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AMBROXOL DRUGDEX® Evaluations OVERVIEW 1) Contraindications a) Absolute contraindications and precautions to this agent have not been determined; no information found at the time of this review DOSING INFORMATION Drug Properties A) Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index) B) Synonyms Ambroxol Adult Dosage Normal Dosage Intravenous route 1) For ATELECTACTIC PROPHYLAXIS a dose of 1 gram daily 3 days before and 2 days after the operation is recommended [19] ; 1 gram daily for 6 days has also been used in surgical prophylaxis [18] . 2) In the PROPHYLAXIS OF HYALINE MEMBRANE DISEASE, antenatal maternal ambroxol has been given in doses of 1 gram via intravenous infusion daily for 5 doses [13] . Oral route 1) The optimal dose of ambroxol has not been defined. In ALVEOLAR PROTEINOSIS, CHEMOTHERAPY INDUCED PULMONARY INJURY, BRONCHITIS, OTITIS MEDIA, and SJOGREN'S SYNDROME, most studies have used oral adult doses of 60 to 180 milligrams/day in 2 or 3 divided doses [1] [3] [4] [9] [8] [5] [20] ; (Passali et al, 1987) [16] . Pediatric Dosage Normal Dosage Intravenous route 1) The recommended daily mucolytic dose for children is 1.2 to 1.6 milligrams/kilogram [19] . 2) In the treatment of HYALINE MEMBRANE DISEASE, ambroxol has been used in doses of 10 milligrams/kilogram twice a day for 7 days via intravenous infusion [15] . Oral route 1) Recommended oral doses are as follows: children up to 2 years 15 milligrams (mg) daily; children ages 2 to 5 years - 15 to 30 mg daily; children 5 to 12 years - 30 to 45 mg daily and children 12 years and older - 60 to 90 mg daily [21] . 2) As a mucolytic, oral ambroxol has been given to children in doses of 1.5 to 2 milligrams/kilogram/day in 2 divided doses [22] . PHARMACOKINETICS Drug Concentration Levels A) Time to Peak Concentration 1) Oral: approximately 2 hours [26] . a) After a single 30-mg oral dose of AMBROXOL, the mean peak plasma concentration was 88.8 ng/mL [26] . ADME Absorption A) Bioavailability 1) ORAL: approximately 70% to 80% [26] . a) AMBROXOL is rapidly absorbed after oral administration [26] . Distribution A) Distribution Kinetics 1) Distribution Half-Life a) 1.3 hours [26] . 1) Elimination of AMBROXOL is biphasic, with an alpha half-life of 1.3 hours and a beta half-life of 8.8 hours [26] . Metabolism A) Metabolites 1) Dibromoanthranilic acid (activity unspecified) [27] . Excretion A) Kidney 1) Renal Clearance (rate) a) approximately 53 mL/minute [26] . 1) Approximately 5% to 6% of a dose is excreted unchanged in the urine [26] . Elimination Half-life A) Parent Compound 1) ELIMINATION HALF-LIFE a) 8.8 hours [26] . 1) Elimination of AMBROXOL is biphasic, with an alpha half-life of 1.3 hours and a beta half-life of 8.8 hours [26] . CAUTIONS Contraindications A) Absolute contraindications and precautions to this agent have not been determined; no information found at the time of this review Precautions A) Absolute contraindications and precautions to this agent have not been determined; no information found at the time of this review Adverse Reactions Dermatologic Effects Contact dermatitis 1) Summary a) A case of contact ALLERGY was reported in a 60-year-old woman who used a 0.75% ambroxol solution via oral nebulization. Approximately 10 days after starting therapy, the patient developed PRURITIC ERYTHEMA and VESICULAR ERUPTIONS about the nose, upper lips, and cheeks, and PHARYNGEAL SORENESS and spasm. Symptoms resolved promptly upon discontinuation of the ambroxol solution. Subsequent patch testing was positive to ambroxol, but not to the paraben preservatives used in the product [25] . Dermatological finding 1) Contact dermatitis, urticaria, exanthema, itching, pruritic erythema and vesicular eruptions about the nose, upper lips, and cheeks, and pharyngeal soreness and spasm have been reported with therapeutic use. Pruritus 1) Summary a) Approximately 4% of patients taking ambroxol, 75 milligram per day, developed itching [24] . Rash 1) Summary a) EXANTHEMA has been reported with therapeutic use [25] . Urticaria 1) Summary a) Urticaria has been reported with therapeutic use [25] . 