Dvace 200

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT Dvace 200

Composition:

Active substance: acetylcysteine;

One effervescent tablet contains 200 mg of acetylcysteine;

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

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: round-shaped tablets with a flat surface, white to almost white in color.

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, which increase the viscosity of the vitreous and purulent components of sputum and other secretions. Additional properties include reduction of induced hyperplasia of mucocytes, 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 radicals. It has been established 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 allows 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 primary 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 capacity, possibly due to reduced air trapping.

In patients with idiopathic pulmonary fibrosis (IPF), oral administration of acetylcysteine at 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 for carbon monoxide measured by the single-breath method.

When used as inhalation therapy for one year, NAC contributed to reduced disease progression in patients with IPF.

When administered at very high doses (up to 3000 mg daily for 4 weeks) to patients with cystic fibrosis, NAC did not cause 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 decrease 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, acetylcysteine is completely absorbed after oral administration. Due to metabolism in the intestinal wall and first-pass effect, the bioavailability of acetylcysteine after oral intake is very low (approximately 10%). No differences have been observed among various dosage forms. In patients with various respiratory and cardiovascular diseases, maximum plasma concentrations of NAC are reached within 1–3 hours after administration and remain 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% at 4 hours after administration and decreases to 20% by 12 hours.

Metabolism

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

Excretion

Approximately 30% of the administered 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

Hypersensitivity to acetylcysteine or to any of the excipients. Active gastric or duodenal ulcer, hemoptysis, pulmonary hemorrhage, severe exacerbation of bronchial asthma.

Interaction with other medicinal products and other forms of interaction

Interaction studies have been conducted only in adults.

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

Activated charcoal reduces the efficacy of acetylcysteine.

Acetylcysteine is pharmacologically incompatible with antibiotics and proteolytic enzymes. When used concomitantly with antibiotics such as tetracyclines (except doxycycline), ampicillin, amphotericin B, cephalosporins, and aminoglycosides, interaction with the thiol group of acetylcysteine may occur, leading to reduced activity of both medicinal products. Therefore, the interval between administration of these medicinal products should be at least 2 hours. This does not apply to cefixime and loracarbef.

Concomitant use of nitroglycerin and acetylcysteine has been associated with marked hypotension and dilation of temporal arteries due to potentiation of the vasodilatory effect of nitroglycerin. If concomitant use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for hypotension, which may be severe, and should be warned about the possible occurrence of headache.

Acetylcysteine can act as a cysteine donor and increase glutathione levels, promoting detoxification of oxygen free radicals and certain toxic substances in the body. Acetylcysteine reduces the hepatotoxic effect of paracetamol.

It is not recommended to dissolve acetylcysteine with other medicinal products in the same glass. Synergism of acetylcysteine with bronchodilators has been observed.

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 test results

Acetylcysteine may interfere with quantitative colorimetric assays for salicylates and with tests for 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 should 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 skin or mucous membrane changes occur, the drug should be discontinued immediately and a physician should be consulted regarding further use.

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

Acetylcysteine should be administered with caution in patients with hepatic or renal impairment to avoid accumulation of nitrogen-containing substances in the body.

Acetylcysteine may cause liquefaction of bronchial secretions and increase their volume, particularly at the beginning of treatment. 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, itching).

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

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

Important information about excipients

This medicinal product contains sodium compounds. 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, labor, or postnatal development when the drug is used at recommended doses.

As a precautionary measure, the use of Dvatsye, effervescent tablets, during pregnancy should be avoided.

Breastfeeding

There is no information available on the excretion of acetylcysteine in human breast milk.

The drug should be used during breastfeeding only after careful assessment of the benefit-risk ratio.

Effect on the ability to drive vehicles or operate machinery

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

Dosage and Administration

Adults

400–600 mg per day, divided into 1–3 doses depending on clinical condition.

Children

Aged 2–6 years: 200–400 mg per day, divided into 1–3 doses;
Aged 6–12 years: 400–600 mg per day, divided into 1–3 doses;
Aged 12 years and older: adult doses.

Effervescent tablets of 200 mg should be dissolved in 1/3 glass of water.

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

The duration of treatment is determined individually by the 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 administered without delay, immediately after solution preparation.

Children

For use in children aged 2 years and older.

Overdose

There are no reported cases of overdose with oral administration of acetylcysteine. Volunteers took 11.6 g of acetylcysteine per day for 3 months without experiencing any serious adverse effects.

Acetylcysteine administered at doses of up to 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.

Adverse reactions

All adverse reactions are listed by system organ class 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).

Ear and labyrinth disorders: uncommon — tinnitus.

Respiratory, thoracic and mediastinal disorders: rare — dyspnoea, bronchospasm (mainly in patients with bronchial hyperreactivity associated with bronchial asthma); frequency not known — rhinorrhoea.

Gastrointestinal disorders: uncommon — vomiting, diarrhoea, stomatitis, abdominal pain, nausea, heartburn; rare — dyspepsia; frequency not known — unpleasant odour from the mouth.

Nervous system disorders: uncommon — headache.

Cardiac disorders: uncommon — tachycardia, hypotension.

Vascular disorders: very rare — haemorrhages.

Blood and lymphatic system disorders: frequency not known — anaemia; cases of bleeding have been reported during acetylcysteine use, sometimes due to hypersensitivity reactions.

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

Skin and subcutaneous tissue disorders: uncommon — urticaria, rash, Quincke's oedema, pruritus; frequency not known — exanthema, eczema, angioneurotic oedema.

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

In very rare cases, severe skin reactions (Stevens-Johnson syndrome and Lyell's syndrome) have been reported in association with acetylcysteine intake. In most cases, at least one other medicinal product could more likely have been the cause of the mucocutaneous syndrome. Therefore, if any new skin or mucosal changes occur, acetylcysteine should be discontinued immediately and medical advice should be sought.

Cases of decreased platelet aggregation have been observed; however, the clinical significance of this finding is not established.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicinal product authorization is important. It allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and/or lack of efficacy 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 the reach of children.

Incompatibilities

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

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

Antibiotics and acetylcysteine should not be mixed prior to administration due to the possibility of in vitro inactivation of antibiotics (mainly β-lactam antibiotics).

Packaging. 20 tablets in a tube; 1 tube in a carton.

Availability. Over-the-counter.

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

Manufacturer's address

Via Provincia 2, Trento, 38123, Italy.

Marketing Authorization Holder. JSC "Pharmaceutical Company "Darnytsia".

Address of the Marketing Authorization Holder

13 Boryspylska Street, Kyiv, 02093, Ukraine.