Ambroxol

INSTRUCTION for medical use of the medicinal product AMBROXOL (AMBROXOL)

Composition:

Active substance: ambroxol;

1 tablet contains ambroxol hydrochloride 30 mg;

Excipients: colloidal anhydrous silicon dioxide, sodium croscarmellose, microcrystalline cellulose, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties: round white tablets with a score line on one side.

Pharmacotherapeutic group.

Medicinal products used for cough and colds. Mucolytic agents. ATC code R05C B06.

Pharmacological properties.

Pharmacodynamics.

Hydrochloride ambroxol is a substituted benzylamine and a metabolite of bromhexine. It has been demonstrated that hydrochloride ambroxol enhances the production of the serous component of bronchial secretion and stimulates pulmonary surfactant release by direct action on type II pneumocytes in the alveoli and Clara cells in the bronchioles. Hydrochloride ambroxol also stimulates ciliary activity, thereby reducing the viscosity of sputum and improving its clearance (mucociliary clearance). Improved mucociliary clearance has been confirmed in clinical pharmacological studies.

Enhanced production of serous secretion and improved mucociliary clearance facilitate expectoration and reduce cough.

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

The local anesthetic effect of hydrochloride ambroxol, which may be explained by sodium channel blocking properties, was observed in a rabbit eye model.

In vitro studies showed that hydrochloride ambroxol blocks neuronal sodium channels; binding was reversible and concentration-dependent.

Hydrochloride ambroxol demonstrated anti-inflammatory effects in vitro. Thus, hydrochloride ambroxol 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 during treatment of upper respiratory tract disorders was rapidly achieved, as observed in clinical efficacy studies of ambroxol inhalation forms.

Administration of hydrochloride ambroxol increases the concentration of antibiotics (amoxicillin, cefuroxime, erythromycin, and doxycycline) in bronchopulmonary secretions and sputum. To date, no clinical significance has been established for this effect.

Antiviral properties in vitro and in experimental animal models

In vitro studies on human tracheal epithelial cells showed reduced rhinovirus (RV 14) replication. In a murine respiratory tract model, reduced replication of influenza A virus was observed following prior administration of ambroxol.

To date, the clinical relevance of this effect has not been confirmed.

Pharmacokinetics.

Absorption. Absorption of hydrochloride ambroxol from immediate-release oral formulations is rapid and complete, with linear dose-dependency 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 sustained-release formulations.

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

Distribution. After oral administration, distribution of hydrochloride ambroxol from blood to tissues is rapid and extensive, with the highest concentration of active substance found in the lungs. The expected volume of distribution after oral administration is 552 L. In plasma within the therapeutic dose 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. Hydrochloride ambroxol is mainly metabolized in the liver through glucuronidation and cleavage to dibromoantranilic acid (approximately 10% of the dose). The metabolism of hydrochloride ambroxol to dibromoantranilic acid involves CYP3A4. Within 3 days of oral administration, about 6% of the dose is excreted unchanged in urine, and approximately 26% of the dose – in conjugated form.

The elimination half-life from plasma is approximately 10 hours. Total clearance ranges within 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 hydrochloride ambroxol is reduced, resulting in plasma levels 1.3–2 times higher. However, since the therapeutic range of hydrochloride ambroxol is sufficiently wide, dosage adjustment is not required.

Age and sex have no clinically significant impact on the pharmacokinetics of hydrochloride ambroxol; therefore, no dose adjustment is necessary.

Food intake does not affect the bioavailability of hydrochloride ambroxol.

Clinical characteristics.

Indications.

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

Contraindications.

Ambroxol tablets must not be used in patients with known hypersensitivity to ambroxol hydrochloride or to any of the excipients of the product.

Ambroxol tablets are not intended for use in children under 6 years of age. For children under 6 years of age, ambroxol in an appropriate dosage form is recommended.

Interaction with other medicinal products and other forms of interaction.

When using the medicinal product Ambroxol 30 mg tablets in combination with antitussive agents in patients with 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

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 symptoms or signs of progressive skin rash (sometimes associated with blistering or mucosal involvement) occur, ambroxol hydrochloride treatment should be stopped immediately and medical advice should be sought.

Ambroxol 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 tablets only after consultation with a physician. When ambroxol hydrochloride, like any active substance metabolized in the liver and subsequently excreted by the kidneys, is administered, metabolites formed in the liver may accumulate in patients with severe renal insufficiency.

Excipients

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding

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

Clinical data on the use of ambroxol hydrochloride after the 28th week of pregnancy have not shown any adverse effects on the fetus. However, usual precautions regarding medication use during pregnancy should be observed. In particular, ambroxol tablets are not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride is excreted in breast milk. Ambroxol tablets are not recommended during breastfeeding.

Fertility. Preclinical studies have not indicated any direct or indirect harmful effects of ambroxol hydrochloride on fertility.

Effect on ability to drive and use machines.

There are no data on the effect of ambroxol on the ability to drive or operate machinery. Studies on the influence of ambroxol on driving performance or operating machinery have not been conducted.

Dosage and Administration.

If not otherwise prescribed, the recommended dose of Ambroxol tablets is as follows:

Children aged 6 to 12 years: The usual dose is 1/2 tablet 2–3 times daily (equivalent to 30–45 mg of ambroxol hydrochloride per day).

Adults and adolescents aged 12 years and older: The usual dose is 1 tablet 3 times daily for the first 2–3 days (equivalent to 90 mg of ambroxol hydrochloride per day). Treatment should then continue with 1 tablet twice daily (equivalent to 60 mg of ambroxol hydrochloride per day).

If necessary, the therapeutic effect in adults and adolescents aged 12 years and older may be enhanced by taking 2 tablets twice daily (equivalent to 120 mg of ambroxol hydrochloride per day).

The tablets should be swallowed whole with sufficient fluid (e.g., water, tea, or fruit juice), regardless of food intake.

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

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

Children.

To be used in children aged 6 years and older who cannot tolerate syrup or solution for inhalation and oral use.

Overdose.

Currently, there are no reports of overdose cases. Symptoms reported in isolated cases of overdose and/or medication misuse correspond to the known adverse effects of ambroxol hydrochloride at recommended doses and require symptomatic treatment.

Adverse Reactions

The adverse reactions listed below are categorized by system organ class and frequency:

Very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000, including isolated cases), frequency not known (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, angioedema, 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 (Lyell's syndrome), acute generalized exanthematous pustulosis).

Nervous system disorders: frequency not known – dysgeusia (taste disturbance).

Gastrointestinal disorders: common – nausea; uncommon – vomiting, diarrhea, dyspepsia, abdominal pain; rare – dry throat; very rare – hypersalivation; frequency not known – decreased oral sensitivity, dry mouth, heartburn, constipation.

Respiratory, thoracic and mediastinal disorders: frequency not known – dyspnea (as a symptom of hypersensitivity reaction), dyspnea and bronchospasm, rhinorrhea, dryness of respiratory tract, decreased pharyngeal sensitivity.

Renal and urinary disorders: frequency not known – dysuria.

General disorders: uncommon – mucosal reactions, fever.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine registration is important. It allows ongoing monitoring of the benefit-risk balance of the medicine. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all 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 in the original packaging.

Keep out of reach of children.

Packaging.

10 tablets in a blister; 2 blisters in a cardboard package.

Availability.

Over-the-counter.

Manufacturer.

KUSUM HEALTHCARE PVT LTD.

Manufacturer's address and location of operations.

SP-289 (A), RIICO Industrial area, Chopanki, Bhiwadi, Dist. Alwar (Rajasthan), India.