Bifradual^® (Solution) Instructions for Use

Marketing Authorization Holder

YUGPHARM, LLC (Russia)

ATC Code

R03AL01 (Fenoterol and ipratropium bromide)

Active Substances

Fenoterol (Rec.INN registered by WHO)

Ipratropium bromide (Rec.INN registered by WHO)

Dosage Form

Bifradual®

Solution for inhalation 0.5 mg+0.25 mg/ml: fl. 10 ml, 15 ml, 20 ml or 30 ml 1 pc.

Dosage Form, Packaging, and Composition

Solution for inhalation clear, colorless or with a yellowish tint.

Excipients: benzalkonium chloride – 0.1 mg, disodium edetate dihydrate – 0.5 mg, sodium chloride – 8.6 mg, hydrochloric acid 1M solution – 0.946 mg (to pH 3.1-3.5), purified water – to 1 ml.

10 ml – bottles (1) – cardboard packs.
15 ml – bottles (1) – cardboard packs.
20 ml – bottles (1) – cardboard packs.
30 ml – bottles (1) – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator drug

Pharmacotherapeutic Group

Drugs for the treatment of obstructive airway diseases; adrenergic agents for inhalation administration; adrenergic agents in combination with anticholinergic agents, including triple combinations with glucocorticoids

Pharmacological Action

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

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. Bronchodilation upon inhalation of ipratropium bromide is mainly due to local, rather than systemic, anticholinergic action. Ipratropium bromide inhibits reflexes mediated by the vagus nerve, counteracting the effects of acetylcholine, a neurotransmitter released from vagus nerve endings. Anticholinergic agents prevent the increase in intracellular calcium ion concentration that occurs as a result of the interaction of acetylcholine with muscarinic receptors located on bronchial smooth muscles. The release of calcium ions is mediated by a system of secondary mediators, including inositol triphosphate and diacylglycerol. Ipratropium bromide does not adversely affect mucus secretion in the airways, mucociliary clearance, or gas exchange.

Fenoterol selectively stimulates β₂-adrenergic receptors at therapeutic doses. Stimulation of β₁-adrenergic receptors occurs when fenoterol is 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 hypersensitivity reactions). Immediately after administration, fenoterol blocks the release of inflammatory and bronchoconstrictive mediators from mast cells. Furthermore, when fenoterol was used in higher doses, an increase in mucociliary clearance was noted.

The drug’s effect on cardiac activity, such as increased heart rate and contractility, 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.

The most common adverse effect of β-adrenergic receptor agonists is tremor. Unlike the effect on bronchial smooth muscle, tolerance to the systemic effects of β-adrenergic receptor agonists may develop, but 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 for bronchopulmonary diseases accompanied by airway obstruction. The complementary action is such that a lower dose of the beta-adrenergic component is required to achieve the desired effect, allowing for the individual selection of an effective dose with virtually no side effects.

In patients with bronchospasm associated with COPD (chronic bronchitis and pulmonary emphysema), a 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.

Pharmacokinetics

The therapeutic effect of the combination of ipratropium bromide and fenoterol hydrobromide is a consequence of local action in the airways. There is no evidence that the pharmacokinetics of the combined drug differ from those of each individual component.

Ipratropium bromide

With the inhalation route of administration, ipratropium bromide is characterized by extremely low absorption from the respiratory mucosa. The concentration of the active substance in plasma is at the lower limit of detection and can only be measured when high doses of the active substance are used. After inhalation, typically 10-30% of the administered dose of the drug reaches the lungs (depending on the dosage form and inhalation method). Most of the dose is swallowed and enters the gastrointestinal tract. The portion of the drug dose that reaches the lungs quickly enters the systemic circulation (within minutes). The overall systemic bioavailability of inhaled ipratropium bromide is 7-28%.

Being a quaternary nitrogen derivative, it is poorly soluble in fats and poorly penetrates biological membranes. Does not accumulate. Ipratropium bromide binds to plasma proteins to a minimal extent (less than 20%).

