Berodual® n

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BERODUAL® N (BERODUAL® N)

Composition:

Active substances: ipratropium bromide, fenoterol hydrobromide;

1 inhalation contains ipratropium bromide monohydrate 21 mcg, equivalent to anhydrous ipratropium bromide 20 mcg; fenoterol hydrobromide 50 mcg;

Excipients: norflurane (propellant), anhydrous citric acid, anhydrous ethanol, purified water.

Excipient with known effect: this medicinal product contains 14 mg of alcohol (ethanol) per inhalation.

Pharmaceutical form. Metered dose aerosol.

Main physicochemical properties: clear, colorless or slightly yellowish, or slightly brownish liquid, free from suspended particles.

Pharmacotherapeutic group. Drugs for treatment of obstructive airway diseases. Adrenergic agents in combination with anticholinergic agents. Fenoterol and ipratropium bromide. ATC code R03AL01.

Pharmacological properties.

Pharmacodynamics

Berodual N contains two active bronchodilator ingredients: ipratropium bromide, which has an anticholinergic effect, and fenoterol hydrobromide, a beta-adrenergic agonist.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it inhibits vagal reflexes through antagonistic interaction with acetylcholine, the neurotransmitter responsible for vagus nerve impulse transmission. Anticholinergic agents prevent the increase in intracellular Ca++ concentration caused by acetylcholine binding to muscarinic receptors on bronchial smooth muscle. The release of Ca++ is mediated by a second messenger system consisting of IP3 (inositol trisphosphate) and DAG (diacylglycerol). Bronchodilation following inhaled ipratropium bromide is primarily due to a local, specific action of the drug, rather than a systemic effect.

Fenoterol hydrobromide is a direct-acting sympathomimetic that selectively stimulates beta2-adrenergic receptors within the therapeutic dose range. Stimulation of beta1-adrenergic receptors occurs only at higher doses. Binding to beta2-adrenergic receptors activates adenylate cyclase via a stimulatory Gs-protein. Increased levels of cyclic AMP lead to activation of protein kinase A and phosphorylation of target proteins in smooth muscle cells. This results in phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and opening of specific calcium-activated potassium channels.

Fenoterol hydrobromide induces relaxation of bronchial and vascular smooth muscles and protects against bronchoconstrictor stimuli such as histamine, methacholine, cold air, and allergens (immediate-type reactions). After administration, fenoterol inhibits the release of bronchoconstrictor and pro-inflammatory mediators from mast cells. Following fenoterol administration at a dose of 0.6 mcg, an increase in mucociliary clearance has been observed.

At higher plasma concentrations of fenoterol—more commonly achieved with oral administration and even more so with intravenous administration—a reduction in uterine contractility has been noted. Metabolic effects observed at high doses include lipolysis, glycogenolysis, hyperglycemia, and hypokalemia, the latter due to increased uptake of K+ ions, primarily into skeletal muscle. Beta-adrenergic effects of fenoterol on the heart, such as increased heart rate and cardiac frequency, are caused by vascular effects of fenoterol, stimulation of cardiac beta2-adrenergic receptors, and, at supratherapeutic doses, stimulation of beta1-adrenergic receptors. As with other beta-adrenergic agents, QTc interval prolongation has been observed. For fenoterol in metered-dose aerosol form, these effects were discrete and occurred only at doses exceeding the recommended levels. However, systemic effects of fenoterol after nebulizer use (solution for inhalation) may be greater than those observed with recommended doses of metered-dose aerosol. Clinical significance has not been established. Tremor is the most commonly observed side effect of beta-agonists. Unlike the effect on bronchial smooth muscle, systemic effects of beta-mimetics on skeletal muscle lead to the development of tolerance.

When these two active ingredients are used concomitantly, bronchodilation occurs through two distinct pharmacological mechanisms. Thus, the two active substances exert a combined spasmolytic effect on bronchial smooth muscle, allowing broad application in respiratory diseases associated with impaired airway patency. Effective combined action requires only a very small amount of beta-mimetic, enabling individual dose titration for each patient with reduced incidence of adverse effects.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is exerted via local action on the respiratory tract. Therefore, the pharmacodynamics of bronchodilation are not related to the pharmacokinetics of the active ingredients.

