Berodual®

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

Composition:

Active substances: ipratropium bromide, fenoterol hydrobromide;

1 ml (20 drops) of inhalation solution contains ipratropium bromide monohydrate 261 µg, equivalent to 250 µg of anhydrous ipratropium bromide; fenoterol hydrobromide 500 µg;

Excipients: benzalkonium chloride, disodium edetate, sodium chloride, concentrated hydrochloric acid, purified water.

Excipient with known effect: benzalkonium chloride (100 µg/ml, corresponding to 10 µg per inhalation) (see section "Special precautions for use").

Pharmaceutical form. Inhalation solution.

Main physicochemical characteristics: clear, colorless or almost colorless liquid, free from suspended particles, with a barely perceptible odor.

Pharmacotherapeutic group.

Drugs for the treatment of obstructive respiratory tract diseases. Adrenergic agents in combination with anticholinergic agents.

ATC code R03AL01.

Pharmacological Properties

Pharmacodynamics

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

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (antimuscarinic) properties. Preclinical studies have shown that it inhibits vagal reflexes through competitive antagonism 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 involving IP3 (inositol trisphosphate) and DAG (diacylglycerol).

Bronchodilation following inhaled ipratropium bromide is primarily due to local, site-specific action rather than systemic effects.

Fenoterol hydrobromide is a direct-acting sympathomimetic agent 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 cyclic AMP levels 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 calcium-dependent 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 bronchoconstrictive and pro-inflammatory mediators from mast cells. Additionally, following a 0.6 mg dose of fenoterol, increased mucociliary clearance has been observed.

At higher plasma concentrations—more commonly achieved with oral or even more frequently with intravenous administration—fenoterol suppresses uterine contractility. Metabolic effects observed with higher doses include lipolysis, glycogenolysis, hyperglycemia, and hypokalemia, the latter resulting from enhanced potassium ion uptake, primarily into skeletal muscle. Beta-adrenergic cardiac effects of fenoterol, such as increased heart rate and pulse rate, are due to vascular effects of fenoterol, stimulation of cardiac beta2-receptors, and, at supratherapeutic doses, stimulation of beta1-receptors. As with other beta-adrenergic agents, QTc interval prolongation may occur. With fenoterol in metered-dose aerosol form, these effects have been minimal and observed only at doses exceeding recommendations. However, systemic effects of fenoterol (solution for inhalation) after administration via nebulizer may be greater than with recommended doses of metered-dose aerosol. Clinical significance remains undetermined. Tremor is the most commonly observed beta-agonist effect. In contrast to its effect on bronchial smooth muscle, systemic beta-mimetic effects on skeletal muscle lead to the development of tolerance.

When these two active ingredients are used together, 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 airway obstruction. For effective combined action, only a small amount of beta-mimetic is required, enabling individual dose adjustment for each patient and reducing the incidence of adverse effects.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is achieved through local action on the airways. Therefore, the pharmacodynamics of bronchodilation are not directly related to the pharmacokinetics of the active ingredients.

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

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

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

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

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

Approximately 40% of the drug is protein-bound in plasma. Preclinical studies in rats indicate 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 excretion balance studies, total renal excretion (over 2 days) of radioactivity (including parent compound and all metabolites) accounted for 65% of the dose after intravenous administration, while fecal excretion of radioactivity accounted for 14.8% of the dose. After oral administration, total urinary excretion of radioactivity was approximately 39% and fecal excretion 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. 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 is unlikely to contribute significantly to systemic effects.

Kinetic parameters characterizing ipratropium disposition were calculated from 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 is minimally bound 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 excretion balance studies, total renal excretion (over 6 days) of radioactivity (including parent compound and all metabolites) accounted for 72.1% of the dose after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation. Fecal excretion of radioactivity 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 radioactivity after intravenous administration is renal. The elimination half-life of radioactivity (parent compound and all metabolites) is 3.6 hours. Binding of major metabolites in urine to muscarinic receptors is negligible, and metabolites are considered pharmacologically inactive.

Clinical characteristics.

Indications.

Prevention and treatment of dyspnea in chronic obstructive respiratory diseases: allergic and non-allergic (endogenous) bronchial asthma; exercise-induced asthma; and chronic obstructive bronchitis with and without emphysema.

If long-term treatment is required, it must always be accompanied by anti-inflammatory therapy.

Contraindications.

BERODUAL 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 or tachyarrhythmia.

Interaction with other medicinal products and other types of interactions.

Concomitant chronic use of BERODUAL 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 efficacy of BERODUAL.

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, these may potentiate cardiovascular effects.

Reduced effect:

• concomitant administration of beta-blockers.

Other possible interactions:

Hypokalemia associated with the use of beta-mimetics may be intensified by concomitant treatment with xanthine derivatives, glucocorticosteroids, and diuretics. This should be given particular attention in 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 for use") is increased both by inadvertent ocular exposure to aerosolized ipratropium and by its use in combination with beta2-agonists.

