Ascoril LS (Solution) Instructions for Use

Marketing Authorization Holder

Glenmark Pharmaceuticals, Ltd. (India)

Contact Information

GLENMARK IMPEX LLC (Russia)

ATC Code

R05C (Expectorants, excluding combinations with antitussives)

Active Substances

Guaifenesin (Rec.INN registered by WHO)

Ambroxol (Rec.INN registered by WHO)

Levosalbutamol (Rec.INN registered by WHO)

Dosage Form

Ascoril LS

Oral solution 30 mg+100 mg+1 mg/10 ml: fl. 100 ml with a measuring cap

Dosage Form, Packaging, and Composition

Oral solution in the form of a colorless, transparent liquid with a characteristic odor.

Excipients : citric acid monohydrate, sodium benzoate, sodium citrate dihydrate, sodium chloride, sucralose, hypromellose (HPMC 6 cps), Mango Supreme flavor, Cool Mint Special 521-00159-02 flavor, Maskin 2522 flavor, menthol (levomenthol), purified water.

100 ml – dark-colored polyethylene terephthalate bottles (1) with a 10 ml measuring cap – cardboard packs.

Clinical-Pharmacological Group

Drug with mucolytic, expectorant and bronchodilatory action

Pharmacotherapeutic Group

Drugs used for cough and colds; expectorants, excluding combinations with antitussives

Pharmacological Action

Mechanism of action and pharmacodynamic effects

Ambroxol

Studies have shown that Ambroxol increases secretion in the airways, reduces sputum viscosity, enhances pulmonary surfactant production, and stimulates the motor activity of the ciliated epithelium. These effects lead to enhanced mucus flow and transport (mucociliary clearance), which improves sputum expectoration and alleviates cough.

When used concomitantly with antibiotics (amoxicillin, cefuroxime, erythromycin, doxycycline), it increases their concentration in the bronchial secretion.

In vitro and in animal studies, Ambroxol has been shown to have local anesthetic (by blocking sodium channels in neurons) and anti-inflammatory (by reducing cytokine release from mononuclear or polymorphonuclear cells present in both blood and tissues) effects.

In patients with COPD, long-term therapy with ambroxol (for 6 months) led to a significant reduction in the number and duration of exacerbations, as well as a significant decrease in the duration of antibiotic use, which was evident after 2 months of therapy. The use of ambroxol also resulted in a statistically significant improvement in clinical symptoms of the disease (difficult sputum expectoration, cough, shortness of breath, pathological auscultatory signs) compared to placebo.

Guaifenesin

Guaifenesin has a stimulating effect on the receptors of the gastric mucosa, leading to increased secretion of the gastrointestinal glands and a reflex increase in the secretion of the respiratory tract glands. As a result, the viscosity of the bronchial secretion decreases and its volume increases. Other effects may include stimulation of vagus nerve endings in the bronchial glands and stimulation of certain brain centers, which, in turn, leads to improved sputum expectoration. Guaifenesin exerts an expectorant effect for 24 hours.

Levosalbutamol

Levosalbutamol is the R-enantiomer of the β₂-adrenergic receptor agonist salbutamol. The bronchodilatory activity of levosalbutamol is higher than that of racemic salbutamol. Furthermore, due to the absence of the S-enantiomer, fewer adverse reactions are observed with the use of levosalbutamol. Levosalbutamol belongs to the selective β₂-adrenergic receptor agonists. In therapeutic doses, it acts on the β₂-adrenergic receptors of bronchial smooth muscle, having a minor effect on the β₂-adrenergic receptors of the myocardium. Levosalbutamol inhibits the release of histamine, leukotrienes, prostaglandin D2, and other biologically active substances from mast cells for a prolonged period. It suppresses early and late bronchial reactivity. It has a pronounced bronchodilatory effect, preventing or relieving bronchospasm, and reduces airway resistance. It increases vital lung capacity. It increases mucociliary clearance, stimulates mucus secretion, and activates the functions of the ciliated epithelium.

Pharmacokinetics

Absorption

Ambroxol. All immediate-release dosage forms of ambroxol are characterized by rapid and almost complete absorption with a linear dose-dependency within the therapeutic concentration range. C_max of ambroxol in plasma after oral administration is reached within 1-2.5 hours. The absolute bioavailability is 79%. Food intake does not affect the bioavailability of ambroxol.

