30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5520 Send a question via our website www.ema.europa.eu/contact 25 June 2015 EMA/CHMP/282380/2015 Committee for Medicinal Products for Human Use (CHMP) Assessment report Pregabalin Accord International non-proprietary name: pregabalin Procedure No. EMEA/H/C/004024/0000 Note Assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted.
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30 Churchill Place ● Canary Wharf ● London E14 5EU ● United Kingdom
AUC Area under the plasma concentration versus time curve
BE Bioequivalence
Ca2+ Calcium ion
CEP Certificate of Suitability
CoA Certificate of Analysis
CLcr Creatinine clearance
Cmax Maximum measured concentration of drug in plasma
CNS Central Nervous System
CHMP Committee for Medicinal Products for Human Use
CTD Common Technical Document
DSC Differential Scanning Calorimetry
EDQM European Directorate for the Quality of Medicines
EU European Union
GABA Gamma-aminobutyric acid
GAD Generalized Anxiety Disorder
GC Gas Chromatography
HDPE High Density Polyethylene
HPLC High Performance Liquid Chromatography
ICH International Conference on Harmonisation
IR Infrared
KF Karl Fisher (titration)
L Liters
LLOQ Lower Limit of Quantification
LoD Limit of Detection
LoQ Limit of Quantitation
MAA Marketing Authorization Application
MAH Marketing Authorization Holder
µg Microgram
mg Milligram
NMT Not More Than
Ph. Eur. European Pharmacopoeia
PK Pharmacokinetic
PL Package Leaflet
ppm Parts per million
PVC Polyvinyl Chloride
PVdC Polyvinylidene Chloride
PPCP Polypropylene Copolymer
QC Quality Control
QWP Quality Working Party
Assessment report
EMA/CHMP/282380/2015 Page 4/26
RH Relative Humidity
SAE Serious Adverse Event
SmPC Summary of Product Characteristics
t1/2 Elimination half life
TSE Transmissible Spongiform Encephalopathy
UV Ultraviolet
XRD X-Ray Diffraction
Assessment report
EMA/CHMP/282380/2015 Page 5/26
1. Background information on the procedure
1.1. Submission of the dossier
The applicant Accord Healthcare Limited submitted on 31 July 2014 an application for Marketing
Authorisation to the European Medicines Agency (EMA) for Pregabalin Accord, through the centralised
procedure under Article 3 (3) of Regulation (EC) No. 726/2004– ‘Generic of a Centrally authorised product’.
The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 22 May 2014.
The application concerns a generic medicinal product as defined in Article 10(2)(b) of Directive 2001/83/EC
and refers to a reference product for which a Marketing Authorisation is or has been granted in the Union on
the basis of a complete dossier in accordance with Article 8(3) of Directive 2001/83/EC.
The applicant applied for the following indication:
Treatment of - adjunctive therapy in adults with partial seizures with or without secondary generalisation. - the treatment of Generalised Anxiety Disorder (GAD) in adults.
The legal basis for this application refers to:
Generic application (Article 10(1) of Directive No 2001/83/EC).
The application submitted is composed of administrative information, complete quality data and a
bioequivalence study with the reference medicinal product Lyrica instead of non-clinical and clinical unless
justified otherwise.
The chosen reference product is:
■ Medicinal product which is or has been authorised in accordance with Community provisions in accordance with Community provisions in force for not less than 6/10 years in the EEA:
Product name, strength, pharmaceutical form: Lyrica 25 mg hard capsules
Lyrica 50 mg hard capsules Lyrica 75 mg hard capsules Lyrica 100 mg hard capsules
Lyrica 150 mg hard capsules Lyrica 200 mg hard capsules Lyrica 225 mg hard capsules
Lyrica 300 mg hard capsules
Marketing authorisation holder: Pfizer Limited
Date of authorisation: 06/07/2004
Marketing authorisation granted by:
Community
- Community Marketing authorisation numbers: For 25mg - EU/1/04/279/001-005, EU/1/04/279/026 & EU/1/04/279/036 For 50mg - EU/1/04/279/006-010 & EU/1/04/279/037 For 50mg - EU/1/04/279/011-013, EU/1/04/279/027, EU/1/04/279/030 & EU/1/04/279/038
For 100mg - EU/1/04/279/014-016 & EU/1/04/279/039
Assessment report
EMA/CHMP/282380/2015 Page 6/26
For 150mg - EU/1/04/279/017-019, EU/1/04/279/028, EU/1/04/279/031 & EU/1/04/279/040 For 200mg - EU/1/04/279/020-021 & EU/1/04/279/041
For 225mg - EU/1/04/279/033-035 & EU/1/04/279/042
For 300mg - EU/1/04/279/023-025, EU/1/04/279/029, EU/1/04/279/032 & EU/1/04/279/043
■ Medicinal product authorised in the Community/Members State where the application is made or European reference medicinal product:
