Ambroxol

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

Composition:

Active ingredient: ambroxol hydrochloride;

5 ml of syrup contains: ambroxol hydrochloride 15 mg;

Excipients: aspartame (E 951), sorbitol (E 420), benzoic acid (E 210), glycerol (E 422), hypromellose (E 464), red berry flavor, purified water.

Pharmaceutical form. Syrup.

Main physicochemical properties: clear or almost clear, colorless or almost colorless, slightly viscous syrup with a berry taste.

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

Pharmacological Properties

Pharmacodynamics

The active ingredient of Ambroxol Syrup – ambroxol hydrochloride – increases the serous component of bronchial secretion. Ambroxol enhances pulmonary surfactant secretion through direct action on type II pneumocytes in the alveoli and Clara cells in the bronchioles, and also stimulates ciliary epithelial motility, 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, and improved mucociliary clearance promote expectoration and facilitate sputum expulsion.

A local anesthetic effect of ambroxol hydrochloride, potentially explained by sodium channel blocking properties, was observed in a rabbit eye model. In vitro studies showed 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 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 its pharmacological properties, ambroxol rapidly alleviates pain during treatment of upper respiratory tract disorders, as observed in clinical efficacy studies of ambroxol inhalation forms.

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

Pharmacokinetics

Absorption. Ambroxol hydrochloride is rapidly and almost completely absorbed after oral administration of immediate-release formulations, with linear kinetics within the therapeutic dose range. Maximum plasma concentrations are reached within 1–2.5 hours after oral administration of immediate-release dosage forms and on average after 6.5 hours with sustained-release formulations.

Absolute bioavailability after a single 30 mg tablet is 79%.

Distribution. After oral administration, distribution of ambroxol hydrochloride from blood to tissues is rapid and extensive, with the highest concentrations found in lung tissue. The volume of distribution after oral administration is 552 L. In plasma, approximately 90% of the drug is protein-bound within the therapeutic range.

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 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 after 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 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 gender 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 transport.

Contraindications.

Ambroxol, syrup 15 mg/5 ml, must not be used in patients with known hypersensitivity to ambroxol hydrochloride or to any other components of the medicinal product.

Ambroxol, syrup, should not be administered to children under 2 years of age except under medical supervision.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Ambroxol, syrup, 15 mg/5 ml, with cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination should only be used after careful assessment by a physician of the benefit-risk ratio.

Special precautions for use

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

Ambroxol syrup 15 mg/5 ml 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 syrup 15 mg/5 ml only after consultation with a physician. In patients with severe renal insufficiency, administration of ambroxol—as with any active substance metabolized in the liver and subsequently excreted by the kidneys—may lead to accumulation of metabolites formed in the liver.

Ambroxol syrup 15 mg/5 ml contains 4.0 mg of sorbitol in 5 ml (equivalent to 32 mg at the maximum recommended daily dose). Patients with diagnosed intolerance to certain sugars should consult their doctor before taking this medicinal product.

Ambroxol syrup 15 mg/5 ml contains aspartame, a phenylalanine derivative; therefore, the medicinal product should not be used in patients with phenylketonuria.

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, parturition, 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, standard precautionary measures regarding medication use during pregnancy should be observed. In particular, Ambroxol syrup 15 mg/5 ml is not recommended during the first trimester of pregnancy.

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

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of administration and dosage.

If not otherwise prescribed, the recommended dose of Ambroxol syrup, 15 mg/5 ml, is as follows:

• Children under 2 years of age: 2.5 ml (½ teaspoon) twice daily (equivalent to 15 mg of ambroxol hydrochloride per day);
• Children aged 2–5 years: 2.5 ml (½ teaspoon) three times daily (equivalent to 22.5 mg of ambroxol hydrochloride per day);
• Children aged 6–12 years: 5 ml (1 teaspoon) 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 teaspoons) three times daily (equivalent to 90 mg of ambroxol hydrochloride per day) for the first 2–3 days, followed by 10 ml (2 teaspoons) 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 twice daily (equivalent to 120 mg of ambroxol hydrochloride per day).

For adults and children aged 12 years and older, ambroxol hydrochloride at a higher dosage (e.g., ambroxol hydrochloride 30 mg tablets) is recommended.

Ambroxol syrup 15 mg/5 ml can be taken regardless of food intake. The dose of Ambroxol syrup 15 mg/5 ml can be measured using the dosing cup or measuring spoon provided.

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

Ambroxol syrup 15 mg/5 ml should not be used for longer than 4–5 days without consulting a physician.

Ambroxol syrup 15 mg/5 ml is suitable for use in patients with diabetes mellitus; 5 ml contains 4.0 mg of carbohydrates.

Ambroxol syrup 15 mg/5 ml is alcohol-free.

Children.

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

Overdose.

There are no reports of specific overdose symptoms. Symptoms reported in isolated cases of overdose and/or medication errors correspond to the known adverse effects of Ambroxol syrup 15 mg/5 ml observed 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;

frequency not known – cannot be estimated based on available data.

Immune system disorders:

rare – hypersensitivity reactions;

frequency not known – anaphylactic reactions, including anaphylactic shock, angioneurotic edema, 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, oral hypoaesthesia;

uncommon – vomiting, diarrhea, dyspepsia, abdominal pain, dry mouth;

rare – dry throat;

very rare – hypersalivation.

Respiratory, thoracic and mediastinal disorders:

common – pharyngeal hypoaesthesia;

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

General disorders:

uncommon – pyrexia, mucosal site reactions.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicine authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients or their legal representatives are encouraged to report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life. 2 years.

Storage conditions.

Keep out of the reach of children.

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

Shelf life after first opening – 6 months.

Do not use after the expiry date.

Packaging.

100 ml in polymer bottles No. 1 in a carton, with a measuring cup or measuring spoon.

100 ml in glass bottles No. 1 in a carton, with a dosing cup or measuring spoon.

Supply category. Over-the-counter.

Manufacturer.

JSC "CHEMICAL PHARMACEUTICAL PLANT "CHERVONA ZIRKA".

Manufacturer's address and location of its business activity.

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