RAPIRA® 100

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAPIRA® 100 (RAPIRA100)

Composition:

Active substance: acetylcysteine;

1 sachet contains 100 mg of acetylcysteine;

Excipients: sorbitol (E 420), aspartame (E 951), riboflavin (E 101), orange-flavored flavoring.

Pharmaceutical form. Oral powder for solution.

Main physicochemical properties: light yellow powder with a creamy tint, free from foreign mechanical inclusions, with a characteristic orange odor and a slightly sulfurous note.

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 direct antioxidant activity due to the presence of a nucleophilic free thiol (SH) group, capable of directly interacting with electrophilic groups of reactive oxygen species. NAC prevents the inactivation of α-1-antitrypsin — an enzyme that inhibits elastase — by hypochlorous acid (HOCl), a strong oxidizing agent 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, part 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 reducing glutathione levels. NAC plays a crucial role in maintaining adequate glutathione levels, thus 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), oral administration of acetylcysteine 600 mg three times daily for one year, in combination with standard IPF therapy (prednisolone and azathioprine), helped preserve vital capacity (VC) and diffusing capacity of the lungs measured by the single-breath carbon monoxide method.

When used as inhalation therapy over one year, NAC contributed to reducing the progression rate of the disease 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, after oral administration, acetylcysteine is completely absorbed. Due to metabolism in the intestinal wall and the 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 cardiac diseases, maximum plasma concentrations of NAC are reached within 1–3 hours after administration and remain elevated for 24 hours.

Distribution

Acetylcysteine is distributed in the body both in unchanged form (20%) and as metabolites (active) (80%), with predominant detection 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 resulting metabolite, 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 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 mucus production.

Paracetamol overdose.

Contraindications.

Known hypersensitivity to acetylcysteine or to any of the excipients.

Acute phase of gastric or duodenal ulcer, hemoptysis, pulmonary hemorrhage.

Children under 2 years of age.

Interaction with other medicinal products and other forms of interaction.

It is not recommended to dissolve acetylcysteine in the same container with other drugs.

Interaction studies have been conducted only in adults.

Concomitant use of antitussive agents with acetylcysteine may enhance mucus retention due to suppression of the cough reflex.

Activated charcoal reduces the effectiveness of acetylcysteine.

Data on antibiotic inactivation by acetylcysteine have so far been obtained only in in vitro experiments with direct mixing of substances. If simultaneous 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.

Concomitant administration of nitroglycerin and acetylcysteine has been shown to cause significant arterial hypotension and dilation of temporal arteries. If simultaneous use of nitroglycerin and acetylcysteine is required, patients should be monitored for arterial hypotension, which may be severe, and should be warned about the possibility of headache.

Concomitant use of acetylcysteine and carbamazepine may result in subtherapeutic levels of carbamazepine.

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. If bronchospasm occurs, acetylcysteine therapy should 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 administered with caution in 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 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, postural drainage and bronchoaspiration may be required.

A mild sulfurous odor is not an indication 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 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.

Rapiра® 100 contains aspartame, a source of phenylalanine. This should be taken into account in patients with phenylketonuria.

The medicinal product contains sorbitol and therefore should not be administered to patients with hereditary fructose intolerance.

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, labor, or postnatal development.

As a precautionary measure, the use of the medicinal product Rapiра® 100 during pregnancy should be avoided.

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

Breastfeeding

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

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

Ability to affect reaction rate when driving vehicles or operating machinery.

There is no evidence that acetylcysteine affects the ability to drive vehicles or operate other machinery.

Method of Administration and Dosage

Adults

400–600 mg per day, divided into 1–3 doses depending on clinical conditions.

Children

2–6 years: 200–400 mg per day, divided into 1–3 doses;
6–18 years: 400–600 mg per day, divided into 1–3 doses.

Dissolve the powder in 1/3 cup of water.

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 the toxic substance, administer Rapira® 100 as soon as possible at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.

Rapira® 100 must be taken immediately 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.

Volunteers have taken 11.6 g of acetylcysteine per day for 3 months without 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; 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, angioneurotic edema, rash, and pruritus, occurred less frequently.

The adverse reactions listed in the table below are classified by system organ class and frequency of occurrence: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the 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 skin or mucosal changes occur, a physician should be consulted immediately and administration of acetylcysteine should be discontinued without delay.

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

Reporting of adverse reactions

Reporting suspected adverse reactions after the medicinal product has been authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of therapeutic efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 2 years.

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

Storage conditions. Store in the original packaging 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 should be avoided.

Dissolving acetylcysteine together with other medicinal products in the same glass is not recommended.

Packaging. 100 mg/0.5 g in sachets. 10 or 20 sachets per cardboard pack.

Availability. Over-the-counter.

Manufacturer. JSC "Farmak".

Manufacturer's address and site of operations.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.