Public Assessment Report UKPAR Carbocisteine 375 mg ... · Public Assessment Report UKPAR Carbocisteine 375 mg Capsules, hard (carbocisteine) UK Licence No: PL 34088/0044 Alkaloid

Public Assessment Report

UKPAR

Carbocisteine 375 mg Capsules, hard

(carbocisteine)

UK Licence No: PL 34088/0044

Alkaloid – INT d.o.o.,

PAR Carbocisteine 375 mg Capsules, hard PL 34088/0044

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LAY SUMMARY Carbocisteine 375 mg Capsules, hard

(carbocisteine)

This is a summary of the Public Assessment Report (PAR) for Carbocisteine 375 mg Capsules, hard

(PL 34088/0044). This medicinal product will be referred to as Carbocisteine Capsules for the remainder

of the lay summary for ease of reading.

This summary explains how the application for Carbocisteine Capsules was assessed and its

authorisation recommended as well as its conditions of use. It is not intended to provide practical advice

on how to use Carbocisteine Capsules.

For practical information about using Carbocisteine Capsules, patients should read the package leaflet or

contact their doctor or pharmacist.

What are Carbocisteine Capsules and what are they used for?

Carbocisteine Capsules are a ‘generic medicine’. This means that Carbocisteine Capsules are similar to a

‘reference medicine’ already authorised in the European Union (EU) called Mucodyne 375 mg

Capsules, Hard (Aventis Pharma Limited TA Sanofi; PL 04425/0203).

Carbocisteine Capsules are used for respiratory tract disorders when too much mucus is made or the

mucus is too sticky.

How do Carbocisteine Capsules work?

Carbocisteine Capsules contain the active ingredient carbocisteine, which belongs to a group of

medicines called ‘mucolytics’. Mucolytics work by making the mucus (phlegm) less sticky, which

makes the mucus easier to cough up.

How are Carbocisteine Capsules used?

CARBOCISTEINE Capsules are taken orally.

In adults and elderly, the recommended dose is two capsules, 3 times each day. If symptoms improve,

the dose should be lowered to one capsule, 4 times, each day. If it is felt that the medicine is too weak or

too strong, the dose should be discussed with the patient’s doctor.

CARBOCISTEINE Capsules are not recommended for use in children.

This medicine can only be obtained on prescription.

Please read Section 3 of the patient information leaflet (PIL) for detailed information on dosing

recommendations, the route of administration, and the duration of treatment.

How have CARBOCISTEINE Capsules been studied?

Because CARBOCISTEINE Capsules are a generic medicine, studies in patients have been limited to

tests to determine that it is bioequivalent to the reference medicine, Mucodyne 375 mg Capsules. Two

medicines are bioequivalent when they produce the same levels of the active substance in the body.

What are the benefits and risks of CARBOCISTEINE Capsules?

Because CARBOCISTEINE Capsules are a generic medicine, and are bioequivalent to the reference

medicine, Mucodyne 375 mg Capsules, their benefits and risks are taken as being the same as the

reference medicine.


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Why are CARBOCISTEINE Capsules approved?

It was concluded that, in accordance with EU requirements, CARBOCISTEINE Capsules have been

shown to have comparable quality and to be bioequivalent to Mucodyne 375 mg Capsules. Therefore,

the view was that, as for Mucodyne 375 mg Capsules, the benefits outweigh the identified risks.

What measures are being taken to ensure the safe and effective use of CARBOCISTEINE

Capsules?

A risk management plan has been developed to ensure that CARBOCISTEINE Capsules are used as

safely as possible. Based on this plan, safety information has been included in the Summary of Product

Characteristics (SmPC) and the PIL for CARBOCISTEINE Capsules, including the appropriate

precautions to be followed by healthcare professionals and patients.

Known side effects are continuously monitored. Furthermore new safety signals reported by patients and

healthcare professionals will also be monitored and reviewed continuously.

Other information about Carbocisteine Capsules

A Marketing Authorisation was granted in the UK on 14 February 2017.

The full PAR for Carbocisteine Capsules follows this summary.

This summary was last updated in March 2017.


