Berodual^® N (Aerosol) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Boehringer Ingelheim Pharma, GmbH & Co. KG (Germany)

ATC Code

R03AL01 (Fenoterol and ipratropium bromide)

Active Substances

Fenoterol (Rec.INN registered by WHO)

Ipratropium bromide (Rec.INN registered by WHO)

Dosage Form

Berodual® N

Metered dose inhalation aerosol 50 mcg+20 mcg/1 inhalation dose: canister 10 ml (200 doses) with metering valve and mouthpiece

Dosage Form, Packaging, and Composition

Metered dose inhalation aerosol in the form of a clear, colorless or slightly yellowish, or slightly brownish liquid, free from suspended particles.

Excipients: absolute ethanol – 13.313 mg, purified water – 0.799 mg, citric acid – 0.001 mg, tetrafluoroethane (HFA 134a, propellant) – 39.070 mg.

10 ml (200 doses) – metal canisters with a metering valve and mouthpiece (1) – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator drug

Pharmacotherapeutic Group

Combined bronchodilator agent (m-cholinergic blocker + selective beta2-adrenomimetic)

Pharmacological Action

Combined bronchodilator drug. It contains two components with bronchodilator activity: ipratropium bromide – an m-cholinergic blocker, and Fenoterol hydrobromide – a beta₂-adrenomimetic.

Bronchodilation upon inhalation of ipratropium bromide is mainly due to local, rather than systemic, anticholinergic action.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. Ipratropium bromide inhibits reflexes mediated by the vagus nerve. Anticholinergic agents prevent the increase in intracellular calcium concentration that occurs due to the interaction of acetylcholine with the muscarinic receptor located on bronchial smooth muscles. Calcium release is mediated by a system of secondary mediators, which include IP₃ (inositol triphosphate) and DAG (diacylglycerol).

In patients with bronchospasm associated with COPD (chronic bronchitis and emphysema), significant improvement in lung function (increase in FEV₁ and peak expiratory flow by 15% or more) was noted within 15 minutes, the maximum effect was achieved after 1-2 hours and lasted in most patients up to 6 hours after administration.

Ipratropium bromide does not adversely affect mucus secretion in the airways, mucociliary clearance, or gas exchange.

Fenoterol hydrobromide selectively stimulates β₂-adrenergic receptors at therapeutic doses. Stimulation of β₁-adrenergic receptors occurs when used in high doses.

Fenoterol relaxes bronchial and vascular smooth muscles and counteracts the development of bronchospastic reactions caused by histamine, methacholine, cold air, and allergens (immediate-type hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory and bronchoconstrictive mediators from mast cells. Furthermore, when fenoterol was used at a dose of 600 mcg, an increase in mucociliary clearance was noted.

The beta-adrenergic effect of the drug on cardiac activity, such as increased heart rate and force of contraction, is due to the vascular action of fenoterol, stimulation of cardiac β₂-adrenergic receptors, and, when used in doses exceeding therapeutic ones, stimulation of β₁-adrenergic receptors.

As with the use of other beta-adrenergic drugs, QT_c interval prolongation was noted when used in high doses. When fenoterol was used via metered dose aerosol inhalers (MDI), this effect was inconsistent and noted in cases of using doses exceeding the recommended ones. However, after using fenoterol via nebulizers (solution for inhalation in vials with a standard dose), systemic exposure may be higher than when using the drug via MDI at recommended doses. The clinical significance of these observations has not been established.

The most commonly observed effect of beta-adrenergic receptor agonists is tremor. Unlike the effects on bronchial smooth muscles, tolerance to the systemic effects of beta-adrenergic receptor agonists may develop. The clinical significance of this manifestation is not clear.

When ipratropium bromide and fenoterol are used together, the bronchodilator effect is achieved by acting on different pharmacological targets. These substances complement each other, thereby enhancing the spasmolytic effect on bronchial muscles and providing a broader therapeutic range in bronchopulmonary diseases accompanied by airway constriction. The complementary action is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, allowing for the selection of an effective dose with virtually no side effects.

