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#Post#: 871--------------------------------------------------
(Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: July 22, 2015, 8:13 pm
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From Multiple Sclerosis Journal, July 22, 2015:
--- Quote ---
> Fatal toxic epidermal necrolysis in a patient on teriflunomide
treatment for relapsing multiple sclerosis
>
> Gaspard Gerschenfeld
> Service de Réanimation Médicale, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier,
Créteil, France
>
> Amandine Servy
> Service de Dermatologie et Centre de Référence des dermatoses
bulleuses immunologiques et toxiques, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier,
Créteil, France
>
> Laurence Valeyrie-Allanore
> Service de Dermatologie et Centre de Référence des dermatoses
bulleuses immunologiques et toxiques, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier,
Créteil, France
>
> Nicolas de Prost
> Service de Réanimation Médicale, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier,
Créteil, France/Université Paris est Créteil, Faculté de
Médecine de Créteil, Groupe de Recherche Clinique CARMAS,
Créteil, France
>
> Jérôme Cecchini
> Service de Réanimation Médicale, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier,
Créteil, France/Université Paris est Créteil, Faculté de
Médecine de Créteil, Groupe de Recherche Clinique CARMAS,
Créteil, France
> Service de Réanimation Médicale, Assistance Publique –
Hôpitaux de Paris, Groupe Henri Mondor – Albert Chenevier, 51,
Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil Cedex,
France. jerome.cecchini@hmn.aphp.fr
>
>
> We report a case of toxic epidermal necrolysis in a
46-year-old woman on teriflunomide treatment. Such a severe
adverse cutaneous drug reaction with this new therapy for
relapsing forms of multiple sclerosis should be early recognized
in order to ensure the rapid withdrawal of the drug.
--- End Quote ---
The abstract can be seen here
HTML http://msj.sagepub.com/content/early/2015/07/10/1352458515596601?papetoc.
#Post#: 872--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: July 24, 2015, 12:31 am
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I've been trying to find out more about this but so far haven't
had any further information.
The Aubagio Website does have a .pdf file called "A Guide to the
Accelerated Elimination Procedure for Aubagio" which includes
this statement:
--- Quote ---
> Stevens-Johnson syndrome and toxic epidermal necrolysis have
been reported rarely in rheumatoid arthritis patients receiving
leflunomide, with a similar risk expected for teriflunomide;
therefore, stop treatment and use accelerated elimination if a
severe skin reaction develops.
--- End Quote ---
The accelerated elimination procedure involves 11 days of
cholestyramine and activated charcoal. Aubagio usually takes up
to 2 years to be eliminated from the body but with the
accelerated elimination procedure eliminating it takes 11 days.
HTML http://www.aubagio.com/media/pdf/Guide_to_Accelerated_Elimination_Procedure_for_AUBAGIO(R)(teriflunomide).pdf
HTML http://www.aubagio.com/media/pdf/Guide_to_Accelerated_Elimination_Procedure_for_AUBAGIO(R)(teriflunomide).pdf
#Post#: 874--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: July 25, 2015, 1:16 am
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I came across these revised guidelines for Aubagio by the
Department of Veterans Affairs--they were revised in June 2015:
HTML http://www.pbm.va.gov/PBM/clinicalguidance/criteriaforuse/Teriflunomide_Criteria_for_Use_Rev_June_2015.pdf
HTML http://www.pbm.va.gov/PBM/clinicalguidance/criteriaforuse/Teriflunomide_Criteria_for_Use_Rev_June_2015.pdf
#Post#: 908--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: August 21, 2015, 7:30 pm
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This is the text of the article by Gerschenfeld et al. in
Multiple Sclerosis Journal (July 2015), with illustrations and
references omitted:
--- Quote ---
> Teriflunomide is a new disease-modifying therapy for
> relapsing forms of multiple sclerosis (RMS) which
> has been shown to reduce relapse rate and disability
> progression. Until now, no lethal adverse event had
> been reported. We herein report the first case of a fatal
> toxic epidermal necrolysis (TEN) in a patient on teriflunomide
> treatment.
