Value-Based Care in Neurology - May 2015 Volume 2, No 1

MAY 2015 • VOL 2 • NO 1

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Should Neurologists Prescribe Opioids for the Management of Chronic Pain?

By Chase Doyle

Teriflunomide Demonstrates Significant Efficacy in Patients with Multiple Sclerosis

By Chase Doyle

Washington, DC—In the treatment of patients with multiple sclerosis, a drug’s effect on time to first relapse is an important indicator of patient response to therapy. According to analyses presented at the 2015 annual meeting of the American Academy of Neurology, teriflunomide (Aubagio) significantly increased time to first relapse in 3 separate studies—TEMSO, TOWER, and TOPIC. These trials are part of an ongoing teriflunomide clinical development program that has involved more than 5000 patients in 36 countries, and is among the

largest of any multiple sclerosis research program. Some patients in the extension clinical trials have received teriflu­ nomide for up to 10 years.

“The results from these 3 studies demonstrate the efficacy of teriflunomide on reducing relapses across a range of patients, including those with early MS [multiple sclerosis] and relapsing MS,” reported William D. Honeycutt, MD, Neurologist, Neurology Associates Clinical Research Unit, Maitland, FL. “Treatment with teriflunomide not only delayed the time to first relapse but was Continued on page 5

Washington, DC—Experts at the 2015 annual meeting of the American Academy of Neurology engaged in a series of debates addressing cur-

rent issues in neuroscience. During one of the more controversial debates, Charles E. Argoff, MD, Professor of Neurology, Albany Medical College, Continued on page 22

RRMS Treatment Is Cost-Effective After 6 Years

By Rosemary Frei, MSc

T

reatment of relapsing-remitting multiple sclerosis (RRMS) is clinically effective as well as cost-effective after 6 years, according to an analysis conducted to satisfy the United Kingdom’s National Institute for Health and Care Excellence (for-

merly the National Institute for Clinical Excellence [NICE]) criteria for longterm cost-effectiveness (Palace J, et al.

Lancet Neurol. 2015;14:497-505).

Jacqueline Palace, MD, Consultant Neurologist, Department of Clinical Neurology, Oxford University Hospitals Continued on page 5

Stroke Center Reduces Doorto-Needle Times to Less Than 30 Minutes

By Corbin Davis Washington, DC—When a stroke occurs, every second counts. A minute may feel like a lifetime, or, to a neurologist, like 1.9 million neurons—the average loss of neurons per minute during which a patient with stroke goes untreated.

Despite the urgency of stroke care, in 2009 less than one-third of US hospitals had a mean door-to-needle time of

less than 60 minutes. According to a study presented at the 2015 annual meeting of the American Academy of Neurology, however, a stroke center in metropolitan Denver is making the seemingly impossible a reality: door-toneedle times that have bested the 15-minute mark.

“There is plenty of substantiation in the literature that patients’ outcomes Continued on page 10

INSIDE MULTIPLE SCLEROSIS. . . . . . . . . . .

4

HEALTH ECONOMICS . . . . . . . . . 16

IN THE LITERATURE . . . . . . . . . . . . .

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PARKINSON’S DISEASE. . . . . . . 18

Biotin improves physical, neurologic function Deep brain stimulation for patients with Parkinson’s disease

Disease relapse increases economic burden in multiple sclerosis

Course of treatment varies by race, sex

CLINICAL TRIALS IN STROKE . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 NEUROLOGY. . . . . . . . . . . . . . . . . . . . . 18 Are active interventions for caregivers cost-effective?

The role of stem-cell science is debated

Cannabidiol helps children with severe epilepsy

Experts discuss whole-exome sequencing in neurology

PERSONALIZED MEDICINE EPILEPSY . . . . . . . . . . . . . . . . . . . . . . . . . . 12 in Neurology™ . . . . . . . . . . . . . . . . . . . . . 19 © 2015 Engage Healthcare Communications, LLC

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In This Issue

PUBLISHING STAFF

Senior Vice President/Group Publisher Nicholas Englezos nenglezos@the-lynx-group.com Vice President/Group Publisher John W. Hennessy jhennessy2@the-lynx-group.com Publisher Joe Beck jbeck@the-lynx-group.com Senior Editorial Director Dalia Buffery dbuffery@the-lynx-group.com Editorial Director Anne Cooper, MA acooper@the-lynx-group.com Production Manager Melissa Lawlor

CHRONIC PAIN

FDA NEWS

Should opioids be prescribed for the management of chronic pain?

Namzaric approved for patients with Alzheimer’s-type dementia More…

STROKE Stroke center reduces door-to-needle times to less than 30 minutes Mobile stroke units gaining traction in the United States More…

MULTIPLE SCLEROSIS Teriflunomide effective in patients with multiple sclerosis Treatment of relapsing-remitting multiple sclerosis is cost-effective More…

THE LYNX GROUP

President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Human Resources Jennine Leale Director, Strategy & Program Development John Welz Director, Quality Control Barbara Marino Quality Control Assistant Theresa Salerno Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistants Lora LaRocca Wayne Williams Content Marketing Director Samantha Weissman Web Content Manager Anthony Trevean Content Digital Manager Allison Musante Digital Programmer Michael Amundsen Jr Digital Media Specialist Charles Easton IV Meeting & Events Planner Linda Mezzacappa Project Managers Deanna Martinez Jeremy Shannon Project Coordinator Rachael Baranoski IT Manager Kashif Javaid Sales Assistant Aadam Mohamed Administrative Assistant Amanda Hedman Office Coordinator Robert Sorensenn

IN THE LITERATURE

HEALTH ECONOMICS Costs of disease relapse in multiple sclerosis impacted by age, sex Coordination of poststroke care could reduce length of hospital stays More…

PARKINSON’S DISEASE Treatment of patients with Parkinson’s disease varies by race and sex

CLINICAL TRIALS IN NEUROLOGY The role of stem-cell science in neurology is debated

Socioeconomic adversity affects brain development in children More counseling, less tests could offset costs of headache management More…

Should whole-exome sequencing be integrated into neurologic care?

