Download HALLS DRY COUGH LOZENGES PL 00094/0248 UKPAR TABLE

HALLS DRY COUGH LOZENGES
PL 00094/0248
UKPAR
TABLE OF CONTENTS
Lay Summary
Page 2
Scientific discussion
Page 3
Steps taken for assessment
Page 14
Steps taken after authorisation – summary
Page 15
Summary of Product Characteristics
Page 16
Combined Patient Information Leaflet/ Label
Page 19
MHRA-UKPAR – Halls Dry Cough Lozenges
PL 00094/0248
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HALLS DRY COUGH LOZENGES
PL 00094/0248
LAY SUMMARY
The Medicines Healthcare products Regulatory Agency granted Ernest Jackson &
Company Limited a Marketing Authorisation (licence) for the medicinal product Halls Dry
Cough Lozenges (PL 00094/0248) on 2 August 2012. This pharmacy only medicine (P)
and can be purchased at pharmacies under the supervision of a pharmacist.
Halls Dry Cough Lozenges contains 7.5 mg of the active ingredient, dextromethorphan
hydrobromide per lozenge. Halls Dry Cough Lozenges provides relief from dry coughs.
The active ingredient acts as an antitussive (to suppress coughing without drowsiness).
No new or unexpected safety concerns arose from this application and it was, therefore,
judged that the benefits of taking Halls Dry Cough Lozenges (PL 00094/0248) outweigh
the risks; hence a Marketing Authorisation has been granted.
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HALLS DRY COUGH LOZENGES
PL 00094/0248
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction
Page 4
Pharmaceutical assessment
Page 6
Non-clinical assessment
Page 9
Clinical assessment
Page 10
Overall conclusions and risk benefit assessment
Page 13
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INTRODUCTION
The UK granted a Marketing Authorisation for the medicinal product Halls Dry Cough
Lozenges (PL 00094/0248) to Ernest Jackson & Co Ltd on 2 August 2012. This is a
pharmacy-only medicine and can be purchased at pharmacies under the supervision of a
pharmacist.
The product contains the active ingredient, dextromethorphan hydrobromide, which is a
cough suppressant; it exerts its antitussive activity by acting on the cough centre of the
medulla oblongata.
This application was submitted as abridged, bibliographic application according to Article
10a (well-established use) of Directive 2001/83/EC, as amended.
No new non-clinical or clinical efficacy studies were necessary for this application, which
is acceptable given that this is a bibliographic application for a product containing an active
ingredient of well-established use. Bioequivalence studies are not necessary to support this
bibliographic application.
There are at least three products containing the single active ingredient, dextromethorphan
hydrobromide, as an oral solution in the UK:

Benylin Dry Coughs (Non-Drowsy), Pfizer Consumer Healthcare, PL 15513/0051,
authorised to Pfizer Consumer Healthcare on 16 June 1997; the Marketing
Authorisation held by Pfizer Consumer Healthcare was granted following a Change
of Ownership Application from Park Davis & Co Limited, Benylin Dry Cough
Linctus, PL 00018/0111 and 00018/0111R, authorisations first granted on 13
October 1976 and 27 June 1990, respectively.

Dry Cough Syrup, Wrafton Laboratories Limited, PL 12063/0024, authorised to
Wrafton Laboratories Limited on 7 March 1997.

Nyrolex Dry Cough or Nyrolex for Dry Coughs, The Boots Company PLC, PL
00014/0460, authorised to The Boots Company PLC on 10 January 1995.
The MHRA has been assured that acceptable standards of Good Manufacturing Practice
(GMP) are in place for this product type at all sites responsible for the manufacture and
assembly of these products. Evidence of compliance with GMP has been provided for the
named manufacturing and assembly sites.
The MHRA considers that the pharmacovigilance system as described by the Marketing
Authorisation Holder (MAH) fulfils the requirements and provides adequate evidence that
the MAH has the services of a Qualified person (QP) responsible for pharmacovigilance
and has the necessary means for the notification of any adverse reaction suspected of
occurring either in the Community or in a third country.
The MAH has provided adequate justification for not providing a Risk Management Plan
(RMP). Dextromethorphan hydrobromide is a well-known active drug substance and has
been used to treat the symptoms of persistent dry coughs for many years. The safety profile
of this product is therefore well-characterised and considered to be acceptable in the patient
population in which it is indicated.
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No new or unexpected safety concerns arose during review of information provided by the
Marketing Authorisation Holder and it was, therefore, judged that the benefits of taking
Halls Dry Cough Lozenges (PL 00094/0248) outweigh the risks; hence a Marketing
Authorisation was granted.
