Esogno 2 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel - Esogno 2 mg Filmtabletten

ADMINISTRATIVE INFORMATION

Proposed name of the medicinal product in the RMS	Esogno 1 / 2 / 3 mg Filmtabletten
Name of the drug substance (INN name):	Eszopiclone
Pharmaco-therapeutic group (ATC Code):	N05CF04
Pharmaceutical form(s) and strength(s):	Film-coated tablet; 1 / 2 / 3 mg
Reference Number(s) for the Decentralised Procedure	DE/H/5813/001–003/DC
Reference Member State:	DE
Concerned Member States:	DE 5813 : AT, BG, CZ, EE, HU, LT, LV, PL, SK
Legal basis of application:	Article 8(3) application
Applicant (name and address)	DE 5813 G.L. Pharma GmbH Schlossplatz 1 8502 Lannach, Austria

I INTRODUCTION

Based on the review of the data on quality, safety and efficacy, the application for “Esogno 1 / 2 / 3 mg Filmtabletten” with the following indication:

“<Invented name> is indicated for the treatment of insomnia, in adults, usually for short-term duration.

Benzodiazepines or benzodiazepine-like substances are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress”,

is approved.

Proposal for Inspection.

GCP inspection is not considered necessary.

New Active Substance Status

Based on the data provided by the applicant eszopiclone was not considered for new active substance status in the PrAR. New active substance status in no longer claimed by the applicant.

II EXECUTIVE SUMMARY

II.1 Problem statement

Insomnia is a heterogeneous report reflecting reduced quality, duration, or efficiency of sleep. In the DSM-IV Manual (APA, 1994) and ICD-10 (WHO, 1992), insomnia is a common condition characterised by sleep disruption lasting at least one month. Disruption of sleep may include difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening. An additional complaint is diminished sleep quality or nonrestorative sleep. In addition the DSM-IV has a report of daytime impairment or distress as a diagnostic criterion. Typically this is evidenced by a report of fatigue and poor concentration.

Newer classifications of insomnia (DSM-V and International Classification of Sleep Disorders (ICSD-3)) require symptoms of insomnia for at least three nights a week and do not distinguish between primary and secondary insomnia. According to ICSD-3 main features of insomnia comprise persistent sleep difficulty, non-adequate sleep opportunity and associated daytime dysfunction; if duration of symptoms is less than 3 months, the diagnosis is short-term insomnia disorder and if duration is at least three months chronic insomnia is being diagnosed.

II.2 About the product

(S)-Zopiclone, hereafter referred to as eszopiclone, is a positive allosteric agonist at gammaaminobutyric acid type A receptors (GABAA ). Racemic zopiclone is a 1:1 mixture of the enantiomers (S)-zopiclone and ®-zopiclone. Racemic zopiclone (also referred to as (RS)-zopiclone) is a shortacting hypnotic agent developed by Rhone-Poulenc Rorer and marketed in Europe under the trade names of Imovane and Zimovane. The applicant has developed eszopiclone as a treatment for the relief of insomnia in adult patients, at a proposed dosage of up to a maximum of 3.0 mg once daily.

II.3 General comments on the submitted dossier

This application for the marketing authorisation for the drug product Eszopiclone 1 mg, 2 mg, and 3 mg film-coated tablets is made under article 8(3) full application of Directive 2001/83/EC as amended.

With Germany as the Reference Member State in these Decentralized Procedures the applicants Alfred E. Tiefenbacher (GmbH & Co. KG) and G.L. Pharma GmbH are applying for the Marketing Authorisation for Lunivia and Esogno 1 mg, 2 mg, 3 mg Film-coated tablets, in the following CMSs:

1. DE/H/5812/001–003/DC with BE, FI, FR, IT, LU and NO
2. DE/H/5813/001–003/DC with AT, BG, CZ, EE, HU, LV, LT, PL and SK.

The Marketing Authorsation Applications in DK, ES, IE and SE were withdrawn during clock stop.

Development Rationale

Racemic zopiclone is a 1:1 mixture of the enantiomers (S)-zopiclone and ®-zopiclone which is currently marketed in Europe by Sanofi-Aventis, for example in Germany as XIMOVAN and Imovane in UK. Eszopiclone is the S-enantiomer of zopiclone, belongs to the group of hypnotics and sedatives and is classified as benzodiazepine-related drug (ATC Code N05CF04).

The prior knowledge of racemic zopiclone properties facilitated the development of eszopiclone, and some studies also incorporated concurrent zopiclone groups for comparison, including one clinical safety study (ESZ111503), one pharmacokinetic study (190–001), and one bioavailability study (190010).

Overall, within the clinical development programme of eszopiclone, 41 studies (including 4 studies in adolescents and children) were conducted between 1975 and 2011.

The development of eszopiclone focused on optimising the dose response with respect to efficacy (including a rapid onset of action and sleep maintenance throughout the night) as well as safety and tolerability, whilst minimising next day effects. One of the discoveries of the removal of the ®-isomer (which does not contribute to the therapeutic activity of racemic zopiclone) was that the resultant improvements in efficacy and safety of eszopiclone were achieved at a lower dose (3 mg) than that of the (S)-isomer in conjunction with the ®-isomer in racemic zopiclone (3.75 mg).

Overall, the development program addressed two important medical needs: long-term safety and efficacy in primary insomnia, and safety and efficacy in comorbid insomnia.

II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles

Quality:

The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.

For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.

GMP active substance:

Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.

GLP

The main studies with eszoplicone were conducted according to GLP.

GCP

The clinical trials (sponsored by Sunovion, formerly Sepracor) were performed in accordance with GCP as claimed by the applicant. The applicant has provided a statement to the effect that clinical trials conducted outside the community were carried out in accordance with the ethical standards of Directive 2001/20/EC.

II.5 Type of application and other comments on the submitted dossier

The application is a full application.

III SCIENTIFIC OVERVIEW AND DISCUSSION
III.1 Quality aspects

Drug substance

The active substance is Eszopiclone, which is a single isomer comprising pure (S)-zopiclone. There is no Ph. Eur. monograph for Eszopiclone available. A monograph “Eszopiclone” is included in the USP. The ASMF procedure is followed for the drug substance. Two manufacturers of Eszopiclone are approved for this drug product.

Eszopiclone from manufacturer A:

The synthesis of Eszopiclone consists of two main stages.

A detailed discussion on possible impurities has been provided.

The drug substance is controlled by an in-house specification, which bases on the USP monograph for Eszopiclone. The specification includes description, identification (IR, HPLC), assay (HPLC), organic impurities (HPLC), enantiomeric purity (enantioselective HPLC), loss on drying, residue on ignition, residual solvents (GC), particle size (laser diffraction) and microbiological tests.

The batch results of validation batches of the drug substance showed compliance with the specification.

Stability studies of the validation batches at 40°C±2°C / 75±5% RH are finalised, the long term stability studies at 25°C±2° / 60±5% RH are in progress and results over 24 months available. No degradation was visible. From the stability data, the proposed retest period of 36 months is considered justified.

Eszopiclone from manufacturer B:

The synthesis of Eszopiclone consists of two main stages.

A detailed discussion on possible impurities has been provided.

The drug substance is controlled by an in-house specification.

The specification includes description, identification (IR, HPLC, XRD), solubilities, water content (KF), residue on ignition, related substances (HPLC), assay (HPLC), chiral purity (enantioselective HPLC), residual solvents (GC), particle size (laser diffraction) and BOSE-V content (HPLC). Validation of the analytical procedures is presented.

The batch results of validation batches of the drug substance showed compliance with the specification.

Stability data of production size batches stored at long term conditions (25ºC / 60% RH) are available over 60 months storage (three batches) or are still in progress. Accelerated stability studies (6 months at 40°C / 75% RH) are finalised. No degradation was visible. From the stability data, the proposed expiry data of 60 months under the storage conditions “Preserve in tight containers. Store at 25°C, excursions permitted between 15 and 30°C” is considered justified.

Drug Product

The proposed drug products are film-coated tablets for oral use. Three strengths are presented: Film-coated tablets containing 1mg, 2mg or 3mg of Eszopiclone.

The excipients of the core are commonly used for immediate-release formulations. The film coating, intended for taste masking and product differentiation, is light blue (1mg), white (2mg) or blue (3mg). All excipients comply with the respective Ph. Eur. monograph, except indigotine (E 132).

The manufacturing process for the 1 mg, 2 mg and 3 mg strengths is identical, utilizing dry blending – compression – film coating.

The product specifications cover relevant parameters for this dosage form, and are fully justified. Acceptable limits for assay and and related substances have been set.

Validation results of the analytical methods have been presented.

Batch analysis results are provided for the three process validation batches for each strength. The specified parameters were met.

For packaging, three blisters are proposed: blisters made of white opaque PVC/PVdC/PVC – Aluminium, white PVC/PCTFE – Aluminium or oPA/Alu/PVC – Aluminium.

The to date provided stability data do justify the proposed shelf life of 24 months, by extraploation.

Conclusion:

The drug product is considered approvable from a quality point of view.

III.2 Non clinical aspects

Pharmacology

Eszopiclone [(S)-zopiclone] is a non-benzodiazepine hypnotic agent of the cyclopyrrolone pharmacological class. As proposed for zopiclone and other sedative/hypnotic drugs, the effect of eszopiclone is believed to result from allosteric modulation of gamma-aminobutyric acid (GABA) type A (GABAA ) receptor, which results in neuronal hyperpolarisation via increase of GABA evoked chloride conductance and thereby inhibiting neuronal transmission and causing sleep.

Eszopiclone is the pure (S)-enantiomer of the racemic zopiclone, which is a 1:1 mixture of the enantiomers (S)-zopiclone and ®-zopiclone.

Primary Pharmacodynamics

In vitro binding studies with Eszopiclone confirmed selective binding to GABAA receptor, receptor -associated activation of chloride ion channels and subsequent induction of ion current as the relevant mode of action. In comparison to the racemic zopiclone or R-enantiomer eszopiclone exhibited a higher affinity to central benzodiazepine receptor and chloride channels, suggesting that the S-enantiomer is the primary component responsible for the action of the racemic (1:1) zopiclone. Also, the corresponding metabolites, -zopiclone oxide and – desmethylzopiclone (DMZ), exhibit much lower affinity than the parent compounds (RS or S forms).

Interestingly, stereoselective effects of zopiclone enantiomers are observed at individual (recombinant) GABAA receptors. Whereas eszopiclone potentiates the effects at all four GABAA receptor subtypes effectively at 1 μM (predominantly through α2 and α3 subunits), ®-zopiclone shows only a certain effect on one GABAA receptor subtype (α1) at 10 μM.

A series of in vivo studies demonstrated that (S)-zopiclone is the component primarily responsible for the sedative and anxiolytic effects of zopiclone. Zopiclone, (S)-zopiclone, and possibly ®-zopiclone (only one animal), but not (S)-DMZ, were shown to produce BZD-like discriminative effects.

Whether the noted small binding properties and effect of the R-enantiomer contribute to the known zopiclone response at clinically relevant doses is not clear. Thus, removal of R-enantiomer and its potential influence on clinical efficacy and safety can not be conclusively predicted based on the nonclinical data but has to be investigated in a clinical head-to head comparison of eszopiclone versus zopiclone.

Secondary Pharmacodynamics

The results of a series of receptor binding and activity studies with eszopiclone, zopiclone, and the R-enantiomer show no relevant other target than the known benzodiazepine receptor site.

Following a screen of 83 receptor sites (including hERG channel) and 23 enzymes, greater than 50% binding inhibition was only observed at the central benzodiazepine site and rat cerebral cortical chloride channels with zopiclone and (S)-zopiclone.

Safety Pharmacology

Investigation of anticholinergic effects in animals in vivo did not reveal any significant effects on induced salivation or mydrasis. Zopiclone and its enantiomers were weak antimuscarinic agents, only 10% inhibition of oxotremorine-induced salivation was observed at the highest (300 mg/kg) dose.

In vivo studies in dogs suggest only minor cardiovascular effects (decreased MAP, increased HR, decreased action potential duration) for (S)-Zopiclone, (S)-DMZ, racemic zopiclone, and racemic DMZ at exposures and doses well above clinically relevant exposure/doses, and no effects on myocardial contractility or ECG were noted.

(S)-Zopiclone and (S)-DMZ have no significant effect on hERG tail current at concentrations 100 times the free plasma concentrations at Cmax following a 3.0 mg dose in humans. Removal of the ®-isomer did not unmask an effect of the (S)-isomer.

Eszopiclone appears to have a high safety margin with no indication of deleterious peripheral effects.

Withdrawal syndrome has been previously associated with chronically administered zopiclone to Rhesus monkeys (16 or 32 mg/kg b.i.d for 4 weeks) manifested by tremor, muscle rigidity, apprehension, piloerection, and hyperirritability. Results from dependence studies in mice suggest that

eszopiclone, zopiclone and S-DMZ displayed a very low potential to induce physical dependence (convulsions) after acute to short-term administration.

Pharmacokinetics

No in vivo ADME studies for eszopiclone were performed, instead, the applicant refers to data from a series of pharmacokinetic studies for zopiclone.

(RS)-zopiclone is rapidly absorbed (also rapid crossing of the blood-brain barrier), well distributed and extensively metabolised. Tmax varied between 0.1–0.5 hours in the rat (Study 190–546) and 0.5–1.0 hours in the dog (Study 190–550) and terminal half- lives were 10.9 hours (female) and 13 hours (male) in the rat and 3 hours (female) and 2,8 hours (male) in the dog. Oral bioavailibility of zopiclone was 42% and 46% in the rat (male and female) and 108% and 115 % in the dog (male and female), respectively. The majority of the dose was excreted in the first 24 hours, mainly in urine and feces. The major metabolic pathways in rats and dogs was mainly characterized as oxidative processes.

Comparative toxikokinetic data of (S)-zopiclone versus zopiclone were generated in the 1– and 3-month toxicology studies in rats and dogs. In all four studies three doses of eszopiclone but only a single high dose of zopiclone were investigated.

No evidence of conversion from the (S)- to the ®-enantiomer was observed.

However, the toxicokinetics of zopiclone in rats and dogs was stereoselective with greater systemic exposure to the (S)-enantiomer than to the ®-enantiomer. Whether the observed differences at high dose were also true for the lower doses, is still unclear due to the lack of a complete comparative study of zopiclone and eszopiclone.

Protein binding was moderate across all species. In vitro plasma protein binding was determined to be 52.2–58.9% in humans and 28.8–46.7% in rat, 36.7–56.5% in mouse and 31.9–43.5% in the dog.

In vitro metabolism studies of [14 C]-eszopiclone in animal and human hepatocytes in the absence or presence of (R )-zopiclone indicate that the presence of ®-zopiclone did not affect the in vitro metabolism of (S)-zopiclone in mouse, rat, dog, and human hepatocytes.

(RS)-zopiclone was demonstrated to undergo extensive first pass metabolism, and in vitro investigation with cytochrome P450 isoforms indicated that CYP2E1 and CYP3A4 may be responsible for the metabolism of (S)-zopiclone.

Additional studies conducted as part of the three month toxicology studies to evaluate the liver microsomal cytochrome P450 and UDP-glucuronosyl-transferase enzymes in mice and rats indicated that (S)-zopiclone was a moderate phenobarbital-type inducer.

In vitro investigations revealed (S)-zopiclone to be highly permeable across human intestinal Caco-2 monolayer via transcellular pathway.

Toxicology

Single dose toxicity

Eszopiclone possesses a low order of acute toxicity. The median lethal dose following oral administration in mice exceeds 900 mg/kg for eszopiclone. In comparison, the median lethal doses were 1500 mg/kg for zopiclone. With ®-zopiclone, deaths were seen at 900 mg/kg and its median lethal oral dose in mice was >1500 mg/kg. In rats, the median lethal intravenous dose of eszopiclone was between 1 and 10 mg/kg for males and 100–250 mg/kg for females. Similarly, the median lethal intravenous doses in rats for zopiclone were between 25 and 50 mg/kg for males and 150–200 mg/kg for females, and those of ®-zopiclone were between 100 and 150 mg/kg in males and 150–250 mg/kg in females. All deaths occurred within 4 days following oral administration and within 1 hour for intravenous administration. Signs of toxicity included those effects expected for GABAA -mediated sedative hypnotics and were comparable across test articles at the toxic doses evaluated. On a mg/kg basis, the safety margin for an acute oral dose of eszopiclone in animals is high in relation to to the maximum clinical daily dose of eszopiclone, 3 mg (i.e., 0.06 mg/kg in a 50 kg human).

Repeat-dose toxicity

Repeat-dose toxicity studies were performed in mice, rats and dogs with eszopiclone at duration of up to 3 months. Rats and dogs were the primary rodent and non-rodent species of choice. Long-term studies up to 12 months in dogs and up to 18 months in rats were performed with (RS)-zopiclone. These long-term studies with (RS)-zopiclone can be bridged to the long-term studies required for eszopiclone.

