cardiac system:
infrequently – tachycardia, rapid heartbeat;
rare – arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia;*
unknown - anginal pain, ventricular extrasystole.
From the respiratory system, chest organs and mediastinum:
often - cough;
infrequently – pharyngitis, dysphonia;
rare – bronchospasm, throat irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm (induced by inhalation)*, dry throat;*
unknown – local irritation.
From the gastrointestinal tract:
infrequently - nausea, vomiting, dry mouth;
rare – stomatitis, glossitis, gastrointestinal motility disorders**, diarrhea, constipation*, oral edema*, heartburn.
Skin and subcutaneous tissue disorders:
rare - urticaria, rash, itching, angioedema*, petechiae, hyperhidrosis*.
Musculoskeletal and connective tissue disorders:
rare – muscle weakness, muscle spasms, myalgia.
From the kidneys and urinary system:
isolated - urinary retention.
Research:
infrequently - increased systolic blood pressure;
rare – decreased diastolic blood pressure, thrombocytopenia.
* Adverse reactions not observed in any clinical trial. The frequency is given by the upper limit of the 95% confidence interval calculated from the total number of patients treated according to the EU guideline on the summary of product characteristics (3/4968 = 0.00060, meaning "isolated" events).
** Patients with cystic fibrosis in particular may be more prone to developing gastrointestinal motility disorders when using inhaled anticholinergic drugs (which are contained in BERODUAL N).
As with other inhalation therapy, BERODUAL N may cause symptoms of local irritation. The most common adverse reactions observed during clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure and nervousness.
Expiration date
3 years.
Storage conditions
Store at a temperature not exceeding 25 °C, out of the reach of children. Protect from direct sunlight, heat and frost.
Packaging
10 ml (200 doses) in a metal can with a dosing valve.
1 canister in a cardboard box.
Vacation category
According to the recipe.
Producer
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Location of the manufacturer and its business address
Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.
