Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Safety of ambroxol in the treatment of airway

diseases in adult patients

Dorothea Cazan, Ludger Klimek, Annette Sperl, Manuel Plomer, Thomas

Pohlmann & Stephan Kölsch

To cite this article: Dorothea Cazan, Ludger Klimek, Annette Sperl, Manuel Plomer, Thomas
Pohlmann & Stephan Kölsch (2018): Safety of ambroxol in the treatment of airway diseases in adult
patients, Expert Opinion on Drug Safety, DOI: 10.1080/14740338.2018.1533954

To link to this article: https://doi.org/10.1080/14740338.2018.1533954

Accepted author version posted online: 29

Oct 2018.

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Publisher: Taylor & Francis
Journal: Expert Opinion on Drug Safety
DOI: 10.1080/14740338.2018.1533954
Article type: review

Safety of ambroxol in the treatment of airway diseases in adult patients

Dorothea Cazan1, Ludger Klimek2, Annette Sperl2, Manuel Plomer3, Thomas Pohlmann3, Stephan Kölsch3

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1
Department of Otorhinolaryngology, Head and Neck Surgery, Sleep Disorders Center, University

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Hospital Mannheim, Mannheim, Germany
2
Wiesbaden Center for Rhinology and Allergology, Wiesbaden, Germany
3
Sanofi Aventis Deutschland GmbH, Frankfurt am Main, Germany

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Corresponding author
Manuel Plomer

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CHC Global Medical Affairs, Sanofi-Aventis Deutschland GmbH, Industriepark Höchst, D-65926 Frankfurt
am Main, Germany
Email: manuel.plomer@sanofi.com
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Abstract

Introduction: Ambroxol is a widely used secretolytic and mucoactive over-the-counter agent primarily
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used to treat respiratory diseases associated with viscid mucus. Following post-marketing reports of
hypersensitivity reactions and severe cutaneous adverse reactions (SCARs) possibly linked to ambroxol,
the European Union’s Pharmacovigilance Risk Assessment Committee (PRAC) initiated in April 2014 a
review of the safety of ambroxol in all its registered indications, which was finalized in 2016.
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Areas covered: Here, we evaluate the clinical safety of ambroxol and provide an expert opinion on the
benefit-risk balance of ambroxol in the treatment of adult patients with bronchopulmonary diseases.
The evidence for this review is derived from clinical trials of ambroxol that were provided to the PRAC by
the marketing authorization holders of ambroxol-containing medicines.
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Expert opinion: Clinical experience accumulated from randomized clinical trials and observational
studies suggests that ambroxol is a safe and well-tolerated treatment of bronchopulmonary diseases,
with a well-balanced and favorable benefit-risk profile. All reported adverse events were mild and self-
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limiting, and the risk of SCARs with ambroxol is low. Further investigations could address the safety and
efficacy of ambroxol in pediatric lung diseases and in additional therapeutic indications, such as biofilm-
dependent airway disease and lysosomal storage disorders.
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Keywords: acute bronchitis, adult patients, ambroxol, benefit-risk, chronic lung diseases, drug safety,
expectorant, mucolytic

Abbreviations
COPD Chronic Obstructive Pulmonary Disease
FEV1 Forced Expiratory Volume in 1 Second
GCP Good Clinical Practice
OECD Organization for Economic Co-operation and Development
PRAC Pharmacovigilance Risk Assessment Committee
SCAR Severe Cutaneous Adverse Reaction

1
SP Surfactant-Specific Protein
WHO World Health Organization

Article highlights

• The paper evaluates the safety of ambroxol in adult populations with acute or chronic
bronchopulmonary diseases, with its mechanism of action and clinical application
• The main pharmacological effect of ambroxol is exerted through stimulation of surfactant

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production, associated with effective mucokinetic and secretolytic activities. In addition,

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ambroxol possesses anti-oxidant, anti-inflammatory, anti-infective, and local anesthetic
properties
• Ambroxol was found to improve respiratory symptoms, such as difficulty of expectoration and

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cough in both acute and chronic respiratory diseases. Long-term treatment with ambroxol was
also able to prevent exacerbations in patients with chronic bronchitis and COPD
• Cumulative evidence from randomized clinical trials and observational studies demonstrated

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that ambroxol is a safe and well-tolerated treatment of bronchopulmonary diseases, with
neither serious adverse events nor SCARs reported
• The European Medicines Agency considered that there is a reasonable possibility of a risk of
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SCARs associated with ambroxol. However, the evidence of risk of SCARs associated with
ambroxol was considered weak for several reasons. The possible risk of SCARs was, however,
addressed by its inclusion in the product information accompanied by a warning for patients and
caregivers to recognize the prodromes of SCARs
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• Overall, the benefit-risk balance of ambroxol in adults suffering from airway diseases is
favorable. Although ambroxol is considered as an “old molecule”, ambroxol is still being
investigated in both preclinical and clinical trials by research groups worldwide
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1. Introduction
According to the WHO’s Anatomical Therapeutic Chemical classification system, ambroxol (2-
amino-3,5-dibromo-N-[trans-4-hydroxycyclohexyl]benzylamine) is considered as a mucolytic agent, and
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has been widely used for the treatment of acute and chronic respiratory tract disorders since the late
1970s [1,2]. Ambroxol, a substituted benzylamine, is the active N-desmethyl metabolite of bromhexine,
another widely used mucolytic drug of the same class that is a semi-synthetic derivative of the alkaloid
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vasicine [2,3]. The deletion of a methyl group and the introduction of a hydroxyl group in a para-trans
position of the cyclohexyl ring have enriched ambroxol to acquire several pharmacological properties,
namely, surfactant stimulatory, anti-inflammatory, anti-oxidant, and local anesthetic effects in addition
to the mucokinetic and mucociliary effects of its parent compound [4]. Due to its local anesthetic
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properties, ambroxol, administered as lozenges or oral sprays, is also indicated for the symptomatic
treatment of pharyngitis or acute sore throat in viral airway infections [2,5-7].
In addition to lozenges and oral sprays, there are various pharmaceutical formulations of
ambroxol developed since its first marketing authorization in 1978 [2]. Ambroxol is available as
intravenous solutions, suppositories, syrup, granules, tablets, capsules, slow-release oral formulations,
and nebulized solutions [8]. For the treatment of adults with airway diseases associated with altered
mucus rheology (viscid mucus), it is recommended to orally administer ambroxol at a daily dosage of 60
up to 120 mg given in two or three divided doses (for immediate-release ambroxol capsules) or 75 mg
once daily (for extended-release capsules) [9].