Treatment with BERODUAL may also reduce the hypoglycemic effect of antidiabetic medicinal products. However, this is expected only at high doses, typically used for systemic administration (in tablet form or by injection/infusion).

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

Special precautions for use.

In case of acute dyspnea (difficulty breathing) that rapidly progresses, immediate medical attention should be sought.

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

BEROQUA should be used only after careful risk/benefit assessment in the following conditions, especially if doses exceed the recommended ones:

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

Cardiovascular effects may occur with the use of sympathomimetic medicinal agents, including BEROQUA. Post-marketing data and literature publications report 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) receiving BEROQUA should be advised to seek medical help if they experience chest pain or other symptoms indicating worsening cardiac function. Symptoms such as dyspnea and chest pain should be carefully evaluated, as they may be of respiratory or cardiac origin.

BERODUAL, 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 ocular 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-adrenergic agonists.

Caution! Patients must be thoroughly instructed on the proper use of BERODUAL, solution for inhalation. 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;
• seeing halos around lights;
• 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 resolve after discontinuation of treatment.

Long-term use.

• Patients with bronchial asthma should use BEROQUA only as needed. For patients with mild forms of chronic obstructive pulmonary disease (COPD), "on-demand" treatment (symptomatic therapy) may be more appropriate than regular use.
• It is important to remember the need for initiating or intensifying anti-inflammatory therapy to control airway inflammation and prevent symptom worsening in patients with bronchial asthma or steroid-dependent forms of COPD.

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

If bronchial obstruction worsens, simply increasing the dose of beta2-agonists—including BERODUAL—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 reviewed, particularly the adequacy of anti-inflammatory therapy with inhaled corticosteroids. The dose of existing anti-inflammatory therapy should be adjusted or additional medications added.

There have been reports of increased risk of serious complications of the underlying disease, including fatalities, in patients with bronchial asthma treated long-term with high or 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 a life-threatening risk factor.

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

Hypokalemia, potentially serious, may occur with high-dose beta2-agonist therapy (see section "Overdose"). Monitoring of serum potassium levels is recommended in patients with initially low 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 allergic reactions may occur after BERODUAL administration.

The medicinal product contains the preservative benzalkonium chloride (100 µg/mL). Benzalkonium chloride may cause bronchospasm, particularly in patients with asthma.

Note for athletes. Use of BERODUAL may lead to positive doping test results.

Use during pregnancy or breastfeeding.

Pregnancy. Preclinical data and available human experience do not indicate harmful effects of fenoterol and ipratropium on pregnancy. However, standard precautions for drug use during pregnancy should be observed. The uterine inhibitory effect of fenoterol should be considered. Use of beta2-sympathomimetics at the end of pregnancy or in high doses may adversely affect the neonate (tremor, tachycardia, blood glucose fluctuations, hypokalemia).

Breastfeeding. Preclinical studies indicate that fenoterol hydrobromide passes into breast milk. Data on the passage of ipratropium into breast milk are lacking. It is unlikely that ipratropium reaches the infant in significant amounts, especially when administered by inhalation. BERODUAL should be used with caution in breastfeeding women.

Fertility. Data on the effects of combined or individual use of ipratropium bromide and fenoterol hydrobromide on fertility are lacking. Preclinical studies with the individual components—ipratropium bromide and fenoterol hydrobromide—showed no adverse effects on fertility.

Ability to influence reaction speed while driving or operating machinery.

No studies on the effect of the medicinal product on the ability to drive or operate machinery have been conducted. However, patients should be warned about the possible occurrence of adverse reactions such as dizziness, tremor, accommodation disorders, mydriasis, and blurred vision during BERODUAL use. Caution should be exercised when driving or operating machinery. If such adverse reactions occur, patients should avoid potentially hazardous activities, including driving or operating technical equipment.

Method of Administration and Dosage

For inhalation only using a nebulizer.

Treatment should be initiated and conducted under medical supervision, for example, in a hospital setting.

Home treatment, following consultation with an experienced physician, may be recommended for patients in whom low-dose, short-acting beta-agonists such as Berodual N, metered-dose aerosol, have been insufficient to relieve symptoms. Home treatment may also be recommended for patients requiring a nebulizer for other reasons (e.g., difficulty using aerosols) or for patients requiring higher doses who are familiar with nebulizer use. Therapy should always be initiated with the lowest recommended dose.

The dose should be individually adjusted according to the severity of the acute episode.

Treatment should be discontinued once symptom relief is achieved.

The inhalation solution is intended solely for inhalation via a suitable nebulizer and must not be taken orally.

For administration, the recommended dose of BERODUAL must be diluted with physiological saline (0.9%) to a final volume of 3–4 mL. The diluted, ready-to-use solution should be inhaled until adequate symptom relief is achieved.

The diluted, ready-to-use solution must be freshly prepared each time before use. The prepared solution should be used immediately after preparation; any remaining diluted solution must be discarded. Patients must follow the manufacturer's instructions for the nebulizer.

