Ambroxol-darnitsa

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

Composition:

Active substance: ambroxol;

One tablet contains ambroxol hydrochloride 30 mg;

Excipients: lactose monohydrate, maize starch, microcrystalline cellulose, colloidal anhydrous silicon dioxide, stearic acid.

Pharmaceutical form. Tablets.

Main physico-chemical properties: white or almost white tablets, cylindrical in shape, with beveled edges and a score line; slight greyish specks may be present.

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

Pharmacological properties.

Pharmacodynamics.

It has been demonstrated that the active substance of the medicinal product, ambroxol hydrochloride, increases the secretion of the serous component of bronchial mucus. Ambroxol enhances the release of pulmonary surfactant by directly affecting type II pneumocytes in the alveoli and Clara cells in the bronchioles, and also stimulates ciliary activity, thereby facilitating mucus clearance and its expulsion (mucociliary clearance). Activation of fluid secretion and increased mucociliary clearance ease mucus elimination and reduce coughing.

Local anesthetic effect of ambroxol was observed in a rabbit eye model, which may be explained by its sodium channel blocking properties. In vitro studies have shown that ambroxol blocks neuronal sodium channels; binding is reversible and concentration-dependent. In vitro studies have also demonstrated that ambroxol hydrochloride significantly reduces cytokine release from mononuclear and polymorphonuclear blood and tissue cells.

In clinical trials involving patients with pharyngitis, significant reduction in throat pain and redness was demonstrated upon administration of the medicinal product. These pharmacological properties result in rapid relief of pain and pain-related discomfort in the nasal cavity, ear area, and trachea during inhalation, consistent with additional symptom observation data from clinical efficacy studies of ambroxol in the treatment of upper respiratory tract disorders.

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

Pharmacokinetics.

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

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, approximately 90% of the drug is protein-bound within the therapeutic dose range.

Metabolism and elimination. Approximately 30% of the dose is eliminated via presystemic metabolism after oral administration. Ambroxol hydrochloride is metabolized mainly in the liver through glucuronidation and cleavage to dibromanthranilic acid (approximately 10% of the dose). 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 in urine, and approximately 26% of the dose – as conjugated metabolites.

The elimination half-life from plasma is 10 hours. Total clearance is approximately 660 mL/min, with renal clearance accounting for about 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 the drug is quite wide, dosage adjustment is not required.

Age and sex do not have a clinically significant effect on the pharmacokinetics of ambroxol; therefore, dosage adjustment is not 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 clearance.

Contraindications.

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

In rare inherited conditions leading to incompatibility with an excipient of the medicinal product (see section "Special precautions for use"), administration of the medicinal product is contraindicated.

Interaction with other medicinal products and other forms of interactions.

Following administration of ambroxol hydrochloride, concentrations of antibiotics (amoxicillin, cefuroxime, cephalexin, oxytetracycline, erythromycin, doxycycline) increase in bronchopulmonary secretions and sputum.

Concomitant use of the medicinal product with cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination should be used only after careful assessment by a physician of the benefit-risk ratio.

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

Special precautions for use.

At the beginning of treatment, cough may be intensified.

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

Only a few reports have been received regarding severe skin reactions: erythema multiforme, Stevens–Johnson syndrome (SJS) / toxic epidermal necrolysis (TEN, Lyell’s syndrome), and acute generalized exanthematous pustulosis (AGEP), associated with the use of expectorants such as ambroxol hydrochloride. These cases were mostly attributable to the severity of the underlying disease in patients and/or concomitant use of other medicinal products. Additionally, in the initial stages of Stevens–Johnson syndrome or Lyell’s syndrome, patients may present nonspecific, flu-like symptoms such as fever, malaise, rhinitis, cough, and sore throat. Due to these nonspecific, flu-like symptoms, symptomatic treatment with cough and cold medications may be mistakenly initiated. Therefore, if new skin lesions or mucosal lesions appear, immediate medical attention should be sought and treatment with ambroxol hydrochloride should be discontinued.

The medicinal product contains lactose; therefore, patients with rare hereditary forms of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take Ambroxol-Darnitsia.