2) EXANTHEMA has been reported with therapeutic use [25] . Gastrointestinal Effects Constipation 1) Summary a) Constipation occurred in 2 of 63 patients receiving ambroxol 60 to 120 milligrams/day for bronchitis [23] . Diarrhea 1) Summary a) Approximately 3% of patients taking ambroxol, 75 milligrams per day, subsequently developed diarrhea [24] . Excessive salivation 1) Summary a) Sialorrhea was observed in 3 of 63 patients receiving ambroxol 60 to 120 milligrams/day for bronchitis [23] . Gastrointestinal tract finding 1) Dry mouth, diarrhea, constipation, nausea and vomiting, and sialorrhea have all been reported with therapeutic use. Nausea and vomiting 1) Summary a) Approximately 13% of patients taking ambroxol 75 milligrams per day subsequently developed nausea, and 2.6% experienced vomiting [24] . Xerostomia 1) Summary a) DRY MOUTH and dryness of the airways were reported in 5 of 63 patients receiving ambroxol 60 to 120 milligrams/day for bronchitis [23] . Neurologic Effects Central nervous system finding 1) Fatigue was infrequently reported in patients receiving ambroxol therapy. Renal Effects Dysuria 1) Summary a) Dysuria occurred in 1 of 63 patients receiving ambroxol 120 milligram/day for bronchitis [23] . Urogenital finding 1) Dysuria occurred infrequently with ambroxol therapy. Respiratory Effects Nasal discharge 1) Summary a) Rhinorrhea was observed in 3 of 63 patients receiving ambroxol 60 to 120 mg/day for bronchitis [23] . Respiratory finding 1) Rhinorrhea reported in patients with ambroxol therapy. Other Fatigue 1) Summary a) Fatigue was reported in 1 of 63 patients receiving ambroxol 60 to 120 milligrams/day for bronchitis [23] . CLINICAL APPLICATIONS Monitoring Parameters A) Therapeutic 1) Physical Findings a) Patients should be monitored for symptomatic improvement. Place In Therapy A) The primary role of ambroxol in contemporary therapeutics is likely to be in pulmonary medicine as an expectorant/mucolytic. Its main use will probably be in the treatment of bronchitis and pulmonary infections to facilitate the removal of secretions from the respiratory tract. B) The mucolytic and pulmonary surfactant stimulating properties of ambroxol have generated interest in its use in the prevention and treatment of neonatal respiratory distress syndrome, also known as hyaline membrane disease, and in the prophylaxis of antineoplastic-induced pulmonary injury. Although initial research has been encouraging, further study is needed to determine the role of ambroxol in these disorders. Mechanism of Action / Pharmacology A) MECHANISM OF ACTION 1) Ambroxol is an active N-desmethyl metabolite of the mucolytic bromhexine. Although its mechanism of action has not been fully defined, it may increase the quantity and decrease the viscosity of tracheobronchial secretions. It may also act as an expectorant, increasing mucociliary transport via stimulation of ciliary motility [28] . 2) Ambroxol may stimulate the synthesis and secretion of pulmonary surfactant [28] [29] ; the drug has been referred to as a "surfactant activator" [30] . 3) The effects of ambroxol in preventing bronchial hyper-reactivity were investigated [31] . Methacholine provocation doses were significantly higher (p less than 0.01) after ambroxol treatment versus placebo. It was postulated that ambroxol decreased airway hyper-reactivity by either increasing lysophosphatidyl-choline turnover and/or modifying epithelial secretions. 4) Recent research attributes antioxidative characteristics to ambroxol. Ambroxol has been demonstrated to be a direct scavenger of reactive oxygen metabolites. In an in-vitro study using specimens from 46 healthy human volunteers, ambroxol significantly reduced reactive oxygen species (ROS) produced by activated human polymorphonuclear cells (PMN) after 1 hour (p less than 0.001); after 2 hours, the level was comparable to that of nonactivated PMN (p less than 0.001); the reduction of mononuclear cells mimicked that of PMNs; reduction in the prooxidative metabolism of inflammatory cells is another postulated mechanism of action [32] . B) REVIEW ARTICLES 1) A review of the animal pharmacology of ambroxol has been provided [28] . 2) One article reviewed the risks and benefits of antenatal prevention of hyaline membrane disease for both the mother and infant, including ambroxol therapy [33] . 