Guaifenesin.Guaifenesin is well absorbed from the gastrointestinal tract after oral administration. After a 600 mg dose of guaifenesin in healthy adult volunteers, C_max was approximately 1.4 µg/ml, and T_max was approximately 15 minutes after drug administration.

Levosalbutamol. The enantiomers of salbutamol, taken separately or as a racemate, are well absorbed from the gastrointestinal tract and reach C_max within 45-360 minutes. (S)-salbutamol, when taken orally as a pure enantiomer compared to taking the racemate, has a longer T_max. This phenomenon may be associated with altered gastrointestinal motility following stimulation of β-adrenergic receptors by (R)-salbutamol in the racemate. The bioavailability of (S)-salbutamol is approximately 70% both at steady state and after a single oral dose, whereas the bioavailability of (R)-salbutamol increases from 9% after a single oral dose to 30% after concentration stabilization.

Distribution

Ambroxol. Within the therapeutic concentration range, plasma protein binding is approximately 90%. Ambroxol is rapidly and extensively distributed from the blood into various tissues. V_d is 552 L. The highest concentrations of the active drug component are observed in the lungs.

Guaifenesin. Information on the distribution of guaifenesin in the human body is not available.

Levosalbutamol. The ratio of total salbutamol content in blood and plasma in healthy volunteers is close to one (0.96±0.13), suggesting that after concentration stabilization, the total clearance of salbutamol in blood is equal to the total clearance in plasma. The values for binding to blood components, along with similar volumes of distribution for the salbutamol enantiomers, suggest that protein binding plays a relatively minor role in the elimination of the salbutamol enantiomers.

Metabolism

Ambroxol. Approximately 30% of an oral dose undergoes a first-pass effect in the liver. Ambroxol is metabolized primarily in the liver, where it undergoes glucuronidation and breakdown (approximately 10% of the dose) to dibromanthranilic acid, in addition to the formation of some minor metabolites.
Studies using human liver microsomes have shown that the metabolism of ambroxol to dibromanthranilic acid occurs with the participation of the CYP3A4 isoenzyme.

Guaifenesin.Guaifenesin is metabolized in the liver.

Levosalbutamol . (R)-salbutamol was metabolized 12 times more efficiently than its antipode, with significant interindividual variations observed in human tissue samples, the distribution of which followed a normal distribution law. From these studies, it is clear that the expression of SULT1A3 in the intestine is higher than in other investigated tissues, particularly in liver tissue. This supports clinical observations that the main site of enantioselective presystemic metabolism of salbutamol after absorption from the gastrointestinal tract is the intestine.

Elimination

Ambroxol. Within 3 days after oral administration of ambroxol, approximately 6% of the administered dose is detected in the urine as the free compound and approximately 26% of the dose as the conjugate. The terminal T_1/2 of ambroxol is approximately 10 hours. The total clearance is approximately 660 ml/min; renal clearance after oral administration of ambroxol is approximately 8% of the total clearance. It was found that the amount of ambroxol excreted in the urine over 5 days was 83% of the dose (using a radiolabeled method).

Guaifenesin. T_1/2 is about 1 hour, Guaifenesin was not detected in the blood after approximately 8 hours. It is excreted mainly by the kidneys.

Levosalbutamol. The calculated renal clearance values for both enantiomers were significantly greater than the glomerular filtration rate, indicating active renal excretion. This leads to relatively higher drug concentrations in the urine than in plasma. (S)-salbutamol is almost always found in the urine in greater quantities than (R)-salbutamol, regardless of the route of administration.

Special patient groups

Patients with renal impairment. In severe renal impairment, accumulation of ambroxol metabolites should be expected. No specific studies have been conducted on the use of guaifenesin in patients with renal impairment. Caution is recommended when prescribing guaifenesin to individuals with severe renal impairment.

Patients with hepatic impairment. The clearance of ambroxol in severe liver disease is reduced by 20-40%. No specific studies have been conducted on the use of guaifenesin in patients with hepatic impairment. Caution is recommended when prescribing guaifenesin to individuals with severe hepatic impairment.

Indications

The drug Ascoril LS is indicated for use in adults (over 18 years old)

Symptomatic treatment of productive cough associated with various respiratory diseases, including, among others, the following:

• Acute bronchitis, including tracheobronchitis;
• Exacerbation of chronic bronchitis;
• Exacerbation of chronic obstructive pulmonary disease (COPD);
• Pneumonia.

ICD codes

Dosage Regimen

Administer orally.

For adults (18 years and older), the dose is 10 ml taken three times daily.

Use the provided measuring cap to ensure accurate dosage.