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SCIENTIFIC DISCUSSION

TABLE OF CONTENTS

I Introduction Page 5

II Quality aspects Page 6

III Non-clinical aspects Page 7

IV Clinical aspects Page 8

V User consultation Page 10

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 11

Table of content of the PAR update

Page 19


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I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the Medicines and Healthcare products

Regulatory Agency (MHRA) granted ALKALOID-INT d.o.o., a Marketing Authorisation for the

medicinal product Carbocisteine 375 mg Capsules, hard (PL 34088/0044) on 14 February 2017.

This product is a prescription-only medicine (legal classification POM).

This application was submitted according to Article 10(1) of Directive 2001/83/EC, as amended,

claiming to be a generic medicinal product of the UK Reference Product, Mucodyne 375 mg Capsules,

Hard, which was originally granted a Marketing Authorisation to May and Baker Limited (PL

00012/0238) on 12 March 1992. Following a Change of Authorisation Holder, granted on 07 February

2009, the current Marketing Authorisation holder is Aventis Pharma Limited, TA Sanofi (PL

04425/0203).

Carbocisteine is a mucolytic agent indicated for the adjunctive therapy of respiratory tract disorders

characterized by excessive, viscous mucus, including chronic obstructive airways disease.

Carbocisteine (S-carboxymethyl L-cysteine) has been shown in normal and bronchitic animal models to

affect the nature and amount of mucus glycoprotein which is secreted by the respiratory tract. An

increase in the acid: neutral glycoprotein ratio of the mucus and a transformation of serous cells to

mucus cells is known to be the initial response to irritation and will normally be followed by

hypersecretion. The administration of carbocisteine to animals exposed to irritants indicates that the

glycoprotein that is secreted remains normal; administration after exposure indicates that return to the

normal state is accelerated. Studies in humans have demonstrated that carbocisteine reduces goblet cell

hyperplasia. Carbocisteine can therefore be demonstrated to have a role in the management of disorders

characterised by abnormal mucus.

With the exception of the bioequivalence study, no new clinical or non-clinical studies were conducted.

This is acceptable given that the application was based on being a generic medicinal product of an

originator product that has been licensed for over 10 years.

The MHRA has been assured that acceptable standards of Good Manufacturing Practice are in place for

this product type at all sites responsible for the manufacture, assembly and batch release of this product.

A summary of the pharmacovigilance system and a detailed Risk Management Plan (RMP) have been

provided with this application, and these are satisfactory.


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II QUALITY ASPECTS

II.1 Introduction

The finished product is formulated as immediate release hard gelatin capsules and contains 375 mg

carbocisteine, as the active ingredient. The excipients present are mannitol, maize starch, croscarmellose

sodium, sodium laurilsulfate, grade K12, colloidal anhydrous silica, magnesium stearate making up the

capsule content, and the capsule shell is composed of gelatine, red iron oxide E172, titanium dioxide

E171 and yellow iron oxide E172.

All excipients comply with their respective European Pharmacopoeia monographs with the exception of

red iron oxide E172 and yellow iron oxide E172 which comply with the United States Pharmacopeia.

Satisfactory Certificates of Analysis have been provided for all excipients showing compliance with

their proposed specifications.

The only excipient used that contains material of animal or human origin is gelatin. Satisfactory

documentation has been provided by the gelatin supplier/s stating that the gelatin they provide

complies with the criteria described in the current version of the monograph ‘Products with risk of

transmitting agents of animal spongiform encephalopathies’.

Confirmation has been given that the magnesium stearate used in the capsule is of vegetable

origin.

No genetically modified organisms (GMO) have been used in the preparation of these excipients.

The capsules are packaged in a transparent polyvinylchloride (PVC)/polyvinylidenechloride

(PVdC)/aluminium hard foil blister. Each blister strip contains 10 capsules. The capsules are

available in pack sizes of 20, 30, 50 or 120 capsules. Not all pack sizes may be marketed.

Satisfactory specifications and Certificates of Analysis have been provided for all packaging

components.

II.2 Drug substance rINN: Carbocisteine

Chemical name: (2R)-2-amino-3-[(carboxymethyl)sulphanyl]-propanonic acid (R)-2-Amino-4-

thia-adipinic acid

Structural formula:

Molecular formula: C5H9NO4S

Molecular weight: 179.2 g/mol

Appearance: White or almost white, crystalline powder.