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 Though ambroxol is considered well-tolerated, the European Union’s Pharmacovigilance Risk
Assessment Committee (PRAC) has completed a review of the safety of ambroxol- and bromhexine-
containing medicines that was published in September 2015. The review of ambroxol and bromhexine
was initiated in April 2014, triggered by the Belgian health authorities, following post-marketing reports
of hypersensitivity reactions including anaphylactic reactions and severe cutaneous adverse reactions
(SCARs) [2]. As outcome of this referral, the PRAC concluded in January 2016 that the risk of
anaphylactic reactions is in line with the previous knowledge of the safety profile of ambroxol, and that
the risk of SCARs related to ambroxol is low. However, the PRAC was of the view to update the product
information for ambroxol-containing medicines with information about this small risk of allergic

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reactions and SCARs. This was applicable for ambroxol’s originator product (Mucosolvan®) and its

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generic equivalents [10]. No further changes concerning indications, age groups or dosage were
considered necessary, and it was concluded that the benefit-risk assessment of ambroxol is still
favorable.

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Evidence for this review was derived from clinical trials and post-marketing data of ambroxol in
adult patients with acute or chronic respiratory tract disorders that were provided to the PRAC by the
marketing authorization holders of ambroxol-containing medicines. In this article, we evaluate the

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safety of ambroxol in adult populations with airway diseases, with its mechanism of action and clinical
application, and provide an expert opinion on the benefit-risk balance and the role of ambroxol in the
treatment of these patients within the context of the current clinical landscape.
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2. Review of ambroxol
2.1 Mechanisms of action
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The mechanisms of action of ambroxol are complex and remain incompletely explored.
Nevertheless, the main pharmacological effect of ambroxol is exerted through stimulation of surfactant
production, associated with effective mucokinetic and secretolytic (mucolytic) activities [11]. Ambroxol
is a secretolytic agent that decreases mucus viscosity through depolymerisation of acidic polysaccharide
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fibers in the bronchial secretion and stimulation of neutral polysaccharide production by glandular cells
[2]. Ambroxol also stimulates the synthesis and release of endogenous surfactant by type II
pneumocytes [2,12]. The surfactant-stimulating mechanism of ambroxol is also not exactly known and
appears to be quite complex [8,13]. Analyzing the lungs of 14 rats treated with ambroxol,
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heterogeneous modifications in the concentrations of the four surfactant-specific proteins (SP) were
detected in different specific cellular sites. Ambroxol treatment resulted in a marked increase of SP-B
and in a decrease of SP-D in whole lung tissue with enhanced immunostaining for SP-B in Club cells,
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whereas SP-A and SP-D were considerably decreased in the bronchoalveolar lavage fluid of the
ambroxol-treated animals. Hence, these data suggest that ambroxol may exert its positive effects in the
treatment of diseases related to surfactant deficiency via a cell-specific modulation of surfactant protein
expression [13]. By providing adequate rheological properties to the airway secretion, the surfactant
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reduces epithelial lining fluid adherence to the airway epithelial cells and facilitates an effective mucus
clearance [14]. Finally, ambroxol is also a mucokinetic agent that may improve the rheological properties
of the airway secretion and increase mucociliary clearance, by acting directly on ciliated epithelial cells
and by increasing ciliary beat frequency, as shown on isolated ciliated cells from trachea of guinea pigs
[15]. Figure 1 illustrates the main mechanisms of action of ambroxol.
Beyond its mucokinetic and secretolytic effects, ambroxol also appears to possess antioxidant
(due to direct scavenging and protection of cellular structures from reactive oxygen species), anti-
inflammatory (through inhibition of the generation of pro-inflammatory mediators by leukocytes), and
local anesthetic properties (through inhibition of the neuronal sodium channels), according to several in
vitro and experimental animal studies [2,8,16-19]. In addition, a protective effect of ambroxol against

3
viral and bacterial airway infections has been postulated, related respectively to its ability to increase
the concentrations of factors (such as SP-A and immunoglobulins A and G) able to suppress virus
multiplication and to affect the bacterial biofilm structure [20,21].

2.2 Pharmacokinetics
Following oral administration, ambroxol is rapidly and almost completely absorbed, with a
bioavailability of 79% and plasma protein binding of 90% [4]. Maximum plasma levels are reached within
1 to 2.5 hours following oral administration of the immediate-release formulation and after a median of
5.4 to 6.5 hours for the extended-release formulation, as shown in Figure 2 which illustrates the mean

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steady state plasma levels of ambroxol after oral administration for 5 days of the immediate-release and

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the extended-release formulations in 12 healthy volunteers [22-25].
Distribution of ambroxol from blood to tissue is rapid and pronounced, with the highest
concentration found in the lungs; accumulation of ambroxol in human lung tissue was detected at

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concentrations 15- to 20-fold higher than those found in the circulation [11,23].
Ambroxol is metabolized in the liver, and its elimination is through a two-phase oxidative
biotransformation to dibromoanthranilic acid and glucuronides through cytochrome P450 3A4 [26]. The

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terminal elimination half-life of ambroxol is approximately 10 hours with a total clearance of 660
mL/min [4]. A recent study investigating the pharmacokinetics of 30 mg ambroxol hydrochloride tablets
in nine Chinese healthy volunteers after oral administration of single or multiple dosages revealed no
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obvious accumulation of ambroxol in the body after repeated dosing. Figure 3 shows the mean plasma
concentration-time curves of ambroxol after single-dose and multidose administration [24].
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3. Clinical efficacy
Most clinical studies investigating the efficacy and/or safety of ambroxol in the treatment of
adult patients with bronchopulmonary diseases arise from the 1970s to 1980s, and are mostly related to
the long-term use of ambroxol in chronic bronchitis to prevent or ease exacerbations [27]. According to
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the PRAC, these clinical studies that were performed during the development of ambroxol-containing
products are less standardized than would be necessary today, in terms of validated endpoints,
statistical confirmation, and Good Clinical Practice (GCP) [2].
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3.1 Effect in acute bronchitis

One randomized controlled clinical trial investigating the efficacy and tolerability of ambroxol in
adult patients with acute bronchitis has been published [28]. In this large, four-parallel arm (with around
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170 patients in each arm), double-blind, quadruple-dummy, randomized trial in which ambroxol was
administered at a dose of 30 mg three times a day for days 1 to 3 followed by 30 mg twice a day for days
4 to 14 of the study in 163 patients. All three active treatments (a phytotherapeutic extract [Myrtol®
standardized], cefuroxime, and ambroxol) were similarly effective and significantly better than placebo
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(the responder rate after two weeks of treatment was around 63% for placebo versus more than 80% in
the three active treated groups). The superiority of ambroxol and the other active treatments compared
to placebo, with little difference among the active treatments, was confirmed for all further criteria of
evaluation (such as signs, symptoms, absence of relapse, and overall efficacy), resulting in a faster and
more complete resolution of acute bronchitis [28]. Table 1 provides further details on the characteristics
and the results of the Matthys et al. (2000) trial. Two pharmacy-based observational cohort studies
further confirmed the real-world effectiveness of ambroxol in treating acute cough and respiratory
symptoms associated with chronic bronchitis [29,30] (Table 2).
3.2 Effect in chronic bronchopulmonary diseases

