Atrovent^® (Solution) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

Instituto De Angeli S.r.l. (Italy)

ATC Code

R03BB01 (Ipratropium bromide)

Active Substance

Ipratropium bromide

Dosage Form

Atrovent®

Solution for inhalation 250 mcg/1 ml: 20 ml bottle with dropper

Dosage Form, Packaging, and Composition

Solution for inhalation clear, colorless or almost colorless, practically free from particles.

Excipients : benzalkonium chloride – 0.1 mg, disodium edetate dihydrate – 0.5 mg, sodium chloride – 8.8 mg, hydrochloric acid 1N (to adjust pH to 3.4) – 0.659 mg, purified water – up to 1 ml.

20 ml – dark glass bottles with a polyethylene dropper and a screw-on polypropylene cap with first-opening control (1) – cardboard packs.

Clinical-Pharmacological Group

Bronchodilator drug – m-cholinergic receptor blocker

Pharmacotherapeutic Group

M-cholinoblocker

Pharmacological Action

Bronchodilator agent. It blocks m-cholinergic receptors of the smooth muscles of the tracheobronchial tree and suppresses reflex bronchoconstriction. Having a structural similarity to the acetylcholine molecule, it is its competitive antagonist.

Anticholinergic agents prevent the increase in intracellular calcium ion concentration, which occurs as a result of the interaction of acetylcholine with muscarinic receptors located in the bronchial smooth muscles.

The release of calcium ions occurs with the help of mediators, which include IP3 (inositol triphosphate) and DAG (diacylglycerol).

It effectively prevents bronchospasm resulting from inhalation of cigarette smoke, cold air, the action of various drugs, and also relieves bronchospasm associated with the influence of the vagus nerve. When used by inhalation, it has practically no resorptive effect. The bronchodilation that occurs after inhalation of Atrovent^® is mainly a consequence of the local and specific effect of the drug on the lungs, and not the result of its systemic effect. Ipratropium bromide does not have a negative effect on mucus secretion in the airways, mucociliary clearance, and gas exchange.

In controlled 85-90-day studies conducted in patients with bronchospasm due to COPD, chronic bronchitis, and pulmonary emphysema, a significant improvement in lung function was observed within 15 minutes, reached a maximum after 1-2 hours, and lasted up to 4-6 hours.

Pharmacokinetics

The therapeutic effect of Atrovent^® is a consequence of its local action in the respiratory tract. The development of bronchodilation is not parallel to pharmacokinetic parameters.

Absorption

After inhalation, usually 10-30% of the administered dose of the drug enters the lungs (depending on the dosage form and inhalation method). Most of the dose is swallowed and enters the gastrointestinal tract. The part of the drug dose that reaches the lungs quickly enters the systemic circulation (within a few minutes).

Total renal excretion (within 24 hours) of the parent compound is approximately 46% of the intravenously administered dose, less than 1% of the orally administered dose, and approximately 3-13% of the inhalation dose of the drug. Based on these data, it is calculated that the total systemic bioavailability of orally and inhalationally administered ipratropium bromide is 2% and 7-28%, respectively. Thus, the effect of the swallowed portion of tiotropium bromide on systemic exposure is negligible.

Distribution

Binding to plasma proteins is minimal (less than 20%).

Kinetic parameters describing the distribution of ipratropium bromide were calculated based on its plasma concentrations after intravenous 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).

Ipratropium bromide, being a quaternary ammonium compound, does not penetrate the placental barrier and the blood-brain barrier.

Metabolism

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

Known metabolites formed by hydrolysis, dehydration, or removal of the hydroxymethyl group from tropic acid and excreted in the urine bind weakly to muscarinic receptors and are considered inactive.

Excretion

T_1/2 in the terminal phase is approximately 1.6 hours. The total clearance of ipratropium bromide is 2.3 L/min, and renal clearance is 0.9 L/min. Total renal excretion (within 6 days) of the isotopically labeled dose (including the parent compound and all metabolites) was 72.1% after intravenous administration, 9.3% after oral administration, and 3.2% after inhalation administration. The total isotopically labeled dose excreted via the intestine was 6.3% after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation administration. Thus, excretion of the isotopically labeled dose after intravenous administration occurs mainly by the kidneys. T_1/2 of the parent compound and metabolites is 3.6 hours.

Indications

• COPD (including chronic obstructive bronchitis, pulmonary emphysema);
• Mild to moderate bronchial asthma.