Subchronic studies in rats indicated that eszopiclone was tolerated at oral dosages of 25 and 100 mg/kg/day in males and females, respectively, for 3 months. Subchronic studies in dogs demonstrated that eszopiclone was tolerated at oral dosages of 2.5 mg/kg/day and 10 mg/kg/day in females, for 3 months. In these species, treatment-related findings were consistent with exaggeration of the known pharmacologic effects of eszopiclone and ceased to occur following the termination of dosing. In male rats, pathologic changes in reproductive organs and suppressed spermatogenic parameters were observed. The spermatogenic effects were fully reversible at all dosages. These findings were comparable between eszopiclone and zopiclone. In a separate fertility study where male rats were treated for over 2 months at 5 mg/kg/day, there were no treatment-related pathologic or spermatogenic alterations.

Liver findings (increased liver weight, liver cell hypertrophy) were also common in the repeated dose toxicity studies in mice, rats and dogs with eszopiclone and zopiclone. However, these findings were considered secondary to induction of liver microsomal enzymes by these substances and were regarded of limited clinical relevance.

The exposure margins of eszopiclone alone or combined eszopiclone and (S)-DMZ in animals were high compared to those of humans following the maximum recommended human dosage (3 mg/day). The dosages evaluated in the 1– and 3-month oral studies with eszopiclone in animals provided sufficiently high systemic exposures of eszopiclone to assess the potential toxicities. In these studies, zopiclone was included as a comparator. These subchronic studies in mice, rats and dogs demonstrate that the toxicology of zopiclone is comparable to that of eszopiclone, indicating that elimination of the ®-enantiomer did not unmask any unexpected toxicity of the (S)-enantiomer. There was no enantiomeric conversion from the (S)- to the ®-isomer in any species evaluated.

No additional toxic effects have been revealed during the 12-months chronic toxicity study in dogs and the 18-months chronic toxicity study in rats. No thyroid follicular cell adenomas have been observed in 2-years carcinogenicity studies with eszopiclone in mice and rats.

Genotoxicity

Eszopiclone

Genotoxicity testing of eszopiclone was carried out in vitro (bacterial and mammalian mutation assays, chromosome aberration assays) and in vivo (mouse micronucleus test, unscheduled DNA synthesis in rat hepatocytes). Dependent on the study, ®-zopiclone, zopiclone, and the metabolite (S)-DMZ were used as comparator. The cytotoxic threshold concentration is higher than that to be obtained in the clinic. Furthermore, the in vivo Micronucleus test in mice and the unscheduled DNA synthesis study in rats as well as the six month carcinogenicity study in p53+/- transgenic mice, was negative and thus the genotoxic potential of eszopiclone is negligible.

(S)-DMZ (metabolite)

Genotoxicity testing of (S)-DMZ was carried out in in vitro (bacterial mutation assay, chromosome aberration assays and 32P-postlabeling of DNA adducts) and in vivo (Cytogenetic assay in rat). The in vivo Cytogenetic assay in mice and the 6 month carcinogenicity study in p53+/- transgenic mice, was negative and thus the genotoxic potential of (S)-DMZ is negligible.

Carcinogenicity

Long-term carcinogenicity testing of eszopiclone was carried out in lifespan studies in mice and rats. Additional short-term carcinogenicity testing of eszopiclone and the metabolite (S)-DMZ was carried out in heterozygous p53+/- transgenic mice

Long-term studies

Major findings in long-term studies in rats and mice were in general dose-dependent, transient PD-related effects of eszopiclone. Neoplastic findings observed in the studies were common spontaneous

neoplasms of the strain, showed neither dose dependency nor reached statistical significance. No treatment-related neoplastic findings were detected in both species with eszopiclone.

Short-term studies

In short term studies with eszopiclone and (S)-DMZ in heterozygous p53+/- transgenic mice, mortality occurred and was distributed across all groups without clinical signs or macroscopic and microscopic findings indicative of toxicity as cause of lethality. No difference in incidence of mortality between treated groups, vehicle, and negative controls was detected. Major findings were dose-dependent, transient PD-related effects, slight changes in different hematology parameters and non-neoplastic findings in the liver with eszopiclone only (high dose). Dose-dependent signs of degeneration of the male reproductive organs (testis, epididymis) are in line with other studies conducted in rats using related doses of eszopiclone and (S)-DMZ. No treatment-related neoplastic findings were detected.

Reproductive and developmental toxicity (q.v. Mechanistic studies concerning reproductive toxicity findings)

Pivotal reproductive and developmental toxicity testing of eszopiclone and the pharmacological active metabolite (S)-DMZ were carried out in several segment I, II and III studies. Substance-induced effects on fertility and early embryonal development as well as embryo-foetal development were investigated in rats (Segment I/II/III), while rabbits were used as second species for assessment of adverse effects on embryo-foetal development (Segment II). To qualify potential impurities an additional embryo-foetal development study with (S)-DMZ and 2 % (spiked) impurities (2– amino-5-chloropyridine, pyrazine acid aldehyde, 1-methylpiperazine) was conducted in rats. Several studies used zopiclone as comparator.

Fertility and early embryonic development

Eszopiclone

Two fertility and early embryonic development studies with eszopiclone were conducted in rats. In one study males were mated with females both treated with eszopiclone whereas in the second study treated males were mated with non-treated females. In both studies a mid-dose zopiclone was used as comparator. Toxicological findings were in general dose-dependent, transient PD-related effects accompanied by dose-dependent and transient maternal toxicity (body weight loss, reduced food consumption), observed in both eszopiclone and zopiclone. In both studies, mating indices were not affected whereas fertility indices, confirmed by signs of degeneration of the male reproductive organs (testis, epididymides), were reduced for both males and females. In one study the reduction of fertility indices were not statistically significant but values were out of the range of the historical control data of the testing facility and therefore attributed to treatment.

(S)-DMZ (metabolite)

Two fertility and early embryonic development studies with the metabolite (S)-DMZ were conducted in rats. In one study treated males were mated with untreated females whereas in in the second study non-treated males were mated with treated females. In the first study a low dose eszopiclone was used as comparator. Toxicological findings seen in both studies were in general dose-dependent, transient PD-related effects for both (S)-DMZ and eszopiclone. In one study the fertility indices, confirmed by signs of degeneration in the male reproductive organs (testis, epididymides), were reduced for males and consequential for non-treated females. In the eszopiclone group, the fertility indices were not affected for both genders. In the second study mating and fertility indices for treated female rats were not affected.

Embryo- foetal development studies in rats and rabbits

Eszopiclone

Major findings for eszopiclone (± 2% Impurities) and the comparator zopiclone were restricted to dosedependent, transient PD-related effects and transient maternal toxicity (body weight loss, reduced food consumption) leading to delays in foetal intrauterine development in rats and rabbits. External variations and visceral skeletal variations and malfunctions observed in rats were typical seen for this strain of rats, incidental and not dose-related, statistically not significant and thus non-treatment related. No effects on the embryo-fetal development of rabbits were observed. No TK data was determined for pregnant rat and rabbits.

(S)-DMZ (metabolite)

In the embryo-fetal development studies with (S)-DMZ in rats and rabbits major findings were restricted to dose-dependent, transient PD-related effects and transient maternal toxicity (body weight loss, reduced food consumption) leading to foetal intrauterine developmental delays observed in the

high dose group only. No treatment related embryo-foetal developmental effects were observed in both species. In conclusion eszopiclone and the pharmacologic active metabolite (S)-DMZ were not teratogenic, neither in rats nor rabbits.

Prenatal and postnatal development, including maternal function in rats with eszopiclone

In the F0 generation major findings were dose-dependent, transient PD-related effects accompanied by transient maternal toxicity (reduced food consumption). In the high dose group reduced mean litter sizes caused by cannibalization were observed and probably resulted from PD effects.

In the F1 generation reproductive toxicity including dose-dependent decreased body weight gains and a reduction in post-natal survival during the pre-weaning period were observed. Physical and functional development as well as mating and fertility indices were not affected.

In the F2 generation no signs of toxicity were detected.

Mechanistic studies concerning reproductive toxicity findings

Mechanistic studies were performed in rat to evaluate potential hormonal and endocrine effects of eszopiclone. In particular thyroid effects and liver enzyme induction, enzyme induction and male reproductive effects (relationship to liver enzyme induction), and female fertility were further investigated for eszopiclone.

1. Hormonal function and reproductive effects in male rats

Toxicological macroscopic and microscopic findings of eszopiclone and zopiclone observed on reproductive organs (testes, epididymides) were equivalent in this study and were observed in all other toxicology studies in a dose-dependent manner. In this study effects on reproductive organs at high dosages tend to be reversible based on lower incidence and lower severity of findings after the recovery period. The thyroidal effects observed are consistent with the known effects specific to rats, and were not considered to be of human relevance. To date neither eszopiclone nor zopiclone exhibited any adverse effects on reproductive organs at therapeutic doses in humans and therefore the findings in the rats did probably not translate to a human risk.

2. Reproductive senescence in rats following chronic oral administration of eszopilcone

To assess whether chronic oral administration of eszopiclone or zopiclone could disrupt oestrous cyclicity and accelerate the time to onset of reproductive senescence female rats with normal and abnormal estrus cycling were treated for 11 months with eszopiclone. The dose levels of zopiclone were chosen to mimic the exposures to produce an increase in mammary gland adenocarcinomas detected in the 2-year carcinogenicity study in females. In this study chronically administered eszopiclone and zopiclone at high doses lead to irregular cycling and accelerate the time to onset of reproductive senescence. Sensitive subpopulation with abnormal cycling appears to be pre-disposed to these effects.

No influences on menstrual cycling, duration of menses, and early reproductive senescence, were observed in a six month clinical study (190–050) with 505 women (828 subjects in total).

3. Uterotrophic assay of eszopiclone and zopiclone in ovariectomised rats

Due to the formation of mammary adenomas in the two-year carcinogenicity in rats with zopiclone, estrogenic activity of eszopiclone and zopiclone was determined. Neither eszopiclone nor zopiclone demonstrated agonistic activities of natural estrogens.

Juvenile toxicity studies

Juvenile toxicity studies were conducted with eszopiclone in juvenile rats (age 21d) and dogs (age 9/10w). An additional DRF study was conducted in juvenile dogs for histopathology evaluation.

No new effects of eszopiclone were obseved in toxicity studis conductd in juvenile animals. Ezopiclon is not indicted to be treated to pediatric patients.

Local tolerance

Eszopiclone, (S)-DMZ (metabolite)

The local tolerance and (skin) sensitization potential of eszopiclone and the metabolite (S)-DMZ was carried out according the Magnusson and Kligman Maximization Technique in guinea pig. Based on the results of the studies eszopiclone and (S)-DMZ were nonsensitizing in guinea pigs under the conditions of this study, and were essentially non-irritating.

Dependence

Escopiclone

No specific non-clinical studies to assess dependence potential of eszopiclone were performed. The toxicology studies performed with eszopiclone did not produce data suggestive of withdrawal syndromes after test substance discontinuation. In addition, clinical information does not seem to raise concern. Together with the existing experience with zopiclone from safety pharmacology assessment and literature data, further non-clinical testing to assess the dependence potential of eszopiclone is considered not necessary.

Metabolites

An extensive set of toxicology studies were performed with (S)-Desmethylzopiclone [(S)-DMZ], the pharmacological active metabolite of eszopiclone. The total number of studies performed with (S)-DMZ is more extensive than the standard toxicological evaluation of metabolites. Completed studies of up to 3-months duration in mice, rats, and dogs with (S)-DMZ did not identify any new target organs different than were identified with eszopiclone.

The primary findings with (S)-DMZ consisted of exaggerated PD effects in both genders and effects in reproductive organs (testis, epididymides) and spermatogenesis in male animals of all species. In general, these findings were observed at lower dosages than with eszopiclone. This is in line with effects observed in safety pharmacology and secondary pharmacodynamic studies, showing activity, but at a lower level than seen for eszopiclone, an indication for a lower pharmacological activity. The toxicological profile of (S)-DMZ is therefore in line with eszopiclone.

Impurities

Impurity qualification studies were performed, including a 28-day toxicity study in rats, a rat embryotoxicity/teratogenicity study, and in vitro bacterial and mammalian mutagenicity studies.

In the 28-day toxicity study no difference in the toxicological profile between eszopiclone alone or eszopiclone spiked with impurities were observed.

In conclusion, a comprehensive program for impurity qualification was conducted and the results did not raise any concerns in addition to those identified with eszopiclone alone.

Environmental Risk Assessment (ERA)

The applicant provided a Phase I ERA in accordance with the Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2).

The PECsurface water has been calculated based on the standard equation as per guideline, taking into account a maximum daily dose of 3 mg. The resulting PEC value exceeds the action limit of 0.01 µg/l and a Phase II ERA is deemed necessary.

An estimated octanol-water partition coefficient of 1.54 had been provided, indicating that further screening for persistence, bioaccumulation and toxicity might not be necessary.

The applicant agreed to perform a complete Phase I and II ERA in accordance with the Guideline on the environmental risk assessment of medicinal products for human use (EMEA/CHMP/SWP/4447/00 corr 2) as post-authorisation measure.

Conclusions on studies and proposed list of recommendations not falling under Article 21a/22 of Directive 2001/83/EC

A final conclusion on the environmental risk of eszopiclone cannot be drawn until the complete ERA has been submitted. The applicant committed to perform a complete ERA as post-authorisation measure.

III.3 Clinical aspects

The completed clinical study program has been summarised in the following listing:

Type	Study#	Objective^) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (treated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Bioavailability and Bioequivalence Study Reports
	190–010	Compare PK profiles of ESZ solution, ESZ tablets and racemic zopiclone Determine relative BE	Single-center, daytime, randomized, open-label, active-controlled, three-way crossover, single and multiple QD dose (4 days) bioavailability study of eszopiclone solution, eszopiclone tablet and racemic zopiclone (Imovane*)	Eszopiclone 3.5 mg liquid formulation, single oral dose	IS	Healthy males and females, fasted	4 days	Complete; Full	Module 5.3.1.2
	190–011	Bioavailability study of eszopiclone clinical trial and intended-for-market tablet	Two-centre, daytime, randomized, openlabel, two-way crossover, single dose	2 × 1.0 mg, 2 × 1.5 mg clinical service formulation 2.0 and 3.0 mg intended-for-market formulation	79	Healthy males and females	Single dose per formulation	Complete; Full	Module 5.3.1.2
Plasma Protein Binding Study Reports
Plasma Protein Binding (human biomaterials)	190–528	Determine blood-to-plasma portioning ratios and the percent of protein binding in mouse, rat, dog and human plasma	In vitro plasma protein binding using ultra filtration methods	Eszopiclone concentrations of 5 to 5000 ng/mL	NA	Human Plasma	NA	Complete; Full	Module 5 3.2.1
Reports of hepatic metabolism and drug interaction studies

Type	Study#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (treated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Metabolism (human biomaterials)	190–516	Determine the relative contribution of different CYP450 isoforms to the metabolism of (S)-zopiclone	In vitro study evaluating effects of CYP450 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 inhibitors on ESZ metabolism	Eszopiclone concentrations of 10, 100, or 200 microM,	NA	Human Plasma	NA	Complete; Full	Module 5 3.2.2
Metabolism (human biomaterials)	190–518	Determine the IC50 of (S)-zopiclone against CYP450 isoforms.	In vitro study evaluating effects of eszopiclone on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1 and 3A4	Eszopiclone concentrations of 1 to 100 microM	NA	Human Hepatocytes	NA	Complete; Full	Module 5 3.2.2
Metabolism (human biomaterials)	190–536	Compare the in vitro metabolism of (S)-zopiclone in animal and human hepatocytes in the absence or presence of ®-zopiclone	In vitro study of effect of ®- zopiclone on eszopiclone metabolism	Eszopiclone 1 or 2 microM	.NA	Human Hepatocytes	NA	Complete; Full	Module 5 3.2.2
Reports of studies using other human biomaterials

Type	Study#	Objectives) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
BA (human biomaterials)	190–542	Determine the permeability of (S)-zopiclone across human intestinal Caco-2 monolayers	In vitro monolayer permeability study	Eszopiclone concentrations of 1, 10 or 100 microM	NA	Human Intestinal Caco-2 cells	NA	Complete; Full	Module 5 3.2.3
Healthy subject PK and initial tolerability Study reports
	rprzd-0008	Evaluation of PK, elimination and metabolism of C14 labeled zopiclone in humans	Single-centre, daytime, open-label, single radio-labeled oral dose	C14 labeled – (RS)-zopiclone 7.5 mg oral capsules [equivalent to 3.75 (S)- zopiclone]	6	Healthy subjects	Single dose	Complete; Full	Module 5 3.3.1
	190–554	Evaluation of racemic zopiclone concentrations in serum and urine, for comparison to dog.	TLC/Florescence method to determine zopiclone levels in serum and urine	(RS)-zopiclone: 15, 20 mg oral tablets	9	Healthy subjects	Single dose	Complete; Full	Module 5 3.3.1
	190–555	Evaluation of racemic zopiclone concentrations in blood, urine and feces, for comparison to rat, rabbit and dog.	Zopiclone in feces and urine isolated by TLC and structures determined by IR, NMR and mass spectrometry. Serum protein binding determined in vitro and in vivo	(RS)-zopiclone: 5,10 mg oral tablets	8	Healthy subjects	Single dose	Complete; Full	Module 5 3.3.1