After inhalation, approximately 10–39% of the administered dose deposits in the lungs, depending on the formulation, inhalation technique, and delivery device. The remainder remains in the inhaler mouthpiece, mouth, and upper respiratory tract (oropharynx). A similar proportion of the dose deposits in the airways after inhalation of the metered-dose aerosol. Specifically, inhalation of the aqueous solution via the Respimat inhaler results in more than twice the amount of drug deposited in the lungs compared to the metered-dose aerosol. Consequently, the amount deposited in the oropharynx is reduced and significantly lower with the Respimat inhaler compared to the metered-dose aerosol. The portion of the dose deposited in the lungs is rapidly absorbed into the systemic circulation (within minutes). The portion deposited in the oropharynx is slowly swallowed and passes through the gastrointestinal tract. Therefore, systemic exposure is a function of both oral and pulmonary bioavailability.

There is no evidence that the pharmacokinetics of the combination differ from those of the individual components.

Fenoterol hydrobromide. The swallowed portion of the drug is primarily metabolized to sulfate conjugates. Absolute bioavailability after oral administration is low (approximately 1.5%).

After intravenous administration, free fenoterol and conjugated fenoterol account for 15% and 27% of the administered dose, respectively, in cumulative 24-hour urine. After inhalation via the metered-dose aerosol of BERODUAL N, approximately 1% of the inhaled dose is excreted as free fenoterol in 24-hour urine. Based on this, the total systemic bioavailability of inhaled fenoterol hydrobromide is estimated to be 7%.

Kinetic parameters characterizing fenoterol disposition were calculated based on plasma fenoterol concentrations after intravenous administration. After intravenous dosing, the plasma concentration-time profile can be described by a three-compartment model, with an elimination half-life of approximately 3 hours. According to this model, the steady-state volume of distribution (Vdss) of fenoterol is approximately 189 L (≈ 2.7 L/kg).

Approximately 40% of the drug is protein-bound in plasma. Preclinical studies in rats showed that fenoterol and its metabolites do not cross the blood-brain barrier. Total fenoterol clearance is 1.8 L/min, with renal clearance at 0.27 L/min.

In an excretion balance study, total renal clearance (over 2 days) of radiolabeled drug (including parent compound and all metabolites) accounted for 65% of the dose after intravenous administration, while 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. Cumulative renal excretion (0–24 hours) of ipratropium (parent compound) was approximately 46% of the intravenously administered dose, less than 1% after oral administration, and approximately 3–13% after inhalation via the metered-dose inhaler BERODUAL N. Based on these data, total systemic bioavailability of ipratropium bromide after oral and inhaled administration is estimated at 2% and 7–28%, respectively. Therefore, the swallowed portion of ipratropium bromide has minimal impact on systemic effects.

Kinetic parameters characterizing ipratropium disposition were calculated based on plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentration is observed. The steady-state volume of distribution (Vdss) is approximately 176 L (≈ 2.4 L/kg). The drug binds minimally to plasma proteins (less than 20%). Preclinical studies in rats and dogs 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, with renal clearance at 0.9 L/min. After intravenous administration, approximately 60% of the dose is metabolized, likely primarily in the liver via oxidation.

In an excretion balance study, total renal clearance (over 6 days) of radiolabeled drug (including parent compound and all metabolites) was 72.1% of the dose after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation. Total radioactivity in feces was 6.3% of the dose after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation. The primary route of elimination of radiolabeled drug after intravenous administration is renal. The elimination half-life of total radioactivity (parent compound and all metabolites) is 3.6 hours. Binding of major urinary metabolites to muscarinic receptors is negligible, and metabolites are considered inactive.

Clinical characteristics.

Indications.

Prophylaxis and symptomatic treatment of dyspnea in chronic obstructive airway 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, hypertonic saline solutions, cromoglycic acid, and antibiotics.

In cases requiring long-term treatment, it must always be accompanied by anti-inflammatory therapy.

Contraindications.

BERODUAL N is contraindicated in patients with known hypersensitivity to fenoterol hydrobromide and/or ipratropium bromide, substances similar to atropine, or to any other components of the medicinal product; in patients with hypertrophic obstructive cardiomyopathy and tachyarrhythmia.