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PHARMACEUTICAL ASSESSMENT
ACTIVE SUBSTANCE
DEXTROMETHORPHAN HYDROBROMIDE
INN:
Chemical name:
Dextromethorphan hydrobromide
ent-3-Methoxy-17-methylmorphinan hydrobromide monohydrate
Structure:
Molecular formula:
Molecular weight:
C18H26BrNO, H2O
370.3
General Properties
Description:
Almost white, crystalline powder.
Solubility:
Sparingly soluble in water, freely soluble in alcohol.
Dextromethorphan hydrobromide is the subject of a European Pharmacopoeia (Eur Ph.)
monograph.
Manufacture
All aspects of the manufacture and control of the active substance dextromethorphan
hydrobromide are covered by a European Directorate for the Quality of Medicines
(EDQM) Certificate of Suitability.
MEDICINAL PRODUCT
Description and Composition
The finished product is presented as a lozenge and contains 7.5 mg of dextromethorphan
hydrobromide
Other ingredients
Other ingredients consist of pharmaceutical excipients, sucrose granulated, glucose liquid,
blackcurrant flavour, citric acid monohydrate, sucralose, masking flavour, levomenthol and
carrot anthocyanin E163 .
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All ingredients comply with their relevant Ph. Eur monographs; with the exception of
masking flavour, sucralose, blackcurrant flavour and carrot anthocyanin E163 which show
compliance to in-house specifications. Appropriate justification for the inclusion of each
excipient has been provided. Satisfactory Certificates of Analysis have been provided for
all the excipients.
None of the excipients used contain material derived from animal or human origin.
Furthermore, no genetically modified organisms are used in the manufacture of any of the
excipients.
Manufacture
A description and flow-chart of the manufacturing method has been provided.
In-process controls are appropriate considering the nature of the product and the method of
manufacture. Process validation studies have been conducted and are accepted. The validation data
demonstrated consistency of the manufacturing process.
Finished Product Specification
Finished product specifications are provided for both release and shelf-life, and are
satisfactory; they provide an assurance of the quality and consistency of the finished
product. Acceptance limits have been justified with respect to conventional pharmaceutical
requirements and, where appropriate, safety. Test methods have been described and
adequately validated, as appropriate. Satisfactory batch analysis data are provided and
accepted. The data demonstrate that the batches are compliant with the proposed
specifications. Certificates of Analysis have been provided for any reference standards
used.
Container Closure System
The finished product is marketed in blister packs composed of white/opaque polyvinylchloride
(PVC) coated with polyvinylidene chloride (PVDC) and lidded with aluminium foil. The blister
packs are placed into cardboard outer cartons in 6, 8, 10 or 20 lozenges.
Satisfactory specifications and Certificates of Analysis for all packaging components used have
been provided. All primary product packaging complies with EU legislation, Directive
2002/72/EC (as amended), and is suitable for contact with foodstuffs.
Stability
Finished product stability studies have been conducted in accordance with current
guidelines and results were within the proposed specification limits. Based on the results, a
shelf-life of 24 months has been approved, with the following storage instructions, “Do not
store above 25oC”.
Expert Report
A satisfactory quality overview is provided, and has been prepared by an appropriately qualified
expert. The CV of the expert has been supplied.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL),
Labels
The SmPC, PIL and labelling are pharmaceutically acceptable. Colour mock-ups of the
PIL/label have been provided. The labelling is satisfactory and fulfils the statutory
requirements for Braille.
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The applicant has submitted results of PIL user testing. The results indicate that the PIL is
well-structured and organised, easy to understand and written in a comprehensive manner.
The test shows that the patients/users are able to use the information that it contains.
MAA Forms
The MAA forms are pharmaceutically satisfactory.
Conclusion
There are no objections to approval of Halls Dry Cough Lozenges from a pharmaceutical
point of view.
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NON-CLINICAL ASSESSMENT
These are abridged applications submitted under Article 10a (well-established use) of
Directive 2001/83/EC, as amended, for Halls Dry Cough Lozenges.
The pharmacodynamic, pharmacokinetic and toxicological properties of dextromethorphan
hydrobromide are well-known. Therefore, no further studies are required and the applicant
has provided none.
No formal Environmental Risk Assessment has been provided and none was required. The
active substance has been used for over 10 years, the use of this product is not expected to
increase the overall use of dextromethorphan hydrobromide and so no additional increase in
environmental risk has been identified.
The SmPCs are satisfactory from a non-clinical viewpoint.
There are no objections to the approval of Halls Dry Cough Lozenges from a non-clinical
point of view.