Product name, strength, pharmaceutical form: Lyrica 25 mg hard capsules Lyrica 50 mg hard capsules
Lyrica 75 mg hard capsules Lyrica 100 mg hard capsules Lyrica 150 mg hard capsules Lyrica 200 mg hard capsules
Lyrica 225 mg hard capsules
Lyrica 300 mg hard capsules
Marketing authorisation holder: Pfizer Limited
Date of authorisation: 06/07/2004
Marketing authorisation granted by:
Community
- Community Marketing authorisation numbers: For 25mg - EU/1/04/279/001-005, EU/1/04/279/026 & EU/1/04/279/036 For 50mg - EU/1/04/279/006-010 & EU/1/04/279/037 For 50mg - EU/1/04/279/011-013, EU/1/04/279/027, EU/1/04/279/030 & EU/1/04/279/038 For 100mg - EU/1/04/279/014-016 & EU/1/04/279/039 For 150mg - EU/1/04/279/017-019, EU/1/04/279/028, EU/1/04/279/031 & EU/1/04/279/040
For 200mg - EU/1/04/279/020-021 & EU/1/04/279/041 For 225mg - EU/1/04/279/033-035 & EU/1/04/279/042
For 300mg - EU/1/04/279/023-025, EU/1/04/279/029, EU/1/04/279/032 & EU/1/04/279/043
■ Medicinal product which is or has been authorised in accordance with Community provisions in force and to which bioequivalence has been demonstrated by appropriate bioavailability studies:
Product name, strength, pharmaceutical form: Lyrica 50 mg hard capsules & Lyrica 300 mg hard capsules
Marketing authorisation holder: Pfizer Limited
Date of authorisation: 06/07/2004
Marketing authorisation granted by:
Community
Community Marketing authorisation numbers:
For 50mg: EU/1/04/279/006-010 & EU/1/04/279/037
For 300mg: EU/1/04/279/023-025, EU/1/04/279/029, EU/1/04/279/032 & EU/1/04/279/043
Bioavailability study numbers: 169-12 (For 50mg)
170-12 (For 300mg)
Information on paediatric requirements
Not applicable
Assessment report
EMA/CHMP/282380/2015 Page 7/26
Scientific advice
The applicant did not seek scientific advice at the CHMP.
Licensing status
The product was not licensed in any country at the time of submission of the application.
1.2. Manufacturers
Manufacturers responsible for batch release
Accord Healthcare Ltd
Ground Floor
Sage House
319 Pinner Road
North Harrow, Middlesex
HA1 4HF
United Kingdom
WESSLING Hungary Kft.
Fóti út 56.
Budapest
H-1047
Hungary
1.3. Steps taken for the assessment of the product
The Rapporteur and appointed by the CHMP and the evaluation team were:
Rapporteur: Outi Mäki-Ikola
• The application was received by the EMA on 31 July 2014.
• The procedure started on 20 August 2014.
• The Rapporteur's first Assessment Report was circulated to all CHMP members on 4 November 2014.
• During the meeting on 18 December 2014, the CHMP agreed on the consolidated List of Questions to be
sent to the applicant.
• The applicant submitted the responses to the CHMP consolidated List of Questions on 10 March 2015.
• The Rapporteur circulated the Assessment Report on the applicant’s responses to the List of Questions to
all CHMP members on 23 April 2015.
• During the CHMP meeting on 21 May 2015, the CHMP agreed on a list of outstanding issues to be
addressed in writing and/or in an oral explanation by the applicant.
• The applicant submitted the responses to the CHMP consolidated List of Outstanding Issues on 22 May
Assessment report
EMA/CHMP/282380/2015 Page 8/26
2015.
The Rapporteur circulated the Assessment Report on the applicant’s responses to the List of Questions to
all CHMP members on 16 June 2015.
• During the meeting on 25 June 2015, the CHMP, in the light of the overall data submitted and the
scientific discussion within the Committee, issued a positive opinion for granting a Marketing
Authorisation to Pregabalin Accord.
2. Scientific discussion
2.1. Introduction
Pregabalin Accord is a generic medicinal product of Lyrica, which has been authorised in the EU since 6 July
2004.
The active substance of Pregabalin Accord is pregabalin, an analogue of the neurotransmitter gamma-
aminobutyric acid (GABA). Pregabalin decreases central neuronal excitability by binding to an auxiliary
subunit (α2-δ protein) of a voltage-gated calcium channel on neurons in the central nervous system.
Pregabalin reduces the release of several neurotransmitters, including glutamate, noradrenaline, and
substance P.
The safety and efficacy profile of pregabalin has been demonstrated in several clinical trials, details of which
can be found in the EPAR for Lyrica. In addition, there is a long-term post-marketing experience contributing
to the knowledge of the clinical use of this product. Since this application is a generic application referring to
the reference medicinal product Lyrica, summary of the clinical data of pregabalin is available and no new
clinical studies regarding pharmacology, pharmacokinetics and efficacy and safety have been conducted.
