Dwice long

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT DVATSE LONG (DVATSE LONG)

Composition:

Active substance: acetylcysteine;

One sachet contains 600 mg of acetylcysteine;

Excipients: sorbitol (E 420), acesulfame potassium, orange flavor.

Pharmaceutical form. Granules for oral solution.

Main physicochemical characteristics: granules or powder ranging from white to light yellow in color with a characteristic odor. The presence of agglomerates that easily disintegrate is possible.

Pharmacotherapeutic group. Medicinal products used for cough and colds. Mucolytic agents. Acetylcysteine. ATC code R05CB01.

Pharmacological properties.

Pharmacodynamics.

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

N-acetyl-L-cysteine 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. Of particular interest is the fact that NAC prevents inactivation of α-1-antitrypsin—an enzyme that inhibits elastase—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 form L-cysteine, an essential amino acid for glutathione synthesis. In addition, as a precursor of glutathione, NAC exerts an indirect antioxidant effect. Glutathione is a highly active tripeptide found in various animal tissues and is indispensable for maintaining cellular functional capacity and morphological integrity. It is, in fact, part of the most important intracellular 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 is 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 (FVC), 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 (VC) and diffusing capacity of the lungs measured by single-breath carbon monoxide 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) in 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 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, acetylcysteine is completely absorbed after oral administration. 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 24 hours.

Distribution

Acetylcysteine is distributed in the body both in unchanged form (20%) and as metabolites (active) (80%), with predominant presence 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 about 50% four hours after administration and decreases to 20% after 12 hours.

Metabolism and elimination

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. Approximately 30% of the dose is excreted by the kidneys. The elimination half-life (T_1/2) of NAC is 6.25 hours.

Clinical Characteristics.

Indications.

Treatment of acute and chronic diseases of the bronchopulmonary system associated with increased mucus production.

Contraindications.

Known hypersensitivity to acetylcysteine or to any of the excipients of the medicinal product. Peptic ulcer of the stomach and duodenum in the acute phase, hemoptysis, pulmonary hemorrhage, severe exacerbation of bronchial asthma.

Interaction with other medicinal products and other types of interactions.

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

Interaction studies have been conducted only in adults.

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

Activated charcoal reduces the effectiveness of acetylcysteine.

When administered simultaneously with antibiotics such as tetracyclines (except doxycycline), ampicillin, amphotericin B, cephalosporins, 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 administration of nitroglycerin and acetylcysteine may cause significant hypotension and dilatation of the temporal artery. When simultaneous use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for hypotension, which may be severe; the possibility of headache should also be considered.

Synergism between acetylcysteine and bronchodilators has been observed.

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.

Effect on laboratory tests

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

Special precautions for use.

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.

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

Caution is recommended when administering this medicinal product to patients with a history of gastric or duodenal ulcer, especially when concomitantly taking other medicinal products that irritate the gastric mucosa.

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

Acetylcysteine affects histamine metabolism; therefore, it should not be used for prolonged periods in patients with histamine intolerance, as this may lead to symptoms of intolerance (headache, vasomotor rhinitis, itching).

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

Mucolytic agents 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 product deterioration but is characteristic of the active substance.

Important information about excipients.

The medicinal product contains sorbitol; therefore, it should not be administered to patients with hereditary fructose intolerance.

Use during pregnancy or breastfeeding.

Pregnancy

Clinical data on the use of acetylcysteine in pregnant women are limited. Animal studies have not shown any direct or indirect adverse effects on pregnancy, embryofetal development, parturition, or postnatal development.

Breastfeeding period

There is no information available on the passage of acetylcysteine into breast milk.

The medicinal product should be used during pregnancy or breastfeeding only after careful assessment of the benefit-risk ratio.

Ability to influence reaction rate while driving or operating machinery.

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

Method of Administration and Dosage.

Adults and children aged 12 years and older

Administer 600 mg once daily.

The medicinal product should be taken after food.

Dissolve the granules in a glass of water and drink the solution immediately after preparation without delay.

When dissolving acetylcysteine, use glassware and avoid contact with metallic and rubber surfaces.

Additional fluid intake enhances the mucolytic effect of the drug.

The duration of treatment is determined individually by a physician depending on the nature of the disease. In acute uncomplicated conditions, acetylcysteine should be used for 4–5 days.

Children.

To be used in children aged 12 years and older.

Overdose.

There are no reports of overdose cases with oral administration of acetylcysteine.

Volunteers have taken 11.6 g of acetylcysteine per day for three months without developing any serious adverse effects.

Acetylcysteine administered at a dose of 500 mg/kg/day does not cause overdose.

Symptoms.

Overdose may manifest with gastrointestinal symptoms such as nausea, vomiting, and diarrhea. In children, there is a risk of hypersecretion.

Treatment.

There is no specific antidote in case of acetylcysteine poisoning; treatment is symptomatic.

Adverse reactions.

Below are the adverse reactions following the oral administration of acetylcysteine.

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), 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 – dyspnea, bronchospasm (mainly in patients with bronchial hyperreactivity associated with bronchial asthma); frequency not known – rhinorrhea.

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

Nervous system disorders: uncommon – headache.

Cardiac disorders: uncommon – tachycardia, hypotension; 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 – pruritus, urticaria, exanthema, rash, angioneurotic edema (Quincke's edema); frequency not known – eczema.

General disorders: uncommon – hyperthermia; frequency not known – facial swelling.

In very rare cases, severe skin reactions (e.g., Stevens-Johnson syndrome and Lyell's syndrome) have been reported in association with acetylcysteine intake.

In most cases, at least one other medicinal product is more likely to be the cause of the mucocutaneous syndrome. If any new skin or mucosal changes occur, acetylcysteine should be discontinued immediately and medical advice sought.

Very rarely, bleeding has been reported during acetylcysteine use, mostly associated with hypersensitivity reactions.

Cases of reduced platelet aggregation have been reported, although there is no clinical confirmation.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization of a medicinal product is an important procedure. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions via the national reporting system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibilities.

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. 600 mg/3 g in sachets, 10 sachets per pack.

Supply category. Over-the-counter.

Manufacturer. JSC "Pharmaceutical Company "Darnitsya".

Manufacturer's address and location of its business activities.

13, Boryspylska Street, Kyiv, 02093, Ukraine.