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 The effect of ambroxol in adult patients with chronic bronchitis or chronic obstructive pulmonary
disease (COPD) is supported by the results of six randomized, placebo-controlled trials that were
published between the years 1986 and 2004 [1,31-36]. In these studies, 919 patients were included and
were treated for a duration ranging from two weeks to two years. In the active treatment groups, 325
patients received extended-release ambroxol capsules administered at a daily dose of either 75 mg (in
the Olivieri et al. study and the Cegla study) [31,32] or 150 mg (in the Malerba et al. study) [33], whereas
110 patients received immediate-release oral forms of ambroxol at a dose of 60 mg given once or twice
daily [1,34,35]. For the 35 patients in the ambroxol-treated group of the Michnar and Milanowski trial
[36], dosing details were not provided. These 470 patients were matched to 441 patients receiving

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placebo. The characteristics and the results of these six randomized, placebo-controlled studies are

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described in Table 1.
Various efficacy endpoints were used across these six trials, including the number of working
days lost, proportion of exacerbation-free patients, number of days on antibiotic treatment, and

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improvement in respiratory symptoms, such as coughing, difficulty in expectoration, and sputum
production. Although the Malerba et al. (2004) trial [33] did not find a statistically significant difference
(p=0.36) between long-term (one year) ambroxol therapy and placebo in preventing exacerbation

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episodes in patients with COPD, ambroxol therapy was associated with a higher percentage of patients
free from exacerbations compared to placebo in the overall study population (56% versus 53%) and with
a significantly higher percentage of exacerbations-free patients in patients with more severe baseline
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symptoms (63% versus 38%; p<0.05). These results are in accordance with the Olivieri et al. (1987) trial
[31] and the Michnar and Milanowski (1996) trial [36] which reported significantly lower exacerbation
rates in ambroxol-treated patients compared to the placebo groups (p<0.01). Moreover, two studies
have consistently found a significant reduction in the number of working days lost and in the number of
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days on antibiotic treatment with ambroxol therapy compared to placebo (p<0.01) [31,32]. Consistent
results in improving respiratory symptoms (such as difficulty of expectoration, cough, dyspnea and
auscultatory signs) were also shown across all six studies [1,31-36].
These beneficial effects of ambroxol in patients with chronic bronchopulmonary diseases are in
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line with the findings of a systematic review and meta-analysis of 34 randomized controlled trials aimed
to compare the efficacy and safety of mucolytics to placebo in patients with chronic bronchitis and
COPD [37]. The tendency for participants given mucolytics to have fewer exacerbations or to be more
likely to be exacerbation-free was seen in all the studies included in this review, with the exception of a
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long-term, head-to-head trial of fluticasone and N-acetylcysteine in 286 primary care patients with
COPD or chronic bronchitis [38]. This was the first study that found an increased number of
exacerbations in the mucolytic-treated group compared with the placebo-treated group; however, this
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difference was not statistically significant (p>0.05). Moreover, the exacerbation rate was generally low
in this study, and data were skewed by two participants in the N-acetylcysteine-treated group who had
very frequent exacerbations. Additionally, this study reported a high dropout rate [38].
The PRAC concluded in its 2015 revised assessment report investigating the safety and efficacy of
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ambroxol-containing products that despite the methodological issues identified in these studies
(reported in Table 1), these six randomized, placebo-controlled trials constituted evidence of the
efficacy of ambroxol in the treatment of adults with chronic bronchopulmonary diseases. Furthermore,
the PRAC noted that due to the known difficulties of conducting clinical trials in this area, conflicting
results can be expected and the absence of statistical significance alone, which was the case in the
Guyatt et al. trial and in the Malerba et al. trial [1,33], does not lead to the conclusion that the product is
ineffective [2].
The efficacy of ambroxol in patients with chronic respiratory diseases is further supported by the
results of a large, observational study in which 5,635 patients were treated with 75 mg/day of extended-
release ambroxol for 6 months (Table 2). The results achieved in a large and heterogeneous population

5
confirm the positive effects of ambroxol in patients with chronic bronchitis. Particularly noteworthy is
the decrease in the incidence of exacerbations with time, above all in patients with more than two or
three daily episodes [39]. Similarly, in a randomized, double-blind trial in which 23 patients with
exacerbations of chronic bronchitis were treated for 10 days with either amoxicillin 1,500 mg/day (n=13)
or amoxicillin 1,500 mg/day combined with ambroxol 90 mg/day (n=10), improvement in cough, as well
as expectoration difficulties and sputum purulence were statistically more evident and occurred earlier
in the ambroxol + amoxicillin group than in the amoxicillin only group (p<0.005) [40].

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4. Safety evaluation

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Ambroxol has been available on the market since 1978, and is currently used in more than 50
countries worldwide [2,23]. According to a 2008 update report, the safety of ambroxol is well-
established, since it is based on its use in more than 15,000 patients in more than 100 studies, with a

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total patient exposure estimated at 4,789,563 patient-years [41]. According to the PRAC 2015 report,
the worldwide patient exposure is even higher, estimated to be 31,881,769 patient-years for ambroxol-
containing products indicated in secretolytic therapy, but also in the treatment of infant respiratory

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distress syndrome and in the prophylaxis of postoperative complications. When looking only at the last
decade (2004-2013) in the European Union, the exposure was estimated to be 4,356,482 patient-years
for ambroxol-containing products indicated in secretolytic therapy, infant respiratory distress syndrome,
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and in prophylaxis of postoperative complications [2].