Maintain an interval of approximately 6-8 hours between doses.

Do not exceed the recommended daily dose of 30 ml.

The duration of treatment is determined by the physician based on clinical response.

Discontinue use if symptoms persist or worsen after 3-5 days of therapy.

The safety and efficacy in children and adolescents under 18 years have not been established.

Use in this population is contraindicated.

Adverse Reactions

Adverse reactions are classified according to WHO, according to their frequency of occurrence 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), frequency not known (cannot be estimated from the available data).

Adverse reactions occurring with the use of the drug Ascoril LS

In an open-label, randomized clinical trial conducted in Russia, studying the efficacy and safety of the combined drug Ambroxol + Guaifenesin + Levosalbutamol compared to the combined drug Ascoril expectorant syrup in the treatment of productive cough in adult patients with acute bronchitis, 28 adverse events (AE) were reported in 16.39% (20/122) of patients in the Ambroxol + Guaifenesin + Levosalbutamol group and 23 AEs in 15.57% (19/122) of patients in the Ascoril expectorant group. The study groups did not differ statistically significantly in the frequency of AE detection (p>0.999). None of the reported AEs met the seriousness criteria. A relationship with the study therapy was suspected in 8 out of 51 AE cases in 3.28% (8/244) of patients – in 3 out of 28 cases in the study drug group and in 5 out of 23 cases in the comparator drug group. The most frequent AE that occurred during the use of the drug was throat irritation, which was noted by 2 patients out of 122 (1.64%) in the study drug group and 1 patient out of 122 (0.82%) in the comparator group. All AEs were mild in severity and resolved without consequences.

Nervous system disorders frequency not known – drowsiness, hand tremor.

Cardiac disorders common – QTc interval prolongation, PR interval shortening; frequency not known – palpitations.

Respiratory, thoracic and mediastinal disorders common – throat irritation.

Gastrointestinal disorders uncommon – exacerbation of chronic gastritis or its symptoms (nausea, discomfort in the upper abdomen); frequency not known – abdominal discomfort, digestive disorders.

Musculoskeletal and connective tissue disorders frequency not known – muscle weakness.

General disorders and administration site conditions frequency not known – chills.

Investigations frequency not known – increased heart rate.

Other frequency not known – decreased performance.

Ambroxol

Immune system disorders rare – hypersensitivity reactions; frequency not known – anaphylactic reactions, including anaphylactic shock, angioedema, pruritus.

Nervous system disorders common – dysgeusia.

Gastrointestinal disorders common – nausea, hypoesthesia in the oral cavity and pharynx; uncommon – vomiting, dry mouth, diarrhea, dyspepsia and abdominal pain; frequency not known – dry throat.

Skin and subcutaneous tissue disorders rare – rash, urticaria; frequency not known – severe skin adverse reactions, incl. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis and acute generalized exanthematous pustulosis.

General disorders uncommon – fever.

Guaifenesin

Immune system disorders frequency not known – hypersensitivity reactions (hypersensitivity, pruritus and urticaria), rash.

Gastrointestinal disorders frequency not known – upper abdominal pain, diarrhea, nausea, vomiting.

Investigations frequency not known – pink discoloration of urine.

Levosalbutamol

Immune system disorders very rare – hypersensitivity reactions, including angioedema, urticaria, bronchospasm, decreased blood pressure and collapse.

Metabolism and nutrition disorders rare – hyperglycemia, hypokalemia. Therapy with β₂-adrenergic receptor agonists may lead to clinically significant hypokalemia.

Nervous system disorders common – tremor, headache; very rare – hyperactivity.

Cardiac disorders uncommon – myocardial ischemia, palpitations; very rare – arrhythmias, including atrial fibrillation; supraventricular arrhythmia and extrasystole.

Vascular disorders rare – peripheral vasodilation.

Musculoskeletal and connective tissue disorders uncommon – muscle cramps.

Contraindications

• Hypersensitivity to ambroxol, guaifenesin, levosalbutamol or to any of the excipients;
• Tachyarrhythmia, myocarditis, heart defects (including aortic stenosis);
• Uncontrolled arterial hypertension;
• Decompensated diabetes mellitus;
• Hyperthyroidism;
• Glaucoma;
• Hepatic and/or renal failure;
• Peptic ulcer of the stomach and duodenum in the acute phase, gastric bleeding;
• Pregnancy;
• Breastfeeding period.