Type	Study#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
	190–556	Evaluation of racemic zopiclone concentrations in plasma and urine, for comparison to rat, rabbit and dog.		[C14 labeled ](RS)-zopiclone: 5, 7.5,10 mg oral tablets	Unknown	Healthy subjects	Single dose	Complete; Full	Module 5 3.3.1
	190–001	Determine safety and tolerability of ESZ compared to placebo Determine PK profile of (S)-zopic lone in the presence of ®-zop ic lone Determine effect of daytime sleepmess and psychomotor performance of single dose (S)-zop ic lone compared to placebo, (RS)-zopiclone and zolpidem	Single-center, daytime, randomized, double-blind, placebo- and active-controlled, single oral dose, dose-escalation study	Eszopiclone: 1, 2, 2.5, 3, 3.75, 5 and 7.5 mg (oral solution) 5 and 10 mg zolpidem oral tablets 2.5, 5 and 7.5 mg (RS)-zopiclone oral solution Placebo, oral solution	108	Healthy subjects	Single dose	Complete; Full	Module 5 3.3.1
BA	190–002	Determine steady state PK and effect of food in healthy adult subjects	Multi-center, daytime, double-blind, randomized, placebo-controlled, multiple oral dose, parallel group study	Eszopiclone: 1, 3, 6 mg oral solution Placebo oral solution	48	Healthy males and females, fasted and fed	7 days	Complete; Full	Module 5 3.3.1

Patient PK and initial tolerability Study reports

Type	Study#	Objectives) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (treated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
	190–201	ESZ safety, tolerability, and PK PD u/ adolescents with ADHD and insomnia	Multicenter; openlabel; single-dose inclinic dose escalation study	Eszopiclone; 1, 2, or 3 mg tablet once daily, oral administration	36 (enrolled)	Male or female subjects between 12 and 17 years of age (inclusive) subjects with a prior diagnosis of ADHD and inso mni a	Single Dose	Complete; Full	Module 5 3.3.2
	190–202	ESZ safety, tolerability, and PK PD in children with ADHD and insomnia	Multicenter; openlabel; single-dose; inclinic dose escalation study	Eszopiclone; 0.6,1,2, or 3 mg tablet once daily, oral a dmini stration	49 (enrolled) 48 (completed)	Male or female subjects between 6 and 11 years of age (inclusive) subjects with a prior diagnosis of ADHD and inso mni a	Single dose	Complete; Full	Module 5 3.3.2
Intrinsic factor PK Study reports
PK	190–013	PK of ESZ and metabolite in subjects with impaired hepatic function vs. healthy subjects Safety and tolerability	Multicenter, daytime, open-label, singledose, PK in subjects with hepatic impairment and normal matched control subjects	Eszopiclone 2 mg (2 × 1 mg) oral tablets	40	Male and female hepatically impaired subjects Child-Pugh Score: Mild-Mod.: 5–6 Mod-Severe: 7–9 Severe: 10–12 Healthy subjects	Single dose	Complete; Full	Module 5 3.3.3

Type	Study#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
PK	190–014	PK of ESZ and metabolite in subjects with renal insufficiency vs. healthy subjects Safety and tolerability	Multi-center, daytime, open-label, singledose, PK in subjects with renal impairment and normal matched control subjects	Eszopiclone 3 mg (2 × 1.5 mg) oral tablets	40	Male and female renally impaired subjects Creatinine Clearance (mL min): Normal: > 80 Mild: 50–79 Moderate: 30–49 Severe: <30	Single dose	Complete; Full	Module 5 3.3.3
(Intrinsic)	190–005		Multi-center, daytime, double-blind, randomized. placebo-controlled, rising, multi-dose study	Eszopiclone 1, 2,3, or 5 mg oral solution Placebo oral solution	36	Healthy elderly subjects	7 days	Complete; Full	Module 5 3.3.3
(Intrinsic)	190–003	Determine and compare safety, tolerability, and PK profile of ESZ and S-DMZ in healthy Japanese and Caucasian adults. Determine the effect of ESZ on psychomotor performance measured by DSST	Multi-center, daytime, double-blind, randomized, placebo-controlled, multi-dose study	Eszopiclone 1, 2,3, or 4(1 +3) mg Oral tablets Or placebo	96	Healthy Japanese or Caucasian subjects	7 days	Complete; Full	Module 5 3.3.3
	190–101	Safety, tolerability, and PK profile of ESZ and (S)-DMZ in healthy elderly Japanese subjects	Double-blind, randomized, placebo-controlled, ascending dose	Eszopiclone tablets 1.0, 2.0, 3.0 mg Placebo	24	Japanese males and females aged 65 to 85 inclusive	7 days	Complete; Full	Module 5 3.3.3

Type	Study#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Extrinsic factor Study reports
PK Diug-Drug Interaction	190–018	Compare the PKPD interaction of olanzapine and ESZ monotherapy to combination in healthy subjects	Single-center, daytime, randomized, placebo-controlled, 4 arm parallel, single dose, single blind	Eszopiclone, 3 mg (2 × 1.5 mg) oral tablet Placebo Olanzapine, 10 mg Eszopiclone, 3 mg and Olanzapine 10 mg	40	Healthy male and female volunteers	Single dose	Complete; Full	Module 5.3.3 4
PK Diug-Drug Interaction	190–019	Compare the PKPD interaction of lorazepam and ESZ in healthy subjects	Single-center, daytime, randomized, placebo-controlled, single-blind. 4 arm parallel, single dose	Eszopiclone, 3 mg (2 × 1.5 mg) oral tablets Placebo Lorazepam, 2 mg Eszopiclone 3 mg and Lorazepam 2 mg	36	Healthy male and female volunteers	Single dose	Complete; Full	Module 5.3.3 4
PK Diug-Drug Interaction	1904)20	Compare the PKPD interaction of paroxetine and ESZ in healthy subjects	Single-center, daytime, randomized, placebo-controlled, single-blind. 4 arm parallel, single dose	Eszopiclone 3 mg (2 × 1.5 mg) oral tablets Placebo Paroxetine 20 mg Eszopiclone 3 mg and Paroxetine 20 mg	40	Healthy male and female volunteers	Single dose	Complete; Full	Module 5.3.3.4
PK Diug-Drug Interaction	190–021	Compare the PKPD effect of ESZ on (RS)-warfarin in healthy subjects	Single-center, daytime, randomized. 2 period. 2 treatment, crossover, open-label, multiple dose	Eszopiclone 3 mg (2 × 1.5 mg), oral tablets and (RS)-warfarin 25 mg (RS)-warfarm 25 mg	12	Healthy male and female volunteers	Multiple dose eszopiclone, 5 days Single dose (RS)-warfarin	Complete; Full	Module 5.3.3.4
PK Diug-Drug Interaction	190–022	Compare the PKPD interaction of digoxin and ESZ in healthy subjects	Single-center, daytime, sequential, open-label, multiple dose	Eszopiclone 3 mg (2 × 1.5 mg), oral tablets Digoxin, 0.5 mg, oral tablets	12	Healthy male and female volunteers	7 days digoxin Single dose eszopiclone	Complete; Full	Module 5.3.3 4

Type	Study#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
PK Diug-Drug Interaction	190–023	Compare the PKPD interaction of ketoconazole and ESZ in healthy subjects	Single-center, daytime, randomized. 3-way crossover, open-label, multiple dose	Eszopiclone 3 mg (2 × 1.5 mg), oral tablets Ketoconazole. 400 mg, oral tablets Eszopiclone 3 mg and 400 mg Ketoconazole	18	Healthy male and female volunteers	Multiple dose, 5 days	Complete; Full	Module 5.3.3 4
Population PK Study reports
Population PK	190–000-K01		Meta-analysis of Studies 190–001, 190002, 190–010, 190011, 190–013, 190014, 190–018, 190019, 190–020 and 190–023	Eszopiclone tablets 2, 3, 3.5 mg Eszopiclone oral solution, dose ranging from 1.0 mg to 7.5 mg	262 single dose; 94 steady state	Healthy male and female volunteers	Single dose and multiple doses up to 7 days	Complete; Full	Module 5 3.3.5
Population PK	008037	Population PK Evaluation of ESZ in Adolescents and Children with ADHD-Associated Insomnia	Meta-analysis of Studies 190–201, 190202	See studies 190–201, 190–202	See studies 190–201, 190–202	See studies 190201, 190–202	See studies 190–201, 190–202	Complete; Full	Module 5 3.3.5
Healthy subject PD and PK/PD Study reports
PD	190–024	Next-day performance of ESZ and flurazepam vs placebo in healthy subjects	Single-center, nighttime, doubleblind, randomized, placebo-controlled, 4 way crossover	Eszopiclone 2 mg (2 × 1.0 mg), or 3.0 mg (2 × 1.5 mg), oral tablets Flurazepam, 30 mg, oral capsules Placebo	12	Healthy male and female volunteers	Single dose of each of 4 treatments	Complete; Full	Module 5 3.4.1
Patient PD and PK PD Study reports

Type	Study#	Objectives) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Locahon
PD	190–025	Next-day performance of ESZ and flurazepam vs placebo in subjects with insomnia	Single-center, nighttime, doubleblind, randomized, placebo-controlled, 4 way crossover	Eszopiclone 2 mg (2 × 1.0 mg), or 3 mg (2 × 1.5 mg), oral tablets Flurazepam, 30 mg, oral capsules Placebo	13	Males and females who met DSM IV criteria for primary insomnia	Single dose of each of 4 treatments	Complete; Full	Module 5 3.4.2
Study Reports of Controlled Clinical Studies
Efficacy	190–026	Efficacy of ESZ in healthy adults with transient inso mni a	Multi-center, randomized, doubleblind, placebo-controlled, 5-arm. parallel-group. nighttime efficacy and safety in transient insomnia	Eszopiclone 1.0,2.0, 3.0, or 3.5 mg of oral solution or Placebo	436	Healthy male and female volunteers	Single dose	Complete; Full	Module 5 3.5.1
Efficacy	190–045	Efficacy of ESZ in healthy adults with primary' insomnia	Multi-center, sleep laboratory, randomized, doubleblind, placebo-controlled, 6-way crossover	Eszopiclone 1.0,2.0, 2.5, and 3.0 mg. oral tablets Placebo. Zolpidem. 10 mg, oral tablet	65	Males or females between 21 and 64 years of age who met DSM-IV criteria for primary insomnia	Multiple dose for 2 days per treatment	Complete; Full	Module 5 3.5.1
Efficacy	190–047	Efficacy and safety of ESZ compared to placebo in elderly subjects with primary insomnia	Multi-center, randomized, doubleblind, placebo-controlled, parallel group	Eszopiclone 1.5 or 2.0 mg, tablets, oral; 1.5 mg dose removed per protocol amendment 2, n=28 received 1.5 mg dose Placebo tablets, oral	292	Males and females. 65–85 years of age who met DSM IV criteria for primary insomnia	2 weeks	Complete; Full	Module 5 3.5.1

Type	Study#	Objectives) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Locahon
Efficacy	190–048	Efficacy and safety of ESZ compared to placebo in elderly subjects with primary insomnia	Multi-center, randomized, doubleblind, placebo-controlled, 3-arm parallel-group	Eszopiclone 1.0 mg or 2.0 mg tablets, oral Placebo, oral tablets	231	Males and Females. 65 to 85 years of age who met DSM IV criteria for primary insomnia	2 weeks	Complete; Full	Module 5 3.5.1
Efficacy	190–046	Efficacy and safety of ESZ compared to placebo in adult subjects with primary' inso mnia Tolerance	Multi-center, randomized, doubleblind, placebo-controlled. parallel group, sleep lab outpatient	Eszopiclone 2.0 mg or 3.0 mg, oral tablets Placebo, oral tablets	308	Males or females between 21 and 64 years of age who met DSM-IV criteria for primary insomnia	44 days	Complete; Full	Module 5 3.5.1
Efficacy	190–054	Efficacy of ESZ in women with insomnia secondary to perimenopause or menopause QOL	Multi-center, randomized, doubleblind, placebo-controlled. parallel-group	Eszopiclone 3.0 mg tablets, oral Placebo	407	Females 40– 60 years with insomnia secondary to perimenopause or menopause	4 weeks	Complete; Full	Module 5 3.5.1
Efficacy	190–055	Efficacy of ESZ in subjects with insomnia related to rheumatoid arthiritis	Multi-center, randomized, doubleblind, placebo-controlled. parallel group	Eszopiclone 3.0 mg tablets, oral Placebo	153	Male or females, aged 25–64. diagnosed with rheumatoid arthritis and insomnia	4 weeks	Complete; Full	Module 5 3.5.1
Efficacy	190–052	Efficacy of ESZ when coadministered with fluoxetine hydrochloride, in subjects with insomnia related to MDD	Multi-center, randomized, doubleblind, placebo-controlled. parallel group	Eszopiclone 3.0 mg + 20 mg or 40 mg fluoxetine Placebo + 20 mg or 40 mg fluoxetine	543	Males and females. 21 to 64 years of age who met DSM IV criteria for primary insomnia related to major depression	8 weeks	Complete; Full	Module 5 3.5.1

Type	Study#	Objectives) of the Study		Test Product: Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Efficacy	190–902	Efficacy of ESZ in subjects with insomnia related to GAD	Mui tic enter randomized, doubleblind. placebo-controlled. parallel group	Eszopiclone 3 0 mg + 10 mg escitalopram oxalate, tablets, oral Placebo +10 mg escitalopram oxalate, tablets, oral	593	Males and females. 18 to 64 years of age who met DSM IV criteria for insomnia related to Generalized Anxiety Disorder	8 weeks	Complete; Full	Module 5 3 5 1
Efficacy	190–050	Long-term efficacy of ESZ administered for up to 6 months compared to placebo based on subjective sleep measures in subjects with primär}' insomnia.	Multi-center, randomized, doubleblind, placebo-controlled, parallel group	Eszopiclone 3.0 mg. tablets, oral Placebo tablets, oral	828	Males and females. 21 to 64 years of age who met DSM IV criteria for primary insomnia	6 months	Complete; Full	Module 5 3.5.1
Efficacy	190–049	Safety and efficacy of ESZ administered for 12 months in adults subjects with insomnia.	Multi-centre, randomized, doubleblind, placebo-controlled, parallel group and open label, safety extension	Eszopiclone 3.0 mg, tablets, oral Placebo tablets, oral	788	Males and females, 21 to 64 years of age who met DSM IV criteria for primary insomnia	12 months: 6 months DB placebo or eszopiclone, followed by 6 months open-label eszopiclone or placebo	Complete; Full	Module 5 3.5.1

Type	Studs-#	Objectives) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
	ESZ111503	Determine the existence and time course of potential next-day residual psychomotor effects of a single evening dose of ESZ. zopiclone. and placebo	Single-center, randomized, doubleblind, double-dummy, placebo-controlled, 3way crossover	Eszopiclone 3.0 mg, oral Zopiclone 7.5mg, oral Placebo, oral	91	Male and female subjects aged 2540	Single dose of each of the 3 treatments	Complete; Full	Module 5 3.5.1
	190–904	Long-term safety and efficacy of ESZ admimstered for 12 weeks in elderly subjects with primary' chronic insomnia	Double-blind, randomized, placebo-controlled, parallel group	Eszopiclone 2.0 mg, ox al tablet Placebo	388	Elderly male and female patients with primary chronic insomnia, ages 65 to 85 years	12 weeks	Complete; Full	Module 5 3.5.1
Efficacy and Safety	190–246	Determine the efficacy and safety of ESZ compared to placebo in children and adolescents with ADHD-associated insomnia.	Multicenter randomized, doubleblind, placebo controlled	Eszopiclone; 1 or 2 mg once daily at bedtime for 6 to 11 year old children and 2 or 3 mg once daily at bedtime for 12 to 17 year old adolescents; oral a dmini stration Placebo	483	Male and female subjects 6 to 11 and 12 to 17 years of age (inclusive) with ADHD-associated insomnia	12 weeks	Complete; Full	Module 5 3.5.1
*Stud} Reports of Uncontrolled Clinical Studies**

Type	Study#	Objective^) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Safety	190–247	Determine the long-term safety of ESZ in children and with ADHD-associated insomnia.	Multicenter; longterm open-label extension	Eszopiclone; 2 mg once daily at bedtime for 6 to 11 year old children and 3 mg once daily at bedtime for 12 to 17 year old adolescents; oral	304 (enrolled) 121 (completed)	Male and female subjects 6 to 11 and 12 to 17 years of age (inclusive) with ADHD-associated insomnia	1 year	Complete; Full	Module 5 3.5.2
Other Clinical Study reports
Safety Pharmacology	190–015		Single-center, daytime, randomized, double-blind, singledose, placebo-controlled, 4-way crossover	Eszopiclone 3.5 mg, oral tablets (2×10 mg, 1 × 1.5 mg) Placebo, oral tablets Alcohol, oral Alcohol placebo, oral	24	Healthy male and female volunteers who scored as moderate or less than moderate drinker according to the Alcohol Dependence Scale (ADS)	Single dose	Complete; FuU	Module 5.3.5.4
Safety Pharmacology	190–012	Effect of ESZ and codeine sulfate vs placebo on respiratory drive in healthy adult subjects	Single-center, daytime, randomized, double-blind, placebo -controlied, and active controlled, single-dose, 4-way crossover	Eszopiclone 3.0 mg or 7.0 mg oral solution codeine sulfate 60 mg. oral tablet Placebo oral tablet or placebo oral solution	14	Healthy male subjects	Single dose	Complete; FuU	Module 5.3.5.4
Safety	190–059	Investigate the impact of an evening dose of ESZ on next day performance	Single-center, randomized, doubleblind, placebo-controlled cross-over study	Eszopiclone 3.0 mg, tablets, oral Placebo	32	Healthy male and female subjects, 18 to 55 years of age	Single dose	Complete; FuU	Module 5.3.5.4