EPILEPSY

DRUG UPDATE

Cannabidiol may benefit patients with treatment-resistant epilepsy

PERSONALIZED MEDICINE in Neurology™

Lemtrada approved for patients with relapsing multiple sclerosis

Editorial Advisory Board Robert J. Adams, MS, MD Professor of Neuroscience University Eminent Scholar Director, South Carolina Stroke Center of Economic Excellence Director, REACH MUSC Telemedicine Services, Charleston, SC June Halper, MSN, APN-C, MSCN, FAAN CEO, Consortium of Multiple Sclerosis Centers Executive Director, IOMSN Hackensack, NJ

Engage Healthcare Communications, LLC 1249 South River Road, Ste 202A Cranbury, NJ 08512 Telephone: 732-992-1882 Fax: 732-992-1881 Value-Based Care in Neurology, ISSN (applied), is published 3 times a year by Engage Healthcare Com­ munications, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2014 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Neurology is a trademark of Engage Health­ care Communi­ cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

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Atheer A. Kaddis, PharmD Senior Vice President Diplomat Specialty Pharmacy Flint, MI

Maria Lopes, MD, MS Chief Medical Officer CDMI Health Cresskill, NJ

Daniel Kantor, MD Medical Director Neurologique President-Elect Duval County Medical Society Immediate Past President Florida Society of Neurology Ponte Vedra, FL Patricia Kennedy, RN, CNP, MSCN Nurse Educator Can Do Multiple Sclerosis Avon, CO

Matthew Mitchell, PharmD, MBA Director Pharmacy Services Murray, UT Gary M. Owens, MD President, Gary Owens Associates Ocean View, DE Charles Stemple, DO Corporate Medical Director, Policy Humana, OH

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Mission Statement

Value-Based Care in Neurology provides a forum for payers, providers, and the entire neurology team to consider optimal, value-based care to patients with neurologic conditions. This publication is focused on evaluating the impact of cost and quality of care on patient outcomes via news coverage from major neurology meetings and the neurologic literature, supplemented with commentaries and perspectives from a variety of stakeholders involved in managing patients and paying for patient care.

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Multiple Sclerosis

High Doses of Biotin Improve Physical, Neurologic Function in Patients with Progressive Multiple Sclerosis

By Chase Doyle Washington, DC—Patients with primary and secondary progressive multiple sclerosis (MS) showed improvements in standard measures of physical and neurologic disability after taking high doses of biotin (300 mg daily) for 1 year, according to results of a phase 3 clinical trial presented at the 2015 annual meeting of the American Academy of Neurology.

“The primary end point of this study was the proportion of patients who improved at month 9 and confirmed at month 12 [P = .005],” said Ayman Tourbah, MD, PhD, CHU de Reims, Hospital Maison Blanche and Faculté de Médecine, URCA, in Reims, France.

“That primary end point was met, and supportive analyses indicated a decreased risk of progression in patients under MD1003 [biotin].”

at a glance ➤ Past treatments for patients with multiple sclerosis have been effective on relapsed disease but have failed to show sustained impact on disability • Biotin has the potential to protect neurons from degeneration while increasing energy supply to oxygendeprived cells in a state of virtual hypoxia • After taking high doses of biotin, patients with primary and secondary progressive multiple sclerosis demonstrated improvements in physical and neurologic disability • Patients taking biotin did not demonstrate a major difference in adverse events such as infections, nervous system disorders, and gastrointestinal disorders compared with patients taking a placebo

A disabling, inflammatory, and demyelinating disease of the central nervous system, MS often begins with a

tion while increasing energy supply to oxygen-deprived cells in a state of virtual hypoxia.

“The primary end point, which was the percentage of patients who improved under high doses of biotin, was met. The safety profile between groups was similar…and supportive analyses showed a decreased risk for progression in patients under MD1003.”

—Ayman Tourbah, MD, PhD

relapsing-remitting period that is followed several years later by a secondary phase, according to Dr Tourbah. In primary onset progressive MS, however, the disease progresses from onset, with patients experiencing gradual disease worsening. Although past treatments have demonstrated efficacy on patients with relapsed disease corresponding to the inflammatory component of the disease, the treatments have failed to show significant and sustained impact on disability, which is mostly related to axonal loss and neurodegeneration.

The Solution

According to Dr Tourbah, biotin, a water-soluble vitamin, acts as a coenzyme for carboxylases involved in key steps of energy metabolism and fatty acid synthesis.

“Biotin is thought to act in MS through 2 possible mechanisms,” Dr Tourbah explained. “On one hand, it promotes myelination by activating acetylCoA carboxylase, a potentially key enzyme in myelin synthesis….On the other hand, high doses of biotin may feed the Krebs cycle to increase ATP [adenosine triphosphate] synthesis and energy production.”

In other words, biotin has the potential to protect neurons from degenera-

MS-SPI Trial

After positive results came from a 23-patient pilot study, researchers ini­ tiated MS-SPI, a randomized, double-blind, multicenter, placebo-controlled trial, to study the efficacy of biotin over placebo in progressive MS-related myelinopathy.

