Dvace long

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DVACE LONG

Composition:

Active substance: acetylcysteine;

One effervescent tablet contains acetylcysteine 600 mg;

Excipients: maltodextrin, citric acid anhydrous, sodium hydrogen carbonate, orange flavor, leucine, sodium saccharin.

Pharmaceutical form. Effervescent tablets.

Main physico-chemical properties: white-colored, round-shaped tablets with a flat surface.

Pharmacotherapeutic group. Medicinal products used for cough and colds. Mucolytic agents. ATC code R05C B01.

Pharmacological properties.

Pharmacodynamics.

N-acetyl-L-cysteine (NAC) exerts a pronounced mucolytic effect on mucous and mucopurulent secretions by depolymerizing mucoprotein complexes and nucleic acids that increase the viscosity of the vitreous and purulent components of sputum and other secretions. Additional properties include reduction of induced mucocyte hyperplasia, increased surfactant production due to stimulation of type II pneumocytes, and stimulation of mucociliary apparatus activity, thereby improving mucociliary clearance.

NAC also exerts a direct antioxidant effect due to the presence of a nucleophilic free thiol (SH) group capable of directly interacting with electrophilic groups of reactive oxygen species. It has been demonstrated that NAC protects α-1-antitrypsin (an enzyme that inhibits elastase) from inactivation by hypochlorous acid (HOCl), a strong oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC enables it to easily penetrate cell membranes. Inside the cell, NAC is deacetylated to L-cysteine, an amino acid required for glutathione synthesis. Glutathione is a highly active tripeptide widely distributed in various animal tissues and essential for maintaining cellular functional capacity and morphological integrity. Glutathione participates in the defense mechanism against both exogenous and endogenous reactive oxygen species and certain cytotoxic substances, including paracetamol.

Paracetamol exerts cytotoxic effects by progressively depleting glutathione levels. NAC plays a crucial role in maintaining adequate glutathione levels, thereby enhancing cellular protection. As a result, NAC serves as a specific antidote in paracetamol poisoning.

In patients with chronic obstructive pulmonary disease (COPD), administration of 1200 mg NAC daily for 6 weeks led to a significant increase in inspiratory volume and forced vital lung capacity, possibly due to reduced air trapping.

In patients with idiopathic pulmonary fibrosis (IPF), administration of oral acetylcysteine 600 mg three times daily for one year, in combination with standard IPF therapy (prednisolone and azathioprine), helped preserve lung vital capacity and diffusing capacity measured by the single-breath carbon monoxide method.

When used as inhalation therapy for one year, NAC reduced the rate of disease progression in patients with IPF.

When administered at very high doses (up to 3000 mg daily for 4 weeks) in patients with cystic fibrosis, NAC did not produce significant toxic effects.

The antioxidant efficacy of NAC is associated with a marked reduction in elastase activity in sputum, which is the most significant indicator of lung function in patients with cystic fibrosis. In addition, during treatment, a reduction was observed in the number of neutrophils in the airways, as well as in the number of neutrophils actively releasing elastase-rich granules.

Pharmacokinetics.

Absorption

In humans, after oral administration, NAC is completely absorbed. Due to metabolism in the intestinal wall and first-pass effect, the bioavailability of acetylcysteine after oral administration is very low (approximately 10%). No differences have been observed among various dosage forms. In patients with various respiratory and cardiovascular diseases, maximum plasma concentration of NAC is reached within 1–3 hours after administration and remains elevated for up to 24 hours.

Distribution

Acetylcysteine is distributed in the body both in unchanged form (20%) and as metabolites (active) (80%), with predominant distribution in the liver, kidneys, lungs, and bronchial secretions. The volume of distribution of NAC ranges from 0.33 to 0.47 L/kg. Plasma protein binding is approximately 50% four hours after administration and decreases to 20% after 12 hours.

Metabolism

After oral administration, acetylcysteine is rapidly and extensively metabolized in the intestinal wall and liver. The resulting metabolite, cysteine, is considered active. Subsequently, both acetylcysteine and cysteine are metabolized via the same pathway.

