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#Post#: 595--------------------------------------------------
Increased risk of zoster infections with Gilenya
By: agate Date: December 22, 2014, 11:15 pm
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From MedPage Today, November 24, 2014:
[quote]MS Focus: Gilenya Ups Zoster Risk
Risk with fingolimod doubled compared with placebo but still
low.
by John Gever
Managing Editor, MedPage Today
Patients taking the oral multiple sclerosis drug fingolimod
(Gilenya) in clinical trials were more likely to develop new
varicella-zoster virus (VZV) infections than those in the
placebo groups, researchers said, although the absolute risk was
still relatively small.
Among patients enrolled in the drug's phase II and III trials,
the rate of new zoster infections was 11 per 1,000 patient-years
of drug exposure in those receiving fingolimod compared with six
per 1,000 patient-years with placebo, according to Norman
Putski, MD, of drugmaker Novartis Pharma in Basel, Switzerland,
and colleagues.
The researchers, who also included several prominent academic
scientists in the multiple sclerosis (MS) field, also examined
postmarketing reports on fingolimod and calculated a rate of
seven zoster infections per 1,000 patient-years, on the basis of
some 54,000 patient-years of drug exposure, they reported online
in JAMA Neurology.
Although these rates indicated that the risk to a given patient
remained low, Putski and colleagues noted that adverse event
reports indicated that it was higher than the average for all
other disease-modifying MS treatments.
The issue of zoster risk has come to the fore with fingolimod
because of two fatal cases. One involved a clinical trial
participant who died of a disseminated primary VZV infection in
2008 after taking the drug for 10 months. The second was
reported in April 2013 and involved a case of reactivated zoster
infection in a patient who had taken fingolimod in a
postmarketing observational study for 6 months following
treatment with natalizumab (Tysabri) and a 3-month washout
period.
Fingolimod's current label does not indicate a specific risk of
zoster infection, but it does suggest VZV vaccination in
patients without a history of chickenpox or previous vaccination
and a 1-month waiting period after vaccination before starting
the drug.
In an accompanying editorial, Kenneth Tyler, MD, of the
University of Colorado School of Medicine in Aurora, said these
and other data suggest a special relationship between fingolimod
and VZV, such that the drug increases risk of infection more
than with other MS drugs, yet this infection risk does not
extend to all pathogens across the board.
He noted that fingolimod's method of action -- preventing
migration of T lymphocytes out of the lymphatic system -- may
increase susceptibility to infections that would be suppressed
by pathogen-specific memory T cells, of which VZV is one. Tyler
also raised the possibility, thus far unproven, that VZV relies
on fingolimod's specific target (the sphingosine-1-phosphate
receptor) for its life cycle.
Both Tyler and the study authors generally supported the label
recommendations for VZV vaccination in patients without evidence
of previous infection or vaccination, including antibody testing
to confirm past exposure status. Putski and colleagues also
suggested that patients at potential risk for shingles without a
recent vaccination should be considered for it. The risk might
be exacerbated with concomitant steroid therapy, they noted,
such that antiviral prophylaxis may be an option for patients on
fingolimod who need such treatment.
Tyler and Putski and colleagues also concurred that clinicians
and patients should be vigilant about infection, so that
treatment can begin early enough to keep cases from becoming
severe. Fingolimod treatment can continue in most cases, but the
drug should generally be stopped in complicated infections, they
agreed.
____________
The study was funded by Novartis, and the authors included two
Novartis employees. Other authors reported relevant
relationships with Novartis and with a large number of other
pharmaceutical companies. One author is also listed on a patent
for a zoster vaccine.
