UK Licence Numbers: PL 20117/0096 Morningside Healthcare Ltd · UK Licence Numbers: PL 20117/0096...

Public Assessment Report

Lymecycline 408 mg Capsules, hard

(lymecycline)

UK Licence Numbers: PL 20117/0096

Morningside Healthcare Ltd

UKPAR Lymecycline 408 mg Capsules, hard PL 20117/0096

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Lay Summary Lymecycline 408 mg Capsules, hard

(lymecycline)

This is a summary of the Public Assessment Report (PAR) for Lymecycline 408 mg

Capsules, hard (PL 20117/0096). This medicinal product will be referred to as

Lymecycline Capsules in this summary, for ease of reading.

This summary explains how Lymecycline Capsules were assessed and their

authorisation recommended, as well as the conditions of use. It is not intended to

provide practical advice on how to use Lymecycline Capsules.

For practical information about using Lymecycline Capsules, patients should read the

Patient Information Leaflet (PIL) or contact their doctor or pharmacist.

What are Lymecycline Capsules and what are they used for?

Lymecycline Capsules are a generic medicine. This means that this product is similar

to a ‘reference medicine’ already authorised in the UK called Tetralysal 300 mg

Capsules (Galderma (UK) Limited).

Lymecycline Capsules are used to treat acne; which appears as blackheads or

whiteheads, which people often refer to as pimples or spots.

This medicine can also be used to treat other infections, such as:

Acute sinusitis

Bronchitis

Infections in the abdomen

Some types of eye infection called trachoma

Soft skin infection

How are Lymecycline Capsules used?

Lymecycline Capsules are taken by mouth. The whole capsule should be swallowed

with a glass of water, preferably in the morning.

The recommended dose in adults and children over 12 years for treatment of acne is

one capsule per day. The duration of this medication depends on how quickly the

patient’s condition improves. For acne it will normally be a minimum of eight weeks.

For other infections the usual dose is one Lymecycline capsule twice a day. A doctor

may recommend a higher or lower dose; this depends upon the type and severity of

the infection.

Lymecycline capsules are not recommended for use in children under 12 years of age

as the medicine can cause permanent discolouration of tooth enamel and affect bone

development.

Lymecycline Capsules can only be obtained on prescription from a doctor.


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For further information on how Lymecycline Capsules are used, please see the

Summary of Product Characteristics and package leaflet available on the MHRA

website.

How do Lymecycline Capsules work?

Lymecycline Capsules contain the active ingredient lymecycline which belongs to a

group of medicines called tetracycline antibiotics. This medicine helps to treat

infections.

How have Lymecycline Capsules been studied?

Because Lymecycline Capsules are a generic medicine, studies in patients have been

limited to tests to determine that it is bioequivalent to the reference medicine,

Tetralysal 300 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 Lymecycline Capsules?

As Lymecycline Capsules are a generic medicine of the reference medicine,

Tetralysal 300 mg Capsules, their benefits and risks are taken as being the same as

those for the reference medicine.

Why are Lymecycline Capsules approved?

It was concluded that, in accordance with EU requirements, Lymecycline Capsules

have been shown to have comparable quality and to be bioequivalent to Tetralysal 300

mg Capsules. Therefore, the view was that, as for the reference product, the benefits

outweigh the identified risks.

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

Lymecycline Capsules?

A risk management plan has been developed to ensure that Lymecycline Capsules are

used as safely as possible. Based on this plan, safety information has been included in

the Summary of Product Characteristics and the package leaflet for Lymecycline

Capsules, including the appropriate precautions to be followed by healthcare

professionals and patients.

Other information about Lymecycline Capsules

A Marketing Authorisation was granted in the UK on 23 August 2016.

The full PAR for Lymecycline Capsules follows this summary.

For more information about treatment with Lymecycline Capsules, read the package

leaflet, or contact your doctor or pharmacist.

This summary was last updated in October 2016.


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Table of Contents

I Introduction Page 5

II Quality aspects Page 7

III Non-clinical aspects Page 8

IV Clinical aspects Page 9

V User consultation Page 16

VI Overall conclusion, benefit/risk assessment and

recommendation

Page 17

Table of content of the PAR update

Page 19


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I INTRODUCTION The Medicines and Healthcare products Regulatory Agency (MHRA) granted

Morningside Healthcare Ltd a Marketing Authorisation for the medicinal product

Lymecycline 408 mg Capsules, hard (PL 20117/0096) on 23 August 2016. This

product is a prescription-only medicine (POM), indicated for the treatment of the

following infections caused by tetracycline sensitive organisms including the

following:

Acne, moderate to severe.

