LASOLVAN

INSTRUCTIONS for medical use of the medicinal product LАЗОLВАN®

Composition:

Active substance: ambroxol hydrochloride;

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

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

Pharmaceutical form. Solution for inhalation and oral administration.

Main physicochemical characteristics: clear, colourless or slightly brown solution.

Pharmacotherapeutic group.

Medicinal products used for cough and colds. Mucolytic agents.

ATC Code R05C B06.

Pharmacological Properties

Pharmacodynamics

Ambroxol hydrochloride, a substituted benzylamine, is 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 confirmed that ambroxol hydrochloride increases the serous component of bronchial secretions. Ambroxol enhances mucus clearance by reducing viscosity and stimulating ciliary epithelium.

Ambroxol activates the surfactant system by directly affecting type II pneumocytes in alveoli and Clara cells in the region of the small airways. It promotes the formation and release of surfactant in the alveoli and bronchial tree of both fetuses and adults. These effects have been demonstrated in various biological species, in cell cultures, and in vivo.

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

Pharmacokinetics

Absorption

Ambroxol is almost completely absorbed after oral administration. Tmax after oral intake is 1–3 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 in breast milk.

Biotransformation

Metabolite formation capable of entering the kidneys (e.g., dibromanthranilic acid, glucuronide) occurs in the liver.

Elimination

Approximately 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 via dialysis or forced diuresis is unlikely.

Terminal 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 and 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. Secretolytic therapy in acute and chronic bronchopulmonary diseases associated with impaired bronchial secretion and weakened mucus clearance.

Contraindications.

Lazolvan**®**, solution for inhalation and oral administration, must not be used in patients hypersensitive to ambroxol hydrochloride or other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Lazolvan**®** and antitussive agents may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination should only be used after careful assessment by a physician of the expected benefit versus potential risk.

Concomitant administration of ambroxol and antibiotics (amoxicillin, cefuroxime, doxycycline, and erythromycin) results in higher concentrations of antibiotics in bronchopulmonary secretions and sputum.

Special precautions for use

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

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 worsening skin rash (sometimes associated with blistering or mucosal involvement) appear, treatment with ambroxol hydrochloride should be immediately discontinued and medical advice sought.

Lazolvan**®**, solution for inhalation and oral use, should be used 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 secretion accumulation.

Patients with renal impairment or severe hepatic insufficiency should take Lazolvan**®** only after consultation with a physician. When ambroxol is administered, as with any active substance metabolized in the liver and subsequently excreted by the kidneys, metabolites formed in the liver may accumulate in patients with severe renal insufficiency.

Lazolvan**®**, solution for inhalation and oral use, contains 42.8 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 have shown no adverse effects on the fetus or course of pregnancy when the drug is used after the 28th week of gestation. Animal studies have not revealed any 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. Particularly during the first trimester of pregnancy, the use of Lazolvan**®** is not recommended.

Breastfeeding. Ambroxol hydrochloride passes into breast milk. Lazolvan**®** 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 vehicles or operating machinery.

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

Method of Administration and Dosage

1 ml of oral and inhalation solution = 25 drops.

Inhalation Solution

Adults and children aged 6 years and older: 1–2 inhalations daily, each with 2–3 ml of solution.

Children under 6 years of age: 1–2 inhalations daily, each with 2 ml of solution.

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

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

Lasolvan**®** inhalation solution must not be mixed with cromoglicic acid. It should also not be mixed with other solutions where the mixture's pH exceeds 6.3, for example, with 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 Lasolvan**®** is recommended.

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

Patients with bronchial asthma should use bronchodilators 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, equivalent to 90 mg of ambroxol per day; thereafter, 2 ml three times daily, equivalent to 45 mg of ambroxol per day. The dosage of 4 ml three times daily may be continued after consultation with a physician.

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

Children aged 2 to 6 years: 1 ml (25 drops) three times daily, equivalent to 22.5 mg of ambroxol per day.

Children under 2 years of age: 1 ml (25 drops) twice daily, equivalent to 15 mg of ambroxol per day.

Dosage in patients with renal and/or hepatic impairment

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

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

In acute conditions, a physician should be consulted if symptoms persist or worsen despite treatment with Lasolvan**®**.

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

The secretolytic effect of Lasolvan**®** is supported by adequate fluid intake.

Children

The drug may be used in children. In children under 2 years of age, the drug should be administered only on a physician's prescription.

Overdose

There are currently no reports of cases of overdose. Symptoms reported in isolated cases of overdose and/or medication misuse correspond to the known adverse effects observed with Lasolvan**®** at recommended doses and require symptomatic treatment.

Side effects.

The following classification was used to assess the frequency of adverse events:

Immune system side effects:

Rare – hypersensitivity reactions;

Unknown – anaphylactic reactions, including anaphylactic shock, angioneurotic edema, and pruritus.

Skin and subcutaneous tissue side effects:

Rare – rash, urticaria;

Unknown – serious skin adverse reactions (including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).

Nervous system side effects:

Common – dysgeusia (altered taste sensation).

Gastrointestinal side effects:

Common – nausea, oral numbness;

Uncommon – vomiting, diarrhea, dyspepsia, abdominal pain, dry mouth;

Rare – throat dryness;

Very rare – hypersalivation.

Respiratory, thoracic and mediastinal side effects:

Common – pharyngeal numbness;

Very rare – dyspnea and bronchospasm;

Unknown – dyspnea (as a symptom of hypersensitivity reaction).

General disorders:

Uncommon – fever, mucosal reactions.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions to the State Expert Center of the Ministry of Health of Ukraine.

Shelf life. 3 years.

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

Shelf life after first opening of the bottle – 12 months.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children!

Packaging.

100 ml in a glass bottle equipped with a polyethylene dropper and closed with a screw cap; 1 bottle with a polystyrene measuring cap in a cardboard box.

Supply category.

Over-the-counter (without prescription).

Manufacturer.

Istituto de Angeli S.r.l., Italy.

Manufacturer's address and place of business.

Localita Prulli, 103/c - 50066 Reggello (FI), Italy.

Marketing Authorization Holder.

Opella HealthCare Ukraine LLC, Ukraine.

Address of the Marketing Authorization Holder and/or its representative.

48-50A Zhylianska St., Kyiv, 01033, Ukraine.