>
> A 46-year-old Caucasian woman was admitted to our
> intensive care unit (ICU) for TEN. Her medical history
> included a RMS diagnosed in 2005, with an
> Expanded Disability Status Scale of one and two sensitive
> relapses per year. Previous treatments, including
> β-1a interferon and dimethyl-fumarate, had been
> suspended for poor tolerance (flu-like symptoms and
> rash). Teriflunomide was initiated as an alternative
> treatment. No other medication was reported except
> for occasional self-medication with paracetamol and
> ibuprofen with good tolerance. At day 19 of drug
> onset, she had transitory flu-like symptoms with complete
> healing in five days with paracetamol. Fever and
> asthenia appeared on day 28. Teriflunomide was discontinued.
> The following day, she presented with
> catarrh, vulvar pruritus, odynophagia and an erythematous
> macular eruption of the face and upper trunk.
> She was hospitalized on day 30 and developed acute
> respiratory failure requiring mechanical ventilation.
> TEN was suspected and she was referred to our ICU
> on day 34. Upon admission, clinical features included
> diffuse erythema, confluent flaccid blisters with positive
> Nikolsky’s sign, 95% of detached-detachable
> skin leading to extensive areas of de[bride]d skin
> and erosions of all mucosae. The TENspecific
> severity-of-illness score was 5 (predictive
> mortality of 83%). Fibre-optic bronchoscopy showed
> mucosal detachment of the trachea and the bronchial
> tree. Microbiologic (human immunodeficiency virus
> serology, Mycoplasma pneumoniae serology and polymerase
> chain reaction, blood and urine cultures) and
> auto-immunity tests were negative. Skin biopsy
> revealed bullous disjunction at the dermo-epidermal
> junction, non-specific C3 granular deposit
> on immunostaining and epidermal necrosis, ruling out
> alternative causes and confirming the diagnosis of
> TEN. Supportive skin cares were performed.
> Ciclosporin (1.5 mg/kg per 12h) was introduced.
>
> Teriflunomide was the only causative drug retained
> according to an algorithm of drug causality for TEN
> based on the following criteria: time latency between
> beginning of drug and index-day, drug present in the
> body before index-day, information on prechallenge/
> rechallenge and dechallenge, notoriety of the drug,
> and alternative causes. Its clearance was accelerated
> with daily enteral administration of cholestyramine
> (24g). Plasma concentrations decreased from 11.3 to
> 3.0 μg/ml in four days, corresponding to a theoretical
> 2.1-day half-life. Still, the patient’s clinical condition
> worsened with no cutaneous healing and multiple
> organ dysfunctions, leading to death on day 39.
>
> TEN is a rare mucocutaneous disease, most frequently
> caused by medications. Death often follows infections
> complications or hydroelectrolytic disorders. Although
> leflunomide has been previously associated with TEN,
> this case is, to the best of our knowledge, the first
> reported with its active metabolite, teriflunomide.
> Whether predisposing conditions, such as peculiar
> HLA type, may be involved in the occurrence of TEN
> associated with leflunomide or teriflunomide is
> unknown. Teriflunomide is a non-dialysable biliary excreted
> drug with an intestinal reabsorption cycle
> accounting for a long 19-day half-life. Early drug
> withdrawal of the causative drug is a key aspect of the
> early management of TEN patients. However, in this
> case, the long half-life of teriflunomide, albeit accelerated
> by a washout procedure, was associated with a
> fatal outcome. Patients under teriflunomide should be
> carefully monitored during the first weeks following
> treatment initiation. When TEN is suspected, teriflunomide
> should be stopped and cholestyramine administration
> considered in order to accelerate its biliary
> clearance.
>
> Acknowledgements
>
> We thank doctors Anne Hulin and Raymond
> Karkouche for their respective help in performing
> teriflunomide plasma concentrations and histologic
> examination of skin biopsy.
>
> Conflict of interest
>
> The authors declare that there is no conflict of
> interest.