Acute sinusitis.

Acute exacerbation of chronic bronchitis.

Helicobacter pylori infection.

Urogenital infections caused by Chlamydia trachomatis.

Trachoma.

Rickettsial fever.

Soft tissue infection.

Consideration should be given to official guidance on the appropriate use of

antibacterial agents.

This application was submitted as an abridged national application, according to

Article 10(1) of Directive 2001/83/EC, as amended, claiming to be a generic

medicinal product. The applicant has cross-referred to Tetralysal 300 mg Capsules,

which was originally authorised to Galderma (UK) Limited (PL 10590/0019) on 29

September 1995. This reference product was also used for the purpose of the

bioequivalence study.

Tetracyclines exert bacteriostatic action at the available plasma and tissue

concentrations and are effective against intracellular and extracellular organisms. The

mechanism of action is mediated via inhibition of ribosomal protein synthesis.

Tetracyclines block access of the bacterial aminoacyl – transfer ribonucleic acid

(tRNA) to the messenger ribonucleic acid (mRNA) – ribosome complex by binding to

the 30S subunit of the ribosome, thereby preventing addition of amino acids to the

growing peptide chain in protein synthesis. Administration at therapeutically

attainable concentrations limits their toxic effects to the bacterial cells.

The exact mechanism of action whereby tetracyclines reduce lesions of acne vulgaris

has not been fully elucidated; the effect appears to result in part from the antibacterial

activity of the drugs.

No new non-clinical studies were conducted, which is acceptable given that this

application was based on being a generic medicinal product of an originator product

that has been licensed for over 10 years.

With the exception of one bioequivalence study, no new clinical data were provided

with this application A bioequivalence study was submitted to support this application

comparing the applicant’s test product Lymecycline 300 mg Capsules with the

reference product Tetralysal 300 mg Capsules (Galderma (U.K) Ltd, U.K) in healthy,


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adult, male subjects under fasting conditions The applicant has stated that the

bioequivalence study was carried out in accordance with Good Clinical Practice

(GCP).

The MHRA has been assured that acceptable standards of Good Manufacturing

Practice (GMP) are in place for this product type at all sites responsible for the

manufacturing and assembly of this product. Evidence of compliance with GMP has

been provided for the named manufacturing and assembly sites.

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

have been provided with this application, and these are satisfactory.

No new or unexpected safety concerns arose during the review of information

provided by the Marketing Authorisation Holder and it was, therefore, judged that the

benefits of taking Lymecycline 408 mg Capsules, hard outweigh the risks and a

Marketing Authorisation was granted.


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II QUALITY ASPECTS

II.1 Introduction This product is a hard capsule. Each capsule contains 408 mg of lymecycline

equivalent to 300 mg tetracycline base as the active ingredient.

The excipients present are colloidal anhydrous silica, magnesium stearate making up

the capsule content; gelatin, indigo carmin (E132), erythrosine (E127), titanium

dioxide (E171) making up the capsule cap; and the capsule body composed of gelatin,

tartrazine (E102) and titanium dioxide (E171).

All the excipients used in the manufacture of the proposed formulations comply with

their respective European Pharmacopoeia monographs with the exception of colloidal

anhydrous silica which complies with the United States Pharmacopeia and indigo

carmine lake (E132) and tartrazine (E102) comply with satisfactory in-house

specifications. Satisfactory Certificates of Analysis have been provided for all

excipients showing compliance with their proposed specifications.

None of the excipients contain material of animal or human origin. Confirmation has

been given that the magnesium stearate used in the capsules is of vegetable origin.

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

excipients.

The finished product is packaged in aluminium (Al) – aluminium (Al) blister strips

with pack sizes of 7, 14, 28, 56, and 112 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 Lymecycline

INN: Lymecycline

Chemical Name: (2S)-2-Amino-9-[[[[[(4S, 4aS, 5aS,6S,12aS)-4-(dimethyl-

amino)-3,6,10,12,12apentahydroxy-6-methyl-1,11-dioxo-

1,4,4a,5,5a,6,11,12a-octahydrotetracen-2-yl]

carbonyl]amino]-methyl]amino]hexanoic acid.