Interaction with other medicinal products and other forms of interactions.

Chronic concomitant use of BERODUAL N with other anticholinergic agents has not been studied and is therefore not recommended.

Concomitant administration of the following medicinal products/classes of medicinal products may affect the effect of BERODUAL N.

Enhanced effect and/or increased risk of adverse reactions:

• 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). In particular, they may potentiate cardiovascular effects.

Reduced effect:

• concomitant administration of beta-blockers.

Other possible interactions:

Hypokalemia associated with the use of beta2-agonists may be potentiated by concomitant treatment with xanthine derivatives, glucocorticosteroids, and diuretics. This should be given special attention in the treatment of patients with severe airway obstruction.

Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. In addition, hypoxia may potentiate the negative effects of hypokalemia on cardiac rhythm. In such cases, monitoring of serum potassium levels is recommended.

The risk of acute glaucoma attack (see section "Special precautions") is increased both by the accidental exposure of nebulized ipratropium to the eyes and by its combination with beta2-agonists.

Treatment with BERODUAL N may also reduce the hypoglycemic effect of antidiabetic medicinal products. However, this is expected only at high doses, typically used for systemic administration (tablets or injections/infusions).

If inhalational anesthetics are planned, it should be noted that fenoterol administration should be discontinued at least 6 hours prior to the start of anesthesia.

Special precautions for use

In case of acute dyspnea (difficulty breathing) that progresses rapidly, patients should be warned to seek immediate medical attention.

Like other inhaled medicinal products, BERODUAL N may cause paradoxical bronchospasm, which can be life-threatening. If paradoxical bronchospasm occurs, BERODUAL N must be discontinued immediately and alternative therapy initiated.

Conditions in which BERODUAL N should be used only after careful risk-benefit assessment, especially if the dose exceeds the recommended one:

• poorly controlled diabetes mellitus;
• recent myocardial infarction;
• myocarditis;
• severe organic heart or vascular disease (particularly in the presence of tachycardia);
• hyperthyroidism;
• pheochromocytoma;
• patients receiving cardiac glycosides;
• severe and untreated hypertension;
• aneurysm.

When using sympathomimetic medicinal agents, including BERODUAL N, cardiovascular effects may occur. Evidence from post-marketing data and scientific publications indicates isolated cases of myocardial ischemia associated with beta-agonists. Patients with underlying severe cardiac disease (e.g., ischemic heart disease, arrhythmia, or severe heart failure) who are receiving BERODUAL N should be advised to seek medical help if they experience chest pain or other symptoms indicating worsening cardiac function. Careful evaluation of symptoms such as dyspnea and chest pain is essential, as they may be of respiratory or cardiac origin.

BERODUAL N, like other anticholinergic agents, should be used with caution in:

• patients predisposed to narrow-angle glaucoma;
• patients with existing urinary tract obstruction (e.g., benign prostatic hyperplasia or intravesical obstruction);
• patients with renal impairment;
• patients with hepatic impairment.

There have been reports of isolated cases of ocular complications (such as mydriasis, increased intraocular pressure, narrow-angle glaucoma, eye pain) resulting from accidental exposure of ipratropium bromide aerosol or its combination with beta2-adrenergic agonists to the eyes.

Caution! Patients must be thoroughly instructed on the correct use of the metered-dose inhaler BERODUAL N. Care should be taken to avoid spraying the medication into the eyes.

Symptoms of acute narrow-angle glaucoma include:

• eye pain or discomfort;
• blurred vision;
• perception of halos;
• perception of colored spots before the eyes;
• eye redness due to conjunctival or corneal hyperemia.

If any combination of the above symptoms occurs, treatment with miotic eye drops should be initiated immediately and specialized medical help sought without delay.

Patients with cystic fibrosis may be more susceptible to gastrointestinal motility disorders when using inhaled anticholinergic agents. Symptoms usually resolve after discontinuation of therapy.