The nebulized solution intended for nebulizer use must be inhaled through a mouthpiece. If a mouthpiece is not available, a face mask that fits snugly over the face should be used. Patients predisposed to developing glaucoma should take particular care to protect their eyes.

BERODUAL inhalation solution can be used with various nebulizer models. Pulmonary and systemic exposure to the drug depends on the nebulizer used and may be higher than with BERODUAL N aerosol, depending on the device efficiency.

Recommended Dosage Regimens

Adults and children aged 12 years and older.

Acute treatment of sudden bronchospasm attacks.

Depending on the severity of the acute attack, 10–25 inhalations (1.0–2.5 mL) of BERODUAL, diluted with physiological saline to a volume of 3–4 mL, should be administered.

In exceptionally severe cases, up to 40 inhalations (4.0 mL) of BERODUAL, diluted with physiological saline to a volume of 3–4 mL, may be used.

For prevention of exercise-induced asthma or anticipated allergic exposure, 1–2 inhalations (0.1–0.2 mL) of BERODUAL, diluted with 2–3 mL of physiological saline, should be administered, if possible, 10–15 minutes before the event.

Children aged 6–12 years.

Acute treatment of asthma attacks.

Depending on the severity of the acute attack and the patient's age, 5–20 inhalations (0.5–2.0 mL) of BERODUAL, diluted with physiological saline to a volume of 3–4 mL, should be administered.

For prevention of exercise-induced asthma or anticipated allergic exposure, 1–2 inhalations (0.1–0.2 mL) of BERODUAL, diluted with 2–3 mL of physiological saline, should be administered, if possible, 10–15 minutes before the event.

Children under 6 years of age (with body weight less than 22 kg).

Due to limited data on use in this age group, BERODUAL is recommended at the dose specified below only under medical supervision:

1 inhalation (0.1 mL) per 1 kg body weight, up to a maximum of 5 inhalations (0.5 mL) per single dose, diluted with physiological saline to a volume of 3–4 mL.

BERODUAL is compatible for co-inhalation with the medicinal product "Lasolvan" inhalation and oral solution.

Special Precautions for Handling and Disposal

For administration, the recommended dose of BERODUAL inhalation solution should be diluted with physiological saline (0.9%) to a volume of 3–4 mL. The ready-to-use solution should be inhaled immediately after preparation. Inhalation should be performed, if possible, in a sitting or standing position. The nebulizer manufacturer's instructions must be followed.

The duration of inhalation can be adjusted by modifying the dilution volume.

Patients must be instructed on the correct use of BERODUAL solution. Contact of the solution or nebulized droplets with the eyes must be avoided.

The nebulized solution intended for nebulizer use must be inhaled through a mouthpiece. If a mouthpiece is not available, a face mask that fits snugly over the face should be used. Patients predisposed to developing glaucoma should take particular care to protect their eyes.

Children

BERODUAL is used in pediatric practice. For children under 6 years of age, the medicinal product should be prescribed only under medical supervision.

Overdose

Symptoms

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

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

When fenoterol is used at doses higher than recommended for BERODUAL 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

BERODUAL treatment 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, should be provided. Beta-adrenoreceptor blockers (preferably beta1-selective) may be used as specific antidotes for fenoterol; however, the potential for increased bronchial obstruction due to beta-blockers must be considered, 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, including ECG, is recommended.

Side effects

Like all medicinal products, BERODUAL may cause adverse reactions.

Most of the adverse effects listed below can be explained by the anticholinergic and beta-adrenergic properties of BERODUAL.

Adverse reactions to the medicinal product have been identified based on data obtained during 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 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 – excitement, psychiatric disorders.

Psychiatric disorders 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*, visual halos*.

Cardiac disorders:

uncommon – tachycardia, palpitations;

rare – arrhythmias, 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)*, dry throat*;

not known – local irritation.

Gastrointestinal disorders:

uncommon – vomiting, nausea, dry mouth;

rare – stomatitis, glossitis, gastrointestinal motility disorders**, diarrhoea, constipation*, oedema of the oral mucosa*, heartburn.

Skin and subcutaneous tissue disorders:

rare – urticaria, rash, pruritus, angioedema*, petechiae, hyperhidrosis*.

Musculoskeletal and connective tissue disorders:

rare – muscle weakness, muscle spasm, 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 of BERODUAL. Frequencies indicated based on 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 = 0.0006, indicating "rare" events).

** Patients with cystic fibrosis may be particularly susceptible to gastrointestinal motility disorders when using inhaled anticholinergic agents (contained in BERODUAL).

Like other inhaled medicinal products, BERODUAL may cause symptoms of local irritation. The most commonly reported 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as 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.

Individually prepared solution is intended for immediate use.

Shelf life after first opening of the bottle – 12 months.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging

20 ml or 40 ml in a dropper bottle; 1 bottle per cardboard box.

Prescription status

Prescription only.

Manufacturer

Istituto de Angeli S.r.l., Italy

Manufacturer's address

Localita Prulli 103/c - 50066 Reggello (Firenze), Italy