Metabolized in the liver. Up to 8 metabolites of ipratropium are known, which weakly bind to muscarinic receptors. Excreted primarily through the intestines and also by the kidneys. About 25% is excreted unchanged, the rest in the form of numerous metabolites.

Fenoterol

Depending on the inhalation method and the inhalation system used, about 10-30% of the active substance reaches the lower respiratory tract, the rest is deposited in the upper respiratory tract and swallowed. As a result, some of the inhaled fenoterol enters the gastrointestinal tract. Absorption is biphasic – 30% of fenoterol is rapidly absorbed with a T_1/2 of 11 minutes, 70% is absorbed slowly with a T_1/2 of 120 minutes. There is no correlation between the plasma concentrations of fenoterol achieved after inhalation and the AUC. The prolonged bronchodilator effect of the drug after inhalation, comparable to the corresponding effect achieved after intravenous administration, is not supported by high concentrations of the active substance in the systemic circulation. After oral administration, about 60% of fenoterol is absorbed. Time to reach C_max in plasma is 2 hours.

Plasma protein binding is 40-55%. Fenoterol in unchanged form crosses the placental barrier and is excreted in breast milk.

Metabolized in the liver. Within 24 hours, 60% of the intravenously administered dose and 35% of the orally taken dose are excreted in the urine. This portion of the active substance undergoes biotransformation due to the first-pass effect through the liver, resulting in the drug’s bioavailability after oral administration dropping to approximately 1.5%. This explains why the swallowed amount of the drug has practically no effect on the level of the active substance in the plasma achieved after inhalation. Biotransformation of fenoterol in humans occurs mainly through conjugation with sulfates in the intestinal wall.

Excreted by the kidneys and in bile as inactive sulfate conjugates. When administered parenterally, fenoterol is excreted according to a three-phase model with T_1/2 – 0.42 min, 14.3 min, and 3.2 hours.

Indications

Prevention and symptomatic treatment of obstructive airway diseases with reversible airway obstruction, such as bronchial asthma and, especially, COPD, chronic bronchitis with or without pulmonary emphysema.

ICD codes

Dosage Regimen

Solution for inhalation

The dose should be selected individually, depending on the severity of the attack. Treatment usually begins with the lowest recommended dose and is stopped after sufficient symptom reduction is achieved.

Treatment should be carried out under medical supervision (e.g., in a hospital setting). Treatment at home is only possible after consultation with a doctor in cases where a fast-acting β-adrenergic agonist in a low dose is insufficiently effective. The solution for inhalation may be recommended for patients when an inhalation aerosol cannot be used or when higher doses are required.

In adults (including the elderly) and adolescents over 12 years with acute bronchospasm attacks, depending on the severity of the attack, doses can vary from 1 ml (1 ml=20 drops) to 2.5 ml (2.5 ml=50 drops). In particularly severe cases, the drug may be used in doses up to 4 ml (4 ml=80 drops).

In children aged 6-12 years with acute bronchial asthma attacks, depending on the severity of the attack, doses can vary from 0.5 ml (0.5 ml=10 drops) to 2 ml (2 ml=40 drops).

In children under 6 years of age (body weight <22 kg), due to limited information on the use of the drug in this age group, the following dose is recommended (only under medical supervision): 0.1 ml (2 drops) per kg of body weight, but not more than 0.5 ml (10 drops).

Rules for using the drug

The solution for inhalation should be used only for inhalations (with a suitable nebulizer) and not administered orally.

The recommended dose should be diluted with 0.9% sodium chloride solution to a final volume of 3-4 ml and used (completely) with a nebulizer.

The solution for inhalation should not be diluted with distilled water.

Dilution of the solution should be performed each time before use; residues of the diluted solution should be discarded.

The diluted solution should be used immediately after preparation.

The duration of inhalation can be controlled by the consumption of the diluted solution.

The solution for inhalation can be used with various commercial models of nebulizers. The dose reaching the lungs and the systemic dose depend on the type of nebulizer used and may be higher than the corresponding doses when using a metered-dose aerosol (which depends on the type of inhaler). In cases where wall oxygen is available, the solution is best used at a flow rate of 6-8 l/min.

