Ambroxol
Ukraine
Table of Contents
INSTRUCTIONS for medical use of the medicinal product AMBROXOL (AMBROXOL)
Composition:
Active substance: ambroxol;
Each tablet contains ambroxol hydrochloride equivalent to 100% substance – 30 mg;
Excipients: potato starch; lactose monohydrate; calcium stearate.
Pharmaceutical form. Tablets.
Main physico-chemical characteristics: white or white with yellowish hue, round-shaped tablets with flat surface and bevelled edge.
Pharmacotherapeutic group. Medicinal products used for cough and colds. Mucolytic agents. Ambroxol. ATC code R05C B06.
Pharmacological properties.
Pharmacodynamics.
Preclinical studies have demonstrated that ambroxol hydrochloride enhances the production of the serous component of bronchial secretion. Ambroxol enhances pulmonary surfactant secretion by directly affecting pneumocytes (type II) in alveoli and Clara cells in bronchioles, and also stimulates ciliary activity, thereby reducing sputum viscosity and improving its clearance (mucociliary clearance). Improvement in mucociliary clearance has been confirmed in clinical pharmacological studies.
Enhanced serous secretion and improved mucociliary clearance facilitate expectoration and reduce coughing.
In patients with chronic obstructive pulmonary disease who received ambroxol hydrochloride prolonged-release capsules 75 mg once daily for 6 months, a significant reduction in the number of exacerbations was observed compared to placebo, starting from the end of the second month of treatment. In patients treated with ambroxol hydrochloride, the duration of illness was significantly shorter, and fewer days of antibiotic therapy were required. A statistically significant reduction in symptoms such as difficulty in expectoration, cough, dyspnea, and auscultatory sounds was also observed compared to placebo.
Local anesthetic effect of ambroxol hydrochloride has been observed in a rabbit eye model, which can be explained by its sodium channel-blocking properties. In vitro studies have shown 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 the release of cytokines from mononuclear and polymorphonuclear blood and tissue cells.
Clinical trials involving patients with pharyngitis have demonstrated a significant reduction in throat pain and redness upon administration of the medicinal product.
Due to its pharmacological properties, ambroxol rapidly alleviates pain during treatment of upper respiratory tract disorders, as observed in clinical efficacy studies of inhaled ambroxol formulations.
Administration of ambroxol hydrochloride 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 observation.
Pharmacokinetics.
Absorption. Absorption of ambroxol hydrochloride 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 within 6.5 hours with 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 ambroxol hydrochloride 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 dibromanthranilic acid (approximately 10% of the dose). Studies with human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid.
After 3 days of oral administration, about 6% of the dose is excreted in urine unchanged, 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. After 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 transport.
Contraindications.
The medicinal product must not be used in patients with known hypersensitivity to ambroxol hydrochloride or to other components of the medicinal product.
Interaction with other medicinal products and other forms of interaction.
Concomitant use of ambroxol and cough-suppressant agents may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such a combination should only be used after careful assessment by a physician of the expected benefit versus the potential risk of use.
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 worsening skin rash (sometimes associated with blistering or mucosal lesions) occur, treatment with ambroxol hydrochloride should be discontinued immediately and medical advice should be sought.
Ambroxol tablets contain 176 mg of lactose in the maximum recommended daily dose (120 mg).
This medicinal product is contraindicated in patients with galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
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 renal impairment or severe hepatic insufficiency should take Ambroxol tablets only after consultation with a physician. In patients with severe renal insufficiency, administration of ambroxol—like any other drug metabolized in the liver and subsequently excreted by the kidneys—may lead to accumulation of metabolites formed in the liver.
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 administered after the 28th week of pregnancy.
However, standard precautionary measures regarding medication use during pregnancy should be observed. In particular, the use of this medicinal product is not recommended during the first trimester of pregnancy.
Breastfeeding period. Ambroxol hydrochloride passes into breast milk. The drug is not recommended for use 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 the medicinal product on the ability to drive or operate machinery. Appropriate studies have not been conducted.
Method of administration and dosage.
If not otherwise prescribed, the recommended dosage of Ambroxol, tablets is as follows:
Adults and children aged 12 years and older: usually, the 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 2 times daily (equivalent to 120 mg of ambroxol hydrochloride/day).
Tablets should be swallowed whole with a sufficient amount 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, tablets, should not be used for longer than 4–5 days without consulting a physician.
Children. Ambroxol in this pharmaceutical form is contraindicated for use in children under 12 years of age.
Overdose.
There are currently no reports of cases of overdose in humans. Symptoms reported from isolated cases of overdose and/or accidental drug administration correspond to the known adverse effects of the medicinal product 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 from the available data. |
Immune system disorders:
Rare – hypersensitivity reactions;
Frequency unknown – anaphylactic reactions, including anaphylactic shock, angioedema, and pruritus.
Skin and subcutaneous tissue disorders:
Rare – rash, urticaria;
Frequency unknown – serious skin adverse reactions (including erythema multiforme, Stevens–Johnson syndrome/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).
Gastrointestinal disorders:
Common – nausea;
Uncommon – vomiting, diarrhea, dyspepsia, abdominal pain;
Very rare – hypersalivation.
Respiratory, thoracic and mediastinal disorders:
Frequency unknown – dyspnea (as a hypersensitivity reaction).
General disorders:
Uncommon – fever, mucosal reactions.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy of the medicinal product through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life. 5 years.
Storage conditions. In the original packaging at a temperature not exceeding 25 °C.
Keep out of reach of children.
Packaging. 10 tablets in a blister, 2 blisters in a carton.
Supply category. Over-the-counter.
Manufacturer.
JSC "Kyivmedpreparat".
LLC "MARIFARM".
Manufacturer's address and location of its business operations.
139 Saksaganskogo Street, Kyiv, 01032, Ukraine.
8 Minarikova Street, Maribor, 2000, Slovenia.