Scientific discussion 2.1.

Introduction
Ambroxol, a substituted benzylamine, is the active N-desmethyl metabolite of
bromhexine, which itself is a synthetic derivative of vasicine, the active
principle of Adhatoda vasica. The pharmacological properties of ambroxol are
claimed to be:
� secretolytic (mucolytic) agent: decreasing mucus viscosity through
depolymerisation of acidic polysaccharide fibres in the bronchial secretion and
stimulation of neutral polysaccharide production by glandular cells
� mucokinetic agent: stimulation of cilia activity and mucociliary clearance (MCC)

EMA/PRAC/800767/2015 Page 4

� enhancement of availability of surfactant (through its stimulating effect on the

synthesis and release of surfactant by type II pneumocytes)
� antioxidant actions � anti-inflammatory actions � anti-viral and anti-bacterial
properties � local anaesthetic (through inhibition of the neuronal sodium channels)
Ambroxol- and bromhexine-containing medicinal products have first been registered
in a European Union (EU) Member State (MS) in 1978 and 1963, respectively, and are
currently authorised in all EU MS (as well as in Norway and Iceland) except the
United Kingdom. Ambroxol- and bromhexinecontaining products were first authorised
in secretolytic therapy. Additional indications were authorised in some EU MS at a
later point in time.
The authorised indications of ambroxol, as listed in the Company Core Data Sheet of
the originator, are presented below:
� Secretolytic therapy (oral, inhalative, rectal and intravenous administration) �
Prophylaxis and treatment of Infant respiratory distress syndrome (IRDS)
(intravenous administration)
� Prophylaxis and treatment of postoperative bronchopulmonary complications (PPC)
(intravenous administration)
� Pain relief in acute sore throat (oromucosal administration in adult and children
>12) The authorised indications of bromhexine, as listed in the Company Core Data
Sheet of the originator, are presented below:
� Secretolytic therapy (oral, inhalative and intravenous administration) �
Alteration in the production or elimination of mucus � acute sinusitis, chronic
sinusitis (oral and inhalative administration)
� Sj�gren�s syndrome (oral administration) In addition, ambroxol and bromhexine
have been approved in some EU MS in airway diseases indications in fixed dose
combinations with various active substances (e.g. ambroxol/doxycycline,
ambroxol/clenbuterol, ambroxol/theophylline and bromhexine/amoxicillin). These
products are contraindicated in different subsets of the paediatric population in
the EU MS.
Ambroxol and bromhexine are marketed in several formulations for oral, nasal,
oromucosal, intravenous or rectal administration under various invented names.
Ambroxol- and bromhexinecontaining medicines are available as over-the-counter
(OTC) as well as prescription-only medicines (POM).
As mentioned above, one of the triggers for this review was the identification of
severe cutaneous adverse reactions (SCARs) reports, possibly linked to ambroxol.
SCARs comprise Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and
the overlapping condition, erythema multiforme (EM) especially when mucous
membranes are involved (EM majus: EMM), acute generalised exanthematous pustulosis
(AGEP) and drug reaction (hypersensitivity) with eosinophilia and systemic symptoms
(DRESS). EM and EMM may also result from several underlying causes, mostly
infections (herpes virus, mycoplasma pneumonia, upper respiratory tract infections
and influenza-like illness) but