Viscojoy AB Product Monograph

PRODUCT MONOGRAPH



TABLE OF CONTENTS INTRODUCTION 01 AIRWAY MUCUS HYPERSECRETION AND CHRONIC AIRWAY INFLAMMATORY DISEASE 01 01 Airway Mucus Hypersecretion and COPD 02 Airway Mucus Hypersecretion and Bronchial Asthma 02 Airway Mucus Hypersecretion and Bronchiectasis 03 Airway Mucus Hypersecretion and Pulmonary Cystic Fibrosis 03 CURRENT MANAGEMENT STRATEGIES 04 N-ACETYLCYSTEINE (NAC): Pharmacodynamics & Pharmacokinetics 05 RATIONALE FOR COMBINATION OF ACETYLCYSTEINE AND ACEBROPHYLLINE 06 ACEBROPHYLLINE: Pharmacodynamics & Pharmacokinetics 08 CLINICAL TRIALS: N-ACETYLCYSTEINE 08 Exacerbation Rates in Patients with Moderate to Severe COPD are Reduced by N-Acetylcysteine 09 Oral Acetylcysteine: Efficacy and Tolerability in Chronic Bronchitis 10 Oxidative Stress and N-Acetylcysteine in COPD 12 CLINICAL TRIALS: ACEBROPHYLLINE 12 Acebrophylline in the Treatment of COPD 14 A Comparative Study of Acebrophylline vs. Sustained Release Theophylline in COPD Patients 15 CLINICAL TRIALS: COMBINATION OF AMBROXOL AND ACETYLCYSTEINE 15 Use of Combination Therapy in COPD Patients 17 PRODUCT INFORMATION 17 Composition, Indication & Dosage 17 Acetylcysteine 17 18 Adverse Events 18 Contraindications 18 Drug-Drug Interactions 18 Pregnancy and Lactation 19 Overdose 19 Acebrophylline 19 Adverse Events, Contraindications 19 Drug-Drug Interactions 20 Pregnancy and Lactation 20 Overdose 20 SUMMARY REFERENCES



INTRODUCTION Chronic respiratory diseases, such as chronic obstructive pulmonary disease (COPD) and asthma, are among the leading causes of mortality and morbidity around the world.¹ COPD is the fourth leading cause of death worldwide. COPD is described as a state characterised by airflow limitation that is not completely reversible, according to the global initiative of chronic obstructive lung disease (GOLD). It is linked to long-term exposure to tobacco smoke, poisonous gases, and biomass fuel combustion. COPD affects about 5% of males and 2.7% of females over the age of 30 in India.² Also, bronchial asthma is the most common chronic respiratory condition, with 358.2 million cases reported in 2015.³ In India, the contribution of chronic respiratory diseases to total DALYs rose from 45% in 1990 to 64% in 2016. COPD and asthma were responsible for 75.6% and 20% of the chronic respiratory disease disability-adjusted life-years (DALYs), respectively.⁴ COPD cases in India rose from 281 million in 1990 to 553 million in 2016, with a prevalence of 33% to 42%.⁴,⁵ AIRWAY MUCUS HYPERSECRETION AND CHRONIC AIRWAY INFLAMMATORY DISEASE Hypersecretion of mucus in the airways can block the respiratory tract lumen, restrict airflow, and hasten the deterioration of lung function.⁵ At the same time, inflammatory responses impair cilia's ability to clear mucus, expel alveolar surface-active substances like surfactants, and change the biophysical properties of mucus.⁶ This can lead to chronic airway inflammation, which can block and remodel the airway further, creating a vicious loop. Sputum production, excessive mucus in the airway lumen, goblet cell hyperplasia, and submucosal gland hypertrophy are all symptoms of airway mucus hypersecretion in patients with asthma, chronic obstructive pulmonary disease (COPD), or cystic fibrosis (CF).⁷ AIRWAY MUCUS HYPERSECRETION AND COPD COPD is a widespread disease with constant, progressive airflow restriction and recurrent irregular inflammatory responses to harmful particles or gases in the respiratory tract and lungs. COPD has a significant impact on patients' ability to function and quality of life, and it is linked to a high mor- tality rate.⁸ Chronic cough and expectoration are symptoms of airway mucus hypersecretion. COPD is almost three times more common in people who have those symptoms than in people who are healthy.9,10 01

