Public Assessment Report
Scientific discussion
Rivendra
Ambroxol hydrochloride
DK/H/2364/001-002/DC
Date: 01-06-2015
This module reflects the scientific discussion for the approval of Rivendra. The procedure was
finalised at 22nd April 2015. For information on changes after this date please refer to the
module ‘Update’.
I.
INTRODUCTION
Based on the review of the quality, safety and efficacy data, the Member States have granted
marketing authorisations for Rivendra 3 mg/ml and 6 mg/ml oral solution, from Actavis Group
PTC ehf.
The products are indicated for mucolytic therapy of productive cough in acute or chronic
bronchopulmonary diseases associated with abnormal mucus secretion and impaired mucus
transport. A comprehensive description of the indication and posology is given in the SmPC.
Ambroxol, an active metabolite of bromhexine, is a mucoactive agent that possesses manifested
secretolytic effect, regulates the production of mucus and normalizes its viscosity by
intracellular activation at formation of serous secretion and reduction of sulfomucine synthesis
in cells.
The marketing authorisation has been granted pursuant to Article 10(1) of Directive
2001/83/EC., a so-called generic application.
The reference products are Mucosolvan 3 mg/mL, syrup and Mucosolvan Kindersaft 6 mg/mL
marketed by Boehringer Ingelheim. No bioequivalence studies have been conducted to compare
the bioavailability of the reference and the Actavis products
Agreement between Member States was reached during a written procedure. There was no
discussion in the CMDh.
II.
II.1
QUALITY ASPECTS
Introduction
Each ml of oral solution contains 3 mg or 6 mg of ambroxol hydrochloride.
The oral solution is colourless or pale yellow with strawberry flavor.
The oral solution is provided in amber glass bottle with child proof cap (HDPE), outer cap (PP)
and an adaptor (PE). An oral syringe 5 ml (PP) with plunger (HDPE) is included in the package.
Approved pack sizes are 100 ml and 200 ml of oral solution.
The excipients are:
 Sodium benzoate (E211)
 Sorbitol (Е420)
 Sucralose
 Hydroxyethylcellulose
 Citric acid monohydrate
 Purified water
 Strawberry flavour (501440 T):
 Propylene glycol (E1520)
 Flavouring substances
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Compliance with Good Manufacturing Practice (GMP)
The RMS has been assured that acceptable standards of GMP (see Directive 2003/94/EC) are
in place for this product type at all sites responsible for the manufacturing of the active
substance as well as for the manufacturing and assembly of this product prior to granting its
national authorisation.
II.2
Drug Substance
The product contains the active substance ambroxol hydrochlororide which is sourced from one
manufacturer. The manufacturer of ambroxol hydrochloride holds a valid Certificate of
Suitability (CEP) which verifies that the active substance is suitably controlled by the
monograph if supplemented by additional tests for residual solvents as specified in the CEP.
INN:
Chemical name:
Molecular formula:
Molecular mass:
Structural formula:
Ambroxol hydrochloride
trans-4-[(2-Amino-3,5-dibromobenzyl)amino]cyclohexanol hydrochloride
C13H19Br2ClN2O
414.6 g/mol
Ambroxol hydrochloride is described in the European pharmacopoeia (Ph. Eur.). It is a white
or yellowish crystalline powder. It is soluble in methanol, sparingly soluble in water and
practically insoluble in methylene chloride.
All relevant aspects of the manufacturing process have been evaluated by the European
Directorate for the Quality of Medicines (EDQM) prior to granting the CEP.
The finished product manufacturer employs the analytical methods described in Ph. Eur.
II.3
Medicinal Product
The drug product is an oral solution with strawberry flavor in strengths 3 mg/mL and 6 mg/mL
packaged in dark glass bottles (type III) with a child proof cap (HDPE), outer cap (PP) and an
adaptor (PP). The drug product is also packaged with an oral syringe.