In acute bronchoconstriction, the effect of Berodual^® N develops rapidly, which allows its use for acute bronchospasm attacks.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is a consequence of local action in the airways. The development of bronchodilation does not parallel the pharmacokinetic parameters of the active substances.

After inhalation, typically 10-39% of the administered dose of the drug reaches the lungs (depending on the dosage form and inhalation method). The remaining part of the dose is deposited on the mouthpiece, in the oral cavity, and oropharynx. The portion of the dose deposited in the oropharynx is swallowed and enters the gastrointestinal tract.

The portion of the drug dose that reaches the lungs quickly enters the systemic circulation (within minutes).

There is no evidence that the pharmacokinetics of the combined drug differ from those of each individual component.

Fenoterol hydrobromide

Absorption and Distribution

The absolute oral bioavailability is low (about 1.5%). The total systemic bioavailability of the inhaled dose of fenoterol hydrobromide is estimated at 7%.

The binding of fenoterol to plasma proteins is about 40%.

Kinetic parameters describing the distribution of fenoterol were calculated from plasma concentrations after IV administration. After IV administration, plasma concentration-time curves can be described by a 3-compartment pharmacokinetic model, according to which T_1/2 is approximately 3 hours. In this 3-compartment model, the apparent V_d at steady state is approximately 189 L (about 2.7 L/kg).

Metabolism and Excretion

The swallowed portion of the dose is metabolized to sulfate conjugates.

After IV administration, free and conjugated fenoterol accounted for 15% and 27% of the administered dose, respectively, in the 24-hour urine analysis.

Preclinical studies have shown that fenoterol and its metabolites do not cross the BBB. The total clearance of fenoterol is 1.8 L/min, renal clearance is 0.27 L/min. Total renal excretion (over 2 days) of the isotopically labeled dose (including the parent compound and all metabolites) was 65% after IV administration. The total isotopically labeled dose excreted via the intestine was 14.8% after IV administration and 40.2% after oral administration over 48 hours. The total isotopically labeled dose excreted by the kidneys after oral administration was about 39%.

Ipratropium bromide

Absorption and Distribution

The total systemic bioavailability of ipratropium bromide, administered orally and by inhalation, is 2% and 7-28%, respectively. Thus, the influence of the swallowed portion of ipratropium bromide on systemic exposure is negligible.

Binding to plasma proteins is minimal – less than 20%.

Kinetic parameters describing the distribution of ipratropium were calculated from its plasma concentrations after IV administration. A rapid biphasic decrease in plasma concentration is observed. The apparent V_d at steady state is approximately 176 L (about 2.4 L/kg). Preclinical studies have shown that ipratropium, being a quaternary ammonium derivative, does not cross the BBB.

Metabolism and Excretion

After IV administration, approximately 60% of the dose is metabolized by oxidation, mainly in the liver.

Total renal excretion (over 24 hours) of the parent compound is approximately 46% of the IV administered dose, less than 1% of the orally administered dose, and approximately 3-13% of the inhaled drug dose.

T_1/2 in the terminal phase is approximately 1.6 hours.

The total clearance of ipratropium is 2.3 L/min, and renal clearance is 0.9 L/min.

Total renal excretion (over 6 days) of the isotopically labeled dose (including the parent compound and all metabolites) was 72.1% after IV administration, 9.3% after oral administration, and 3.2% after inhalation. The total isotopically labeled dose excreted via the intestine was 6.3% after IV administration, 88.5% after oral administration, and 69.4% after inhalation. Thus, excretion of the isotopically labeled dose after IV administration occurs mainly via the kidneys. T_1/2 of the parent compound and metabolites is 3.6 hours. The main metabolites excreted in the urine bind weakly to muscarinic receptors and are considered inactive.

Indications

Prevention and symptomatic treatment of obstructive airway diseases with reversible bronchospasm

• Bronchial asthma;
• COPD;
• Chronic bronchitis, complicated or uncomplicated by emphysema.

ICD codes

Dosage Regimen

The dose is set individually.

For relief of attacks, adults and children over 6 years are prescribed 2 inhalation doses. If breathing does not ease within 5 minutes, 2 more inhalation doses can be prescribed.

