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PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5
PER CENT ORAL SOLUTION
PECTODRILL FOR CHESTY COUGHS 5 PER CENT
ORAL SOLUTION
PL 05630/0031-2
UKPAR
TABLE OF CONTENTS
Lay summary Page 2
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PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL
SOLUTION
PECTODRILL FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION
PL 05630/0031-2
LAY SUMMARY
The Medicines and Healthcare products Regulatory Agency (MHRA) granted MarketingAuthorisations (licences) for the medicinal products PectoDrill sugar-free for chesty coughs 5
per cent oral solution and PectoDrill for chesty coughs 5 per cent oral solution (Product
Licence numbers: 05630/0031-2).
These medicines belong to a group known as the mucolytics or expectorants, which are used
for the treatment of chesty coughs. These types of medicines work by modifying secretions
(mucus or phlegm) in your lungs making them easier to remove by coughing or spitting.
PectoDrill sugar-free for chesty coughs 5 per cent oral solution and PectoDrill for chesty
coughs 5 per cent oral solution raised no clinically significant safety concerns and it was,
therefore, judged that the benefits of using these products outweigh the risks; hence
Marketing Authorisations have been granted.
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PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL
SOLUTION
PECTODRILL FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION
PL 05630/0031-2
SCIENTIFIC DISCUSSION
TABLE OF CONTENTS
Introduction Page 4
Pharmaceutical assessment Page 5
Preclinical assessment Page 7
Clinical assessment Page 10
Overall conclusions and risk benefit assessment Page 12
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INTRODUCTION
Based on the review of the data on quality, safety and efficacy, the UK granted marketing
authorisations for the medicinal products PectoDrill sugar-free for chesty coughs 5 per cent
oral solution and PectoDrill for chesty coughs 5 per cent oral solution to Pierre Fabre
Medicament on 17 September 2009. These medicines are only available on prescription.
These are bibliographic applications submitted under article 10a of Directive 2001/83/EC.
Carbocisteine, also known as S-carboxymethylcarbocisteine, is a well-established activeingredient with documented efficacy and acceptable safety in clinical use. It is a
mucoregulator that affects the secretory functions of the bronchial mucosa by increasing
sialomucins over fucomicins and sulphomucins, thereby normalising and increasing the
elasticity of the secretions, and increasing mucociliary transport. It also has an anti-
inflammatory effect.
These products are indicated for the treatment of bronchial secretion disorders, particularly
during acute bronchial impairments such as acute bronchitis and acute episode of chronicbronchopneumopathies. One 15 ml measure should be given three times daily initially; after
a satisfactory response this may be reduced to three 10 ml measures daily.
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PHARMACEUTICAL ASSESSMENT
DRUG SUBSTANCE
Carbocisteine
C5H9NO4S
Mr179.2
Physical form: a white, crystalline powder, practically insoluble in water, in alcohol and in
ether. It dissolves in dilute mineral acids and in dilute solutions of alkali hydroxides.
An appropriate specification has been provided.
Analytical methods have been appropriately validated and are satisfactory for ensuring
compliance with the relevant specifications.
Active carbocisteine is stored in appropriate packaging. The specifications and typical
analytical test reports are provided and are satisfactory.
Batch analysis data are provided and comply with the proposed specification.
Satisfactory certificates of analysis have been provided for working standards used by the
active substance manufacturer and finished product manufacturer during validation studies.
Appropriate stability data have been generated supporting an acceptable retest period.
DRUG PRODUCT
Description and Composition of the Drug Product
PectoDrill sugar-free for chesty coughs 5 per cent oral solution contains the following
excipients: sodium saccharin, methyl parahydroxybenzoate (E218), hydroxyethylcellulose,
aromatic flavour, sodium hydroxide and purified water. PectoDrill for chesty coughs 5 per
l l i i i ll h i i b l i i d
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Manufacture
The methods of manufacture of the sugar free and sugar containing solutions are basically
similar. Descriptions and flow-charts of the manufacturing methods have been provided.
In-process controls are appropriate considering the nature of the products and the method of
manufacture. Process validation has been carried out on product batches. The results are
satisfactory.
Finished product specification
The finished product specification is satisfactory. Acceptance limits have been justified with
respect to conventional pharmaceutical requirements and, where appropriate, safety. Test
methods have been described and have been adequately validated, as appropriate. Batch data
have been provided and comply with the release specification. Certificates of analysis have
been provided for any working standards used.