Type	Studs-#	Objective(s) of the Study		Test Product; Dosage Regimen: Route of Admin	Number of Subjects (heated)	Health of Subjects and/or Diagnosis	Treatment Duration	Study Status; Type of Report	Location
Safety	190–060	Investigate the impact of an evening dose of ESZ on next day performance	Single-center, randomized, doubleblind, placebo-controlled cross-over study	Eszopiclone 3.0 mg, tablets, oral Placebo	32	Male or female subjects, 18–55 years who met DSM IV criteria for insomnia	Single dose	Complete; FuU	Module 5.3.5 4
Safety	190–028	To evaluate the hypnotic efficacy of eszopiclone in subjects with mild to moderate obstructive sleep apnea syndrome compared to placebo	Multi-center, randomized, doubleblind, placebo-controUed, crossover efficacy and safetystudy in subjects with obstructive sleep apnea syndrome	Eszopiclone 3 mg tablets, oral Placebo	22	Male or female subjects, between 35 and 64 years, inclusive, with an Apnea -Hypopnea Index (AHI) >10 and <40 episodes per hour	Twice each formulation for 2 days	Complete; FuU	Module 5.3.5 4
Safety	190–016	Assess and compare to diazepam and placebo the potential abuse liability of ESZ in subjects with a history of benzodiazepine abuse	Single-center, doubleblind, randomized. placebo-c ontro Ued. 6 way complete crossover, inpatient	Eszopiclone 3 mg (2 × 1.5 mg), 6 mg (4×1.5 mg) or 12 mg (8 × 1.5 mg), oral tablets Diazepam 10 mg (1 × 10 mg capsule) 20 mg (2 × 10 mg capsule) oral capsules Placebo	28	Healthy males and females with history of benzodiazepine abuse	Each treatment single dose	Complete; FuU	Module 5.3.5 4
Safety	190–029	Evaluate effects of ESZ on sperm motility, sperm concentration, semen volume, sperm count, and percentage of cells with normal morphology	Multi-center, doubleblind, randomized, pla cebo -contro Ued, parallel group	Eszopiclone 3.0 mg oral tablet or Placebo	95	Healthy males (1845 yrs) with following semen analysis criteria; Min sperm count of 20 × 106/ml; nun of 50% sperm motility; min 30% sperm with normal morphology	12 weeks	Complete; FuU	Module 5.3.5 4

III.3.1 CLINICAL PHARMACOLOGY

Pharmacokinetics

Introduction

(S)-Zopiclone, hereafter referred to as eszopiclone, is a positive allosteric agonist at gammaaminobutyric acid type A receptors (GABAA ). Racemic zopiclone is a 1:1 mixture of the enantiomers

(S)-zopiclone and ®-zopiclone. Racemic zopiclone (also referred to as (RS)-zopiclone is a shortacting hypnotic agent developed by Rhone-Poulenc Rorer and marketed in Europe under the trade names of Imovane and Zimovane. Eszopiclone was developed as a treatment for the relief of insomnia in adult patients, at a proposed maximum dose of 3.0 mg once daily (immediately before bedtime). A reduced maximum dose of 2.0 mg once daily is proposed in elderly patients (≥ 65 years of age).

Eszopiclone was fully developed as a new chemical entity, but with the knowledge that racemic zopiclone (of which eszopiclone is an enantiomer) was commercially available in many countries since the 1980’s. The eszopiclone pharmacology programme consists of in vitro studies of human biomaterials as well as in vivo human pharmacokinetic and pharmacodynamic studies. The clinical pharmacology development programme for eszopiclone is comprised of 17 studies in human subjects. Clinical development of eszopiclone was undertaken to optimise the dose required for efficacy in reducing sleep latency and night-time awakenings and increasing total sleep time, while minimising next day effects.

Methods

Analytical methods

Several studies were carried out to validate the measurement of eszopiclone and (S)-desmethylzopiclone, substances were determined in human plasma and in human urine.

The applicant conducted extensive validation of the assay methods for eszopiclone. The assay was sensitive and linear.

Pharmacokinetic data analysis

Pharmacokinetic variables, e.g. AUC0-t , AUCinf , Cmax , C24h , tmax , and t½ were calculated according to standard procedures.

Statistical analysis

Descriptive statistics were provided. For comparison in most cases the 90% confidence intervals were calculated. Conventional methods were used and no problem arose.

Absorption

Eszopiclone is rapidly absorbed following oral administration, with tmax occurring at approximate 1 hour post-dose in healthy subjects. The plasma concentration profile of eszopiclone was characterized by a bi-exponential decline with an apparent terminal phase t½ of approximately 6 hours. Eszopiclone exhibited dose-proportional pharmacokinetics over the range of 1.0 to 6.0 mg once daily.

Bioavailability

The bioavailability of the clinical trial tablet formulation relative to the oral solution formulation that was used in early clinical studies was established in the combined bioavailability & bioequivalence study 190–010 (101%). Additionally, following QD dosing for four days, eszopiclone 3.5 mg tablet and (RS)-zopiclone 7.5 mg tablet formulations exhibited bioequivalent eszopiclone pharmacokinetics. Thus, the absence of the ®-isomer does not generally impact the human exposure to eszopiclone in terms of Cmax and AUC. Removal of the R-isomer at steady-state, however, did result in a reduction in exposure to (S)-desmethylzopiclone [(S)-DMZ], the primary metabolite – with a relative bioavailability of 83% compared to (RS)-zopiclone. The confidence interval for the AUC(0-τ) comparison was outside the standard range of 80%-125% (reported 90% CI 71.7%-95.0%). However, this has been considered unlikely to be clinically relevant. Median eszopiclone tmax was 1.0 hour for solution (Day 1) and tablet (Days 1 and 4) eszopiclone, and 1.5 hours for (RS)-zopiclone (Days 1 and 4).

Bioequivalence

The bioavailability of the clinical trial tablet formulation relative to the oral solution formulation which was used in early clinical studies was established in the combined bioavailability & bioequivalence study 190–010 (101%).

Influence of food

The effects of food on single dose pharmacokinetics of eszopiclone, administered as an oral solution, were investigated as part of Study 190–002. The results of this study demonstrated that eszopiclone can be taken with or without food with the exception of following a high-fat meal. In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours.

Information about food effect was included in section 5.2 of SmPC and in the package leaflet.

Distribution

Racemic zopiclone is widely distributed with an absolute volume of distribution of approximately 90 L. Eszopiclone would be expected to exhibit similar distributive properties, based on the similarity of the pharmacokinetics (clearance) of eszopiclone.

The percent of binding of [14 C]-eszopiclone to protein in mouse, rat, dog and human plasma was determined in study 190–528 using ultrafiltration methods. In vitro protein binding of eszopiclone in human plasma was 52.2–58.9% over the concentration range of 5–500 ng/mL of [14 C]-eszopiclone. Non-specific binding of eszopiclone was less than 5% at concentrations of 1000 ng/mL or below. The relatively low plasma protein binding suggest that reduction in albumin concentration typically observed in severe renal and liver diseases would be expected to result in a negligible change in unbound eszopiclone concentration.

Elimination

Excretion

Renal excretion is the principal route of elimination of eszopiclone and its metabolites. Up to 75% of an oral dose of racemic zopiclone is excreted in the urine primarily as metabolites. A similar excretion profile would be expected for eszopiclone, because of the observed equivalency in the metabolic clearance of eszopiclone in the presence or absence of ®-zopiclone and the formation of the same metabolites. Less than 10% of the dose was excreted in the urine as unchanged drug.

The plasma concentration profile of eszopiclone was characterized by a bi-exponential decline with an apparent terminal phase t½ of approximately 6 hours. Eszopiclone exhibited dose-proportional pharmacokinetics over the range of 1.0 to 6.0 mg once daily. No accumulation of eszopiclone was observed following 7 days of once daily drug administration.

Metabolism

In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.

Inter-conversion

No interconversion from eszopiclone to ®-zopiclone was observed in the combined bioavailability & bioequivalence Study (Study 190–010 ) or in Study 190–001.

Pharmacokinetics of metabolites

The pharmacokinetics of metabolites have been adequately established in a number of studies in the clinical pharmacology programme.

Consequences of possible genetic polymorphism

This has not been studied. However, based on the many years of experience with zopiclone, no problems are expected with eszopiclone.

Dose proportionality and time dependency

Dose-proportionality of eszopiclone pharmacokinetics has been extensively examined and the pharmacokinetic data were consistent across two studies. Eszopiclone demonstrated dose proportional pharmacokinetics (AUC0–24 and Cmax ) following both single and multiple dosing.

Pharmacokinetics in target population

PK studies were not conducted in subjects with insomnia. This was regarded as acceptable given the available data and the underlying condition. In the meantime, the pharmacokinetics of eszopiclone was investigated in children and adolescents with a prior diagnosis of ADHD and insomnia (190–201 & 190–202). However, as efficacy of eszopiclone has not been established in paediatric patients with ADHD-associated insomnia no indication is being sought in this MAA for this population.

Special populations

Impaired renal function

Systemic exposure increased by 47% in subjects with severe renal impairment.

Therefore, a decrease of eszopiclone dose from 3.0 to 2.0 mg has been proposed in patients with severe renal impairmentwhich is considered justified from a safety and efficacy perspective. Based on the provided data, reducing the eszopiclone dose to 2 mg in patients with severe renal impairment should lead to similar exposure and efficacy as has been shown for patients aged 65 years and older. No dosage adjustment appears necessary in subjects with mild to moderate renal impairment.

Impaired hepatic function

Moderate hepatic insufficiency had no clinically relevant effect on the pharmacokinetics of eszopiclone.

However, in line with the product information for racemic zopiclone (see Ximovan by Sanofi) and the SPC Guideline for Benzodiazepines and Benzodiazepine like agents, “severe hepatic impairment” has been contraindicated. No dose adjustment is required in patients with mild or moderate hepatic impairment.

With respect to the results of the population PK analysis, please refer to section “Population pharmacokinetic analysis”.

Gender, Race and Weight

The pharmacokinetics of eszopiclone in men and women are similar.

The pharmacokinetics for all ethnic groups studied appear similar.

A population PK analysis was conducted investigating the effect of covariates on the PK of eszopiclone in healthy volunteers and patients with hepatic / renal impairment. Gender and race were not found to be significant covariates impacting the PK after single and multiple dose administration (please refer to the section “Population pharmacokinetic analysis”).

Elderly

The exposure in healthy elderly subjects was approximately 50% greater than the exposure observed in healthy adults (study190–005, 190–002 ). For this reason, the recommended maximum therapeutic dose in elderly was reduced from 3.0 to 2.0 mg.

Children

The pharmacokinetics of eszopiclone was investigated in children and adolescents with a prior diagnosis of ADHD and insomnia (190–201 & 190–202).

In both studies a lot of subjects received concomitant medication during the study as the analgetic – ibuprofen or as psychoanaleptics – Methylphenidate). It was described that the ADHD medication was to be administered in such a manner that no pharmacologic activity was predicted at the time of study drug dose (at least 10 hours distance between ADHD treatment and study drug administration). The applicant gave additional, detailed information regarding interactions between concomitant medications and now the concomitant medication is considered not to have any influence on the pharmacokinetic results (drug interaction, pharmacokinetic analysis).

However, as efficacy of eszopiclone has not been established in paediatric patients with ADHD-associated insomnia no indication is being sought in this MAA for this population.

A product specific waiver for eszopiclone (EMEA-002309-PIP01–17) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council was granted on 7 May 2018.

Overall comments on pharmacokinetics in special populations

The PK profiles have been categorised in special populations. Severe hepatic impairment has been contraindicated to be in line with the Product Information for racemic zopiclone and the class labeling for benzodiazepines and benzodiazepine-like agents. A decrease of maximum eszopiclone dose from 3.0 to 2.0 mg has been proposed in older patients as well as in patients with severe renal impairment.

Interactions

In vitro

Eszopiclone did not cause inhibition of the metabolism of specific substrates of the CYP450 isoforms 1A2, 2A6, 2C8, 2C9, 2C19, 2D6, 2E1, and 3A4 in human hepatocytes at concentrations up to 100 µM. This demonstrated that eszopiclone was not a CYP450 inhibitor.

In vivo

A reduction in eszopiclone dose to 2.0 mg is endorsed upon co-administration with very potent CYP 3A4 inhibitors (i.e., inhibition constant ≤ 1 µM). Rifampicin, a potent inducer of CYP3A4, was shown to substantially decrease exposure to racemic zopiclone and to some measures of its pharmacological activity. A similar effect may also occur with eszopiclone. A dose adjustment for warfarin or digoxin is not required when co-administered with eszopiclone. Co-administration of lorazepam or paroxetine and eszopiclone did not have a clinically meaningful effect. Significant impairment of psychomotor performance was, however, observed when eszopiclone was coadministered with olanzapine.

As might be anticipated from its mechanism of action, downward dose adjustment of eszopiclone may be necessary when eszopiclone is administered with agents having known CNS-depressant effects. In line with the findings of the interaction study of eszopiclone and ethanol, Section 4.5 of the proposed SPC advises against concomitant use with alcohol as the sedative effect of eszopiclone may be enhanced.

Exposure relevant for safety evaluation

The mean plasma exposure levels and numbers of patients studied were acceptable for safety evaluation.

Overall conclusions on pharmacokinetics

The pharmacokinetics of eszopiclone have been investigated in healthy subjects (adult and elderly), children and adolescents with a prior diagnosis of ADHD and insomnia and in patients with hepatic disease or renal disease. In healthy subjects, the pharmacokinetic profile was examined after single doses of up to 7.5 mg and after once-daily administration of 1, 3, and 6 mg for 7 days. Eszopiclone is rapidly absorbed, with a time to peak concentration (tmax ) of approximately 1 hour and a terminal-phase elimination half-life (t1/2 ) of approximately 6 hours. In healthy adults, eszopiclone does not accumulate with once-daily administration, and its exposure is dose-proportional over the range of 1 to 6 mg. Less than 10% of the orally administered eszopiclone dose is excreted in the urine apparent drug.

Following oral administration, eszopiclone is extensively metabolized by oxidation and demethylation. The primary plasma metabolites are (S)-zopiclone-N-oxide and (S)-N-desmethyl zopiclone; the latter compound binds to GABA receptors with substantially lower potency than eszopiclone, and the former compound shows no significant binding to this receptor. In vitro studies have shown that CYP3A4 and CYP2E1 enzymes are involved in the metabolism of eszopiclone. Eszopiclone did not show any inhibitory potential on CYP450 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 in cryopreserved human hepatocytes.

In healthy adults, administration of a 3 mg dose of eszopiclone after a high-fat meal resulted in no change in AUC, a reduction in mean Cmax of 21%, and delayed tmax by approximately 1 hour. The half-life remained unchanged, approximately 6 hours.

Thus, the absence of the ®-isomer does not generally impact the human exposure to eszopiclone in terms of Cmax and AUC. Removal of the R-isomer at steady-state, however, did result in a reduction in exposure to (S)-desmethylzopiclone [(S)-DMZ], the primary metabolite – with a relative bioavailability of 83% compared to (RS)-zopiclone. The confidence interval for the AUC(0-τ) comparison was outside the standard range of 80%-125% (reported 90% CI 71.7%-95.0%). However, this has been considered unlikely to be clinically relevant. Median eszopiclone tmax was 1.0 hour for solution (Day 1) and tablet (Days 1 and 4) eszopiclone, and 1.5 hours for (RS)-zopiclone (Days 1 and 4).

Bioequivalence between the eszopiclone clinical trial tablet formulation and the eszopiclone commercial tablet formulation has been adequately established. Additional changes to the composition of the non-functional coating (used only for taste-masking) are considered to have no effect on bioavailability.

The PK profiles have been categorised in special populations. Severe hepatic impairment has been contraindicated to be in line with the Product Information for racemic zopiclone and the class labeling for benzodiazepines and benzodiazepine like agents. A decrease of maximum eszopiclone dose from 3.0 to 2.0 mg has been proposed in older patients as well as in patients with severe renal impairment.

The pharmacokinetics of eszopiclone was investigated in children and adolescents with a prior diagnosis of ADHD and insomnia. However, as efficacy of eszopiclone has not been established in paediatric patients with ADHD-associated insomnia no indication is being sought in this MAA for this population.

