Acetal soluble

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACETAL SOLUBLE

Composition:

Active substance: acetylcysteine;

One tablet contains acetylcysteine 200 mg;

Excipients: sodium hydrogen carbonate, citric acid, aspartame (E 951), lemon flavour containing maltodextrin; gum arabic (E 414); citric acid.

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: white, round, flat-surfaced tablets with bevelled edges and a score line on one side, with a characteristic lemon and slightly sulphurous odour. Effervescence (gas bubble release) is observed when dissolved in water. Slight opalescence and characteristic lemon and slightly sulphurous odour are permissible.

Pharmacotherapeutic group. Mucolytics. 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 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 due to 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, which can directly interact with electrophilic groups of reactive oxygen species. Of particular interest is the fact that NAC prevents the inactivation of α1-antitrypsin — an enzyme that inhibits elastase — by hypochlorous acid (HOCl), a potent oxidant produced by myeloperoxidase in activated phagocytes.

Moreover, the molecular structure of NAC allows it to easily penetrate cellular 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 exhibits an indirect antioxidant effect. Glutathione is a highly active tripeptide widely distributed in various animal tissues and essential for maintaining cellular functional capacity and morphological integrity. It is, in fact, a key component 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 through progressive depletion of glutathione. 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 improvement 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 1 year, in combination with standard IPF therapy (prednisolone and azathioprine), helped preserve vital lung capacity (VLC) and diffusing capacity of the lungs measured by the single-breath carbon monoxide method.

When used as inhalation therapy for 1 year, NAC contributed to a reduction in the progression rate of the disease 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 exhibit 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 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 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 detection 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 and elimination. After oral administration, NAC is rapidly and extensively metabolized in the intestinal wall and liver. The resulting metabolite, cysteine, is considered active. Acetylcysteine and cysteine are further metabolized via the same pathway. Approximately 30% of the dose is excreted by the kidneys. The half-life (T½) 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 to any of the excipients of the medicinal product.

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

Interaction with other medicinal products and other forms of interaction.

Interaction studies have been conducted only in adults.

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

Activated charcoal reduces the effectiveness of acetylcysteine.

Data on inactivation of antibiotics by acetylcysteine have so far been obtained only from in vitro experiments with direct mixing of substances. If concomitant administration of acetylcysteine and any oral preparations (including antibiotics) is necessary, they should be taken with an interval of at least 2 hours. This does not apply to cefixime and loracarbef.

Significant arterial hypotension and dilatation of the temporal artery have been observed with concomitant use of nitroglycerin and acetylcysteine. When simultaneous administration of nitroglycerin and acetylcysteine is required, patients should be monitored for arterial hypotension, which may be severe; they should also be warned about the possibility of headache.

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

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

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 the drug 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 in patients with liver or kidney disease to avoid accumulation of nitrogen-containing substances in the body.

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).

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 mucus, postural drainage and bronchoaspiration may be required.

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

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

The medicinal product contains aspartame, a phenylalanine derivative, which may be harmful for patients with phenylketonuria.

This medicinal product contains 5.94 mmol (or 136.86 mg) of sodium per 200 mg dose. Caution should be exercised 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 shown any direct or indirect adverse effects on reproductive toxicity.

As a precautionary measure, the use of the medicinal product during pregnancy should be avoided.

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

Breastfeeding period

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

A decision must be made whether to discontinue breastfeeding or to discontinue/abstain from using the medicinal product, taking into account the benefits of breastfeeding for the infant and the benefits of therapy for the woman.

Fertility

There are no data available 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.

Method of Administration and Dosage

Children aged 2 to 6 years: ½ tablet of 200 mg (100 mg of acetylcysteine) 2–3 times daily (200–300 mg of acetylcysteine per day).

Children aged 6 to 12 years: 1 tablet of 200 mg twice daily (400 mg of acetylcysteine per day).

Adults and children aged 12 years and older: 1 tablet of 200 mg 2–3 times daily (400–600 mg of acetylcysteine per day).

The duration of treatment is determined individually by the physician, depending on the nature of the disease (acute or chronic).

Paracetamol overdose

Within the first 10 hours after ingestion of the toxic substance, administer the medicinal product as soon as possible at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.

The medicinal product must be taken without delay, immediately after dissolving in a glass of water.

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

Children: May be used in children aged 2 years and older.

Overdose.

There are no data on cases of overdose with oral formulations of acetylcysteine.

It has been reported that volunteers took 11.2 g of acetylcysteine per day for 3 months without experiencing any serious adverse effects.

Acetylcysteine, when 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 for acetylcysteine poisoning; treatment is symptomatic.

Adverse Reactions

The most common adverse reactions 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.

The adverse reactions listed below are categorized by system organ class and frequency of occurrence: 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), and not known (cannot be estimated from available data).

Within each group, adverse reactions are listed in order of decreasing severity.

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

Blood and lymphatic system disorders:
Not known – anemia.

Nervous system disorders:
Uncommon – headache.

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac disorders:
Uncommon – tachycardia.

Vascular disorders:
Very rare – hemorrhages.

Thoracic organ and mediastinum disorders:
Rare – bronchospasm, dyspnea.

Respiratory system disorders:
Not known – rhinorrhea.

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

Skin and subcutaneous tissue disorders:
Uncommon – urticaria, rash, Quincke's edema (angioedema), pruritus; not known – eczema.

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

Investigations:
Uncommon – decreased blood pressure.

In very rare cases, severe skin reactions such as Stevens-Johnson syndrome and Lyell's syndrome have been reported in association with acetylcysteine use. In most of these cases, at least one other medicinal product is more likely to have caused the mucocutaneous syndrome. Therefore, if any new skin or mucous membrane changes occur, patients should consult a physician immediately and discontinue acetylcysteine treatment without delay.

Cases of decreased platelet aggregation have been reported; however, the clinical significance of this effect has not been established.

Reporting of adverse reactions

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

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. Effervescent tablets: № 10 (2×5), № 20 (2×10) in a strip pack within a carton.

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

Manufacturer. LIMITED LIABILITY COMPANY "CORPORATION "ZDOROVYA".

Manufacturer's address and location of business operations.
22, Shevchenka Street, Kharkiv, Kharkiv Oblast, 61013, Ukraine.