The patient should be informed to seek immediate medical attention if there is no effect after 4 inhalation doses and if additional inhalations are needed.

For long-term and intermittent therapy, 1-2 inhalations per dose are prescribed, up to 8 inhalations/day (on average, 1-2 inhalations 3 times/day).

For bronchial asthma, the drug should be used only as needed.

Berodual^® N in children should be used only as prescribed by a doctor and under adult supervision.

Rules for using the drug

The patient should be instructed on the correct use of the metered dose aerosol.

Before first use of a new inhaler, hold the inhaler upside down, remove the protective cap, and spray 2 times into the air by pressing the bottom of the canister twice.

Each time the metered dose aerosol is used, the following rules must be observed:

1. Remove the protective cap.

2. Take a slow, full exhalation.

3. Holding the inhaler, tightly grasp the mouthpiece with your lips. The arrow and the bottom of the canister should point upwards.

4. Begin to inhale and simultaneously press firmly on the bottom of the canister until one inhalation dose is released. Continue to inhale slowly to the maximum and hold your breath for a few seconds. Then remove the mouthpiece from your mouth and exhale slowly.

To get a second inhalation dose, repeat the steps from step 2.

5. Put on the protective cap.

6. If the aerosol canister has not been used for more than 3 days, before use, press the bottom of the canister once until an aerosol cloud appears.

Since the canister is not transparent, it is impossible to determine visually if it is empty. The canister is designed for 200 inhalations. After using this number of doses, a small amount of solution may remain. Nevertheless, the inhaler should be replaced, otherwise the necessary therapeutic dose may not be obtained.

The amount of drug remaining in the canister can be checked as follows:

• Shake the canister, this will show if any liquid remains in it;
• Another way is to remove the plastic mouthpiece from the canister and place the canister in a container of water. The contents of the canister can be assessed depending on its position in the water (Fig. 1).

The inhaler should be cleaned at least once a week. It is important to keep the inhaler mouthpiece clean to prevent the drug from entering it, which could block the release of the aerosol.

During cleaning, first remove the protective cap and remove the canister from the inhaler. Rinse the inhaler under a stream of warm water, ensuring the removal of the drug and/or visible dirt.

After cleaning, shake the inhaler and let it air dry without using heating appliances. Once the mouthpiece is dry, insert the canister into the inhaler and put on the protective cap.

The plastic mouthpiece is specifically designed for use with the Berodual^® N metered dose aerosol and serves for accurate dosing of the drug. This mouthpiece should not be used with other metered dose aerosols. The Berodual^® N aerosol should also not be used with other adapters except the mouthpiece supplied with the canister.

The contents of the canister are under pressure.

The canister must not be opened or heated above 50°C (122°F).

Adverse Reactions

Many of the listed adverse effects may be a consequence of the anticholinergic and beta-adrenergic properties of Berodual^® N. Berodual^® N, like any inhalation therapy, can cause local irritation. Adverse drug reactions were determined based on data obtained from clinical studies and during pharmacological surveillance of the drug’s use after its registration.

The most common side effects reported in clinical studies were cough, dry mouth, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure, and nervousness.

Definition of frequency categories for adverse reactions that may occur during treatment: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000); frequency not known (frequency cannot be estimated from available data).

Immune system disorders rare* – anaphylactic reaction, hypersensitivity, angioedema; rare – urticaria.

Metabolism and nutrition disorders rare* – hypokalemia.

Nervous system and psychiatric disorders uncommon – nervousness, headache, tremor, dizziness; rare – agitation, mental disorders.

Eye disorders rare* – glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, halo vision.

Cardiac and vascular disorders uncommon – tachycardia, palpitations, increased systolic blood pressure; rare – arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischemia*, increased diastolic blood pressure.

Respiratory, thoracic and mediastinal disorders common – cough; uncommon – pharyngitis, dysphonia; rare – bronchospasm, pharyngeal irritation, pharyngeal edema, laryngospasm*, paradoxical bronchospasm*, pharyngeal dryness*.

Gastrointestinal disorders uncommon – vomiting, nausea, dry mouth; rare – stomatitis, glossitis, gastrointestinal motility disorders, diarrhea, constipation*, oral cavity edema*.