A product specific waiver for eszopiclone (EMEA-002309-PIP01–17) in accordance with Regulation (EC) No 1901/2006 of the European Parliament and of the Council was granted on 7 May 2018.

In line with the findings of the interaction study of eszopiclone and ethanol, Section 4.5 of the proposed SPC advises against concomitant use of alcohol as the sedative effect of eszopiclone may be enhanced.

Overall, pharmacokinetics of eszopiclone has been investigated extensively. No dose adjustement is required in patients with mild to moderate renal or hepatic impairment. While eszopiclone is contraindicated in patients with severe hepatic impairment, the maximum dose should be limited to 2 mg in patients with severe renal insufficiency and in patients 65 years and older, respectively.

Pharmacodynamics

Mechanism of action

A series of in vitro and in vivo binding studies and in vitro functional assays demonstrate that the mechanism of action of zopiclone is to allosterically modulate the effects produced by central GABAA receptor activation via binding to a central binding site or one that is closely linked to benzodiazepine receptors. The net result of zopiclone’s interactions with the GABAA receptor macromolecular complex is the augmentation of GABA-induced chloride conductance, resulting in inhibition of

neurotransmission. Evidence indicates that potentiation of inhibitory synaptic transmission mediated by GABA acting at GABAA receptors is one of the primary mechanisms of action of drugs with sedative/hypnotic properties. Several studies have shown that zopiclone was not bound to the benzodiazepine receptor, per se , but rather it interacted with yet another distinct site on the GABAA receptor complex. This binding and receptor activation of zopiclone is attributed to the binding of eszopiclone, as ®-zopiclone demonstrates minimal binding to the central benzodiazepine site.

The applicant presents no new studies of the mechanism of action of eszopiclone. However, the mechanism of action of zopiclone is well-established and it is accepted that the desired pharmacologic activity of the racemic drug resides primarily with eszopiclone.

Primary pharmacology

DSST (Digit Symbol Substitution Test) and SSS scores (Stanford Sleepiness Scale) were measured during three randomized, placebo-controlled, single and multiple dose, daytime drug administration, dose-escalation studies conducted in healthy adults (18 to 46 years of age) (Study 190–001 and Study 190–002) and in healthy elderly (65 to 79 years of age) (Study 190–005).

The dose-response relationship including its time course and the justification for the dose regimen have been adequately described. The proposed dose of 3 mg (and 2 mg in subgroups of the population, most notably the elderly), is accepted as maintenance dose.

Secondary pharmacology

The studies (190–024, 190–025) conducted relating to next-day or ‘hangover’ effects support the concept that eszopiclone is well-tolerated.

Other studies performed demonstrated no effect on respiratory function (including at twice the recommended dose in healthy volunteers) or on semen quality or on sleep apnoea.

Relationship between plasma concentration and effect

There is no specific study of plasma concentration and effect – either the intended hypnotic effect or unwanted effects. However, there is reasonable evidence from the clinical studies of a relationship between increasing dose and increasing effect, both intended and unintended and the lack of specific data on this issue is not regarded as a problem.

Pharmacodynamic interactions with other medicinal products or substances

The interaction with alcohol is addressed by advising against concomitant use in Section 4.5 of the SPC.

Study 190–016 was a single centre six-way crossover evaluation of the effect of the abuse potential of eszopiclone 3 mg, 6 mg, 12 mg, diazepam 10 mg, 20 mg, and placebo. The findings of the study of abuse potential are noted.

Genetic differences in PD response

No studies have been conducted regarding the potential differences arising from genetic polymorphism; given the extensive clinical experience with zopiclone this is acceptable.

Overall conclusions on pharmacodynamics

The mechanism of action of zopiclone is well-established and it is accepted that the desired pharmacologic activity of the racemic drug resides primarily with eszopiclone.

DSST and SSS scores were measured during three randomized, placebo-controlled, single and multiple dose, daytime drug administration, dose-escalation studies conducted in healthy adults (18 to 46 years of age) (Study 190–001 and Study 190–002) and in healthy elderly (65 to 79 years of age) (Study 190005).

The dose-response relationship including its time course and the justification for the dose regimen has been adequately described. The proposed maximum dose of 3mg (and 2 mg in subgroups of the population, most notably the elderly), is accepted.

The studies conducted relating to next-day or ‘hangover’ effects support the concept that eszopiclone is well-tolerated.

Other studies performed demonstrated no effect on respiratory function (including at twice the recommended dose in healthy volunteers) or on semen quality or on sleep apnoea.

The interaction with alcohol is addressed by advising against concomitant use in Section 4.5 of the SPC. The findings of the study of abuse potential are noted.

In general, the evaluation of the pharmacodynamics of eszopiclone has been carried out well and no major objections arise.

III.3.2 CLINICAL EFFICACY

Eleven pivotal studies have been conducted to investigate the efficacy of eszopiclone in the treatment of insomnia in adults. Five of them were short-term studies in subjects with transient or primary insomnia, two were long-term studies (6–12 months) in subjects with primary insomnia (190–049, 190050) and the remaining four studies of 4– to 8-weeks duration were conducted in subjects with comorbid insomnia.

An additional 12-week study in 388 older patients with primary insomnia (Study 190–904 ) was conducted; patients received double-blind treatment with 2 mg eszopiclone (194) or placebo (194) for 12 weeks.

One head-to-head comparative study (ESZ111503 ) of eszopiclone and racemic zopiclone conducted by Glaxo-Smith Kline has been completed in 91 healthy volunteers that incorporated the use of actigraphy to monitor sleep parameters during the night.

Of the studies listed in Table 1, one additional study (190–026) was conducted in healthy volunteers using a validated model of transient insomnia.

Table 1: Efficacy Studies

Study

Diagnosis

Subjects

Treatment duration

Eszopiclone dose (mg)

Comparator

Type of

Assessment

Transient Insomnia

190–026

Healthy volunteers (first night transient insomnia model)

436

Single Dose

1.0, 2.0,

3.0, 3.5

Placebo

PSG and

Subjective

Primary Insomnia
190–045	Adults with primary insomnia	65	2 days	1.0, 2.0, 2.5, 3.0	Placebo, Zolpidem 10 mg	PSG and Subjective
190–046	Adults with primary insomnia	308	44 days	2.0, 3.0	Placebo	PSG and Subjective
190–047	Elderly patients with primary insomnia.	292	2 weeks	1.5", 2.0	Placebo	PSG and Subjective
190–048	Elderly patients with primary insomnia.	231	2 weeks	1.0, 2.0	Placebo	Subjective
190–050	Adults with primary insomnia	828	6 months	3.0	Placebo	Subjective
190–049	Adults with primary insomnia	788	12 months (6 months DB+6 month OL)	3.0	Placebo	Subjective
190–904	Elderly with primary chronic insomnia	388	12 weeks	2.0	Placebo	Subjective

Co-morbid Insomnia
190–054	Females with insomnia secondary to peri menopause or menopause	407	4 weeks	3.0	Placebo	Subjective
190–055	Adults with insomnia and rheumatoid arthritis	153	4 weeks	3.0	Placebo	Subjective
190–052	Adults with insomnia and Major Depressive Disorder	543	8 weeks	3.0	*Placebo’1’**	Subjective
190–902	Adults with insomnia and Generalized Anxiety Disorder	593	8 weeks	3.0	Placebo“	Subjective

---------------------------------------------------1-----------------------------------------------------------------------------1------------------------------------------1-----------------------------------------------------------1--------------------------------------------------------1---------------------------------------------------------1-----------------------------------------------------------

Active Comparator Study

ESZ1115C3

Healthy volunteers

Single evening (3way crossover)

3.0

7.5 racemic zopiclone

Actigraphy

1.5 mg dose removed per protocol amendment 2, n=28 received 1.5 mg dose; b All subjects received fluoxetine (20 mg or 40 mg);

All subjects received escitalopram 10 mg.

Study design and evaluated doses:

All studies were randomised, double-blind and placebo-controlled.

Study 190–045 employed a 6-way crossover design to evaluate four doses of eszopiclone tablets, placebo and zolpidem 10 mg tablets. Study ESZ111503 had a 3-way crossover design of a single evening dose of 3 mg eszopiclone, 7.5 mg of racemic zopiclone, and placebo.

The remaining studies employed a parallel group design.

Study 190–049 included a 6-month open-label extension, during which all subjects received eszopiclone 3.0 mg. Study 190–026 used oral solutions of 1.0, 2.0, 3.0 and 3.5 mg eszopiclone. In the remaining studies, different eszopiclone doses within the range of 1.0 mg to 3.0 mg (in non-older adults) and up to 2.0 mg (in older adults) have been evaluated, however, efficacy of a dose of 1.0 mg was only evaluated in few studies.

The primary efficacy measures of the studies were:

1. objective latency to persistent sleep (LPS) in studies 190–026, 190–045 and 190–046;
2. objective LPS and objective sleep efficiency in study 190–047 (co-primary endpoints);
3. subjective sleep latency in studies 190–048, 190–049, 190–050, 190–054 190–902, 190–904;
4. subjective mean wake time after sleep onset (WASO) in studies 190–052 and 190–055;

Study ESZ111503 was designed as a safety study.

The duration of the double-blind period in these studies ranged from a single-dose (study 190–026) to 6 months (studies 190–049 and 190–050) of treatment.

Dose-finding:

The maximum recommended adult dose of eszopiclone 3.0 mg was initially evaluated utilizing objective and patient-reported parameters in dose ranging studies 190–026 and 190–045, which contained several doses greater and less than the recommended dose, including 2.0 mg, 2.5 mg, and 3.5 mg. All doses above 1 mg were effective in improving sleep latency. 3.0 mg was the effective dose that consistently improved WASO, total sleep time (TST) and other measures of sleep maintenance. Compared to non-elderly adults, subjects 65 years and older had an increase of 41% in exposure (AUC). In efficacy studies in older subjects doses of 2 mg (190–047, 190–904) and of 1 mg or 2 mg (190–048), respectively were evaluated, and a dose of 2 mg appeared more effective than the 1 mg dose.

Overall, efficacy results for the 1 mg dose were inconsistent. However, in all clinical studies evaluating the 1 mg dose (i.e. No. 190–026 performed in healthy volunteers, No. 190–045 in non-older adults and No. 190–048 in older adults), the numerical improvements in sleep latency reached statistical significance except for sleep latency measured by polysomnography in study 190–026.

Efficacy results:

Across all the efficacy clinical studies Eszopiclone 2 mg and 3 mg consistently showed statistically significant improvement of the primary variable – latency to persistent sleep – measured either objectively or subjectively, and both in the short- and in the long-term.

Efficacy was also consistently demonstrated with regard to the secondary efficacy measures, which measured sleep maintenance, sleep quality and daytime functioning.

Eszopiclone 3 mg also improved insomnia associated to the co-morbid conditions, major depression, generalised anxiety, menopausal symptoms and rheumatoid arthritis.

The derived differences between Eszopiclone and placebo for each endpoint for all efficacy studies are shown in Table 2 below. The clinical patient reported outcomes were used in order to provide consistency of the comparison across all studies. The calculations were weighted averages based on the overall sample size of the study.

Table 2: Summary of Treatment Effect versus Placebo for Sleep Parameters and the Difference between Eszopiclone and Placebo Results

Study	Sleep Latency (Minutes)			WASO (Minutes)			TSE (Minutes)
Study	PBO	ESZ 3.0mg	A	PBO	ESZ 3.0mg	A	PBO	ESZ 3.0ing	A
Short Term Insomnia
190–045	47.5 n=65	25.0 h =64	22.5	30.8 n=65	23.3 n=64	7.5	375.0 n=65	420.0 n=64	45
190–046	46.0 u=99	27.7 n=105	18.3	44.1 11 =99	33.8 n=105	10.3	366.0 n=99	406 n=105	40
190–047 t" ms)	55.0 n=128	26.5* i=136	28.5	91.2 n=128	81.7* n=136	9.5	324.4 n=128	386.9* n=136	62.5
190–048 (’ 2 mg)	52.0 n=30	36.2* n=79	15.8	58.1 11=30	49.5* n=79	8.6	345.0 n=80	383.2* n=79	38.2
190–049 4 weeks	52.5 n=l 95	31.3* n=593	21.2	36.7 >1=195	23.8* n=593	12.9	337.5 n=195	375.0* n=593	37.5
190–050 4 weeks	52.5 n=2SO	28.8* >1 = 548	23.7	32.5 u=2S0	17.5* x=54S	15	336.8 11=280	390.0* ii=54S	53.2
Ave. Diff, between ESZ anti Placebo			19.0			10.9			43.8
Long-Term Insomnia
190–049	64.7 >i=295	46.7 n=593	18	35.7 n=195	22.5 n=593	13.2	345.1 n=195	381.7 ii=593	36.6
190–050	59.0 n=2S0	38.5 >1=548	20.5	26.1 >1=230	14.7 ii=54S	11.4	345.0 11=280	396.5 n=54S	51.5
Ave. Diff, between ESZ and Placebo			19.2			12.3			44.0
Comarbid Insomnia
190–054	38.6 n=186	26.3 >1=181	12.3	27.5 >1=183	15.0 n=177	12.5	377.3 n=186	411.4 ti=181	34.1
190–055	32.7 n=56	22.2 n=66	10.5	27.9 n=67	15.0 n=76	12.9	383.5 n=68	400.8 n=76	17.3
190–052	47.5 n=261	30.0 >1 =253	17.5	26.7 >1=255	8.75 n=249	IS	360.0 n=261	405.0 n=253	45
190–902	42.0 >i=299	30.2* >1=294	11.8	18.9 n=297	13.0 n=294	5.9	398.6 ri=299	421.2 n=294	22.6
Ave. Diff, between ESZ and Placebo			13			11			38

A post hoc responder analysis was also performed, using the criterion where responders were defined as achieving an improvement of 10 minutes or more on sleep latency or 10 minutes or more on WASO or 20 minutes or more on TST.

A responder analysis is regarded as useful in judging the clinical relevance of the benefit observed on the pivotal efficacy measures. The results are shown in Table 3 below.

Table 3: Responder Analysis for Sleep Parameters in Eszopiclone Development

Study	Sleep Latency (% Responders)			WASO (% responders)			1ST (% responders)
Study	PBO	ESZ 3.0 mg	A	PBO	ESZ 3.0 mg	A	PBO	ESZ 3.0mg	A
Primary Insomnia
190–045	58.7 n=65	85.9 n=64	27.2	41.3 n=65	70.3 n=64	29	61.9 n=65	76.2 n=64	14.3
190–046	52.1 »=99	76.0 »=105	23.9	54.3 n=99	52 »=105	–2.3	59.6 n=99	69 n=105	9.4
190–049 4 week	56.6 »=195	75.9 »=598	19.3	43.3 »=195	67.6 h=593	24.3	57.0 »=195	78.7 »=593	21.7
190–050 4 week	58.2 »=280	82.8 »=548	24.6	48.4 ri=2S0	66.1 n=548	17.7	58.7 »=280	84.6 n=54S	25.9
190–047 (" mg)	50.4 n=12S	65.9* n=136	15.5	57.0 »=128	59.8* n=136	2.8	53.7 »=12S	63.6* n=136	9.9
190–048 (" mS)	52.9 >i=80	56.3* »=79	3.4	39.7 »=80	62.9* n = 79	23.2	50.0 »=80	74.6* n = 79	24.6
Ave. Diff, between ESZ and PBO % Responders			20.5			17.5			20.6
Long-Term Insomnia
190–049 6 month	60.8 n=195	73.8 n=593	13	53.3 n=195	69.9 n=593	16.6	25.4 n=195*	78.4 n=593	23
190–050 6 month	60.9 >i=2S0	77.9 n=54S	17	57.1 »=280	71.4 »=548	14.3	62.1 »=280	80.6 »=548	18.5
Ave. Diff, between ESZ and PBO % Responders			15.0			15.4			20.7
Comorbid Insomnia
190–054	55.4 n=186	73.9 n=I81	18.5	63 »=183	74.1 »=177	11.1	59.7 »=186	76.7 »=181	17
190–055	60.7 n=56	73.8 n=66	13.1	67.2 n=67	77.3 n=76	10.1	55.9 »=68	68.0 n=76	12.1
190–052	73.9 >1=261	80.8 n=258	6.9	70.7 n=255	84.4 n=249	13.7	79.6 n=261	83.2 n=253	3.6
190–902	65.7 >1=299	72.1 »=294	6.4	66.1 n=297	73.2 n=294	7.1	68.2 »=299	81.3 »=294	13.1
Ave. Diff, between ESZ and PBO % Responders			9.9			10.4			10.9

Additional efficacy studies

Study 190–904

This phase IV study was a 12-weeks, multi-centre, randomised, double-blind, placebo-controlled, parallel group, efficacy and safety study of eszopiclone in older subjects with primary chronic insomnia.

A total of 388 patients were randomised and received placebo (n=194) or eszopiclone 2.0 mg (n=194) once a day at bedtime.