Solubility: Practically insoluble in water and in alcohol. It dissolves in dilute mineral acids

and in dilute solutions of alkali hydroxides.

Carbocisteine is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, carbocisteine, are covered by

European Directorate for the Quality of Medicines Healthcare (EDQM) Certificates of Suitability

II.3 Medicinal Product


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The objective of the development programme was to formulate a safe, efficacious and stable product

that could be considered a generic medicinal product of the UK Reference Product, Mucodyne 375 mg

Capsules, Hard (Aventis Pharma Limited, TA Sanofi). A satisfactory account of the pharmaceutical

development has been provided.

Comparative dissolution and impurity profiles have been presented for the test and reference products.

Manufacture of the product

Satisfactory batch formulae have been provided for the manufacture of the product, along with an

appropriate account of the manufacturing process. Suitable in-process controls are in place to ensure the

quality of the finished product. The manufacturing process has been validated using commercial-scale

batches and has shown satisfactory results.

Finished Product Specification

The finished product specification proposed is acceptable. The test methods have been described that

have been adequately validated. Batch data have been provided that comply with the release

specification. Certificates of Analysis have been provided for all working standards used.

Stability of the Product

Finished product stability studies were performed in accordance with current guidelines on batches of

finished product in the packaging proposed for marketing. The data from these studies support a

shelf-life of 2 years. In accordance to EP monograph for capsules the storage conditions are defined

“Store below 30°C”. This is acceptable.

Suitable post approval stability commitments have been provided to continue stability testing on batches

of finished product.

II.4 Discussion on chemical, pharmaceutical and biological aspects

There are no objections to the approval of this application from a pharmaceutical viewpoint.

III Non-Clinical Aspects III.1 Introduction

As the pharmacodynamic, pharmacokinetic and toxicological properties of carbocisteine are

well-known, no new non-clinical studies are required and none have been provided. An overview based

on the literature review is, thus, appropriate.

The Applicant’s non-clinical expert report has been written by an appropriately qualified person and is

satisfactory, providing an appropriate review of the relevant non-clinical pharmacology,

pharmacokinetics and toxicology.

III.2 Pharmacology

Not applicable for this product type. Refer to section ‘III.1; Introduction’ detailed above.

III.3 Pharmacokinetics


III.4 Toxicology


III.5 Ecotoxicity/environmental risk assessment (ERA)

Since this product is intended for generic substitution, its use will not lead to an increased exposure to

the environment. An environmental risk assessment is therefore not deemed necessary.

III.6 Discussion on the non-clinical aspects


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No new non-clinical studies were conducted, which is acceptable given that the application was based

on being a generic medicinal product of the originator product that has been licensed for over 10 years.

There are no objections to the approval of this application from a non-clinical viewpoint.

IV Clinical Aspects IV.1 Introduction

The clinical pharmacology of carbocisteine is well-known. With the exception of data from the

bioequivalence study detailed below, no new pharmacodynamics or pharmacokinetic data are provided

or are required for this type of application.

The Applicant submitted one bioequivalence study in support of this application in order to demonstrate

bioequivalence with the reference product.

No new efficacy or safety studies have been performed and none are required for this type of

application. A comprehensive review of the published literature has been provided by the Applicant,

citing the well-established clinical pharmacology, efficacy and safety of carbocisteine.

Based on the data provided, Carbocisteine 375 mg Capsules can be considered bioequivalent to

Mucodyne 375 mg capsules (Sanofi)

IV.2 Pharmacokinetics

In support of this application, the Applicant submitted the following bioequivalence study:

STUDY

This is an open-label, balanced, randomized, single-dose, two-treatment, two-period, two-

sequence, two- way crossover oral bioequivalence study comparing the pharmacokinetics of the

Applicant’s test product Carbocisteine 375 mg Capsules, hard with the reference product

Mucodyne 375 mg Capsules (Sanofi) in healthy volunteers, under fasting conditions.

Blood samples were collected before dosing and up to and including 24 hours after each administration.