3) One author reviewed the alternatives to antenatal glucocorticoid administration for the prophylaxis of hyaline membrane disease, including the use of ambroxol [34] . Therapeutic Uses Antineoplastic adverse reaction - Pulmonary toxicity 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL has reduced pulmonary toxicity caused by some antineoplastic agents 3) Adult: a) AMBROXOL showed efficacy against lung injury induced by NITROSOUREA and BLEOMYCIN in 24 patients undergoing chemotherapy [2] . Patients received either AMBROXOL 30 milligrams or placebo every 8 hours from day 9 to day 45 of the intervals between courses of chemotherapy. There were statistically significant decreases in pulmonary function test parameters in patients receiving placebo; such deterioration was not seen in patients receiving AMBROXOL. Although these results were encouraging, more study was suggested to define the role of AMBROXOL in chemotherapy-induced lung injury. b) Another study demonstrated beneficial effects of AMBROXOL in the prevention of pulmonary toxicity in patients receiving nitrosourea antineoplastic drugs [3] . In this double-blind, placebo-controlled study, 40 patients with malignant glioma were randomized to receive AMBROXOL 40 milligrams or placebo orally 3 times a day for 40 days starting 10 days after therapeutic courses of CARMUSTINE (BCNU). No cases of pulmonary fibrosis were seen in either the group treated with AMBROXOL or the control group. However, pulmonary function test parameters were significantly impaired in the control group compared to the group treated with AMBROXOL. Bronchiolar disease, Stasis 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL may be helpful in patients with bronchial stasis Doses of 120 milligrams/day were effective, but 30-milligram/day doses were not 3) Adult: a) A placebo-controlled trial found AMBROXOL to be efficacious in the treatment of patients admitted to the hospital for bronchial stasis due to acute or OBSTRUCTIVE AIRWAY DISEASE [4] . A total of 120 patients were evaluated; 30 patients received AMBROXOL 120 milligrams/day and 30 patients received placebo orally for 10 days. AMBROXOL was shown to increase sputum volume, decrease sputum viscosity, and reduce the severity of cough in all patients, while placebo had no effect. The difference between groups was statistically significant (p less than 0.05). In a subsequent trial, 30 milligrams/day AMBROXOL was ineffective. Bronchitis 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL has been shown to be effective in ameliorating symptoms of bronchitis in controlled studies Doses of 75 to 120 illigrams/day were efficacious, but 60 milligrams/day had little effect Two small studies did not confirm statistically significant beneficial effects, but the small size of these studies may have limited their ability to detect differences 3) Adult: a) AMBROXOL was effective and well-tolerated for the prophylaxis of exacerbations of chronic bronchitis in an open, long-term multicenter study [5] . Prophylactic effects of AMBROXOL were assessed in 5635 patients with chronic bronchitis. Patients received 75 milligrams oral AMBROXOL daily for 6 months. After the first, third, and sixth months, the percentage of patients who did not experience exacerbations of symptoms was 81.6%, 58%, and 44.9%, respectively. The number of patients without difficulty in expectorating increased by 51.6% over basal values at 6 months. Pathological auscultatory signs were judged as intense by 19.8 and 0.9% of patients at the beginning and end of the study, respectively. b) Other studies have failed to confirm the positive effects of AMBROXOL on tracheobronchial clearance [6] or the ability to clear secretions in chronic bronchitics [7] . Both trials were limited in the ability to detect significant differences due to small sample sizes. c) AMBROXOL was effective for prophylaxis of acute exacerbations of chronic bronchitis in 110 patients enrolled in a placebo-controlled, doubleblind study [8] . One hundred ten patients received AMBROXOL 75 milligrams/day in a sustained-release dosage form and 104 received placebo for 6 months. Initially, there were no differences between treatment groups. By the end of the 2nd month of treatment, 67.2% of patients receiving AMBROXOL had no exacerbations, compared