Elimination

Approximately 30% of the dose is excreted by the kidneys. After oral administration, the elimination half-life (T_1/2) of NAC is 6.25 (4.59–10.6) hours.

Clinical characteristics.

Indications.

Treatment of acute and chronic diseases of the bronchopulmonary system accompanied by increased sputum production.

Paracetamol overdose.

Contraindications.

Known hypersensitivity to acetylcysteine or any of the excipients.

Peptic ulcer of the stomach and duodenum in the stage of exacerbation, hemoptysis, pulmonary hemorrhage, severe exacerbation of bronchial asthma.

Children under 12 years of age. This is not a contraindication for use in the treatment of paracetamol overdose.

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adults.

Concurrent use of acetylcysteine with antitussive agents may enhance sputum retention due to suppression of the cough reflex.

Activated charcoal reduces the effectiveness of acetylcysteine.

Information on inactivation of antibiotics by acetylcysteine has so far been obtained only from in vitro experiments involving direct mixing of substances.

If simultaneous administration of acetylcysteine and any oral medications (including antibiotics) is necessary, they should be taken at an interval of at least 2 hours. This does not apply to loracarbef.

Concurrent use of nitroglycerin and acetylcysteine has been associated with significant hypotension and dilation of temporal arteries due to potentiation of the vasodilatory effect of nitroglycerin. If simultaneous administration of nitroglycerin and acetylcysteine is required, patients should be monitored for hypotension, which may be severe, and should be warned about the possibility of headache.

Concomitant use of acetylcysteine and carbamazepine may lead to subtherapeutic levels of carbamazepine.

Upon contact with metals or rubber, sulfides with a characteristic odor are formed; therefore, glassware should be used for dissolving the medicinal product.

Effect on laboratory tests

Acetylcysteine may interfere with the results of colorimetric assays for quantitative determination of salicylates and with the detection of ketone bodies in urine.

Special precautions for use

Patients with bronchial asthma should be under strict medical supervision during treatment, due to the possible development of bronchospasm. If bronchospasm occurs, treatment with acetylcysteine must be discontinued immediately.

There have been isolated reports of severe skin reactions (Stevens-Johnson syndrome and Lyell's syndrome) associated with the use of acetylcysteine. Therefore, if any changes in the skin or mucous membranes occur, the drug should be discontinued immediately and a physician should be consulted regarding further treatment.

The drug should be used with caution in patients with a history of gastric or duodenal ulcer, especially when used concomitantly with other medications that irritate the gastric mucosa.

Acetylcysteine should be administered with caution in patients with liver or kidney disease to avoid accumulation of nitrogen-containing compounds in the body.

Mucolytic agents may cause bronchial obstruction in children under 2 years of age. Due to physiological peculiarities of the respiratory system in this age group, the ability to clear respiratory secretions is limited. Therefore, mucolytics should not be administered to children under 2 years of age.

Use of acetylcysteine, particularly at the beginning of treatment, may lead to liquefaction of bronchial secretions and an increase in their volume. If the patient is unable to effectively expectorate sputum, postural drainage and bronchoaspiration may be required.

Acetylcysteine affects histamine metabolism; therefore, prolonged therapy should not be prescribed to patients with histamine intolerance, as it may lead to symptoms of intolerance (headache, vasomotor rhinitis, pruritus).

A mild sulfurous odor is not indicative of altered drug properties but is characteristic of the active substance.

Important information about excipients

A single dose of DwaCe Long 600 mg effervescent tablets contains 8.43 mmol (193.902 mg) of sodium. Caution is advised when administering to patients on a sodium-restricted diet.

Use during pregnancy or breastfeeding

Pregnancy

Clinical data on the use of acetylcysteine in pregnant women are limited. Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryofetal development, delivery, or postnatal development when the drug is used at recommended doses.

Before using the drug during pregnancy, potential risks should be weighed against the expected benefits.

Breastfeeding

There is no information available on the passage of acetylcysteine and/or its metabolites into breast milk. The risk to the infant cannot be excluded.

