Flavamed® max effervescent tablets

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FLAVAMED® MAX EFFERVESCENT TABLETS

Composition:

Active substance: ambroxol hydrochloride;

One effervescent tablet contains 60 mg of ambroxol hydrochloride;

Excipients: citric acid, anhydrous; sodium hydrogencarbonate; anhydrous sodium carbonate; sodium saccharin; sodium cyclamate; sodium chloride; sodium citrate; lactose anhydrous; mannitol (E 421); sorbitol (E 420); cherry flavor "ALH" (code 801); simethicone.

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: white, round tablets with a score line on one side.

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

Pharmacological properties.

Pharmacodynamics.

The active substance of the medicinal product Flavamed® Max effervescent tablets, ambroxol hydrochloride, increases the proportion of serous secretion. In addition, ambroxol hydrochloride enhances surfactant production by directly affecting alveolar type II pneumocytes and Clara cells in the area of small airways, and stimulates ciliated epithelium activity. As a result of these effects, mucus viscosity is reduced and its clearance is improved (mucociliary clearance). Improvement of mucociliary clearance has been demonstrated in clinical pharmacological studies.

Increased secretion of diluted mucus and improved mucociliary clearance promote sputum liquefaction and facilitate expectoration.

Local anesthetic effect of ambroxol hydrochloride was observed in studies on rabbit eyes and is likely due to its ability to block sodium channels: in in vitro studies, ambroxol hydrochloride blocked hyperpolarized channels in a model of cloned voltage-dependent neuronal sodium channels; binding was weakly reversible and concentration-dependent.

In vitro studies have shown that ambroxol hydrochloride exerts anti-inflammatory effects. In vitro studies have demonstrated that ambroxol hydrochloride significantly reduces cytokine release from mononuclear and polymorphonuclear blood and tissue cells.

After administration of ambroxol hydrochloride, concentrations of the antibiotics amoxicillin, cefuroxime, erythromycin, and doxycycline are increased in sputum and bronchial secretions. The clinical significance of this effect has not yet been established.

Pharmacokinetics.

Absorption. Ambroxol hydrochloride is rapidly and completely absorbed after oral administration of immediate-release dosage forms and shows 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 after 6.5 hours for sustained-release formulations.

Distribution. 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 apparent volume of distribution after oral administration is approximately 552 L.

Plasma protein binding in the therapeutic range is approximately 90%.

Biotransformation and elimination. Approximately 30% of the orally administered dose undergoes hepatic first-pass metabolism. Ambroxol hydrochloride is mainly metabolized in the liver via glucuronidation and cleavage to dibromobenzylamine acid (approximately 10% of the dose), in addition to several minor metabolites. Studies with human liver microsomes have shown that CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromobenzylamine acid.

Within 3 days after oral administration, approximately 6% of the dose is excreted unchanged in urine and approximately 26% as conjugates.

The terminal half-life of ambroxol hydrochloride is approximately 10 hours. Total clearance is 660 mL/min, with renal clearance accounting for approximately 8% of total clearance. Within 5 days, approximately 83% of the total dose (with radioactive labeling) is excreted in urine.

Special patient groups. In patients with hepatic dysfunction, elimination of ambroxol hydrochloride is reduced, leading to an increase in its plasma levels by approximately 1.3–2 times. Due to the wide therapeutic range of ambroxol hydrochloride, dose adjustment is not required.

Age and sex have no clinically significant effect on the pharmacokinetics of ambroxol hydrochloride; therefore, dosage regimen adjustment is not necessary.

Food 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 weakened mucus clearance.

Contraindications.

Flavamed® Max effervescent tablets should not be used in cases of hypersensitivity to the active substance or to any of the excipients of the medicinal product.

Interaction with other medicinal products and other forms of interaction.

Concomitant use of Flavamed® Max effervescent tablets and antitussive agents may lead to dangerous accumulation of mucus due to suppression of the cough reflex. Therefore, they should be used together only after careful assessment of the benefit-risk ratio by a physician.

Special precautions for use

Cases of severe skin reactions, including erythema multiforme, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), have been reported in association with the use of ambroxol hydrochloride. If symptoms or signs of progressive skin rash (sometimes associated with blisters or mucosal lesions) occur, treatment with ambroxol should be discontinued immediately and medical advice should be sought.

Due to the potential for mucus retention in cases of impaired bronchial motility and excessive secretion (e.g., in rare primary ciliary dyskinesia), Flavamed® Max effervescent tablets should be used with caution.

Flavamed® Max effervescent tablets should be taken only after consultation with a physician in patients with renal impairment or severe hepatic pathology. As with any other drugs metabolized in the liver and subsequently excreted by the kidneys, accumulation of ambroxol metabolites formed in the liver may be expected in patients with severe renal insufficiency.

