Abrol®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ABROL® (ABROL®)

Composition:

Active substance: ambroxol hydrochloride (ambroxol hydrochloride);

2 ml of solution for inhalation and oral administration contains 15 mg of ambroxol hydrochloride;

Excipients: citric acid monohydrate; sodium chloride; benzalkonium chloride solution; sodium hydrogen phosphate, dihydrate; purified water.

Pharmaceutical form. Solution for inhalation and oral administration.

Main physicochemical properties: clear, colorless or slightly yellowish solution with a characteristic odor.

Pharmacotherapeutic group.

Medicines used for cough and colds. Mucolytic agents.

ATC code R05C B06.

Pharmacological properties.

Pharmacodynamics.

The active ingredient of the solution for inhalation and oral use, Abrol® – ambroxol hydrochloride – is a substituted benzylamine and a metabolite of bromhexine. It differs from bromhexine by the absence of a methyl group and the presence of a hydroxyl group in the para-trans-position of the cyclohexyl ring.

Studies have demonstrated its secretolytic and secretomotor effects in the bronchial tract.

After oral administration, the effect begins on average within 30 minutes and lasts 6–12 hours, depending on the individual dose.

Preclinical studies have shown that ambroxol hydrochloride increases the serous component of bronchial secretion. Ambroxol enhances mucus clearance by reducing viscosity and activating ciliary epithelium.

Ambroxol activates the surfactant system through a direct effect on type II pneumocytes in the alveoli and Clara cells in the region of the small airways. It stimulates the formation and release of surfactant material in the alveoli and bronchial tree of both fetus and adult. These effects have been demonstrated in various biological species using cell cultures and in vivo.

Furthermore, antioxidant effects of ambroxol have been demonstrated in various preclinical studies.

Following administration of ambroxol hydrochloride, concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin, and doxycycline) increase in bronchopulmonary secretions and sputum. To date, the clinical significance of this finding has not been established.

Antiviral properties in vitro and in experimental animal models

In in vitro studies on human tracheal epithelial cells, reduced replication of rhinovirus (RV 14) was observed. In a murine respiratory model, reduced replication of influenza A virus was observed following pretreatment with ambroxol. To date, the clinical relevance of this effect has not been confirmed.

Pharmacokinetics.

Absorption. Ambroxol is almost completely absorbed after oral administration. Tmax after oral intake ranges from 1 to 3 hours. Absolute bioavailability of ambroxol after oral administration is reduced by approximately one-third due to presystemic metabolism.

Distribution. Approximately 85% (80–90%) of the drug is bound to plasma proteins. In lung tissue, ambroxol reaches higher concentrations than in plasma after parenteral administration. Ambroxol can penetrate into cerebrospinal fluid, cross the placental barrier, and is excreted into breast milk.

Metabolism. Formation of metabolites capable of renal excretion (e.g., dibromanthranilic acid, glucuronide) occurs in the liver.

Elimination. Nearly 90% of the drug is excreted by the kidneys in the form of metabolites produced in the liver. Less than 10% of ambroxol is excreted unchanged by the kidneys. Due to the high degree of protein binding, large volume of distribution, and slow redistribution of the drug from tissues into blood, significant elimination of ambroxol by dialysis or forced diuresis is unlikely.

Terminal elimination half-life from plasma is 7–12 hours. The elimination half-life of ambroxol and its metabolites from plasma is approximately 22 hours.

Patients with hepatic or renal impairment. In patients with severe hepatic dysfunction, ambroxol clearance is reduced by 20–40%. In patients with severe renal impairment, accumulation of ambroxol metabolites may occur.

Clinical characteristics.

Indications.

Mucolytic therapy in acute and chronic bronchopulmonary diseases associated with impaired bronchial secretion and reduced mucus clearance.

Contraindications.

Abral® solution for inhalation and oral use must not be administered to patients with hypersensitivity to ambroxol hydrochloride or other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

When using Abral® in combination with antitussive agents in patients with existing respiratory diseases associated with mucus hypersecretion, such as cystic fibrosis or bronchiectasis, accumulation of secretions (potentially dangerous) may occur due to suppression of the cough reflex.

Special precautions for use

Since all inhalation products may cause bronchospasm, the medicinal product Abrol should not be used in patients with known bronchial hyperreactivity and/or diagnosed atopy.

There have been reports of severe skin reactions: erythema multiforme, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP) associated with the use of ambroxol hydrochloride. If signs of progressive skin rash (sometimes associated with blistering or mucosal involvement) appear, treatment with ambroxol hydrochloride should be discontinued immediately and medical advice sought.

Abrol® solution for inhalation and oral use should be administered with caution in patients with impaired bronchial motility and increased mucus secretion (e.g. in rare conditions such as primary ciliary dyskinesia) due to the risk of promoting secretion accumulation.

Patients with impaired renal function or severe hepatic insufficiency should take Abrol® only after consultation with a physician. In patients with severe renal impairment, administration of ambroxol—like any active substance metabolized in the liver and subsequently excreted by the kidneys—may lead to accumulation of metabolites formed in the liver.
Excipients

Abrol® solution for inhalation and oral use contains benzalkonium chloride solution as a preservative. When inhaled, benzalkonium chloride may cause bronchospasm.

Abrol® solution for inhalation and oral use contains 49.8 mg of sodium in the recommended daily dose. This should be taken into account for patients on a controlled sodium diet.