A total of 154 patients with a baseline Expanded Disability Status Scale (EDSS) score of between 4.5 and 7 were enrolled from 16 MS reference centers across France. Over the course of 1 year, high-concentrated, pharmaceuticalgrade biotin (MD1003) was taken orally at a total daily dose of 300 mg by 103 patients in the active arm. The remaining 51 patients were given placebo. According to Dr Tourbah, “MD1003 has no taste and no color, and thus cannot be recognized by patients.”

The primary end point of the study was the proportion of patients who improved at month 9 and confirmed at month 12 using either EDSS or a timed 25-foot walk (TW25) compared with baseline measures. EDSS was considered improved if it decreased by at least 1 point from baseline EDSS ≤5.5 and 0.5 points for EDSS ≥6. TW25 was considered improved if it decreased by at least 20% compared with baseline measures.

At the end of the study, 13 patients in the active arm met the primary end point, whereas no patients did so in the placebo arm. According to Dr Tourbah, this difference was significant.

“The active-treated arm showed mean change in EDSS that improved at the initial phase and remained improved throughout the duration of the study,” noted Dr Tourbah. “Concerning the placebo group, after the initial phase where the mean EDSS decreased, it then worsened at all the other time points of the study.…After 12 months, the difference between the 2 groups in the mean change in EDSS was statistically significant. Overall, this shows that patients under MD1003 not only did not progress, but they even slightly improved.”

Although twice as many patients met the primary end point with the EDSS than with the TW25 end point, Dr Tourbah still interpreted the latter’s measures as indicative of the same positive trend.

“Patients under placebo showed worse progression than patients under MD1003,” said Dr Tourbah. “The difference [with TW25] was not statistically significant, but this is probably due to large variations in measure.”

Finally, there were no major differences between groups concerning the most frequent adverse events, including infections, nervous system disorders, or gastrointestinal disorders. Although both arms had patients with relapsed disease, twice as many patients had relapsed disease in the placebo group than in the active treatment arm.

“The primary end point, which was the percentage of patients who improved under high doses of biotin, was met. The safety profile between groups was similar,” concluded Dr Tourbah.

“In the active arm, 12.6% of patients improved over a year, and supportive analyses showed a decreased risk for progression in patients under MD1003.

This study supports the fact that under MD1003 and as compared with placebo, a significant proportion of patients improve and fewer patients worsen.” n

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Multiple Sclerosis

RRMS Treatment Is Cost-Effective After...

Trust, is principal investigator with the UK Risk Sharing Scheme (RSS), a joint endeavor initiated in 2002 between several UK health departments and drug manufacturers to determine whether multiple sclerosis therapies coming to market met long-term cost-effectiveness targets. Patients enrolled in the RSS system were ambulatory adults with multiple sclerosis who had had 2 clinically significant relapses in the 2 years before enrollment. They were assigned by their physicians to receive glatiramer acetate (Copaxone) or 1 of 3 interferon beta formulations (Rebif [interferon beta-1a], Avonex [interferon beta-1a], or Betaferon [interferon beta-1b]); the choice of drug was based on patient and physician preference.

The investigators used as the control set data modeled from the British Columbia multiple sclerosis (BCMS) database, Canada, using patient data through the end of 1995, when disease-modifying treatments (DMTs) became available within that province.

These patients had the same eligibility criteria as those in the RSS, but none was treated with DMTs. The research-

ers used 2 mathematical models—a continuous Markov model and a multilevel model—to calculate the expected progression of the RSS patients if they had been untreated.

Continued from cover

by the investigators as a marker of slower progression with treatment compared with expected progression off treatment.

A threshold of 62% or less on the utility progression ratio was required to meet the

“If this benefit were sustained over 20 years, it would meet a cost-effectiveness target of £36,000 per QALY, although cost-effectiveness would not necessarily be achieved for countries where drug costs are substantially higher.”

—Jacqueline Palace, MD

Primary outcomes were the progression ratios of Expanded Disability Status Scale (EDSS) scores and loss of utility, with utility defined as a measure of society’s perception of the quality of life of a patient in a given health state. Progression ratios were measured as the ratios of observed to predicted change among RSS patients. A progression ratio of less than 100% using EDSS scores was used

NICE cost-effectiveness targets per quality-adjusted life-year (QALY).

Among the 4304 patients with RRMS who were eligible for the study and received treatment, 4137 had adequate data available for analysis and were included in the primary analysis.

Of these, 2639 (64%) patients had valid data collected at the year 6 follow-up, and 3533 (85%) had valid data at the

year 4 follow-up. The mean follow-up time of the patients in the RSS system was 5.1 years (median, 6 years). The investigators used 898 patients from the BCMS database as controls.

Patients in the RSS system at year 6 progressed significantly slower than predicted. There was a 75.8% EDSS progression ratio in the primary analysis for the Markov model and a 60% EDSS progression ratio in the multilevel model. Furthermore, the utility progression ratio met the criteria for cost-effectiveness of the DMTs, at 58.5% for the Markov model and 57.1% with the multilevel model. The team also reported that there was slightly more benefit at year 4 than at year 6.

“If this benefit [at year 6] were sustained over 20 years, it would meet a cost-effectiveness target of £36,000 per QALY, although cost-effectiveness would not necessarily be achieved for countries where drug costs are substantially higher,” Dr Palace and her colleagues wrote. “We cannot comment on the benefits of specific DMTs, because our analyses included DMTs only in aggregate.” n

Teriflunomide Demonstrates Significant Efficacy in... associated with a reduction in the risk of relapse as well.”

Teriflunomide is a once-daily oral immunomodulator approved for the treatment of patients with relapsingremitting multiple sclerosis. Although the exact mechanism of action of teriflunomide is not fully understood, it may involve a reduction in the number of activated lymphocytes in the central nervous system.