Long-term use

• BERODUAL N should be used on an as-needed basis in patients with bronchial asthma. In patients with mild forms of COPD, as-needed treatment (symptomatic therapy) may be more appropriate than regular use, depending on clinical circumstances.
• It is important to remember the need for initiating or intensifying anti-inflammatory therapy to control airway inflammation and prevent worsening symptom control in patients with bronchial asthma or steroid-dependent forms of COPD.

Regular use of increased doses of drugs containing beta2-agonists, such as BERODUAL N, to relieve symptoms of bronchial obstruction in patients with bronchial asthma may lead to worsening disease control.

In cases of worsening bronchial obstruction, simply increasing the dose of beta2-agonists, including BERODUAL N, over a prolonged period beyond the recommended dose is not only unjustified but also dangerous. In such cases, to prevent potentially life-threatening deterioration, the patient's treatment plan should be re-evaluated, particularly the adequacy of anti-inflammatory therapy with inhaled corticosteroids, and the dose of existing anti-inflammatory therapy adjusted or additional agents prescribed.

There have been reports of several cases of increased risk of serious complications of the underlying disease, including fatalities, associated with long-term treatment of bronchial asthma using high and excessively high doses of inhaled beta2-sympathomimetics without adequate anti-inflammatory therapy. A causal relationship has not been fully established. However, inadequate anti-inflammatory therapy is considered critically important.

Other sympathomimetic bronchodilators should be used concomitantly with BERODUAL N only under medical supervision (see section "Interaction with other medicinal products and other forms of interaction").

Excessive therapy with beta2-agonists may lead to potentially serious hypokalemia (see section "Overdose"). Serum potassium levels should be monitored in patients with low baseline potassium levels. Increased blood glucose levels may also occur. Therefore, blood glucose levels should be monitored in diabetic patients.

Rarely, immediate hypersensitivity reactions such as urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and anaphylactic reactions may occur after administration of BERODUAL N.

The medicinal product contains 14 mg of alcohol (ethanol) per inhalation. The amount of alcohol in each inhalation is equivalent to less than 1 ml of beer or 1 ml of wine. The small amount of alcohol in this medicinal product is not expected to have noticeable effects.

Note for athletes: Use of BERODUAL N may result in a positive doping test.

Use during pregnancy or breastfeeding

Pregnancy. Preclinical data, combined with human experience, do not indicate adverse effects of fenoterol and ipratropium on pregnancy. However, precautionary measures related to drug use during pregnancy should be observed.

It should be remembered that fenoterol has an inhibitory effect on uterine contractility. Use of beta2-sympathomimetics at the end of pregnancy or in high doses may adversely affect the neonate (tremor, tachycardia, fluctuations in blood glucose levels, hypokalemia).

Breastfeeding. Preclinical studies have shown that fenoterol passes into breast milk. There are no data on the passage of ipratropium into breast milk. It is unlikely, especially with the use of the aerosol formulation, that ipratropium would significantly affect the infant. BERODUAL N should be used with caution during breastfeeding.

Fertility. Clinical data on the effect on fertility are lacking for both the combination of ipratropium bromide and fenoterol hydrobromide and for each component individually. Preclinical studies on the separate use of ipratropium bromide and fenoterol hydrobromide showed no adverse effects on fertility.

Ability to affect reaction speed when driving or operating machinery

No studies on the effect of the medicinal product on the ability to drive a car or operate machinery have been conducted. However, patients should be warned about possible adverse reactions such 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 such adverse reactions occur, patients should avoid potentially hazardous activities, such as driving or operating technical equipment.

Method of Administration and Dosage.

The dosage should be adjusted according to the nature and severity of the disease. The following dosage regimens are recommended for adults and children aged 6 years and older:

For the relief of acute bronchospasm and acute episodes of breathlessness, an inhaled dose of 100 mcg fenoterol hydrobromide and 40 mcg ipratropium bromide (2 inhalations) is recommended. Generally, 1 inhalation is sufficient to rapidly alleviate breathing difficulties during an acute attack. If breathing does not significantly improve within 5 minutes after 1–2 inhalations, an additional 1–2 inhalations may be administered. If no improvement occurs after a total of 4 inhalations, additional medical measures may be required. In such cases, the patient must seek immediate medical attention.

