Freeway® combo nebulizer

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FREEWAY® COMBI NEBULA

Composition:

Active substances: ipratropium bromide, fenoterol hydrobromide;

1 ml of solution contains: ipratropium bromide 0.1305 mg, equivalent to anhydrous ipratropium bromide 0.125 mg; fenoterol hydrobromide 0.3125 mg;

Excipients: sodium chloride; 0.1 M hydrochloric acid solution; water for injections.

Pharmaceutical form. Solution for inhalation.

Main physicochemical properties: clear, colorless liquid.

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

ATC code R03AL01.

Pharmacological Properties.

Pharmacodynamics.

Freway® Combi Nebula contains two active bronchodilator ingredients: ipratropium bromide, which exerts an anticholinergic effect, and fenoterol hydrobromide, a beta-adrenomimetic agent.

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (antimuscarinic) properties. 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 smooth muscle. The release of Ca++ is facilitated by another mediator system consisting of IP3 (inositol trisphosphate) and DAG (diacylglycerol).

Bronchodilation following inhaled ipratropium bromide is primarily due to the local, site-specific action of the drug, which is not systemic.

Fenoterol hydrobromide is a direct sympathomimetic agent that selectively stimulates beta2-adrenergic receptors within the therapeutic dose range. At higher doses, stimulation of beta1-adrenergic receptors also occurs. Binding to beta2-adrenergic receptors activates the Gs-protein, leading to activation of adenylate cyclase. Increased levels of cyclic AMP result in activation of protein kinase A and phosphorylation of specific proteins in smooth muscle cells. This leads to phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and opening of large 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 single administration, fenoterol inhibits the release of bronchoconstrictor and pro-inflammatory mediators from mast cells. Following administration of fenoterol at a dose of 0.6 mg, improvement in mucociliary clearance has been observed. At higher plasma concentrations of fenoterol, more commonly achieved with oral or even intravenous administration, a reduction in uterine contractility has been noted. Additionally, metabolic effects may occur at high doses: lipolysis, glycogenolysis, hyperglycemia, and hypokalemia, the latter due to increased potassium uptake, particularly in skeletal muscle. Beta-adrenergic effects of fenoterol on the heart, including increased heart rate and frequency of cardiac contractions, are related to 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 prolongation has been observed. For fenoterol in the form of a metered-dose aerosol, these effects are minimal and occur only at doses exceeding the recommended levels. However, systemic effects of fenoterol (solution for inhalation) following administration via nebulizer may be higher than with recommended doses of metered-dose aerosol. The clinical significance of this is not established. The most commonly observed adverse effect of beta-mimetics is tremor. In contrast to its effect on bronchial smooth muscle, systemic effects of beta-mimetics on skeletal muscle lead to the development of tolerance.

When two active bronchodilators are used simultaneously, bronchodilation occurs through two distinct pharmacological mechanisms. Thus, the two active substances exert a combined spasmolytic effect on bronchial smooth muscle, allowing their broad application in respiratory diseases associated with impaired airway patency. For effective combined action, only a very small amount of beta-mimetic is required, enabling individual dose adjustment and reduction in 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 respiratory tract. Therefore, the pharmacokinetics of bronchodilation are not related to the pharmacokinetics of the active ingredients of the drug.

After inhalation, approximately 10–39% of the total dose deposits in the lungs, depending on the formulation, inhalation technique, and delivery device, while the remainder remains in the inhaler mouthpiece, mouth, and upper airways (oropharynx).

There is no evidence that the pharmacokinetics of the combination of both ingredients differ from those of the individual substances.

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

After intravenous administration, the fractions of free fenoterol and conjugated fenoterol excreted in urine over 24 hours reach 15% and 27% of the administered dose, respectively. After inhalation using a metered-dose aerosol, approximately 1% of the inhaled dose is excreted in urine over 24 hours as free fenoterol. Based on this, the total systemic bioavailability of inhaled fenoterol hydrobromide is estimated to be 7%.

Kinetic parameters characterizing the disposition of fenoterol were calculated based on plasma concentrations after intravenous administration. After intravenous dosing, the area under the plasma concentration-time curve (AUC) can be described by a three-compartment model, with a terminal elimination half-life of approximately 3 hours. According to this three-compartment model, the expected 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 animals have shown that fenoterol and its metabolites cross the blood-brain barrier. Total clearance of fenoterol is 1.8 L/min, and renal clearance is 0.27 L/min.