TEMSO and TOWER Studies

TEMSO and TOWER were phase 3, placebo-controlled studies that were designed to assess the efficacy and safety of teriflunomide 14 mg and 7 mg in patients with relapsing forms of multiple sclerosis.

TEMSO (N = 1086) and TOWER (N = 1165) enrolled patients with relapsing forms of multiple sclerosis, aged 18 to 55 years, with Expanded Disability Status Scale (EDSS) scores ≤5.5, and ≥1 relapses in the previous 12 months or ≥2 relapses in the previous 24 months.

TOPIC was a phase 3, placebo-controlled study of teriflunomide in 614 patients with a first clinical episode suggestive of multiple sclerosis. The study included patients aged 18 to 55 years with a first acute or subacute neurologic event consistent with demyelination (eg, optic neuritis, spinal cord syndrome, and

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brainstem and cerebellar syndromes) occurring within 90 days of randomization, and magnetic resonance imaging lesions characteristic of multiple sclerosis.

TEMSO was a 2-year clinical trial, and the treatment duration in the TOWER clinical trial was variable (ie, 48-152 weeks; treatment ended 48 weeks after the last patient was randomized).

The treatment duration in the TOPIC clinical trial was ≤108 weeks.

In all 3 studies, a relapse was defined as the appearance of a new clinical symptom or a clinical worsening of a previous symptom that had been stable for at least 30 days. Relapses were confirmed when they were associated with a minimum increase in EDSS score and/or functional system score.

Results

Efficacy “Teriflunomide 14 mg consistently demonstrated a significant reduction in both annualized relapse rate and risk for disability progression confirmed for 12 weeks versus placebo,” Dr Honeycutt reported. “Teriflunomide 7 mg significantly reduced the annualized relapse rate, but not disability progression, in both studies [TEMSO and TOWER].”

Teriflunomide demonstrated similar efficacy in the TOPIC study. Flavia

Nelson, MD, Neurologist, University of Texas Health Science Center, Houston, who presented a separate analysis, reported that “In TOPIC, teriflunomide 14 mg reduced the risk of relapse determining conversion to clinically definite MS by 42.6% compared with placebo (P = .008)….The 7-mg dose also showed statistically significant superiority to placebo on both end points, with a smaller effect.”

“Teriflunomide 14 mg consistently demonstrated a significant reduction in both annualized relapse rate and risk for disability progression confirmed for 12 weeks versus placebo.”

—William D. Honeycutt, MD

Demographic and baseline characteristics were broadly similar in the TEMSO and TOWER clinical trials, but patients in the TOPIC study were younger, had shorter time since their first neurologic event or symptom, and had lower baseline EDSS scores. The time since first

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symptom was longer for patients in the TEMSO clinical trial (8.7 years) than for patients in the TOWER clinical trial (8.0 years), Dr Honeycutt noted. In addition, more patients in the TEMSO study had secondary progressive or progressive-relapsing disease than did patients in the TOWER study.

Safety Both doses of teriflunomide, 7 mg and 14 mg, showed similar safety profiles across all 3 studies. The most common treatment-emergent adverse events that were more frequent with teriflunomide than with placebo included headache, diarrhea, alanine aminotransferase increase, nausea, and hair thinning. A long-term safety analysis with teriflunomide revealed that the majority of the adverse events were mild to moderate, and the nature of these events was similar to that observed in the 3 placebocontrolled studies.

“The findings from these 3 studies are clinically relevant, given the disruption to patients’ quality of life and increase in healthcare utilization associated with relapses,” Dr Honeycutt concluded. “The risk for relapse was significantly lower for patients who received teriflunomide than for those who received placebo.” n

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In the Literature

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VALUE-BASED CARE IN NEUROLOGY

that these models for predicting cognitive outcome are unstable.”

The quality-of-life scores were not significantly different among patients demonstrating cognitive decline at 12 months and those who did not; in fact, the quality of life seemed to improve in patients with or without cognitive decline.

João Massano, MD, University of Porto in Portugal, wrote in an accompaS:7.25”

nying comment to the article, “This important research shows that STN DBS does not associate with substantial cognitive safety issues in comparison to GPi DBS, at least in cognitively intact patients. In addition, current evidence suggests that STN DBS conveys higher efficacy regarding motor symptoms and disability, lower battery depletion, and larger dopaminergic drug reduction.

T:14.5” These data support STN as the pre-

For the adjunctive treatment of partial-onset seizures in patients aged 12 years and older1

Ind

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ADD ON THE STRENGTH OF FYCOMPA (perampanel) ®

Im

FYCOMPA is the first and only antiepileptic drug (AED) that targets glutamate activity at postsynaptic AMPA receptors1-3

•

•

•

• •

REDUCTION IN SEIZURE FREQUENCY (PLACEBO-ADJUSTED) MEDIAN PERCENT REDUCTION IN SEIZURE FREQUENCY (PLACEBO-ADJUSTED)†‡

Se Ho clin 12 eff tre 37 int The inc Pa inc tre esp the Su An tho oth un are sui inf or har or sym Diz FYC dis and 12 dis to 2% the So FYC eve rec 7% and 12 con mo haz or To re

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Median Seizure Reduction (%)

An in-depth analysis from the randomized, controlled Netherlands Subthalamic and Pallidal Stimulation (NSTAPS) clinical trial found no substantial differences in neuropsychological outcomes in patients with Parkinson disease who received globus pallidus internus (GPi) deep brain stimulation (DBS) or subthalamic nucleus (STN) DBS. The only differences observed 12 months after DBS were small, reported Vincent J. Odekerken, MD, and colleagues, who analyzed these outcomes and investigated whether baseline parameters could predict cognitive decline (Odekerken VJ, et al. Neurology. 2015; 84:1355-1361).

