4. Clinical aspects - Zāļu valsts aģentūra

Scientific Discussion
Somnols 7,5 mg film-coated tablets
Applicant: JSC Grindeks, Latvia
Date of the PAR: April 2011
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Information about the initial procedure:
Application type/Legal basis
Name of the product
Active substance
Pharmaceutical form, strength
Pharmacotherapeutic group
ATC code
Applicant’s name and address
EU-procedure number
Reference Member State
Member States Concerned
Generic application Art.10.1 Dir.2001/83/EC
Somnols 7,5 mg film-coated tablets
Film-coated tablets, 7,5 mg
Hypnotics and sedatives
JSC Grindeks,
53 Krustpils Street, Riga, LV-1057, Latvia
End of procedure
22 February 2011
Based on the review of the data on quality, safety and efficacy, the State Agency of
Medicines (SAM) considered that the application for Somnols 7,5 mg film-coated
tablets indicated for treatment of transient, short-term insomnia for adults (including
difficulties in falling asleep, nocturnal awakening and early awakening) and a
support therapy for a limited period of time in the treatment of chronic insomnia,
could be approvable. Zopiclone is only indicated when the disorder is severe, which
limits patient activity or is subjecting the individual to extreme distress.
National marketing authorisation for the above mentioned product was granted on
April 14 1999.
This mutual recognition procedure concerns a generic application claiming essential
similarity with the reference product Imovane 7,5 mg film-coated tablets (LV MA
number – 98-0590) which has been authorised in Latvia by Sanofi-aventis Latvia
Ltd. since 14th October 1998.
The marketing authorisation is granted based on article 10.1 of Directive
This type of application refers to information that is contained in the
pharmacological-toxicological and clinical part of the dossier of the authorisation of
the reference product. A reference product is a medicinal product authorised and
marketed on the basis of a full dossier, i.e. including chemical, biological,
pharmaceutical pharmacological-toxicological and clinical data. This information is
not fully available in the public domain. Authorisations for generic products are
therefore linked to the ‘original’ authorised medicinal product, which is legally
allowed once the data protection time of the dossier of the reference product has
expired. For this kind of application, it has to be demonstrated that the
pharmacokinetic profile of the product is similar to the pharmacokinetic profile of
the reference product. To this end the applicant has submitted a bioequivalence study
in which the pharmacokinetic profile of the product is compared with the
pharmacokinetic profile of the reference product Imovane 7,5 mg film-coated tablets
registered in Latvia.
The active component Zopiclone is a hypnotic and sedative agent. It also exhibits
anticonvulsant, muscle relaxant and hypnosedative properties in animals. It is a
gamma amino butyric agonist (GABA), which binds to receptor subtype GABAA.
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Zopiclone possesses high affinity for benzodiazepine receptors in rat brain region
(cerebral cortex, cerebellum and hippocampus) and inhibits the binding of diazepam
and nitrazepam to benzodiazepine receptors.
The clinical efficacy of Somnols 7,5 mg film-coated tablets for the indications stated
in the Summary of Product Characteristics may be concluded without any reasonable
doubt. The clinical overview on the clinical pharmacology, efficacy and safety is
adequate. The adverse events that can be expected are listed in the SmPC.
The chemical-pharmaceutical documentation and Quality Overall Summary in relation
to Somnols 7,5 mg film-coated tablets are of sufficient quality in view of the present
European regulatory requirements.
Drug substance
The drug substance zopiclone is known substance described in a Ph. Eur. monograph.
Drug substance is manufactured by JSC Grindeks, Ph. Eur. certificate of suitability
(CEP) is available. Drug substance specification and control tests have been developed
according to the Ph.Eur. requirements.
The proposed retest period of 5 years is justified and stated in the CEP.
Medicinal product
The development of the product has been described, the choice of excipients is
justified and their functions explained.
The manufacturing process is adequately described. The used in-process controls and
the performed validation studies are considered as sufficient to guarantee an
appropriate quality of the drug product.
The product specifications cover appropriate parameters for this dosage form.
Validation of the analytical methods has been presented. Specifications and tests are
described adequately. Batch analysis has been performed on 3 pilot batches and 2
production batches. The batch analysis results show that the finished product meet the
specification proposed.
The conditions used in the stability studies are according to the ICH stability
guideline. The control tests and specifications for drug product are adequately drawn
The proposed shelf-life of 2 years with storage conditions “Do not store above 25°C.
Store in original packaging in order to protect from light and moisture” for the drug
product is considered acceptable.
This product is a generic formulation of Imovane 7,5 mg film-coated tablets, which is
available on the European market. Pharmacodynamics, pharmacokinetics, toxicology
and interactions of zopiclone are well known. No new data have been submitted, and
therefore the application has not undergone preclinical assessment. In the view of the
long-term clinical experience, presentation of new data is not necessary for approval of
the Marketing Application. Overview based on literature review is thus appropriate.
Information on pharmacokinetics is comprehensively presented in the clinical section.
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Zopiclone is a well-known active substance with established efficacy and tolerability.
No new data have been submitted. No new data are required for an essentially similar
product. Provided bioequivalence has been satisfactorily demonstrated.
The use of zopiclone is based on the fact that it is a cyclopyrrolone agent that enhances
the inhibitory effects of gamma aminobutyric acid (GABA) as a result of its agonist
activity at GABAA receptors. Zopiclone and the benzodiazepines appear to bind to the
same recognition site, enhancing the function of the GABAA receptor. Zopiclone binds
to specific benzodiazepine receptor subtypes, with greater affinity for ω1 than ω2
receptors. It has been shown that zopiclone and other cyclopyrrolones act on a
different site to those of benzodiazepines including different conformational changes
in the receptor complex. Zopiclone rapidly initiates and sustains sleep without
reduction of total REM sleep and with preservation of slow wave sleep.
The safety profile of zopiclone is well known through its extensive use in clinical
The side effects of zopiclone are well known. The SPC adequately reflects current
knowledge on the safety of zopiclone and provides details of precautions and possible
side effects. Safety data are adequately summarised in the clinical expert report.
To support the application, the applicant has submitted one bioequivalence study
performed on the 7.5 mg strength under fasting conditions. The study was a
randomized, single centre, single dose, two-way crossover design in healthy male and
female subjects.
The test product Zopiclone 7.5 mg film-coated tablet is considered equivalent to the
reference product Imovane 7.5 mg film-coated tablet.
Somnols 7,5 mg film-coated tablets has a proven chemical-pharmaceutical quality and
is a generic form of Imovane 7,5 mg film-coated tablets. Imovane 7,5 mg film-coated
tablets is a well-known medicinal product with an established favourable efficacy and
safety profile.
Bioequivalence has been shown to be in complience with the requirements of
European guidance documents. As Somnols is subject of a generic application, no
additional pharmacovigilance activities and/or risk minimisation measures are
proposed for this product by the applicant, which the RMS finds acceptable.
Based on the data on quality, safety and efficacy the SAM considered that the benefit
risk balance could be favourable for Somnols 7,5 mg film-coated tablets. No
additional toxicological or clinical studies were deemed necessary for this application.
The summary of product characteristics, package leaflet and labelling are in the
agreement with other zopiclone containing products.
A European harmonised birth date has been allocated on 10 December 1984 and
subsequently the next data lock point (DLP) for zopiclone is May 2012 and the PSUR
should be submitted no later than 60 days after this date. A 3- yearly PSUR cycle will
apply hereafter. Therefore, the second PSUR will cover the period May 2012 until
May 2015.
The date for the first renewal will be: 21.02.2016.
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