COPD patients have significantly more goblet cells in their airway epithelium than healthy people, and they secrete significantly more mucoprotein than healthy people.11 Mucus-clogged airways result in decreased airflow, which contributes to the pathogenesis of COPD. Patients with COPD who have airway mucus hypersecretion have a 3.5-fold higher chance of dying.12 Airflow and exercise potential are reduced as a result of airway mucus hypersecretion, which raises the risk of acute exacerbation, mortality, and poor prognosis in COPD patients. AIRWAY MUCUS HYPERSECRETION AND BRONCHIAL ASTHMA Bronchial asthma, also known as \"asthma,\" is a chronic inflammatory disease of the airways with reversible airflow restriction as its main clinical function.13 Asthmatics have significantly poorer mucociliary clearance from the airways than healthy people. Increased sputum volume and signs of airway mucus hypersecretion affect approximately 20%–40% of patients.14 Exfoliation of ciliated cells, goblet cell hyperplasia, and submucosal gland hypertrophy all result in airway mucus hypersecretion in bronchial asthma, which is caused by over secretion of mucin com- ponents MUC5AC and MUC5B in the airway, as well as damage to the epithelium.⁷ Their airways are also easily obstructed by colloidal mucus plugs. Since airway mucus hypersecretion facilitates bacterial colonisation of airways, restricts airflow, and compromises ventilation, asthma symptoms can be difficult to control. AIRWAY MUCUS HYPERSECRETION AND BRONCHIECTASIS Bronchiectasis is the breakdown of smooth muscles and elastic tissues on the bronchial wall as a result of chronic purulent inflammation and fibrosis of the bronchus and underlying lung tissues, resulting in bronchial deformation and recurrent bronchial expansion. Patients with bronchiectasis have less mucociliary activity in the airway and less expectoration potential, and their mucus has different biophysical properties, such as being more viscous.15 Long-term mucus accumulation in the airway promotes bacterial invasion as well as repeated coughing and expectoration.15 02

AIRWAY MUCUS HYPERSECRETION AND PULMONARY CYSTIC FIBROSIS Cystic fibrosis of the lungs is a congenital lung condition caused by a mutation in the cystic fibrosis transmembrane conductance regulator, which is responsible for the production of sweat, digestive juices, and other mucus fluids. Patients with pulmonary cystic fibrosis have serious airway mucus hypersecretion, and many have recurrent pulmonary infections, all of which can hasten lung deterioration. In patients with pulmonary cystic fibrosis, airway mucus hypersecretion is linked to a chronic cough, expectoration, and dyspnea.16 CURRENT MANAGEMENT STRATEGIES17 Class Examples Mechanism of Action Expectorants Hypertonic saline Increases secretion volume and/or hydration Guaifenesin Stimulates secretion and reduces mucus viscosity Carbocisteine Metabolism of mucus-producing cells, antioxidant and anti- inflammatory effects, modulates mucus production Mucus regulators Anticholinergic agents Decreases secretion volume Glucocorticoids Reduces airway inflammation and mucin secretion Macrolide antibiotics Reduces airway inflammation and mucin secretion N-acetylcysteine Breaks disulphide bonds linking mucin polymers, antioxidant and anti-inflammatory effects Nacystelyn Increases chloride secretion and disulphide bonds Erdosteine Modulates mucus production and increases mucociliary transport Mucolytics Dornase alfa Hydrolyses the DNA in mucus and reduces viscosity in the lungs Gelsolin Severs actin filament cross-links Thymosin β4 Severs actin filament cross-links Dextran Breaks hydrogen bonds and increases secretion hydration Heparin Breaks hydrogen bonds and ionic bonds Bronchodilators Improve cough clearance by increasing expiratory flow Mucokinetics Surfactants Decrease sputum/mucus adhesiveness Ambroxol Stimulates surfactant production and inhibits neuronal sodium channels 03

N ACETYLCYSTEINE NAC Figure 1. Chemical structure of N-Acetylcysteine NAC is a thiol and mucolytic agent, a precursor of L-cysteine and reduced glutathione (Figure 1).18 PHARMACODYNAMICS18,19 Due to its mucolytic activity, there is a reduction in the viscosity of mucous secretions. Another poten- tial effect is the detoxification of free radicals through interaction with acetylcysteine's active sul ydryl group. Additionally, acetylcysteine boosts glutathione synthesis (Figure 2). Acetylcysteine is also suggested as a particular antidote in paracetamol poisoning due to this mechanism of action. Figure 2. Mechanism of action of N-Acetylcysteine18 NAC Breaking of disulfide Direct antioxidant Indirect antioxidant bonds in mucoprotein effect effect ROS scavenging Increased intracellular GSH Reduces viscosity of mucus secretion Reduced oxidative stress/inflammation Improves mucociliary Reduces mucus secretion clearance Protects alfa1-antitrysin Improves lung function, symptom control, reduced exacerbation rate 04

