Ambrolitin

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT AMBROLYTIN® (AMBROLYTIN®)

Composition:

Active substance: ambroxol;

5 ml of syrup contain ambroxol hydrochloride 15 mg;

Excipients: sorbitol (E 420); citric acid monohydrate; methylparahydroxybenzoate (E 218); propylparahydroxybenzoate (E 216); glycerol; propylene glycol; sodium saccharin; raspberry flavoring; purified water.

Pharmaceutical form. Syrup.

Main physico-chemical properties: clear syrup-like liquid ranging from pale yellow to light brown with a characteristic raspberry odor.

Pharmacotherapeutic group.

Medicinal products used in cough and common cold disorders. Mucolytic agents.

ATC code R05C B06.

Pharmacological properties.

Pharmacodynamics.

The active substance of the drug, ambroxol, is an active metabolite of bromhexine and increases secretion of the respiratory tract glands. Ambroxol enhances pulmonary surfactant secretion by directly affecting type II pneumocytes in the alveoli and Clara cells in the bronchioles, and also stimulates ciliary activity. This leads to increased mucus secretion and expectoration, and improved mucociliary clearance. Improvement of mucociliary clearance has been demonstrated in clinical pharmacological studies.

Activation of fluid secretion and enhanced mucociliary clearance facilitate mucus elimination and reduce coughing.

The local anesthetic effect of ambroxol hydrochloride, which may be 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 have demonstrated a significant reduction in throat pain and redness upon administration of the drug.

Due to the pharmacological properties of ambroxol, pain relief during treatment of upper respiratory tract diseases occurred rapidly, as observed in clinical efficacy studies of ambroxol inhalation forms.

After administration of ambroxol hydrochloride, concentrations of antibiotics (amoxicillin, cefuroxime, erythromycin) increase in bronchopulmonary secretions and sputum.

Pharmacokinetics.

Absorption. Absorption of ambroxol hydrochloride from immediate-release oral dosage forms is rapid and sufficiently complete, with linear dependence within the therapeutic range. Maximum plasma concentrations are reached within 1–2.5 hours after oral administration of immediate-release formulations.

Distribution. After oral administration, distribution of ambroxol hydrochloride from blood to tissues is rapid and pronounced, with the highest concentration of the active substance found in the lungs. 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. Approximately 30% of the dose is eliminated via presystemic metabolism after oral administration. Ambroxol hydrochloride is metabolized primarily in the liver through conjugation and degradation to dibromanthranilic acid (approximately 10% of the dose).

Clinical studies using human liver microsomes have shown that the CYP3A4 isoenzyme predominantly mediates the metabolism of ambroxol hydrochloride to dibromanthranilic acid.

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

Elimination. 90% of ambroxol hydrochloride is excreted by the kidneys. It does not accumulate in renal insufficiency. The half-life of ambroxol hydrochloride is approximately 10 hours. Total clearance is approximately 660 mL/min, with renal clearance accounting for up to 8% of total clearance. Within 5 days, approximately 83% of the total dose (radiolabeled) is excreted in urine.

Pharmacokinetics in special patient populations.

In patients with impaired liver function, elimination of ambroxol hydrochloride is reduced. As a result, plasma concentrations are approximately 1.3 to 2 times higher. However, due to the wide therapeutic range of the active substance, dose adjustment is not necessary.

Others.

Age and sex have no clinically significant effect on the pharmacokinetics of ambroxol hydrochloride; therefore, no dose adjustment is required.

Food intake does not affect the bioavailability of ambroxol hydrochloride.

Clinical characteristics.

Indications.

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

Contraindications.

Hypersensitivity to ambroxol or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other types of interactions.

When administered concomitantly with ambroxol, the concentration of certain antibiotics (amoxicillin, cefuroxime, erythromycin) increases in bronchopulmonary secretions and lung tissue.

Concomitant use of ambroxol with cough suppressants is not recommended, as this may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such a combination is possible only after careful assessment by a physician of the expected benefit versus potential risk of use.

There are no reports of clinically significant adverse interactions of ambroxol with other medicinal products.

Special precautions for use

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

There have been a few reports of severe skin reactions: erythema multiforme, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome, and Lyell's syndrome (toxic epidermal necrolysis), occurring in temporal association with ambroxol use. In most cases, these reactions can be explained by the severity of the underlying disease and/or concomitant use of other medications. The early phase of Stevens-Johnson syndrome or Lyell's syndrome may present with non-specific flu-like symptoms such as high fever, body aches, rhinitis, cough, and sore throat. This may be misleading and lead to symptomatic treatment with cough and cold remedies. Therefore, if new skin or mucosal lesions appear, immediate medical attention should be sought and treatment with ambroxol hydrochloride should be discontinued.