Use during pregnancy or breastfeeding

Pregnancy

Ambroxol hydrochloride crosses the placental barrier. Clinical studies of the use of the drug after the 28th week of pregnancy have not shown any harmful effects on the fetus or the course of pregnancy. Preclinical studies have not revealed direct or indirect harmful effects on pregnancy, embryonal/fetal development, parturition, or postnatal development. However, usual precautions regarding medication use during pregnancy should be observed. Abrol® is not recommended during the first trimester of pregnancy.

Breastfeeding

Ambroxol hydrochloride passes into breast milk. Abrol® is not recommended during breastfeeding.

Fertility

Preclinical studies do not indicate a direct or indirect harmful effect on fertility.

Ability to influence reaction speed when driving or operating machinery

There are no data on the effect on reaction speed when driving or operating machinery. Studies on the influence on reaction speed when driving or operating machinery have not been conducted.

Method of Administration and Dosage

Inhalation Solution

Adults and children aged 6 years and older: 1–2 inhalations of 2–3 mL of solution per day.

Children under 6 years of age: 1–2 inhalations of 2 mL of solution per day.

Abral**®** inhalation solution can be used with all modern inhalation devices (except steam inhalators).

Abral**®** inhalation solution should be diluted in a 1:1 ratio with physiological saline to ensure optimal humidification of the air delivered by the device.

Abral**®** inhalation solution must not be mixed with cromoglycic acid. It should also not be mixed with other solutions resulting in a mixture pH exceeding 6.3, for example, alkaline inhalation salt (Emser Salt). An increase in pH may lead to precipitation of the free base of ambroxol hydrochloride or clouding of the solution.

The inhalation solution is generally recommended to be warmed to body temperature before starting inhalation.

If only one daily inhalation is possible, additional oral administration of Abral**®** is recommended.

Since the inhalation process itself may provoke coughing, patients are advised to breathe normally during inhalation.

Patients with bronchial asthma should use bronchospasmolytics prior to inhalation to open the airways.

Oral Solution

Adults and children aged 12 years and older: 4 mL three times daily during the first 2–3 days, totaling 90 mg of ambroxol per day; thereafter, 2 mL three times daily, totaling 45 mg of ambroxol per day. The dosage of 4 mL three times daily may be continued after consultation with a physician.

Children aged 6 to 12 years: 2 mL two to three times daily, totaling 30–45 mg of ambroxol per day.

Children aged 2 to 6 years: 1 mL three times daily, totaling 22.5 mg of ambroxol per day.

Children under 2 years of age: 1 mL twice daily, totaling 15 mg of ambroxol per day.

Dosing in patients with renal and/or hepatic impairment.

In patients with severe renal or severe hepatic impairment, the medication should be administered only after consultation with a physician, as it may be necessary to reduce the maintenance dose or prolong the dosing interval.

Abral**®** inhalation and oral solution should not be used for longer than 4–5 days without consulting a physician.

In acute conditions, consult a physician if symptoms persist or worsen despite treatment with Abral**®**.

Abral**®** oral solution may be diluted in water, tea, fruit juice, or milk. Abral**®** can be taken independently of food intake.

The mucolytic effect of Abral**®** is supported by adequate fluid intake.

Children.

The medication may be used in pediatric practice. For children under 2 years of age, use only on medical advice.

Overdose.

There have been no reports of specific overdose symptoms. Symptoms described in isolated cases of overdose and/or medication misuse correspond to the known adverse reactions associated with ambroxol hydrochloride at recommended doses and require symptomatic treatment.

Side effects

The adverse reactions listed below are classified by organ systems and frequency:

Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1,000, <1/100), rare (≥1/10,000, <1/1,000), very rare (<1/10,000, including isolated cases), frequency not known (frequency cannot be estimated from available data).

Within each group, adverse reactions are listed in order of decreasing severity.

Immune system disorders: rare – hypersensitivity reactions; frequency not known – anaphylactic reactions, including anaphylactic shock, angioneurotic edema, pruritus.

Skin and subcutaneous tissue disorders: rare – rash, urticaria; frequency not known – serious skin adverse reactions (including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).

Nervous system disorders: common – dysgeusia (taste disturbance).

Gastrointestinal disorders: common – nausea, oral numbness; uncommon – vomiting, diarrhea, dyspepsia, abdominal pain, dry mouth; rare – dry throat; very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders: common – pharyngeal numbness; very rare – dyspnea and bronchospasm; frequency not known – dyspnea (as a symptom of hypersensitivity reaction).

General disorders: uncommon – pyrexia, mucosal reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life

3 years.

Storage conditions

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging

100 ml in a glass bottle with a tamper-evident cap; 100 ml in a glass bottle with a child-resistant cap. Each bottle is packaged in a cardboard box together with a 5 ml dosing syringe and a syringe adapter.

Prescription status

Over-the-counter (without prescription).

Manufacturer

LLC "KUSUM PHARM".

Manufacturer's location and address of place of business

54 Skryabina Street, Sumy, Sumy Oblast, 40020, Ukraine.

or

Manufacturer

LLC "GLEDFARM LTD".

Manufacturer's location and address of place of business

54 Davydovskoho Hryhorii Street, Sumy, Sumy Oblast, 40020, Ukraine.