There has been lingering concern about cognitive decline following DBS. In particular, STN DBS has been associated with unfavorable outcomes, although data directly comparing STN DBS and GPi DBS, which are both effective in treating motor symptoms and dyskinesias, have been limited. The NSTAPS clinical trial indicated greater functional improvement during the medication off-drug phase with STN DBS compared with GPi DBS. In addition, the NSTAPS clinical trial showed no difference between the groups on a composite score for cognition, mood, and behavior. These findings conflict with several previous studies, which showed more cognitive problems with STN DBS versus GPi DBS. This current analysis focused on the results of the extensive battery of neuropsychological tests used for the cognitive evaluation of the study’s 128 patients.

There were significant differences in Stroop word reading, Stroop color naming, Trail Making Test Part B, and Wechsler Adult Intelligence Scale similarities, with STN DBS showing greater negative change than GPi DBS. The effect sizes of these differences, however, were small to medium.

“These results suggest a larger decline in mental speed, attention, and possibly language after STN DBS, however, this effect was not reproduced on the Trail Making Test Part A (TMTA) and Stroop color-word interference, respectively. These differences in cognitive change are similar to previous randomized controlled trials comparing GPi DBS and STN DPB,” the researchers reported.

There was no significant difference between the 2 groups regarding cognitive decline based on the composite score after DBS. Following GPi DBS, 29.3% of patients experienced cognitive decline; after STN DBS, 39.3% experienced decline (P = .26). In a logistic regression model, age at baseline (P = .003)

and semantic fluency at baseline (P = .032) were independent predictors of cognitive decline after DBS. No satisfactory explanation was found for the association with baseline semantic fluency.

Although a stable predictive model could be helpful to physicians in selecting treatment, the authors reported that “the results from our regression analysis, as well as the variation in predictors between different studies thus far, suggest

In three phase 3 clinical trials, FYCOMPA achieved a decrease in seizure frequency vs placebo1,4*

33

35

26

30 25 20

15

15

8

10

2 mg/day

45

40

40

35

35

30

30

20

16

16

19

20 15

10

10

5

5

(n=72) (n=69) 4 mg/day

(n=152) (n=117) 8 mg/day

33 24

25

20

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(n=72) (n=70) 2 mg/day

12 mg/day

50

45

22

8 mg/day

55

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REDUCTION IN SEIZURE FREQUENCY WITH ENZYME-INDUCING AEDs (NON PLACEBO-ADJUSTED)†‡

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REDUCTION IN SEIZURE FREQUENCY WITHOUT ENZYME-INDUCING AEDs (NON PLACEBO-ADJUSTED)†‡

50

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19

1

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Median Seizure Reduction (%)

Neuropsychological Outcomes After Deep Brain Stimulation for Parkinson Disease

(n=80) (n=35) 12 mg/day

14

16

(n=94) (n=90) 2 mg/day

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Placebo FYCOMPA

14

(n=94) (n=84) 4 mg/day

12

(n=196) (n=170) 8 mg/day

9

(n=102) (n=79) 12 mg/day

One daily dose at bedtime1

• Starting dose is 2 mg once daily in patients not taking enzyme-inducing AEDs and 4 mg in patients taking enzyme-inducing AEDs‡ • Dose may be increased based on clinical response and tolerability by a maximum of 2-mg increments to a dose of 4 mg to 12 mg. Dose increases should occur no more frequently than at weekly intervals1 • A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions *Pooled results of 3 randomized, double-blind, placebo-controlled, multicenter trials of FYCOMPA. All trials had a 6-week baseline period followed by a 19-week treatment period (6-week titration and 13-week maintenance), and patients were required to have >5 seizures at baseline to be randomized. The intent-to-treat (ITT) population from Studies 1, 2, and 3 equals 1037 patients who received FYCOMPA and 441 patients who received placebo.1,4 • The primary endpoint was the percent change in seizure frequency per 28 days during the treatment period as compared with the baseline period1

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• More than 85% of patients were taking 2 to 3 concomitant AEDs with or without concurrent vagal nerve stimulation (VNS); approximately 50% were taking at least 1 enzyme-inducing AED1 Patients from Latin American regions are excluded because of a significant treatment-by-region interaction due to high placebo response.1

†

The presence of concomitant enzyme-inducing AEDs (carbamazepine, oxcarbazepine, or phenytoin) increases the clearance of FYCOMPA.1

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In the Literature ferred DBS target in most patients with Parkinson disease.”

Socioeconomic Status Linked to Child’s Brain Size

In the largest study of its kind, a team of neuroscientists concluded that socioeconomic adversity affects brain development in children. Children in the lowest socioeconomic strata had signifiT:14.5” cantly smaller brain surface area than

children from more well-off parents, as reported in the multicenter study led by Kimberly Noble, MD, PhD, of Columbia University, New York (Noble KG, et al. Nat Neurosci. 2015;18:773-778).

Dr Noble and colleagues recorded brain images of 1099 children, adolescents, and young adults in several US cities. Because individuals with lower incomes are more likely to be from minority ethnic groups, they also mapped S:7.25”

each child’s genetic ancestry, and adjusted the calculations so that the effects of poverty would not be skewed by small differences in the brain structure among various ethnic groups.

“To the best of our knowledge, this is the first study of socioeconomic status and the brain to include as covariates continuously varying measures of degree of genetic ancestry,” the authors explained.