to 50.3% in the placebo group. At the end of the 6-month period, 45.5% of patients who received AMBROXOL had not experienced exacerbations while only 14.4% of controls had not had exacerbations. These differences were statistically significant (p less than 0.01). In addition, AMBROXOL produced statistically significant symptomatic improvement compared to controls; symptoms measured included severity of coughing, presence of dyspnea, difficulty of expectoration, and auscultatory signs. d) Positive effects were associated with use of AMBROXOL in patients with early hypersecretory chronic bronchitis [9] . In a double-blind, randomized, placebo-controlled trial, 92 patients received AMBROXOL 60 or 120 milligrams/day or placebo orally for 2 weeks. At the end of the treatment period, significantly more patients treated with AMBROXOL 120 milligrams/day showed improvement in symptoms, including cough, dyspnea, color and consistency of sputum, and ease of expectoration, when compared to placebo (p less than 0.05). AMBROXOL in doses of 60 milligrams/day had little effect. In addition, pulmonary function tests showed no difference between any of the groups. However, little or no airway obstruction was present, so no influence on spirometry values was expected. 1) COMBINATION THERAPY a) AMBROXOL combined with AMOXICILLIN was superior to AMOXICILLIN alone in the treatment of acute exacerbations of chronic bronchitis [10] . Twenty-three patients with clinical signs of bronchitis with concurrent infection were randomized to receive either AMOXICILLIN 500 milligrams (mg) 3 times a day (n=13) or AMOXICILLIN 500 mg 3 times a day plus AMBROXOL 30 milligrams 3 times a day orally for 10 days (n=10). Patients were evaluated according to severity of symptoms, ie, dyspnea, difficulty in expectoration, and cough. Cough and ease of expectoration improved in both groups, but improvement was greater and occurred earlier in the group receiving AMOXICILLIN plus AMBROXOL (p less than 0.001). The daily sputum volume was increased in the group receiving both drugs, but decreased in those receiving AMOXICILLIN alone. Before treatment, all patients had purulent sputum (more than 50 neutrophils/microscopic field). On the third day of treatment, 7 patients in the group receiving both drugs had non-purulent sputum (neutrophil counts under 10/microscopic field); only 3 of those receiving AMOXICILLIN alone had non-purulent sputum. Chronic obstructive pulmonary disease 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Ineffective Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Long-term ambroxol therapy was not effective in the prevention of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD) Some benefit was seen in a subset of COPD patients with more severe respiratory symptoms 3) Adult: a) Overall, long-term ambroxol therapy was not effective in the prevention of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD), however, some benefit was seen in a subset of COPD patients with more severe respiratory symptoms. In a randomized, doubleblind, placebo-controlled, multicenter study, patients with COPD with a clinical history of chronic bronchitis and with a forced expiratory volume in one second (FEV-1) between 60% and 80% of predicted value received oral ambroxol (retard formulation) 75 milligrams twice daily (n=115) or placebo (n=119) for 12 months. A higher percentage of patients treated with ambroxol as compared with placebo were exacerbation-free at 6 months (63% vs 59%, respectively) and at 12 months (56% vs 53%, respectively), however the difference was not statistically significant (p=ns, both values). In a subgroup analysis of patients with more severe symptoms at baseline (overall symptom score of at least 5 of a possible 12), a significantly greater number of ambroxol-treated patients were exacerbation-free at 12 months as compared with placebo (63%(15/24) vs 38%(8/21), respectively; p=0.038). Ambroxol treatment was well tolerated throughout the study and was not associated with a greater risk of adverse events than placebo [11] . Otitis media 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive Recommendation: Adult, Class III; Pediatric, Class III Strength of Evidence: Adult, Category B; Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL may be beneficial in the treatment of otitis media based on limited data 3) Adult: a) AMBROXOL produced improvement of symptoms in 413 adult and pediatric patients with SECRETORY OTITIS MEDIA in a multicenter, placebo-controlled, double-blind trial (Passali et al, 1987). Patients were randomized to receive oral AMBROXOL (30 milligrams 3 times a day in adults; 9 milligrams 4 times a day in children) or placebo for 15 days. Concurrent antibiotic therapy was allowed. At the end of the 15-day study period, the group treated with AMBROXOL showed definite improvement. In the ambroxol-treated group, patients reporting serious occlusion of the ear dropped from 22.1% to 3.2% and those reporting a "fair" degree of occlusion fell from 51.7% to 14.3%. With placebo, serious occlusion fell from 13.8% to 5%, and fair occlusion fell from 59.2% to 24.3%. The difference was statistically significant. Other parameters measured showed no significant difference between groups except audiometry and overall improvement, which were significantly improved over placebo at the end of the study. AMBROXOL was of benefit in the treatment of secretory otitis media. 4) Pediatric: a) AMBROXOL produced improvement of symptoms in 413 adult and pediatric patients with SECRETORY OTITIS MEDIA in a multicenter, placebo-controlled, double-blind trial (Passali et al, 1987). Patients were randomized to receive oral AMBROXOL (30 milligrams 3 times a day in adults; 9 milligrams 4 times a day in children) or placebo for 15 days. Concurrent antibiotic therapy was allowed. At the end of the 15-day study period, the group treated with AMBROXOL showed definite improvement. In the ambroxol-treated group, patients reporting serious occlusion of the ear dropped from 22.1% to 3.2% and those reporting a "fair" degree of occlusion fell from 51.7% to 14.3%. With placebo, serious occlusion fell from 13.8% to 5%, and fair occlusion fell from 59.2% to 24.3%. The difference was statistically significant. Other parameters measured showed no significant difference between groups except audiometry and overall improvement, which were significantly improved over placebo at the end of the study. AMBROXOL was of benefit in the treatment of secretory otitis media. Pain in throat 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence favors efficacy Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: In lozenges, relieved sore throat to greater degree than a mint lozenge 3) Adult: a) Ambroxol hydrochloride-containing lozenges were more effective for relieving the pain of sore throat than were similar lozenges that contained no active drug. In a randomized, double-blind study, 215 subjects with acute, uncomplicated sore throat of recent onset suspected of being of viral cause were given mint-flavored lozenges containing either ambroxol hydrochloride 20 milligrams or no active ingredient. Subjects were instructed to suck up to 6 lozenges per day for 2 days. Pain scores were recorded before the first lozenge and at 30 minutes, 60 minutes, 2 hours, and 3 hours after the first lozenge. Both treatments led to a reduction in pain intensity; the reduction was significantly more in the ambroxol hydrochloride group (p=0.0058). By the end of 2 days, significantly more subjects in the ambroxol group than in the placebo group scored the treatment as good or very good (p=0.0035). Nine occurrences of adverse events, including application site reactions, paraesthesias, dysphagia, dry mouth, nausea, and coughing, were considered to be related to treatment with ambroxol [17] . Pulmonary alveolar proteinosis 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category C See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL may be efficacious in the treatment of proteinosis, based on limited data. 3) Adult: a) AMBROXOL was used successfully in a 39-year-old patient with alveolar proteinosis [1] . The patient had a 3-month history of dyspnea, fever, chest pain, cough, and clubbing of the fingers. Serial alveolar lavage, the treatment of choice for this condition, was refused. The patient was subsequently started on AMBROXOL nebulizations and 30 milligrams orally every 6 hours. Dyspnea decreased rapidly and clubbing of the fingers subsided promptly. Six months