If long-term treatment with BEROdual N is indicated, the recommended dosage is 1–2 inhalations 3–4 times daily. For asthma treatment, the BEROdual N metered-dose aerosol should be used only as needed. In general, the timing and dosage of each inhalation should be determined based on symptom severity. At least a 3-hour interval should be maintained between inhalations. The total daily dose should not exceed 12 inhalations, as higher doses do not provide additional therapeutic benefit but may increase the risk of potentially severe adverse reactions.

To prevent asthma attacks triggered by physical exertion or anticipated exposure to allergens, 2 inhalations should be administered, if possible, 10–15 minutes before the triggering event.

Patients must be instructed on the correct use of the metered-dose aerosol to ensure effective treatment (see Instructions for Use).

Instructions for Use.

Proper use of the metered-dose aerosol is essential for successful treatment. Patients must be instructed on the correct use of the metered-dose aerosol. During inhalation, the arrow on the canister should point straight upward and the mouthpiece downward, regardless of the inhalation position. Use while sitting or standing, if possible.

Before the first use of the metered-dose aerosol: remove the protective cap and press the valve twice.

Before each use of the metered-dose aerosol:

1. Remove the protective cap (Fig. 1).

If the metered-dose aerosol canister has not been used for more than 3 days, press the valve once before use.

Fig. 1  Fig. 2

1. Breathe out deeply.
2. Holding the inhaler as shown in Fig. 2, place the mouthpiece between your lips. The arrow on the canister must point upward and the mouthpiece downward.
3. Breathe in as deeply as possible, simultaneously pressing down fully on the canister to release 1 (one) metered dose. Hold your breath for several seconds, then remove the mouthpiece from your mouth and breathe out slowly.
4. After use, replace the protective cap.

Patients must be instructed on the correct use of the metered-dose aerosol. If the metered-dose aerosol canister has not been used for more than 3 days, press the valve once before use. Avoid spraying the medication into the eyes. BEROdual N metered-dose aerosol should be used in children only on medical advice and under adult supervision.

Clean the inhaler mouthpiece at least once a week. It is important to keep the inhaler mouthpiece clean to ensure that the medication does not clog and nothing obstructs the aerosol flow. To clean the inhaler, first remove the dust cap and detach the canister from the inhaler. Rinse the inhaler thoroughly with water until all residue and/or dirt is completely removed (Fig. 3).

Fig. 3  Fig. 4

After cleaning, shake the inhaler and allow it to air-dry without using any heating device. When the mouthpiece is dry, reattach the canister and dust cap (Fig. 4).

WARNING: The mouthpiece is specifically designed for BEROdual N metered-dose aerosol.

The mouthpiece must not be used with any other metered-dose aerosols. The specially designed mouthpiece may only be used with BEROdual N. The canister contents are under pressure. Do not open the canister by force.

The canister is opaque, so it is not possible to see when it is empty. The aerosol canister is designed to deliver 200 doses. When all doses have been used, a small amount of liquid may remain in the canister. However, the canister must be replaced at this point, as accurate dosing can no longer be guaranteed.

The approximate amount of medication remaining in the aerosol canister can be checked as follows:

• Shake the canister and check for the presence of liquid;
• Detach the plastic mouthpiece from the canister and place the canister in a container of water. The level of medication in the aerosol canister can be estimated by its position in the water (see Fig. 5).

Fig. 5.

Any unused product or waste material must be disposed of properly.

Children.

Use in children aged 6 years and older only as prescribed by a physician and under adult supervision.

Overdose.

Symptoms.

Depending on the duration of overdose, adverse reactions typical of beta2-adrenergic agents may occur: flushing, dizziness, headache, tachycardia, palpitations, arrhythmia, hypotension or even shock, arterial hypertension, restlessness, chest pain, excitement, possible extrasystoles, and pronounced tremor in the fingers and throughout the body. Hyperglycemia may develop.

Gastrointestinal disturbances, including nausea and vomiting, may occur, especially after oral overdose.

When fenoterol is administered in doses higher than recommended for BEROdual N indications, metabolic acidosis and hypokalemia have been observed.

Symptoms of ipratropium bromide overdose (dry mouth, visual accommodation disturbances) are mild due to the very low systemic bioavailability of inhaled ipratropium.

