pectodrill sugar-free for chesty … toxicity studies using carbocisteine by oral gavage in rats ......

MHRA PAR; PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION AND PECTODRILL FOR CHESTY COUGHS 5 PER CENT ORAL SOLUTION, PL 05630/0031-2

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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

UKPAR

TABLE OF CONTENTS

Lay summary

Page 2

Scientific discussion

Page 3

Steps taken for assessment

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Summary of product characteristics

Page 14

Patient information leaflet

Page 21

Labelling Page 30


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PECTODRILL SUGAR-FREE FOR CHESTY COUGHS 5 PER CENT ORAL

SOLUTION


PL 05630/0031-2

LAY SUMMARY

The Medicines and Healthcare products Regulatory Agency (MHRA) granted Marketing Authorisations (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


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 active ingredient 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 chronic bronchopneumopathies. 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 Mr 179.2 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 cent oral solution contains essentially the same excipients, but sucrose solution is used instead of sodium saccharin and caramel flavour is used instead of aromatic flavour. Appropriate justification for the inclusion of each excipient has been provided.

The excipients in PectoDrill are all Ph. Eur. grade, with the exception of the sucrose solution, which is controlled by the French monograph and the flavourings (in the absence of relevant Ph Eur monographs, this is acceptable). Certificate of analysis for all excipients are provided in support of the proposed specifications. The flavours used in these products comply with EC 88/388. No excipient used contains material of animal or human origin.


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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 30°C” 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 were been 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. Assessor’s overall conclusions on quality These products are satisfactory and Marketing Authorisations may be granted.


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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 vitro models 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, in chronic 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 lung have 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. PHARMACO/TOXICOKINETICS No pharmacokinetic studies have been conducted by the applicant and none are needed. Absorption, Distribution, Metabolism and Excretion (ADME) No ADME studies have been conducted by the applicant. The literature has been reviewed and summarised. In rodents, primates and humans, carbocisteine is rapidly and well absorbed by the oral route, with a maximum plasma concentration (Cmax) approximately two hours after administration and the subsequent kinetics fit a one-compartment open model. Distribution in the mouse is


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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 month’s duration at 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 when given 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. GENOTOXICITY AND CARCINOGENICITY No genotoxicity or carcinogenicity studies have been carried out on carbocisteine. This has been addressed in accordance with NfG CPMP/SWP/799/95 and is satisfactory. EXCIPIENTS All the excipients are of EP or suitable grade and are present in acceptable quantities.


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NON-CLINICAL OVERVIEW The non-clinical overview was written by an expert who has experience in pharmaceutical development 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 CLASS

Carbocisteine 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.

INDICATIONS The 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 containing carbocisteine as a single active substance. Therefore, the requested therapeutic indication would be acceptable for use in the UK. DOSE AND DOSE REGIMEN The 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. CONSIDERATION FOR PAEDIATRIC USE

The Applicant is not seeking authorisation in children and, therefore, a clinical programme or bibliographic review is not presented in support of use in this age group. PHARMACODYNAMICS

Carbocisteine is a cysteine derivative and act as 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. .


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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 presented no 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 therapeutic indication. 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 LITERATURE All product literature is medically satisfactory. CONCLUSIONS

This Application has been submitted as a so-called “bibliographical application”; the Applicant has submitted no new data. The pharmacodynamics and pharmacokinetics of carbocisteine are well documented in the literature and it is considered that no further work is required. In respect of clinical efficacy the Applicant presents a literature review and highlights four placebo-controlled studies, and two of studies that incorporated an active control. Carbocisteine has been used in man for some years and would appear to be well tolerated when used within the recommended dose range. In view of the long history of carbocisteine use and the relatively few adverse events it is possible to conclude that the risk/benefit ratio is favourable. Therefore Marketing Authorisations may be granted for these products.


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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 ASSESSMENT The 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


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 MHRA’s requests, providing further information on 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 MHRA’s 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 MHRA’s requests, providing further information on 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 MHRA’s requests, providing further information on the quality dossier on 5 August 2009

11 The application was determined on 17 September 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 ml Excipients: 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. 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.

4.4 Special warnings and precautions for use Special warnings Productive coughs are a fundamental component of the bronchopulmonary defences and should not be suppressed. Precautions for use This medicinal product contains small amounts of ethanol (alcohol), less than 100 mg per 15 ml dose (ethanol content: 0.8 % v/v). 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.


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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 an antitussive 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 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 properties Carbocisteine is rapidly absorbed following oral administration; the plasma peak is reached in two hours.


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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 hydroxide Purified water * Aromatic flavour : Rum, honey, cocoa tincture, orange tincture, cherry tincture, hart’s 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 30°C

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

6.6 Special precautions for disposal No special requirements.

7 MARKETING AUTHORISATION HOLDER

PIERRE FABRE MEDICAMENT 45, Place Abel Gance 92100 Boulogne France


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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 COMPOSITION

CARBOCISTEINE…………………………………5.00 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. 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.

4.4 Special warnings and precautions for use Special warnings


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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-galactose malabsorption 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)

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


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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 properties Carbocisteine 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 excipients Sucrose 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 30 months

6.4 Special precautions for storage Do not store above 30°C

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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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

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LABELLING


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pectodrill sugar-free for chesty … toxicity studies using carbocisteine by oral gavage in rats ......

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