later, chest x-ray, symptoms, and pulmonary function tests showed dramatic resolution of the proteinosis. AMBROXOL appeared effective in the treatment of this condition. Respiratory distress syndrome in the newborn 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Pediatric, Evidence is inconclusive Recommendation: Pediatric, Class III Strength of Evidence: Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Limited data suggest that AMBROXOL may be beneficial for HYALINE MEMBRANE DISEASE TREATMENT in premature neonates 3) Pediatric: a) In preterm neonates with respiratory distress syndrome, early AMBROXOL produced modest improvements in lung mechanics compared with placebo-treated neonates, while no differences occurred in ventilatory parameters, including tidal volume, respiratory frequency, and minute ventilation. The duration of artificial ventilation was a median of 178 hours in the ambroxol group compared with 246 hours in the placebo group (p less than 0.05). After extubation, the ratio of tidal volume to maximal esophageal pressure changes reached the tenth percentile on day 10 in the ambroxol group compared with day 23 in the control group (p less than 0.05). During the first 5 days of life, each neonate randomly received saline (n=50) or ambroxol 30 milligrams/kilogram/day (n=52) in this double-blind, multi-center trial; ambroxol (concentration 15 milligrams (mg) in 2 mL saline) was given in 4 divided doses of 7.5 mg/kg infused over 5 minutes every 6 hours [14] . b) AMBROXOL appeared to confer an advantage to neonates (birth weight 2000 g or less) with severe RESPIRATORY FAILURE due to IDIOPATHIC RESPIRATORY DISTRESS SYNDROME (IRDS) [15] . In a double-blind, placebo-controlled, multicenter study, patients requiring mechanical ventilation within the first 12 hours of life were randomized to receive either AMBROXOL 10 milligrams/kilogram twice a day for 7 days via intravenous infusion (n=13) or placebo (n=15). The mortality rate in the group receiving AMBROXOL was 39%, compared with 53% in the placebo-treated group. IRDS was the cause of death in 1 of 5 patients (20%) receiving AMBROXOL, and in 6 of 8 (75%) receiving placebo. The mean duration of mechanical ventilation was 270 hours in the treated group versus 396 hours in the placebo-treated group. AMBROXOL used as a "rescue" drug was of value in improving survival in premature infants with severe respiratory distress syndrome. Although these initial results are encouraging, more research is needed. Respiratory distress syndrome in the newborn; Prophylaxis 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Pediatric, Evidence is inconclusive Recommendation: Pediatric, Class III Strength of Evidence: Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Mixed and inconsistent results have occurred with use of AMBROXOL for HYALINE MEMBRANE DISEASE PROPHYLAXIS One study reported lack of efficacy in the prevention of hyaline membrane disease in neonates born between 24 and 34 weeks gestation An earlier study indicated AMBROXOL was beneficial in deterring hyaline membrane disease in premature infants of 33 to 36 weeks gestation, but NOT in infants of less than 33 weeks gestation 3) Pediatric: a) Antenatal AMBROXOL treatment was not effective in preventing neonatal respiratory distress syndrome (RDS) or in reducing its severity as measured by frequency of RDS, intermittent mandatory ventilation (IMV), and oxygen therapy at 12 hours of age in a randomized, placebo-controlled trial of 88 infants born between 24 to 34 weeks gestation. RDS was observed in 55% of ambroxol-treated patients versus 65% of the placebo group (p less than 0.318); mechanical ventilation for more than 12 hours was necessary in 71% of the treated versus 72% of the placebo group (p equals 0.974). Also, 74% of the treated and 75% of the placebo group were oxygen dependent for more than 12 hours (p equals 0.992), and 31% of the treated and 25% of the placebo group received natural surfactant (p equals 0.75). No statistical difference could be demonstrated between the two groups in overall RDS severity markers, such as initial and highest mean airway pressure (MAP) and oxygen index, IMV, and oxygen therapy duration [12] . b) A double-blind, placebo-controlled trial found AMBROXOL to be