Efficacy Results:

With regard to the primary efficacy endpoint, a statistically significantly higher mean increase in (subjective) TST over the double-blind 12 week treatment was shown in the eszopiclone compared to the placebo group (with a mean increase of 63.2 min for eszopiclone and 33.2 min of placebo subjects, p< 0,001). Statistically significant improvements compared to placebo were also seen with regard to the key secondary endpoints WASO (subj., mean change compared to baseline: –36.4 minutes in eszopiclone and – 14.75 min in placebo subjects; p< 0.0001) and SL (subj., mean change compared to baseline: –24.62 minutes in eszopiclone and –19.92 minutes in placebo subjects; p=0.0014). Except for actigraphy results, which were captured in a subset of subjects, the efficacy results of the primary and

key secondary endpoints were generally supported by other secondary efficacy endpoints, although not all showed a statistically significant effect.

Study 190–246 was a multicentre randomised double-blind, placebo controlled 12 weeks evaluation of the safety and efficacy in children and adolescents with ADHD-associated insomnia. It was followed by a long-term open-label extension part, study 190–247.

Efficacy was not established in paediatric patients treated with eszopiclone for ADHD-associated insomnia.

Based on the presented efficacy results, it can be concluded that in adults Eszopiclone 2 mg and above consistently produced statistically significant improvements in sleep induction and quality of sleep measures in adults patients. By contrast, only the recommended dose of 3 mg consistently produced significant improvements in sleep maintenance parameters, including several improvements that where not achieved with the comparator zolpidem 10 mg. For the primary and key secondary measures in adult studies investigating primary insomnia, the 3 mg Eszopiclone consistently produced numerically better improvements than the 2 mg dose.

Results in non-older adults appeared sustained throughout each month of the two long-term studies for up to 12 months, however only the first 6 months of treatment were double-blind placebo controlled.

In older subjects the 2 mg dose, i.e. the highest dose evaluated in efficacy studies in patients ≥ 65 years, appeared more effective than the 1 mg dose. Efficacy of 2 mg eszopiclone in older subjects was shown in 2 studies of 2 weeks and one study of 12 weeks duration.

For these reasons, it is believed that nighttime administration of Eszopiclone 3 mg for adults and 2 mg for elderly subjects will provide effective hypnotic activity.

The data from trials in insomnia as co-morbid condition are also supportive of efficacy.

In order to reduce the risk of next-day impairment, the appliant has proposed a general starting dose of 1 mg in all patients. Efficacy results for the 1 mg dose were inconsistent, and respective information is proposed to be included in section 5.1 of the SmPC. However, results regarding sleep latency in particular may be interpreted as indicative, that some patients may already profit from this dose. In order to allow for treatment using the lowest effective individual dose, the proposed low starting dose is therefore considered acceptable.

Overall conclusions on clinical efficacy

The applicant has studied Eszopiclone in a variety of clinical settings involving primary insomnia, and insomnia secondary to various chronic conditions such as rheumatoid arthritis, generalised anxiety disorder, and major depressive illness. The results across studies are consistent and demonstrate shorter sleep latency, longer sleep time, and less wakening after the onset of sleep compared to placebo.

In adults, Eszopiclone 2 mg and 3 mg consistently produced statistically significant improvements in sleep induction and quality of sleep measures.

The derived differences between Eszopiclone and placebo for each endpoint for all efficacy studies listed in Table 1 of this Report, except study 190–026, 190–904 and ESZ111503:

in short-term primary insomnia trials for both adults (3 mg) and older adults (2 mg) were in sleep latency (SL) 19 minutes (range 15.8 – 28.5), in wake time after sleep onset (WASO) 10.9 minutes (range 7.5 – 15) and in TST 43.8 minutes (range 37.5 – 62.5).
in long-term primary insomnia studies in SL were 19.2 minutes (range 18 – 20.5), in WASO 12.3 minutes (range 11.4 – 13.2) and in TST 44 minutes (range 36.6 – 51.5).
in co-morbid insomnia studies in SL were 13 minutes (range 10.5 – 17.5), in WASO 11 minutes (range 5.9 – 18) and in TST 38 minutes (range 17.3 – 45).

Overall, the data of the clinical program presented by the applicant support efficacy of eszopiclone in the treatment of insomnia. In two long-term studies with 6 months blinded treatment in non-older adult patients, the efficacy results were maintained. Efficacy of 2 mg eszopiclone in older patients was shown in studies up to 12 weeks duration. While inconsistent efficacy results were shown regarding the 1 mg

dose, some patients may already profit from this dose. In order to allow for treatment with the lowest effective individual dose, a starting dose of 1 mg is recommended.

III.3.3 CLINICAL SAFETY

Patient exposure

Evidence of safety is derived from analysis of 37 human studies conducted with eszopiclone, four additional studies have been perfored in children and adolescents. Most of these studies were conducted in the USA.

The clinical development programme was conducted in more than 5000 subjects. A total of 777 subjects were exposed to at least 6 months of eszopiclone treatment, exceeding the ICH E1 requirement to obtain six months of exposure data in at least 300 subjects. A total of 300 subjects were exposed to at least 12 months of eszopiclone treatment, exceeding the ICH E1 requirement to obtain 12 months of exposure data in 100 subjects. The vast majority of this exposure was at the highest proposed commercial dose of 3 mg.

Treatment emergent adverse events (TEAEs)

The most common of AEs were unpleasant taste (dysgeusia). Other common adverse events include dizziness, somnolence, and dry mouth, consistent with the known pharmacology of nonbenzodiazepines. Overall, the adverse event profile following short-term (1–7 days, Table 4), chronicdosing (2– 12 weeks, Table 5), chronic-dosing in older subjects (2 weeks, Table 6) and long-term dosing in non-older subjects ( 6 months, Table 7) dosing is stable and predicted by the pharmacology of the compound.

There was no difference in the type or frequency of adverse events following long-term (up to 12 months) administration as compared to short-term (up to 2 weeks) administration or chronic dosing.

Table 4: Treatment emergent adverse events with an incidence >2% in either active group and the percent potentially related for the healthy volunteers/daytime-dosing in the pooled short-term (1–7 days) studies (COSTART coding) (ITT Population)

BODY SYSTEM		All TEAEs		Potentially Related TEAEs
Preferred Term	Placebo	ESZ 2 mg	ESZ 3 mg	Placebo	ESZ 2 mg	ESZ 3 mg
Subject n (%)	(N=124)	(N=52)	(N=135)	(N=124)	(N=52)	(N=135)
AT LEAST ONE AE	55 (44.4)	43 (82.7)	102 (75.6)	41 (33.1)	43 (82.7)	99 (73.3)
BODY AS A WHOLE	18 (14.5)	7 (13.5)	28 (20.7)	7 (5.6)	3 (5.8)	19 (14.1)
Headache	14 (11.3)	5 (9.6)	10 (7.4)	5 (4.0)	3 (5.8)	6 (4.4)
Asthenia	0	0	10 (7.4)	0	0	10 (7.4)
Abdominal pain	1 (0.8)	0	3 (2.2)	1 (0.8)	0	3 (2.2)
Back pain	3 (2.4)	1 (1.9)	3 (2.2)	1 (0.8)	0	0
Injection site haemorrhage	0	0	3 (2.2)	0	0	0
DIGESTIVE	6 (4.8)	6 (11.5)	20 (14.8)	4 (3.2)	5 (9.6)	16 (11.9)
Dry mouth	1 (0.8)	4 (7.7)	3 (2.2)	1 (0.8)	4 (7.7)	3 (2.2)
Nausea	1 (0.8)	1 (1.9)	4 (3.0)	1 (0.8)	0	3 (2.2)
Diarrhoea	0	3 (5.8)	3 (2.2)	0	2 (3.8)	2 (1.5)
Flatulence	0	0	6 (4.4)	0	0	4 (3.0)
Anorexia	1 (0.8)	0	5 (3.7)	1 (0.8)	0	5 (3.7)
Constipation	2 (1.6)	0	4 (3.0)	2 (1.6)	0	4 (3.0)
MUSCULOSKELETAL	4 (3.2)	2 (3.8)	3 (2.2)	1 (0.8)	1 (1.9)	2 (1.5)
Myalgia	3 (2.4)	1 (1.9)	3 (2.2)	1 (0.8)	0	2 (1.5)
NERVOUS	32 (25.8)	29 (55.8)	83 (61.5)	28 (22.6)	29 (55.8)	81 (60.0)
Somnolence	24 (19.4)	23 (44.2)	71 (52.6)	22 (17.7)	23 (44.2)	71 (52.6)
Dizziness	14 (11.3)	10 (19.2)	34 (25.2)	13 (10.5)	10 (19.2)	34 (25.2)
Relaxed feeling	1 (0.8)	0	4 (3.0)	1 (0.8)	0	4 (3.0)
Insomnia	0	0	6 (4.4)	0	0	3 (2.2)
Confusion	1 (0.8)	0	4 (3.0)	0	0	4 (3.0)
Nervousness	1 (0.8)	0	3 (2.2)	1 (0.8)	0	3 (2.2)
RESPIRATORY	6 (4.8)	4 (7.7)	9 (6.7)	1 (0.8)	2 (3.8)	8 (5.9)
Hiccup	0	0	8 (5.9)	0	0	8 (5.9)
Rhinitis	3 (2.4)	3 (5.8)	1 (0.7)	0	1 (1.9)	0
SPECIAL SENSES	14 (11.3)	25 (48.1)	46 (34.1)	11 (8.9)	25 (48.1)	46 (34.1)
Unpleasant taste	11 (8.9)	24 (46.2)	46 (34.1)	11 (8.9)	24 (46.2)	46 (34.1)
TEAE=treatment emergent adverse event		; ESZ=eszopiclone. Includes Studies 190–001, 190–002, 190–005, 190–
010, 190–011, 190–012, 190–015, 190–018, 190–019, 190–020, 190–021, and 190–023.

Table 5: Treatment emergent adverse events and potentially related TEAEs for the healthy volunteers/nighttime-dosing in the chronic-dosing (12 weeks) study (COSTART coding) (ITT population)

BODY SYSTEM	All TEAEs		Potentially Related TEAEs
Preferred Term	Placebo	ESZ 2 mg	ESZ 3 mg	Placebo	ESZ 2 mg	ESZ 3 mg
Subject n (%)	(N=47)	(N=0)	(N=48)	(N=47)	(N=0)	(N=48)
AT LEAST ONE AE	21 (44.7)	--	23 (47.9)	5 (10.6)	--	6 (12.5)
BODY AS A WHOLE	13 (27.7)	--	13 (27.1)	3 (6.4)	--	2 (4.2)
Headache	9 (19.1)	--	7 (14.6)	2 (4.3)	--	1 (2.1)
Pain	1 (2.1)		2 (4.2)	0	--	0
Accidental injury	0		1 (2.1)	0	--	0
Allergic reaction	0		1 (2.1)	0	--	0
Asthenia	2 (4.3)	--	1 (2.1)	2 (4.3)	--	1 (2.1)
Flu syndrome	2 (4.3)		1 (2.1)	0	--	0
Altered hormone level	0		1 (2.1)	0	--	0
DIGESTIVE	8 (17.0)	--	4 (8.3)	3 (6.4)	--	1 (2.1)
Dyspepsia	0	--	1 (2.1)	0	--	1 (2.1)
Abnormal liver function	0	--	1 (2.1)	0	--	0
tests
Oral moniliasis	0	--	1 (2.1)	0	--	0
Tooth caries	1 (2.1)	--	1 (2.1)	0	--	0
METABOLIC AND	1 (2.1)	--	2 (4.2)	1 (2.1)	--	1 (2.1)
NUTRITIONAL
DISORDERS
Hypoglycaemia	0	--	1 (2.1)	0	--	0
Increased iodine isotope	0	--	1 (2.1)	0	--	1 (2.1)
uptake
MUSCULOSKELETAL	2 (4.3)	--	2 (4.2)	0	--	1 (2.1)
Leg cramps	0	--	1 (2.1)	0	--	1 (2.1)
Myalgia	1 (2.1)	--	1 (2.1)	0	--	0
NERVOUS	2 (4.3)	--	3 (6.3)	2 (4.3)	--	1 (2.1)
Anxiety	0	--	1 (2.1)	0	--	0
Dizziness	1 (2.1)	--	1 (2.1)	1 (2.1)	--	0
Insomnia	0	--	1 (2.1)	0	--	1 (2.1)
Decreased libido	0	--	1 (2.1)	0	--	0
RESPIRATORY	6 (12.8)	--	11 (22.9)	1 (2.1)	--	3 (6.3)
Infection	4 (8.5)	--	4 (8.3)	0	--	0
Pharyngitis	0	--	4 (8.3)	0	--	2 (4.2)
Rhinitis	1 (2.1)	--	3 (6.3)	1 (2.1)	--	1 (2.1)
SPECIAL SENSES	1 (2.1)	--	3 (6.3)	0	--	3 (6.3)
Unpleasant taste	0	--	3 (6.3)	0	--	3 (6.3)
TEAE=treatment emergent adverse event; ESZ=eszopiclone.

Table 6: All Treatment Emergent Adverse Events with an Incidence >2% in Either Active Group, and the Percent Potentially Related for the Subjects with Insomnia/Nighttime-Dosing in the Pooled ChronicDosing (2 Weeks) Studies in Elderly Subjects (COSTART Coding)

BODY SYSTEM	All TEAEs		Potentially Related TEAEs
Preferred Term	Placebo	ESZ 2 mg	ESZ 3 mg	Placebo	ESZ 2 mg	ESZ 3 mg
Subject n (%)	(N=208)	(N=215)	(N=0)	(N=208)	(N=215)	(N=0)
AT LEAST ONE AE	91 (43.8)	100 (46.5)	--	53 (25.5)	67 (31.2)	--
BODY AS A WHOLE	48 (23.1)	50 (23.3)	--	26 (12.5)	24 (11.2)	--
Headache	29 (13.9)	29 (13.5)	--	19 (9.1)	15 (7.0)	--
Pain	4 (1.9)	10 (4.7)	--	3 (1.4)	2 (0.9)	--
Asthenia	7 (3.4)	6 (2.8)	--	5 (2.4)	5 (2.3)	--
Abdominal pain	7 (3.4)	5 (2.3)	--	4 (1.9)	4 (1.9)	--
Accidental injury	2 (1.0)	6 (2.8)	--	0	0	--
DIGESTIVE	23 (11.1)	30 (14.0)	--	14 (6.7)	18 (8.4)	--
Dry mouth	4 (1.9)	14 (6.5)	--	4 (1.9)	12 (5.6)	--
Diarrhoea	5 (2.4)	5 (2.3)	--	2 (1.0)	1 (0.5)	--
NERVOUS	21 (10.1)	30 (14.0)	--	18 (8.7)	27 (12.6)	--
Somnolence	14 (6.7)	12 (5.6)	--	13 (6.3)	12 (5.6)	--
Dizziness	5 (2.4)	12 (5.6)	--	5 (2.4)	11 (5.1)	--
Nervousness	3 (1.4)	5 (2.3)	--	3 (1.4)	4 (1.9)	--
SKIN AND	9 (4.3)	10 (4.7)	--	4 (1.9)	5 (2.3)	--
APPENDAGES
Rash	5 (2.4)	5 (2.3)	--	1 (0.5)	1 (0.5)	--
SPECIAL SENSES	9 (4.3)	30 (14.0)	--	6 (2.9)	29 (13.5)	--
Unpleasant taste	1 (0.5)	26 (12.1)	--	1 (0.5)	26 (12.1)	--

TEAE=treatment emergent adverse event; ESZ=eszopiclone.

