Acetylcysteine

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ACETYLCYSTEINE (Acetylcysteine)

Composition:

Active substance: acetylcysteine;

1 sachet (3.0 g of powder) contains 200 mg of acetylcysteine;

Excipients: sucrose, forest berry flavor (black currant juice concentrate, ethyl acetate, terpinen-4-ol natural, D-camphor, hepta-2,4-dienal, maltodextrin, glycerol triacetate, dextrin, acetic acid), ascorbic acid, sodium saccharin.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: crystalline powder from light pink to pink in color, possible presence of agglomerates which easily disintegrate, with a forest berry 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 that contribute to the viscosity of hyaline and purulent components of sputum and other secretions. Additional properties include reduction of induced hyperplasia of mucous cells, 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. 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 enables 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 demonstrates 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, part of the most important intracellular defense mechanism against reactive oxygen species, both exogenous and endogenous, as well as 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), administration of oral acetylcysteine 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 the single-breath carbon monoxide method.

When used as inhaled 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 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 in the number of neutrophils in the airways was observed, as well as a decrease in the number of neutrophils actively releasing elastase-rich granules.

Pharmacokinetics.

Absorption

In humans, 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%). 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 active metabolites (80%), predominantly found 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 metabolite formed, 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 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 types of interactions.

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.

When used simultaneously 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 agents. Therefore, the interval between administration of these drugs should be at least 2 hours. This does not apply to cefixime and loracarbef.

Concomitant administration of nitroglycerin and acetylcysteine has been associated with significant hypotension and dilation of temporal arteries. When simultaneous use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for hypotension, which may be severe, and should also be warned about the possibility 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.

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. When emptying the sachet contents into a container during solution preparation, the powder may become airborne and irritate the nasal mucosa, potentially causing reflex bronchospasm. If bronchospasm occurs, treatment with acetylcysteine should be discontinued immediately.

Caution is recommended when administering the drug to patients with a history of peptic 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, prolonged therapy should not be prescribed to patients with histamine intolerance, as it may provoke 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 mucus, postural drainage and bronchoaspiration may be required.

A mild sulfurous odor is not indicative 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 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 sucrose and therefore should not be administered to patients with rare hereditary forms of fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption syndrome.

This medicinal product contains 0.048 mmol (or 1.12 mg)/dose of sodium. Caution is advised when administering to patients on a controlled sodium intake 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 pregnancy, embryofetal development, parturition, or postnatal development.

Breastfeeding period

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

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

Ability to affect performance while driving or operating 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

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

Dissolve the powder in 1/2 glass of water.

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 Acetylcysteine as soon as possible at a dose of 140 mg/kg initially, followed by 70 mg/kg every 4 hours for 1–3 days.

Acetylcysteine must be administered immediately, right after preparing the solution.

Children

For use in children aged 2 years and older.

Overdose

There are no reported cases of overdose with oral formulations of acetylcysteine.

Available data from studies in volunteers who took 11.6 g of acetylcysteine per day for three months showed no serious adverse reactions.

Acetylcysteine 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 in case of acetylcysteine poisoning; treatment is symptomatic.

Side effects.

Side effects that occur after administration of acetylcysteine for oral use.

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 of these cases, at least one other medicinal product may be more likely to have caused the mucocutaneous syndrome. Therefore, if any new skin or mucous membrane changes occur, a physician should be consulted immediately and administration of acetylcysteine should be discontinued without delay.

Cases of reduced platelet aggregation have been reported; however, the clinical significance of this finding is unclear.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Incompatibility.

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 drugs in the same glass.

Packaging.

3 g of powder in sachets, 20 sachets per cardboard pack.

Availability. Over-the-counter.

Manufacturer/Marketing Authorization Holder. Ternopharm LLC.

Manufacturer's address and location of its business activities / Marketing Authorization Holder's address.

4 Fabrychna Street, Ternopil, Ukraine, 46010.

Tel./Fax: (0352) 521-444, www.ternopharm.com.ua