efficacious in some of 246 infants born to 224 mothers in premature labor (28 to 36 weeks gestation) [13] . Each woman received 1000 milligrams AMBROXOL via intravenous infusion daily for 5 days; this regimen was repeated in mothers who ceased and subsequently reentered premature labor. Of the 246 births, 116 received AMBROXOL and 130 received placebo. A total of 116 infants were born at 36 weeks gestation or less; 56 of these received AMBROXOL, and 60 received placebo. Of the infants in the AMBROXOL group, 23.2% developed hyaline membrane disease compared to 41.7% in the placebo group. The difference was statistically significant (p less than 0.05). However, there was no difference between groups among those born at 32 weeks or less. There was no difference in neonatal mortality between groups. Nausea was reported in 5 mothers receiving AMBROXOL and in 3 receiving placebo; all 8 had also received beta-adrenergic tocolytics. Although AMBROXOL was of benefit in promoting lung maturation and reducing the incidence of hyaline membrane disease, the apparent lack of benefit in premature infants of less than 33 weeks duration was not explainable. More research was recommended to assess the role of AMBROXOL in the prevention of hyaline membrane disease. Sjögren's syndrome 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Ineffective Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: Although AMBROXOL produced no measurable effect on exocrine gland function, some patients with Sjogren's syndrome reported symptom improvement after use of this agent More research is needed 3) Adult: a) Researchers studied the effects of AMBROXOL in the treatment of the exocrine gland insufficiency of Sjogren's syndrome [16] . In a double-blind, placebo-controlled, randomized cross-over trial, 36 patients with keratoconjunctivitis sicca and xerostomia received either AMBROXOL 60 milligrams or placebo orally twice a day for 3 weeks and were crossed over after a 1 week washout period. No demonstrable effect on salivary or tear secretion was observed. However, several patients reported subjective improvement with AMBROXOL, especially with symptoms of xerostomia. AMBROXOL may be of benefit in primary Sjogren's syndrome, despite the lack of objective evidence of efficacy. Surgical procedure on thorax; Prophylaxis 1) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS 2) Summary: AMBROXOL used prior to, during, and after thoracic surgery may result in favorable post-operative effects 3) Adult: a) One study suggested that perioperative AMBROXOL had positive effects related to postoperative morbidity in patients hospitalized for chest surgery [18] . In a double-blind, placebo-controlled trial, 40 patients received either AMBROXOL 1 gram or placebo via intravenous infusion 3 days prior to surgery, on the day of surgery, and for 5 days postoperatively. They found that postoperative recovery of normal pulmonary surfactant levels was faster in patients who received AMBROXOL as measured by surface tension of bronchoalveolar lavage fluid. Better oxygenation, as measured via arterial blood gases, and re-expansion of residual lung tissue demonstrated by chest x-ray were also observed in the group treated with AMBROXOL. Patients receiving AMBROXOL also had a better sputum quality with easier expectoration and reduced intensity of cough. AMBROXOL stimulated surfactant production and appeared to improve the overall clinical picture of patients in this setting. Comparative Efficacy / Evaluation With Other Therapies Acetylcysteine Cystic fibrosis a) A clinical trial compared the efficacy of oral ambroxol and Nacetylcysteine as a mucolytic in 36 pediatric patients with cystic fibrosis [38] . Patients were randomized to receive either ambroxol 30 milligrams (mg), N-acetylcysteine 200 mg, or placebo 3 times a day for 12 weeks. Thirty-two patients completed the study. All changes in pulmonary function test parameters were below the statistical detection limit (p greater than 0.05); no significant clinical differences were found between the 3 groups. Significant impairment was noted in the placebo group, but was felt to be coincidental. None of the patients' parents reported improvement and 66% of the total felt that their child had received placebo. A