Ipraterol-Nativ (Solution) Instructions for Use

ATC Code

R03AL01 (Fenoterol and Ipratropium bromide)

Active Substances

Fenoterol (Rec.INN registered by WHO)

Ipratropium bromide (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Bronchodilator drug

Pharmacotherapeutic Group

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

Pharmacological Action

Ipraterol-Nativ contains two components with bronchodilatory activity: Ipratropium bromide – an m-cholinergic blocker and Fenoterol – a β₂-adrenomimetic.

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

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

Ipratropium bromide does not have a negative effect on mucus secretion in the airways, mucociliary clearance and gas exchange.

Fenoterol selectively stimulates β₂-adrenergic receptors at a therapeutic dose.

Stimulation of β₂-adrenergic receptors occurs when using high doses.

Fenoterol relaxes the smooth muscles of the bronchi and blood vessels and counteracts the development of bronchospastic reactions caused by the influence of 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 using fenoterol in higher doses, an enhancement of mucociliary clearance was noted.

The beta-adrenergic effect of the drug on cardiac activity, such as an increase in heart rate and contractility, is due to the vascular action of fenoterol, stimulation of cardiac β₂-adrenergic receptors, and when using 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 using high doses.

The clinical significance of this manifestation has not been established.

Tremor is the most common adverse effect when using beta-adrenergic receptor agonists.

When these two active substances are used together, the bronchodilatory effect is achieved by acting on different pharmacological targets.

These substances complement each other, resulting in an enhanced antispasmodic effect on the bronchial muscles and providing a broad therapeutic effect 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, which allows for the selection of an effective dose with virtually no side effects.

Pharmacokinetics

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

Absorption

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 using high doses of the active substance, as well as through the use of specific enrichment methods.

When used by inhalation in therapeutic doses, plasma concentrations of ipratropium bromide were 1000 times lower than after oral and intravenous administration.

Fenoterol. Depending on the inhalation method and the inhalation system used, about 10-30% of the active substance reaches the lower respiratory tract, and the remainder is deposited in the upper respiratory tract and swallowed.

As a result, a certain amount of inhaled fenoterol enters the gastrointestinal tract.

Absorption is biphasic – 30% of fenoterol is rapidly absorbed with a half-life of 11 minutes, 70% is absorbed slowly with a half-life of 120 minutes.

There is no correlation between the plasma concentrations of fenoterol achieved after inhalation and the pharmacodynamic “time-effect” curve.

The long-lasting bronchodilatory 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.

The time to reach maximum plasma concentration is 2 hours.

Distribution

Ipratropium bromide. Being a quaternary ammonium derivative, it is poorly soluble in fats and poorly penetrates biological membranes.

Does not accumulate.

Fenoterol. Plasma protein binding is 40-55%.

Fenoterol penetrates the placental barrier unchanged and is excreted in breast milk.

Metabolism

Ipratropium bromide. Metabolized in the liver.

Up to 8 metabolites of ipratropium are known, which weakly bind to muscarinic receptors.

Fenoterol. Metabolized in the liver.

After 24 hours, 60% of the intravenously administered dose and 35% of the oral dose are excreted in the urine.

This fraction of the active substance undergoes biotransformation due to the “first-pass effect” through the liver, as a result of which the bioavailability of the drug after oral administration drops 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 exclusively by conjugation with sulfates, mainly in the intestinal wall.

Excretion

Ipratropium bromide. Excreted mainly through the intestines.

About 25% is excreted unchanged, the rest – in the form of numerous metabolites.

Fenoterol. Excreted by the kidneys and with bile in the form of inactive sulfate conjugates.

With parenteral administration, Fenoterol is excreted according to a three-phase model with half-lives of 0.42 minutes, 14.3 minutes and 3.2 hours.

The pharmacokinetics of the combination of ipratropium bromide and fenoterol in the population of elderly and children, as well as in patients with impaired liver and kidney function, have not been studied.

Indications

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

ICD codes

Dosage Regimen

Solution

The dose should be selected individually.

Medical supervision is required during therapy.

The following doses are recommended

In adults (including the elderly) and adolescents over 12 years

Acute attacks of bronchial asthma

For mild and moderate attacks, 1 ml (20 drops) is recommended in many cases.

In particularly severe cases, for example in patients in intensive care units, if the doses indicated above are ineffective, higher doses, up to 2.5 ml (50 drops), may be required.