Container Closure System
The finished product is packaged in 150 ml or 200 ml glass bottles, with or without a
measuring cup (15 ml).
Specifications are given for packaging materials and these are supported by certificates of
analysis. The glass used to make the bottles complies with the requirements of the Eur. Ph.
The measuring cup is CE marked and a suitable certificate is given.
Stability
Finished product stability studies have been conducted in accordance with current guidelines.
Based on the results, a shelf-life of 30 months with the storage precaution Do not store
above 30C has been set, which is satisfactory.
Bioequivalence / Bioavailability
As the product is in solution no study is reported.
Product literature
All product literature (SPCs, PILs and labelling) are satisfactory. The package leaflets werebeen submitted to the MHRA along with results of consultations with target patient groups
("user testing"), in accordance with Article 59 of Council Directive 2001/83/EC. The results
indicate that the package leaflets are well-structured and organised, easy to understand and
written in a comprehensive manner. The test shows that the patients/users are able to act upon
the information that they contains.
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PRECLINICAL ASSESSMENT
GOOD LABORATORY PRACTICE (GLP) ASPECTS
Most of the preclinical data have been taken from the published literature. Hence,
compliance with GLP regulations cannot be verified. Reports of single-dose toxicity studies
conducted by the applicant do not contain a GLP statement but the studies appear to have
been performed to a suitable standard.
PHARMACODYNAMICS
The non-clinical overview contains a selective review of publications on the effects of
carbocisteine in rheological, biochemical and mucociliary clearance studies relevant to the
proposed indication. Appropriate animal and in vitromodels showed that carbocisteine was
effective in:
normalisation of bronchial mucus secretion
reduction of mucosal goblet cell hyperplasia reduction of purulent mucous obstructions in the tracheobronchial tree
increasing mucociliary transport
increasing respiratory compliance
reduction of inflammation (indirectly)
There are three major classes of glycoproteins in bronchial mucus: the acid sialomucins and
sulphomucins, and the neutral fucomucins. Normally, the sialomucins predominate but, inchronic bronchitis, there is an increase in fucomucins and, as the disease progresses, in
sulphomucins. Carbocisteine increases sialomucins over fucomucins by stimulating
sialyltransferase activity. The reduction in viscosity of the bronchial mucus by carbocisteine
is related to the splitting of disulphide bonds in the long-chain glycoproteins of the mucus
layer.
General pharmacological effects include antioxidant and possible immunostimulant effects,
while, with cimetidine, metabolic interaction and increased levels of amoxicillin in the lunghave been reported. None of these would interfere adversely with the intended therapeutic
effect.
The non-clinical overview provides an adequate summary of the pharmacodynamics relevant
to the clinical indication
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primarily to the lungs and respiratory mucus. Most of the drug is excreted unchanged in the
urine with the main metabolite in rodents and humans being the sulphoxide and minor
pathways being acetylation and decaroboxylation.
The review of ADME of carbocisteine is adequate, given its long-established clinical use.
TOXICOLOGY
Single-dose toxicity studies in rats and mice were conducted to compare the toxicity of a
tablet formulation with that of the active ingredient. The results were compared with those
available in the literature, which date generally from the 1970s and 1980s.
SINGLE-DOSE TOXICITY
Single-dose toxicity studies in mice and rats by various routes showed carbocisteine to be
lethal at doses considerably higher than those used clinically.
REPEAT-DOSE TOXICITY
Repeat-dose toxicity studies using carbocisteine by oral gavage in rats of one months
durationat doses up to 1500 mg/kg and of six months duration at doses up to 700 mg/kg
were conducted. With doses of 750 and 1500 mg/kg, some treatment-related but not dose-
related changes were noted in the blood chemistry. Some dose-related changes in organ
weights were found but there were no histopathological changes. In females dosed for three
months of the six-month study, some dose-dependent changes in blood chemistry were found
but they were not present at six months. At 350 and 700 mg/kg in females at six months,
ketone bodies in the urine were noted but there were no effects on organ weights or any
histopathological changes.