ICD codes

Dosage Regimen

20 drops = 1 ml, 1 drop = 12.5 mcg of anhydrous ipratropium bromide.

The dosage regimen is selected individually. During treatment, patients should be under medical supervision.

The recommended daily dose should not be exceeded, either during emergency or maintenance therapy.

If treatment does not lead to significant improvement or if the patient’s condition worsens, a doctor’s consultation is necessary to develop a new treatment plan. In case of unexpected or rapidly increasing shortness of breath, the patient should immediately consult a doctor.

For maintenance treatment in adults (including elderly patients) and children over 12 years, 2 ml (40 drops = 500 mcg) 3-4 times/day are prescribed. The maximum daily dose is 8 ml (2 mg).

Treatment of children should be carried out under medical supervision.

Children aged 6 to 12 years are prescribed 1 ml (20 drops = 250 mcg) 3-4 times/day. The maximum daily dose is 4 ml (1 mg).

Children under 6 years of age are prescribed 0.4-1 ml (8-20 drops = 100-250 mcg) 3-4 times/day. The maximum daily dose is 4 ml (1 mg).

For the treatment of acute bronchospasm in adults (including elderly patients) and children over 12 years, 2 ml (40 drops = 500 mcg) are prescribed; repeated administration until the patient’s condition stabilizes is possible. The interval between administrations is determined individually by the attending physician. Atrovent^® can be used simultaneously with inhaled beta₂-adrenergic agonists.

Treatment of children should be carried out under medical supervision.

Children aged 6 to 12 years are prescribed 1 ml (20 drops = 250 mcg); children under 6 years of age – 0.4-1 ml (8-20 drops = 100-250 mcg). Repeated administration until the patient’s condition stabilizes is possible. The interval between administrations is determined individually by the attending physician. Atrovent^® can be used simultaneously with inhaled beta₂-adrenergic agonists.

Children under 6 years of age are prescribed 0.4-1 ml (8-20 drops = 100-250 mcg) 3-4 times/day. Repeated administration until the patient’s condition stabilizes is possible. The interval between administrations is determined individually by the attending physician. Atrovent^® can be used simultaneously with inhaled beta₂-adrenergic agonists.

Rules for using the drug

The recommended dose of the drug should be diluted with 0.9% sodium chloride solution to achieve a volume of 3-4 ml, poured into a nebulizer, and inhaled. The drug should be diluted with 0.9% sodium chloride solution each time immediately before use. The solution remaining after inhalation should be discarded.

Dosing 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.

Atrovent^® can be used with various commercially available nebulizers. When using a centralized oxygen system, the solution is best used at a flow rate of 6-8 L/min.

Adverse Reactions

Many of the listed adverse effects may be a consequence of the anticholinergic properties of Atrovent^®. As with any inhalation therapy, local irritation is possible when using Atrovent^®.

Adverse 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 headache, pharyngeal irritation, cough, dry mouth, gastrointestinal motility disorders (including constipation, diarrhea, and vomiting), nausea, and dizziness.

Definition of frequency categories of 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 unknown (frequency cannot be estimated from available data).

Immune system disorders uncommon – hypersensitivity, anaphylactic reactions, angioedema; rare – urticaria.

Nervous system disorders common – headache, dizziness.

Eye disorders uncommon – blurred vision, mydriasis, increased intraocular pressure, glaucoma, eye pain, appearance of halos around objects, conjunctival hyperemia, corneal edema; rare – accommodation disorder.

Cardiac disorders uncommon – palpitations, supraventricular tachycardia; rare – atrial fibrillation, increased heart rate.

Respiratory, thoracic and mediastinal disorders common – irritation of the pharyngeal mucosa, cough; uncommon – bronchospasm, paradoxical bronchospasm, laryngospasm, pharyngeal edema, dry throat.

Gastrointestinal disorders common – dry mouth, nausea, gastrointestinal motility disorder; uncommon – diarrhea, constipation, vomiting, stomatitis, oral mucosa edema.

Renal and urinary disorders uncommon – urinary retention.

Skin and subcutaneous tissue disorders uncommon – rash, pruritus.

Contraindications

• Hypersensitivity to atropine and its derivatives;
• Hypersensitivity to ipratropium bromide and other components of the drug.

With caution the drug should be prescribed for angle-closure glaucoma, urinary tract obstruction, prostatic hyperplasia, during breastfeeding, and to children under 6 years of age.