>
--- End Quote ---
#Post#: 969--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: October 12, 2015, 4:37 pm
---------------------------------------------------------
Presented at the ECTRIMS conference in Barcelona (October 7-10,
2015):
--- Quote ---
> Teriflunomide-induced fatal toxic epidermal necrolysis in a
patient with multiple sclerosis
>
> F. Derouiche, SCF Avicenne, Mulhouse, France
>
> Abstract: EP1339
>
>
> Abstract Category: Risk management for disease modifying
treatments
>
> Introduction:
>
> Teriflunomide is an immunomodulating agent with proven
efficacy in multiple sclerosis. Although its overall safety is
good. We report a case of a fatal toxic epidermal necrolysis
with Teriflunomide.
>
> Case report:
>
> This 46-year-old woman had multiple sclerosis, diagnosed in
2005. She was treated successively with subcutaneous Interferon
beta 1a from 04/2009 to 05/2011, Intramuscular Interferon 1a,
from 03/2013 to 09/2013 and Diméthyl Fumarate from 05/2013 to
11/2014. All these treatments were stopped because of adverse
events. Teriflunomide was started in 01/2015.
>
> Two weeks later, the patient developed febrile maculopapular
rash that rapidly spread to the whole of the integument with
ulceration of the oral, ocular, nasal and vag`inal mucosa.
Despite discontinuing Teriflunomide, initiation of the wash out
procedure and her admission in the Intensive care unit, she died
after a week following an acute respiratory distress syndrome
and a multi organ failure.
>
> Discussion:
>
> The main adverse effects of Teriflunomide consist of diarrhea,
nausea, liver enzyme elevation, hypertension, alopecia, and
allergic skin reactions. A few cases of toxic epidermal
necrolysis have been reported with Leflunomide but never
withTeriflunomide.
>
> Conclusion:
>
> Close monitoring for severe skin reactions is in order when
using Teriflunomide.
>
> Disclosure: No disclosure
--- End Quote ---
#Post#: 1323--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on
teriflunomide for MS
DIR By: agate
Date: August 11, 2016, 3:06 pm
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The risk of TEN (toxic epidermal necrolysis) in connection with
Aubagio is discussed in this article, which is a comprehensive
summary of MS treatments (although Zinbryta has been misspelled
as Zimbrata, apparently). The article is entitled "Steering
through complexity: management approaches in multiple
sclerosis," by Bruce Cree and Hans-Peter Hartung, in Current
Opinion in Neurology (June 2016):
HTML http://journals.lww.com/co-neurology/Fulltext/2016/06000/Steering_through_complexity___management.10.aspx?cid=MR-eJP-Newsletter-Neurology-Neurology-WCO-NoPromo
HTML http://journals.lww.com/co-neurology/Fulltext/2016/06000/Steering_through_complexity___management.10.aspx?cid=MR-eJP-Newsletter-Neurology-Neurology-WCO-NoPromo
This is what the article says about Aubagio:
--- Quote ---
>
>
>
>
>
>
> Teriflunomide is the only oral therapy that has not yet been
associated causally with PML. Unfortunately, a fatal case of
toxic epidermal necrolysis (TEN) was causally linked to
teriflunomide [32]. Several other cases of severe cutaneous
reactions have been reported, and the prescriber information was
updated.
>
> TEN is a known complication of leflunomide, a drug for the
treatment of rheumatoid arthritis that was not observed in the
clinical development program of teriflunomide. A rare but
high-risk adverse event poses challenges for positioning this
oral therapy that also carries boxed warnings regarding
hepatotoxicity and teratogenicity with similar efficacy to
autoinjectable medications. Teriflunomide also has a lengthy
half-life due to gastrointestinal reabsorption and requires
cholestyramine or activated charcoal for rapid elimination.
Otherwise, long-term data from the TEMSO extension trial and the
pooled analysis of all four placebo-controlled trials with
duration of treatment up to 12 years and a cumulative exposure
exceeding 6.800 patient years showed a good safety profile
--- End Quote ---
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