It should not be used in patients with peptic ulcer of the stomach or duodenum, or in patients with respiratory diseases associated with the production of large amounts of liquid sputum. The medicinal product should be used with caution in cases of impaired bronchial motility and increased mucus secretion (e.g., in rare conditions such as primary ciliary dyskinesia), as ambroxol may enhance mucus secretion.

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, embryonic/fetal development, parturition, or postnatal development.

Clinical studies have shown no adverse effects on the fetus when ambroxol hydrochloride is used after the 28th week of pregnancy.

However, usual precautionary measures regarding medication use during pregnancy should be observed. In particular, use of the medicinal product is not recommended during the first trimester of pregnancy.

Breastfeeding period.

The medicinal product passes into breast milk. Although no adverse effects on infants are expected, Ambroxol-Darnitsia is not recommended for use during breastfeeding.

Fertility.

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

Ability to influence reaction speed while driving or operating machinery.

There are no data on the effect on reaction speed while driving or operating machinery. Studies on the influence of the medicinal product on reaction speed during driving or operating machinery have not been conducted. However, the possibility of dizziness occurring during treatment should be taken into account.

Dosage and Administration

For children aged 6 to 12 years: administer 1/2 tablet 2–3 times daily (equivalent to 30–45 mg of ambroxol hydrochloride per day).

For adults and children aged 12 years and older: administer 1 tablet 3 times daily for the first 2–3 days (equivalent to 90 mg of ambroxol hydrochloride per day). Continue treatment with 1 tablet 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 administering 2 tablets twice 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) after meals.

The medicinal product should not be used for longer than 4–5 days without consulting a physician.

Children

To be used in children aged 6 years and older when other dosage forms cannot be used.

Overdose

Symptoms
The medicinal product is well tolerated after oral administration at doses up to 25 mg/kg per day. Severe signs of intoxication have not been observed following ambroxol overdose. Cases of short-term restlessness and diarrhea have been reported.

By analogy with preclinical studies, excessive overdose may lead to hypersalivation, nausea, vomiting, and decreased arterial blood pressure.

Treatment
Emergency measures such as induction of vomiting and gastric lavage are generally not indicated and should only be applied in cases of acute intoxication. Symptomatic treatment is recommended.

Side effects

All adverse reactions are listed by system organ classes and frequency: 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 from the available data).

Sensory organs: frequency not known – dysgeusia (taste disturbance).

Respiratory system, thoracic and mediastinal organs: frequency not known – dry rales, dryness of the mouth and respiratory tract, decreased sensitivity in the pharynx, rhinorrhea, bronchospasm, dyspnea (as a symptom of hypersensitivity reaction).

Gastrointestinal tract: common – nausea; uncommon – vomiting, abdominal pain, dyspeptic symptoms, diarrhea; rare – dryness of the throat; very rare – hypersalivation; frequency not known – decreased sensitivity in the oral cavity, dry mouth, heartburn, constipation.

Nervous system: frequency not known – headache, dizziness, weakness.

Immune system: rare – hypersensitivity reactions, including urticaria; frequency not known – anaphylactic reactions, including anaphylactic shock, angioneurotic edema, and other allergic reactions.

Skin and subcutaneous tissue: rare – skin rash, pruritus, dermatitis; frequency not known – severe skin reactions: erythema multiforme, Stevens-Johnson syndrome / toxic epidermal necrolysis (Lyell's syndrome), acute generalized exanthematous pustulosis, associated with use of mucolytic agents such as ambroxol. These were mostly attributable to the severity of the underlying disease or concomitant use of other medicinal products. If skin reactions or mucosal reactions occur, the patient should discontinue use of the medicinal product and consult a physician.

Renal and urinary system: frequency not known – dysuria.

General disorders: uncommon – increased sweating, fever, mucosal reactions.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

10 tablets in a blister pack; 2 blister packs in a carton.

Availability category. Over-the-counter.

Manufacturer. JSC "Pharmaceutical Company "Darnytsia".

Manufacturer's address and place of business.

13, Borispilska Street, Kyiv, 02093, Ukraine.