Skin and subcutaneous tissue disorders rare – pruritus, hyperhidrosis*.

Musculoskeletal and connective tissue disorders rare – muscle weakness, muscle spasm, myalgia.

Renal and urinary disorders rare – urinary retention.

* these adverse reactions were not identified in clinical studies of Berodual^® N. The assessment is based on the upper limit of the 95% confidence interval calculated for the general patient population.

Contraindications

• Hypertrophic obstructive cardiomyopathy;
• Tachyarrhythmia;
• First trimester of pregnancy;
• Children under 6 years of age;
• Hypersensitivity to the components of the drug;
• Hypersensitivity to atropine-like substances.

Use with caution in angle-closure glaucoma, coronary insufficiency, arterial hypertension, inadequately controlled diabetes mellitus, recent myocardial infarction, severe organic cardiovascular diseases, hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder neck obstruction, in cystic fibrosis, in children over 6 years of age.

Use in Pregnancy and Lactation

The drug is contraindicated for use in the first trimester of pregnancy.

Existing clinical experience has shown that fenoterol and ipratropium do not have a negative effect on pregnancy. Nevertheless, when using these drugs in the second and third trimesters of pregnancy, the usual precautions should be observed.

The inhibitory effect of fenoterol on uterine contractility should be taken into account.

Preclinical studies have shown that Fenoterol hydrobromide can pass into breast milk. No such data are available for ipratropium. Significant exposure of ipratropium to the breastfed infant, especially when the drug is used as an aerosol, is unlikely. However, given the ability of many drugs to be excreted in breast milk, caution should be exercised when prescribing Berodual^® N to women who are breastfeeding.

There are no clinical data on the effect of fenoterol hydrobromide, ipratropium bromide, or their combination on fertility. Preclinical studies did not show an effect of ipratropium bromide and fenoterol hydrobromide on fertility.

Use in Renal Impairment

The drug should be used with caution in cases of bladder neck obstruction.

Pediatric Use

Contraindicated in children under 6 years of age.

The drug should be used with caution in children over 6 years of age.

Special Precautions

Dyspnea

In case of unexpected rapid worsening of dyspnea (breathing difficulties), a doctor should be consulted without delay.

Hypersensitivity

Following the use of Berodual^® H, immediate hypersensitivity reactions may occur, signs of which in rare cases may include urticaria, angioedema, rash, bronchospasm, oropharyngeal edema, and anaphylactic shock.

Paradoxical Bronchospasm

Berodual^® H, like other inhalation drugs, can cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, the use of Berodual^® H should be discontinued immediately and alternative therapy should be instituted.

Long-term Use

In patients with bronchial asthma, Berodual^® H should be used only as needed. In patients with mild COPD, symptomatic treatment may be preferable to regular use. In patients with bronchial asthma, it should be remembered that anti-inflammatory therapy is necessary to control airway inflammation and the course of the disease.

Regular use of increasing doses of drugs containing beta₂-adrenergic agonists, such as Berodual^® H, to relieve bronchial obstruction may cause uncontrolled worsening of the disease. In case of worsening bronchial obstruction, increasing the dose of beta₂-agonists, including Berodual^® H, beyond the recommended dose for a prolonged period is not only unjustified but also dangerous. To prevent life-threatening deterioration of the disease, the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled corticosteroids should be reconsidered.

Other sympathomimetic bronchodilators should be prescribed concurrently with Berodual^® H only under medical supervision.

Gastrointestinal Disorders

In patients with a history of cystic fibrosis, gastrointestinal motility disorders are possible.

Eye Disorders

Contact of the drug with the eyes should be avoided.

Berodual^® H should be prescribed with caution to patients predisposed to the development of angle-closure glaucoma. Isolated reports are known of eye complications (e.g., increased intraocular pressure, mydriasis, angle-closure glaucoma, eye pain) that developed when inhaled ipratropium bromide (or ipratropium bromide in combination with β₂-adrenoceptor agonists) came into contact with the eyes. Symptoms of acute angle-closure glaucoma may include eye pain or discomfort, blurred vision, visual halos or colored images in association with corneal edema and conjunctival injection and redness. If any combination of these symptoms develops, the use of eye drops to reduce intraocular pressure and immediate consultation with a specialist are indicated.

