Rapira® 600

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

Composition:

Active substance: acetylcysteine;

1 sachet contains acetylcysteine 600 mg;

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

Pharmaceutical form. Oral soluble powder.

Main physico-chemical 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 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. NAC prevents 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 allows 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 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 both exogenous and endogenous oxidative radicals and 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 serves as a specific antidote in paracetamol poisoning.

In patients with chronic obstructive pulmonary disease (COPD), administration of 1200 mg of NAC per day over 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 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 inhalation therapy over one year, NAC contributed to a reduction in the progression rate of the disease in patients with IPF.

When administered at 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 was observed in the number of neutrophils in the respiratory tract, 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 first-pass effect, the bioavailability of acetylcysteine after oral administration is very low (approximately 10%). No differences have been found 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 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% 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 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 T_1/2 of NAC is 6.25 hours.

Clinical characteristics.

Indications.

Treatment of acute and chronic diseases of the bronchopulmonary system associated with increased mucus 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.

Age under 12 years. This is not a contraindication for use in the treatment of paracetamol overdose.

Interaction with other medicinal products and other forms of interaction.

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

Interaction studies have been conducted only in adults.

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

Activated charcoal reduces the effectiveness of acetylcysteine.

Information on inactivation of antibiotics by acetylcysteine has so far been obtained only from in vitro experiments involving 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 the temporal artery. When 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 developing headache.

Concomitant use of acetylcysteine and carbamazepine may lead to subtherapeutic levels of carbamazepine.

Acetylcysteine can act as a cysteine donor and increase glutathione levels, which promotes 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 with this medication 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 gastric or duodenal ulcer, especially when concomitantly taking other medicinal products that irritate the gastric mucosa.

Acetylcysteine should be prescribed with caution to patients with liver or kidney disease to avoid accumulation of nitrogen-containing substances in the body.

Acetylcysteine affects histamine metabolism; therefore, long-term 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.

Rapiра® 600 contains aspartame, a source of phenylalanine. This should be taken into account in patients with phenylketonuria.

The medicinal product contains sorbitol; therefore, it should not be used in 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 revealed direct or indirect adverse effects on pregnancy, embryofetal development, labor, or postnatal development.

As a precautionary measure, the use of the medicinal product Rapiра® 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 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 child and the benefits of therapy for the woman.

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 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 the toxic substance, administer Rapira® 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® 600 must be taken immediately after preparing the solution.

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 11.6 g of acetylcysteine per day for 3 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; 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 table below lists adverse reactions by system organ classes 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 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 mucous membrane changes occur, medical advice must be sought immediately and acetylcysteine should be discontinued without delay.

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

Reporting of adverse reactions

Reporting of adverse reactions after registration of the medicinal product is of great importance. It allows continuous monitoring of the benefit–risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance 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 and contact with metal and rubber surfaces should be avoided.

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

Packaging. 600 mg/3 g in sachets. 6 or 10 sachets per cardboard box.

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

Manufacturer. JSC "Farmak".

Manufacturer’s address and location of manufacturing operations.

74 Kyrylivska Street, Kyiv, 04080, Ukraine.