Ambroxol-zdorovya

INSTRUCTIONS FOR MEDICINAL USE OF AMBROXOL-ZDOROVIYA

Composition:

Active ingredient: 5 ml of syrup contains ambroxol hydrochloride 15 mg;

Excipients: sorbitol (E 420); glycerol; propylene glycol; benzoic acid (E 210); citric acid monohydrate; sodium hydroxide; purified water; "Raspberry" flavor containing propylene glycol, ethanol, alpha-tocopherol, ascorbic acid, purified water.

Pharmaceutical form. Syrup.

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

Pharmacotherapeutic group. Medicinal products used in cough and colds. Mucolytic agents. ATC code R05C B06.

Pharmacological properties.

Pharmacodynamics. The active ingredient of the syrup, ambroxol hydrochloride, increases the serous component of bronchial secretions. Ambroxol enhances pulmonary surfactant secretion by directly affecting type II pneumocytes in alveoli and Clara cells in bronchioles, and also stimulates the activity of ciliated epithelium, thereby reducing sputum viscosity and improving its clearance (mucociliary clearance). Improvement of mucociliary clearance has been demonstrated in clinical and pharmacological studies.

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

Long-term use (6 months) of ambroxol hydrochloride (prolonged-release 75 mg 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, treatment with ambroxol hydrochloride 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, which may be explained by sodium channel blocking properties, was observed in a rabbit eye model. In vitro studies demonstrated that ambroxol hydrochloride blocks neuronal sodium channels; binding was reversible and concentration-dependent.

Ambroxol hydrochloride has demonstrated anti-inflammatory effects in vitro. Thus, ambroxol hydrochloride significantly reduces cytokine release from mononuclear and polymorphonuclear blood cells and tissues.

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

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

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

Pharmacokinetics.

Absorption. Absorption of ambroxol hydrochloride from immediate-release oral formulations is rapid and nearly complete, with linear dependence within the therapeutic range. Maximum plasma concentration is reached within 1**–**2.5 hours after oral administration of immediate-release formulations 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 highly pronounced, with the highest concentration of 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 due to presystemic metabolism after oral administration. Ambroxol hydrochloride is metabolized primarily in the liver via glucuronidation and cleavage into 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% is excreted in conjugated form in urine.

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

Pharmacokinetics in special patient populations. 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 gender do not have a clinically significant effect on the pharmacokinetics of ambroxol hydrochloride; therefore, 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 impaired mucus clearance.

Contraindications. The medicinal product must not be used in patients with known hypersensitivity to ambroxol hydrochloride or other components of the preparation.

The medicinal product 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. Concurrent use of ambroxol hydrochloride and antitussive agents may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination is possible only after careful assessment by a physician of the benefit-risk ratio of the treatment.

Special precautions for use

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

The medicinal product 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 impaired renal function or severe hepatic insufficiency should take the medicinal product only after consultation with a physician.

In patients with severe renal insufficiency, 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.

If a patient has known intolerance to certain sugars, medical advice should be sought before taking this medicinal product.

The product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

Use during pregnancy or breastfeeding

Pregnancy. Ambroxol hydrochloride crosses the placental barrier. Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryonal/fetal development, delivery, or postnatal development.
Clinical studies have not shown any harmful effects on the fetus when the drug was used after the 28th week of pregnancy. However, usual precautionary measures regarding medication use during pregnancy should be observed. In particular, the use of the drug is not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride passes into breast milk. The medicinal product is not recommended during breastfeeding.

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

Effect on ability to drive vehicles or operate machinery
There are no data available on the effect of ambroxol on the ability to drive vehicles or operate machinery. No studies have been conducted on the influence of ambroxol on driving or operating machinery.

Method of administration and dosage.

Unless otherwise prescribed, the recommended dose of the drug is as follows:

• Children up to 2 years of age: 2.5 ml (½ measuring spoon or 1 sachet of 2.5 ml) twice daily (equivalent to 15 mg of ambroxol hydrochloride per day);
• Children aged 2–5 years: 2.5 ml (½ measuring spoon or 1 sachet of 2.5 ml) three times daily (equivalent to 22.5 mg of ambroxol hydrochloride per day);
• Children aged 6–12 years: 5 ml (1 measuring spoon or 1 sachet of 5 ml, or 2 sachets of 2.5 ml) 2–3 times daily (equivalent to 30–45 mg of ambroxol hydrochloride per day);
• Adults and children aged 12 years and older: 10 ml (2 measuring spoons or 1 sachet of 10 ml, or 2 sachets of 5 ml, or 4 sachets of 2.5 ml) three times daily (equivalent to 90 mg of ambroxol hydrochloride per day) for the first 2–3 days, followed by 10 ml (2 measuring spoons or 1 sachet of 10 ml, or 2 sachets of 5 ml, or 4 sachets of 2.5 ml) twice daily (equivalent to 60 mg of 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 (4 measuring spoons or 2 sachets of 10 ml, or 4 sachets of 5 ml, or 8 sachets of 2.5 ml) twice daily (equivalent to 120 mg of ambroxol hydrochloride per day).

For adults and children aged 12 years and older, syrup with a higher concentration – Ambroxol-Zdorov'ya Forte (syrup 30 mg/5 ml) – is recommended.

Ambroxol hydrochloride may be administered regardless of food intake. The dose can be measured using the measuring spoon provided.

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

Ambroxol hydrochloride should not be used for longer than 4–5 days without consulting a physician.

The drug is suitable for use in patients with diabetes mellitus; 5 ml contains 1.75 g of carbohydrates.

Children. The drug may 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 reports of overdose and/or accidental ingestion correspond to the known adverse reactions of ambroxol hydrochloride at recommended doses and require symptomatic treatment.

Adverse Reactions

To assess the frequency of adverse events, the following classification was used:

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, decreased sensation in the oral cavity;
Uncommon – vomiting, diarrhea, dyspepsia, abdominal pain, dry mouth;
Rare – dry throat;
Very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders:
Common – decreased sensation in the pharynx;
Frequency not known – dyspnea (as a hypersensitivity reaction).

General disorders:
Uncommon – fever, mucosal reactions.

Reporting suspected adverse reactions
Reporting of suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system of the State Expert Centre of the Ministry of Health of Ukraine.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.

Packaging. 100 ml in a bottle with a measuring spoon in a box; 2.5 ml, 5 ml, or 10 ml in sachets, pack of 20 in a box.

Supply category. Over-the-counter (without prescription).

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROV'YA".

Manufacturer's address and place of business.
22, Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.