Pregabalin Accord hard capsules have the same qualitative and quantitative composition, in terms of active
substance, and the same pharmaceutical form as the reference product Lyrica. Bioequivalence of the 50 mg
dose with the reference 50 mg Lyrica capsule and 300mg dose with the reference 300mg Lyrica capsule was
demonstrated clinically. For the remaining doses, CHMP has accepted a biowaiver.
The indication proposed for Pregabalin Accord is a subset of indication authorized for the reference medicinal
product, namely treatment of
- adjunctive therapy in adults with partial seizures with or without secondary generalisation.
- the treatment of Generalised Anxiety Disorder (GAD) in adults.
The proposed pack sizes are consistent with the dosage regimen and duration of use.
2.2. Quality aspects
2.2.1. Introduction
The finished product is presented as hard capsules containing 25mg, 50mg, 75mg, 100mg, 150mg, 200mg,
The marketing authorisation holder shall submit periodic safety update reports for this product in accordance
with the requirements set out in the list of Union reference dates (EURD list) ) provided for under Article
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.
2.8. Product information
2.8.1. User consultation
No full user consultation with target patient groups on the package leaflet has been performed on the basis
of a double bridging report making reference to Lyrica (for content) and Solifenacin succinate 5/10mg film-
coated tablets (for design and layout). The bridging report submitted by the applicant has been found
acceptable.
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EMA/CHMP/282380/2015 Page 25/26
3. Benefit-risk balance
This application concerns a generic version of pregabalin hard capsules. The reference product Lyrica is
indicated for the treatment of peripheral and central neuropathic pain in adults, adjunctive therapy in adults
with partial seizures with or without secondary generalisation and treatment of Generalised Anxiety Disorder
(GAD) in adults. Pregabalin Accord indication is limited to adjunctive therapy in adults with partial seizures
with or without secondary generalisation and treatment of Generalised Anxiety Disorder (GAD) in adults,
which is acceptable. No nonclinical studies have been provided for this application but an adequate summary
of the available nonclinical information for the active substance was presented and considered sufficient.
From a clinical perspective, this application does not contain new data on the pharmacokinetics and
pharmacodynamics as well as the efficacy and safety of the active substance; the applicant’s clinical
overview based on information from published literature was considered sufficient.
The bioequivalence studies form the pivotal basis with an open-label, balanced, randomized, two-sequence,
two-period, cross-over, single dose design. The design was considered adequate to evaluate the
bioequivalence of this formulation and was in line with the respective European requirements. Choice of
dose, sampling points, overall sampling time as well as wash-out period were adequate. The analytical
method was validated. Pharmacokinetic and statistical methods applied were adequate.
Based on the presented bioequivalence studies, Pregabalin capsules 300 mg are considered bioequivalent
with Lyrica hard capsules 300 mg with respect to rate and extent of absorption of Pregabalin; and Pregabalin
capsules 50 mg are considered bioequivalent with Lyrica hard capsules 50 mg with respect to rate and extent
of absorption of Pregabalin.
The results of study 170-12 with 300 mg formulation can be extrapolated to other strengths: 75 mg,
100 mg, 150 mg, 200 mg and 225 mg, and the results of study 169-12 with 50 mg formulation can be
extrapolated to the other strength 25 mg, according to conditions in the relevant Guideline.
A benefit/risk ratio comparable to the reference product can therefore be concluded.
The CHMP, having considered the data submitted in the application and available on the chosen reference
medicinal product, is of the opinion that no additional risk minimisation activities are required beyond those
included in the product information.
4. Recommendation
Based on the CHMP review of data on quality, safety and efficacy, the CHMP considers by consensus that the
benefit-risk balance of Pregabalin Accord in the treatment of - adjunctive therapy in adults with partial seizures with or without secondary generalisation. - the treatment of Generalised Anxiety Disorder (GAD) in adults
is favourable and therefore recommends the granting of the marketing authorisation subject to the following
conditions:
Conditions or restrictions regarding supply and use
Medicinal product subject to medical prescription.
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EMA/CHMP/282380/2015 Page 26/26
Conditions and requirements of the Marketing Authorisation
Periodic Safety Update Reports
The marketing authorisation holder shall submit periodic safety update reports for this product in accordance
with the requirements set out in the list of Union reference dates (EURD list) provided for under Article
107c(7) of Directive 2001/83/EC and published on the European medicines web-portal.
Conditions or restrictions with regard to the safe and effective use of the medicinal product
Risk Management Plan (RMP)
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed
RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the
RMP.
An updated RMP should be submitted:
At the request of the European Medicines Agency;
Whenever the risk management system is modified, especially as the result of new information
being received that may lead to a significant change to the benefit/risk profile or as the result of an
important (pharmacovigilance or risk minimisation) milestone being reached.
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time.