Mucolvan

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT MUCOLVAN

Composition:

Active substance: ambroxol;

1 ml of solution contains ambroxol hydrochloride 7.5 mg;

Excipients: sodium chloride; citric acid, monohydrate; sodium hydrogen phosphate, dodecahydrate; water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: colorless clear liquid.

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

Pharmacological Properties.

Pharmacodynamics. Ambroxol hydrochloride, a substituted benzylamine, is a metabolite of bromhexine. It differs from bromhexine by the absence of a methyl group and the presence of a hydroxyl group in the para-trans-position of the cyclohexyl ring.

Ambroxol exerts secretolytic and secretomotor effects in the bronchial tract.

In preclinical studies, it increased the serous component of bronchial secretion. Ambroxol promotes mucus clearance by reducing viscosity and activating the ciliary epithelium.

Ambroxol activates the surfactant system through a direct effect on type II pneumocytes in the alveoli and Clara cells in the region of the small airways. It enhances the formation and release of surfactant material in the alveoli and bronchial tree of both fetus and adult. These effects have been demonstrated in various biological species, in cell cultures, and in vivo.

Furthermore, antioxidant effects of ambroxol have been demonstrated in various preclinical studies.

Pharmacokinetics. When administered intravenously, the bioavailability of the drug is by definition 100%. After intravenous administration, the pharmacokinetics of ambroxol within the therapeutic dose range of 15–90 mg are linearly dose-dependent; even after intravenous administration of 1.0 g, no significant deviations from linearity are observed.

Distribution. Approximately 85% (80–90%) of the drug is bound to plasma proteins. In lung tissue, ambroxol reaches higher concentrations than in plasma following parenteral administration. Ambroxol can penetrate into cerebrospinal fluid, cross the placental barrier, and is excreted in breast milk.

Metabolism. The formation of metabolites capable of penetrating into the kidneys (e.g., dibromanthranilic acid, glucuronide) occurs in the liver.

Elimination. Nearly 90% of the drug is excreted by the kidneys in the form of metabolites produced in the liver. Less than 10% of ambroxol is excreted unchanged by the kidneys. Due to the high degree of protein binding, large volume of distribution, and slow redistribution of the drug from tissues into blood, significant elimination of ambroxol by dialysis or forced diuresis is unlikely.

The terminal elimination half-life from plasma is 7–12 hours. The elimination half-life of ambroxol and its metabolites from plasma is approximately 22 hours.

After intravenous administration in healthy patients, total clearance is 660 ml/min, with renal clearance accounting for approximately 4.5% of total clearance.

Patients with hepatic or renal impairment. In patients with severe hepatic disorders, ambroxol clearance is reduced by 20–40%. In patients with severe renal impairment, accumulation of ambroxol metabolites should be considered. In adult patients with impaired liver function, elimination of ambroxol hydrochloride is reduced, resulting in 1.3- to 2-fold higher plasma concentrations. However, since the therapeutic range of ambroxol hydrochloride is sufficiently wide, dosage adjustment is not required.

Children. In newborns receiving repeated intravenous doses of ambroxol, the elimination half-life was approximately doubled, indicating reduced clearance.

Clinical characteristics.

Indications. To enhance pulmonary surfactant production in premature infants and newborns with respiratory distress syndrome.

Contraindications. Known hypersensitivity to ambroxol hydrochloride or other components of the medicinal product.

Interaction with other medicinal products and other forms of interaction. Clinically significant interactions of the drug with other medicinal products have not been established to date.

Concomitant use of the drug with cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex; such combination is possible only after careful assessment by a physician of the benefit-risk ratio.

Laboratory tests

Concomitant administration of ambroxol and antibiotics (amoxicillin, cefuroxime, doxycycline, and erythromycin) results in increased antibiotic concentrations in bronchopulmonary secretions and sputum.

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/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis. If symptoms of progressive skin rash (sometimes associated with blistering or mucosal involvement) occur, treatment with ambroxol hydrochloride should be discontinued immediately and medical attention should be sought.

If administered intravenously too rapidly, very rare cases of headache, increased fatigue, exhaustion, and a feeling of heaviness in the legs may occur.

