What was the main purpose of Sanofi-Aventis’ submission regarding zopiclone under Article 45 of Regulation (EC) No. 1901/2006?

What data sources were used by Sanofi to conduct the safety evaluation of zopiclone online, and which population did the review focus on?

How was the double-dummy technique applied in the clinical study, and why was it necessary?

What were the most common adverse reactions observed in adult participants, and how did they compare with the serious cases in the paediatric population?

According to the findings, how did the frequency and cause of overdose cases differ between adolescents and children?

Why did the regulatory authorities recommend updating the SmPC and Patient Leaflet to include a restriction for patients under 18 years of age?

What specific textual changes were proposed for Sections 4.1, 4.2, and 4.4 of the SmPC as part of the Type IB variation request?

Based on the overall safety assessment, how does the benefit–risk balance of zopiclone remain consistent despite the reported paediatric adverse events?

Sanofi-Aventis submitted a concise expert report on zopiclone in accordance 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 reported one serious adverse event.

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

However, the initial assessment revealed several gaps and inconsistencies, including missing data and insufficient detail, which prevented a definitive conclusion. Therefore, the MAH was asked to provide additional information, including:
– Details regarding study RP27267/ZD 5001-NZL-N/A-NZ;
– CIOMS report forms for fatal cases and for adverse reactions not listed in the product information (SmPC), such as growth retardation, increased libido, coagulopathy, and convulsion;
– Clarifications regarding discrepancies in case counts and percentages across age groups;
– A clear definition of the age categories used in the safety review (for example, whether a 12-year-old was classified as “Child” or “Adolescent”);
– A proposal for harmonised text on paediatric aspects of the product information, aligned with the Guideline on Summary of Product Characteristics (SmPC), September 2009.

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

Clinical Study – 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 made a full recovery.

Among 31 adult participants (aged 25–78 years), non-serious adverse events were reported, with five individuals experiencing multiple reactions. The most common were dysgeusia (n=17), somnolence (n=7), and hangover (n=6). Other mild 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 submitted for review.

60 pills £2.84 £170.27 (UK)

90 pills £2.32 £208.48 (UK)

120 pill £2.05 £245.86 (UK)

180 pills £1.79 £321.44 (UK)

Sanofi conducted a safety evaluation of zopiclone, using data from its global pharmacovigilance database. The analysis included two types of reports:

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

Only cases involving patients under 18 years of age who had been exposed to zopiclone online were considered. The data cut-off date was 31 March 2013. Reports related to exposure during pregnancy or breastfeeding 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 previously described.

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

A total of 77 paediatric reports involving zopiclone were evaluated:
– 4 in neonates,
– 27 in infants and children,
– 46 in adolescents.

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

Out of 77 total reports, 31 involved overdose (intentional or accidental) and 46 involved other adverse events. The outcomes of the overdose cases were:
– Recovered: 24 cases
– Fatal: 2 cases
– Unspecified: 5 cases

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

Assessor’s Comment
– Case 200022402FR: death attributed to fatal methadone concentration.
– Case 200420388GDDC: patient had taken zopiclone, but indication, duration, and dosage were not reported.
– Cases 200420388GDDC and 200513372EU appeared similar, but Sanofi clarified that they were separate reports submitted by different health authorities (UK Health Authority No. 495762 and 478962).

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

Since zopiclone has been licensed in the UK since 1998, and only three fatal cases have been reported over a 15-year period, no revisions to the product information were considered necessary.

Additional Assessment
The applicant described two fatal overdose cases; however, earlier reviews identified three. It appears that case 200420388GDDC was excluded because the term “overdose” was not explicitly used, although post-mortem findings indicated trace levels of zopiclone online.

Most overdose cases in adolescents were intentional, often involving concomitant use of other CNS-active substances, while overdoses in children were primarily accidental.

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

The current SmPC already provides sufficient guidance on the clinical presentation 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 reactions affecting the nervous system and psychiatric disorders categories. The reported reactions were generally consistent with the known safety profile of imovane.

A few cases described unlisted reactions, but the available evidence was insufficient to justify any changes to the product information. The current Summary of Product Characteristics (SmPC) already provides adequate guidance on the presentation and management of overdose.

As zopiclone is not approved for use in patients under 18 years of age, the product information should clearly state this restriction.

Overall Conclusion

The review of safety data confirms that most paediatric reports relate to overdose and neurological or psychiatric events, consistent with the established safety profile of zopiclone. Although a few unlisted reactions were reported, the available evidence is not sufficient to support inclusion in the SmPC.

It is therefore recommended that the SmPC and Patient Leaflet (PL) 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 population have not been established.

Recommendation

A Type IB variation should be requested from the MAH by 6 February 2025 to implement 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: Zopiclone should not be used in children and adolescents under 18 years of age. The safety and efficacy of imovane in this population have not been established.”