4.1 Safety in randomized, placebo-controlled trials

According to the seven randomized, placebo-controlled trials presented in this review (Table 1),
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ambroxol was well-tolerated during short-term and long-term treatments (up to two years), showing no
differences with respect to adverse events compared to the placebo groups. This finding falls in line with
the results of the 2015 meta-analysis of 34 randomized, placebo-controlled clinical trials that compared
oral mucolytic therapy versus placebo administered regularly for at least two months in adults with
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chronic bronchitis or COPD. In a total of 21 studies lasting from 2 to 36 months, 608 adverse events
were reported in 3,170 subjects treated with mucolytics versus 669 adverse events in 3,176 placebo-
treated subjects, with all adverse events being mild and self-limiting (odds ratio, 0.88; 95% confidence
interval, 0.78 to 1.00). Hence, this large systematic review of randomized, controlled trials indicates that
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there is probably no difference between mucolytic and placebo treatments in terms of the total
numbers of adverse effects that they cause [37].
The frequency of adverse events associated with ambroxol therapy was very low in the seven
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placebo-controlled trials. The adverse reactions that were reported in the ambroxol-treated groups
included insomnia, skin rashes, nausea, vomiting, abdominal pain, dry mouth, diarrhea, pyrosis, chest
tightness, headache, dysgeusia, and dyspepsia. All adverse events reported in these trials were mild and
self-limiting. According to the PRAC, in these trials, nausea was reported with the frequency “common”,
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while dyspepsia, vomiting, diarrhea and abdominal pain were reported with the frequency
“uncommon”, and rash with the frequency “rare”. Dry mouth and dysgeusia were classified as being
unrelated to ambroxol [2]. Table 3 illustrates the frequency of the adverse events associated with
ambroxol therapy based on a pooled analysis of these seven randomized clinical trials.
No correlation could be detected between incidence and nature of adverse events and the dose
of ambroxol, as was shown in a 1993 placebo-controlled, double-blind, pharmacokinetic clinical study
that administered ambroxol in doses up to 500 mg twice daily. In this study, no severe adverse events
were reported and no drug-induced changes in the clinical laboratory values were observed with 1 g/day
of ambroxol [42].

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 In the multicenter, randomized, placebo- and actively-controlled, double-blind, parallel-group
study in patients with acute bronchitis conducted by Matthys and colleagues, all four administered
treatments scored comparably well upon evaluation of tolerability by patients and physicians.
Tolerability after one week of therapy was assessed as “good” or “very good” by 85%, 84% and 87%, and
86% of patients in the intention-to-treat population, and by 88%, 90%, 90%, and 86% of the physicians
with Myrtol® standardized, cefuroxime, ambroxol, and placebo, respectively [28].
4.2 Safety/tolerability in observational studies and surveys
Ambroxol has been investigated in several observational, and post-marketing studies which
provide a good overview of its effectiveness and tolerability under “real-life” conditions. Schulz et al.

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(2006) evaluated, in a pharmacy-based observational cohort study, the safety and usage pattern of an

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over-the-counter ambroxol cough syrup in 2,664 consumers with cough and throat symptoms
associated with acute bronchitis (Table 2). Within the 67/2,664 (2.5%) patients who experienced a side
effect, the most frequently reported adverse events were gastrointestinal disorders (n=53) which

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included abdominal pain, diarrhea, nausea, vomiting, and dry mouth. No serious adverse events or
hypersensitivity reactions were recorded in this study, and only adverse events already listed in the
Summary of Product Characteristics were reported. Hence, this study confirmed that ambroxol is used

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according to the patients' leaflet and supports the already established safety of this product [29].
Similarly, 82.7% of all adverse events reported in the Alcozer et al. trial which included 5,635 patients
with chronic bronchitis treated with a 75 mg daily dose of ambroxol extended-release for a 6-month
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period were mild to moderate, and the most commonly reported adverse events (occurring in more
than 1% of patients) included pyrosis, epigastric heaviness, nausea, pruritus, diarrhea, and vomiting [39].
Between September 1990 and January 1992, a total of 1,800 general practitioners enrolled 9,573
patients for safety and effectiveness data collection on the usage of ambroxol administered at a daily
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dosage of 120 mg under real-life conditions. In this large, open-label, uncontrolled post-marketing
surveillance study, the most frequent diagnoses were acute bronchitis (55%), chronic bronchitis (20%),
spastic forms (10%), and asthma (5%). Compared to baseline, patients’ conditions considerably
improved after 7 and 14 days of treatment. The participating physicians rated the tolerability of
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ambroxol after two weeks of treatment as “very good” or “good” in 73% and 22% of patients,
respectively. Only 25 adverse events were reported in this large, observational study: allergic symptoms
(n=9), gastrointestinal symptoms (n=14), and vertigo (n=2). No severe or unknown adverse events were
reported [43].
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The fact that ambroxol is well-tolerated was most recently highlighted through patient-reported
outcomes in a German community pharmacy-based, survey-based, exploratory study in which 97.6% of
all 941 patients with acute respiratory symptoms rated global tolerability of ambroxol as “very good” or
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“good” [30].

4.3 Severe cutaneous adverse drug reactions (SCARs) and hypersensitivity reports
One of the triggers for the review of ambroxol-containing medicines by the PRAC was the
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identification of SCARs reports, possibly linked to ambroxol. As of February 2014, the Belgian national
competent authority identified 210 case reports of SCARs in the EudraVigilance medicines safety
database (for all ambroxol-containing medicines), including at least nine with a causal relationship to
ambroxol assessed as likely to definite. In light of this, the PRAC review of ambroxol, including the
evaluation of the reports of severe allergic reactions or SCARs, was initiated in April 2014 [2,10].
SCARs include erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and
acute generalized exanthematous pustulosis. The safety information submitted by the marketing
authorization holders, from the Eudravigilance database and from the literature, comprised in total
around 300 case reports of suspected SCARs, many of which have possible confounders. Only four cases
of SCARs retrieved from Eudravigilance and three others from the literature have been assessed as

7
related to ambroxol by the PRAC [2]. The three cases retrieved from the literature included one case of
maculopapular erythematous eruption with mucosal involvement, one case of facial vesicular erythema,
and one generalized maculopapulous rash [44-46]. Among the four cases found through the
Eudravigilance analysis, two cases were reported in adult patients (one case of Stevens-Johnson
syndrome and one case of drug eruption) and two in pediatric patients (one case of acute generalized
exanthematous pustulosis and one case of erythema multiforme) [2].
With regards to hypersensitivity reports, around 850 case reports of serious hypersensitivity
reactions (excluding SCARs cases) with ambroxol reported as suspected or interacting medicinal product
were identified. The causal relationship to ambroxol was assessed as certain in three cases retrieved

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from the database of the marketing authorization holders of the ambroxol-containing products, in which

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the reported events were angioedema, laryngeal edema, suffocation sensation in one case (age not
provided), photosensitivity reaction and eosinophilia in the second (82 year old), and dermatitis contact,
rash maculopapular and pruritus in the third (79 year old). In Eudravigilance, four cases for which the

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causality was assessed as certain were identified. These corresponded to two cases of rash (one in an
adult and one in a child below six years of age), one case of hypersensitivity and one case of delayed
onset hypersensitivity without severe skin reactions, both in adults [2].