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CLINICAL ASSESSMENT
Clinical Background
Dextromethorphan hydrobromide is a centrally acting antitussive and at therapeutic doses
does not cause depression of respiration. It is a synthetic phenanthrene derivative of opium
and the synthetic dextroisomer of codeine. Although structurally related to morphine,
dextromethorphan hydrobromide has no analgesic properties. Dextromethorphan
hydrobromide exerts a sedative effect on the central nervous system.
Dextromethorphan hydrobromide is used for the relief of non-productive cough.
Indications
For the relief of persistent dry coughs.
The above stated therapeutic indication is essentially the same as that for other products
containing dextromethorphan hydrobromide as a single active substance in the UK; the
following therapeutic indications are stated in the authorisations for three products.
PL 15513/0051 – Benylin Dry Coughs (Non-Drowsy) – Pfizer Consumer Healthcare
…is indicated as an antitussive, for the relief of persistent, dry, irritating cough.
PL 12063/0024 – Dry Cough Syrup – Wrafton Laboratories Limited
To soothe and control dry coughs.
PL 00014/0460 – Nyrolex Dry Cough or Nyrolex for Dry Coughs – The Boots Company
PLC
For short-term use in the relief of dry, ticklish, unproductive coughs.
PL 00165/0151 – Robitussin Soft Pastilles for Dry Cough – Wyeth Consumer Healthcare
For the relief of persistent dry irritant coughs.
In conclusion the requested therapeutic indication would be acceptable for use in the UK.
Dose and Dose Regimen
Adults the Elderly and Children over 12 years: 2 lozenges (15mg) 3 to 4 times daily.
Children 6 to 12 years: 1 lozenge (7.5 mg) 3 to 4 times daily.
Children under 6 years: Not recommended.
Suck each lozenge until dissolved.
Do not take more than 4 doses in 24 hours.
The posology is in line with other products containing dextromethorphan hydrobromide.
The product is intended for supply through pharmacies only (P).
Paediatric Development Programme
The Applicant is not seeking authorisation in children under 6 and therefore a clinical
programme or bibliographic review is not presented in support of use in this age group.
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CLINICAL PHARMACOLOGY
PHARMACOKINETICS
Introduction and overview
Dextromethorphan hydrobromide is well absorbed from the gut following oral
administration. It is metabolised in the liver and excreted in the urine as unchanged
dextromethorphan and dimethylated metabolites including dextrorphan.
Bioequivalence
No bioequivalence studies have been submitted as this is a bibliographical application.
Overall conclusions on pharmacokinetics
The dose of the active proposed is in-line with other products containing
dextromethhorphan hydrobromide and therefore acceptable.
PHARMACODYNAMICS
Introduction
Dextromethorphan hydrobromide is a centrally acting cough suppressant.
Overall conclusions on pharmacodynamics
No new data have been submitted and none was required for an application of this type;
this is satisfactory.
CLINICAL EFFICACY
The applicant has presented no new data and none are required for an application of this
type. A thorough literature review of controlled studies versus placebo or other antitussive
medications has been conducted. A coherent review of all relevant published literature has
been presented.
Overall conclusions on clinical efficacy
The active, dextromethorphan hydrobromide, has a well established efficacy profile which
has been adequately reviewed by the Clinical Expert.
CLINICAL SAFETY
The clinical expert presents an overview of the safety of dextromethorphan hydrobromide
and discusses cases of abuse.
The Applicant lists adverse events reported in Martindale Pharmacopoeia and these include
dizziness and gastrointestinal upset. Excitation, confusion and respiratory depression may
occur following overdose.
Information from the Toxic Exposure Surveillance System suggests that abuse ore misuse
of dextromethorphan in 13-19 year olds has increased by more than 300% in the 3-year
period from January 2000 to November 2003. There is little published evidence regarding
the extent of dextromethorphan abuse in the UK. The clinical expert concludes that this
should be closely monitored and that warnings not to exceed the maximum recommended
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daily dose and taking the medicine for prolonged periods may lead to addiction should be
included in the SPC.
Use in Pregnancy
The Applicant states that out of 300 women who are known to have taken
dextromethorphan hydrobromide during pregnancy there have been no reports of fetal
malformations. The SPC recommends that although dextromethorphan has been in
widespread use for many years caution should be exercised by balancing the potential
benefit of treatment against any possible hazards.
Dextromethorphan has been used in man since 1954 and would appear to be well tolerated
when used in the recommended dose. The most common adverse effects during normal use
are dizzy states and gastrointestinal disorders. When administered in high dose the most
common adverse effects were drowsiness and sleep. At very high dose/in overdose
drowsiness or even coma, respiratory depression and convulsions may occur. Misuse and
abuse of dextromethorphan hydrobromide is well documented and appropriate warnings
have been included in the SPC.