In children from the poorest families, income disparities of only a few thousand dollars were associated with major differences in brain structure, particularly in areas associated with language and decision-making skills.

Children’s scores on tests measuring cognitive skills, such as reading and memory ability, also declined as parental income dropped. Specifically, the brains of children from the lowest inContinued on page 8

Indication: FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older.

Important Safety Information

WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS • Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA • These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression • Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA • Closely monitor patients particularly during the titration period and at higher doses • FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening

e

s

h y

ne,

Falls Falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebotreated patients.

Withdrawal of AEDs A gradual withdrawal is generally recommended with antiepileptic drugs to minimize the potential of increased seizure frequency.

Most Common Adverse Reactions In clinical trials, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA 8 mg or 12 mg vs placebo (≥4% and at least 1% higher than the placebo group) included dizziness (36% vs 9%), somnolence (16% vs 7%), fatigue (10% vs 5%), irritability (9% vs 3%), falls (7% vs 3%), nausea (7% vs 5%), ataxia (5% vs 0%), balance disorder (4% vs 1%), gait disturbance (4% vs 1%), vertigo (4% vs 1%), and weight gain (4% vs 1%).

Drug Interactions FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel.

Plasma levels of FYCOMPA were decreased when administered with carbamazepine, phenytoin and oxcarbazepine. Concomitant use with strong CYP3A inducers such as St. John’s wort and rifampin should be avoided. Multiple dosing of FYCOMPA 12 mg/day enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants.

Pregnancy Category C and Lactation FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Caution should be exercised when FYCOMPA is administered to a nursing woman.

Hepatic and Renal Impairment Use in patients with severe hepatic or severe renal impairment is not recommended. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Use with caution in patients with moderate renal impairment.

Drug Abuse and Dependence FYCOMPA is a Schedule III controlled drug substance and has the potential to be abused or lead to drug dependence.

Please see Brief Summary of full Prescribing Information, including Boxed Warning, on the next page.

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Serious Psychiatric and Behavioral Reactions Hostility- and aggression-related adverse reactions occurred in 12% and 20% of clinical trial patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients.

The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol.

Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases.

Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts or behavior, thoughts about selfharm, and/or any unusual changes in mood or behavior. Should suicidal thoughts or behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Dizziness and Gait Disturbance FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. Dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients. Gait disturbance related events were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase.

Somnolence and Fatigue FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events. Somnolence was reported in 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 7% of placebo-treated patients. Fatigue-related events were reported in 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 5% of placebo-treated patients. In the controlled Phase 3 epilepsy clinical trials, these adverse reactions occurred mostly during the titration phase. Patients should be advised against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.

To find out more information about FYCOMPA, speak to your representative or visit FYCOMPA.com/HCP.

References: 1. FYCOMPA Prescribing Information. Woodcliff Lake, NJ: Eisai Inc.; June 2014. 2. Rogawski MA. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 2011;11(2):56-63. 3. Hanada T, Hashizume Y, Tokuhara N, et al. Perampanel: a novel, orally active, noncompetitive AMPA-receptor antagonist that reduces seizure activity in rodent models of epilepsy. Epilepsia. 2011;52(7):1331-1340. 4. Data on file.

Eisai Inc., Woodcliff Lake, NJ; 2012.

FYCOMPA® is a registered trademark of Eisai R&D Management Co., LTD., licensed to Eisai Inc. Manufactured and marketed by Eisai Inc., Woodcliff Lake, NJ 07677 ©2015 Eisai Inc. All rights reserved. FYCO1076. May 2015

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In the Literature Socioeconomic Status Linked to... Continued from page 7

come brackets (ie, annual family income of less than $25,000) had up to 6% less surface area than brains of children from families with incomes exceeding $150,000. The authors suggested that the logarithmic association between family income and surface area implies “that for every dollar in increased income, the increase in chil-

dren’s brain surface area was proportionally greater.” The association was steepest at the lowest end of the income spectrum.

Family income was significantly associated with surface area in widespread regions of children’s bilateral frontal, temporal, and parietal cortices as well as right occipital cortex. Relationships were strongest in bilateral inferior temporal, insula, and inferior frontal gyrus,

and in the right occipital and medial prefrontal cortex—regions linked to language and executive function. Income was also significantly correlated with 4 cognitive assessments from the US National Institutes of Health Toolbox Cognition Battery. Furthermore, parental education was linearly associated with total brain surface area, independent of age, scanner site, sex, and genetic ancestry factor. Education was S:7.25”

FYCOMPA® (perampanel) tablets, for oral use, CIII Initial U.S. Approval: 2012 BRIEF SUMMARY-see package insert for full Prescribing Information

WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS • Serious or life-threatening psychiatric and behavioral adverse reactions including aggression,hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA (5.1) • These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression (5.1) • Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA (5.1) • Closely monitor patients particularly during the titration period and at higher doses (5.1) • FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening (5.1)

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INDICATIONS AND USAGE FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older.

DOSAGE AND ADMINISTRATION Dosing Information In the Absence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks. The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability [see Clinical Studies (14)]. In the Presence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg [see Clinical Studies (14)]. When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.

Dosage Adjustments in Patients with Hepatic Impairment Based on higher exposure and the longer halflife of perampanel in patients with mild and moderate hepatic impairment, dosage adjustment is recommended.

