Atrovent^® N (Aerosol) Instructions for Use

Marketing Authorization Holder

Boehringer Ingelheim International, GmbH (Germany)

Manufactured By

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

ATC Code

R03BB01 (Ipratropium bromide)

Active Substance

Ipratropium bromide (Rec.INN registered by WHO)

Dosage Form

Atrovent® N

Metered dose inhalation aerosol 20 mcg/1 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 liquid, free from suspended particles.

Excipients : absolute ethanol – 8.415 mg, purified water – 281 mcg, citric acid – 2 mcg, tetrafluoroethane (HFA 134a, propellant) – 47.381 mg.

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

Clinical-Pharmacological Group

Bronchodilator drug – m-cholinergic receptor blocker

Pharmacotherapeutic Group

M-cholinoblocker

Pharmacological Action

Bronchodilator drug, m-cholinergic receptor blocker. 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 an increase in the intracellular concentration of calcium ions, which occurs as a result of the interaction of acetylcholine with m-cholinergic receptors located in the bronchial smooth muscles.

The release of calcium ions occurs with the help of secondary messengers (mediators), which include inositol triphosphate (ITP) and diacylglycerol (DAG). It effectively prevents bronchoconstriction resulting from inhalation of cigarette smoke, cold air, the action of various bronchoconstrictors, 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^® N 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.

In patients with bronchial asthma, a significant improvement in external respiratory function is noted in 51% of patients.

Pharmacokinetics

The therapeutic effect of Atrovent^® N 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 drug dose (depending on the dosage form and inhalation method) enters the lungs. Most of the dose is swallowed and enters the gastrointestinal tract. The part of the drug dose that enters the lungs quickly reaches the systemic bloodstream (within a few minutes).

The total systemic bioavailability of ipratropium bromide when taken orally and by inhalation is 2% and 7-28%, respectively. Thus, the influence of the swallowed part of tiotropium bromide on systemic exposure is insignificant.

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 (approximately 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 ml/min, and renal clearance is 0.9 L/min. The total renal excretion (over 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. The total isotopically labeled dose excreted through the intestine was 6.3% after intravenous administration, 88.5% after oral administration, and 69.4% after inhalation. Thus, excretion of the isotopically labeled dose after intravenous administration occurs mainly through 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 (especially with concomitant cardiovascular diseases).

ICD codes

Dosage Regimen

The dosage regimen is set individually. During treatment, patients should be under medical supervision. The recommended daily dose should not be exceeded, both during emergency and maintenance therapy.

If treatment does not lead to significant improvement or the patient’s condition worsens, a doctor’s consultation is necessary to change the treatment plan. In case of unexpected or rapid increase in shortness of breath (breathing difficulties), you should immediately consult a doctor.

The following doses are recommended (unless a different dosage regimen is prescribed).

Adults and children over 6 years old are prescribed 2 inhalation doses (puffs) 4 times/day. Since the need to increase doses indicates the possible need for additional treatment methods, as a rule, no more than 12 inhalation doses should be used per day.

For the treatment of sudden exacerbations of chronic obstructive pulmonary disease, Atrovent^® solution for inhalation may be indicated.

In children, Atrovent^® N should be used only as prescribed by a doctor and under adult supervision (due to insufficient information).

Rules for using the drug

For successful therapy, the correct use of the drug is important.

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

Each time you use the metered dose aerosol, you must follow the following rules

1. Remove the protective cap.

2. Exhale deeply.

3. Holding the inhaler, tightly clasp the mouthpiece with your lips. The arrow and the bottom of the canister should be pointing up.

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 the second inhalation dose, repeat the steps from step 2.

5. After using the inhaler, put on the protective cap.

6. If the aerosol inhaler has not been used for more than 3 days, then before use, press the valve once.

The canister is not transparent, so it is impossible to determine by eye when it becomes empty. The inhaler contains 200 inhalation doses. After using all doses, it may seem that the canister still contains a small amount of liquid. Nevertheless, the inhaler should be replaced, otherwise you may not get the necessary therapeutic dose.