PHARMACOKINETICS19 01 Absorption After oral administration, acetylcysteine is quickly and almost fully absorbed. 02 Distribution Volume of distribution of I.V. administered acetylcysteine in humans was 0.47 l/kg. Plasma clearance is 0.11 l/h/kg. Elimination half-life after oral administration is 6.25 hours. 03 Metabolism In the liver, it is metabolised into the active metabolite cysteine, the inactive metabolite diacetylcystine, and cystine, as well as the other disulfides. Bioavailability is very low (approximately 10%). Plasma concentration of the active metabolite cysteine is about 2μmol/l and binding with proteins is about 50%. 04 Elimination It is almost completely excreted via the renal route as inactive metabolites (inorganic sulphates, diacetylcystine). Elimination half-life of acetylcysteine is about 1 hour. In patients with liver dysfunction the elimination half-life increases to 8 hours. COMBINATION OF ACETYLCYSTEINE AND ACEBROPHYLLINE Current oral/inhaled steroids and bronchodilators for COPD and asthma management may not be suffi- cient for effective clearance. It is important to address impaired mucociliary clearance. Acebrophylline as add on to the existing therapies will help in effective mucociliary clearance. 05

ACEBROPHYLLINE Acebrophylline, an airway mucoregulator and anti-inflammatory agent is a combination product of ambroxol and theophylline 7 acetic acid (Figure 3).20 Figure 3. Theophylline-7-Acetate and Ambroxol PHARMACODYNAMICS20,21 Acebrophylline is a compound that has been found to act as a bronchodilating, mucoregulating and anti-inflammatory drug due to its components theophylline-7-acetate and ambroxol. Theophylline-7-acetate, as with other xanthinic derivatives, has a bronchodilator effect due to inhibi- tion of the intracellular phosphodiesterases, followed by an increase of adenosine monophosphate cyclic levels, which promote the relaxation of bronchial muscles. Ambroxol modifies the mucous gel phase of secretions by decreasing the viscosity and increasing the serous gel phase. It increases mucociliary clearance by stimulating cilia motility. Acebrophylline inhibits phospholipase A2 and phosphatidylcholine leading to lesser production of the powerful pro-inflammatory substances like leukotrienes and tumour necrosis factor. By inhibiting the synthesis and release of these inflammatory mediators, acebrophylline reduces inflammation, a key factor in airway obstruction, especially in chronic forms (Figure 4). 06

Figure 4. Mechanism of action of Acebrophylline20 Synthesis & Release of Mucoregulatory Pulmonary Surfactant Action 1. Increases uptake of choline 1. Direct: At glandular level; better quality 2. Acts at two levels in surfactant synthesis mucus production 2. Indirect: Stimulates alveolar surfactant production; reduces viscosity of bronchial secretions Activity on Mucociliary Anti-inflammatory - Clearance Antireactive Activity 1. Increases ciliary activity 1. Inhibits synthesis & release of 2. Stimulation of pulmonary surfactant inflammatory mediators eases transport of secretion 2. Helps reduce bronchial oedema secondary to inflammation PHARMACOKINETICS The two components of the enzyme, ambroxol and theophylline-7 acetic acid, are released in the stomach and absorbed there and in the intestine, reaching optimal ambroxol concentrations and very low levels of theophylline-7 acetic acid in healthy volunteers who were given 200 mg oral acebrophylline. After 2 hours, ambroxol reaches its peak in serum (mean Cmax 0.369 mcg/mL), while theophylline-7 acetic acid reaches its peak after 1 hour (mean Cmax 0.008 mcg/mL).21 As a result, it appears that theophylline-7 acetic acid is either poorly absorbed or metabolised quickly and discarded quickly.22 07

KEY CLINICAL TRIALS: N ACETYLCYSTEINE EXACERBATION RATES IN PATIENTS WITH MODERATE TO SEVERE COPD ARE REDUCED BY N ACETYLCYSTEINE23 Objective: To confirm the effectiveness of a 6-month N-acetylcysteine (NAC; 600 mg/day p.o.) therapy on the occurrence and intensity of exacerbations in patients with chronic obstructive pulmonary disease. Study Design: A total of 159 patients from five Italian clinics were enrolled in an open, randomised, and controlled trial. Over the course of six months, the patients were randomly assigned to either standard therapy plus NAC 600 mg once a day or standard therapy alone. ß2-agonists, anticholinergics, theophylline, and inhaled and/or oral corticosteroids were among the standard treatments. Immunostimulant therapy was not permitted during the research period. At baseline, the patients’ medical history was evaluated and a physical examination performed. The clinical condition, occurrences and severity of exacerbations and side effects were evaluated after 3 and 6 months. Results: In the category of patients treated with NAC against standard care, the number of exacerbations was reduced by 41% (Figure 5). Figure 5. Total number of exacerbations 160 p <0.05 140 Number of Exacerbations 120 Patients with Standard Therapy 100 Patients with NAC on 80 top of Standard Therapy 60 40 20 0 Standard Therapy + NAC Standard Therapy 08

