Muklear

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 gelatinous 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 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—an enzyme that inhibits elastase—by hypochlorous acid (HOCl), a strong oxidant produced by myeloperoxidase in activated phagocytes.

In addition, 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. As a glutathione precursor, NAC also exerts an indirect antioxidant effect. Glutathione is a highly active tripeptide found in various animal tissues and is essential for maintaining cellular functional capacity and morphological integrity. It is 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 by progressively depleting glutathione levels. NAC plays a primary role in maintaining adequate glutathione levels, thus enhancing cellular protection. Consequently, 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 600 mg three times daily for one year, in combination with standard IPF therapy (prednisone 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 a reduction in 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. Additionally, during treatment, a reduction in the number of neutrophils in the airways and in the number of neutrophils actively releasing elastase-rich granules was observed.

Pharmacokinetics.

Absorption

In humans, acetylcysteine is completely absorbed after oral administration. Due to intestinal wall metabolism 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 high for 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. Protein binding in plasma is approximately 50% four hours after administration and decreases to 20% after 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. Acetylcysteine and cysteine are further metabolized via the same pathway.

Elimination

Approximately 30% of the dose is excreted by the kidneys. After oral administration, the elimination half-life (T1/2) of NAC is 6.25 (4.59–10.6) hours.

Clinical characteristics.

Indications.

Treatment of acute and chronic bronchopulmonary diseases associated with 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 acute phase, hemoptysis, pulmonary hemorrhage.

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 forms of interaction.

Interaction studies have been conducted only in adults.

Concomitant 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 antibiotic inactivation by acetylcysteine has been obtained only from in vitro experiments involving direct mixing of substances. If concomitant administration of acetylcysteine and any oral medications (including antibiotics) is necessary, they should be taken at least 2 hours apart. This does not apply to loracarbef.

Concomitant administration of nitroglycerin and acetylcysteine has been associated with significant arterial hypotension and dilation of temporal arteries. If concomitant use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for potentially severe arterial hypotension. Patients should be warned about the possibility of headache.

Concomitant use of acetylcysteine and carbamazepine may result in 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, treatment with acetylcysteine should be discontinued immediately.

The drug should be used with caution in patients with a history of gastric or duodenal ulcer, especially when concomitantly taking other medications 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, prolonged therapy should not be prescribed to patients with histamine intolerance, as it may lead to symptoms of intolerance (headache, vasomotor rhinitis, pruritus).

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.

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

The medicinal product Muclear should be used with caution in patients with phenylketonuria (an inherited metabolic disorder) as it contains aspartame as a source of phenylalanine.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

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 reproductive toxicity.

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

Before administering the drug during pregnancy, the potential risk should be weighed against the expected benefit.

Period of breastfeeding

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

A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from the use of Muclear, taking into account the benefits of breastfeeding for the child and the benefits of therapy for the woman.

Fertility

Data on the effect of acetylcysteine on human fertility are lacking. Animal studies have not revealed any harmful effects on fertility in humans when the drug is used at recommended doses.

Ability to influence reaction rate when 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

Dissolve one 600 mg effervescent tablet in 1/3 glass of water and take 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, administer Muclear 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 Muclear must be taken immediately after dissolution without delay.

No interaction with food has 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 data on cases of overdose with oral formulations of acetylcysteine.

Volunteers took 11.2 g of acetylcysteine daily for three months without experiencing any serious adverse reactions.

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

Symptoms

Overdose may manifest as 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 organ system class and frequency of occurrence (very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

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

In very rare cases, severe skin reactions such as Stevens–Johnson syndrome and Lyell's syndrome have been reported in connection with the use of acetylcysteine. In most cases, at least one other medicinal product is more likely to be the cause of the mucocutaneous syndrome. Therefore, if any new changes appear on the skin or mucous membranes, medical advice must be sought immediately and administration of acetylcysteine should be discontinued without delay.

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

Reporting suspected adverse reactions

Healthcare and pharmacy professionals, as well as patients or their legal representatives, are advised to report all suspected adverse reactions and lack of drug efficacy via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua