Eucabale® 200 sachet

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EUCABAL®200 sachet

Composition:

Active substance: acetylcysteine;

1 sachet contains 200 mg of acetylcysteine;

Excipients: sucrose, orange flavor, colloidal anhydrous silicon dioxide, tartaric acid, sodium chloride.

Pharmaceutical form. Powder for oral solution.

Main physicochemical properties: white or almost white, homogeneous powder without agglomerates and foreign inclusions, which may become partially agglomerated over time.

Pharmacotherapeutic group. Mucolytic agents.

ATC code R05C B01.

Pharmacological properties.

Pharmacodynamics.

Acetylcysteine is a derivative of the amino acid cysteine. Acetylcysteine exerts a secretolytic and secretomotor effect in the bronchial area. It is believed to break disulfide bonds of mucopolysaccharides and exert a depolymerizing effect on DNA (in purulent mucus). This mechanism contributes to a reduction in mucus viscosity. An alternative mechanism of acetylcysteine is probably based on the ability of its chemically active sulfhydryl group to bind and thus neutralize free radicals.

Acetylcysteine promotes increased synthesis of glutathione, which is important for detoxification of harmful agents. This explains the action of acetylcysteine as an antidote in paracetamol poisoning.

Prophylactic administration of acetylcysteine reduced the frequency and severity of bacterial exacerbations in patients with chronic bronchitis/mucoviscidosis.

Pharmacokinetics.

After oral administration, acetylcysteine is rapidly and completely absorbed. It undergoes hepatic metabolism to form the pharmacologically active metabolite cysteine, as well as diacetylcysteine, cystine, and subsequently mixed disulfides. Due to significant first-pass effect, the bioavailability of acetylcysteine after oral administration is very low (approximately 10%). Maximum plasma concentration is reached within 1–3 hours after administration, with peak plasma concentration of the cysteine metabolite reaching approximately 2 μmol/L. Plasma protein binding is approximately 50%.

Acetylcysteine and its metabolites exist in the body in three different forms: partially in the free form, partially bound to proteins via labile disulfide bridges, and partially as incorporated amino acids. Acetylcysteine is excreted by the kidneys as inactive metabolites (inorganic sulfates, diacetylcysteine). The elimination half-life is primarily determined by rapid biotransformation in the liver and is approximately 1 hour. In case of impaired liver function, the elimination half-life is prolonged to 8 hours.

Distribution

Acetylcysteine is distributed in the body both in unchanged form (20%) and as active metabolites (80%). It is predominantly found in the lungs, bronchial secretions, liver, and kidneys. The volume of distribution of acetylcysteine ranges from 0.33 to 0.47 L/kg. Plasma protein binding is about 50% at 4 hours after administration and decreases to 20% at 12 hours.

Metabolism and elimination

After oral administration, acetylcysteine is rapidly and extensively metabolized in the intestinal wall and liver. Approximately 30% of the dose is excreted by the kidneys. The T_1/2 of acetylcysteine is 6.25 hours.

N-acetylcysteine crosses the placental barrier and is detected in umbilical cord blood. Information regarding excretion into breast milk is lacking. There is no information on the penetration of acetylcysteine across the blood-brain barrier.

Clinical characteristics.

Indications. Used to reduce sputum viscosity and improve its expectoration and coughing-out in bronchitis caused by colds.

Contraindications. Known hypersensitivity to acetylcysteine or any of the excipients. Exacerbation stage of gastric and duodenal ulcer, hemoptysis, pulmonary hemorrhage.

Children under 6 years of age.

Interaction with other medicinal products and other types of interactions.

Interaction studies have been conducted only in adults.

Concomitant use of antitussive agents with acetylcysteine may enhance sputum retention due to suppression of the cough reflex; therefore, indications for such combination therapy should be established with particular caution.

Reports on inactivation of antibiotics (tetracycline, aminoglycosides, penicillins) by acetylcysteine were related exclusively to in vitro studies, in which the respective substances were mixed directly. However, for safety reasons, the interval between administration of these drugs should be at least 2 hours. This does not apply to cefixime and loracarbef.

Concomitant use of acetylcysteine and glyceryl trinitrate (nitroglycerin) may lead to potentiation of the vasodilatory and antiplatelet effects of nitroglycerin. When simultaneous administration 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.

Activated charcoal reduces the effectiveness of acetylcysteine.

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

Upon contact with metals or rubber, sulfides with a characteristic odor are formed; therefore, glassware should be used for dissolving the drug.