Figure 6. Effect of NAC on top of standard therapy on the proportion of patients with one or more exacerbations Proportion of Patients 90% p <0.003 NS Patients with Standard Therapy 80% Patients with NAC on 70% top of Standard Therapy 60% 50% Patients with 2 or more exacerbations 40% 30% 20% 10% 0% Patients with > 1 exacerbation In the group treated with regular therapy alone, 46 patients had at least one exacerbation, com- pared to 63 patients in the control group (Figure 6). When compared to the standard therapy group, the NAC group had fewer sick days (82) than the standard therapy group (155). In both groups, there were no variations in the number of side effects recorded. Conclusion: Exacerbations were reduced in patients with mild to serious COPD who were given the antioxidant NAC. Additionally, the once-daily formulation is well tolerated and is expected to increase patient adherence to the prescribed regimen. ORAL ACETYLCYSTEINE: EFFICACY AND TOLERABILITY IN CHRONIC BRONCHITIS24 Objective: To look at the effects of oral N-acetylcysteine on the symptoms of a group of chronic bronchitis patients in the UK over a three-month span. Study Design: Patients received 200 mg N-acetylcysteine three times daily or a matching placebo for the 3-month trial period. Chronic bronchitis was characterised as the occurrence of a recurrent cough with sputum develop- ment for more than 3 months of each year for at least the previous 3 years in patients of either sex. A baseline subjective evaluation of sputum viscosity and character, difficulty in expectoration, and cough severity, as well as a clinical and radiological examination of the respiratory system, were reported for each patient. 09

Results: Sputum viscosity: The mean score for sputum viscosity for each treatment group improved signifi- cantly (Figure 7). Sputum character: The mean score for sputum character for each treatment group also improved significantly (Figure 8). Cough severity: There was also a significant improvement in the mean score for each treatment group over 3 months; most evident over the initial month of the study (Figure 9). Figure 7. Effect of N-acetylcysteine Figure 8. Effect of N-acetylcysteine Figure 9. Effect of N-acetylcysteine on sputum viscosity on sputum character on cough severity Mean Score (Shown with 1 Mean Score (Shown with 1 Mean Score (Shown with 1 standard error of the mean) standard error of the mean) standard error of the mean) 3 3 3 2 2 2 1 1 1 0 23 4 0 23 4 0 23 4 1 Months 1 Months 1 Months N-Acetylcysteine Placebo N-Acetylcysteine Placebo N-Acetylcysteine Placebo Greater proportion of patients receiving N-acetylcysteine was considered to have shown some degree of improvement compared to placebo (85% versus 68%). Conclusion: In patients with chronic bronchitis treated with N-acetylcysteine, this study found a substantial improvement in cough severity and difficulty in expectoration. OXIDATIVE STRESS AND N ACETYLCYSTEINE IN COPD25 Objective: The aim of this study was to determine the dose-dependent effects of NAC on oxidative stress, as well as its safety and efficacy in COPD patients. 10

Study Design: A single-centre, randomised, double-blind, placebo-controlled, parallel group study was conducted in a rural setting. 68 diagnosed cases of COPD according to GOLD criteria (global initiative for chronic obstructive pulmonary disease) were enrolled in the study. Patients were randomly assigned to one of three treatment groups: Study arm I: Control (n=23)/Receiving standard treatment for COPD. Study arm II: NAC 600 mg once daily (n=22) (In addition to the standard treatment) Study arm III: NAC 600 mg twice daily (n=23) (In addition to the standard treatment) Patients were assessed for respiratory signs, oxygen saturation, a chest X-ray, and spirometry at the start of the study (day 0). Malondialdehyde (MDA) was measured in serum samples, and treatment was given according to the randomisation schedule. The patients were followed for two months and tested for symptomatic progress and drug side effects at 15 days, 30 days, and at 6 months. Results: A significant reduction of serum MDA after two months was seen in study arm II (p=0.001) and study arm III (p=0.023) (Figure 10). A significant increase in SpO2 from baseline (day 0) was observed at post-treatment (day 60) (p<0.005)in study arm II (Figure 11). Figure 10. MDA change from baseline to post-treatment (p=0.001) 0 I Treatment Groups III – 0.2 – 0.24 II –0.57 – 0.4 Day 60 - Day 0 – 0.6 –1.27 – 0.8 –1 – 1.2 – 1.4 11