Use in Pregnancy and Lactation

The drug is contraindicated during pregnancy and the breastfeeding period

Use in Hepatic Impairment

Contraindicated in hepatic impairment.

Use in Renal Impairment

Contraindicated in renal impairment.

Pediatric Use

The safety and efficacy of the drug Ascoril LS in children and adolescents under 18 years of age have not been established to date. Data are lacking.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

The drug should be used with caution in patients with the following diseases: diabetes mellitus, cardiovascular diseases (including coronary artery disease, chronic heart failure), pheochromocytoma, peptic ulcer of the stomach and duodenum in remission, impaired bronchial motility and increased mucus secretion (for example, in the rare syndrome of primary ciliary dyskinesia).

Ambroxol

Should not be combined with antitussive agents that impede sputum expectoration.

There are isolated reports of severe skin lesions such as Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis (AGEP) and erythema multiforme, which coincided in time with the prescription of expectorant drugs containing Ambroxol. In most cases, they can be explained by the severity of the underlying disease and/or concomitant therapy. In patients with Stevens-Johnson syndrome or toxic epidermal necrolysis, fever, body aches, rhinitis, cough and sore throat may appear in the early phase. Symptomatic treatment may lead to the erroneous prescription of cold remedies. If new skin and mucous membrane lesions appear, it is recommended to discontinue ambroxol treatment and seek immediate medical attention.

In patients with impaired bronchial motility and a large amount of sputum (for example, in the rare syndrome of primary ciliary dyskinesia), Ambroxol should be used with caution, as it may cause sputum accumulation.

In patients with impaired renal function or severe liver disease, Ambroxol should not be used without a doctor’s prescription. When taking ambroxol, like any drug that is metabolized in the liver and excreted by the kidneys, accumulation of ambroxol metabolites formed in the liver should be expected in patients with severe renal impairment.

Guaifenesin

Do not use simultaneously with cough suppressants or combined cold medications. Guaifenesin should not be taken to treat persistent or chronic cough, cough in bronchial asthma, and cough accompanied by excessive sputum secretion, except in cases where the use of guaifenesin is recommended by a doctor. If the cough persists after 3-5 days of taking guaifenesin or if the cough is accompanied by fever, rash, or prolonged headache, a doctor should be consulted.

In patients with severe impairment of renal or liver function, Guaifenesin should not be used without a doctor’s prescription.

A metabolite of guaifenesin may cause discoloration during the determination of 5-hydroxyindoleacetic acid and vanillylmandelic acid in urine. Guaifenesin intake should be discontinued 24 hours before urine collection for this test.

Levosalbutamol

Cardiovascular effects.Levosalbutamol, like other beta-adrenergic receptor agonists, can have a clinically significant effect on the cardiovascular system in some patients, as determined by heart rate and blood pressure. Although such effects are rare after the use of levosalbutamol at recommended doses, their occurrence may require discontinuation of the drug. In addition, beta-agonists have been reported to cause changes in ECG parameters, such as T-wave flattening, prolongation of the corrected QT interval, and ST-segment depression. The clinical significance of these effects is unknown. Therefore, Levosalbutamol, like all beta-adrenergic receptor agonists, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and arterial hypertension.

Immediate-type hypersensitivity reactions. Immediate-type hypersensitivity reactions may develop after the use of levosalbutamol or racemic salbutamol. Possible symptoms include urticaria, angioedema, rash, bronchospasm, anaphylaxis, and swelling of the mouth and larynx.

Concomitant disorders.Levosalbutamol, like other beta-adrenergic receptor agonists, should be used with caution in patients with cardiovascular disorders, especially coronary insufficiency, arterial hypertension, and cardiac arrhythmias; in patients with seizure disorders, hyperthyroidism, or diabetes mellitus; and in patients who are hypersensitive to sympathomimetic amines. Clinically significant changes in systolic and diastolic blood pressure have been observed in some patients. Changes in blood glucose levels are possible. Intravenous administration of large doses of racemic salbutamol has been reported to aggravate pre-existing diabetes mellitus and ketoacidosis.

Hypokalemia. As with the use of other beta-adrenergic receptor agonists, Levosalbutamol may cause significant hypokalemia in some patients, possibly through intracellular shunting, which can cause undesirable cardiovascular effects. The decrease in potassium levels is usually transient and does not require the use of potassium supplements.

Effect on the ability to drive vehicles and mechanisms

Given the possible side effects associated with the central nervous system (dizziness, drowsiness, tachycardia, hand tremors, and others), driving vehicles and mechanisms, and performing other work that requires concentration and speed of psychomotor reactions should be refrained from during the drug intake.