The development of the drug product has been suitably described, the choice of excipients is
justified and their functions explained. The manufacturing process can be characterised as a
standard process. The process has been sufficiently detailed with respect to the manufacturing
parameters e.g. homogenisation time, temperature of heating, dissolution and cooling.
The product specifications cover appropriate parameters for this dosage form. Validation data
of the analytical methods have been presented to support the suitability of the methods.
Batch analysis has been performed on 3 batches of strength 3 mg/mL and 6 mg/mL. The batch
analysis results of both strengths show that the finished products meet the specifications
proposed and that a consistent drug product is obtainable.
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The conditions used in the stability studies are according to the ICH stability guideline. For
both strengths the stability data support a shelf-life/storage condition of 2 years with no special
storage conditions. Approved shelf-life after first opening is 6 months.
III.
NON-CLINICAL ASPECTS
Pharmacodynamic, pharmacokinetic and toxicological properties of ambroxol are well known.
As ambroxol is a widely used, well-known active substance, the applicant has not provided
additional studies and further studies are not required. Overview based on literature review is,
thus, appropriate.
The provided non-clinical overview on the pre-clinical pharmacology, pharmacokinetics and
toxicology is adequate.
III.1
Ecotoxicity/environmental risk assessment (ERA)
Since Rivendra is intended for generic substitution, this will not lead to an increased exposure
to the environment. An environmental risk assessment is therefore not deemed necessary.
IV.
CLINICAL ASPECTS
The reference products are Mucosolvan 3 mg/mL, syrup and Mucosolvan Kindersaft 6 mg/mL
marketed by Boehringer Ingelheim. No bioequivalence studies have been conducted to compare
the bioavailability of the reference and the Actavis products.
A waiver for not conducting a bioequivalence study is claimed for both strengths referring to
the dosage form i.e. an aqueous oral solution at the time of administration and the
concentrations of the active substance being identical to that of the reference products.
Compositional differences between the Actavis products and the corresponding brand leader
products have been observed. These differences have been adequately justified from a
biowaiver point of view.
IV.1
Risk Management Plan
The Marketing authorisation holder has submitted a risk management plan, in accordance with
the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance
activities and interventions designed to identify, characterise, prevent or minimise risks relating
to Rivendra.
Summary of safety concerns
Important identified risks
Important potential risks
Missing information
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- Accumulation of ambroxol metabolites
(produced in the liver) in patients with
severe renal impairment and in patients with
hepatic impairment
- Anaphylactic reactions including
anaphylactic shock
Allergic reactions including severe skin
reactions (SCARS)
- Use during pregnancy
- Use during lactation
- Use in children
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Safety concern
Routine risk minimisation measures
Accumulation of
ambroxol metabolites
(produced in the liver)
in patients with severe
renal impairment and in
patients with hepatic
impairment
(Proposed) text in SmPC
Additional risk
minimisation
measures
None proposed
A warning is included in section 4.2 d
regarding the use of ambroxol in
patients with renal impairment or
hepatic impairment.
A warning is included in section 4.4
describing that accumulation of the
metabolites of ambroxol generated in
the liver can be expected in the presence
of severe renal impairment. Caution is
advised in patients with renal or hepatic
impairment.
(Proposed) text in PIL
Anaphylactic reactions
including anaphylactic
shock
A warning is included in section 2
advising the patient to talk to a doctor or
pharmacist before taking ambroxol if the
patient has or has had liver or kidney
problems.
(Proposed) text in SmPC
None proposed
Anaphylactic reactions including
anaphylactic shock is listed in section
4.8.
(Proposed) text in PIL
Allergic reactions
includeing severe skin
reactions (SCARS)
Severe allergic reactions including
shock are listed in section 4.
Proposed text in SmPC:
In section 4.4 it is mentioned that very
rarely, the occurrence of severe skin
reactions such as Stevens-Johnson
syndrome and Lyell’s syndrome
coinciding with the use of ambroxol has
been reported. If new skin and mucousmembrane changes occur, the advice of
a doctor should therefore be sought
without delay and the use of ambroxol
discontinued.
