Acetylcysteine

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

Composition:

Active substance: acetylcysteine;

1 sachet (3.0 g of powder) contains acetylcysteine 600 mg;

Excipients: sucrose, forest berry flavor (blackcurrant 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, 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 due to stimulation of type II pneumocytes, and stimulation of mucociliary apparatus activity, thereby promoting improved 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 oxidant 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 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 key component of the most important intracellular defense mechanism against oxidative radicals—both exogenous and endogenous—as well as against certain cytotoxic substances, including paracetamol.

Paracetamol 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 the specific antidote in paracetamol poisoning.

In patients with 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 acetylcysteine orally 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 the single-breath carbon monoxide method.

When used as inhaled 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) 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 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 high for 24 hours.

Distribution

Acetylcysteine is distributed throughout 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. Plasma protein binding is approximately 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. Acetylcysteine and cysteine are further metabolized via the same pathway. Approximately 30% of the dose is excreted by the kidneys. The 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.

Peptic ulcer of the stomach and duodenum in the stage of exacerbation, 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 antitussives with acetylcysteine may increase sputum retention due to suppression of the cough reflex.

Activated charcoal reduces the effectiveness of acetylcysteine.

When used concomitantly 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.

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

Acetylcysteine may 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, acetylcysteine treatment must be discontinued immediately.

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

Acetylcysteine affects histamine metabolism; therefore, prolonged therapy should not be administered 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 product deterioration but is characteristic of the active substance.

The preparation 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) of sodium per dose. Caution is advised when administering to patients on a sodium-controlled diet.

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 pregnancy, embryofetal development, parturition, or postnatal development.

As a precautionary measure, the use of this medicinal product in pregnant women should be avoided. The potential risks should be weighed against the expected benefits before use during pregnancy.

Breastfeeding

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

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

Ability to influence 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.

Adults and children aged 12 years and older

Dissolve 1 sachet of 600 mg in half a glass of water and take once daily.

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

Paracetamol overdose

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

Acetylcysteine must be taken without delay, immediately after preparation of the solution.

Children.

For use in children aged 12 years and older.

Overdose.

There are no data on 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 without experiencing any serious adverse effects.

Acetylcysteine intake at doses of up to 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; therapy is symptomatic.

Adverse reactions.

The following are undesirable reactions following the use of acetylcysteine for oral administration.

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 is more likely to have caused the mucocutaneous syndrome. Therefore, if any new skin or mucous membrane changes occur, medical advice must be sought immediately and acetylcysteine should be discontinued without delay.

Cases of reduced platelet aggregation have been observed; however, the clinical significance of this finding is not established.

Reporting of suspected adverse reactions.

It is important to report suspected adverse reactions after the medicinal product has been authorized. This allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach and sight of children.

Incompatibilities.

When dissolving acetylcysteine, glassware should be used. Contact with metal and rubber surfaces must be avoided.

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

Packaging.

3 g of powder in sachets, 20 sachets in a cardboard box.

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

Manufacturer/Marketing Authorization Holder. Ternopharm LLC.

Address of manufacturer/Marketing Authorization Holder.

4 Fabrychna Street, Ternopil, 46010, Ukraine.

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