Since ambroxol may enhance mucus secretion, the drug 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).

The drug should be used with caution in patients with renal impairment or severe hepatic disease. When ambroxol is administered, as with any active substance metabolized in the liver and subsequently excreted by the kidneys, accumulation of metabolites formed in the liver may occur in patients with severe renal insufficiency.

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

Use during pregnancy or breastfeeding. Data are lacking due to the absence of indications.

Effect on ability to drive and use machines. Not applicable, as the medicinal product is used in premature infants and newborns.

Method of Administration and Dosage

For intravenous infusion.

Dosage

30 mg per kg of body weight per day, divided into 4 single doses.

Dosing in renal and/or hepatic impairment. In cases of severe renal impairment or severe hepatic impairment, the maintenance dose should be appropriately reduced or the dosing interval prolonged.

The solution should be administered using an infusion pump via short-term infusion over at least 5 minutes. The medicinal product can also be administered as an intravenous infusion. The following solutions are suitable for this purpose: physiological saline or Ringer's solution.

Duration of treatment – 5 days.

The contents of 1–6 ampoules should be diluted in 250–500 ml of physiological saline or Ringer's solution. The solution diluted with physiological saline or Ringer's solution is physically and chemically stable for 24 hours at 15–25 °C. The stability of the ready-to-use solution has been confirmed within a concentration range of 0.03 mg/ml to 0.34 mg/ml. From a microbiological standpoint, if opening the ampoules and dilution involve a risk of microbial contamination, the solution should be used immediately after preparation. If not, the responsibility for storage conditions and duration lies with the user. If neither of these diluents is available, 5% glucose solution may be used as an alternative. When using 5% glucose solution, the contents of the ampoules should be diluted immediately before use. If the solution is not used immediately after preparation, it must be discarded.

Children. May be used in preterm infants and neonates as indicated.

Overdose. There are currently no reports of specific overdose symptoms. Symptoms observed in cases of accidental overdose or medical error are similar to the known adverse reactions occurring with use at recommended doses and may require symptomatic treatment.

Adverse reactions.

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

Immune system side effects:

Rare – hypersensitivity reactions;

Unknown frequency – anaphylactic reactions, including anaphylactic shock, angioneurotic edema, and pruritus.

Skin and subcutaneous tissue side effects:

Uncommon – erythema;

Rare – rash, urticaria;

Unknown frequency – serious skin adverse reactions (including erythema multiforme, Stevens-Johnson syndrome/toxic epidermal necrolysis, and acute generalized exanthematous pustulosis).

Gastrointestinal side effects:

Uncommon – dry mouth, constipation, hypersalivation, dry throat;

Unknown frequency – nausea, vomiting, diarrhea, dyspepsia, abdominal pain.

Respiratory, thoracic and mediastinal side effects:

Uncommon – rhinorrhea, dyspnea (as a symptom of hypersensitivity reaction).

Renal and urinary side effects:

Uncommon – urinary disorders.

General disorders and administration site conditions:

Uncommon – increased body temperature and chills, mucosal reactions.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after drug registration is an important procedure. It allows continuous monitoring of the benefit-risk balance for this medicinal product. Healthcare professionals are requested to report all suspected adverse reactions to the State Enterprise "State Expert Center of the Ministry of Health of Ukraine".

Shelf life. 5 years.

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

Keep out of reach of children.

Incompatibilities. The product should not be mixed with other solutions except physiological saline and Ringer's solution.

Packaging. 2 ml in ampoules, 5 ampoules per pack; 5 ampoules in a blister pack per carton.

Prescription status. Prescription only.

Manufacturer.

Limited Liability Company "Research Plant 'GNCLS'".

LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA'".

Manufacturer's address and location of business activity.

8 Vorobiova Street, Kharkiv, Kharkiv Region, 61057, Ukraine.

(Limited Liability Company "Research Plant 'GNCLS')

22 Shevchenka Street, Kharkiv, Kharkiv Region, 61013, Ukraine.

(LIMITED LIABILITY COMPANY "CORPORATION 'ZDOROVIYA')