Lasolvan® with forest berries flavor

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LASOLVAN® WITH WOODBERRY FLAVOUR (LASOLVAN® WITH WOODBERRY FLAVOUR)

Composition:

Active substance: ambroxol hydrochloride;

5 ml of syrup contain ambroxol hydrochloride 15 mg;

Excipients: sucralose, benzoic acid (E 210), hydroxyethylcellulose, "woodberry" flavour (contains propylene glycol (E 1520)), vanilla flavour (contains propylene glycol (E 1520)), purified water.

Pharmaceutical form. Syrup.

Main physicochemical characteristics: clear or almost clear, colourless or almost colourless, slightly viscous syrup with a woodberry flavour.

Pharmacotherapeutic group. Medicinal products used for cough and colds. Mucolytic agents.

ATC code: R05C B06.

Pharmacological Properties.

Pharmacodynamics.

The active ingredient of Lasolvan® syrup with forest fruits flavor, ambroxol hydrochloride, increases the proportion of the serous component of bronchial secretion. Ambroxol enhances pulmonary surfactant secretion through direct action on type II pneumocytes in alveoli and Clara cells in bronchioles, and also stimulates ciliary epithelium beat activity, thereby reducing sputum viscosity and improving its elimination (mucociliary clearance). Improvement of mucociliary clearance has been demonstrated in clinical pharmacological studies.

Enhanced secretion production, reduced viscosity, and improved mucociliary clearance promote expectoration and facilitate sputum clearance.

Long-term use (6 months) of ambroxol hydrochloride (75 mg prolonged-release capsules) in patients with COPD resulted in a significant reduction in exacerbations after a 2-month treatment period. In patients receiving ambroxol hydrochloride, duration of illness and antibiotic therapy was significantly shorter. Compared to placebo, ambroxol hydrochloride treatment with prolonged-release capsules showed statistically significant improvement in symptoms related to expectoration difficulties, cough, dyspnea, and auscultatory findings.

The local anesthetic effect of ambroxol hydrochloride, possibly explained by sodium channel blocking properties, was observed in a rabbit eye model. In vitro studies showed that ambroxol hydrochloride blocks neuronal sodium channels; binding was reversible and concentration-dependent.

Ambroxol hydrochloride demonstrated anti-inflammatory effects in vitro. Thus, ambroxol hydrochloride significantly reduces the release of cytokines from mononuclear and polymorphonuclear blood and tissue cells.

Clinical trials involving patients with pharyngitis demonstrated a significant reduction in throat pain and redness upon administration of the drug.

Due to the pharmacological properties of ambroxol, pain relief occurred rapidly during treatment of upper respiratory tract disorders, as observed in clinical efficacy studies of ambroxol inhalation forms.

After administration of ambroxol hydrochloride, concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin, and doxycycline) increase in bronchopulmonary secretions and sputum. To date, no clinical significance of this effect has been identified.

Pharmacokinetics.

Absorption. Absorption of ambroxol hydrochloride from immediate-release oral formulations is rapid and fairly complete, with linear dependence within the therapeutic range. Maximum plasma concentration is reached within 1–2.5 hours after oral administration of immediate-release dosage forms and on average after 6.5 hours with slow-release formulations.

Absolute bioavailability after administration of a 30 mg tablet is 79%.

Distribution. After oral administration, distribution of ambroxol hydrochloride from blood to tissues is rapid and pronounced, with the highest concentration of the active substance found in the lungs. The volume of distribution after oral administration is 552 L. In plasma within the therapeutic range, approximately 90% of the drug is protein-bound.

Metabolism and Elimination. Approximately 30% of the dose is eliminated via presystemic metabolism after oral administration. Ambroxol hydrochloride is metabolized primarily in the liver via glucuronidation and cleavage to dibromanthranilic acid (approximately 10% of the dose). Clinical studies using human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid.

Within 3 days of oral administration, about 6% of the dose is excreted unchanged, while approximately 26% of the dose – is excreted in conjugated form in urine.

The elimination half-life from plasma is approximately 10 hours. Total clearance is about 660 ml/min. Renal clearance accounts for approximately 8% of total clearance. After 5 days, approximately 83% of the total dose is excreted in urine.

Pharmacokinetics in Special Patient Groups. In patients with impaired liver function, elimination of ambroxol hydrochloride is reduced, resulting in plasma levels 1.3–2 times higher. However, since the therapeutic range of ambroxol hydrochloride is sufficiently wide, dosage adjustment is not required.

Age and sex have no clinically significant effect on the pharmacokinetics of ambroxol hydrochloride, so no dose adjustment is necessary.

Food intake does not affect the bioavailability of ambroxol hydrochloride.

Clinical characteristics.

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

*Contraindications. Lazolvan® with forest berry flavor, syrup, 15 mg/5 ml, must not be used in patients with known hypersensitivity to ambroxol hydrochloride or other components of the medicinal product.

Lazolvan® with forest berry flavor should be used in children under 2 years of age only as prescribed by a physician.

Interaction with other medicinal products and other forms of interaction. Concomitant use of Lazolvan**®** with forest berry flavor, syrup, 15 mg/5 ml, and cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination is possible only after careful evaluation by a physician of the benefit-risk ratio.

Special precautions for use.

Serious skin reactions have been reported: 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 skin rash progression (sometimes associated with blistering or mucosal involvement) occur, ambroxol hydrochloride treatment must be discontinued immediately and medical advice should be sought.

Ambroxol Hydrochloride Syrup with Forest Fruits Flavour, 15 mg/5 ml (Lazolvan**®**) 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 promoting secretion accumulation.

Patients with renal impairment or severe hepatic insufficiency should take Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 ml, only after consultation with a physician. In patients with severe renal insufficiency, administration of ambroxol—as with any active substance metabolized in the liver and subsequently excreted by the kidneys—may lead to accumulation of metabolites formed in the liver.

Use during pregnancy or breastfeeding.

Pregnancy. Ambroxol hydrochloride crosses the placental barrier. Animal studies have not revealed any direct or indirect harmful effects on pregnancy, embryonic/fetal development, delivery, or postnatal development.

Clinical studies have shown no adverse effects on the fetus when the drug was used after the 28th week of pregnancy.

However, standard precautionary measures regarding medication use during pregnancy should be observed. In particular, Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 ml, is not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride is excreted in breast milk. Lazolvan**®** with Forest Fruits Flavour is not recommended during breastfeeding.

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

Ability to influence reaction rate when driving or operating machinery. There are no data on the effect of ambroxol on reaction speed during driving or operating machinery. Studies on this effect have not been conducted.

Method of administration and dosage. Unless otherwise prescribed, the recommended dosage of Lazolvan*®** with Forest Fruits Flavour, Syrup, 15 mg/5 ml, is as follows:*

Children under 2 years of age: 2.5 mL (1/2 teaspoon) twice daily (equivalent to 15 mg ambroxol hydrochloride per day);

Children aged 2–5 years: 2.5 mL (1/2 teaspoon) three times daily (equivalent to 22.5 mg ambroxol hydrochloride per day);

Children aged 6–12 years: 5 mL (1 teaspoon) 2–3 times daily (equivalent to 30–45 mg ambroxol hydrochloride per day);

Adults and children aged 12 years and older: 10 mL (2 teaspoons) three times daily (equivalent to 90 mg ambroxol hydrochloride per day) for the first 2–3 days, followed by 10 mL (2 teaspoons) twice daily (equivalent to 60 mg ambroxol hydrochloride per day).

If necessary, the therapeutic effect in adults and children aged 12 years and older may be enhanced by increasing the dose to 20 mL twice daily (equivalent to 120 mg ambroxol hydrochloride per day).

For adults and children aged 12 years and older, syrup with higher concentration is recommended (Lazolvan**®** with Strawberry-Cream Flavour, Syrup, 30 mg/5 mL).

Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, can be taken independently of food intake. The dose of Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, can be measured using the dosing cap provided.

In general, there are no restrictions on duration of treatment; however, prolonged therapy should be conducted under medical supervision.

Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, should not be used for longer than 4–5 days without consulting a physician.

Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, is suitable for use in patients with diabetes mellitus; 5 mL contains 1.2 g of carbohydrates.

Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, does not contain alcohol.

Children. The product can be used in pediatric practice. For children under 2 years of age, use only as directed by a physician.

Overdose.

There have been no reports of specific overdose symptoms. Symptoms described in isolated cases of overdose and/or accidental ingestion correspond to known adverse reactions during recommended use of Lazolvan**®** with Forest Fruits Flavour, Syrup, 15 mg/5 mL, and require symptomatic treatment.

Adverse Reactions

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

very common ≥1/10;
common ≥1/100 to <1/10;
uncommon ≥1/1,000 to <1/100;
rare ≥1/10,000 to <1/1,000;
very rare <1/10,000;
frequency not known – cannot be estimated based on available data.

Immune system disorders:

rare – hypersensitivity reactions;
frequency not known – anaphylactic reactions, including anaphylactic shock, angioedema, and 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 – throat dryness;
very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders:

common – pharyngeal numbness;
frequency not known – dyspnea (as a hypersensitivity reaction).

General disorders:

uncommon – pyrexia, mucosal reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions through the national reporting system of the State Expert Centre 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. After opening the bottle, the product is suitable for use for 6 months.

Storage conditions. Store at temperatures not exceeding 30 °C, in a place inaccessible to children.

Packaging. 100 ml in a glass bottle with a child-resistant plastic closure; 1 bottle with a plastic measuring cap in a cardboard box.

Availability. Over-the-counter.

Manufacturer.

Boehringer Ingelheim España, S.A.

or

Delpfarm Reims.

Manufacturer's address.

Prat de la Ribera, 50, 08174 SANT CUGAT DEL VALLÈS (Barcelona), Spain

or

10 rue Colonel Carpentier, 51100 Reims, France.

Marketing Authorization Holder.

Opella HealthCare Ukraine LLC, Ukraine.

Address of the Marketing Authorization Holder.

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