Figure 11. Comparison of SpO2 in the study groups (p<0.05) SpO2 Change from baseline over treatment groups 2 1.77 1.8 1.6 1.52 Day 60 - Day 0 1.4 1.2 1 0.8 0.74 0.6 0.4 0.2 0 II III I Treatment Groups It was also observed that all the study arms showed significant reduction in symptoms like cough, sputum production and expectoration, throat irritation and chest tightness. Nausea and stomatitis were the most common reported adverse effects in all the study subjects. Conclusion: The addition of NAC to normal COPD care reduces disease exacerbations, improves symptoms, and lowers oxidative stress parameters, enhancing NAC's antioxidant, anti-inflammatory, and mucolyic properties. CLINICAL TRIALS: ACEBROPHYLLINE ACEBROPHYLLINE IN THE TREATMENT OF COPD26 Objective: To confirm the efficacy and safety of acebrophylline in COPD patients. Study Design: Open-label study Acebrophylline was given at a dosage of 100 mg twice daily for ten days using three different formulations: acebrophylline 100 mg capsules (n = 20), acebrophylline 100 mg granulate for extemporaneous solution (n = 15), and acebrophylline syrup 1% (one spoon = 100 mg) (n = 15). 12

Expectoration CharacteristicsSpirometry was used to calculate functional variables such as forced expiratory volume in one second, vital ability, Tiffeneau's index, residual volume, total lung capacity, Morley's index (residual volume/total lung capacity), and blood gas analysis (arterial oxygen tension [PaO2], arterial carbon dioxide tension [PaC02]) before and after drug administration. Throughout the study, adverse events spontaneously identified by the patient or observed by the physician were tracked and documented in terms of onset, occurrence, length, and outcomes. The volume of expectorant was carefully measured as cubic centimetres per day, and its character- istics were classified according to a 0 to 3 semiquantitative scale either rating aspect (0 = serous; 1 = mucous; 2 = mucopurulent; and 3 = purulent) or viscosity (0 = fluid; 1 = semifluid; 2 = dense; and 3 = very dense). Results: In most patients, the aspect of their expectoration shifted from purulent or mucopurulent to mucous or serous, and the viscosity changed from dense to semifluid or fluid, with major variations (Figure 12). There was an improvement in respiratory function. Forced expiratory volume in 1 second, forced vital capacity, and their relation significantly increased after treatment, whereas residual volume, total lung capacity, and their relation signifi- cantly decreased. At the end of therapy, PaO2 values significantly increased and PaCO2 values significantly decreased as compared to the baseline. Only one patient reported an adverse event (mild gastric pain) with acebrophylline. Figure 12. Expectoration characteristics before, during, and after treatment (P < 0.01 versus baseline, *0 = serous; 1= mucous; 2= mucopurulent; 3= purulent; #0= fluid; 1= semifluid; 2= dense, 3= very dense) Volume (cc/d) Aspect* Viscosity# Days 13

Conclusion: When given to COPD patients, acebrophylline is both safe and effective. For a period of ten days, a dose of 200 mg/d influenced the rheological properties of bronchial secretions significantly. A COMPARATIVE STUDY OF ACEBROPHYLLINE VS. SUSTAINED RELEASE THEOPHYLLINE IN COPD PATIENTS27 Objective: The aim of this study was to compare the efficacy, tolerability, and side effects of these two drugs at prescribed doses. Study design: An open randomised comparative Group 1: longitudinal study among Acebrophylline 100 mg, twice daily 40 moderate-to-severe COPD patients Group 2: Sustained release (SR) Theophylline 300 mg, once daily, orally Additionally, 18μgm Tiotropium inhalation per day via metered dose inhaler was administered. Variables in spirometry, symptomatic benefit and adverse events were recorded on three visits (day 0, 21, and 42). Results: The amount of sputum produced decreased (in 40% patients of group-1 and 55% patients of group-2). 55% of Acebrophylline patients and 45% of SR Theophylline patients said they didn't need reliever medications. Shortness of breath (as measured by the mMRC scale) improved in 65% of group-1 patients and 45% of group-2 patients (Figure 13). 14

Figure 13: Showed improvement (%) of SOB in two groups before and after treatment SOB after treatment 70% 65% Group 1 Group 2 Improvement of SOB (%) 60% 35% 50% 45% 0% Deteriorate 40% 35% 30% 20% 20% 10% 0% Same Improved Amount of sputum, frequency of use of reliever medication and dyspnoea showed improvement with both the drugs but cardiovascular side effects are less with Acebrophylline. Conclusion: The rationale for using Methylxanthines as an add-on therapy for COPD management was reaf- firmed in this study, and the cardiac safety level with Acebrophylline was significant. KEY CLINICAL TRIALS: COMBINATION OF AMBROXOL AND ACETYLCYSTEINE USE OF COMBINATION THERAPY IN COPD PATIENTS28 Objective: The aim of the study is to improve the efficacy of treating COPD group B GOLD II exacerbations with a combination of the combined drug, which contains two components – ambroxol and acetylcysteine, and a halotherapy course. 15