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Finally, with regards to the concerns around an increased reporting of anaphylactic reactions, the
PRAC retrieved from the database of the marketing authorization holders 119 cases for ambroxol-
containing products indicated in secretolytic therapy, infant respiratory distress syndrome and in the
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prophylaxis of postoperative complications, of which nearly half originated from China. However, the
PRAC deemed that the observed increase in reporting of anaphylactic reactions for ambroxol-containing
products was likely an artefact resulting from the implementation of a new pharmacovigilance
regulation in China and did not constitute a new safety concern [2].
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The PRAC considered that the evidence of risk of SCARs associated with ambroxol is weak for
several possible reasons. Firstly, many patients who take mucolytic or secretolytic drugs often receive a
number of drugs concomitantly making causality assessment difficult. Secondly, as SCARs sometimes
start with flu-like symptoms, some patients might start taking ambroxol to alleviate their symptoms.
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However, the typical skin reactions appear later, and ambroxol might be falsely considered as a suspect
drug. Finally, many drug reactions cannot be distinguished from naturally occurring or infection-induced
eruptions, and consequently misdiagnosis is common. Thus, the presence of several possible
confounders and the overall low reporting rate of SCARs lead to question the presence of a causal
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relationship between SCARs and ambroxol. The PRAC was of the view that the possible risk of SCARs can
be adequately addressed by adding delayed-type hypersensitivity reactions associated with SCARs as a
side effect in the product information of ambroxol-containing medicines, with the frequency
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“unknown”. In addition, a warning was introduced in the product information of ambroxol-containing

medicines in order for caregivers and patients to be aware of the first symptoms of SCARs and to be
advised to discontinue treatment immediately and seek medical advice should they occur [2,10].
Concerning hypersensitivity reactions, the PRAC found that ambroxol formulations were
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associated with case reports of immediate and delayed-onset hypersensitivity reactions without severe
skin injury. Hence, the PRAC confirmed the already known risk of allergic reactions, which remains small.
Indeed, these adverse reactions were already listed in the product information of most ambroxol-
containing products before the initiation of this safety review. Thus, no new safety concerns were
identified by the PRAC with regard to the risk of allergic reactions [2,10]. Moreover, the PRAC assessed
the risk of anaphylactic reactions with ambroxol as low [10].
Taking into account the weak evidence of a safety issue from the pharmacovigilance data, the
PRAC could not conclude from the available evidence that risks outweighed benefits in the different
indications [2].

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 4.4 Preclinical safety
Toxicity studies with ambroxol have been conducted in a wide range of animals according to
OECD test guidelines, and the acute oral, intravenous, subcutaneous and intraperitoneal toxicity of
ambroxol in mice, rats, rabbits, guinea pigs and dogs was found to be low [41,47-49]. Overdose toxicity
signs across species included dyspnea, ataxia and convulsions, but subacute and chronic toxicity were
distinctly uncommon and reversible in nature [4]. In repeat-dose studies, oral doses of 150 mg/kg/day
(in mice), 50 mg/kg/day (in rats), 40 mg/kg/day (in rabbits), and 10 mg/kg/day (in dogs) were the no-
observed adverse effect level [50].
Ambroxol was neither embryotoxic nor teratogenic at oral doses up to 3,000 mg/kg in rats and

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200 mg/kg in rabbits [48]. Furthermore, the fertility of male and female rats was not affected up to 500

ip
mg/kg/day of ambroxol [50]. Genotoxicity studies in vitro and in vivo did not reveal any mutagenic
potential of ambroxol. Moreover, ambroxol did not show any tumorigenic potential in carcinogenicity
studies in mice (50, 200 and 800 mg/kg/day) and rats (65, 250 and 1000 mg/kg/day) when treated with

cr
a dietary admixture for 105 and 116 weeks, respectively [50].
Hence, these data suggest that ambroxol has a well-established favorable safety profile in animal
models as well as humans.

us
5. Conclusion
an
Ambroxol is a mucoactive agent with stimulating effects on the mucociliary clearance and on the
production of endogenous surfactant. The efficacy of ambroxol in both acute and chronic
bronchopulmonary diseases has been well-documented in a wide variety of controlled and uncontrolled
studies. Several of these studies were conducted before the implementation of the GCP principles.
M
However, these studies consistently showed a beneficial effect of ambroxol in terms of improvement of
respiratory symptoms, such as cough and expectorations and prevention of acute exacerbations. The
safety and tolerability of ambroxol in adult patients with acute or chronic lung diseases was also well-
demonstrated in multiple clinical trials, with the most common adverse reactions being gastrointestinal
ed

disturbances associated with extremely low rates of study drug discontinuation. Furthermore, most
reported adverse events were mild and self-limiting. The 2015 PRAC review of ambroxol-containing
medicines revealed that the risk of anaphylactic reactions and SCARs with ambroxol is low, and
frequencies of these side effects are unknown.
pt

Overall, this comprehensive review indicates that the benefit-risk balance of ambroxol in adults
suffering from airway diseases is favorable.
ce

6. Expert opinion
Ambroxol is a mucoactive over-the-counter agent widely used to treat a range of respiratory
diseases, mainly acute and chronic respiratory tract disorders associated with viscid mucus. Clinical
Ac

experience accumulated from randomized clinical trials and observational studies suggests that
ambroxol is a safe and well-tolerated treatment of bronchopulmonary diseases, with a well-balanced
and favorable benefit-risk profile. All adverse events reported in the studies included in this article were
mild and appeared to resolve quickly.
The findings of this review are consistent with those of the 2015 revised assessment report of
ambroxol- and bromhexine-containing medicines by the PRAC which shows that the benefit of ambroxol
is well-documented and outweighs its potential risks in its different registered indications [2]. However,
two aspects should be considered: 1) the results of the studies of ambroxol in adult patients with
chronic or acute lung diseases due to the performance of several of these trials in an era where
methodological approaches and GCP were not developed yet; 2) clinical studies of mucolytic agents are

9
rather challenging, particularly in acute respiratory diseases such as acute bronchitis, due to poorly
defined endpoints and a lack of scientific consensus as to the most appropriate clinical trial
methodologies. According to a 2007 review by Rubin evaluating the challenges of designing a clinical
trial to test the effectiveness of potentially mucoactive therapy, there seems to be no consensus on the
endpoints to be used in clinical trials examining the efficacy of mucolytic agents. Some endpoints (such
as lung volume and flow) correlate poorly with other measures of efficacy, while other endpoints (such
as spirometry) are insensitive to the acute or long-term effects of mucoactive therapy. Endpoints, such
as sputum volume are highly variable and usually inaccurate because of patients’ reticence to
expectorate, inadvertent swallowing of secretions, salivary contamination of expectorated secretions,

t
and variability in cough and thus the airflow-dependent mobilization of sputum [51]. Furthermore,

ip
according to Morice and Kardos (2016), it is recommended to consider the various methodologies for
assessing cough as three overlapping circles of the Venn diagram (cough recording, cough challenge, and
Leicester cough questionnaire) [27].

