Acetylcysteine-teva
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Acetylcysteine-Teva
Composition:
Active substance: acetylcysteine;
One effervescent tablet contains: acetylcysteine 600 mg;
Excipients: citric acid anhydrous, sodium hydrogen carbonate, adipic acid, povidone 25, micronized adipic acid, aspartame (E 951), lemon flavor, spray-dried, 213°841 (flavoring preparation, maltodextrin, sucrose, gum arabic (E 414), glycerol triacetate (triacetin) (E 1518), alpha-tocopherol (E 307)).
Pharmaceutical form. Effervescent tablets.
Main physicochemical properties: white or slightly yellowish, round, flat on both sides, effervescent tablets, without a break line, with a lemon odor.
Pharmacotherapeutic group. Cough and cold preparations. Mucolytics. 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 that increase the viscosity of the gelatinous 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.
NAC 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 reactive oxygen species. Of particular interest is the fact that NAC prevents 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, as a precursor of glutathione, NAC exerts 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 both exogenous and endogenous reactive oxygen species 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 COPD, administration of 1200 mg of NAC daily 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), 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 single-breath carbon monoxide method.
When used as inhalation therapy over 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) to 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 decrease in the number of neutrophils in the airways was observed, as well as a reduction in the number of neutrophils actively releasing elastase-rich granules.
Pharmacokinetics.
Absorption. After oral administration, acetylcysteine is rapidly and almost 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 dosage forms. In patients with various respiratory and cardiovascular 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 active metabolites (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. After oral administration, NAC is rapidly and extensively metabolized in the intestinal wall and liver. The resulting metabolite, cysteine, is considered active. Subsequently, both acetylcysteine and cysteine are metabolized via the same pathway.
Elimination. Approximately 30% of the administered dose is excreted by the kidneys. After oral administration, the elimination half-life (T1/2) 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 of the medicinal product.
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 types of interactions.
Interaction studies were conducted only in adults.
Concomitant use of acetylcysteine with antitussive agents may enhance mucus retention due to suppression of the cough reflex.
Activated charcoal reduces the efficacy of acetylcysteine.
Reports of antibiotic inactivation by acetylcysteine were exclusively related to in vitro studies, in which the substances were mixed directly. 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.
Nitroglycerin. Significant hypotension and dilatation of the temporal artery have been observed when nitroglycerin and acetylcysteine are taken concomitantly. If concomitant use of nitroglycerin and acetylcysteine is required, patients should be monitored for hypotension, which may be severe, and should be warned about the possibility of headache.
Concomitant use of acetylcysteine and carbamazepine may lead to subtherapeutic levels of carbamazepine.
Effect on laboratory tests. Acetylcysteine may interfere with colorimetric assays for salicylates and with the determination of ketone bodies in urine.
When dissolving acetylcysteine, glassware should be used; contact with metal and rubber surfaces should be avoided.
It is not recommended to dissolve acetylcysteine with other medicinal products.
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 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, caution is required when administering the drug to patients with histamine intolerance. Long-term therapy should not be prescribed to such patients, as it may lead to symptoms of intolerance (headache, vasomotor rhinitis, pruritus).
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 sputum, 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.
One effervescent tablet contains 150 mg of sodium, which corresponds to 7.65% of the WHO recommended maximum daily sodium intake of 2 g for adults. This should be taken into account by patients on a sodium-controlled diet (low-salt diet).
The medicinal product contains aspartame, a source of phenylalanine, and may be harmful to patients with phenylketonuria.
The medicinal product contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this product.
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 the medicinal product during pregnancy should be avoided.
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.
The drug should be used during pregnancy or breastfeeding only after careful assessment of the benefit-risk ratio.
Fertility
There are no data on the effect of acetylcysteine on human fertility. Animal studies have not revealed any adverse effects on fertility in humans when the drug is used at recommended doses.
Ability to influence reaction speed when driving or operating machinery.
There is no evidence that acetylcysteine affects the ability to drive a vehicle or operate machinery.
Method of Administration and Dosage
For oral use.
The effervescent tablet should be dissolved in 1/3 glass of drinking water and taken once daily. The medicinal product should be taken without delay, immediately after preparing the solution. No interaction between the drug and food has been reported; there are no recommendations regarding administration in relation to food intake.
Adults and children aged 12 years and older
1 effervescent tablet once daily (equivalent to 600 mg of acetylcysteine per day).
The duration of treatment is determined individually by a physician, depending on the nature of the disease (acute or chronic).
Paracetamol overdose
As soon as possible within the first 10 hours after ingestion of the toxic substance, acetylcysteine should be administered at a dose of 140 mg/kg, followed by 70 mg/kg every 4 hours for 1–3 days.
Children
Use in children aged 12 years and older.
Overdose
There are no reported cases of overdose with oral administration of acetylcysteine.
Volunteers took 11.2 g of acetylcysteine per day for 3 months without development of serious adverse reactions.
Acetylcysteine administered orally at doses of 500 mg/kg/day was tolerated without signs of intoxication.
Symptoms: Overdose may manifest with gastrointestinal symptoms such as nausea, vomiting, and diarrhea.
Treatment: There is no specific antidote for 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, angioedema, rash, and pruritus, occurred less frequently.
Adverse reactions are categorized by frequency as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data).
Immune system disorders: uncommon – hypersensitivity; very rare – anaphylactic shock, anaphylactic/anaphylactoid reactions.
Blood and lymphatic system disorders: frequency not known – anemia.
Nervous system disorders: uncommon – headache.
Ear and labyrinth disorders: uncommon – tinnitus.
Cardiac disorders: uncommon – tachycardia.
Vascular disorders: very rare – hemorrhages.
Respiratory system disorders: rare – bronchospasm, dyspnea; frequency not known – rhinorrhea.
Gastrointestinal disorders: uncommon – vomiting, diarrhea, stomatitis, abdominal pain, nausea; rare – dyspepsia; frequency not known – unpleasant breath odor.
Skin and subcutaneous tissue disorders: uncommon – urticaria, rash, Quincke's edema, pruritus; frequency not known – eczema.
General disorders: uncommon – hyperthermia; frequency not known – facial swelling.
Investigations: uncommon – decreased blood pressure.
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 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, medical advice should be sought immediately and acetylcysteine should be discontinued promptly.
Cases of reduced platelet aggregation have been reported, but the clinical significance of this finding is not established.
Reporting of suspected adverse reactions. Reporting suspected adverse reactions after a medicinal product is authorized is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua
Shelf life. 2 years. Shelf life after first opening of the tube – 12 months.
Storage conditions. Store at temperatures not exceeding 25 °C in a tightly closed tube to protect from moisture. Keep out of reach of children.
Packaging. 10 tablets per tube; 1 tube per cardboard box.
Availability. Over-the-counter (without prescription).
Manufacturer.
Merckle GmbH.
Manufacturer's address and place of business.
Graf-Arco-Strasse 3, 89079 Ulm, Germany.