In an excretion balance study, total renal clearance (over 2 days) of radioactivity (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 dose after intravenous administration, less than 1% after oral administration, and approximately 3–13% after inhalation via a metered-dose inhaler. Based on these data, total systemic bioavailability of ipratropium bromide after oral and inhaled administration is estimated to be 2% and 7–28%, respectively. Therefore, the swallowed portion of ipratropium bromide is unlikely to contribute significantly to systemic effects.

Kinetic parameters characterizing the disposition of ipratropium were calculated based on plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentration is observed. The apparent volume of distribution at steady state (Vdss) is approximately 176 L (≈ 2.4 L/kg). The drug binds minimally to plasma proteins (less than 20%). Preclinical animal studies indicate that the quaternary amine ipratropium does not cross the blood-brain barrier.

The terminal elimination half-life is approximately 1.6 hours. Total clearance of ipratropium is 2.3 L/min, and renal clearance is 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 radioactivity (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 radioactivity after intravenous administration is renal. The elimination half-life of radioactivity (parent compound and all metabolites) is 3.6 hours. Binding of the main urinary metabolites to muscarinic receptors is negligible, and metabolites are considered pharmacologically inactive.

Clinical characteristics.

Indications.

Treatment of bronchospasm associated with severe acute exacerbations of bronchial asthma or chronic obstructive pulmonary disease (COPD).

Contraindications.

Hypersensitivity to fenoterol hydrobromide, anticholinergic agents, or any other components of the medicinal product; hypertrophic obstructive cardiomyopathy, tachyarrhythmia.

Interaction with other medicinal products and other forms of interaction.

Concomitant prolonged use of Freeway® Combi Nebula with other anticholinergic agents has not been studied and therefore is not recommended.

Concomitant use of the following medicinal products/classes of medicinal products may affect the efficacy of Freeway® Combi Nebula.

Enhancement of 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). These may particularly enhance cardiovascular effects.

Reduction of effect:

• concomitant administration of beta-blockers.

Other possible interactions

Hypokalemia associated with the use of beta-mimetics may be potentiated by concomitant use of xanthine derivatives, corticosteroids, and diuretics. This should be given particular attention in the treatment of patients with severe airway obstruction.

Hypokalemia may increase the risk of arrhythmias in patients taking digoxin. In addition, hypoxia may potentiate the adverse 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 inadvertent ocular exposure to nebulized ipratropium and by its use in combination with beta2-agonists.

Also, the use of Freeway® Combi Nebula may 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 should be discontinued at least 6 hours prior to the induction of anesthesia.

Special precautions for use

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

Like other inhaled medicinal products, Frevay® Combo Nebula may cause paradoxical bronchospasm, which may be life-threatening. If paradoxical bronchospasm occurs, Frevay® Combo Nebula must be discontinued immediately and alternative therapy initiated.

Conditions in which Frevay® Combo Nebula 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;
• concomitant use of cardiac glycosides;
• severe and untreated arterial hypertension;
• aneurysm.

When using sympathomimetic medicinal products, including Frevay® Combo Nebula, cardiovascular effects may occur. 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 Frevay® Combo Nebula should be warned 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 have either respiratory or cardiac origin.

Frevay® Combo Nebula, like other anticholinergic agents, should be used with caution in:

• patients predisposed to developing angle-closure 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, angle-closure glaucoma, eye pain) resulting from aerosolized ipratropium bromide or its combination with beta2-agonists entering the eye.

Attention! Patients must be thoroughly instructed on the proper use of Frevay® Combo Nebula, solution for inhalation. Precautions should be taken to avoid contact of the medication with the eyes.

Symptoms of acute attack of angle-closure glaucoma include:

• eye pain or discomfort;
• blurred vision;
• seeing halos around lights;
• perception of colored halos;
• eye redness due to conjunctival or corneal hyperemia.

If any of the above symptoms occur in combination, treatment with eye drops that promote pupil constriction should be initiated immediately, and specialized medical help must be sought without delay.

Patients with cystic fibrosis may be more susceptible to gastrointestinal motility disorders when using this medication.

Long-term use

• In patients with bronchial asthma, Frevay® Combo Nebula should be used only as needed. In patients with mild forms of COPD, on-demand treatment (symptomatic therapy) may be more appropriate than regular use.
• It should be remembered that anti-inflammatory therapy should be initiated or intensified to control airway inflammation and prevent worsening disease control in patients with bronchial asthma or steroid-dependent forms of COPD.