Ambrolitin® 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), since ambroxol may enhance mucus secretion.

If the patient's condition does not improve or worsens after 5 days of ambroxol treatment, the patient should consult a physician for reassessment of therapy.

Ambrolitin® contains sorbitol in an amount of 35 g/100 ml. The recommended dose (5 ml) contains 1.75 g of sorbitol. This product must not be used by patients with rare hereditary fructose intolerance. It may cause irritation of the gastric mucosa and has a mild laxative effect. The energy value of 1 g of sorbitol is 2.6 kcal.

Ambrolitin® contains the excipients methyl- and propyl-parahydroxybenzoates, which may cause allergic reactions (possibly delayed).

The product contains glycerol; its use in high doses (10 g per dose) may cause headache, irritation of the gastric mucosa, and diarrhea.

Ambrolitin® contains less than 1 mmol of sodium (23 mg) per dose, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding

Pregnancy. Ambroxol crosses the placental barrier. Extensive clinical observations after the 28th week of pregnancy have not shown any fetal damage. Ambroxol has not demonstrated teratogenic effects in animal studies. However, usual precautionary measures for medication use during pregnancy should be followed. Use of the drug during the first trimester of pregnancy is not recommended.

Breastfeeding. Ambroxol is excreted in breast milk, but when used at therapeutic doses, effects on the breastfed infant are unlikely. However, ambroxol is not recommended for use during breastfeeding.

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

Ability to affect reaction speed when driving or operating machinery

There is no data on the effect of ambroxol on reaction speed when driving or operating machinery. Studies on the influence of ambroxol on reaction speed during driving or operating machinery have not been conducted.

Dosage and Administration

Unless otherwise prescribed, the recommended dosage of Ambrolitin® syrup 15 mg/5 ml is as follows:

Children under 2 years of age: 2.5 ml twice daily (equivalent to 15 mg of ambroxol hydrochloride per day);

Children aged 2–6 years: 2.5 ml three times daily (equivalent to 22.5 mg of ambroxol hydrochloride per day);

Children aged 6–12 years: 5 ml two to three times daily (equivalent to 30–45 mg of ambroxol hydrochloride per day);

Adults and children aged 12 years and older: 10 ml three times daily (equivalent to 90 mg of ambroxol hydrochloride per day) for the first 2–3 days, followed by 10 ml 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).

The medication can be taken regardless of food intake.

Ambrolitin® should not be used for more than 4–5 days without consulting a physician.

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

Ambrolitin® does not contain alcohol.

Children.

The medication may 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 symptoms related to ambroxol overdose. Symptoms reported in isolated cases of overdose and/or accidental misuse correspond to the known adverse reactions of Ambrolitin® observed with recommended dosages and require symptomatic treatment.

Side effects

Side effects are classified by frequency and system-organ classes. Frequency according to MedDRA: very common (≥ 1/10), common (≥ 1/100 and <1/10), uncommon (≥ 1/1,000 and <1/100), rare (≥ 1/10,000 and <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Immune system, skin and subcutaneous tissue disorders:
Rare: skin rash, urticaria, other hypersensitivity reactions.
Frequency not known: anaphylactic reactions (including anaphylactic shock), angioneurotic edema, pruritus, severe skin reactions: Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), acute generalized exanthematous pustulosis, erythema multiforme.

Nervous system disorders:
Common: dysgeusia (taste disturbance).

Respiratory, thoracic and mediastinal disorders:
Common: decreased sensitivity in the pharynx.
Frequency not known: dyspnea (as a symptom of hypersensitivity reaction), rhinorrhea.

Gastrointestinal disorders:
Common: nausea, decreased sensitivity in the oral cavity.
Uncommon: vomiting, diarrhea, dyspepsia, abdominal pain, dry mouth.
Rare: dry throat.
Frequency not known: hypersalivation, constipation.

Renal and urinary disorders:
Frequency not known: dysuria.

General disorders:
Frequency not known: fever, mucosal reactions.

Shelf life. 2 years.

Shelf life after opening the package – 1 month.

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

Storage conditions.

Keep out of the reach of children.

Store in the original packaging (in a dry, light-protected place) at a temperature not exceeding 25 °C.

Do not freeze!

Packaging.

100 ml in a glass bottle with an aluminum or polyethylene cap; 100 ml in a polyethylene terephthalate bottle with a polyethylene cap; 1 bottle with a measuring cup in a cardboard box.

Supply classification. Over-the-counter.

Manufacturer.

JSC "Sofarma".

Manufacturer's address and place of business.

16 Iliensko Shose Str., Sofia, 1220, Bulgaria.