REPRODUCTIVE AND DEVELOPMENTAL TOXICITY
Two abstracts from 1977 on reproductive and developmental toxicity are cited. In rats,
carbocisteine by the oral route at doses up to 500 mg/kg did not affect reproduction whengiven to males before mating and females before mating and during pregnancy, and there was
no indication of teratogenicity. There were no effects on the offspring in rabbits dosed orally
with carbocisteine at doses up to 250 mg/kg during gestation.
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NON-CLINICAL OVERVIEW
The non-clinical overview was written by an expert who has experience in pharmaceuticaldevelopment and is a pharmacologist and toxicologist recognised by the appropriate French
ministry.
PRODUCT LITERATURE
The product literature is acceptable from a preclinical point of view.
CONCLUSION
Marketing Authorisations may be granted for these products.
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CLINICAL ASSESSMENT
THERAPEUTIC CLASSCarbocisteine is a mucolytic agent. It exerts its action on the gel phase of the mucus by
breaking the disulfide bonds of glycoproteins, thereby rendering the mucous less viscous and
aiding expectoration.
Carbocisteine has effects on bronchial secretion by normalisation of mucus hyperviscosity.
INDICATIONSThe Applicant has submitted the following:
Treatment of bronchial secretion disorders, particularly during acute bronchial impairments:
acute bronchitis and acute episode of chronic bronchopneumopathies.
This therapeutic indication is essentially the same as that for other UK products containingcarbocisteine as a single active substance. Therefore, the requested therapeutic indication
would be acceptable for use in the UK.
DOSE AND DOSE REGIMENThe following has been submitted:
For oral use.For use in adults and children over 12 years of age only.
One 15 ml measure three times daily initially; after a satisfactory response, this may be
reduced to three 10 ml measures daily.
One 15 ml measure contains 750 mg of carbocisteine.
The maximum total daily dose is 2250 mg of carbocisteine (45 ml of oral solution).
Not recommended for use in children 12 years of age and younger.
Shake the bottle prior to use.
This posology is essentially in line with the posology for other products containing
carbocisteine authorised in the UK and is, therefore, satisfactory.
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The pharmacological properties of carbocisteine have been well documented in the
literature and the Applicant has reviewed a number of studies The Applicant has presentedno new data and none are required.
PHARMACOKINETCS
The Applicant presents no new data; the Applicant has provided a review of the literature.
Carbocisteine is rapidly adsorbed following oral administration; the plasma peak is reached
in two hours. The bioavailability is low less than 10% of the dose administered, probably
due to intraluminal metabolism and a marked liver first-pass effect. The elimination half-
life is approximately 2 hours. Both it and its metabolites are mainly eliminated via the
kidneys
The Applicant has provided a comprehensive summary of the pharmacokinetics and it is
considered that no further work is required.
CLINICAL EFFICACY
The Applicant presents no new data. The literature has been reviewed and is presented in a
summarised format in both the Expert Report on the Clinical Documentation and in Part IV
of the dossier in a document entitled Clinical Documentation Literature Review Synthesis.
The applicant presents a literature review of four double-blind, placebo-controlled studies,
and two double-blind studies versus an active comparator within the same therapeuticindication. In addition the results of a meta-analysis conducted on studies carried out in
Germany are presented. The review demonstrates adequate efficacy for the product.
CLINICAL SAFETY
No formal data are presented and none are required, a review of the literature is presented.
PRODUCT LITERATUREAll product literature is medically satisfactory.
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OVERALL CONCLUSION AND RISK BENEFIT ASSESSMENT
QUALITY
The important quality characteristics of PectoDrill sugar-free for chesty coughs 5 per cent
oral solution and PectoDrill for chesty coughs 5 per cent oral solution 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.
PRECLINICAL
No new preclinical data were submitted and none are required for applications of this type.
EFFICACY
The efficacy of carbocisteine is well documented.
No new or unexpected safety concerns arise from these applications.
The SPCs, PIL and labelling are satisfactory and consistent with those for other
carbocisteine-containing products.
RISK BENEFIT ASSESSMENTThe quality of these products is acceptable and no new preclinical or clinical safety concerns
have been identified. The risk benefit ratio is, therefore, considered to be acceptable.
.