Regular use of increased doses of medications containing beta2-agonists, such as Frevay® Combo Nebula, to relieve bronchial obstruction symptoms may lead to worsening disease control.

If bronchial obstruction worsens, simply increasing the dose of beta2-agonists, including Frevay® Combo Nebula, over a prolonged period beyond the recommended dose is not only unjustified but also dangerous. To prevent life-threatening deterioration of the disease, the patient's treatment plan should be reassessed and adequate anti-inflammatory therapy with inhaled corticosteroids should be considered.

There have been reports of several cases of increased risk of serious complications of the underlying disease, as well as fatal outcomes, during long-term treatment of bronchial asthma with excessively high doses of inhaled beta2-sympathomimetics without sufficient anti-inflammatory therapy. The causal relationship has not been fully elucidated. However, adequate anti-inflammatory therapy is critically important.

Other sympathomimetic bronchodilators should be co-administered with Frevay® Combo Nebula only under medical supervision (see section "Interaction with other medicinal products and other forms of interaction").

Hypokalemia, potentially serious, may occur due to high-dose beta2-agonist therapy (see section "Overdose"). Monitoring of serum potassium levels is recommended in patients with low baseline potassium. 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 administration of Frevay® Combo Nebula.

The product contains the preservative benzalkonium chloride and the stabilizer disodium edetate. These components may cause bronchospasm in patients with hyperreactive airways.

Use of Frevay® Combo Nebula may lead to positive doping test results.

Use during pregnancy or breastfeeding

Preclinical data have not shown any negative effects of fenoterol and ipratropium on pregnancy. However, standard precautionary measures should be followed regarding the use of medicinal products during pregnancy. The inhibitory effect of fenoterol on uterine contractility should be considered. 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).

Fenoterol hydrobromide passes into breast milk. Data on the passage of ipratropium into breast milk are lacking. It is unlikely that ipratropium would reach the infant in significant amounts, especially when administered by inhalation. Frevay® Combo Nebula should be prescribed with caution to breastfeeding women.

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

Ability to influence reaction speed when driving vehicles or operating machinery

No studies have been conducted. Patients should be warned about the possible occurrence of adverse reactions such as dizziness, tremor, accommodation disorders, mydriasis, and blurred vision when using Frevay® Combo Nebula. Caution should be exercised when driving vehicles or operating machinery. If any adverse reactions occur, patients should avoid potentially hazardous activities.

Administration and Dosage

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 have been insufficient to provide symptom relief.

The drug should be discontinued once symptom relief has been achieved.

COPD: CHRONIC BRONCHITIS AND EMPHYSEMA

The dosage of the inhaled solution of Frovaire® Combi Nebula should be individually adjusted, and the patient's response should be monitored to determine the need for more than one bronchodilator prescribed by a physician on a regular basis. Concomitant anti-inflammatory therapy should be considered in COPD patients who are steroid-sensitive.

Smoking cessation counseling should be the first step in the treatment of smoking patients with COPD, regardless of clinical presentation—i.e., chronic bronchitis (with or without airflow limitation) or emphysema.

Smoking cessation provides symptomatic benefits; it has been proven to improve survival and slow or halt the progression of chronic bronchitis and emphysema.

ASTHMA

The inhaled solution of Frovaire® Combi Nebula should only be administered under medical supervision to patients with severe asthma exacerbations requiring more than one bronchodilator.

According to current asthma treatment guidelines, concomitant anti-inflammatory therapy should be part of the treatment regimen if the inhaled solution Frovaire® Combi Nebula needs to be used regularly on a daily basis.

If a previously effective dosing regimen fails to provide the usual symptom relief, or if the effect of a dose lasts less than 3 hours, the patient should immediately consult a physician, as this indicates a serious asthma exacerbation requiring therapy adjustment.

Recommended Dosage Regimens

Adults and children aged 12 years and older

The usual dose of the inhaled solution Frovaire® Combi Nebula is 4 mL (one polyethylene vial contains 0.5 mg ipratropium bromide and 1.25 mg fenoterol hydrobromide in 4 mL of physiological saline solution).

Not recommended for children under 12 years of age.

Missed Dose

If a dose is missed, the next scheduled dose should be taken at the usual time. Do not take an additional dose.

