Ambroxol

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBROXOL

Composition:

Active substance: ambroxol,

1 tablet contains 30 mg of ambroxol hydrochloride;

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose, magnesium stearate, silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white or almost white tablets with a flat surface, a score line and bevelled edges.

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

ATC code R05C B06.

Pharmacological properties.

Pharmacodynamics.

Clinically proven, the active substance of Ambroxol, 30 mg tablets – ambroxol hydrochloride – increases the serous fraction of bronchial secretion. Ambroxol enhances pulmonary surfactant secretion by direct action on type II pneumocytes in alveoli and Clara cells in bronchioles, and also stimulates ciliary activity, thereby reducing sputum viscosity and improving its clearance (mucociliary clearance). Improvement of mucociliary clearance has been demonstrated in clinical pharmacological studies.

Activation of secretion, reduction of secret viscosity, and improvement of mucociliary clearance promote mucus elimination and facilitate expectoration.

In patients with COPD who received ambroxol hydrochloride prolonged-release capsules 75 mg for 6 months, a significant reduction in the number of exacerbations was observed compared to placebo, by the end of the second month of treatment. In patients treated with ambrox0l hydrochloride, the disease lasted significantly fewer days, and fewer days of antibiotic therapy were required. Compared to placebo, treatment with ambroxol hydrochloride prolonged-release capsules showed statistically significant improvement in patient status regarding sputum expectoration, cough, dyspnea, and auscultatory findings.

In a rabbit eye model, 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 demonstrated anti-inflammatory effects in vitro. Thus, ambroxol hydrochloride significantly reduces the release of cytokines 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.

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.

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

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 mouse respiratory model, prior administration of ambroxol resulted in reduced influenza A virus replication.

Currently, the clinical significance of this effect has not been confirmed.

Pharmacokinetics.

Absorption. Absorption of ambroxol hydrochloride from immediate-release oral formulations is rapid and fairly 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 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 mainly metabolized in the liver via glucuronidation and cleavage to dibromanthranilic acid (approximately 10% of the dose). Studies on human liver microsomes showed that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid.

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

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. 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 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.

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

Contraindications.

Ambroxol, 30 mg tablets, must not be used in patients with known hypersensitivity to ambroxol hydrochloride or to any of the excipients of the medicinal product.

Ambroxol, 30 mg tablets, is not intended for use in children under 6 years of age due to dosage considerations. For children under 6 years of age, Ambroxol, syrup 15 mg/5 ml, is recommended.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Ambroxol, 30 mg tablets, with cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination should be used only after careful assessment by a physician of the expected benefit versus possible risk of use.

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

Ambroxol 30 mg tablets contain 147 mg of lactose in the maximum recommended daily dose (120 mg). Patients with rare hereditary disorders of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicinal product.

Since ambroxol may enhance mucus secretion, Ambroxol 30 mg tablets 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).

Patients with impaired renal function or severe hepatic insufficiency should take Ambroxol 30 mg tablets only after consultation with a physician. When ambroxol, 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.

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, embryonal/fetal development, parturition, 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, general precautions regarding medication use during pregnancy should be observed. In particular, Ambroxol 30 mg tablets are not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride is excreted into breast milk. Ambroxol 30 mg tablets are not recommended during breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery.

There are no data regarding the effect of ambroxol on reaction speed when driving or operating machinery. Appropriate studies have not been conducted.

Dosage and method of 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/day);

Adults and children 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/day). Treatment should continue with 1 tablet 2 times daily (equivalent to 60 mg of ambroxol hydrochloride/day).

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

The tablets should be swallowed whole with plenty of liquid (e.g. water, tea or fruit juice), during or regardless of meals.

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

Ambroxol 30 mg tablets should not be used for longer than 4–5 days without consulting a doctor.

Children.

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

Overdose.

There are currently no reports of overdose cases in humans. Symptoms reported from isolated cases of overdose and/or accidental misuse are consistent with the known adverse effects of Ambroxol 30 mg tablets 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;

Not known – anaphylactic reactions, including anaphylactic shock, angioedema, and pruritus.

Skin and subcutaneous tissue side effects:

Rare – rash, urticaria;

Not known – serious skin adverse reactions (including erythema multiforme, Stevens–Johnson syndrome / toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).

Gastrointestinal side effects:

Common – nausea;

Uncommon – vomiting, diarrhea, dyspepsia, abdominal pain;

Very rare – hypersalivation.

Respiratory, thoracic and mediastinal side effects:

Not known – dyspnea (as a symptom of hypersensitivity reaction).

General disorders:

Uncommon – fever, mucosal reactions.

Reporting suspected adverse reactions

Reporting 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 adverse reactions through the national reporting system.

Shelf life. 4 years.

Storage conditions.

Store in a dry, light-protected place at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

Tablets No. 20 (10 × 2) in blisters.

Prescription status. Over-the-counter.

Manufacturer/Marketing Authorization Holder.

LLC "Ternopharm".

Manufacturer's address and place of business.

LLC "Ternopharm".

46010, 4 Fabrychna St., Ternopil, Ukraine.

Tel./fax: (0352) 521-444, http://www.ternopharm.com.ua