Table 7: Treatment Emergent Adverse Events with an Incidence >2% in Either Active Group, and the Percent Potentially Related for the Subjects with Insomnia/Nighttime-Dosing in the Pooled Long-Term (6-Month Double-Blind) Studies in Non-Elderly Adults (COSTART Coding) (ITT Population)

BODY SYSTEM		All TEAEs	Potentially Related TEAEs
Preferred Term	Placebo	ESZ 2 mg	ESZ 3 mg	Placebo	ESZ 2 mg	ESZ 3 mg
Subject n (%)	(N=475)	(N=0)	(N=1141)	(N=475)	(N=0)	(N=1141)
AT LEAST ONE AE	303 (63.8)	--	896 (78.5)	169 (35.6)	--	629 (55.1)
BODY AS A WHOLE	189 (39.8)	--	518 (45.4)	86 (18.1)	--	231 (20.2)
Headache	79 (16.6)	--	199 (17.4)	55 (11.6)	--	125 (11.0)
Pain	41 (8.6)	--	115 (10.1)	4 (0.8)	--	18 (1.6)
Back pain	26 (5.5)	--	74 (6.5)	3 (0.6)	--	22 (1.9)
Accidental injury	28 (5.9)	--	70 (6.1)	2 (0.4)	--	2 (0.2)
Abdominal pain	20 (4.2)	--	68 (6.0)	13 (2.7)	--	33 (2.9)
Asthenia	19 (4.0)	--	47 (4.1)	13 (2.7)	--	35 (3.1)
Flu syndrome	20 (4.2)	--	42 (3.7)	5 (1.1)	--	9 (0.8)
Viral infection	10 (2.1)	--	34 (3.0)	1 (0.2)	--	4 (0.4)
Chest pain	10 (2.1)	--	31 (2.7)	6 (1.3)	--	11 (1.0)
DIGESTIVE	98 (20.6)	--	322 (28.2)	47 (9.9)	--	208 (18.2)
Nausea	20 (4.2)	--	84 (7.4)	13 (2.7)	--	52 (4.6)
Dyspepsia	28 (5.9)	--	75 (6.6)	14 (2.9)	--	49 (4.3)
Diarrhoea	17 (3.6)	--	68 (6.0)	9 (1.9)	--	38 (3.3)
Dry mouth	11 (2.3)	--	60 (5.3)	11 (2.3)	--	53 (4.6)
Constipation	4 (0.8)	--	28 (2.5)	0	--	20 (1.8)
Vomiting	8 (1.7)	--	27 (2.4)	2 (0.4)	--	13 (1.1)
MUSCULOSKELETAL	39 (8.2)	--	148 (13.0)	10 (2.1)	--	38 (3.3)
Myalgia	17 (3.6)	--	60 (5.3)	4 (0.8)	--	17 (1.5)
Arthralgia	10 (2.1)	--	35 (3.1)	2 (0.4)	--	4 (0.4)
NERVOUS	75 (15.8)	--	324 (28.4)	55 (11.6)	--	249 (21.8)
Somnolence	14 (2.9)	--	102 (8.9)	14 (2.9)	--	95 (8.3)
Dizziness	15 (3.2)	--	79 (8.9)	13 (2.7)	--	63 (5.5)
Depression	5 (1.1)	--	39 (3.4)	3 (0.6)	--	22 (1.9)
Anxiety	5 (1.1)	--	33 (2.9)	2 (0.4)	--	16 (1.4)
Nervousness	8 (1.7)	--	33 (2.9)	5 (1.1)	--	27 (2.4)
Abnormal dreams	11 (2.3)	--	29 (2.5)	11 (2.3)	--	29 (2.5)
RESPIRATORY	103 (21.7)	--	356 (31.2)	21 (4.4)	--	57 (5.0)
Infection	45 (9.5)	--	174 (15.2)	5 (1.1)	--	9 (0.8)
Pharyngitis	21 (4.4)	--	92 (8.1)	5 (1.1)	--	19 (1.7)
Rhinitis	17 (3.6)	--	68 (6.0)	5 (1.1)	--	13 (1.1)
Sinusitis	22 (4.6)	--	50 (4.4)	6 (1.3)	--	7 (0.6)
Bronchitis	3 (0.6)	--	24 (2.1)	0	--	0
SKIN & APPENDAGES	32 (6.7)	--	115 (10.1)	12 (2.5)	--	43 (3.8)
Rash	10 (2.1)	--	46 (4.0)	3 (0.6)	--	19 (1.7)
SPECIAL SENSES	35 (7.4)	--	315 (27.6)	23 (4.8)	--	278 (24.4)
Unpleasant taste	14 (2.9)	--	263 (23.0)	14 (2.9)	--	260 (22.8)
UROGENITAL	32 (6.7)	--	119 (10.4)	11 (2.3)	--	41 (3.6)
Dysmenorrhoea	5 (1.7)	--	20 (2.8)	0	--	5 (0.7)

In the 12 week study in older subjects with insonmina/nighttime-dosing (study 190–904), 59% of the 194 eszopiclone subjects and 51% of the 194 placebo subjects experienced a total of 575 TEAEs during the double-blind period. The most common adverse events were headache, dysgeusia, and nasopharyngitis. The most frequent AEs considered related to eszopiclone were: dysgeusia (12.4% eszopiclone and 1.5% placebo subjects), headache (5.7% eszopiclone and 4.6% placebo subjects, dizziness (3.6% eszopiclone and 1.0% placebo subjects) and somnolence (2.6% eszopiclone and 1.5% placebo subjects).

Clinical results in older subjects with insomnia were collected in patients with no relevant co-morbidity at the time of inclusion in two short-term studies (over two weeks) and in one study over 12 week treatment duration. In general, the safety profile in older appears similar to that in younger subjects. Evaluation of the ADR profile in older subjects according to the applied rules (i.e. considering at least possibly related TEAEs with an incidence above 1 and higher in the total eszopiclone group compared to the placebo group as ADR) compared to the ADR profile in non-older subjects resulted in the following differences: The ADR “vision blurred” was reported in older but not in non-older subjects.

Serious adverse events and deaths

Serious adverse events

In total, 18 placebo-treated subjects and 30 Eszopiclone-treated subjects experienced serious adverse events (SAEs). This includes the double-blind period of the long-term safety studies 190–049 and 190050.

Of these 48 subjects, four experienced serious adverse events in the nighttime, 2-week studies in elderly subjects with insomnia (Studies 190–047 and 190–048), where the incidence was similar between the placebo group (1.0%; 2/208) and the Eszopiclone group (0.7%; 2/277).

During the two night-time 6 month double-blind studies, 190–049 and 190–050, similar rates of SAEs were observed with 24 subjects (2.1%) treated with Eszopiclone 3 mg experiencing 25 SAEs and 10 subjects (2.1%) treated with placebo experiencing 10 SAEs. The most common serious adverse events were accidental injury, chest pain, and gastrointestinal disorder, each observed in 0.3% of Eszopiclone subjects.

Only accidental injury had an event rate greater than the placebo event rate. The incidence of SAEs observed in the 8 week studies in subjects with MDD or GAD were similar for the Eszopiclone group (7 subjects, 1.2%) and the placebo group (8 subjects, 1.4%).

In addition to the above, 2 placebo and 4 eszopiclone subjects treated in study 190–904 experienced SAEs, of the latter 2 were fatal. All SAEs in this study which was performed in older adults were considered not or unlikely related to study drug.

Deaths

No deaths occurred in adult non-elderly subjects treated with eszopiclone. Two deaths occurred in elderly patients with insomnia treated with 2 mg eszopiclone for up to 12 weeks (both cases occurred in study 190–904). One patient committed suicide, another patient died from arteriosclerotic cardiovascular disease; both events with fatal outcome were considered unlikely or not related to study drug by the investigator. In the opinion of the RMS a causal relationship of the completed suicide with eszopiclone can not be fully excluded. A warning regarding depression and suicidality has already been proposed to be included for section 4.4 of the SmPC. In addition, in line with the German SmPC of Ximovan (zopiclon), the following information was added as requested by the RMS: “Several epidemiological studies showed an increased incidence of suicide and suicide attempt in patients with or without depression, who were treated with benzodiazepines or other hypnotics, including zopiclone. A causal relationship was not established”.

Other significant Adverse events

Because of the pharmacologic class, additional adverse events of parasomnia, hallucinations, worsening of depression, overdose, suicide, amnesia, accidental injury and convulsions were evaluated more in depth.

A low incidence of parasomnia was observed in the 6 month long-term studies (190–049 and 190–050) in both Eszopiclone 3 mg and placebo subjects, as well as in Eszopiclone subjects with MDD (study 190–052) or GAD (study 190–902) studies. Parasomnia was not observed in any other study.

Hallucinations were reported in 15 subjects (0.8%; 15/1839). Daytime hallucinations were observed only in subjects taking supratherapeutic doses. Reports of hallucinations at recommended doses were typically similar to a migraine aura or hypnogogic visual hallucinations (occurring at the time of sleep onset) or sleep-onset dreaming.

There were no occurrences of potentially related treatment emergent accidental overdose or intentional overdose reported. One patient commiteted suicide and another patient died from arteriosclerotic cardiovascular disease in study 190–904, both events with fatal outcome considered as not or unlikely related to study drug by the investigator.

Regarding depression, a slightly higher incidence of placebo subjects (1.0%) reported depression compared to Eszopiclone 3 mg subjects (0.5%) in the MDD/GAD studies. In other pooled studies, the incidence of depression was 1.5% (28/1836) with the highest rate occurring in the long-term studies.

The incidence of accidental injury ranged from 0% to 1.5% for placebo subjects compared to the range of 0% to 0.8% for Eszopiclone subjects.

There were no reports of convulsion in any of the studies in adults.

Amnesia

There were 11/1012 (1.1%) events of memory impairment in the less than 60 years age group. There were 3/129 (2.3%) events of memory impairment in the non-elderly population aged 60 years and more. In the elderly population (evaluated in studies 190–047 and 190–048), the occurrence was 2/199 (1.0%) for the less than 75 years age group, and there was one case (1.1%) of memory impairment in the 75 years and older age group.

Laboratory findings

Laboratory abnormalities were infrequent. Most of the subjects in each population group who were normal at baseline remained in the normal range at the end of the study for haematology, serum chemistry, and urinalysis parameters. For the parameters with shifts, there were minor differences in rates between placebo and Eszopiclone. There was no evidence of a clinically meaningful drug effect on any parameter.

Vital Signs, Postural Blood Pressure and ECG Monitoring

There was no evidence of a clinical meaningful drug effect on vital signs (i.e. heart rate, blood pressure, respiration rate or body temperature), postural blood pressure or electrocardiograms.

Orthostatic Hypotension

There were a few, isolated episodes of orthostatic hypotension, all asymptomatic, in adult subjects at doses up to 7.5 mg, with no dose response observed. There were a few episodes in elderly subjects at doses of 1 and 2 mg, with slightly higher rates at 3 and 5 mg. Most events were isolated instances, and only two events were associated with dizziness.

Safety in special populations

There were no apparent overall differences in adverse event profiles when considering age, gender, race, and BMI.

Renal Insufficiency

Eszopiclone was generally safe and well tolerated in subjects with impaired renal function. Systemic exposure increased by 47% in subjects with severe renal impairment. Based on the provided data, reducing the eszopiclone dose to 2 mg in patients with severe renal impairment should lead to similar exposure and efficacy as has been shown for patients aged 65 years and older and is therefore considered justified from a safety and efficacy perspective.

Hepatic Insufficiency

The safety profile of Eszopiclone in subjects with hepatic impairment was similar to that for subjects with normal hepatic function.

Safety derived from studies in paediatric patients with ADHD (studies 190–246 and 190–247) – not assessed during the centralized procedure for Lunivia/Esogno

During the 12 week double blind study 190–246 the most commonly reported TEAEs were headache (13.8%, 11.7%, and 11.8% of subjects in the high-dose eszopiclone, low-dose eszopiclone, and placebo groups, respectively), dysgeusia (13.8%, 4.9%, and 1.2%), and dizziness (8.2%, 3.7%, and 1.9%). The incidence of SAEs was low, i.e. 2 SAEs were reported by 2 (0.4%) of the subjects. Events leading to the discontinuation of more than 1 subject included: psychomotor hyperactivity (3 subjects); irritability (2 subjects); and dizziness (2 subjects).

During the subssequent open-label extension study (190–247) one death (accidental drowning) occurred which appeared not related to the study medication. One SAE of delirium was considered definitely related to eszopiclone by the investigator. This single event of delirium was reported in a paediatric patient, resolved while eszoliclone was continued for further 3 days and delirium is not explicitly given among the known behavioural ADRs known to be associated with zopiclone. While the applicant has added “abnormal behaviour (possibly associated with amnesia)” as an adverse reaction that has been reported for racemic zopiclone, it is agreed that delirium is currently not added to section 4.8 of the SmPC.

Withdrawal, Rebound and other relevant safety studies

Withdrawal- and Rebound-Associated Post-treatment AEs

For the chronic-dosing (4–8 weeks) studies, there were similar overall incidences of withdrawal AEs (12.8%, 8.2%, and 13.7% of placebo, 2 mg Eszopiclone, and 3 mg Eszopiclone subjects, respectively). With respect to events that are recognized to occur in association with termination of a benzodiazepine, there were few reports of anxiety (0.1%, 2.1%, and 0.3%), and insomnia (0.1%, 0%, 0.3%), and no reports of convulsions, hallucinations, or perceptual disturbances. A higher incidence of nausea (0.6%, 2.1%, and 0.4%) was observed in at least one Eszopiclone dose group compared with the placebo group, although this was not consistent across dose groups. These trends are not clinically different from that observed during double-blind treatment.

Study 190–050 included a single-blind wash-out phase after 6 months of long-term double-blind dosing with Eszopiclone 3 mg.

Longer-term treatment (6 months) did not result in higher overall rates of withdrawal adverse events compared to placebo (14.8% and 13.4% of placebo- and 3 mg Eszopiclone-treated subjects). Similar to the data following short-term administration, there were few reports of insomnia (0% and 0.6% for placebo and 3 mg Eszopiclone, respectively), and no reports of anxiety, convulsions, hallucinations, or perceptual disturbances. Report of pain including back pain, chest pain, and abdominal pain were more frequent following Eszopiclone use, however, this is similar to that observed during the activetreatment phase of the study. In comparison to shorter-term withdrawal effects, long-term eszopiclone treatment did not increase the prevalence of any withdrawal adverse event commonly associated with termination of a sedative hypnotic.

Benzodiazepine Withdrawal Symptom Questionnaire

The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) was collected from subjects at the end-of-study visit in Study 190–050. The BWSQ is a subjective assessment of symptoms the subject may be experiencing after discontinuing study medication. There was no significant difference (p=0.1167) between the Eszopiclone 3 mg group (2.96) and the placebo group (2.26) for the total score outcome of the BWSQ.

Rebound insomnia

Rebound insomnia has been defined as the exaggerated expression of the original condition sometimes experienced by subjects following immediate cessation of an effective treatment. For purposes of these analyses, rebound insomnia was defined as a dose-dependent temporary worsening in sleep parameters compared with baseline following discontinuation of treatment.

Occurrence of rebound effects was assessed by objective parameters from polysomnography in study 190–046 (44 days duration) and by subjective parameters in study 190–050 (26 weeks duration).

The data collected suggested that rebound insomnia is mostly limited to the first night. The data available covers both short-term and long term use of Eszopiclone. Given the PK characteristics and the known pharmacology of Eszopiclone it is unlikely that withdrawal and rebound will manifest after the 2 weeks that were studied in this clinical program.

Insomnia patients ≥ 65 years (results derived from study 190–904)

The data provided for the overall eszopiclone group compared to placebo group (including AEs that occurred after single-blinded discontinuation of eszopiclone, BWSQ and rebound sleep parameters) do not indicate an increased risk of withdrawal effects or rebound insomnia in older subjects after 12 weeks of treatment compared to placebo. The overall incidence of AEs observed in the eszopiclone group following discontinuation of treatment (17.9%) was in line with results from previous studies (10–20% in any study) and no relevant differences were found regarding the incidence of individual AEs. However, no evaluation of individual subject data regarding withdrawal or rebound has been presented in this study.

Abuse potential

Abuse potential was evaluated with study 190–016 conducted in patients with a history of benzodiazepines abuse and included diazepam as active control. The results of the trial did not raise a particular concern but they were not fully conclusive either. Particularly because the active control,

diazepam, could not be fully discriminated from placebo. These studies in known abusers are prone to this type of results since the endpoints are highly subjective and the numbers tested small.

Effects on Ability to Drive or Operate Machinery or Impairment of Mental Ability

Eszopiclone 3 mg did not impair healthy volunteers’ ability to function on a variety of tasks related to everyday life, including the skilled task of on-the-road driving (Brake Reaction Time) ability.

Study 190–060, conducted in subjects with primary insomnia, demonstrated that nighttime administration of Eszopiclone 3 mg improved next-morning subjective ratings of sleep quality and ease of getting to sleep in patients. Furthermore, while sleep appeared to be improved, there were no residual impairing effects on car-driving ability or cognitive and psychomotor performance the next day.

Adverse Events of Drowsiness Reported in the Pooled Studies

For the pooled studies with nighttime administration, potentially related treatment emergent somnolence was reported in 7 study types. The incidence of somnolence in each Eszopiclone group was similar to or lower than the incidence in the placebo group for the following study types:

Healthy volunteers in the short-term (1–7 days) studies (3.6% versus 4.3%, 5.5%, 3.6%, and 2.1% for placebo and Eszopiclone 1 mg, 2 mg, 3 mg, and ≥3.5 mg, respectively);
Healthy volunteers in the chronic-dosing (12 weeks) study (2.1% versus 0% for placebo and Eszopiclone 3 mg, respectively);
Subjects with insomnia in the chronic-dosing (2 weeks) studies in elderly subjects (6.3% versus 6.9% and 5.6% for placebo and Eszopiclone 1 mg and 2 mg, respectively);

The incidence of somnolence in at least one Eszopiclone group was somewhat higher than the incidence in the placebo group for the following study types:

Subjects with insomnia in the short-term (1–7 days) studies in non-elderly adults (3.9% for placebo versus 3.2%, 2.7%, 3.1%, and 7.9% for placebo and Eszopiclone 1 mg, 2 mg, 2.5 mg, and 3 mg, respectively);
Subjects with insomnia in the chronic-dosing (4–6 weeks) studies in non-elderly adults (1.3% versus 8.7% for placebo and Eszopiclone 3 mg, respectively);
Subjects with insomnia in the chronic-dosing (8 weeks) studies coadministered with an SSRI (non-elderly adults with insomnia and in comorbid MDD/GAD) (8.6% versus 11.0% for placebo and Eszopiclone 3 mg, respectively);
Subjects with insomnia in the long-term (6-month double-blind) studies in non-elderly adults (2.9% versus 8.3% for placebo and Eszopiclone 3 mg, respectively);

In study 190–904 evaluating older subjects with insomnia over 12 weeks the incidence of somnolence was 2.6% in eszopiclone and 1.5% in placebo treated subjects

The data collected concerning detrimental effects in the ability to perform are reassuring as they support the notion that the ability is minimal affected by the use of Eszopiclone at nighttime. However, there are some instances where a reduction of ability or excessive somnolence was noted. Therefore, respective warnings have been included in the SPC.