None proposed
Proposed text in PIL:
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Safety concern
Use in pregnancy
Use in lactation
Use in children
Routine risk minimisation measures
Additional risk
minimisation
measures
A warning is included in section 2
advising patients to contact a doctor
immediately and stop taking ambroxol if
lesions and blistering appear on the skin
or on mucous membranes.
(Proposed) text in SmPC
None proposed
A warning is included in Section 4.6
describing that in animal studies
ambroxol have not shown any harmful
effects. Extensive clinical experience
after the 28th week of pregnancy has
shown no evidence of harmful effects on
the foetus. Nonetheless, the usual
precautions regarding the use of drugs
during pregnancy should be observed.
Especially during the first trimester, the
use of ambroxol is not recommended.
(Proposed) text in PIL
A warning is included in section 2
describing that pregnant women or
women planning to become pregnant
should seek advice from a doctor or
pharmacist before taking this medicine.
(Proposed) text in SmPC
None proposed
A warning is included in section 4.6
describing that ambroxol is excreted into
breast milk and the use of ambroxol is
not recommended in nursing mothers.
(Proposed) text in PIL
A warning is included in section 2
describing that ambroxol is excreted into
breast milk and the use of ambroxol is
not recommended in nursing mothers.
(Proposed) text in SmPC
None proposed
In section 4.2 of the SmPCs for
ambroxol syrup, dosing
recommendations are given for children
from 6 to 12 years and children from 2
to 6 years. In the SmPC for ambroxol
effervescent tablets, dosing
recommendations are given for children
from 6 to 12 years of age and for the 60
mg strength dosing recommendations
are given for adolescents from 12 years
of age.
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Safety concern
Routine risk minimisation measures
Additional risk
minimisation
measures
In section 4.3 ambroxol syrup is
contraindicated for use in children,
ambroxol effervescent tablets 30 mg are
contraindicated for children below 6
years of age and ambroxol effervescent
tablet 60 mg are contraindicated in
children below 12 years of age.
(Proposed) text in PIL
A contraindication is included in section
2 for both ambroxol syrup and
effervescent tablets, stating that
ambroxol should not be used in children.
The age groups where they are
contraindicated below depend on the
product and strength of the products.
V.
USER CONSULTATION
The package leaflet has been evaluated via a user consultation study in accordance with the
requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC. The language used for the
purpose of user testing the PIL was English.
The results show that the package leaflet meets the criteria for readability as set out in the
Guideline on the readability of the label and package leaflet of medicinal products for human
use.
The test consisted of a pilot test with 3 participants, followed by two rounds with 10 participants
each. The questions covered the areas traceability, comprehensibility and applicability
sufficiently.
VI.
OVERALL CONCLUSION, BENEFIT/RISK ASSESSMENT AND
RECOMMENDATION
Rivendra 3 mg/ml and 6 mg/ml oral solution have a proven chemical-pharmaceutical quality
and are generic forms of Mucosolvan 3 mg/mL syrup and Mucosolvan Kindersaft 6 mg/mL.
Ambroxol hydrochloride is a well-known active substance with an established favourable
efficacy and safety profile.
An adequately justified waiver for not conducting a bioequivalence study has been presented.
The marketing authorisation holder has provided written confirmation that systems and services
are in place to ensure compliance with their pharmacovigilance obligations.
The SmPC, package leaflet and labelling are in the agreed templates and are in agreement with
other ambroxol containing products.
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Agreement between Member States was reached during a written procedure. There was no
discussion in the CMD(h). The Concerned Member States, on the basis of the data submitted,
considered that essential similarity has been demonstrated for Rivendra with the reference
product, and have therefore granted a marketing authorisation. The decentralised procedure was
finalised on 22nd April 2015.
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