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#Post#: 871--------------------------------------------------
(Abst.) Fatal toxic epidermal necrolysis in patient on terifluno
mide for MS
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.[/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 terif
lunomide for MS
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.[/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 terif
lunomide for MS
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 terif
lunomide for MS
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.
[/quote]
#Post#: 969--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on terif
lunomide for MS
By: agate Date: October 12, 2015, 4:37 pm
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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[/quote]
#Post#: 1323--------------------------------------------------
Re: (Abst.) Fatal toxic epidermal necrolysis in patient on terif
lunomide for MS
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[/quote]
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