EMS in Viracept—The course of events in 2007 and 2008 from the non-clinical safety point of view

doi:10.1016/j.toxlet.2009.02.005

Toxicology Letters

Volume 190, Issue 3, 12 November 2009, Pages 243-247

https://doi.org/10.1016/j.toxlet.2009.02.005 Get rights and content

Abstract

Viracept (nelfinavir) is an HIV protease inhibitor supplied by Roche outside the US, Canada and Japan. Viracept was first introduced by Roche in 1998. Although newer protease inhibitors have become available for the treatment of HIV, it is viewed as a useful medicine for patients who are intolerant to ritonavir (since it does not require ritonavir boosting), pregnant women, and patients in resource-limited settings, since the formulation is heat-stable and does not require refrigeration.

The relatively high prevalence of HIV in some of the third world countries means that it was also a product of choice for young women of childbearing age, pregnant and nursing women and young children. On 18 May 2007 F. Hoffmann-La Roche received first reports of a “bad smell” of blisterpacked Viracept tablets and one adverse drug report of nausea and vomiting from patients in Spain. Subsequently, ethyl methanesulfonate (EMS), an established mutagen, carcinogen and teratogen was identified as the potential source of the bad smell. On 6 June 2007, Viracept was globally recalled as the extent of the contamination exceeded the guidances for permissible levels set by regulatory authorities by more than 1000-fold and hence human risk was not readily assessible. In the following, a compilation of the course of events from a non-clinical point of view is presented. This compilation only partially reflects the complexity of the case and the interactions between all parties between May/June 2007 and September 2008 and hence necessarily remains partly a subjective compilation of the authors of this article. This compilation serves also as an introduction into this Special Issue of Toxicology Letters. The data on the cause and levels of contamination, likely duration of intake and affected patient population can be found in the subsequent contributions. Most importantly, we share in other parts of this Special Issue with the scientific community the data and risk assessment arguments that supported the conclusion by the company and regulatory authorities that the levels of contamination with EMS posed no health risk to affected patients.

Section snippets

Introduction and background

The

Regulatory actions and interactions

On the evening of 5 June 2007 the European Medicines Agency (EMEA) was made aware by Roche Registration Limited, the Marketing Authorisation Holder (MAH) of the contamination of Viracept (nelfinavir) with EMS. As a consequence, Roche recalled the product from the markets with immediate effect. All packs of Viracept available on the market were affected, including packs that patients may have had at home. A Direct Healthcare Professional Communication (DHPC) was released by the MAH on 7 June

Necessity for registries as viewed by regulatory authorities

Nevertheless, the CHMP, supported by its Pharmacovigilance working party, thought that registries were necessary to follow-up patient cohorts in various countries to elucidate whether any signal for presumably the most likely side effects such as tumors and birth defects could be observed in excess in patients having taken Viracept contaminated with EMS versus other HIV patients or the general population. Although such registries have many inherent risks and shortcomings, which shall not be

Quality aspects

The following aspects were the critical events on the quality side: Further to the June 2007 CHMP meeting, a meeting was convened at the EMEA on 6 July 2007 between the Rapporteur, Co-Rapporteur, representatives of both Swissmedic and WHO, as well as the MAH to further clarify the conditions to be met in order to convince the CHMP of the satisfactory quality of the product. Based on both the conclusion of the June and July 2007 CHMP meeting, the MAH submitted on 16 August 2007 their dossier in

Events subsequent to clear evidence for a threshold for EMS in animals

An e-mail on Monday, 7 April 2008 at 6:56 p.m. with the consolidated draft data of the decisive transgenic mutation experiment in mice from the study director at Covance, Harrogate, UK, represented a significant moment in the life of the authors of this article. The data were indicative of a clear threshold for mutation induction in all three organs investigated (bone marrow, GI tract and liver) and the threshold was unexpectedly high at 25 mg/(kg day)⁻¹!

On 5 May 2008 fully audited draft reports

Regulatory decisions on animal threshold data and cross-species extrapolation: threshold for mutations of EMS reliably established and no patient registries needed

On 24 July 2008, the CHMP issued a document on “Questions and answers on the follow-up to the contamination of Viracept (nelfinavir) with ethyl mesilate (CHMP, 2008).

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Roche has now completed its in-depth studies into the effects of ethyl mesilate as requested by the EMEA. These animal studies have shown that there is a threshold level below which ethyl mesilate does not have a harmful effect on the DNA (25 mg/(kg day)⁻¹ in the mouse).
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Company experts have used special models that allow results from

Conflict of interest

Lutz Muller and Thomas Singer are employees and shareholders of F. Hoffmann-La Roche, Basel, Switzerland.

References (9)

L. Müller et al.
Ethyl methanesulfonate toxicity in Viracept—a comprehensive human risk assessment based on threshold data for genotoxicity
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CHMP, 2007a. Questions and answers to the follow-up to the Viracept recall. London, June 21, 2007; Doc. Ref....
CHMP, 2007b. Further questions and answers on the follow-up to the Viracept recall. London, July 26, 2007; Doc. Ref....
CHMP, 2007c. Assessment Report for Viracept. London, September 20, 2007; Doc. Ref.: EMEA/CHMP/492059/2007;...

There are more references available in the full text version of this article.

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Citation Excerpt :
Thus, while the route-specific PDEs were generated for illustrative purposes, they were not substantially different from the PDEs generated for “general” routes (See Discussion below on uncertainties in the estimates). Ethyl methanesulfonate (EMS), as a result of contamination in Viracept®, was investigated for its toxic effects to derive a PDE (Gerber and Toelle, 2009; Müller and Singer, 2009). Since a detailed description of toxicology information and derivation of the PDE has been described previously (Gocke et al., 2009a, 2009b; Gocke and Müller, 2009; Gocke et al., 2009c; Müller et al., 2009; Pfister and Eichinger-Chapelon, 2009), EMS toxicology information was not included in the Supplemental Materials.
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