60 moderate to Group 1: (n=30) severe COPD patients Clarithromycin 500 mg twice daily, tiotropium bromide for 1 breath 2 times a day, budesonide 50 micrograms through a nebuliser two times a day for 7 days; Ambroxol and acetylcysteine 200/30. 2 times a day for 7 days, Halotherapy Group 2: (n=30) Clarithromycin 500 mg twice daily, tiotropium bromide for 1 breath 2 times a day, budesonide 50 micrograms Results: Patients who received treatment with a combination of ambroxol and acetylcysteine as well as halother- apy sessions saw a substantial increase in FEV1 of 8.3% (p<0.05) (Table 1), a decrease in Tiffon index of 7.2 percent (p<0.05), and a decrease in reactive anxiety levels (RA) (Table 2) and autonomic dysfunction symptoms, while patients in the control group did not. Table 1. Dynamics of indicators of the function of external respiration in the process of treatment Indicator, Unit Main group (n=30) Control group (n=30) Before Treatment After Treatment Before Treatment After Treatment VC, % 73.1±1.3 79.6±1.2 72.4±1.9 75.9±2.2 FEV, % 72.5±1.12 79.1±1.85* 71.7±1.6 75.7±1.2 FEF 25, % 68.3±1.6 69.2±1.42 62.8±2.1 65.6±1.9 FEF 50, % 62.2±1.4 66.1±1.8 62.1±1.4 64.22±2.1 FEF 75, % 61.4±1.7 64.3±1.9 61.7±1.8 61.3±1.2 FEV1/FVC, % 72.3±1.4 77.6±1.9* 71.2±1.3 74.5±1.9 Note: *(p<0.05)- the differences are reliable before and after treatment Table 2. Dynamics of indicators of reactive and personal anxiety in the process of treatment in patients with the main and control groups Group of Patient Reactive anxiety Personal anxiety Before Treatment After Treatment Before Treatment After Treatment Main group (n=30) 46.1±2.12 30.3±2.43 42.1±3.12 40.3±2.45 Control group (n=30) 45.6±2.8 37.5±3.2 40.8±3.32 39.3±3.02 Note: *(p<0.05)- the differences are reliable before and after treatment Conclusion: Combined drugs ambroxol and acetylcysteine as well as halotherapy sessions, helps patients improve their quality of life. 16

PRODUCT INFORMATION Composition Each effervescent tablet contains: Acetylcysteine BP..............................................600 mg Indications Excipients.................................................................q.s. Dosage Each film coated tablet contains: Acetylcysteine BP..............................................600 mg Acebrophylline...................................................100 mg Colours: Yellow Oxide of Iron and Titanium Dioxide IP Adjunctive therapy for respiratory tract disorders characterised by excessive, viscous mucus secretion. One oral tablet daily is recommended for adults and adolescents, aged 14 years and older. ACETYLCYSTEINE Adverse Events System organ class Uncommon Rare Very Rare Not known (>1/1,000 to <1/100) Immune system disorders (>1/10,000 to <1/1,000) (<1/10,000) Hypersensitivity ACETYLACnYapShTyElaIcNticEshock, Nervous system disorders reactions Ear and labyrinth disorders Headache anaphylactic/anaphylactoid Cardiac disorders Vascular disorders Tachycardia reactions Respiratory, thoracic and mediastinal disorders Vomiting, diarrhoea, stomatitis, Tinnitus Gastrointestinal disorders abdominal pain, nausea Haemorrhage Bronchospasm, dyspnoea Dyspepsia Skin and subcutaneous Urticaria, rash, angioedema, tissue disorders pruritus, exanthema Others Fever Facial oedema While taking acetylcysteine, serious skin reactions such as Stevens-Johnson syndrome and Lyell's syndrome have been documented, but these are uncommon. Various studies have shown that acetyl- cysteine reduces blood platelet aggregation. The clinical significance has yet to be determined. 17

Contraindications29: Hypersensitivity to the active substance or to any of the excipients. Children under 14 years of age. Drug-drug interactions29: Interference with antitussives: If this product is used in combination with cough-relieving medi- cines (antitussives) the suppressed cough reflex may cause a dangerous build-up of secretions. Activated charcoal: Co-administration with activated charcoal can reduce the effectiveness of acetylcysteine. Antibiotics: Reports of inactivation of antibiotics (aminoglycosides, penicillin’s, tetracycline) by acetylcysteine indicate that this inactivation occurs only when these substances are mixed directly together in vitro. Administration of oral doses of antibiotics and acetylcysteine capsules should be separated by a minimum period of two hours. This does not apply to the antibiotics cefixime or loracarbef. Acetylcysteine and glyceryl trinitrate: Simultaneous administration of these drugs may increase the vasodilatory and platelet aggregation-inhibiting effect of glyceryl trinitrate. If such combined treat- ment is considered necessary, the patient should be monitored for possible hypotension, which can be serious and may be indicated by headaches. Interface with the measurement of laboratory parameters: Acetylcysteine can influence the colouri- metric assay of salicylates and results when measuring ketones in the urine. Preganancy and lactation29: Pregnancy: There are no data on the use of acetylcysteine in pregnant women. Animal studies do not indicate direct or indirect adverse effects on pregnancy, embryonic/fetal development, birth or postnatal. Lactation: There is insufficient information on the excretion of acetylcysteine or its metabolites in human milk. Use during pregnancy and while breast-feeding should be subject to careful consider- ation of the risk/benefit balance. Overdose29: There have been no cases of toxic overdose observed with orally-dosed acetylcysteine. No serious undesirable effects were observed in volunteer test subjects dosed over a 3-month period with 11.6g acetylcysteine per day. Oral doses of up to 500 mg/kg of acetylcysteine were tolerated without toxic effects. Overdoses can cause gastrointestinal symptoms such as nausea, vomiting and diarrhoea. In infants, there is a risk of hypersecretion. Treat symptomatically if applicable. 18

