Respix

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RESPIX® (RESPIX®)

Composition:

Active substances: ambroxol hydrochloride, acetylcysteine.

One tablet contains 200 mg of acetylcysteine and 30 mg of ambroxol hydrochloride;

Excipients: microcrystalline cellulose; magnesium stearate; lactose monohydrate; colloidal anhydrous silicon dioxide; hypromellose; talc; polyethylene glycol 6000; titanium dioxide (E 171); yellow FCF colorant (E 110).

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties: orange-colored, round, biconvex, film-coated tablets.

Pharmacotherapeutic group.

Medicinal products used for cough and colds. Mucolytic agents. Combinations. ATC code: R05CB10.

Pharmacological Properties

Pharmacodynamics

Ambroxol is a mucolytic and expectorant agent that exerts pronounced expectorant, anti-inflammatory, immunomodulatory, antioxidant, and mild antitussive effects. It stimulates serous cells of the bronchial mucosal glands, increases the amount of serous secretion, and thereby normalizes the disturbed ratio between serous and mucous components. This normalizes the rheological properties of sputum by reducing its viscosity and adhesive characteristics. Ambroxol directly stimulates the ciliary activity of bronchial epithelium, prevents ciliary clumping, and improves mucociliary clearance of sputum. It increases surfactant content in the lungs and prevents its destruction by pneumocytes. Ambroxol does not cause bronchoconstriction; on the contrary, it improves external respiratory function. It has been demonstrated that the drug reduces bronchial muscle hyperreactivity in asthmatic patients. Ambroxol has anti-inflammatory and antioxidant properties, stimulates local immunity, and promotes restoration of the natural surfactant layer. After ambroxol administration, patients' complaints of cough and sputum production significantly decrease according to treatment intensity.

Acetylcysteine is a mucolytic and expectorant agent. Due to its free sulfhydryl group, it cleaves disulfide bonds of mucopolysaccharides in sputum, thereby reducing the viscosity of bronchial secretions. It enhances mucociliary clearance. It exerts antioxidant effects by scavenging free radicals. It increases glutathione synthesis, which is an important factor in detoxification; due to this property, acetylcysteine is used in the treatment of acute poisoning with paracetamol, phenols, aldehydes, and other substances.

Pharmacokinetics

Ambroxol

Absorption

Absorption of ambroxol hydrochloride is rapid and sufficiently complete, with linear dependence within the therapeutic range. Maximum plasma concentrations are reached within 1–2.5 hours after oral administration of immediate-release dosage forms.

Distribution

Distribution of ambroxol hydrochloride is rapid and highly pronounced, with the highest concentration of the active substance found in the lungs. The volume of distribution is approximately 552 L. In plasma, about 90% of ambroxol hydrochloride is protein-bound within the therapeutic range.

Metabolism

Ambroxol hydrochloride is mainly metabolized in the liver via glucuronidation and degradation to dibromanthranilic acid (approximately 10% of the dose). CYP3A4 is responsible for the metabolism of ambroxol hydrochloride to dibromanthranilic acid.

Elimination

Approximately 30% of the dose is eliminated via presystemic metabolism. Within 3 days after oral administration, about 6% of the dose is excreted unchanged in urine, and approximately 26% is excreted in conjugated form. The elimination half-life is approximately 10 hours.

Acetylcysteine

Absorption

Acetylcysteine is completely absorbed after oral administration. Due to metabolism in the intestinal wall and first-pass effect, bioavailability is very low (approximately 10%). Maximum plasma concentration is reached within 1–3 hours after administration and remains high for 24 hours.

Distribution

The volume of distribution of acetylcysteine ranges from 0.33 to 0.47 L/kg. Protein binding is about 50% at 4 hours after administration and decreases to 20% at 12 hours.

Metabolism

Acetylcysteine is metabolized in the intestinal wall and liver.

Elimination

Acetylcysteine is excreted by the kidneys as inactive metabolites (inorganic sulfates, diacetylcysteine). The elimination half-life is approximately 1 hour. In case of impaired liver function, the elimination half-life is prolonged up to 8 hours.

Clinical characteristics.

Indications.

• Treatment of acute and chronic respiratory tract diseases associated with impaired bronchial secretion and impaired secretion clearance (including acute and chronic bronchitis, chronic obstructive pulmonary diseases, pneumonia, bronchiectasis, bronchial asthma, cystic fibrosis, laryngitis, tracheitis).

Contraindications.

Hypersensitivity to the active substances 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; diseases of the liver, kidneys, adrenal glands, severe exacerbation of bronchial asthma. Rare hereditary conditions leading to incompatibility with an excipient of the medicinal product.

Interaction with other medicinal products and other forms of interactions.

Concomitant use of this medicinal product with cough suppressants may lead to excessive mucus accumulation due to suppression of the cough reflex. Therefore, such combination is possible only after careful evaluation by a physician of the benefit-risk ratio.

Acetylcysteine reduces the hepatotoxic effect of paracetamol; it may act as a cysteine donor and increase glutathione levels, promoting detoxification of oxygen free radicals and certain toxic substances in the body.

Activated charcoal reduces the effectiveness of acetylcysteine.

Ambroxol, included in the composition of the medicinal product, increases the concentration of amoxicillin, cefuroxime, erythromycin, and doxycycline antibiotics in sputum and bronchopulmonary secretions when used concomitantly.

Concomitant use of acetylcysteine with cephalosporins (except cefixime and loracarbef), tetracyclines (except doxycycline), amphotericin B, and aminoglycosides may result in reduced activity of the aforementioned medicinal products. Therefore, the interval between administration of these agents and acetylcysteine should be at least 2 hours.