The amount of the drug in your inhaler can be checked in the following ways

• Shake the canister, this will show if there is any amount of liquid left 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 getting into it, which could block the release of the aerosol.

During cleaning, first remove the protective cap and remove the canister from the inhaler. Run a stream of warm water through the inhaler, making 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 plastic mouthpiece is specially designed for use with the Atrovent^® N metered dose aerosol and serves for accurate dosing of the drug. This mouthpiece should not be used with other metered dose aerosols. The Atrovent^® N metered dose aerosol should also not be used with other mouthpieces.

The aerosol in the canister is under pressure.

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

Adverse Reactions

Many of the listed undesirable effects may be a consequence of the anticholinergic properties of Atrovent^® N. Atrovent^® N, like any inhalation therapy, can cause local irritation. Adverse reactions of the drug were determined based on data obtained in clinical studies and during pharmacological surveillance of the drug 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).

From the immune system uncommon – hypersensitivity, anaphylactic reactions, angioedema; rare – urticaria.

From the nervous system common – headache, dizziness.

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

From the cardiovascular system uncommon – palpitations, supraventricular tachycardia; rare – atrial fibrillation, increased heart rate.

From the respiratory system common – irritation of the pharyngeal mucosa, cough; uncommon – bronchospasm, paradoxical bronchospasm, laryngospasm, pharyngeal edema, dry throat.

From the digestive system common – dry mouth, nausea, gastrointestinal motility disorder; uncommon – diarrhea, constipation, vomiting, stomatitis, oral mucosa edema.

From the urinary system uncommon – urinary retention.

From the skin and subcutaneous tissues uncommon – rash, itching.

Contraindications

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

With caution: angle-closure glaucoma, urinary tract obstruction, cystic fibrosis, childhood.

Use in Pregnancy and Lactation

The safety of using Atrovent^® N during human pregnancy has not been established.

When prescribing the drug during possible or confirmed pregnancy, the ratio of the expected benefit of prescribing the drug for the mother and the possible risk for the fetus should be taken into account.

The use of Atrovent^® N is contraindicated in the first trimester of pregnancy. Prescribing the drug in the second and third trimesters of pregnancy is possible only if the expected benefit of therapy for the mother outweighs the possible risk to the fetus.

In preclinical studies, no embryotoxic or teratogenic effects of the drug were found after its inhalation use 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^® N, 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

The drug should be prescribed with caution to children under 6 years of age.

Special Precautions

Hypersensitivity

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

Paradoxical bronchospasm

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

Eye complications

Atrovent^® N 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, the appearance of halos around objects and colored spots before the eyes in combination with red eyes due to conjunctival vessel 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 aerosol from getting into the eyes. Since the aerosol is released from the canister only when the patient presses it and enters the oral cavity from the mouthpiece, the risk of it getting into the eyes is low.

Effect on the urinary tract

Atrovent^® N should be used with caution in patients with existing urinary tract obstruction (for example, with prostate hyperplasia or bladder neck obstruction).

Gastrointestinal motility disorder

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

The patient should be informed that if inhalation is not effective enough or the condition has worsened, 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.

It should be taken into account that the drug contains a small amount of ethanol (8.415 mg in one dose).

Effect on the ability to drive vehicles and mechanisms

Studies on the effect of the drug on the ability to drive vehicles and mechanisms 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 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^® N, the appearance of any serious anticholinergic symptoms is unlikely. Minor manifestations of systemic anticholinergic action (including dry mouth, visual disturbances, increased heart rate) are possible.

Treatment symptomatic therapy.

Drug Interactions

Long-term combined use of Atrovent^® N 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 bronchodilatory effect of Atrovent^® N.

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

Storage Conditions

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

Shelf Life

Shelf life – 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.