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Why did Sanofi-Aventis fail to provide clinical studies on the pharmacokinetics, pharmacodynamics, and efficacy of zopiclone in children and adolescents, and how does this omission affect the overall safety assessment for paediatric use?
On what basis did regulatory authorities conclude that the three reported fatal overdose cases over a 15-year period did not warrant updates to the product information?
Why does the report list a different number of fatal cases (two versus three), and how was the discrepancy between these data—particularly concerning case 200420388GDDC—explained?
Which specific unlisted adverse reactions were reported in patients under 18 years of age, and why were they considered insufficient to justify inclusion in the official product information (SmPC)?
What are the main differences between overdose cases in children (accidental) and adolescents (intentional), and what preventive measures are recommended to reduce such incidents?
Why is zopiclone not licensed for paediatric use, and what exact wording was proposed for inclusion in the SmPC and Patient Leaflet (PL) under the Type IB variation?

Sanofi-Aventis submitted a concise expert review on zopiclone in compliance with Article 45 of Regulation (EC) No 1901/2006 on medicinal products for paediatric use. The submission contained safety data only, derived from an analysis of the company’s pharmacovigilance database and a local post-marketing surveillance study, which included one serious adverse event.

According to the Marketing Authorisation Holder (MAH), the findings did not alter the overall benefit–risk balance of zopiclone, and no regulatory actions were deemed necessary.

However, the initial assessment revealed several gaps and inconsistencies, including missing data and insufficient detail, preventing a definitive conclusion. The MAH was therefore requested to provide additional information, specifically:

Details regarding study RP27267/ZD 5001-NZL-N/A-NZ.
CIOMS report forms for fatal cases and for cases involving adverse reactions not listed in the SmPC (e.g. growth retardation, increased libido, coagulopathy, convulsion).
Clarifications addressing discrepancies in case counts and percentages across age groups.
A clear definition of age ranges used in the safety review to resolve overlapping categories (for example, whether a 12-year-old falls under “Children” or “Adolescents”).
A proposal for harmonised text on paediatric aspects for the product information, aligned with the Guideline on Summary of Product Characteristics (SmPC), September 2009.

Introduction
The submission comprised safety data only, based on a review of the MAH’s pharmacovigilance database and findings from a local post-marketing surveillance study. No clinical study reports or synopses were included, as no relevant published data were identified regarding paediatric pharmacokinetics, pharmacodynamics, or efficacy.

Clinical Study
Trial RP27267/ZD 5001-NZL-N/A-NZ
This local post-marketing surveillance study was conducted in New Zealand in 1989; no formal clinical study report was available. One serious adverse event was recorded — an overdose in a 17-year-old female who ingested 23 tablets of zopiclone (172.5 mg). The treatment was discontinued, and the patient recovered fully.

Among 31 adult participants (aged 25–78 years), non-serious adverse events were reported, with five individuals experiencing multiple events. The most frequent were dysgeusia (n=17), somnolence (n=7), and hangover (n=6). Other non-serious reactions included ageusia, depression, and dry mouth (each in two patients), as well as abnormal dreams, headache, and nausea (each in one patient).

CIOMS documentation for the serious case and a line-listing of non-serious events were provided for review.

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Safety Review

Sanofi conducted a safety review of zopiclone using data from its global pharmacovigilance database. The search included:

Solicited cases — reports collected directly by investigators or the company.
Unsolicited cases — reports from healthcare professionals, non-healthcare professionals, regulatory authorities, and published literature.

Only reports involving patients under 18 years of age who had been exposed to zopiclone were considered. The data cut-off date was 31 March 2013. Cases related to drug exposure during pregnancy or lactation were excluded.

Adverse events (AEs) and adverse drug reactions (ADRs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 15.1. Zopiclone use was classified as an overdose when explicitly reported as such or when the daily dose exceeded 7.5 mg, the maximum adult dose.

The following age categories were applied:

Neonates: 0 to <28 days
Infants: 28 days to <24 months
Children: 24 months to <12 years
Adolescents: 12 to <18 years

Solicited Cases
One serious case was identified in the paediatric population as part of a local post-marketing surveillance study conducted in New Zealand in 1989 (Study RP27267/ZD 5001-NZL-N/A-NZ). This case has been described previously.

Unsolicited Cases
A total of 262 unsolicited adverse events were reported for 77 patients:

Neonates: 4
Infants and children: 27
Adolescents: 46

Among these, 111 adverse events were classified as serious. Of the 77 cases, 36 were non-serious and 41 were serious.

Out of 77 total reports, 31 involved overdose (either intentional or accidental) and 46 involved other adverse events. The outcomes of overdose cases were as follows:

Recovered: 24
Fatal: 2
Unspecified: 5

Fatal Cases
Three fatal cases were reported among adolescents aged 12–18 years.

Assessor’s Comment

Case 200022402FR: Death was attributed to a fatal methadone concentration.
Case 200420388GDDC: The patient had been taking zopiclone, but the indication, duration, and dosage were not specified.
Case 200420388GDDC and Case 200513372EU* appeared similar; however, Sanofi clarified that they were reported separately by different health authorities (Great Britain Health Authority No. 495762 and 478962). Therefore, they were not considered duplicates.

All three fatal cases were associated with intentional overdose and concurrent use of other central nervous system (CNS) depressants. The current Summary of Product Characteristics (SmPC) already provides sufficient information on the symptoms and management of overdose.

Given that zopiclone online has been licensed in the UK since 1998, and only three fatal cases have been reported over a 15-year period, no changes to the product information were deemed necessary.

Assessor’s Comment

The applicant’s submission described two fatal overdose cases; however, the earlier review identified three. It appears that case 200420388GDDC was excluded because the term “overdose” was not explicitly reported, although post-mortem findings indicated a trace amount of zopiclone.

Most overdose cases in adolescents were intentional, typically involving concomitant use of other CNS-active substances. In contrast, overdose cases in children were largely accidental.

Since zopiclone is not authorised for use in the paediatric population, the product information should explicitly state in sections 4.2 and 4.4 of the SmPC that:
“Zopiclone should not be used in children and adolescents under 18 years of age.”

The current SmPC already provides sufficient guidance on the clinical features and management of overdose.

Discussion on Clinical Aspects and Conclusion

The Marketing Authorisation Holder (MAH) submitted an overview of paediatric adverse event reports from its safety database. Most reports involved overdose or adverse events affecting the nervous system and psychiatric disorders categories. The reported reactions are generally consistent with the known safety profile of zopiclone online.

A few cases described unlisted reactions, but the available evidence was insufficient to warrant any update to the product information. The existing SmPC adequately addresses overdose presentation and treatment.

Given that zopiclone is not licensed for use in patients under 18 years, the product information should be amended to clearly reflect this restriction.

Overall Conclusion

The safety data review confirms that most paediatric reports relate to overdose and neurological or psychiatric events, consistent with the established safety profile of zopiclone. Although some unlisted reactions were reported, the evidence is inadequate for inclusion in the SmPC.

It is therefore recommended that the SmPC and PL (Patient Leaflet) be updated to emphasise that zopiclone is not indicated for children and adolescents under 18 years of age, as its safety and efficacy in this group have not been established.

Recommendation

A Type IB variation should be requested from the MAH by 6 February 2015 to include the following updates:

Section 4.1 – Therapeutic indications:
Add the phrase “in adults”.
Sections 4.2 – Posology and method of administration
and 4.4 – Special warnings and precautions for use:
Add the statement:
“Paediatric population: Buying Zopiclone should not be used in children and adolescents under 18 years of age. The safety and efficacy of zopiclone in this population have not been established.”

Thank you!