Since mucolytic agents may disrupt the gastric mucosal barrier, ambroxol should be administered with caution in patients with a history of peptic ulcer disease.

This medicinal product contains lactose. It should not be administered to patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption.

One effervescent tablet of this medicinal product contains 126.5 mg of sodium, equivalent to 6.33% of the WHO recommended maximum daily intake of 2 g sodium for adults. Caution should be exercised when administering this product to patients with histamine intolerance. Since ambroxol affects histamine metabolism and may provoke symptoms of intolerance such as headache, rhinitis, or pruritus, prolonged therapy should be avoided in such patients.

Use during pregnancy or breastfeeding

Pregnancy. Ambroxol hydrochloride crosses the placental barrier. Animal studies have not indicated any direct or indirect adverse effects on pregnancy, embryonic/fetal development, parturition, or postnatal development. Extensive clinical experience after the 28th week of pregnancy has not revealed any evidence of harmful effects on the fetus. However, standard precautionary measures for drug administration during pregnancy should be observed. In particular, the use of Flavamed® Max effervescent tablets is not recommended during the first trimester of pregnancy.

Breastfeeding. Ambroxol hydrochloride is excreted into breast milk.

Flavamed® Max effervescent tablets should not be used during breastfeeding.

Reproductive function. Preclinical studies have not shown any direct or indirect adverse effects on fertility.

Ability to influence reaction rate while driving or operating machinery

There are no data regarding the effect of this medicinal product on the ability to drive vehicles or operate machinery. Studies on the influence of the drug on the ability to drive vehicles or operate machinery have not been conducted.

Dosage and Administration

Adults and children aged 12 years and older. During the first 2–3 days, the usual dose is ½ effervescent tablet 3 times daily (equivalent to 30 mg of ambroxol hydrochloride 3 times daily). Subsequently, the dose is ½ effervescent tablet 2 times daily (equivalent to 30 mg of ambroxol hydrochloride 2 times daily).

In adults and children aged 12 years and older, if necessary, the efficacy may be enhanced by using 1 effervescent tablet 2 times daily (equivalent to 120 mg of ambroxol hydrochloride per day).

Flavamed® Max effervescent tablets are intended for oral administration.

Dissolve the effervescent tablets in a glass of water and take during or regardless of meals.

Flavamed® Max effervescent tablets should not be taken for longer than 4–5 days without medical supervision.

Children

Due to the high content of active ingredient, Flavamed® Max effervescent tablets are contraindicated in children under 12 years of age.

Overdose

To date, no specific symptoms of overdose in humans have been reported.

Symptoms reported in cases of accidental overdose and/or incorrect use of the medicinal product are similar to the known adverse reactions of Flavamed® Max effervescent tablets, which may occur during administration at recommended doses and may require symptomatic treatment.

Side effects

The following adverse reactions occurred with the following frequency: very common (≥ 1/10); common (≥ 1/100 – < 1/10); uncommon (≥ 1/1000 – < 1/100); rare (≥ 1/10000 – < 1/1000); very rare (< 1/10000); not known (cannot be estimated from the available data).

Immune system disorders. Rare: hypersensitivity reactions; not known: anaphylactic reactions, including anaphylactic shock, angioedema, and pruritus.

Gastrointestinal disorders. Common: nausea, oral hypoaesthesia; uncommon: vomiting, diarrhoea, dyspepsia, abdominal pain, dry mouth; rare: dry throat; very rare: sialorrhoea.

Skin and subcutaneous tissue disorders. Rare: rash, urticaria; not known: serious skin adverse reactions (including erythema multiforme, Stevens–Johnson syndrome, toxic epidermal necrolysis, and acute generalised exanthematous pustulosis).

General disorders and administration site conditions. Uncommon: pyrexia, mucosal reactions.

Respiratory, thoracic and mediastinal disorders. Common: pharyngeal hypoaesthesia; not known: dyspnoea (as a symptom of hypersensitivity reaction).

Nervous system disorders. Common: dysgeusia (e.g. altered taste sensation).

Reporting of suspected adverse reactions. Reporting suspected adverse reactions after authorisation of the medicinal product is important. This allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions.

Shelf life. 3 years.

Storage conditions. Store below 30°C. Keep in the original packaging. Keep the tube tightly closed.

Packaging. 10 tablets in a tube; 1 tube in a cardboard box.

Classification. Over-the-counter.

Manufacturer.

BERLIN-CHEMIE AG.

Manufacturer's address and location of operations.

Glienicker Weg 125, 12489 Berlin, Germany.