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PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL
SOLUTION
PECTODRILL FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION
PL 05630/0031-2
STEPS TAKEN FOR ASSESSMENT
1 The MHRA received the marketing authorisation application on 16 June 2003
2 Following standard checks and communication with the applicant the MHRA
considered the application valid on 29 November 2005
3 Following assessment of the application the MHRA requested further
information relating to the quality dossier on 5 November 2003 and the clinical
dossier on 5 July 2004
4 The applicant responded to the MHRAs requests, providing further informationon the quality and clinical dossiers on 21 September 2005
5 Following assessment of the response the MHRA requested further information
relating to the quality dossier on 1 September 2006
6 The applicant responded to the MHRAs requests, providing further information
on the quality dossier on 21 August 2007
7 Following assessment of the response the MHRA requested further information
relating to the quality dossier on 9 October 2007
8 The applicant responded to the MHRAs requests, providing further informationon the quality dossier on 28 October 2008
9 Following assessment of the response the MHRA requested further information
relating to the quality dossier on 4 August 2009
10 The applicant responded to the MHRAs requests, providing further information
th lit d i 5 A t 2009
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SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
PectoDrill sugar-free for chesty coughs 5 per cent oral solution.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
CARBOCISTEINE 5.0 g per 100 mlExcipients: Methyl parahydroxybenzoate and Sodium
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of bronchial secretion disorders, particularly during acute bronchial
impairments: acute bronchitis and acute episode of chronic bronchopneumopathies.
4.2 Posology and method of administrationFor oral use.
For use in adults and children over 12 years of age only.
One 15 ml measure three times daily initially; after a satisfactory response, this may
be reduced to three 10 ml measures daily.
One 15 ml measure contains 750 mg of carbocisteine.
The maximum total daily dose is 2250 mg of carbocisteine (45 ml of oral solution).
Not recommended for use in children 12 years of age and younger.
Shake the bottle prior to use.
4.3 Contraindications
- Known hypersensitivity to carbocisteine or any of the other constituents.
-
Active peptic ulcer disease.
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4.5 Interaction with other medicinal products and other forms of
interaction
An expectorant or mucolytic medicinal product should not be combined with anantitussive medicinal product or a medicinal product indicated for use to dry
secretions (such as anticholinergics).
4.6 Pregnancy and lactation
Pregnancy
Studies in animals have not revealed any teratogenic effect. In the absence of
available clinical data, the administration of this drug should be avoided during
pregnancy as a precautionary measure.
Lactation
The use of this drug is not recommended while breast-feeding.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.
4.8 Undesirable effects
Frequency is defined as: rare (1/10,000 to 1/1,000),according to the MedDRA
frequency convention and system organ classification.
Gastrointestinal disorders:
Rare: Gastric pain, nausea, diarrhoea.
Skin and subcutaneous tissue disorders:
Rare: rashes as well as allergic reactions caused by parahydroxybenzoate (possibly
delayed)
4.9 Overdose
Symptoms and signs:
Most likely gastrointestinal disturbance.
Treatment:
The treatment should be symptomatic and supportive. Gastric lavage may be
beneficial.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
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The bioavailability is low, less than 10% of the dose administered which is probably
due to intraluminal metabolism and a marked liver first-pass effect.
The elimination half-life is approximately 2 hours.Both it and its metabolites are mainly eliminated via the kidneys.
5.3 Preclinical safety data
Preclinical safety data in literature have not revealed any relevant findings that have
not been mentioned elsewhere in this SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Saccharin
Methyl parahydroxybenzoate (E218)
Hydroxyethylcellulose
Aromatic flavour*
Sodium hydroxidePurified water
* Aromatic flavour : Rum, honey, cocoa tincture, orange tincture, cherry tincture,
harts tongue leaves, tonka bean, liquorice, vanillin, ethyl vanillin, maltol,
acetylmethylcarbinol, ethylacetate, caramel colouring, glycol propylene
6.2 Incompatibilities
Not applicable
6.3 Shelf life
30 months
6.4 Special precautions for storage
Do not store above 30C
6.5 Nature and contents of container- 150 ml glass bottle
- 200 ml glass bottle
- 150 ml glass bottle with a measuring cup (15 ml)
- 200 ml glass bottle with a measuring cup (15 ml)
Not all pack sizes may be marketed
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8 MARKETING AUTHORISATION NUMBER
PL 05630/0031
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/09/2009
10 DATE OF REVISION OF THE TEXT
17/09/2009
1 NAME OF THE MEDICINAL PRODUCT
PectoDrill for chesty coughs 5 per cent oral solution.
