Asibrox

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ASIBROX (ASIBROX)

Composition:

Active substance: acetylcysteine;

One effervescent tablet contains acetylcysteine 200 mg or 600 mg;

Excipients: ascorbic acid, sodium carbonate anhydrous, sodium hydrogen carbonate, anhydrous citric acid, sorbitol (E 420), macrogol 6000, sodium citrate, sodium saccharin, lemon flavor.

Pharmaceutical form. Effervescent tablets.

Main physicochemical properties: flat cylindrical white tablets with a bevel, slight mottling is allowed, with a characteristic odor.

Pharmacotherapeutic group.
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 gel-like 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 promoting improved 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. Of particular interest is the fact that NAC prevents inactivation of α-1-antitrypsin—a protease inhibitor that inhibits elastase—by hypochlorous acid (HOCl), a strong oxidant produced by myeloperoxidase in activated phagocytes.

Furthermore, 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 exerts an indirect antioxidant effect. Glutathione is a highly active tripeptide widely distributed in animal tissues and essential for maintaining cellular functional capacity and morphological integrity. It is, in fact, a component of the most important intracellular defense mechanism against both exogenous and endogenous reactive oxygen species and certain cytotoxic substances, including acetaminophen.

Acetaminophen 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 is a specific antidote in acetaminophen poisoning.

In patients with COPD, administration of 1200 mg of NAC daily over 6 weeks led to a significant increase in inspiratory volume and FEV1 (forced expiratory volume in 1 second), 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 for carbon monoxide measured by the single-breath method.

When used as inhalation therapy for one year, NAC contributed to a reduction in the rate of 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 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.

After oral administration, acetylcysteine 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%). Maximum plasma concentration is reached within 1–3 hours after administration and remains elevated for up to 24 hours.

Distribution.

Acetylcysteine is distributed both in unchanged form (20%) and as metabolites (80%), primarily accumulating in the liver, kidneys, lungs, and bronchial secretions.

The volume of distribution of acetylcysteine ranges from 0.33 to 0.47 L/kg. Protein binding is approximately 50% at 4 hours after administration and decreases to 20% by 12 hours.

Metabolism.

Following oral administration, acetylcysteine is rapidly 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% is excreted by the kidneys. The elimination half-life of acetylcysteine is 6.25 (4.59–10.6) hours.

Clinical characteristics.

Indications.

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

Contraindications.

• Hypersensitivity to acetylcysteine, to other substances with a similar chemical structure, or to any excipients of the medicinal product.
• Peptic ulcer of the stomach and duodenum in the stage of exacerbation, hemoptysis, pulmonary hemorrhage.
• Age under 2 years.

Interaction with other medicinal products and other types of interactions.

Studies on the interaction of acetylcysteine with other medicinal products have been conducted only in adults.

Concomitant use of acetylcysteine with antitussive agents is not recommended, as suppression of the cough reflex may lead to accumulation of secretions.

Activated charcoal may reduce the effect 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 drugs (including antibiotics) is necessary, they should be taken at an interval of at least 2 hours. This does not apply to loracarbef.

When nitroglycerin and acetylcysteine are used concomitantly, marked arterial hypotension and dilatation of the temporal artery with possible headache attacks have been observed. If such combination is necessary, patients should be monitored for potentially severe arterial hypotension, and 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, the drug should be discontinued immediately.

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, mucolytic agents should not be used in children under 2 years of age.

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.

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

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

Acetylcysteine affects histamine metabolism; therefore, the drug should not be used for long-term therapy in patients with histamine intolerance, as it may lead to symptoms of intolerance (headache, vasomotor rhinitis, pruritus).

A sulfur-like odor is possible; this is not a sign of drug deterioration but is characteristic of the active substance.

The drug contains sorbitol. If intolerance to certain sugars has been diagnosed, consult a physician before using this medicinal product.

The medicinal product Asibroks 200 mg contains 403.1 mg of sodium. The medicinal product Asibroks 600 mg contains 356.8 mg of sodium. The sodium content should be taken into account when administering to patients with impaired renal function or those on a low-sodium diet.

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical data on the use of acetylcysteine in pregnant women are limited. Animal studies have not revealed direct or indirect adverse effects on reproductive toxicity.

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

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

Breastfeeding period.

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

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

Fertility.

There are no data on the effect of acetylcysteine on human fertility. Animal studies have not revealed any harmful effects on fertility in humans when the drug is used at recommended doses.

Ability to affect reaction rate while driving or operating machinery.

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

Method of administration and dosage.