Concomitant administration of nitroglycerin and acetylcysteine may enhance the vasodilatory effect of nitroglycerin.

Significant hypotension and marked dilation of the temporal artery have been observed with concomitant use of nitroglycerin and acetylcysteine. When concomitant use of nitroglycerin and acetylcysteine is necessary, patients should be monitored for hypotension, which may be severe; patients should also be warned about the possibility of headache.

Synergism between acetylcysteine and bronchodilators has been reported.

Acetylcysteine may alter the results of quantitative colorimetric determination of salicylates and urine ketone testing.

Special precautions for use

The drug should be used with caution in the following cases:

• Patients with a history of gastric or duodenal ulcer, especially when concurrently using other medicinal products that irritate the gastric mucosa;
• Patients with impaired kidney function or severe liver disease (the dosing interval should be prolonged or the dose reduced); in patients with severe renal insufficiency, accumulation of metabolites formed in the liver may occur;
• Patients with impaired bronchial motility and increased mucus secretion (e.g., in rare conditions such as primary ciliary dyskinesia);
• Patients with bronchial asthma (with monitoring of bronchial patency). If bronchospasm develops, the drug should be discontinued.

There have been a few reports of severe skin reactions—Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome), as well as erythema multiforme—associated with the use of expectorants such as ambroxol or acetylcysteine. These reactions are mostly attributable to the severity of the underlying disease and/or concomitant use of other drugs. In the early stages of Stevens-Johnson syndrome or Lyell's syndrome, patients may present with non-specific, flu-like symptoms such as fever, malaise, rhinitis, cough, and sore throat. These non-specific, flu-like symptoms may lead to inappropriate symptomatic treatment with cough and cold remedies. Therefore, if new skin or mucosal lesions appear, patients should discontinue the drug immediately and seek urgent medical attention.

The drug causes liquefaction of bronchial secretions. If the patient is unable to effectively expectorate mucus, postural drainage and bronchoaspiration may be required.

The drug contains lactose and therefore should not be used in patients with rare hereditary conditions such as galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.

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).

Acetylcysteine may have a slight hydrogen sulfide odor due to the presence of a sulfhydryl group in its molecular structure. A sulfur-like odor is not indicative of drug deterioration but is characteristic of the active substance.

The dye Yellow FCF (E 110) may cause allergic reactions.

Use during pregnancy or breastfeeding

The drug is not recommended during pregnancy.

Ambroxol and acetylcysteine pass into breast milk. Breastfeeding should be discontinued during treatment with this drug.

Ability to influence reaction rate while driving or operating machinery

There are no data regarding the effect of the drug on the ability to drive or operate machinery.

Dosage and Administration.

Adults and children aged 12 years and older: the recommended dose is 1 tablet three times daily. The tablets should be taken after meals with plenty of fluid. Do not use the medication for longer than 4–5 days without consulting a physician.

Children.

The medication is indicated for children aged 12 years and older.

Overdose.

Ambroxol was well tolerated after parenteral administration at doses up to 15 mg/kg/day and after oral administration at doses up to 25 mg/kg/day. In cases of ambroxol or acetylcysteine overdose, no signs of severe intoxication have been observed. Cases of short-term restlessness, diarrhea, and hypersalivation have been reported. According to preclinical studies, overdose may lead to hypersalivation, nausea, vomiting, and decreased blood pressure. Acetylcysteine overdose may cause nausea, vomiting, and diarrhea. In children, there is a risk of hypersecretion.

Treatment: symptomatic and supportive therapy.

Adverse Reactions.

Cardiovascular system: tachycardia, arterial hypotension.

Nervous system: headache, dysgeusia (taste disturbance).

Auditory system: tinnitus.

Respiratory system: rhinorrhea, dryness of the airways, bronchospasm (mainly in patients with bronchial hyperreactivity associated with bronchial asthma), decreased pharyngeal sensitivity, dyspnea (as a hypersensitivity reaction).

Gastrointestinal tract: dry mouth, hypersalivation, heartburn, nausea, vomiting, dyspepsia, stomatitis, abdominal pain, diarrhea, constipation, unpleasant breath odor, decreased oral cavity sensitivity.

Urinary system: dysuria.

Immune system, skin and subcutaneous tissue: hypersensitivity reactions, including anaphylactic and anaphylactoid reactions, anaphylactic shock, rash, urticaria, mucosal reactions, angioneurotic edema, fever, dyspnea, pruritus; multiform erythema, exanthema, eczema, bronchospasm, severe skin reactions: Stevens-Johnson syndrome and Lyell's syndrome, acute generalized exanthematous pustulosis. In case of any changes in the skin or mucous membranes, patients should immediately consult a physician and discontinue the drug.

General disorders: facial swelling, fever, mucosal reactions, hyperthermia.

Blood and lymphatic system: with acetylcysteine use, very rare cases of bleeding have been reported, mostly associated with hypersensitivity reactions; cases of anemia, hemorrhage. Various studies have demonstrated reduced platelet aggregation in the presence of acetylcysteine; however, the clinical significance of these findings has not yet been established.

Reporting of adverse reactions after drug registration is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, are encouraged to report all suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 tablets in a blister. 1, 2, or 4 blisters per cardboard box.

Availability category. Over-the-counter.

Manufacturer.

Evertogen Life Sciences Limited / Evertogen Life Sciences Limited.

Manufacturer's address and location of business activity.

Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India /
Plot No: S-8, S-9, S-13/P & S-14/P TSIIC, Pharma SEZ, Green Industrial Park, Polepally (V), Jadcherla (M), Mahabubnagar, Telangana, IN-509 301, India.