Administration Method

This solution is ready for use and does not require dilution.

Frovaire® Combi Nebula, inhaled solution, can be administered using a variety of commercially available nebulizer devices. Lung deposition and systemic drug exposure depend on the nebulizer used.

When wall oxygen is available, administration is best performed at a flow rate of 6–8 liters per minute.

Patients should follow the instructions provided by the nebulizer manufacturer regarding proper care, maintenance, and cleaning of the device.

DILUTION INSTRUCTIONS:

To administer the entire contents of Frovaire® Combi Nebula, squeeze the plastic vial to transfer its contents into the nebulizer chamber. If a dose less than one full vial is recommended, use a syringe to transfer the required amount of medication into the nebulizer chamber. When wall oxygen is available, the solution should be administered at a flow rate of 6–8 L/min. Any remaining solution in the plastic vial should be discarded, as Frovaire® Combi Nebula does not contain preservatives. In most cases, dilution of the dose with preservative-free sterile physiological saline is not necessary. However, Frovaire® Combi Nebula solution volumes less than 2 mL are unsuitable for nebulization and must be diluted with preservative-free sterile physiological saline or another suitable nebulizer solution so that the total filling volume is 2–5 mL.

Children

The safety of Frovaire® Combi Nebula in children under 12 years of age has not been established; therefore, Frovaire® Combi Nebula is not indicated for this age group.

Overdose

Symptoms

Depending on the duration of overdose, the following 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 in fingers and throughout the body. Hyperglycemia may develop.

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

When fenoterol is administered at doses higher than recommended for Frovaire® Combi Nebula, 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 availability of inhaled ipratropium.

Treatment

Administration of Frovaire® Combi Nebula should be discontinued. Acid-base balance and electrolyte monitoring should be considered.

Administration of sedatives and tranquilizers; in severe cases, intensive therapy including hospitalization is required. 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, including ECG, is recommended.

Adverse reactions

Most of the adverse reactions listed below can be explained by the anticholinergic and beta-adrenergic properties of the medicinal product FRIEVIEW® COMBI Nebula.

Frequency according to the MedDRA Convention: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated from available data).

Immune system disorders:
Rare – anaphylactic reactions*, hypersensitivity*; frequency not known – purpura.

Metabolism and nutritional disorders:
Rare – hypokalaemia; very rare – increased blood glucose levels.

Psychiatric disorders:
Uncommon – nervousness; rare – agitation, psychiatric changes.

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

Nervous system disorders:
Uncommon – headache, tremor, dizziness; frequency not known – hyperactivity.

Eye disorders:
Rare – glaucoma*, increased intraocular pressure*, accommodation disorder*, mydriasis*, blurred vision*, eye pain*, corneal oedema*, conjunctival hyperaemia*, visual halos*.

Cardiac disorders:
Uncommon – tachycardia, palpitations; rare – arrhythmia, atrial fibrillation, supraventricular tachycardia*, myocardial ischaemia*; frequency not known – anginal pain, 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*; frequency not known – local irritation.

Gastrointestinal disorders:
Uncommon – nausea, vomiting, dry mouth; rare – stomatitis, glossitis, gastrointestinal motility disorder**, diarrhoea, constipation*, oedema of 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 the medicinal product. Frequency stated at 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 = 0.00060, meaning "isolated" events).

** Patients with cystic fibrosis may be particularly susceptible to gastrointestinal motility disorders when using inhaled anticholinergic components (contained in FRIEVIEW® COMBI Nebula).

Like other medicinal products for inhalation therapy, FRIEVIEW® COMBI Nebula may cause symptoms of local irritation. The most commonly reported adverse reactions observed during clinical trials were cough, dry mouth sensation, headache, tremor, pharyngitis, nausea, dizziness, dysphonia, tachycardia, palpitations, vomiting, increased systolic blood pressure, and nervousness.

Shelf life. 2 years.

After first opening of the foil pouch, unused nebulisers should be stored in the same pouch for no longer than 3 months.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach and sight of children.

Packaging.
4 ml in a polyethylene nebuliser, in a foil pouch.

10 or 20 nebulisers are packed in a carton.

Prescription category. Prescription only.

Manufacturer. JSC "Farmak".

Manufacturer's address and place of business.
74, Kyrylivska Street, Kyiv, 04080, Ukraine.