ACEBROPHYLLINE Adverse events21: Transient nausea and dizziness may occur on taking this drug, but these effects are reversible. On cessation of therapy, these symptoms tend to disappear. The commonly reported adverse effects with acebrophylline include abdominal discomfort, stom- ach/abdominal distension, vomiting, abdominal pain, diarrhoea, constipation, heart burn, loss of appetite, esophageal bleeding, rashes, urticaria, itching, drowsiness, difficulty in breathing, leuko- cytosis, and nasal inflammation. If chills and fevers occur, the drug should be immediately discon- tinued. Other rarely reported adverse events to include headache, occasional numbness including numb- ness in the arm, insomnia, tachycardia, fatigue, hypertension, albuminuria, glycosuria, hypotension and occasionally hyperglycaemia. Contraindications21: While the two components of acebrophylline have generally been found to be safe in earlier studies, the following contraindications have to be noted: Hypersensitivity to ambroxol, acebrophylline, theophylline or any other xanthine derivative Patients suffering from acute myocardial infarction Patients with hypotension, haemodynamic instability, and arrhythmias Patients with renal disease or liver disorder Drug-drug interactions21: The following reduce clearance and a reduced dosage may therefore be necessary to avoid side-ef- fects: allopurinol, cimetidine, ciprofloxacin, corticosteroids, diltiazem, erythromycin, furosemide, isoprenaline, oral contraceptives, thiabendazole and verapamil, doxycycline, amoxicillin etc. Xanthines can potentiate hypokalaemia resulting from beta2-agonist therapy, steroids, diuretics and hypoxia. Particular caution is advised in severe asthma. It is recommended that serum potassi- um levels are monitored in such situations. No clinically relevant unfavourable interactions with other medications have been reported. Preganancy and lactation29: Pregnancy: Acebrophylline is not recommended in pregnancy as well as during parturition. Lactation: The safety of acebrophylline is nor established during lactation period. Hence the use of acebrophylline is not advisable in lactating mothers. 19

Overdose29: Nausea, vomiting (which is often severe), epigastric pain and haematemesis. Pancreatitis if abdom- inal pain persists. Restlessness, hypertonia, exaggerated limb reflexes and convulsions. Tachycardia is common. Symptomatic treatment should be provided. SUMMARY Mucolytic agents like Acebrophylline and N-acetylcysteine will change the way mucus is secreted and its physical properties, resulting in improved mucociliary clearance. These medications appear to be successful in the treatment of chronic obstructive pulmonary disease, asthma, and acute bronchitis, according to current evidence. They boost symptom management and lung function to a minor extent. They also serve as reactive oxygen species scavengers. Acebrophylline inhibits the release of mediators that play a role in the pathogenesis of allergic inflammation. Mucolytics are useful in the treatment of patients with respiratory tract disorders because they are inexpensive and well-tolerated. REFERENCES 1. Bachh AA, Shah NN, Bhargava R, Ahmed Z, Pandey DK, Dar KA, et al. Effect of oral N- acetylcysteine in COPD-A random- ized controlled trial. JK Practioner. 2007;14(1):12-6. 2. Shankar PS. COPD etiopathogenesis: interplay of environmental and genetic factors. Indian J Chest Dis Allied Sci. 2006;23(1):15-9. 3. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. GBD 2015 Chronic Respiratory Disease Collaborators. Lancet Respir Med. 2017; 5(9):691-706. 4. India State-Level Disease Burden Initiative CRD Collaborators. The burden of chronic respiratory diseases and their heterogeneity across the states of India: the Global Burden of Disease Study 1990-2016. Lancet Glob Health. 2018;6(12):e1363-e1374. 5. Allinson JP, Hardy R, Donaldson GC, Shaheen SO, Kuh D, Wedzicha JA. The presence of chronic mucus hypersecretion across adult life in relation to chronic obstructive pulmonary disease development. Am J Respir Crit Care Med. 2016;193(6):662–672. 6. Reid KB, Clark H, Palaniyar N. Surfactant and lung inflammation. Thorax. 2005;60(8):620– 622. 7. Rogers DF. Mucoactive agents for airway mucus hypersecretory diseases. Respir Care. 2007;52(9):1176-93; discussion 1193-7. 8. Zhonghua Jie, He He, Hu Xi, Za Zhi. COPD group of Chinese Thoracic Society. [Guideline for diagnosis and treatment of chronic obstructive pulmonary disease (updated 2013)]. 2013;36(4):255–265. Chinese. 20