Systemic Effects

In the following conditions: recent myocardial infarction, diabetes mellitus with inadequate glycemic control, severe organic cardiovascular disease, hyperthyroidism, pheochromocytoma, or urinary tract obstruction (e.g., due to prostatic hyperplasia or bladder neck obstruction), Berodual^® H should be prescribed only after careful assessment of the risk/benefit ratio, especially at doses exceeding the recommended ones.

Effect on the Cardiovascular System

In post-marketing studies, rare cases of myocardial ischemia have been reported with the use of β-adrenoceptor agonists. Patients with concomitant serious heart disease (e.g., coronary artery disease, arrhythmias, or severe heart failure) receiving Berodual^® H should be warned to consult a doctor if they experience heart pain or other symptoms indicating worsening heart disease. Attention should be paid to symptoms such as shortness of breath and chest pain, as they may be of either cardiac or pulmonary origin.

Hypokalemia

The use of β₂-adrenoceptor agonists may cause hypokalemia.

In athletes, the use of Berodual^® H, due to the presence of fenoterol in its composition, may lead to positive doping test results.

It should be taken into account that the drug contains a small amount of ethanol (13.313 mg per dose).

Effect on Driving and Operating Machinery

Studies on the effect of the drug on the ability to drive vehicles and operate machinery have not been conducted.

Caution should be exercised when performing these activities, as dizziness, tremor, impaired visual accommodation, mydriasis, and blurred vision may develop. If the above-mentioned undesirable sensations occur, the patient should refrain from such potentially hazardous activities as driving vehicles and operating machinery.

Overdose

Symptoms of overdose are usually primarily related to the effects of fenoterol. Symptoms associated with excessive stimulation of β-adrenoceptors may occur. The most likely symptoms are tachycardia, palpitations, tremor, arterial hypotension or hypertension, increased pulse pressure, anginal pain, arrhythmia, flushing, metabolic acidosis, hypokalemia.

Symptoms of ipratropium bromide overdose, such as dry mouth, impaired visual accommodation, are generally mild and transient due to the wide therapeutic margin and the inhalation route of administration.

Treatment: administration of the drug should be discontinued. Data from blood acid-base balance monitoring should be taken into account. Sedatives, tranquilizers are indicated; in severe cases, intensive therapy is required.

Beta-adrenergic blockers, preferably selective beta₁-adrenergic blockers, can be used as a specific antidote. However, it should be remembered that beta-adrenergic blockers may worsen bronchial obstruction, and the dose should be carefully selected for patients suffering from bronchial asthma or COPD due to the risk of severe bronchospasm, which can be fatal.

Drug Interactions

Long-term concurrent use of Berodual^® H with other anticholinergic drugs is not recommended due to a lack of data.

Beta-adrenergic agonists and anticholinergic agents, xanthine derivatives (including theophylline) may enhance the bronchodilatory effect of Berodual^® H.

Concomitant use of other beta-adrenergic agonists, systemically absorbed anticholinergic agents, or xanthine derivatives (including theophylline) may increase the incidence of adverse effects.

The bronchodilatory effect of Berodual^® H may be significantly reduced with the concomitant administration of beta-adrenergic blockers.

Hypokalemia associated with the use of beta-adrenergic agonists may be potentiated by the concomitant administration of xanthine derivatives, corticosteroids, and diuretics. Particular attention should be paid to this when treating patients with severe forms of obstructive airway diseases.

Hypokalemia may increase the risk of arrhythmias in patients receiving digoxin. Furthermore, hypoxia may enhance the adverse effect of hypokalemia on heart rhythm. In such cases, monitoring of serum potassium levels is recommended.

Beta₂-adrenergic agonists should be used with caution in patients who have received MAO inhibitors and tricyclic antidepressants, as these drugs may potentiate the effect of beta-adrenergic agents.

Inhalation anesthetics containing halogenated hydrocarbons (including halothane, trichloroethylene, enflurane) may enhance the adverse cardiovascular effects of beta₂-adrenergic agents.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.