Study ESZ111503 :

A safety study, evaluating next day residual effects and overall safety of a single dose of eszopiclone 3 mg compared to zopiclone 7.5 mg and placebo in healthy adults. Study ESZ111503 has failed to reject the pre-specified primary null hypothesis, that there is no difference between eszopiclone 3mg and zopiclone 7.5 mg in the mean tracking error assessed during the Continuous Tracking Test (CTT), and the additionally conducted analyses cannot compensate this flaw. Study ESZ111503 is therefore considered a negative study. Some of the multiple analyses of secondary endpoints addressing residual effects reached p values (mainly just) below 0.05, however, after failure of the confirmatory analysis of the study, the analyses of the secondary endpoints are only regarded as exploratory.

In study ESZ111503, the adverse event profile did not indicate any advantage of a single evening dose of 3 mg eszopiclone compared to 7.5 mg zopiclone in healthy adults.

The presented efficacy results of this study are based on post-hoc evaluations; they have not been preplanned in the protocol, therefore, the data can be considered at best as hypothesis generating.

Discontinuation due to adverse events

In general, adverse events leading to discontinuation did not raise any safety concerns.

In the nighttime 4–6 week studies in non-elderly adult subjects with insomnia (190– 046 and 190–054), there were slightly higher rates of subjects who discontinued due to adverse events in the Eszopiclone groups (2.3% Eszopiclone 3 mg; 1.9% Eszopiclone 2 mg) compared to the placebo group (0.7%). The incidence of subjects discontinuing due to individual adverse events was less than 1% for each event with the exception of headache, in the Eszopiclone 2 mg group. However, no one discontinued due to headache in the Eszopiclone 3 mg group.

In the nighttime, 2-week studies in elderly subjects with insomnia (190–047 and 190– 048), the incidence of subjects who discontinued due to an AE was slightly lower in the Eszopiclone group (1.4% for Eszopiclone 2 mg and 2.3% for Eszopiclone 3 mg) than in the placebo group (3.8%).

In the nighttime, 6-month double-blind studies in non-elderly adult subjects with insomnia (190–049 and 190–050), there were slightly higher rates of subjects who discontinued due to adverse events in the Eszopiclone group (11.1%) than in the placebo group (7.6%). The most common reason for discontinuation in the Eszopiclone group was somnolence (2.0%) followed by unpleasant taste (1.2%) and depression (1.1%).

During the open-label phase of Study 190–049, 18 subjects (3.8%) discontinued due to adverse events. Of these subjects, seven previously received double-blind placebo treatment and 11 previously received double-blind Eszopiclone.

In the 12-week double blind study in elderly patients with insomnia (190–904), there were slightly higher rates of subjects who discontinued due to AEs in the eszopiclone group (7.2%) than in the placebo group (4.1%). The most common reason for discontinuation in the eszopiclone group was dysgeusia (1.5%).

Post marketing experience/Risk management

LUNESTA (eszopiclone) was approved in the United States of America (USA) for the treatment of insomnia on Dec 15, 2004 and is marketed by Sunovion Pharmaceuticals, Inc. under the trade name LUNESTA. Eszopiclone was approved in Japan for the treatment of insomnia on Jan 18, 2012 and is marketed by Eisai Pharmaceuticals under the same trade name. Eszopiclone was approved in Canada for the treatment of insomnia on Mar 17, 2016 and is pending product launch.

Safety reports covering reporting periods beginning on December 14, 2004 through to April 14, 2017 have been briefly summarized in Module 2.7.4 Summary of Clinical safety.

As of October 2017, over 45 million prescriptions of LUNESTA have been sold [source: IMS NPA Monthly Data] representing more than 3 million person years of exposure.

Overall, the safety profile characterized during clinical development is consistent with post-marketing experience.

Eszopiclone has been marketed in the USA since April 2005 under the trade name of Lunesta.

However, in May 2014 the U.S. Food and Drug Administration (FDA) was warning that eszopiclone could cause next-day impairment of driving and other activities that require alertness. As a result, the recommended starting dose of Lunesta was decreased to 1 mg at bedtime. Taking into consideration that eszopiclone should be used at the lowest effective dose possible for the individual patient and that some patients may already profit from 1 mg of eszopiclone, a general starting dose of 1 mg is also proposed for Eszopiclone.

Overall conclusions on clinical safety

The safety database for Eszopiclone includes thorough testing in controlled clinical trials that exceed the ICH minimum requirements. The vast majority of adult patients was exposed at the highest proposed commercial dose of 3 mg, in older adults doses up to 2 mg were evaluated.

The most common of AEs were unpleasant taste (dysgeusia). Other common adverse events include dizziness, somnolence, and dry mouth, consistent with the known pharmacology of nonbenzodiazepines. Headache, dyspepsia, and pain including back pain, have also been frequently observed, however, the incidence of these have not been as notably different from placebo treatment groups in clinical trials.

Evaluation of central nervous system and other potentially related effects such as orthostatic

hypotension and falls demonstrate that the likelihood of clinically meaningful increase in risk is low. However, orthostatic hypotension might be seen as a problem rarely in particularly sensitive patients. An array of psychomotor performance evaluations were performed, including effects on driving ability, all of which show no clinically meaningful next-day effects.

In May 2014 the U.S. Food and Drug Administration (FDA) warned that eszopiclone could cause nextday impairment of driving and other activities that require alertness. As a result, the recommended starting dose of Lunesta was decreased to 1 mg at bedtime. In order to allow for treatment with the lowest effective individual dose, a general starting dose is also recommended for Eszopiclone.

Duration of treatment

Long-term use has been evaluated in two large controlled clinical trials with up to 6 months doubleblind and in one of the studies up to 12 months uncontrolled treatment duration and the safety profile, including risk of dependence, was not different from that observed with shorter-term use of Eszopiclone.

Withdrawal effects have been examined following both short-term and long-term use. The data demonstrated a low frequency of potential withdrawal effects (e.g., anxiety and insomnia) following discontinuation of Eszopiclone after both short-term and long-term use. Analysis of aggregate data did not demonstrate the presence of rebound insomnia overall after short-term or long-term use. Examination of individual subject data demonstrated that when rebound insomnia does occur, it was mild and self-limited, lasting one to two nights. The post-marketing data support these findings in the development plan.

There is no pattern of adverse events suggestive of increased abuse potential, and evaluation in a population of benzodiazepine-experienced subjects did not raise new concerns. However, the data of study 190–016 was not completely conclusive because it failed to discriminate the active comparator from placebo.

In summary, although the risk appears rather low, eszopiclone may lead to development of physical dependence and consequently to withdrawal symptoms and rebound phenomena even at therapeutic doses. Psychological dependence may also occur, and abuse of benzodiapezine-like drugs has been reported.

In addition, benzodiazepines and benzodiazepine-like agents, such as eszopiclone, may induce anterograde amnesia and psychomotor impairment, including accidental injury and falls.

Therefore, treatment with benzodiazepines and benzodiazepine-like drugs should usually be restricted to short-term duration, and respective information has been added to section 4.1 of the SmPC.

However, further sustained improvement of sleep was shown in placebo-controlled studies in primary insomnia up to 6-months duration, and it is therefore considered acceptable, that for a certain sub-set of patients, who need longer treatment, duration of treatment may be extended to a maximum of 6 months. However, patients with extended treatment should be regularly monitored for potential signs of dependence. Respective information has been included in sections 4.2 and 4.4 of the SmPC.

In general, the safety profile in older subjects as derived from 3 clinical studies up to 12 weeks duration appears similar to that in younger patients, and as requested, differences in the ADR profile have been clarified and are given in section 4.8 of the SmPC.

The safety profile of eszopiclone at nighttime at a dose of 3 mg in non-older adults and of 2 mg in older adults as described is considered acceptable for the treatment of insomnia in adults, usually for short-term duration. The wording of the indication has been further amended in order to add the class labelling information, that benzodiazepines or benzodiazepine-like substances are only indicated when the disorder is severe, disabling or subjecting the individual to extreme distress. Consequently, the ‘specification’ of insomnia “including difficulty falling asleep, nocturnal awakening or early awakening” has been deleted and the wording proposed for section 4.1 is now considered acceptable.

Legal Status

Medicinal product is subject to medical prescription.

User Testing

Regulatory Resources Group (RRG) performed a consultation with target patient groups (user test) on the Lunivia/Esogno patient leaflet (PL), with positiv outcome in 2007.

The package leaflet of Lunivia/Esogno 2 mg and 3 mg film-coated tablets passed success criteria of at least 80 % of subjects in round 1 and 2 of user testing to find and understand the information requested by each question.

Evaluation of content/bridging of content

The tested package leaflet of Lunivia/Esogno covers the strengths of 2 mg and 3 mg whereas the current package leaflet for Eszopiclone film-coated tablets covers three strengths, 1 mg, 2mg, 3mg. Furthermore, the current package leaflet includes scientific updates as applied for the corresponding SmPC of Eszopiclone film-coated tablets. However, in summary the wording of the two package leaflets are highly similar and a bridging of content is feasible.

A detailed comparison with appraisal of texts content has been provided in Appendix 1 ( Module 1.3.4 – app1-bridging-comparison). Mainly differences derive from QRD adaptation. Other differences are justified as not affecting readability.

Evaluation of layout/bridging of layout

A bridging for the layout is proposed. The applicant has established a corporate PL layout, which has been tested in several Readability User Tests on products of the applicant. All tests have proven the patient friendliness of the layout, which supports patients in finding key safety messages in PLs.

In accordance with QRD Bridging requirements, the following key elements have been considered:

Key elements	Critical comparison'
Font and text size	Will be the same as in established corporate PL layout.
Headings and sub-headings including formatting consistency.	Will be the same as in established corporate PL layout.
Leaflet dimensions including whether the document is laid out	Exact dimension cannot be provided at this stage of the application. However the layout will
in portrait or landscape format.	be the same as in established corporate PL layout using portrait format.
Use of colour and choice of colour.	Will be the same as in established corporate
Style of writing and language used.	Patient friendly style of writing has been used. The language used for the testing was English.
Layout of critical safety sections of the leaflet	Where considered necessary critical sections are highlighted in bold italic and/or with bullet points. Only in exceptional circumstances capital letters shall be used within the text.
Use of pictograms	Not applicable.

Conclusion

A text comparison shows that results of the earlier performed user test can be considered applicable for the currently proposed package leaflet with regard to the text content.

With regard to the layout, the corporate layout style as tested and proven patient friendly will be used by all marketing authorisation holders of this decentralised procedure.

It can be concluded that the proposed package leaflet for Eszopiclone 1 mg, 2 mg, 3 mg film-coated tablets is compliant with article 59(3) of Council Directive 2001/83EC (Consultation with Target Patient Groups).

The user test consultation provided was regarded as satisfactory for Lunivia/Esogno. A detailed comparison of the user tested version of Lunivia/Esogno and the current proposed version with appraisal of texts content has been provided. Mainly differences derive from QRD adaptation. Other differences are justified as not affecting readability. In addition, the applicant has established a corporate PL layout, which has been tested in several Readability User Tests on products of the applicant.

In conclusion, the bridging approach is regarded as acceptable and no new user testing is necessary.

Summary Pharmacovigilance system

The applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.

Risk Management Plan

The MAH has submitted a risk management plan, version 1.1, 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 the medicinal product(s) applied for authorisation.

The following safety concerns have been proposed by the applicant:

Important identified risks	Drug dependence Psychiatric and paradoxical reactions Sleep walking and associated behaviours
Important potential risks	Not applicable
Missing information	Not applicable

No additional pharmacovigilance activities or additional risk minimization measures have been proposed.

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 RMS;
– 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.

Periodic Safety Update Report (PSUR)

With regard to PSUR submission, the MAH should take the following into account:

1) PSURs shall be submitted 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. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR.
2) For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list.
3) For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list.

IV BENEFIT RISK ASSESSMENT
IV.1 Benefits

The applicant has demonstrated in a series of well-conducted clinical studies that Eszopiclone has a rapid onset of action, has an apparently linear dose response curve over the dose range tested, and has

a relatively short plasma half-life (in the region of six hours) leading to little carry-over effect on the day after dosing. Although the mechanism of action is incompletely understood at a molecular level it can be assumed to be similar to that of the racemic substance zopiclone.

Eszopiclone has been studied in a variety of clinical settings involving primary insomnia, and insomnia secondary to various chronic conditions such as rheumatoid arthritis, generalised anxiety disorder, and major depressive illness. The results across studies in adults are consistent and demonstrate shorter sleep latency, longer sleep time, and less wakening after the onset of sleep compared to placebo.

Considering the primary endpoint (sleep latency) in primary insomnia studies, Eszopiclone in nonolder adults (3 mg) and older adults (2 mg) reduced time to sleep onset by 19 minutes (range 15.8 – 28.5) as compared to placebo in short-term trials and, at a dose of 3 mg in non-older adults, Eszopiclone reduced time to sleep onset by 19.2 minutes (range 18 – 20.5) as compared to placebo in long-term trials.

Eszopiclone demonstrated to be an effective hypnotic. Efficacy results for the 1 mg dose were inconsistent, and respective information has been included in section 5.1 of the SmPC. However, in particular results regarding sleep latency may be interpreted as indicative that some patients may already profit from this dose.

IV.2 Risks

Eszopiclone is associated with well-defined but moderate adverse effects, the most common being unpleasant taste (dysgeusia). Other common adverse events include dizziness, somnolence, and dry mouth, consistent with the known pharmacology of non-benzodiazepines.

Eszopiclone even at therapeutic doses may lead to development of physical dependence and consequently to withdrawal symptoms and rebound phenomena although the risk appears rather low. Psychological dependence may also occur, and abuse of benzodiapezine-like drugs has been reported. In addition, benzodiazepines and benzodiazepine-like agents, such as eszopiclone, may induce anterograde amnesia and psychomotor impairment, including accidental injury and falls. In order to reduce the risk associated with regard to next day psychomotor impairment, a general starting dose of 1 mg has been proposed in order to allow for treatment with the inidvidual minimum dose.

IV.3 Balance

Overall, from a clinical point of view, eszopiclone is considered to be a safe and effective hypnotic with a positive risk/benefit balance in the short-term treatment of insomnia in adults.

Eszopiclone is associated with the risk of tolerance, dependence, rebound phenomena or withdrawal effects and abuse and further accidental injury and falls may occur. Therefore, treatment with eszopiclone-like benzodiazepines and other benzodiazepine-like drugs should usually be restricted to short-term duration and is only indicated, when the disorder is severe, disabling or subjecting the individual to extreme distress. Section 4.1 of the SmPC has been amended accordingly.

The SmPC and PL has been updated as indicated in the attached documents.

From a quality perspective, a positive benefit risk assessment could be stated.

IV.4 New Active Substance Status

In the PrAR the RMS concluded, that the applicant had not shown sufficient evidence in order to determine espizoclone as new active substance (NAS). NAS status is no longer claimed by the applicant.

IV.5 Conclusions

Esogno 2 mg Filmtabletten - Beipackzettel, Nebenwirkungen, Wirkung, Anwendungsgebiete

Beipackzettel - Esogno 2 mg Filmtabletten

I INTRODUCTION

Proposal for Inspection.

New Active Substance Status

II EXECUTIVE SUMMARY

III SCIENTIFIC OVERVIEW AND DISCUSSION

Drug Product

Pharmacokinetics

Toxicology

Genotoxicity

Carcinogenicity

Mechanistic studies concerning reproductive toxicity findings

Juvenile toxicity studies

Local tolerance

Dependence

Metabolites

Impurities

Environmental Risk Assessment (ERA)

Conclusions on studies and proposed list of recommendations not falling under Article 21a/22 of Directive 2001/83/EC

Pharmacokinetic data analysis

Statistical analysis

Bioavailability

Bioequivalence

Influence of food

Metabolism

Inter-conversion

Pharmacokinetics of metabolites

Consequences of possible genetic polymorphism

Dose proportionality and time dependency

Pharmacokinetics in target population

Impaired hepatic function

Gender, Race and Weight

Elderly

Children

Overall comments on pharmacokinetics in special populations

III.3.2 CLINICAL EFFICACY

Study design and evaluated doses:

Dose-finding:

Efficacy results:

Other significant Adverse events

Vital Signs, Postural Blood Pressure and ECG Monitoring

Withdrawal, Rebound and other relevant safety studies

Study ESZ111503 :

Discontinuation due to adverse events

Legal Status

User Testing

Summary Pharmacovigilance system

Risk Management Plan

Periodic Safety Update Report (PSUR)

IV BENEFIT RISK ASSESSMENT