Use in Pregnancy and Lactation

The safety of Atrovent^® during human pregnancy has not been established. When prescribing the drug during possible or confirmed pregnancy, the ratio of the expected benefit from prescribing the drug and the possible risk to the fetus should be taken into account.

Preclinical studies did not reveal embryotoxic or teratogenic effects of the drug after its inhalation administration in doses significantly exceeding the doses recommended for humans.

It is not known whether Ipratropium bromide is excreted in breast milk. However, it is unlikely that Ipratropium bromide, especially when used by inhalation, can enter the child’s body in significant quantities with milk. But during the use of Atrovent^®, breastfeeding mothers should exercise caution.

There are no clinical data on the effect of ipratropium bromide on fertility. During the use of ipratropium bromide in preclinical studies, no negative effect on fertility was found.

Use in Renal Impairment

Use with caution in urinary tract obstruction.

Pediatric Use

Prescribe with caution to children under 6 years of age.

Special Precautions

Atrovent^® can be used for combined inhalations simultaneously with ambroxol (inhalation solution), bromhexine (inhalation solution), and the drug Berotec^® (inhalation solution).

Hypersensitivity

After using Atrovent^®, immediate-type hypersensitivity reactions may occur, as indicated by rare cases of rash, urticaria, angioedema, oropharyngeal edema, bronchospasm, and anaphylaxis.

Paradoxical bronchospasm

Atrovent^®, like other inhaled drugs, can cause paradoxical bronchospasm, which can be life-threatening. In case of paradoxical bronchospasm, the use of Atrovent^® should be discontinued immediately and alternative therapy should be prescribed.

Eye complications

Atrovent^® should be used with caution in patients predisposed to the development of angle-closure glaucoma.

There are isolated reports of eye complications (including the development of mydriasis, increased intraocular pressure, development of angle-closure glaucoma, eye pain) in cases where inhaled Ipratropium bromide (used alone or in combination with a beta₂-adrenergic receptor agonist) entered the eyes.

Symptoms of acute angle-closure glaucoma may be pain or discomfort in the eye, blurred vision, seeing halos around objects and colored spots in front of the eyes in combination with red eyes due to conjunctival injection and corneal edema. If any combination of these symptoms develops, the use of eye drops that reduce intraocular pressure and immediate specialist consultation are indicated.

Care should be taken to prevent the solution from getting into the eyes. It is recommended that the solution used with a nebulizer be administered through a mouthpiece. If a mouthpiece is not available and a nebulizer mask is used, it must be used properly.

Effect on the urinary tract

Atrovent^® should be used with caution in patients with existing urinary tract obstruction (e.g., prostatic hyperplasia or bladder neck obstruction).

Gastrointestinal motility disorders

Patients with cystic fibrosis may be predisposed to gastrointestinal motility disorders.

Local effects

The drug Atrovent^® contains the preservative benzalkonium chloride and the stabilizer disodium edetate dihydrate. During inhalation, these components can cause bronchospasm in sensitive patients with airway hyperreactivity.

The patient should be informed that if inhalation is not effective enough or if the condition worsens, they should consult a doctor to change the treatment plan. In case of sudden onset and rapid progression of shortness of breath, the patient should also immediately consult a doctor.

Effect on the ability to drive vehicles and operate 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 types of activities, as dizziness, tremor, accommodation disorder of the eyes, 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 no specific symptoms of overdose have been identified. Given the breadth of therapeutic action and the local method of application of Atrovent^®, the appearance of any serious anticholinergic symptoms is unlikely. Minor manifestations of systemic anticholinergic action (including dry mouth, visual impairment, increased heart rate) are possible.

Treatment symptomatic therapy.

Drug Interactions

Long-term combined use of Atrovent^® inhalations with other anticholinergic drugs has not been studied, so long-term combined use is not recommended.

Beta-adrenergic agents and xanthine derivatives may enhance the bronchodilator effect of Atrovent^®.

In case of simultaneous use via nebulizer of ipratropium bromide and beta-adrenergic agonists in patients with a history of angle-closure glaucoma, the risk of developing acute glaucoma may increase.

Atrovent^® inhalation solution should not be prescribed simultaneously with cromoglicic acid inhalation solution, given the possibility of precipitation.

The anticholinergic effect is enhanced with simultaneous use with antiparkinsonian drugs, quinidine, and tricyclic antidepressants.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F); do not freeze.

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.