It is necessary to follow the instructions for use, maintenance, and cleaning of the nebulizer.

Metered-dose inhalation aerosol

The dose is set individually.

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

The patient should be informed to immediately consult a doctor if there is no effect after 4 inhalation doses and if additional inhalations are needed.

The metered-dose aerosol in children should be used only as prescribed by a doctor and under adult supervision.

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.

Rules for using the drug

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

Before using the metered-dose aerosol for the first time, press 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, deep exhalation.
3. Holding the canister, place the mouthpiece between the lips. The canister should be directed with the bottom up.
4. While taking a maximum deep breath, simultaneously quickly press the bottom of the canister to release 1 inhalation dose. Hold your breath for a few seconds, then remove the mouthpiece from your mouth and exhale slowly. Repeat the actions to obtain the 2nd inhalation dose.
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.

The canister is designed for 200 inhalations. After that, the canister should be replaced. Although some contents may remain in the canister, the amount of medicinal substance released during inhalation decreases.

Since the canister is opaque, the amount of drug in the canister can be determined as follows: after removing the plastic mouthpiece from the canister, immerse the canister in a container filled with water. The amount of the drug is determined depending on the position of the canister in the water.

The inhaler should be cleaned at least once a week. It is important to keep the inhaler mouthpiece clean so that particles of the medicinal substance do not block the release of the aerosol.

During cleaning, first remove the protective cap and remove the canister from the inhaler. Rinse the inhaler with a stream of warm water; make sure to remove 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 contents of the canister are under pressure. The canister must not be opened or heated above 50°C (122°F).

Adverse Reactions

The frequency of adverse reactions was determined in accordance with WHO recommendations: very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10 000, <1/1000); very rare (<1/10 000), including isolated reports; frequency unknown (frequency cannot be calculated from available data).

Immune system disorders rare – hypersensitivity reactions, anaphylactic reactions.

Metabolism and nutrition disorders rare – hypokalemia, metabolic acidosis.

Psychiatric disorders uncommon – nervousness; rare – feeling of anxiety, mental disorders.

Nervous system disorders uncommon – headache, dizziness, tremor.

Eye disorders rare – glaucoma, increased intraocular pressure, accommodation disorders, mydriasis, blurred vision, eye pain, corneal edema, conjunctival hyperemia, appearance of halos around objects and colored spots before the eyes.

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

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

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

Skin and subcutaneous tissue disorders rare – urticaria, skin rash, skin itching, angioedema, hyperhidrosis.

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

Renal and urinary disorders rare – urinary retention.

Contraindications

Hypertrophic obstructive cardiomyopathy; tachyarrhythmia; I and III trimesters of pregnancy; children under 6 years of age (inhalation aerosol); hypersensitivity to fenoterol and other components of the drug; hypersensitivity to atropine-like drugs.

With caution closed-angle glaucoma, arterial hypertension, diabetes mellitus, recent myocardial infarction (within the last 3 months), heart and vascular diseases (chronic heart failure, coronary artery disease, arrhythmia, aortic stenosis, severe cerebral and peripheral arterial lesions), hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder neck obstruction, cystic fibrosis, II trimester of pregnancy, lactation period, children and adolescents aged 6 to 18 years (inhalation aerosol).

Use in Pregnancy and Lactation

Preclinical data and experience with the combination of ipratropium bromide and fenoterol show that the components of the drug do not have a negative effect during pregnancy. The possibility of an inhibitory effect of fenoterol on uterine contractility should be considered. The drug is contraindicated in the I and III trimesters of pregnancy (possibility of fenoterol weakening labor). The drug should be used with caution in the II trimester of pregnancy.

Fenoterol is excreted in breast milk. Data confirming that ipratropium bromide passes into breast milk have not been obtained. Use of the drug during breastfeeding is possible only if the potential benefit to the mother outweighs the potential risk to the child.

Pediatric Use

The inhalation aerosol is contraindicated for use in children under 6 years of age.

The drug in the form of an inhalation aerosol should be prescribed with caution to patients aged 6 to 18 years.