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

The drug should be administered with caution to patients with a history of gastric or duodenal ulcer, especially when used concomitantly with other medicinal products that irritate the gastric mucosa.

Severe skin reactions (Stevens-Johnson syndrome and Lyell's syndrome) have been reported during acetylcysteine administration. Therefore, if skin or mucous membrane changes occur, the drug should be discontinued immediately and medical advice should be sought regarding further treatment.

Acetylcysteine should be prescribed with caution to patients with bronchial asthma due to the possible development of bronchospasm. When pouring the contents of the sachet 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 the drug should be discontinued immediately and medical advice should be sought.

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

Administration of acetylcysteine, particularly at the beginning of treatment, causes liquefaction of bronchial secretions and thus increases their volume. If the patient is unable to effectively expectorate sputum, postural drainage and bronchoaspiration may be necessary.

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, pruritus).

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.

A mild sulfurous odor is not an indication of drug deterioration; it is characteristic of the active substance.

One sachet of «EUCABAL®200sachet» contains less than 1 mmol (23 mg) of sodium, i.e. it is practically sodium-free.

The drug contains sucrose; therefore, it should not be administered to patients with rare hereditary forms of fructose intolerance, sucrase-isomaltase deficiency, or glucose-galactose malabsorption syndrome.

One sachet of «EUCABAL®200sachet» contains 2.7 g of sucrose (approximately 0.23 bread units). This should be taken into account when administering the drug to patients with diabetes mellitus.

The drug contains orange flavoring, which includes lactose. Patients with rare hereditary galactose intolerance, lactase deficiency, or glucose-galactose malabsorption should not take «EUCABAL®200sachet».

Use during pregnancy or breastfeeding

Pregnancy

There are insufficient clinical data on the effects of acetylcysteine in pregnant women. Animal studies have not revealed any direct or indirect adverse effects on pregnancy, embryofetal development, parturition, or postnatal development. 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. The drug should be used during pregnancy or breastfeeding only after careful assessment of the benefit-risk ratio.

Fertility

Animal studies have not revealed any harmful effects on human fertility when the drug is used at recommended doses.

Ability to affect reaction speed when driving or operating machinery.
There is no evidence that acetylcysteine affects the ability to drive vehicles or operate machinery.

Dosage and Administration.

The medicine should be taken after meals, dissolved in a glass of water.

If not otherwise prescribed, the recommended dosage for this medicine is as follows:

Adults and children aged 14 years and older:

2–3 sachets of powder (corresponding to 400–600 mg of acetylcysteine per day), divided into 2–3 doses.

Children aged 6–14 years:

2 sachets of powder (corresponding to 400 mg of acetylcysteine per day), divided into 2 doses.

The medicine should not be used for more than 4–5 days without consulting a doctor.

Children: Use in children under 6 years of age is contraindicated. Children aged 6 to 14 years should take 1 sachet of powder twice daily (corresponding to 400 mg of acetylcysteine per day).

Overdose.

There are no reports of overdose with oral formulations of acetylcysteine. Volunteers have taken up to 11.2 g of acetylcysteine per day for three months without experiencing any serious adverse effects. Acetylcysteine administered orally in doses of 500 mg/kg/day was well tolerated without signs of intoxication.

Symptoms.

Overdose may cause gastrointestinal symptoms such as nausea, vomiting, and diarrhea. In children, there is a risk of hypersecretion.

Treatment.

Treatment is symptomatic.

Adverse reactions.

Adverse reactions are categorized by frequency as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), and not known (frequency cannot be estimated from available data).

In addition, there have been very rare reports of bleeding during the use of acetylcysteine, sometimes due to hypersensitivity reactions.

In very rare cases, severe skin reactions such as Stevens−Johnson syndrome and Lyell’s syndrome have been reported in association with acetylcysteine use. In most of these cases, at least one other medicinal product could have been responsible for the occurrence of the mucocutaneous syndrome.

If any new skin or mucous membrane changes occur, medical advice must be sought 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 suspected adverse reactions.

Reporting suspected adverse reactions after product authorization is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions in accordance with applicable regulatory requirements.

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging. 3 g of powder (200 mg active substance) in sachets. Pack of 20 or 50 sachets in a cardboard box.

Availability. Over-the-counter (without prescription).

Manufacturer.

Lindopharm GmbH.

Manufacturer’s address and place of business.

Neustrasse 82, 40721 Hilden, Germany.

Marketing authorization holder.

Esparma GmbH.

Address of the marketing authorization holder.

Bielefelder Strasse 1, 39171 Salzetal, Germany.