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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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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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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


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


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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