cr
Nevertheless, from a broad clinical perspective, the extensive dataset available for ambroxol
punctuated by the 2015 PRAC review supports its well-established safety and efficacy in the treatment
of adult patients with chronic and acute respiratory conditions.

us
The choice of safety and efficacy measures in a clinical trial is largely driven by the mechanism of
action of the intervention and how that would affect disease process. However, there remains gaps in
the understanding of the exact mechanisms of action of ambroxol at cellular and molecular levels. Thus,
an
an improved understanding of the various mechanisms of action of ambroxol would be of great benefit
to the conduct of future large-scale and high-quality randomized controlled trials. In addition to its
mucokinetic and secretolytic effects, ambroxol possesses multiple other pharmacological properties
(antioxidant, anti-inflammatory, anti-bacterial, anti-viral, and local anesthetic properties). Hence, based
M
on ambroxol’s multifaceted profile, further studies could be conducted to address the safety and
efficacy of ambroxol in additional therapeutic indications, such as biofilm-dependent airway diseases.
Indeed, although ambroxol is considered as an “old molecule”, ambroxol is still being investigated in
both preclinical and clinical trials by research groups worldwide. A new potential treatment area for
ed

ambroxol, as suggested by the rising number of publications in this field, is the treatment of lysosomal
storage disorders, such as Gaucher disease [52-55]. Although extensive literature on the safety and
efficacy of ambroxol in the treatment of airway diseases in adults exists, cumulative data could increase
the understanding of the clinical impact and safety of ambroxol in pediatric lung diseases. Finally, given
pt

the unknown risk of SCARs associated with ambroxol administration, SCARs cases should be
continuously monitored and analyzed in detail in future reports.
ce

Funding
This work was funded by Sanofi-Aventis.

Declaration of interest
Ac

SK, MP, and TP are all employees of Sanofi Aventis. LK has received research grants from ALK-Abelló,
Denmark; Allergopharma, Germany; Bionorica, Germany; Biomay, Austria; Boehringer Ingelheim,
Germany, Circassia, USA; Stallergenes, France; Sanofi Aventis, Germany; HAL Allergy, The Netherlands;
Allergy Therapeutics/Bencard, Great Britain/Germany; Hartington, Spain; Lofarma, Italy; MEDA, Sweden;
MSD, USA; Novartis, Switzerland; Leti, Spain; ROXALL Medizin GmbH, Germany; GlaxoSmithKline (GSK),
Great Britain; Cytos, Switzerland; Curalogic, Denmark; and/or has served as a consultant or on the
speaker’s bureau for the above mentioned pharmaceutical companies. The authors have no other
relevant affiliations or financial involvement with any organization or entity with a financial interest in or
financial conflict with the subject matter or materials discussed in the manuscript apart from those
disclosed

10
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments
The authors would like to thank Thomas Rohban, MD and Magalie El Hajj, BPharm (Partner 4 Health,
France) for providing medical writing support in accordance with Good Publication Practice (GPP3)

t
guidelines.

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47. Püschmann S, Engelhorn R. [Pharmacological study on the bromhexine metabolite ambroxol
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Figure 1. K
Known Mecchanisms off Action of Ambroxol
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F
Figure 2. M
Mean Steadyy State Plaasma Levelss of Ambrooxol in 12 V
Volunteerss after Orall
A
Administrattion of Imm
mediate-Rellease and S
Sustained-R
Release Formmulations ffor 5 days
M
B
Bid, twice dailly; Conc, conncentration; IR
R, immediate--release; od, oonce daily; SR
R, sustained-rrelease. Source:
T
Thomae et al. (1990)
( [25].
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16
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Figure 33. Mean Drrug Plasmaa Concentraation-Timee Curves of Ambroxol in
ne Volunteeers after Orral Administration of Ambroxol Tablets
Nin
C, concentrattion; t, time. S
Source: Yang eet al. (2015) [224].
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17
Table 1. Characteristics and Results of Published Randomized, Placebo-Controlled Trials of Ambroxol in Acute and Chronic Lung Diseases
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm

t
Matthys et al., Multicenter, four- - Phytotherapeutic Responder rate The responder rate A total of 131 Statistical significance

rip
2000 [28] parallel arm, double- extract (Myrtol® (non-responders after 2 weeks was adverse events in was not always
(Germany) blind, randomized, standardized): 1,200 were patients 63.4% in the placebo, 104/676 subjects provided in the
placebo-controlled mg/day for 14 days whose symptoms 88.2% in the Myrtol® (15.4%) were publication

c
trial (n=170) did not improve or standardized, 83.6% reported

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4 weeks: 2 deteriorated to such in the cefuroxime, Responder rate, which
weeks of Aim: To describe - Cefuroxime: 500 extent that and 82.2% in the 15.9%, 16.3%, was the primary
treatment + 2 and compare the mg/day for 6 days discontinuation was ambroxol group in 14.0%, and 15.3% of endpoint in this study,

an
weeks of follow- efficacy, safety and (n=171) indicated) as the intention-to-treat patients treated with is not considered
up tolerability of a 2- assessed by the population Myrtol® standardized, relevant for self-
week treatment with - Ambroxol: 90 mg/day investigators; diary placebo, cefuroxime limiting conditions
Myrtol® for days 1-3 and 60 data on nightly In the two and ambroxol, such as acute bronchitis

M
standardized, mg/day for days 4-14 cough and comparators and respectively,
cefuroxime, (n=163) coughing bouts ambroxol group, less experienced at least
ambroxol, and during the day; patients had coughing one adverse event

d
matched placebo in - Placebo over 14 days FEV1; absence of fits (about 70%
adult patients with
acute bronchitis of
recent onset with a
(n=172)
te relapse; safety and
tolerability
(adverse events,
versus 50% at nights
and 50% versus 30%
at daytime) and felt
17/676 (2.5%)
patients were
discontinued because
ep
FEV1 value >75% of laboratory screens, good or very good of an adverse event:
the predicted value, vital signs and compared to placebo 5, 2, 8 and 2 patients
and without physical treated with Myrtol®
c

evidence or examination) There was no standardized,

Ac

suspicion of chronic evidence of placebo, cefuroxime

pulmonary diseases bronchoconstriction and ambroxol,
or relapse in any respectively
treatment group for
the patients
continuing treatment