The maximum dose can reach 4.0 ml (80 drops).

The maximum daily dose is 8.0 ml (160 drops).

Course and long-term treatment

If repeated use is necessary, 1-2 ml (20-40 drops) are used for each administration up to 4 times a day.

In case of moderate bronchospasm or as an aid during lung ventilation, a dose with a lower limit of 0.5 ml (10 drops) is recommended.

In children aged 6-12 years:

Acute attacks of bronchial asthma

In many cases, 0.5 – 1 ml (10 -20 drops) is recommended for rapid relief of symptoms.

In severe cases, if a dose of 1 ml (20 drops) is ineffective, higher doses, up to 2 ml (40 drops), may be required.

In particularly severe cases, if a dose of up to 2.0 ml (40 drops) is ineffective, it is possible to use (subject to medical supervision) a maximum dose of up to 3.0 ml (60 drops).

The maximum daily dose can reach 4.0 ml (80 drops).

Course and long-term treatment

If repeated use is necessary, 0.5 – 1 ml (10-20 drops) are used for each administration up to 4 times a day.

In cases of moderate bronchospasm or as an aid during lung ventilation, the recommended dose is 0.5 ml (10 drops).

In children under 6 years of age (with a body weight of less than 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): about 25 mcg of ipratropium bromide and 50 mcg of fenoterol hydrobromide = 0.1 ml (2 drops) per kg of body weight (per single dose), but not more than 0.5 ml (10 drops) (per single dose).

The maximum daily dose is 1.5 ml.

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

Treatment should usually be started with the lowest recommended dose.

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.

Ipraterol-Nativ inhalation solution should not be diluted with distilled water.

Dilution of the solution should be carried out each time before use, and the residues of the diluted solution should be discarded.

The diluted solution should be used immediately after preparation.

Dosage may depend on the inhalation method and the type of nebulizer.

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

Ipraterol-Nativ inhalation solution can be used with various commercial models of nebulizers.

In cases where wall oxygen is available, the solution is best applied at a flow rate of 6-8 liters per minute.

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

Adverse Reactions

Frequency definition: very common (>1/10), common (from 1/100 to 1/10), uncommon (from 1/1000 to 1/100), rare (from 1/10000 to 1/000), very rare (1/10000).

Nervous system disorders common – fine tremor of skeletal muscles, nervousness; rare – headache, dizziness, very rare – mental changes.

Cardiovascular system disorders common – tachycardia, including supraventricular tachycardia; palpitations (especially in patients with aggravating factors); rare (when used in high doses)
– decrease in diastolic blood pressure, increase in systolic blood pressure, arrhythmia (including
Atrial fibrillation).

Respiratory system disorders rare – cough, local irritation of the respiratory tract, pharyngitis; very rare paradoxical bronchospasm, laryngospasm.

Gastrointestinal disorders common – dry mouth; uncommon – impaired gastrointestinal motility, vomiting, constipation, diarrhea (especially in patients with cystic fibrosis).

Eye disorders if the drug gets into the eye – mydriasis, increased intraocular pressure, glaucoma, eye pain; sometimes during treatment with the drug, reversible accommodation disturbances and glaucoma are noted.

Eye pain or discomfort, blurred vision, sensation of halos or colored spots before the eyes, combined with conjunctival hyperemia and corneal edema may be symptoms of acute glaucoma.

Pupil-constricting drops should be used and an ophthalmologist should be consulted immediately.

Allergic reactions rare – skin rash, angioedema of the tongue, lips and face, urticaria.

Other urinary retention, increased sweating, hypokalemia, feeling of general weakness, myalgia.

Contraindications

• Hypersensitivity to fenoterol or atropine-like drugs or other components of the drug Ipraterol-Nativ;
• Hypertrophic obstructive cardiomyopathy;
• Tachyarrhythmia;
• I and III trimesters of pregnancy.

With caution angle-closure glaucoma, arterial hypertension, diabetes mellitus, recent myocardial infarction (within the last 3 months), heart and vascular diseases such as chronic heart failure, coronary artery disease, aortic stenosis, severe lesions of cerebral and peripheral arteries, hyperthyroidism, pheochromocytoma, prostatic hyperplasia, bladder neck obstruction, cystic fibrosis, II trimester of pregnancy, breastfeeding, children under 6 years of age.