Structure:

Molecular formula: C29H38N4O10

Molecular weight: 603.0 g/mol

Appearance: Yellow, hygroscopic powder.


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Solubility: Very soluble in water, slightly soluble in ethanol (96 per cent)

and practically insoluble in methylene chloride.

Lymecycline is the subject of a European Pharmacopoeia monograph.

All aspects of the manufacture and control of the active substance, lymecycline are

covered by a European Directorate for the Quality of Medicines and Healthcare

(EDQM) Certificate of Suitability.

II.3 Medicinal Product Pharmaceutical development

The objective of the development programme was to formulate safe, efficacious,

capsules containing 408 mg of lymecycline (equivalent to 300 mg tetracycline base)

per capsule that are generic versions of the reference product Tetralysal 300 mg

Capsules (Galderma (UK) Limited).

Comparative dissolution profiles have been presented for the proposed and reference

products.

Manufacture of the products

A satisfactory batch formula has been provided for the manufacture of the product,

along with an appropriate account of the manufacturing process. A validation report

for commercial scale batches has been provided. The process validation data provided

is satisfactory.

Finished Product Specification

The finished product specification is acceptable. The test methods have been

described and have been adequately validated. Batch data have been provided that

complies with the release specification. Certificates of Analysis have been provided

for all working standards used.

Stability of the product

Stability studies were performed in accordance with current guidelines on batches of

the finished product, packed in the packaging proposed for marketing. The data from

the studies support a shelf-life of 2 years, with storage conditions “Store below 25oC”

and “Store in the original package”.

Suitable post approval stability commitments have been provided.

II.4 Discussion on chemical, pharmaceutical and biological aspects The grant of a Marketing Authorisation is recommended.

III NON-CLINICAL ASPECTS III.1 Introduction As the pharmacodynamic, pharmacokinetic and toxicological properties of

lymecycline 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.


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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 these product type. Refer to section ‘III.1; Introduction’ detailed

above.

III.3 Pharmacokinetics


above.

III.4 Toxicology


above.

III.5 Environmental Risk Assessment (ERA)

Since Lymecycline 408 mg Capsules are intended for generic substitution, their 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

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

application was based on being a generic medicinal product of originator product that

has been licensed for over 10 years.

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

view.

IV CLINICAL ASPECTS

IV.1 Introduction The clinical pharmacology of lymecycline is well-known. With the exception of

bioequivalence data, no new clinical data have been submitted and none are required

for an application of this type. The applicant’s clinical overview has been written by

an appropriately qualified person and is considered acceptable.

IV.2 Pharmacokinetics In support of this application, the Marketing Authorisation holder has submitted the

following bioequivalence study:

An Open-label, balanced, randomised, two-period, two-sequence, single-dose,

crossover, oral bioequivalence study of the test product Lymecycline 300 mg

Capsules with the reference product Tetralysal 300 mg Capsules (Galderma

(U.K) Ltd, U.K) in healthy, adult, male subjects under fasting conditions.

Blood-samples were collected before, upto and including 48.00 hours after

administration of each product with a washout period of 7 days between study drug

administrations.


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Results

Pharmacokinetic parameters for Lymecycline

The 90% confidence intervals of the test/reference formulations for AUC0-t and Cmax

values 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**). Bioequivalence has been shown for the test formulation (Lymecycline 300

mg Capsules), and the reference formulation (Tetralysal 300 mg Capsules) under

fasting conditions.

IV.3 Pharmacodynamics No new pharmacodynamics data are required for this application and none have been

submitted.

IV.4 Clinical efficacy No new clinical efficacy data are required for this application and none have been

submitted.

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) 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 Lymecycline 408 mg Capsules, hard.

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

in the RMP, is listed below:


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Routine pharmacovigilance and routine risk minimisation are proposed for all safety

concerns.

IV.7 Discussion on the clinical aspects

The grant of a Marketing Authorisation is recommended for this application.

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. 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.


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VI Overall conclusion, benefit/risk assessment and

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

have been identified. Bioequivalence has been demonstrated between the applicant’s

product and the reference product. The benefit-risk assessment is, therefore,

considered to be positive.


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Summary of Product Characteristics, Patient Information Leaflet &

Labels In accordance with Directive 2012/84/EU, the current approved UK versions of the

SmPCs and PIL for these products are available on the MHRA website.

The currently approved labelling is provided 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 (Type II variations, PSURs, commitments)

Date

submitted

Application

type

Scope Outcome

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