Overall conclusions on clinical safety
The above safety aspects as well as use in pregnancy and information about overdose has
also been summarised by the Clinical Expert and all these aspects are adequately addressed
in the proposed product literature which is consistent with similar products currently
licensed in the UK.
Expert Report
A satisfactory clinical overview is provided, and has been prepared by an appropriately
qualified physician. The curriculum vita of the expert has been provided.
Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and
Labels
The SmPC and the combined label/PIL are acceptable from a clinical perspective, and
consistent with those for the reference product. The labelling is acceptable and in line with
current requirements.
MAA (Marketing Authorisation Application) form
The MAA form is satisfactory.
Conclusion
There are no objections to the approval of Halls Dry Cough Lozenges from a clinical point
of view.
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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of Halls Dry Cough Lozenges are well-defined and
controlled. The specifications and batch analytical results indicate consistency from batch
to batch. There are no outstanding quality issues that would have a negative impact on the
benefit/risk balance.
NON-CLINICAL
No new non-clinical data were submitted and none are required for an application of this
type.
EFFICACY
No new data are submitted and none are required for applications of this type.
The published literature supports the efficacy of this product in the proposed indications.
The efficacy of dextromethorphan hydrobromide is well-known. The presented evidence
for well-established use of the active substance is sufficient.
The literature review identifies no new safety issues or concerns. The safety profile of
dextromethorphan hydrobromide is well-known.
No new or unexpected safety concerns arose from this application.
PRODUCT LITERATURE
The SmPC, PIL and labelling are satisfactory.
The approved labelling artwork complies with statutory requirements. In line with current
legislation, the name of the product appears in Braille on the outer packaging.
The applicant has stated that all relevant patient information is to be displayed on the outer
carton as there are no plans to produce a leaflet for this product. This approach has been
used for other OTC products of a similar nature and is therefore deemed acceptable.
A user consultation with target patient groups on the package information leaflet (PIL) has
been performed on the basis of a bridging report making reference to similar product- Halls
Chesty Cough Lozenges (PL 00094/0247). The bridging report submitted by the applicant
has been found acceptable.
RISK BENEFIT ASSESSMENT
The quality of the product is acceptable, and no new non-clinical or clinical safety concerns
have been identified. Dextromethorphan hydrobromide is an active substance of wellknown safety and efficacy and has been used for a number of decades in the EC. Extensive
clinical experience with dextromethorphan hydrobromide is considered to have
demonstrated the therapeutic value of the active substance. The benefit/risk ratio is
therefore considered to be positive.
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HALLS DRY COUGH LOZENGES
PL 00094/0248
STEPS TAKEN FOR ASSESMENT
1
The MHRA received the marketing authorisation application on 13 March 2006.
2
Following standard checks and communication with the applicant the MHRA
considered the application valid on 23 March 2006.
3
Following assessment of the applications the MHRA requested further
information relating to the quality dossiers on 28 July 2006, 19 November 2009
and 19 January 2011 and information relating to the clinical dossiers on 26
February 2007.
The applicant responded to the MHRA’s requests, providing further information
on the quality dossier on 6 November 2006, 27 September 2010 and 12 April
2011 further information on the clinical dossier on 10 May 2007.
4
5
The applications were determined on 2 August 2012.
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HALLS DRY COUGH LOZENGES
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STEPS TAKEN AFTER AUTHORISATION - SUMMARY
Date
Application
submitted type
Scope
Outcome
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HALLS DRY COUGH LOZENGES
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SUMMARY OF PRODUCT CHARACTERISTICS
The UK Summary of Product Characteristics (SmPC) for Halls Dry Cough Lozenges is as
follows:
1
NAME OF THE MEDICINAL PRODUCT
Halls Dry Cough Lozenges
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Dextromethorphan hydrobromide Ph.Eur. 7.5mg per lozenge.
For full list of excipients, see section 6.1
3
PHARMACEUTICAL FORM
Lozenge
4
4.1
CLINICAL PARTICULARS
Therapeutic indications
For the relief of persistent dry coughs.
4.2
Posology and method of administration
Adults the Elderly and Children over 12 years: 2 lozenges (15mg) 3 to 4 times daily.
Children 6 to 12 years: 1 lozenge (7.5 mg) 3 to 4 times daily.
Children under 6 years: Not recommended.
Suck each lozenge until dissolved.
Do not take more than 4 doses in 24 hours.
For oral use.
4.3
Contraindications
Hypersensitivity to any of the ingredients.