Starting dose should be 2 mg per day with weekly increments of 2 mg per day every two weeks until target dose is achieved. The maximum recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with moderate hepatic impairment. Dose increases in patients with mild and moderate hepatic impairment, as with all patients, should be based on clinical response and tolerability. Use in patients with severe hepatic impairment is not recommended [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Patients with Renal Impairment FYCOMPA can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered based on clinical response and tolerability. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Psychiatric and Behavioral Reactions In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. FYCOMPA-treated patients experienced more hostilityand aggression- related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety which occurred in 2% or greater of perampanel treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with perampanel treatment and more commonly than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel treated patients in controlled and open label studies, including non-epilepsy studies. In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger [see Drug Interactions (7.3)]. Patients taking FYCOMPA should avoid the use of alcohol. In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state. In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than placebo-treated subjects included disorientation, delusion, and paranoia. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.

In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebotreated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1. Risk by indication for antiepileptic drugs in the pooled analysis Relative Risk: Risk Difference: Incidence of Drug Patients Placebo Patients Additional Drug Indication with Events Per with Events Per Events in Drug Patients/ Patients with Events Incidence in Placebo 1000 Patients 1000 Patients Per 1000 Patients Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 1.8 1.9 0.9 Total 2.4 4.3 1.8 1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers. Neurologic Effects Dizziness and Gait Disturbance FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination [see Adverse Reactions (6.1)]. In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10% of placebo-treated patients.

The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12% and 16% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated subjects compared to 1% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Somnolence and Fatigue FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the controlled Phase 3 epilepsy clinical trials, 16% and 18% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12% and 15% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebotreated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Risk Amelioration Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the titration phase. Falls An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5% and 10% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3% of placebotreated patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and adolescents. Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In antiepileptic clinical trials FYCOMPA was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.

ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: • Serious Psychiatric and Behavioral Reactions [see Warnings and Precautions (5.1)] • Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)] • Dizziness and Gait Disturbance [see Warnings and Precautions (5.3)] • Somnolence and Fatigue [see Warnings and Precautions (5.3)] • Falls [see Warnings and Precautions (5.4)] Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51% of patients were female and the mean age was 35 years. Adverse Reactions Leading to Discontinuation In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3%, 8% and 19% in patients randomized to receive FYCOMPA at the recommended doses of 4 mg, 8 mg and 12 mg/ day, respectively, and 5% in patients randomized to receive placebo [see Clinical Studies (14)]. The adverse events most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria [see Warnings and Precautions (5.1 and 5.3)]. Most Common Adverse Reactions Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in ≥2% of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported doserelated adverse reactions in patients receiving FYCOMPA at doses of 8 mg or 12 mg (≥4% and occurring at least 1% higher than the placebo group) included dizziness (36%), somnolence (16%), fatigue (10%), irritability (9%), falls (7%), nausea (7%), ataxia (5%), balance disorder (4%), gait disturbance (4%), vertigo (4%), and weight gain (4%). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation.

Table 2. Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures (Reactions ≥2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo) Placebo

Ear and Labyrinth Disorders Vertigo Eye Disorders Diplopia Blurred vision Gastrointestinal Disorders Constipation Nausea Vomiting Infections and Infestations Upper respiratory tract infection

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also positively correlated to the left hippocampal volume.

The factors driving these differences are unclear, but could include differences in the prenatal environment or ongoing disparities in postnatal experience and exposures, such as family stress, cognitive stimulation, environmental toxins, or nutrition.

In their discussion of the findings, T:14.5” Noble and colleagues cautioned, “Our

n=442 %

4 mg n=172 %

FYCOMPA 8 mg n=431 %

12 mg n=255 %

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In the Literature results should in no way imply that a child’s socioeconomic circumstances lead to an immutable trajectory of cognitive or brain development.”

They hope that “by elucidating the structural brain differences associated with socioeconomic disparities, we may be better able to identify more precise endophenotypic biomarkers to serve as targets for intervention, with T:14.5” the ultimate goal of reducing socioeco-

nomic disparities in development and achievement.”

Disturbing Trends in Headache Management

The treatment of headache for more than 12 million Americans costs more than $31 billion yearly. Some of this cost could be offset if physicians ordered fewer tests and counseled patients more about positive lifestyles, researchers S:7.25”

Table 2. Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures (Reactions ≥2% of Patients in Highest FYCOMPA Dose (12 mg) Group and More Frequent than Placebo) (cont.)

r c al e s r . s d , e n d o . n d d d d s e d e d e s s f y g t s d s n f al s e f

1 3 1 <1 1

0 2 1 1 0

2 5 1 1 2

2 10 3 2 2

1

4

4

4

<1

0

0

2

1 2 1 2 1 1

0 2 1 1 0 1

3 2 1 1 2 1

2 5 2 3 3 2

1 0 1 0 9 0 5 1 11 0 1 1 1 7

1 1 0 1 16 1 8 1 11 1 0 0 0 9

2 3 5 <1 32 3 8 4 11 2 0 1 1 16

2 8 3 2 43 4 12 4 13 3 3 2 2 18

1 <1 1 <1 0 3 <1

1 0 2 1 0 4 1

2 1 3 1 <1 7 <1

3 3 4 2 2 12 2

3 1

1 2

1 2

4 2

Weight gain Weight gain has been observed with FYCOMPA use in adults. In the controlled Phase 3 epilepsy clinical

e f el o s e % / e r d e f t y d e

trials, FYCOMPA-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in FYCOMPA-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively. Clinical monitoring of weight is recommended. Comparison of Sex and Race No significant sex differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidences of adverse reactions compared to Caucasian patients were observed.