18
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm
Olivieri et al., Multicenter, - Ambroxol extended- Frequency of After 6 months, Ambroxol was well Measuring only during
1987 [31] (Italy) randomized, double- release: 75 mg/day for exacerbations; ambroxol was found tolerated, and winter season as was
blind, placebo- 6 months (n=110) number of lost to significantly compliance was good the case for this study

t
controlled trial working days; reduce the incidence (October-December

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6 months - Placebo for 6 months number of days of exacerbations Total side effects, 1983 to March-May
Aim: To compare (n=104) with antibiotic compared to placebo including mild ones, 1984) may tend to
the effects of daily treatment; (45.5% of patients were 20% for the overestimate the

c
administration of improvement of treated with ambroxol placebo group and number of
ambroxol extended- clinical symptoms and 14.4% of patients 24% for the ambroxol exacerbations per year

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release (75 mg) with (difficulty in receiving placebo had group. 79% of the and lead to an
those of placebo in expectoration, no episodes of total side effects in overestimation of the
preventing coughing, dyspnea) exacerbation; p<0.01) the placebo group effect on the frequency

an
exacerbations and and 82.7% in the of exacerbations
improving Patients in the ambroxol group were
symptoms and ambroxol group lost gastrointestinal A study-duration of a

M
clinical signs in significantly fewer disturbances (pyrosis year is considered
adult patients, aged working days due to and dyspepsia) necessary to evaluate
40–80 years, with illness (442 versus the influence of a

d
chronic bronchitis 837; p<0.01) and had medicinal product on
fewer days when they the frequency of
te needed antibiotic
therapy (371 versus
exacerbations in order
to exclude the influence
ep
781; p<0.01) of seasonal fluctuations
c
Ac

19
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm
Cegla, 1988 [32] Multicenter, - Ambroxol extended- Loss of working Patients treated with No serious side The concomitant use of
(Germany) randomized, double- release: 75 mg/day for days; improvement ambroxol were found effects were reported, antibiotics,
blind, placebo- 2 years (n=86) in clinical to have significantly and there was good bronchodilators,

t
controlled trial symptoms; hospital fewer lost working tolerance in both glucocorticoids or

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2 years - Placebo for 2 years admissions; need days due to their groups antitussives was not
Aim: To assess the (n=87) for antibiotics; bronchopulmonary considered in
long-term efficacy overall assessment disease: 1,216 versus Main side effects of sensitivity analyses

c
and safety of of efficacy by the 1,789 days (ambroxol ambroxol were of
ambroxol compared investigator; versus placebo; gastrointestinal

us
to placebo in adult adverse events p<0.01) nature
patients (mean age,
51.1 years) with Overall assessment of

an
chronic bronchitis. therapeutic efficacy
Co-medication with by the investigator
antibiotics, after 2 years of

M
bronchodilators, treatment was
glucocorticosteroids significantly better
and antitussives for the patients

d
were allowed in this treated with ambroxol
study (p<0.05) compared to
te placebo
c ep
Ac

20
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm
Malerba et al., Prospective, - Ambroxol extended- Number of patients At 6 months, 72 Ambroxol was not The significance of this
2004 [33] (Italy) randomized, double- release: 75 mg/day free from patients out of 115 associated with a study is limited as in
(AMETHIST blind, placebo- twice a day for 12 exacerbation over were exacerbation- greater risk of addition to the high

t
Trial) controlled, months (n=118) the first 6 months free in the ambroxol adverse events, placebo response

rip
multicenter, parallel- (winter period) and group, as compared including those to the observed
group study - Placebo capsule twice at 12 months; to 70 out of 119 in digestive tract, or
1 year a day for 12 months cough intensity and the placebo group (63 with more severe The selection bias was

c
Aim: To investigate (n=123) frequency; difficult versus 59%; adverse events than assessed as unclear
the efficacy of long- expectoration; p=0.366), and at 12 with placebo

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term ambroxol dyspnea; number of months, 56% with
treatment in days on antibiotic ambroxol and 53%
preventing acute treatment; number with placebo were

an
exacerbations in of working days exacerbation-free
adult patients, aged lost; number of (p=0.363)
40–75 years, with days of

M
COPD hospitalization A post-hoc analysis
revealed that in a
subset of 45 patients

d
with more severe
baseline symptoms,
te ambroxol therapy
was associated with a
ep
significant higher
percentage of patients
free from
exacerbation
c

compared to placebo
Ac

(63 versus 38;

p=0.038)

21
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm
Guyatt et al., Double-blind, - Ambroxol: 60 mg/day Peak flow Despite a small Five subjects The trial was not
1987 [1] randomized, twice a day for 4 weeks measurements; deterioration in mean receiving ambroxol carefully controlled,
(Canada) placebo-controlled (n=45) FEV1; forced vital FEV1 in both groups reported experiencing and double-blinding

t
trial capacity; mid- (0.004 L in the a bad taste in their was not rigorous

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- Matching placebo expiratory flow ambroxol group and mouth (n=5),
4 weeks Aim: To assess the twice a day for 4 weeks rates; symptom 0.021 L in the headaches, chest
efficacy of ambroxol (n=45) score (7-point placebo group), and tightness, and a rash

c
in adult patients symptom essentially stable (n=1, for each side
(mean age, 56 years) questionnaire) mid-expiratory flow effect)

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with chronic rates (increase of 16
bronchitis who had mL/s in the ambroxol Five patients
difficulty raising group and receiving placebo

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secretions deterioration of 123 also reported side
mL/s in the placebo effects: muscle
group), questionnaire spasms (n=1), sore

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scores improved in legs (n=1), swelling
the major areas in of the legs (n=2), and
which benefit with sensation of sputum

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ambroxol was in the throat (n=1)
anticipated. This
te improvement was
maintained over the 4
ep
weeks of the trial, but
was closely
comparable in the
two groups
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22
Study; Study Design and Study Arms and Outcome Efficacy Findings Safety Findings Study Limitations
Duration Aim Number of Patients in Measures
Each Arm
Ericsson et al., Randomized, - Ambroxol: 60 mg/day Improvement in Comparison with the Reported side effects No correction for the
1986 and 1987 double-blind, for 2 weeks (n=32) respiratory placebo group at the were mild, and use of multiple
[34,35] placebo-controlled symptoms; lung end of the treatment appeared to be dose- outcomes was made

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(Sweden) trial using 3 parallel - Ambroxol: 120 function tests period showed that related

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groups mg/day for 2 weeks significantly more
(n=33) subjects in the 120
6 weeks, with Aim: To evaluate mg group reported

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the 2 middle the effects of two - Matching placebo for improvement in
weeks being the dose levels of 2 weeks (n=32) respiratory symptoms