Tyler reported relevant relationships with Biogen, Genentech,
Johnson and Johnson, Pfizer, and Roche.[/quote]
#Post#: 617--------------------------------------------------
(Abst.) Varicella-zoster virus infections in patients treated wi
th fingolimod
By: agate Date: January 14, 2015, 8:30 pm
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From JAMA Neurology, January 14, 2015:
[quote]Varicella-Zoster Virus Infections in Patients Treated
With Fingolimod:
Risk Assessment and Consensus Recommendations for Management
Ann M. Arvin, MD1; Jerry S. Wolinsky, MD2; Ludwig Kappos, MD,
PhD3; Michele I. Morris, MD4; Anthony T. Reder, MD5; Carlo
Tornatore, MD, PhD6; Anne Gershon, MD7; Michael Gershon, MD8;
Myron J. Levin, MD9; Mauritz Bezuidenhoudt, MSc10; Norman
Putzki, MD10
Author Affiliations
1Department of Pediatrics, Stanford University School of
Medicine, Stanford, California
2Department of Neurology, The University of Texas Health Science
Center at Houston
3Department of Neurology, University Hospital Basel, Basel,
Switzerland
4Department of Infectious Diseases, University of Miami, Miami,
Florida
5Department of Neurology, University of Chicago Medical Center,
Chicago, Illinois
6Department of Neurology, MedStar Georgetown University
Hospital, Washington, DC
7Department of Pediatrics, Columbia University, New York, New
York
8Department of Pathology and Cell Biology, Columbia University,
New York, New York
9Department of Pediatrics, University of Colorado Anschutz
Medical Campus, Aurora
10Novartis Pharma AG, Basel, Switzerland
Importance
Varicella-zoster virus (VZV) infections increasingly are
reported in patients with multiple sclerosis (MS) and constitute
an area of significant concern, especially with the advent of
more disease-modifying treatments in MS that affect
T-cell–mediated immunity.
Objective
To assess the incidence, risk factors, and clinical
characteristics of VZV infections in fingolimod-treated patients
and provide recommendations for prevention and management.
Design, Setting, and Participants
Rates of VZV infections in fingolimod clinical trials are based
on pooled data from the completed controlled phases 2 and 3
studies (3916 participants) and ongoing uncontrolled extension
phases (3553 participants). Male and female patients aged 18
through 55 years (18-60 years for the phase 2 studies) and
diagnosed as having relapsing-remitting MS were eligible to
participate in these studies. In the postmarketing setting,
reporting rates since 2010 were evaluated.
Interventions
In clinical trials, patients received fingolimod at a dosage of
0.5 or 1.25 mg/d, interferon beta-1a, or placebo. In the
postmarketing setting, all patients received fingolimod, 0.5
mg/d (total exposure of 54 000 patient-years at the time
of analysis).
Main Outcomes and Measures
Calculation of the incidence rate of VZV infection per 1000
patient-years was based on the reporting of adverse events in
the trials and the postmarketing setting.
Results
Overall, in clinical trials, VZV rates of infection were low but
higher with fingolimod compared with placebo (11 vs 6 per 1000
patient-years). A similar rate was confirmed in the ongoing
extension studies. Rates reported in the postmarketing settings
were comparable (7 per 1000 patient-years) and remained stable
over time.
Disproportionality in reporting herpes zoster infection was
higher for patients receiving fingolimod compared with those
receiving other disease-modifying treatments (empirical Bayes
geometric mean, 2.57 [90% CI, 2.26-2.91]); the proportion of
serious herpes zoster infections was not higher than the
proportion for other treatments (empirical Bayes geometric mean,
1.88 [90% CI, 0.87-3.70]). Corticosteroid treatment for relapses
might be a risk factor for VZV reactivation.
Conclusions and Relevance
Rates of VZV infections in clinical trials were low with
fingolimod, 0.5 mg/d, but higher than in placebo recipients.
Rates reported in the postmarketing setting are comparable. We
found no sign of risk accumulation with longer exposure. Serious
or complicated cases of herpes zoster were uncommon.
We recommend establishing the patient’s VZV immune status before
initiating fingolimod therapy and immunization for patients
susceptible to primary VZV infection. Routine antiviral
prophylaxis is not needed, but using concomitant pulsed
corticosteroid therapy beyond 3 to 5 days requires an individual
risk-benefit assessment. Vigilance to identify early VZV
symptoms is important to allow timely antiviral
treatment.[/quote]
The abstract can be seen here
HTML http://archneur.jamanetwork.com/article.aspx?articleID=1934722&utm_source=Silverchair%20Information%20Systems&utm_medium=email&utm_campaign=ArchivesofNeurology%3ANewIssue01%2F12%2F2015.
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