therapeutic effect with either drug was not demonstrated, thus more study is needed. Betamethasone Respiratory distress syndrome in the newborn a) Betamethasone and ambroxol were compared for the prevention of respiratory distress syndrome (RDS; hyaline membrane disease) of prematurity [37] . In a randomized multicenter trial, women at 27 to 34 weeks gestation with threatened or planned premature labor received either betamethasone phosphate 6 mg with betamethasone acetate intramuscularly, repeated 24 hours later, or ambroxol either 1 gram/day intravenously for 5 days or 1 gram every 12 hours for a total of 4 doses. Of 169 evaluable neonates born before the 37th week of gestation, 86 received betamethasone and 83 received ambroxol. All patients in the betamethasone group received a full course of treatment, but 14 patients in the ambroxol group received an incomplete course due to the onset of labor. The overall incidence of RDS was 31% in the betamethasone group and 13% in the ambroxol group. The difference was statistically significant. Nausea and headache were noted in approximately 10% of the mothers who received ambroxol. Ambroxol was well tolerated and was at least as effective as steroids for the in utero prevention of hyaline membrane disease. Carbocysteine Chronic obstructive pulmonary disease, Reversible a) Ambroxol and cineol were clinically equivalent and significant when compared to placebo in improving lung function in a crossover, randomized, double-blind 4-day trial with 23 evaluable patients with chronic obstructive pulmonary disease; a statistically significant increase of ciliary frequency of 8.2% (p less than 0.001) and decrease in saccharine-time by 241 seconds (p value no available)was only seen with Cineol. Forced vital capacity (FVC) rose by 5.5% following ambroxol and 5.3% after cineol treatment (p less than 0.01 compared to initial measurements) and forced expiratory volume in 1 second (FEV1) increased by 4.8% and 4.2% following ambroxol and cineol treatments, respectively (p less than 0.05 compared to initial values); peak-flow values rose by 7.2% and 9.1%, respectively but were only clinically significant for cineol (p less than 0.05); cough scores did not improve significantly with any treatment. Adverse reactions were rare with a gastrointestinal complaint reported in all three treatment groups (ambroxol, cineol, placebo) [36] . Cystic fibrosis a) Carbocysteine showed similar improvement in symptoms, respiratory functions and expectorate properties (viscosity and elasticity) as compared with ambroxol in patients with cystic fibrosis. In a randomized, single-blind trial twenty-six patients, 8 to 40-yearsold, were treated for 80 consecutive days with a S-carboxymethyl-Lcysteine (SCMC-Lys) or an ambroxol syrup. In the SCMC-Lys group, children under 14 years received 270 milligrams (mg) three times a day, whereas adults received 900 mg three times a day; in the ambroxol group, dosages were 10 mg four times a day and 33 mg three times a day, respectively. With SCMC-Lys improvement in cough and chest sounds scores was better than with ambroxol, whereas dyspnea and tachypnea did not improve with respect to baseline. Respiratory function test showed similar results in both groups. Viscosity and elasticity of the expectorate decreased and amount increased during both treatments, without any significant difference between the groups. Carbocysteine lysine salt (SCMCLys) showed the same effect as ambroxol in the respiratory impairment associated with cystic fibrosis [35] . Erdosteine Bronchitis, chronic a) In a double-blind trial of 29 patients with exacerbated chronic bronchitis receiving treatment for 7 days, erdosteine 300 milligrams (mg) twice daily reduced sputum adhesiveness from baseline by 89%, versus 60% reduction with ambroxol 30 mg twice daily. Both regimens produced significant, comparable reductions in severity of cough and sputum purulence, compared to baseline [39] . REFERENCES 1. Diaz JP, Manresa Presas F, Benasco C, et al: Response to surfactant activator (Ambroxol) in alveolar proteinosis (letter). Lancet 1984; 1:1023. 2. Luisetti M, Peona V, Salmona M, et al: Ambroxol and pulmonary toxicity induced by antineoplastic drugs. 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