Treatment. Treatment with BEROdual N must be discontinued. Acid-base balance and electrolyte monitoring should be considered.

Administration of sedatives and tranquilizers; in severe cases, intensive supportive therapy, which may include hospitalization. Beta-adrenoreceptor blockers (preferably beta1-selective) may be used as specific antidotes for fenoterol; however, the potential for increased bronchial obstruction caused by beta-blockers must be taken into account, and dosage must be carefully selected in patients with bronchial asthma or COPD due to the risk of acute bronchospasm, which may be fatal.

Cardiac monitoring, particularly ECG, is recommended.

Adverse Reactions

Adverse reactions may occur during the use of BEROBUAL N, as with all medicinal products.

Most of the adverse effects listed below can be attributed to the anticholinergic and beta-adrenergic properties of BEROBUAL N.

The adverse reactions associated with this medicinal product are based on data obtained from clinical trials and post-marketing pharmacovigilance.

Frequency according to MedDRA:

very common (≥ 1/10)
common (≥ 1/100, < 1/10)
uncommon (≥ 1/1,000, < 1/100)
rare (≥ 1/10,000, < 1/1,000)
very rare (<1/10,000)
not known (cannot be estimated from the available data)

Immune system disorders:

rare – anaphylactic reactions*, hypersensitivity*;
not known – purpura.

Metabolism and nutrition disorders:

rare – hypokalaemia*;
very rare – increased blood glucose levels.

Psychiatric disorders:

uncommon – nervousness;
rare – agitation, psychiatric disorders.

Psychiatric disorders may manifest as increased excitability, hyperactive behaviour, sleep disturbances, and hallucinations. These have been observed primarily in children under 12 years of age.

Nervous system disorders:

uncommon – headache, tremor, dizziness;
not known – hyperactivity.

Eye disorders:

rare – glaucoma*, increased intraocular pressure*, accommodation disorders*, mydriasis*, blurred vision*, eye pain*, corneal oedema*, conjunctival hyperaemia*, appearance of halos around lights*.

Cardiac disorders:

uncommon – tachycardia, palpitations;
rare – arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischaemia*;
not known – angina pectoris, ventricular extrasystoles.

Respiratory, thoracic and mediastinal disorders:

common – cough;
uncommon – pharyngitis, dysphonia;
rare – bronchospasm, throat irritation, pharyngeal oedema, laryngospasm*, paradoxical bronchospasm (induced by inhalation)*, dryness of the throat*;
not known – local irritation.

Gastrointestinal disorders:

uncommon – vomiting, nausea, dry mouth;
rare – stomatitis, glossitis, gastrointestinal motility disorders**, diarrhoea, constipation*, oedema of the oral cavity*, heartburn.

Skin and subcutaneous tissue disorders:

rare – urticaria, rash, pruritus, angioneurotic oedema*, petechiae, hyperhidrosis*.

Musculoskeletal and connective tissue disorders:

rare – muscle weakness, muscle spasms, myalgia.

Renal and urinary disorders:

rare – urinary retention.

Investigations:

uncommon – increased systolic blood pressure;
rare – decreased diastolic blood pressure, thrombocytopenia.

* Adverse reactions not observed in any clinical trial. Frequency is based on the upper limit of the 95% confidence interval calculated from the total number of patients treated, according to EU guidelines for the summary of product characteristics (3/4968 = 0.0006, indicating "rare" reactions).

** Patients with cystic fibrosis may be particularly susceptible to gastrointestinal motility disorders when using inhaled anticholinergic medicinal products (such as those contained in BEROBUAL N).

As with other inhaled therapies, BEROBUAL N may cause symptoms of local irritation. The most commonly reported adverse reactions in clinical trials were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure, and nervousness.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C, in a place inaccessible to children. Protect from direct sunlight, heat, and frost.

Packaging. 10 ml (200 inhalations) in an aluminium pressurized canister with a metering valve.

One canister per cardboard box.

Prescription status. Prescription only.

Manufacturer. Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.

Manufacturer's address and place of business.

Binger Strasse 173, 55216 Ingelheim am Rhein, Germany.