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arznei-telegramm: 2014; 45: 112

 


PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY NOW ALSO WITH THE MULTIPLE SCLEROSIS DRUG DIMETHYL FUMARATE (TECFIDERA)*

A female patient from Germany with multiple sclerosis (MS), who had taken dimethyl fumarate (TECFIDERA) for more than four years during a clinical trial, and who had developed serious, persistent lymphopenia of several years duration, became ill with progressive multifocal leukoencephalopathy (PML) in August, and died two months later. Apart from the intake of dimethyl fumarate, there were no other risk factors for PLM. As the Competence Network Multiple Sclerosis was to write in a statement to the press, the lymphopenia had been classified as of no clinical relevance, as the total white blood cell count was not significantly reduced (1).

PML with dimethyl fumarate for MS was not described at the time of marketing authorisation (a-t 2014; 45: 28-9). However, several reports of PLM associated with severe lymphopenia were known with the dimethyl fumarate combination FUMADERM and another combination containing dimethyl fumarate for psoriasis (a-t 2013; 44: 47-8) (2). Even though the manufacturer Biogen and the Federal Institute for Drugs and Medical Devices (BfArM) had been aware of the suspicion of PLM with FUMADERM for years, they first became active after the public were warned by two reports in the New England Journal of Medicine at the beginning of 2013 (a-t 2013; 44: 63-4) (3-5).

The risk management, however, was to continue to remain inadequate: It is inconceivable that there still continues to be no mention of PLM in the Summary of Product Characteristics (SPC) of FUMADERM, a mention which should also be required in the SPC of TECFIDERA within the framework of preventive consumer protection, but which is missing here, too (6,7). In contrast to FUMADERM, which must be discontinued in cases of severe lymphopenia (< 500/µl), according to the updated SPC (6), an analogue provision does not exist for TECFIDERA (7), even though 6% of users were affected by severe lymphopenia in the registration clinical trials (2). Furthermore, for FUMADERM (6), significantly more frequent blood count monitoring is required as for TECFIDERA (7). Instead of orienting measures for risk minimisation towards the experience with FUMADERM that has been tested longer, it is expressly emphasised in the TECFIDERA SPC that there has been no increase of serious infections in cases of severe lymphopenia in Phase III studies (7). This information is correct, but it creates a false sense of security, when post-marketing experiences with FUMADERM are not pointed out at the same time, as registration clinical trials do not normally show rare, serious adverse effects.

In the present case, too, the manufacturer Biogen has maintained a veil of secrecy towards doctors and patients. A "Dear Doctor Letter" is long overdue. The investors, on the other hand, were informed more than two weeks ago, and the stock market reacted promptly with a fall in share price (8). Further, possible moves are currently under discussion by the regulatory authorities (9).

We continue to advise the immediate discontinuation of TECFIDERA in cases of severe blood count changes, such as severe lymphopenia, as we did in our evaluation at market launch, and as does the Competence Network Multiple Sclerosis at the present time (1). It would also appear to us to be logical that the blood count should be monitored as closely with TECFIDERA as it is with FUMADERM (initially once a fortnight, then monthly), -Ed.

 

1

Competence Network Multiple Sklerosis: press release as at 24 Oct. 2014; http://www.a-turl.de/?k=rsee

 

2

EMA: European public assessment report TECFIDERA, as at Nov. 2013; http://www.a-turl.de/?k=ngst

 

3

ERMIS, U. et al.: N. Eng. J. Med. 2013; 368: 1657-8

 

4

VAN OOSTEN, B.W. et al.: N. Eng. J. Med. 2013; 368: 1658-9

 

5

Biogen: Rote-Hand-Brief (Dear Doctor Letter) as at 25 June 2013; http://www.a-turl.de/?k=choc

 

6

Biogen: SPC FUMADERM, as at Sept. 2013

 

7

Biogen: SPS TECFIDERA, as at July 2014

 

8

JACKSON, M.: Scrip as at 31 Oct. 2014, page 9

 

9

BfArM: letter dated 6 Nov. 2014


A reader's comment to blitz-a-t*:

The existence of different Summaries of Product Characteristics despite same effect (see pharmacodynamics) and same adverse effects (lymphopenia) is a scandal. The manufacturer of TECFIDERA was obviously prepared to accept a case such as this, which they must have expected. And, that the manufacturer was able to get the Summary of Product Characteristics through the regulatory authorities is no less scandalous.

NN (Name known to the editor)
Conflict of interests: none.

We agree, -Ed.

*

 

Previous version published online on 6 Nov. 2014 as blitz-a-t.





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