9. de Marco R, Accordini S, Cerveri I, Anto J, Kunzil N, Janson C, et al. Incidence of chronic obstructive pulmonary disease in a cohort of young adults according to the presence of chronic cough and phlegm. Am J Respir Crit Care Med. 2007;175(1):32–39. 10. Yamane T, Hattori N, Kitahara Y, et al. Productive cough is an inde- pendent risk factor for the development of COPD in former smokers. Respirology. 2010;15(2):313–318. 11. Ma R, Wang Y, Chen G, Zhang HZ, Wan HY, Huang SG. [Goblet cell hyperplasia and abnormalities in mucin expression in COPD patients]. Shanghai Di Er Yi Ke Da Xue Xue Bao. 2004;24(12):1031–1033, 1044. Chinese 12. Hogg JC, Chu FS, Tan WC, et al. Survival after lung volume reduction in chronic obstructive pulmonary disease: insights from small airway pathology. Am J Respir Crit Care Med. 2007;176(5):454–459. 13. Asthma Workgroup, Chinese Thoracic Society, Chinese Society of General Practitioners. Chinese guideline for the prevention and management of bronchial asthma (Primary Health Care Version). J Thorac Dis. 2013;5(5):667–677. 14. de Marco R, Marcon A, Jarvis D, et al. Prognostic factors of asthma severity: a 9-year international prospec- tive cohort study. J Allergy Clin Immunol. 2006;117(6):1249–1256. 15. Tambascio J, de Souza HC, Martinez JA, Afonso JL, Jardim JR, Gastaldi AC. The influence of purulence on ciliary and cough transport in bronchiectasis. Respir Care. 2013;58(12):2101– 2106. 16. Shen Y, Huang S, Kang J, Lin J, Lai K, Sun Y, et al. Management of airway mucus hypersecretion in chronic airway inflammatory disease: Chinese expert consensus (English edition). Int J Chron Obstruct Pulmon Dis. 2018;13:399-407. 17. Balsamo R, Lanata L, Egan CG. Mucoactive drugs. Eur Respir Rev. 2010;19(116):127-33. 18. Santus P, Corsico A, Solidoro P, Braido F, Di Marco F, Scichilone N. COPD. 2014;11(6):705– 717. Published online 2014 Apr 30. 19. https://www.medicines.org.uk/emc/product/11586/smpc#gref Accessed on 07/03/2021. 20. Pozzi E. Acebrophylline: an airway mucoregulator and anti-inflammatory agent. Monaldi Arch Chest Dis. 2007;67(2):106-15. 21. Acebrophylline Prescribing information, 2021. 22. Sved S, McGilveray IJ, Beaudoin N. The assay and absorption kinetics of oral theophylline-7 acetic acid in the human. Biopharm Drug Disposit. 1981; 2: 177-84. 23. Pela R, Calcagni AM, Subiaco S, Isidori P, Tubaldi A, Sanguinetti CM. N-acetylcysteine reduces the exacerba- tion rate in patients with moderate to severe COPD. Respiration. 1999;66(6):495-500. 24. Jackson IM, Barnes J, Cooksey P. Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study. J Int Med Res. 1984;12(3):198- 206. 25. Kale SB, Patil AB, Kale Anita. Effects of administration of oral n-acetylcysteine on oxidative stress in chronic obstructive pulmonary disease patients in rural population. Int J Basic Clin Pharmacol. 2016;5(3):775-781. 26. Agliata G. Acebrophylline in the treatment of chronic obstructive pulmonary disease. Curr Ther Res. 1995;56(2):169-175. 27. Tapadar SR, Das M, Chaudhuri AD, Basak S, Mahapatra AB. The Effect of Acebrophylline vs Sustained Release Theophylline in Patients of COPD- A Comparative Study. J Clin Diagn Res. 28. Potyazhenko MM, Ishcheikin KY, Nastroga TV, Sokolyuk NL, Kitura OY, Gorodnytska IM. Optimization of pathogenetic therapy in patients with chronic obstructive lung disease. Wiad Lek. 2020;73(4):773-776. 29. Acetylcysteine Prescribing Information, 2021. 21

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