Instructions Berodual inhalation solution bottle with dropper 20 ml No. 1
Composition
active ingredients: ipratropium bromide, fenoterol hydrobromide;
1 ml (20 drops) of inhalation solution contains ipratropium bromide 261 mcg, equivalent to 250 mcg of ipratropium bromide anhydrous; fenoterol hydrobromide 500 mcg;
Excipients: benzalkonium chloride, disodium edetate, sodium chloride, concentrated hydrochloric acid, purified water.
Dosage form
Solution for inhalation.
Main physicochemical properties: clear, colorless or almost colorless liquid, free from suspended particles, with an almost imperceptible odor.
Pharmacotherapeutic group
Drugs for the treatment of obstructive airway diseases. Adrenergic agents in combination with anticholinergic agents.
ATX code R03A L01.
Pharmacological properties
Pharmacodynamics.
Berodual contains two active bronchodilator ingredients: ipratropium bromide, which exhibits 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 another system of mediators, which consists 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. Binding of beta2-adrenoceptors leads, via the activating Gs protein, to the 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 the phosphorylation of myosin light chain kinase, blocking the hydrolysis of phosphoinositide and opening of large calcium-dependent potassium channels.
Fenoterol hydrobromide causes relaxation of bronchial and vascular smooth muscles 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 mg, 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 uterine contractility 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 (inhalation solution) after administration by nebulizer may be higher than when using the recommended doses of metered-dose aerosol. The clinical significance has not been established. The most common adverse 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 it possible to widely use them 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 the metered dose aerosol BERODUAL, 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 excretory 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 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 and without emphysema.
With long-term therapy, concomitant anti-inflammatory therapy should be prescribed.
Contraindication
Hypersensitivity to fenoterol hydrobromide, atropine-like substances or to other components of the drug; hypertrophic obstructive cardiomyopathy, 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 concomitant administration of the following drugs/classes of drugs may affect the effectiveness of BERODUAL.
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 enhance the negative effects of hypokalemia on heart rhythm. In such cases, monitoring of blood potassium levels is recommended.
The risk of acute glaucoma attack (see section "Special precautions for use") is increased both when sprayed ipratropium enters the eyes and when used in combination with beta2-agonists.
Treatment with BERODUAL may also reduce the hypoglycaemic effect of antidiabetic medicinal products. However, this is only expected at the high doses usually used for systemic administration (in the form of 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 medications, BERODUAL may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, BERODUAL should be discontinued and alternative therapy instituted.
Conditions in which BERODUAL should be used only after careful risk/benefit assessment, especially if the dose is higher than recommended:
poorly controlled diabetes mellitus; recent myocardial infarction; myocarditis; severe organic heart or vascular diseases (especially in the presence of tachycardia); hyperthyroidism; pheochromocytoma; use of cardiac glycosides; severe and untreated arterial hypertension; aneurysm.
Cardiovascular effects may occur with sympathomimetic medicinal products, including BERODUAL. Post-marketing data and published literature indicate 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 should be advised to seek medical attention if they experience chest pain or other symptoms of cardiac dysfunction. 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, 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 visual complications (such as mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) resulting from ocular exposure to ipratropium bromide aerosol or its combination with beta2-agonists.
Attention! Patients should be instructed in detail on the rules for using Berodual, inhalation solution. Care should be taken to avoid contact with 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 using the drug.
Long-term use.
· In patients with bronchial asthma, BERODUAL should be used only when necessary. In patients with mild forms of COPD, "on-demand" treatment (symptomatic treatment) may be more appropriate than regular use.
· It should be remembered about the need to use or increase anti-inflammatory therapy to control the inflammatory process of the airways and to prevent deterioration of disease control in patients with bronchial asthma or with steroid-dependent forms of COPD.
In case of increased bronchial obstruction, simply increasing the dose of beta2-agonists, including Berodual, over a long period of time above the recommended dose 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, adequate anti-inflammatory therapy is of vital importance.
Other sympathomimetic bronchodilators should be administered concomitantly with Berodual only under medical supervision (see section "Interaction with other medicinal products and other types of interactions").
Potentially serious hypokalaemia may occur with high doses of beta2-agonists (see section 4.8). In case of low initial blood potassium levels, monitoring of blood potassium levels is recommended. 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 allergic reactions may develop immediately after taking Berodual.
The drug contains the preservative benzalkonium chloride and the stabilizer disodium edetate dihydrate. These components may cause bronchospasm in patients with hyperreactive airways.
The use of BERODUAL may lead to positive results in doping tests.
Use during pregnancy or breastfeeding
Preclinical data have not revealed any adverse effects of fenoterol and ipratropium on pregnancy. However, the usual precautions for use of drugs during pregnancy should be observed. The inhibitory effect of fenoterol on uterine contractility should be taken into account. The use of beta-2-sympathomimetics in late pregnancy or in high doses may have adverse effects on the infant (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia).
Fenoterol hydrobromide passes into breast milk. There is no data on the passage of ipratropium into breast milk. It is unlikely that ipratropium can reach the infant in significant amounts, especially if administered by inhalation. Caution should be exercised when BERODUAL is administered to breastfeeding women.
There are no data on the effects on fertility when ipratropium bromide and fenoterol hydrobromide are used in combination or separately. Preclinical studies with the individual components - ipratropium bromide and fenoterol hydrobromide - have shown no adverse effects on fertility.
The ability to influence the reaction speed when driving or working with other mechanisms
No studies have been conducted. Patients should be warned about the possibility of adverse reactions such as dizziness, tremor, accommodation disorders, mydriasis and blurred vision when using BERODUAL. Caution should be exercised when driving or operating other machinery. If any of the adverse reactions occur, the patient should avoid potentially hazardous activities.
