10 September 2015 EMA/PRAC/800767/2015 Pharmacovigilance Risk Assessment Committee (PRAC) Revised assessment report Procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data Ambroxol and bromhexine containing medicinal products INN: ambroxol and bromhexine Procedure number: EMEA/H/A-31/1397 Note Assessment report as adopted by the PRAC and considered by the CMDh with all information of a commercially confidential nature deleted. 30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union © European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 3 2. Scientific discussion ................................................................................ 3 2.1. Introduction......................................................................................................... 3 2.2. Clinical aspects .................................................................................................... 5 2.2.1. Safety .............................................................................................................. 5 2.2.2. Efficacy .......................................................................................................... 13 2.2.3. Consultation of the Paediatric Committee ........................................................... 37 2.3. Risk management plan ........................................................................................ 37 2.4. Overall benefit/risk assessment ............................................................................ 37 2.5. Changes to the product information ...................................................................... 38 2.6. Communication plan ........................................................................................... 39 3. Conclusion and grounds for the revised recommendation ..................... 39 Appendix 1 ................................................................................................ 41 EMA/PRAC/800767/2015 Page 2 1. Background information on the procedure Further to the evaluation of a Worksharing PSUR of ambroxol-containing medicinal products started in January 2012 and of follow-up submissions as well as signal detection activities, the Belgian national competent authority (FAMHP) identified an increase in reporting of hypersensitivity reactions over the years 2012-2014 - indeed 43% of the 132 cases of anaphylactic reactions registered in Eudravigilance (EV) were collected over that period. In addition the Belgian national authority was of the view that accumulating evidence from case reports and the literature demonstrated that ambroxol is responsible for severe cutaneous adverse reactions (SCARs). As of the 28th of February 2014 there were 210 case reports of SCARs in EV, including at least 9 with a causal relationship to ambroxol assessed as likely to definite. Finally the FAMHP conducted a benefit risk evaluation in children below 6 years of age after having observed a relatively high proportion of AEs reported in children below 6 years of age (27%) over the reporting period 2008-2011. This evaluation concluded that, while this was not indicative of a different safety profile, insufficient evidence of efficacy was available in secretolytic therapy in this age group, leading to a negative benefit-risk balance. As ambroxol is a metabolite of bromhexine and hypersensitivity reactions are not dependent on the dose of the allergenic substance absorbed, the FAMHP considered that any confirmed risk with ambroxol could also be found in bromhexine-containing medicinal products with regards to these reactions. In light of the above, on 4 April 2014, the FAMHP informed the European Medicines Agency, of their decision to notify a referral procedure to ask for the PRAC’s recommendation pursuant to Article 31 of Directive 2001/83/EC, on whether the balance of benefits and risks for these products is still positive in the approved indications, and whether the marketing authorisations for ambroxol- and bromhexine- containing medicinal products should be maintained, varied, suspended or withdrawn. On 25 February 2015, pursuant to Article 107k(1) and (2) of Directive 2001/83/EC, the CMDh, having considered the PRAC recommendation dated 9 January 2015 with regards to ambroxol- and bromhexine-containing medicinal products, reached by majority the position that the marketing authorisations for the concerned medicinal products should be varied. The CMDh position was forwarded to the European Commission. During the decision making process, at a meeting of the Standing Committee on Medicinal Products for Human Use, some EU Member States raised new questions of technical nature which they considered had not been sufficiently addressed in the PRAC recommendation and CMDh position. In light of this, the PRAC recommendation and CMDh position were referred back to the Agency for further consideration. 2. 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 3 • 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 bromhexine- containing 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) • Sjögren’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 contra- indicated 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 bromhexine- containing 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 EMA/PRAC/800767/2015 Page 4 can also be drug-induced. SJS, TEN, AGEP and DRESS are most often drug-induced and, in more rare cases, of infectious aetiology. SJS and TEN present with a prodromal period with influenza-like symptoms such as fever, aching body, malaise, headaches, rhinitis, pharyngitis, sore throat, myalgia, arthralgia, nausea and/or diarrhoea that may last up to 14 days. Then the eruption starts, it is usually distributed symmetrically on the face, upper trunk and proximal extremities. However, the exanthema can rapidly extend to the entire body. Nikolsky’s sign is positive, flaccid blisters develop and detachment of necrotic epidermis on slight pressure reveals large areas of denuded skin. The principal difference is the extent of detachment, limited in SJS and more widespread in TEN. Mucous