Overdose

Ambroxol

Symptoms specific symptoms of ambroxol overdose in humans have not been described. In case of overdose, symptoms of known side effects of ambroxol are possible – nausea, dyspepsia, diarrhea, vomiting, abdominal pain.

Treatment is symptomatic.

Guaifenesin

Symptoms effects of acute guaifenesin toxicity include discomfort in the digestive organs, nausea, and drowsiness. Excessive intake of Guaifenesin may cause kidney stone formation.

Treatment symptomatic and supportive therapy should be administered. Emergency measures, such as the administration of an antiemetic and gastric lavage, are generally not indicated, as these symptoms are expected to develop only in cases of extremely high overdose.

Treatment of Ascoril LS overdose should be primarily symptomatic and supportive.

Levosalbutamol

Symptoms the expected symptoms are excessive beta-adrenergic stimulation and/or the occurrence or intensification of any of the side effects, such as tachycardia, nervousness, headache, tremor, nausea, dizziness, fatigue, insomnia. Hypokalemia may also occur. As with all sympathomimetic drugs, abuse of levosalbutamol may be associated with cardiac arrest and even death.

Treatment discontinue the use of levosalbutamol along with appropriate symptomatic therapy. The advisability of using a cardioselective beta-adrenergic blocker may be considered, taking into account that such a drug may cause bronchospasm. There is insufficient evidence to determine whether dialysis is beneficial in the treatment of levosalbutamol overdose.

Drug Interactions

Ambroxol

No clinically significant undesirable interactions with other drugs have been reported.

When used concomitantly, it increases the penetration into bronchial secretions of amoxicillin, cefuroxime, erythromycin, doxycycline.

Concomitant use of ambroxol and antitussive drugs (e.g., codeine) is not recommended, as suppression of the cough reflex may lead to the danger of sputum accumulation in the airway lumen with difficulty in its discharge.

Guaifenesin

Concomitant use with antitussive drugs, including codeine-containing drugs, is not recommended.

It is compatible with bronchodilators, antibacterial agents, and other drugs used in the treatment of bronchopulmonary diseases.

Levosalbutamol

Short-acting bronchodilators

The use of other short-acting sympathomimetic bronchodilators or ephedrine is not recommended. Caution should be exercised to prevent enhancement of cardiovascular effects when using other adrenergic drugs via a different route of administration.

Beta-adrenergic receptor blockers .

Concomitant use of Levosalbutamol and non-selective beta-adrenergic receptor blockers, such as propranolol, is not recommended.

Diuretics

ECG changes or hypokalemia may result from the concomitant use of levosalbutamol and diuretics that increase potassium excretion (such as “loop” or thiazide diuretics) and may be aggravated when the recommended dose of beta-adrenergic receptor agonists is exceeded. Although the clinical significance of these effects is unknown, caution is advised when using levosalbutamol concomitantly with “loop” and thiazide diuretics. Monitoring of plasma potassium concentration is recommended.

Corticosteroids

Corticosteroids enhance the hypokalemia that Levosalbutamol may cause.

Methylxanthines

Concomitant use of methylxanthines and beta-adrenergic receptor agonists may lead to the development of hypokalemia. Theophylline and other xanthines, when used concomitantly with levosalbutamol, increase the likelihood of tachyarrhythmias.

MAO inhibitors or tricyclic antidepressants

Levosalbutamol should be administered with extreme caution to patients who are being treated with MAO inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such drugs, because the effect of levosalbutamol on the vascular system may be enhanced. In patients receiving MAO inhibitors or tricyclic antidepressants, alternative therapy should be considered.

Cardiac glycosides

Levosalbutamol increases the likelihood of extrasystoles while taking cardiac glycosides.
After intravenous and oral administration of racemic salbutamol in healthy volunteers who received digoxin for 10 days, an average decrease in serum digoxin concentration of 16-22% was observed. The clinical significance of these effects for patients receiving Levosalbutamol and digoxin concomitantly has not been established. However, digoxin concentration should be carefully monitored in patients receiving it concomitantly with levosalbutamol.

Other drugs

Concomitant use of beta-adrenergic receptor agonists with agents for inhalation anesthesia and levodopa preparations increases the risk of severe ventricular arrhythmias.

Concomitant use with anticholinergic agents (including inhaled ones) may contribute to increased intraocular pressure.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F). Do not freeze.

Shelf Life

The shelf life is 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.