Ambroxol-zdorovya forte

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBROXOL-ZDOROVIYA FORTE

Composition:

Active substance: 5 ml of syrup contains ambroxol hydrochloride 30 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. Drugs used for cough and colds. Mucolytic agents. ATC code R05C B06.

Pharmacological Properties

Pharmacodynamics

Preclinical studies have demonstrated that the active substance of the syrup – ambroxol hydrochloride – increases the serous fraction of bronchial secretion. Ambroxol enhances pulmonary surfactant secretion by directly affecting type II pneumocytes in the alveoli and Clara cells in the bronchioles, and also stimulates ciliary activity, thereby reducing sputum viscosity and improving its expectoration (mucociliary clearance). Improvement in mucociliary clearance has been confirmed during clinical pharmacological studies.

Activation of secretion, reduction in secretory viscosity, and improved mucociliary clearance promote mucus elimination and facilitate expectoration of sputum.

In patients with COPD who received ambroxol hydrochloride 75 mg prolonged-release capsules for 6 months, a significant reduction in the number of exacerbations was observed compared to placebo, evident by the end of the second month of treatment. Patients treated with ambroxol hydrochloride experienced significantly fewer days of illness and required fewer days of antibiotic therapy. Compared to placebo, treatment with ambroxol hydrochloride prolonged-release capsules demonstrated statistically significant improvement in patient status regarding sputum expectoration, cough, dyspnea, and auscultatory findings.

In a rabbit eye model, a local anesthetic effect of ambroxol hydrochloride was observed, which may be explained by sodium channel blocking properties. In vitro studies showed that ambroxol hydrochloride blocks voltage-dependent 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 and tissue cells.

In clinical trials involving patients with pharyngitis, significant reduction in throat pain and redness was demonstrated with ambroxol hydrochloride use.

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

The use of ambroxol hydrochloride increases concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin, and doxycycline) in bronchopulmonary secretions and in sputum. The clinical significance of this effect has not yet been established.

Pharmacokinetics

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

Distribution. After oral administration, distribution of ambroxol hydrochloride from blood to tissues is rapid and extensive, with the highest concentration of the active substance found in the lungs. The volume of distribution after oral administration is 552 liters. 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 primarily metabolized in the liver through glucuronidation and cleavage to dibromoaniline acid (approximately 10% of the dose). Studies using human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromoaniline acid.

Within 3 days after oral administration, ambroxol hydrochloride is excreted in urine, with approximately 6% of the dose excreted unchanged and about 26% as conjugated metabolites.

The elimination half-life of ambroxol hydrochloride is approximately 10 hours. Total clearance is approximately 660 mL/min, with renal clearance accounting for approximately 8% of total clearance. Within 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; 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 reduced mucus clearance.

Contraindications.

Should not be used in patients with hypersensitivity to ambroxol hydrochloride or other components of the medicinal product.

Should not be used in children under 2 years of age without a physician's prescription.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of this medicinal product with cough-suppressant agents may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination is possible only after careful physician assessment of the benefit-risk ratio.

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 progressive skin rash (sometimes associated with blistering or mucosal involvement) occur, ambroxol hydrochloride therapy should be discontinued immediately and medical advice sought.

Ambroxol hydrochloride 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 ambroxol hydrochloride 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.

The medicinal product contains 1.75 g of sorbitol in 5 mL (equivalent to 7 g when the maximum recommended daily dose is used). If a patient has been diagnosed with intolerance to certain sugars, consultation with a physician is necessary 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. Preclinical studies have not revealed any direct or indirect harmful effects of the drug on pregnancy, embryonic/fetal development, delivery, or postnatal development. Clinical experience with the use of the drug after the 28th week of pregnancy has not shown any harmful effects on the fetus. However, usual precautionary measures regarding medication use during pregnancy should be observed. Particularly during the first trimester of pregnancy, the use of this medicinal product is not recommended.

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.

Ability to influence reaction speed when driving or operating machinery

There are no data regarding the effect of ambroxol hydrochloride on the ability to drive vehicles or operate machinery. Studies on the influence of the drug on reaction speed during driving or operating machinery have not been conducted.

Dosage and Administration.

If otherwise not specified, the following dosage regimen is recommended:

• Children up to 2 years of age: 1.25 mL twice daily (equivalent to 15 mg of ambroxol hydrochloride per day).
• Children from 2 to 5 years of age: 1.25 mL three times daily (equivalent to 22.5 mg of ambroxol hydrochloride per day).
• Children from 6 to 12 years of age: 2.5 mL two to three times daily (equivalent to 30–45 mg of ambroxol hydrochloride per day).
• Adults and children aged 12 years and older: the usual dose is 5 mL three times daily (equivalent to 90 mg of ambroxol hydrochloride per day) for the first 2–3 days, followed by 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 10 mL twice daily (equivalent to 120 mg of ambroxol hydrochloride/day).

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

In cases where syrup doses are multiples of 5 mL, the preparation in sachets may be used.

Generally, 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 preparation is suitable for use in patients with diabetes mellitus; 5 mL of syrup corresponds to 1.75 g of carbohydrates.

Children.

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

Overdose.

There are currently no reports of specific symptoms of overdose. Symptoms reported in isolated cases of overdose and/or accidental ingestion correspond to the known adverse effects of the medicinal product at recommended doses and require symptomatic treatment.

Adverse Reactions

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

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
Not known – cannot be estimated based on available data

Immune system and skin and subcutaneous tissue disorders:

Rare – hypersensitivity reactions, rash, urticaria;
Not known – anaphylactic reactions including anaphylactic shock, angioedema and pruritus, 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 – dryness in the throat;
Very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders:

Common – decreased sensation in the pharynx;
Not known – dyspnea (as a symptom of hypersensitivity reaction).

General disorders:

Uncommon – fever, mucosal reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorization of the medicinal product 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 to the State Enterprise "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; 5 mL in sachets № 20 in a box.

Supply category. Over-the-counter.

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

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