UK Licence Numbers: PL 20117/0096 Morningside Healthcare Ltd · UK Licence Numbers: PL 20117/0096...
Transcript of 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
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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
Not applicable for these product type. Refer to section ‘III.1; Introduction’ detailed
above.
III.4 Toxicology
Not applicable for these product type. Refer to section ‘III.1; Introduction’ detailed
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