2 QUALITATIVE AND QUANTITATIVE COMPOSITIONCARBOCISTEINE5.00 g per 100 ml
Excipients: Sucrose, Methyl parahydroxybenzoate and Sodium
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Oral solution
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of bronchial secretion disorders, particularly during acute bronchial
impairments: acute bronchitis and acute episode of chronic bronchopneumopathies.
4.2 Posology and method of administration
For oral use.
For use in adults and children over 12 years of age only.
One 15 ml measure three times daily initially; after a satisfactory response, this may
be reduced to three 10 ml measures daily.
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Productive coughs are a fundamental component of the bronchopulmonary defences
and should not be suppressed.
Patients with rare hereditary problems of fructose intolerance, glucose-galactosemalabsorption or sucrase isomaltase insufficiency should not take this medicine.
This product may be harmful for teeth.
Precautions for use
In the event of either diabetes mellitus or low-sugar diet, the content of 6 g of sucrose
per 15 ml measure should be taken into account.
In the event of low sodium diet, the content of 0.1g of sodium per 15 ml measure
should be taken into account.
Do not exceed the stated dose.Keep out of the reach and sight of children.
4.5 Interaction with other medicinal products and other forms of
interaction
An expectorant or mucolytic medicinal product should not be combined with an
antitussive medicinal product or a medicinal product indicated for use to dry
secretions (such as anticholinergics).
4.6 Pregnancy and lactation
Studies in animals have not revealed any teratogenic effect. In the absence of
available clinical data, the administration of this drug should be avoided during
pregnancy as a precautionary measure.
Lactation
The use of this drug is not recommended while breast-feeding.
4.7 Effects on ability to drive and use machines
No studies on the effects on the ability to drive and use machines have been
performed.
4.8 Undesirable effects
Frequency is defined as: rare (1/10,000 to 1/1,000),according to the MedDRA
frequency convention and system organ classification.Gastrointestinal disorders:
Rare: Gastric pain, nausea, diarrhoea.
Skin and subcutaneous tissue disorders:
Rare: rashes as well as allergic reactions caused by parahydroxybenzoate (possibly
delayed)
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5.1 Pharmacodynamic properties
MUCOLYTIC
ATC code: R05CB03(R: respiratory system)
Carbocisteine is a mucolytic-type mucomodifier. It exerts its action on the gel phase
of the mucus, probably by breaking the disulphide bonds of the glycoproteins and thus
aids expectoration.
Moreover, carbocisteine has effects on bronchial secretion by normalization of mucus
hyperviscosity.
5.2 Pharmacokinetic propertiesCarbocisteine is rapidly absorbed following oral administration; the plasma peak is
reached in two hours.
The bioavailability is low, less than 10% of the dose administered which is probably
due to intraluminal metabolism and a marked liver first-pass effect.
The elimination half-life is approximately 2 hours.
Both it and its metabolites are mainly eliminated via the kidneys.
5.3 Preclinical safety data
Preclinical safety data in literature have not revealed any relevant findings that have
not been mentioned elsewhere in this SPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipientsSucrose solution
Methyl parahydroxybenzoate (E218)
Hydroxyethylcellulose
Caramel flavour*
Sodium hydroxide
Purified water
* Caramel flavour : aromatic caramel, coffee extract, vanillin.
6.2 Incompatibilities
Not applicable
6.3 Shelf life
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6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
PIERRE FABRE MEDICAMENT
45, Place Abel Gance
92100 Boulogne
France
8 MARKETING AUTHORISATION NUMBER(S)
PL 05630/0032
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
17/09/2009
10 DATE OF REVISION OF THE TEXT
17/09/2009
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PATIENT INFORMATION LEAFLET
PectoDrill sugar-free for chesty coughs 5 per cent oral solution:
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:
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PectoDrill for chesty coughs 5 per cent oral solution:
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LABELLING
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MHRA PAR;PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION AND PECTODRILL FOR CHESTY COUGHS 5 PERCENT ORAL SOLUTION, PL 05630/0031-2
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MHRA PAR;PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION AND PECTODRILL FOR CHESTY COUGHS 5 PERCENT ORAL SOLUTION, PL 05630/0031-2
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