Geriatric Use

The drug is approved for use in elderly patients

Special Precautions

The patient should be informed that in case of an unexpected rapid increase in shortness of breath (difficulty breathing), they should immediately consult a doctor.

Paradoxical Bronchospasm

The drug can cause paradoxical bronchospasm, which may be life-threatening. In the event of paradoxical bronchospasm, the use of the drug should be discontinued immediately and alternative therapy should be initiated.

Long-term Use

In patients with bronchial asthma, the drug 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 is necessary to remember the need to initiate or intensify anti-inflammatory therapy to control airway inflammation and the course of the disease.

Regular use of increasing doses of drugs containing beta₂-adrenergic agonists to relieve bronchial obstruction can cause an uncontrolled worsening of the disease. In case of worsening bronchial obstruction, increasing the dose of beta₂-agonists beyond the recommended dose for a prolonged period is not only unjustified but also dangerous. To prevent life-threatening worsening 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 the drug only under medical supervision.

Eye Disorders

The drug should be prescribed with caution to patients predisposed to developing angle-closure glaucoma. Isolated reports exist of eye complications (e.g., increased intraocular pressure, mydriasis, angle-closure glaucoma, eye pain) developing when inhaled ipratropium bromide (or ipratropium bromide in combination with β₂-adrenoceptor agonists) has entered 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 redness due to conjunctival injection. If any combination of these symptoms occurs, the use of eye drops to reduce intraocular pressure and immediate consultation with a specialist are indicated. Patients should be instructed on the correct use of the inhalation solution. To prevent the solution from getting into the eyes, it is recommended that the solution used with a nebulizer be inhaled through a mouthpiece. If a mouthpiece is not available, a tightly fitting face mask should be used. Particular care should be taken to protect the eyes of patients predisposed to glaucoma.

Systemic Effects

In conditions such as recently experienced myocardial infarction, diabetes mellitus with inadequate glycemic control, severe organic heart and vascular disease, hyperthyroidism, pheochromocytoma, or urinary tract obstruction (e.g., due to prostatic hyperplasia or bladder neck obstruction), the drug should be prescribed only after a careful risk/benefit assessment, especially when used at doses exceeding the recommended ones.

Effect on the Cardiovascular System

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

Hypokalemia

Hypokalemia may occur with the use of β₂-adrenoceptor agonists.

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

Excipients

The drug in the form of an inhalation aerosol contains the preservative benzalkonium chloride and the stabilizer disodium edetate dihydrate. During inhalation, these components can cause bronchospasm in sensitive patients with airway hyperreactivity.

Effect on Driving and Operating Machinery

The effect of the drug on the ability to drive vehicles and use machinery has not been specifically studied. However, patients should be informed that during treatment with the drug, adverse reactions such as dizziness, tremor, accommodation disturbance, mydriasis, and blurred vision may occur. Therefore, caution should be recommended when driving vehicles or using machinery. If patients experience the aforementioned adverse sensations, they should refrain from such potentially hazardous activities as driving vehicles or operating machinery.

Drug Interactions

Concomitant use of other beta-adrenergic agonists, anticholinergic drugs, and xanthine derivatives (e.g., theophylline) may enhance the bronchodilatory effect of the drug.

A significant weakening of the bronchodilatory effect of the drug is possible with the concomitant administration of beta-blockers.

Hypokalemia associated with the use of beta-adrenergic agonists may be enhanced by the concomitant use of xanthine derivatives, corticosteroids, and diuretics. This fact should be given special attention 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 negative effect of hypokalemia on heart rhythm. In such cases, monitoring of serum potassium levels is recommended.

Beta₂-adrenergic agonists should be prescribed with caution to patients who have been taking MAO inhibitors and tricyclic antidepressants, as these drugs can potentiate the effect of beta-adrenergic agents.

The use of inhaled halogenated anesthetics, e.g., halothane, trichloroethylene, or enflurane, may enhance the effect of beta-adrenergic agents on the cardiovascular system.

Concomitant use of the drug with cromoglicic acid and/or corticosteroids increases the effectiveness of therapy.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.