Use in Pregnancy and Lactation

Data from preclinical studies and experience with the use of 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 taken into account.

The drug is contraindicated in the I and III trimesters of pregnancy (possibility of weakening of labor by fenoterol).

The drug should be used with caution in the II trimester of pregnancy.

Fenoterol passes into breast milk.

No data confirming that Ipratropium bromide passes into breast milk have been obtained.

However, the drug Ipraterol-Nativ should be prescribed with caution to nursing mothers.

Pediatric Use

With caution in children under 6 years of age

Special Precautions

In case of unexpected rapid increase in shortness of breath (breathing difficulties), a doctor should be consulted without delay.

Long-term use

• In patients suffering from bronchial asthma or mild to moderate COPD, symptomatic treatment may be preferable to regular use;
• In patients with bronchial asthma or severe forms of COPD, it should be remembered that it is necessary 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 β₂-adrenomimetics, such as the drug Ipraterol-Nativ, to relieve bronchial obstruction can cause uncontrolled worsening of the disease.

In case of increased bronchial obstruction, increasing the dose of β₂-agonists, including the drug Ipraterol-Nativ, beyond the recommended one for a long time is not only unjustified, but also dangerous.

To prevent life-threatening deterioration of the disease, the issue of revising the patient’s treatment plan and adequate anti-inflammatory therapy with inhaled glucocorticosteroids should be considered.

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

Other sympathomimetic bronchodilators should be prescribed simultaneously with the drug Ipraterol-Nativ only under medical supervision.

Patients should be instructed on the correct use of the Ipraterol-Nativ 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.

Patients predisposed to the development of glaucoma should take particular care to protect their eyes.

Effect on ability to drive vehicles and operate machinery

No studies have been conducted on the effect of the drug on the ability to drive vehicles and operate machinery.

Cases of dizziness and blurred vision when using the drug may have a negative impact on the aforementioned ability.

Overdose

Symptoms of overdose are usually associated with the action of fenoterol.

The appearance of symptoms associated with excessive stimulation of beta-adrenergic receptors is possible.

The most likely are tachycardia, palpitations, tremor, increased blood pressure, increased difference between systolic and diastolic blood pressure, angina pectoris, arrhythmia and a feeling of “flushing” of the face, a feeling of heaviness behind the sternum, increased bronchial obstruction, metabolic acidosis.

Possible overdose symptoms caused by ipratropium bromide (such as dry mouth, accommodation disturbance) are mild and transient, which is explained by its local application.

Treatment it is recommended to prescribe sedatives, anxiolytic drugs (tranquilizers), in severe cases – intensive therapy.

As a specific antidote, the use of beta-blockers, preferably selective β₁-blockers, is possible.

However, in patients with bronchial asthma or COPD, the possibility of increased bronchial obstruction, which can be fatal under the influence of beta-blockers, should be taken into account and their dose should be carefully selected.

Drug Interactions

Simultaneous use of other beta-adrenergic agents, systemic anticholinergic drugs and xanthine derivatives (for example, theophylline) may enhance the bronchodilatory effect of the drug Ipraterol-Nativ.

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

Hypokalemia associated with the use of beta-adrenergic agents may be enhanced by the simultaneous administration of xanthine derivatives, glucocorticosteroids and diuretics.

This fact should be given special attention in the treatment of patients with severe forms of obstructive airway diseases.

Hypokalemia can lead to an increased risk of arrhythmias in patients receiving digoxin.

Furthermore, hypoxia can enhance the negative effect of hypokalemia on heart rhythm.

In such cases, it is recommended to monitor the level of potassium in the blood serum.

Beta-adrenergic agents should be prescribed with caution to patients who have received MAO inhibitors and tricyclic antidepressants, as these drugs can enhance the effect of beta-adrenergic agents.

Inhalation of general anesthetics, halogenated hydrocarbon anesthetics, for example, halothane, trichloroethylene or enflurane, can enhance the effect of beta-adrenergic agents on the cardiovascular system.

Concomitant use of the drug Ipraterol-Nativ with cromoglicic acid and/or glucocorticosteroids increases the effectiveness of therapy.

Storage Conditions

In a dry place, protected from light, at a temperature not exceeding 25°C (77°F). Do not freeze. Keep out of reach of children.

Shelf Life

The shelf life is 2 years.

Dispensing Status

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.