In patients at risk of developing respiratory failure, for example, during an acute asthmatic attack or
in patients with Chronic Obstructive Pulmonary Disease (COPD).
4.4
Special warnings and precautions for use
Do not exceed the maximum recommended daily dose. . Prolonged use of dextromethorphan may
lead to addiction.
Use with caution in patients taking monoamine oxidase inhibitors or within 14 days of stopping such
treatment.
Use with caution in patients with .hepatic impairment.
Contains 2.4g sucrose and glucose per lozenge. This should be taken into account in patients with
diabetes mellitus. Unsuitable in fructose intolerance, glucose-galactose malabsorption syndrome or
sucrase-isomaltase deficiency.
Use with caution in patients with a history of asthma.
As there are no specific studies of dextromethorphan hydrobromide in patients with renal
impairment caution should be exercised if this drug is prescribed to patients with any degree of renal
impairment.
Keep all medicines out of reach of children.
If symptoms persist consult your doctor or pharmacist.
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4.5
Interaction with other medicinal products and other forms of interaction
Concomitant use of a dextromethorphan containing product and monoamine oxidase inhibitors can
occasionally result in symptoms such as hyperpyrexia, hallucinations, gross excitation or coma.
Toxicity may occur if dextromethorphan is taken with SSRIs or other medicines which increase
synaptic levels of serotonin.
Accumulation of dextromethorphan may occur if Halls Dry Cough Lozenges are taken with
medicines which inhibit cytochrome P450 2D6.
The concomitant ingestion of alcohol may increase the sedative effect of centrally acting atitussives.
4.6
Fertility, pregnancy and lactation
There is no or inadequate evidence of the safety of dextromethorphan in human pregnancy therefore
dextromethorphan should not be used in pregnancy unless the potential benefit to the mother will
exceed all possible risks to the foetus or neonate, consult a doctor or pharmacist before using Halls
Dry Cough Lozenges during this period. It is not known whether dextromethorphan or any of its
metabolites are excreted in the human milk.
4.7
Effects on ability to drive and use machines
This medicinal product may have some influence on the ability to drive and use machines. This
product may cause drowsiness or dizziness and patients experiencing these effects should not drive
or operate machinery.
4.8
Undesirable effects
Occasionally dizziness, nausea, vomiting, allergic skin reactions or gastro-intestinal disturbance may
occur but these are rare.
4.9
Overdose
Overdosage may lead to nausea, vomiting, abdominal discomfort, drowsiness, dizziness, excitation,
mental confusion, hallucinations, respiratory depression, hypotension and ataxia.
Treatment should consist of gastric lavage and general supportive measures. Activated charcoal may
be of use if given within one hour of the overdose.
5
5.1
PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
ATC code R05DA09; Opium Alkaloids and Derivatives
Dextromethorphan hydrobromide is a cough suppressant, it exerts its antitussive activity by acting
on the cough centre of the medulla oblongata.
5.2
Pharmacokinetic properties
Dextromethorphan hydrobromide is well absorbed from the gut following oral administration. It is
metabolised in the liver and excreted in the urine as unchanged dextromethorphan and dimethylated
metabolites including dextrorphan.
5.3
Preclinical safety data
None stated.
6
6.1
PHARMACEUTICAL PARTICULARS
List of excipients
Sucrose Granulated
Glucose Liquid
Blackcurrant flavour (contains propylene glycol and nature-identical flavouring substances)
Citric acid monohydrate
Sucralose
Masking flavour (contains propylene glycol)
Levomenthol
Carrot anthocyanin E163 (contains anthocyanin extract in water and citric acid)
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6.2
Incompatibilities
Not applicable.
6.3
Shelf life
24 months.
6.4
Special precautions for storage
Do not store above 25oC.
Store in the original package.
6.5
Nature and contents of container
Blister packs of 250m white/opaque PVC coated with 60 gsm PVDC lidded with 20m hard
temper aluminium foil contained in an outer carton.
Pack sizes are 6, 8,10 lozenges (1blister strip) or 20 lozenges ( 2 blister strips) in a carton.
6.6
Special precautions for disposal
No special requirements
7
MARKETING AUTHORISATION HOLDER
Ernest Jackson & Co Ltd
29 High Street,
Crediton,
Devon EX17 3AP
United Kingdom
8
MARKETING AUTHORISATION NUMBER(S)
PL 00094/0248
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
02/08/2012
10
DATE OF REVISION OF THE TEXT
02/08/2012
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AUTHORISATION
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HALLS DRY COUGH LOZENGES
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PATIENT INFORMATION LEAFLET /LABEL
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