The washout period between the treatment phases was 7 days. The pharmacokinetic results are presented

below:

Table 1. Pharmacokinetic parameters (ln-transformed values; mean ± SD, geometric 90%

confidence Intervals, tmax median, range) for carbocisteine

Treatment AUC0-t

ng/ml/h

AUC0-∞

ng/ml/h

Cmax

ng/ml

tmax

h (median and range)

Test

9161.91±1792.03 9276.26±1786.38 2421.43 ±693.96 2.00 (1.00-6.00)

Reference

9277.08±1676.84 9383.13±1668.46 2471.19±647.59 2.00 (1.00-6.00)

*Ratio (90% CI)

98.46 (95.10 to

101.93)

98.57 (95.27 to

101.97)

97.48 (91.27 to

104.11)

AUC0-t Area under the plasma concentration curve from administration to last observed concentration at time t. AUC0-24h can be reported instead of AUC0-t, in studies with sampling period of 24 h, and where the concentration at 36 h is quantifiable.

AUC0-∞ Area under the plasma concentration curve extrapolated to infinite time.

Cmax Maximum plasma concentration tmax Time until Cmax is reached

The 90% confidence intervals of the test/reference ratio for ln-transformed AUC and Cmax values for

carbocisteine, lie within the acceptable limits of 80.00% to 125.00%, in line with the ‘Guideline on the

Investigation of Bioequivalence (CPMP/EWP/QWP/1401/98 Rev 1/Corr**). Thus, the data support the

claim that the Applicant’s test product is bioequivalent to the reference product.

IV.3 Pharmacodynamics


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No new pharmacodynamics data were submitted and none were required for an application of this type.

IV.4 Clinical efficacy

No new efficacy data were submitted and none were required for an application of this type.

IV.5 Clinical safety

No new clinical safety data are required for this application and none have been submitted.

IV.6 Risk Management Plan (RMP) and Pharmacovigilance system

The Marketing Authorisation Holder (MAH) has submitted an RMP, in accordance with the

requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and

interventions designed to identify, characterise, prevent or minimise risks relating to Carbocisteine 375

mg Capsules, hard.


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A summary of safety concerns and planned risk minimisation activities, as approved in the RMP,

is listed below:

Routine pharmacovigilance and routine risk minimisation are proposed for all safety concerns.


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IV.7 Discussion of the clinical aspects

It is recommended that a Marketing Authorisation is granted for Carbocisteine 375 mg Capsules.

V. USER CONSULTATION The package leaflet has been evaluated via a user consultation study, in accordance with the

requirements of Articles 59(3) and 61(1) of Directive 2001/83/EC, as amended. The language used for

the purpose of user testing the PIL was English.

The results show that the package leaflet meets the criteria for readability, as set out in the guideline on

the readability of the label and package leaflet of medicinal products for human use.

VI OVERALL CONCLUSION AND BENEFIT/RISK ASSESSMENT AND

RECOMMENDATION

The quality of the product is acceptable, and no new non-clinical or clinical concerns have been

identified. The data provided by the applicant showed that the product is bioequivalent to the authorised

reference product. Extensive clinical experience with carbocisteine is considered to have demonstrated

the therapeutic value of the compound. The benefit-risk assessment is, therefore, considered to be

positive.


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Summary of Product Characteristics (SmPC), Patient Information Leaflet (PIL) and Labels

In accordance with Directive 2010/84/EU the Summaries of Product Characteristics (SmPC) and Patient

Information Leaflets (PIL) for products granted Marketing Authorisations at a national level are

available on the MHRA website.

The approved labelling for Carbocisteine 375 mg Capsules, hard is presented below:


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Representative colour mock-ups of each of the Own label suppliers are presented below:

Glenmark Pharmaceuticals Europe Limited cartoon


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Mylan cartoon

The OLS distributors will use the blister proposed from the MAH – Alkaloid INT as presented below.


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Table of content of the PAR update

Steps taken after the initial procedure with an influence on the Public Assessment Report

Date

submitted

Application type Scope Outcome

Documents

Public Assessment Report UKPAR Carbocisteine 375 mg ... · Public Assessment Report UKPAR Carbocisteine 375 mg Capsules, hard (carbocisteine) UK Licence No: PL 34088/0044 Alkaloid