The medicinal product is intended for oral administration. The effervescent tablet should be dissolved in 1/3 of a glass of water and taken as quickly as possible. It is recommended to take it after food. To enhance the mucolytic effect of acetylcysteine, additional fluid intake is recommended.

Effervescent tablets 200 mg

Adults and children aged 12 years and older.

The medicinal product should be administered at a dose of 400–600 mg per day, divided into 1–3 doses.

Children aged 6–12 years.

The medicinal product should be administered at a dose of 400–600 mg per day, divided into 1–3 doses.

Children aged 2–6 years.

The medicinal product should be administered at a dose of 200–400 mg per day, divided into 1–3 doses.

Effervescent tablets 600 mg

Adults and children aged 12 years and older.

The medicinal product should be administered at a dose of 600 mg once daily.

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, 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.

The medicinal product should be taken without delay, immediately after preparing the solution.

Children.

Effervescent tablets 200 mg are indicated for children aged 2 years and older. Effervescent tablets 600 mg are indicated for children aged 12 years and older.

Overdose.

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

Volunteers took 11.6 g of acetylcysteine per day for 3 months without any serious adverse reactions.

Acetylcysteine does not cause overdose when administered at doses of 500 mg/kg/day.

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

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.

Adverse reactions are listed by system organ class and frequency of occurrence: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (<1/10000); frequency not known (frequency cannot be estimated from the available data). Within each group, adverse reactions are presented in order of decreasing severity.

Blood and lymphatic system disorders:

Frequency not known – anaemia.

Immune system disorders:

Uncommon – hypersensitivity; very rare – anaphylactic shock, anaphylactic/anaphylactoid reactions.

Nervous system disorders:

Uncommon – headache.

Ear and labyrinth disorders:

Uncommon – tinnitus.

Cardiac disorders:

Uncommon – tachycardia.

Vascular disorders:

Very rare – haemorrhages.

Respiratory, thoracic and mediastinal disorders:

Rare – dyspnoea, bronchospasm; frequency not known – bronchial obstruction, rhinorrhoea.

Gastrointestinal disorders:

Uncommon – vomiting, diarrhoea, stomatitis, abdominal pain, nausea; rare – dyspepsia; frequency not known – unpleasant odour of breath.

Skin and subcutaneous tissue disorders:

Uncommon – urticaria, rash, Quincke's oedema, 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 such as Stevens–Johnson syndrome and Lyell's syndrome have been reported in association with acetylcysteine use. In most cases, at least one other medicinal product is more likely to be the cause of the mucocutaneous syndrome. Therefore, if any new skin or mucous membrane changes occur, medical advice should be sought immediately and the drug should be discontinued promptly.

Cases of reduced platelet aggregation have been reported, but the clinical significance of this is not known.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after marketing authorization is extremely important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are urged to report any suspected adverse reactions via the national reporting system.

Shelf life.

3 years.

Storage conditions.

For tablets in strips:

Store at a temperature not exceeding 25 °C in a dry, light-protected place, out of reach of children.

For tablets in a bottle:

Store at a temperature not exceeding 25 °C in a dry, light-protected place, out of reach of children. Keep the bottle tightly closed.

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 agents in the same glass.

Packaging.

Effervescent tablets 200 mg:

24 tablets in a bottle, 1 bottle in a cardboard box; 2 tablets in a strip, 5 or 10 strips in a cardboard box.

Effervescent tablets 600 mg:

12 tablets in a bottle, 1 bottle in a cardboard box; 2 tablets in a strip, 5 or 10 strips in a cardboard box.

Pharmaceutical category.

Over-the-counter (without prescription).

Manufacturer.

PharmaEstica Manufacturing (PharmaEstica Manufacturing LLC), Estonia /
PharmaEstica Manufacturing (PharmaEstica Manufacturing OU), Estonia.

S.C. WORLD MEDICINE EUROPE S.R.L., Romania /
S.C. WORLD MEDICINE EUROPE S.R.L., Romania

Manufacturer's address and place of business.

Vanapere tee 3, Pringi, Viimsi, 74011 Harju county, Estonia /
Vanapere tee 3, Pringi, Viimsi, 74011 Harju county, Estonia.

Otopeni city, Eroilor str. № 1C, 075100, jud. Ilfov, Romania /
Otopeni city, Eroilor str. № 1C, 075100, jud. Ilfov, Romania.

Marketing Authorization Holder.

WORLD MEDICINE, LLC, Ukraine /
WORLD MEDICINE, LLC, Ukraine.