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actual treatment ambroxol (60 and (p<0.05), mainly due
period 120 mg daily) versus to improved
placebo in adult expectoration

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subjects with (p<0.05)
uncomplicated
chronic bronchitis

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Michnar and Randomized, - Ambroxol for 2 General well-being; Breathlessness while Throughout the 2- Limited information
Milanowski, double-blind, months (n=33) the symptoms of a at rest and the rate of month period of was available on this
1996 [36] placebo-controlled cold and of fever; exacerbations was therapy, the study and the primary

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(Poland) study - Placebo for 2 months the need for significantly lower in tolerability of endpoint appears not to
(n=34) treatment with the ambroxol group ambroxol was good; have been assessed

8 weeks
Aim: To examine
the efficacy and
te antibiotics; the
amount, viscosity
after 2 weeks of
therapy. Similarly,
there was no
significant difference Comparison of the
ep
tolerability of and color of sputum viscosity, in the number of side frequency of
ambroxol on the sputum; the difficulty in effects between the exacerbations over 1
symptomatology of difficulty in expectoration and two groups year is considered more
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chronic bronchitis expectoration; the severity of coughing appropriate, in order to

among adult in- and severity of were reduced in this take into account
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out-patients coughing and any group after 4 or 8 seasonal fluctuations

changes in weeks
breathlessness
while at rest
COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second.

23
Table 2. Characteristics and Results of Published Observational Trials of Ambroxol in Acute and Chronic Lung Diseases
Study; Study Design and Study Drug and Outcome Efficacy Findings Safety Findings Study
Duration Aim Number of Measures Limitations
Patients
Schulz et al., Community Mucosolvan® cough Tolerability; 92% of the patients assessed 67 patients (2.5%) The information
2006 [29] pharmacy-based, syrup (containing 30 self-perceived the self-perceived reported a total of 81 collected in this

t
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(Germany) post-marketing mg/5 mL of effectiveness; effectiveness as "very good" adverse events which study is derived
surveillance, Ambroxol), which usage pattern (29%) or "good" (63%), and were usually mild in from a non-
multicenter study was administered up 89% were willing to nature and mostly random,
From January to 120 mg/day for a purchase this ambroxol affecting the uncontrolled

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to June 2003 Aim: To evaluate median duration of cough syrup again gastrointestinal tract population

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the "real-life" 7.6 days (range, 1 to (n=53), followed by
behavior of 78) skin and subcutaneous The
consumers (mean tissue disorders (n=9) reproducibility of

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age, 45 years) with 2,707 participants the self-
non-prescription were recruited in In general, 97% of the administered
access to an 266 pharmacies. participants assessed questionnaire is

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ambroxol cough 2,664 questionnaires the safety as "very not accurately
syrup with special were evaluable good" (51%) or known, and its
focus on tolerability "good" (46%) validation is
and the pattern of limited

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product usage
Alcozer et
al., 1989 [39]
(Italy)
Open-label,
observational,
multicenter study
Ambroxol te
extended-release: 75
mg/day for 6
Number of
acute
exacerbations;
A high percentage of
patients did not experience
recurrent exacerbations:
444 adverse events
were reported in the
first, 205 in the third,
The information
collected in this
study is derived
ep
months (n=5,635) effects on 81.6% in the first month, and 91 in the sixth from a non-
Aim: To evaluate respiratory 58% in the third and 44.9% month. The majority random,
6 months the effect of symptoms in the sixth month of of adverse events were uncontrolled
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during winter ambroxol on the therapy of gastrointestinal population

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prevention of nature (pyrosis,

exacerbations in Percentage of patients 37.6%; epigastric
outpatients with without difficulty in heaviness, 31.6% of
chronic bronchitis expectorating increased by the total reported
(mean age, 59.5 51.6% compared to baseline adverse events)
years) after 6 months of therapy

24
Study; Study Design and Study Drug and Outcome Efficacy Findings Safety Findings Study
Duration Aim Number of Measures Limitations
Patients
Kardos et al., Community - Ambroxol Symptom Time to start of symptom Patients rated global The use of
2018 [30] pharmacy-based, extended-release severity relief among all participants tolerability of anonymous
(Germany) multicenter (126 capsules (n=231) assessed by a was within 1 to 15 minutes ambroxol as very responses implies

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pharmacies), patient- in 12.2% of patients, within good, good, moderate that source data

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survey-based study - Ambroxol adult adapted 15 to 30 minutes in 38.4%, or poor in 56.4, 41.2, verification was
Patient syrup (n=233) version of the 30 to 60 minutes in 37.2%, 2.1 and 0.3% of cases, not possible
recruitment Aim: To explore the Bronchitis and >60 minutes in 12.1% respectively

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was between different profiles of - Ambroxol Severity The resulting data
October 2016 adult customers pediatric syrup Scale; patient Across all formulations, Adverse events were are not expected

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and May obtaining four (n=244) assessment of treatment with ambroxol registered in 99/965 to have the same
2017 ambroxol- global reduced the Bronchitis patients (10.3%); none quality as those
containing - Ambroxol soft treatment Severity Scale by 5.5 points of them had an collected by a

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formulations and pastilles (n=233) success; (mean end-of-treatment outcome that was fatal physician or other
the efficacy and tolerability; score), i.e. by 59%. The or considered serious. healthcare
tolerability of these satisfaction strongest improvements This included two professionals

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formulations with treatment were reported for chest pain cases of diarrhea
against acute (0.2%), three with
respiratory Participants rated global poor global tolerability

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symptoms efficacy of ambroxol across (0.3%) and four with
formulations as very good, poor global efficacy
te good, moderate or poor in
36.1, 57.5, 6.0 and 0.4% of
(0.4%); the other 90
cases were based on
ep
cases, respectively worsening of items in
the symptom and
impairment scores
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25
Table 3. Adverse Reactions Related to Ambroxol Listed in the Published Randomized, Placebo-Controlled Trials of Ambroxol
in Acute and Chronic Lung Diseases
System Organ Class Adverse Event Frequency
Gastrointestinal disorders Nausea Common
(≥1/100 to <1/10)

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Dyspepsia, Vomiting, Uncommon

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Abdominal Pain, Diarrhea (≥1/1,000 to <1/100)
General disorders Rash, Urticaria Rare
(≥1/10,000 to <1/1,000)

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Source: European Medicines Agency (EMA) Pharmacovigilance Risk Assessment Committee (PRAC). Revised assessment report: Ambroxol and bromhexine

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containing medicinal products. 2015. Available from:
http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Ambroxol_and_bromhexine_31/Recommendation_provided_by_Pharmacovigilance_R
isk_Assessment_Committee/WC500184106.pdf. Accessed September 09, 2018 [2].

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