Rapira® efertab 600

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAPIRA® EFFERTAB 600 (RAPIRA EFFERTAB 600)

Composition:

Active substance: acetylcysteine;

One tablet contains 600 mg of acetylcysteine;

Excipients: anhydrous citric acid, maltodextrin, sodium bicarbonate, orange flavor, leucine, sodium saccharin.

Pharmaceutical form. Effervescent tablets.

Main physicochemical characteristics: white, round-shaped tablets with a flat surface.

Pharmacotherapeutic group. Mucolytic agents. ATC code R05CB01.

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 vitreous and purulent components of sputum and other secretions. Additional properties include reduction of induced hyperplasia of mucocytes, 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 oxidative radicals. Of particular interest is the fact that NAC prevents the inactivation of α-1-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 enables it to readily penetrate cell membranes. Inside the cell, NAC is deacetylated to form L-cysteine, an essential amino acid for glutathione synthesis. In addition to this, NAC, as a glutathione precursor, exhibits an indirect antioxidant effect. Glutathione is a highly active tripeptide found in various animal tissues and is indispensable for maintaining cellular functional capacity and morphological integrity. It is, in fact, part of the most important intracellular defense mechanism against oxidative radicals, both exogenous and endogenous, and against certain cytotoxic substances, including paracetamol.

Paracetamol exerts cytotoxic effects by progressively reducing glutathione levels. NAC plays a primary role in maintaining adequate glutathione levels, thus enhancing cellular protection. As a result, NAC serves as 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 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 administered as inhalation therapy over one year, NAC contributed to reducing the progression rate of the disease in patients with IPF.

When used in very high doses (up to 3000 mg daily for 4 weeks), NAC did not exert significant toxic effects in patients with cystic fibrosis.

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 pharmaceutical forms. In patients with various respiratory and cardiovascular diseases, maximum plasma concentration of NAC is reached within 1–3 hours after administration and remains elevated 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. Plasma protein binding is approximately 50% at 4 hours after administration and decreases to 20% at 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. Subsequently, acetylcysteine and cysteine are metabolized via the same pathway.

Excretion

Approximately 30% of the dose is excreted by the kidneys. After oral administration, the elimination half-life (T_1/2) of NAC 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 or to any of the excipients.

Acute gastric or duodenal ulcer, hemoptysis, pulmonary hemorrhage.

Children under 12 years of age. However, age under 12 years 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 enhance mucus retention due to suppression of the cough reflex.

Activated charcoal reduces the effectiveness of acetylcysteine.

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

Concomitant administration of nitroglycerin and acetylcysteine has been shown to cause significant hypotension and dilation of the temporal artery. In cases where concomitant use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for hypotension, which may be severe. Patients should be warned about the possibility of headache.

Concomitant use of acetylcysteine and carbamazepine may lead to a reduction in carbamazepine levels to subtherapeutic concentrations.

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 must be discontinued immediately.

The drug should be administered with caution to patients with a history of peptic ulcer of the stomach or duodenum, especially when other medications that irritate the gastric mucosa are taken concomitantly.

Acetylcysteine should be administered with caution to 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 sulfur-like odor is not an indication of a change in the quality of the drug—it is characteristic of the active substance.

Mucolytic agents may cause bronchial obstruction in children under 2 years of age. Due to physiological characteristics 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.

One effervescent tablet of 600 mg contains 8.4 mmol (194.2 mg) of sodium. This should be taken into account if the patient is 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 revealed direct or indirect adverse effects on reproductive toxicity.

As a precautionary measure, the use of the medicinal product "Rapira® Efertab 600" during pregnancy should be avoided.

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

Breastfeeding

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

A decision should be made either to discontinue breastfeeding or to discontinue/abstain from the use of the medicinal product "Rapira® Efertab 600," taking into account the benefits of breastfeeding for the child and the therapeutic benefits for the woman.

Fertility

There are no data available 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 influence the reaction rate while driving or operating machinery.

There is no evidence that acetylcysteine affects the ability to drive a vehicle or operate machinery.

Dosage and Administration.

For adults and children aged 12 years and older

Dissolve one effervescent tablet 600 mg in 1/3 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 dose, administer the medicinal product "Rapira® Efertab 600" as soon as possible at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.

"Rapira® Efertab 600" must be taken immediately after dissolution without delay.

No interactions with food have 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 is no data on cases of overdose with oral formulations of acetylcysteine.

Volunteers have taken 11.2 g of acetylcysteine per day for three months without developing any serious adverse effects.

Acetylcysteine administered at a dose 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; 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, angioneurotic edema, rash, and pruritus, have been reported less frequently.

The table below lists adverse reactions by organ systems and frequency of occurrence.

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 of the reported cases, at least one other medicinal product was more likely to have caused the mucocutaneous syndrome. Therefore, if any new changes appear on the skin or mucous membranes, acetylcysteine should be discontinued immediately and medical advice should be sought.

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

It is important to report adverse reactions following the drug's registration. This allows ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions through the national reporting system.

Shelf life. 3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions. Keep the tube tightly closed. No special temperature storage conditions are required for this medicinal product. Keep out of reach of children.

Incompatibilities.

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

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

Packaging. 10 tablets in a tube. 1 tube in a carton.

Category of supply. Over-the-counter.

Manufacturer. E-Farma Trento S.P.A. / E-Pharma Trento S.P.A.

Manufacturer's address.
Frazione Ravina - Via Provina, 2 - Trento (TN), Italy / Frazione Ravina - Via Provina, 2 -Trento (TN), Italy.

Marketing Authorization Holder. JSC "Farmak"

Address of the Marketing Authorization Holder. 63, Kyrylivska Street, Kyiv, 04080, Ukraine.