Ambroxol hydrochloride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBROXOL HYDROCHLORIDE (AMBROXOL HYDROCHLORIDE)

Composition:

Active substance: ambroxol hydrochloride;

One tablet contains ambroxol hydrochloride 30 mg;

Excipients: potato starch, lactose monohydrate, microcrystalline cellulose, colloidal anhydrous silicon dioxide, calcium stearate.

Pharmaceutical form. Tablets.

Main physico-chemical properties: tablets of white or white with a yellowish tint color.

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

Pharmacological Properties

Pharmacodynamics

Preclinical studies have shown that the active substance of the medicinal product, ambroxol hydrochloride, enhances the formation of the serous component of bronchial secretion. Ambroxol potentiates the release of pulmonary surfactant through a direct effect on type II pneumocytes in alveoli and Clara cells in bronchioles, and also stimulates ciliary activity, thereby reducing the viscosity of sputum and improving its expulsion (mucociliary clearance). Enhanced mucociliary clearance has been confirmed by clinical pharmacological studies. Increased production of serous secretion and enhanced mucociliary clearance facilitate expectoration and reduce coughing.

In patients with chronic obstructive pulmonary disease who received ambroxol hydrochloride in 75 mg prolonged-release capsules for 6 months, a significant reduction in the number of exacerbations was observed by the end of the second month of treatment compared to the placebo group. In patients treated with ambroxol hydrochloride, the illness lasted significantly fewer days, and fewer days of antibiotic therapy were required. These patients also showed a statistically significant reduction in symptoms such as difficulty in expectoration, cough, dyspnea, and auscultatory sounds compared to the placebo group.

The local anesthetic effect of ambroxol hydrochloride was observed in a rabbit eye model, which may be explained by its sodium channel-blocking properties. In vitro studies have shown that ambroxol hydrochloride blocks neuronal sodium channels; the 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, a significant reduction in throat pain and redness was confirmed upon administration of the drug.

The pharmacological properties of ambroxol hydrochloride, leading to rapid relief of pain and pain-related discomfort in the nasal cavity, ear area, and trachea during inhalation, are consistent with the data from symptom monitoring in clinical efficacy studies of ambroxol in the treatment of upper respiratory tract disorders.

The use of ambroxol hydrochloride increases the concentration of antibiotics (amoxicillin, cefuroxime, erythromycin, and doxycycline) in bronchopulmonary secretions and sputum. The clinical significance of this phenomenon 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 concentration is reached within 1–2.5 hours after oral administration of immediate-release formulations and on average within 6.5 hours after administration of 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 extensive, with the highest concentration of the 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. Ambroxol hydrochloride is metabolized primarily in the liver via glucuronidation and cleavage to dibromoantranilic acid (approximately 10% of the dose). Studies on human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromoantranilic acid.

Within 3 days after oral administration, about 6% of the dose is excreted unchanged in urine, and approximately 26% of the dose 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, dose 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 weakened mucus clearance.

Contraindications.

Ambroxol hydrochloride must not be administered to patients with known hypersensitivity to ambroxol hydrochloride or to any other components of the medicinal product.

Ambroxol hydrochloride 30 mg tablets are not intended for use in children under 12 years of age due to the strength of the formulation.

Interaction with other medicinal products and other forms of interaction.

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

Special precautions for use

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

Ambroxol hydrochloride tablets contain 270.8 mg of lactose in the maximum recommended daily dose (120 mg). Patients with rare hereditary problems of galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

Ambroxol hydrochloride 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) due to the risk of mucus accumulation.

Patients with impaired renal function or severe hepatic insufficiency should take ambroxol hydrochloride tablets only after consultation with a physician. When ambroxol is administered, as with any active substance metabolized in the liver and subsequently excreted by the kidneys, 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 adverse effects on pregnancy, embryonic/fetal development, labor, or postnatal development.

Clinical studies have not shown any harmful effects on the fetus when the drug is used after the 28th week of pregnancy.

However, usual precautionary measures regarding medication use during pregnancy should be observed. In particular, ambroxol hydrochloride tablets are not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride passes into breast milk. Ambroxol hydrochloride tablets are not recommended during breastfeeding.

Fertility. Preclinical studies have not shown any direct or indirect adverse effects on fertility.

Ability to influence reaction speed when driving or operating machinery

There are no data on the effect of ambroxol hydrochloride on the ability to drive or operate machinery. Specific studies have not been conducted.

Method of Administration and Dosage

For oral use in adults and children aged 12 years and older: 1 tablet 3 times daily during the first 2–3 days (equivalent to 90 mg of ambroxol hydrochloride per day). Treatment should be continued with 1 tablet administered 2 times 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 administering 2 tablets 2 times daily (equivalent to 120 mg of ambroxol hydrochloride per day).

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

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

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

Children

For use in children aged 12 years and older.

Overdose

There are currently no reports of overdose cases in humans. Symptoms reported from isolated cases of overdose and/or accidental misuse correspond to the known adverse effects of ambroxol hydrochloride at recommended doses and require symptomatic treatment.

Side effects

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

Very common >10 %;

Common >1 % and <10 %;

Uncommon >0.1 % and <1 %;

Rare >0.01 % and <0.1 %;

Very rare <0.01 %;

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 – skin rash, urticaria;

Frequency not known – serious skin adverse reactions (e.g., erythema multiforme, Stevens-Johnson syndrome / toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).

Gastrointestinal disorders:

Common – nausea;

Uncommon – vomiting, dyspepsia, abdominal pain, diarrhea;

Very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders:

Frequency not known – dyspnea (as a hypersensitivity reaction).

General disorders:

Uncommon – fever, mucosal reactions.

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Do not use after the expiry date stated on the packaging.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 or 20 tablets in a blister. 2 blisters of 10 tablets or 1 blister of 20 tablets in a cardboard box.

Prescription status.

Over-the-counter.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and place of business.

1, Gordienkivska Street, Kharkiv, Kharkiv Oblast, 61010, Ukraine.

Date of last review.