Method of administration and doses
For inhalation using a nebulizer only.
Treatment should be initiated and carried out under the supervision of a physician, for example in a hospital setting.
Home treatment, after consultation with an experienced physician, may be recommended for patients who have not been adequately relieved by low-dose, rapid-acting beta-agonists such as Berodual N, metered-dose aerosol. Home treatment may also be recommended for patients who require nebulization for other reasons (e.g., problems with aerosol administration). Or to obtain higher doses for patients who are familiar with nebulization. Therapy should always be initiated at the lowest recommended dose.
The dose should be selected individually depending on the severity of the acute episode.
Use should be discontinued when symptom relief is achieved.
The inhalation solution is intended for inhalation only using a suitable nebulizer and should not be taken orally.
For administration, the recommended dose should be diluted with saline (0.9%) to a final volume of 3–4 ml. The diluted, ready-to-use solution should be inhaled until sufficient relief of symptoms is achieved.
It is recommended to inhale the nebulized solution through the mouthpiece, intended for use with a nebulizer. If a mouthpiece is not available, a mask that fits tightly to the face should be used. Patients with a predisposition to glaucoma should take special care to protect their eyes.
BERODUAL inhalation solution can be used with different models of nebulizers. The total dose and the dose reaching the lungs depend on the nebulizer used and may be higher than with BERODUAL N aerosol, depending on the efficiency of the device.
Recommended dosage regimens
Adults and children aged 12 and over.
Emergency treatment of sudden attacks of bronchospasm.
Depending on the severity of the acute attack, 1.0-2.5 ml of BERODUAL is used after dilution with saline to a volume of 3-4 ml.
In exceptionally severe cases, up to 4 ml of BERODUAL can be used after diluting with saline to a volume of 3-4 ml.
For the prevention of asthma caused by physical exertion or suspected allergic contact, 0.1-0.2 ml of BERODUAL diluted in 2-3 ml of saline is used, if possible, 10-15 minutes before the incident.
Children aged 6 – 12 years.
Emergency treatment of acute asthma attacks.
Depending on the severity of the acute attack and the patient's age, 0.5-2.0 ml of BERODUAL is used after dilution with saline to a volume of 3-4 ml.
For the prevention of asthma caused by physical exertion or suspected allergic contact, 0.1-0.2 ml of BERODUAL diluted in 2-3 ml of saline is used, if possible, 10-15 minutes before the incident.
Children under 6 years of age (weighing less than 22 kg).
Given that information on the use of the drug in this age group is limited, it is recommended to use the drug in the following dose only under medical supervision of the patient's condition:
0.1 ml per 1 kg of body weight (maximum up to 0.5 ml) per dose after dilution with saline to a volume of 3-4 ml.
BERODUAL inhalation solution cannot be diluted with distilled water.
BERODUAL is suitable for concomitant inhalation with LAZOLVAN, a solution for inhalation and oral administration.
Children.
BERODUAL is used in pediatric practice. Children under 6 years of age are prescribed the drug only under medical supervision of the patient's condition.
Overdose
Symptoms.
Depending on the duration of the overdose, the following adverse reactions typical of beta-2-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 complaints, 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.
It is recommended to monitor cardiac activity, namely ECG.
Adverse reactions
Most of the undesirable effects listed below can be attributed to the anticholinergic and beta-adrenergic properties of BERODUAL.
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 Convention:
very common (≥ 1/10);
common (≥ 1/100, < 1/10);
uncommon (≥ 1/1,000, < 1/100);
rare (≥ 1/10,000, < 1/1,000);
rare (<1/10,000);
unknown (cannot be determined from available data).
On the part of the immune system:
rare – anaphylactic reactions*, hypersensitivity*;
unknown – purpura.
Metabolic disorders:
rare – hypokalemia;
rare - increased blood glucose levels.
Mental disorders:
infrequent – nervousness;
isolated – agitation, mental changes.
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:
infrequent – 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 before the eyes*.
infrequent – tachycardia, rapid heartbeat;
rare – arrhythmias, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia*;
unknown - anginal pain, ventricular extrasystole.
On the part of the respiratory system:
frequent – cough;
uncommon – pharyngitis, dysphonia;
rare – bronchospasm, throat irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm (induced by inhalation)*, dry throat*;
unknown – local irritation.
From the digestive system:
infrequent - nausea, vomiting, dry mouth;
rare – stomatitis, glossitis, gastrointestinal motility disorders**, diarrhea, constipation*, swelling of the oral mucosa*, heartburn.
From the skin and subcutaneous tissue:
rare - urticaria, rash, itching, angioedema*, petechiae, hyperhidrosis*.
Musculoskeletal and connective tissue disorders:
isolated - muscle weakness, muscle spasm, myalgia.
From the urinary system:
isolated cases – urinary retention.
Research results:
uncommon – increased systolic blood pressure;
rare – decreased diastolic blood pressure, thrombocytopenia.
* Adverse reactions not observed in any clinical trial of BERODUAL. 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 preparation of 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 components (which are contained in BERODUAL).
As with other inhalation therapy medicinal products, BERODUAL 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
5 years.
Storage conditions
Store in original packaging at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Packaging
20 or 40 ml in a bottle with a dropper; 1 bottle in a cardboard box.
Vacation category
According to the recipe.
Producer
Istituto De Angeli Srl, Italy.
Location of the manufacturer and its address of the place of implementation of the activity
Localita Prulli 103/c - 50066 Reggello (Firenze), Italy/Localita Prulli 103/c - 50066 Reggello (Florence), Italy.
