Author Topic: Increased risk of zoster infections with Gilenya  (Read 189 times)

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Offline agate

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Increased risk of zoster infections with Gilenya
« on: December 22, 2014, 07:15:53 pm »
From MedPage Today, November 24, 2014:

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.
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Offline agate

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From JAMA Neurology, January 14, 2015:

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


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.


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.


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.


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.

The abstract can be seen here.
MS Speaks--online for 13 years

SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.