A decision should be made whether to discontinue breastfeeding or to discontinue/abandon treatment with DwaCe Long, taking into account the benefits of breastfeeding for the infant and the benefits of therapy for the mother.

Fertility

There are no data on the effect of acetylcysteine on human fertility. Animal studies have not shown any harmful effects on fertility at recommended doses.

Ability to affect reaction speed while driving or operating machinery

There is no evidence that acetylcysteine affects the ability to drive or operate machinery.

Dosage and Administration

Adults and children aged 12 years and older

Effervescent 600 mg tablets should be dissolved in 1/3 glass of water and taken once daily.

Additional fluid intake enhances the mucolytic effect of the medicinal product.

The duration of treatment is determined individually by a physician, depending on the nature of the disease (acute or chronic). The medicinal product should not be used for more than 4–5 days without consulting a physician.

Paracetamol overdose

Within the first 10 hours after ingestion of a toxic dose, acetylcysteine should be administered as soon as possible at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.

Acetylcysteine must be taken without delay immediately after dissolution.

No interactions with food have been reported; there are no recommendations regarding administration in relation to food intake.

Children

For use in children aged 12 years and older.

Overdose

There are no reports of overdose cases following oral administration of acetylcysteine. Volunteers took 11.2 g of acetylcysteine per day for 3 months without developing any serious adverse effects.

Acetylcysteine administered at doses of 500 mg/kg/day does not cause overdose. Symptoms: Overdose may manifest with gastrointestinal symptoms such as nausea, vomiting, and diarrhea.

Treatment: There is no specific antidote in case of acetylcysteine poisoning; therapy is symptomatic.

Side effects.

The most common side effects associated with oral administration of acetylcysteine are gastrointestinal reactions. Hypersensitivity reactions, including anaphylactic shock, anaphylactic/anaphylactoid reactions, bronchospasm, angioedema, rash, and pruritus, occurred less frequently.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 – < 1/10), uncommon (≥ 1/1,000 – < 1/100), rare (≥ 1/10,000 – < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Ear and labyrinth disorders: uncommon – tinnitus.

Respiratory, thoracic and mediastinal disorders: rare – dyspnea, bronchospasm; frequency not known – rhinorrhea.

Gastrointestinal disorders: uncommon – vomiting, diarrhea, stomatitis, abdominal pain, nausea; rare – dyspepsia; frequency not known – unpleasant breath odor.

Nervous system disorders: uncommon – headache.

Cardiac disorders: uncommon – tachycardia.

Vascular disorders: very rare – hemorrhages.

Blood and lymphatic system disorders: frequency not known – anemia.

Immune system disorders: uncommon – hypersensitivity; very rare – anaphylactic shock, anaphylactic/anaphylactoid reactions.

Skin and subcutaneous tissue disorders: uncommon – urticaria, rash, Quincke's edema, pruritus; frequency not known – eczema.

General disorders and administration site conditions: uncommon – hyperthermia; frequency not known – facial swelling.

Investigations: uncommon – decreased blood pressure.

In very rare cases, severe skin reactions (Stevens-Johnson syndrome and Lyell's syndrome) have been reported in association with acetylcysteine use. In most cases, at least one other medicinal product may be more likely responsible for the occurrence of mucocutaneous syndrome. Therefore, if any new skin or mucosal changes occur, patients should consult a physician and discontinue acetylcysteine immediately.

Cases of reduced platelet aggregation have been reported; however, the clinical significance of this is not established.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after authorization of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report any suspected adverse reactions and/or lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Incompatibilities.

When dissolving acetylcysteine, glassware should be used; avoid contact with metal and rubber surfaces.

It is not recommended to dissolve acetylcysteine together with other medicinal products in the same glass.

Packaging.

10 tablets in a tube; 1 tube in a carton.

Pharmaceutical category. Over-the-counter (without prescription).

Manufacturer. E. Pharma Trento S.p.A.

Manufacturer's address and place of business.

Via Provincia 2, Trento, 38123, Italy.

Marketing authorization holder. JSC "Pharmaceutical Company "Darnytsia".

Address of the marketing authorization holder.

13 Borispilska Street, Kyiv, 02093, Ukraine.