DRUG INTERACTIONS Contraceptives With concomitant use, FYCOMPA at a dose of 12 mg/day reduced levonorgestrel exposure by approximately 40% [see Clinical Pharmacology (12.3)]. Use of FYCOMPA with oral or implant contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended. Cytochrome P450 (CYP) Inducers The concomitant use of known CYP enzyme inducers including carbamazepine, phenytoin, or oxcarbazepine with FYCOMPA decreased the plasma levels of perampanel by approximately 50~67% [see Clinical Pharmacology (12.3)]. The starting doses for FYCOMPA should be increased in the presence of enzyme-inducing AEDs [see Dosage and Administration (2.1)]. When these enzyme-inducing AEDs are introduced or withdrawn from a patient’s treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary.

As noted, however, the decrease in the therapeutic effect seen in patients on concomitant treatment, was not affected by use of higher doses (8 mg to 12 mg) [see Dosage and Administration (2.1)]. Concomitant use of FYCOMPA with other strong CYP3A inducers (e.g., rifampin, St. John’s wort) should be avoided. Alcohol and Other CNS Depressants The concomitant use of FYCOMPA and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of FYCOMPA on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol [see Clinical Pharmacology (12.3)]. Multiple dosing of FYCOMPA 12 mg/day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression.

These effects may also be seen when FYCOMPA is used in combination with other CNS depressants. Care should be taken when administering FYCOMPA with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g. benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on FYCOMPA to gauge whether it adversely affects these activities.

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses.

FYCOMPA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rats throughout organogenesis resulted in an increase in visceral abnormalities (diverticulum of the intestine) at all doses tested. In a dose-ranging study at higher oral doses (10, 30, or 60 mg/kg/day), embryo lethality and reduced fetal body weight were observed at the mid and high doses tested. The lowest dose tested (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2). Upon oral administration of perampanel (1, 3, or 10 mg/kg/day) to pregnant rabbits throughout organogenesis, embryo lethality was observed at the mid and high doses tested; the no effect dose for embryo-fetal developmental toxicity in rabbit (1 mg/kg/day) is approximately 2 times a human dose of 8 mg/day based on body surface area (mg/m2). Oral administration of perampanel (1, 3,

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or 10 mg/kg/day) to rats throughout gestation and lactation resulted in fetal and pup deaths at the mid and high doses and delayed sexual maturation in males and females at the highest dose tested. No effects were observed on measures of neurobehavioral or reproductive function in the offspring. The no-effect dose for pre- and postnatal developmental toxicity in rat (1 mg/kg/day) is similar to a human dose of 8 mg/day based on body surface area (mg/m2). Pregnancy Registry To provide information regarding the effects of in utero exposure to FYCOMPA, physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website: http://www.aedpregnancyregistry.org. Nursing Mothers Perampanel and/ or its metabolites are excreted in rat milk, and are detected at concentrations higher than that in maternal plasma. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when FYCOMPA is administered to a nursing woman. Pediatric Use The safety and efficacy of FYCOMPA for the adjunctive therapy of partial-onset seizures was established by three randomized double blind, placebo-controlled, multicenter studies which included 72 pediatric patients between 12 and 16 years old exposed to perampanel [see Clinical Studies (14.1), Clinical Pharmacology (12.3)].

The safety and effectiveness of FYCOMPA in pediatric patients <12 years old have not been established.

Juvenile Animal Data Oral administration of perampanel (1, 3, 3/10/30 mg/kg/day; high dose increased on postnatal days [PND] 28 and 56) to young rats for 12 weeks starting on PND 7 resulted in reduced body weight, reduced growth, neurobehavioral impairment (water maze performance and auditory startle habituation) at the mid and high doses, and delayed sexual maturation at the high doses. CNS signs (reduced activity, incoordination, excessive grooming/scratching), pup death, decreased hindlimb splay, and decreased hindlimb grip strength were observed at all doses. Effects on pup body weight, pup growth, hindlimb splay, impairment in the water maze performance and auditory startle persisted after dosing was stopped. A no-effect dose for postnatal developmental toxicity was not identified in this study. Oral administration of perampanel (1, 5, 5/10 mg/kg/day; high dose increased on PND 56) to juvenile dogs for 33 weeks, starting on PND 42, resulted in CNS signs (incoordination, excessive grooming/licking/scratching, spatial disorientation, and/or ataxic gait) at all doses tested. Geriatric Use Clinical studies of FYCOMPA did not include sufficient numbers of patients aged 65 and over to determine the safety and efficacy of FYCOMPA in the elderly population. Because of increased likelihood for adverse reactions in the elderly dosing titration should proceed slowly in patients aged 65 years and older [see Dosage and Administration (2.1)]. Patients with Hepatic Impairment Use of FYCOMPA in patients with severe hepatic impairment is not recommended and dosage adjustments are recommended in patients with mild or moderate hepatic impairment [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. Patients with Renal Impairment Dose adjustment is not required in patients with mild renal impairment. FYCOMPA should be used with caution in patients with moderate renal impairment and slower titration may be considered. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].

DRUG ABUSE AND DEPENDENCE Controlled Substance FYCOMPA contains perampanel and is listed as a Schedule III controlled substance.

Abuse Prescription drug abuse is the intentional non-therapeutic use of a drug, even once, for its rewarding psychological or physiological effects. Drug addiction, which develops after repeated drug abuse, is characterized by a strong desire to take a drug despite harmful consequences, difficulty in controlling its use, giving a higher priority to drug use than to obligations, increased tolerance, and sometimes physical withdrawal.

Drug abuse and drug addiction are separate and distinct from physical dependence (for example, abuse may not be accompanied by physical dependence) [see Drug Abuse and Dependence (9.3)]. Studies of human abuse potential were performed to evaluate the abuse potential of FYCOMPA (8 mg, 24 mg, and 36 mg) as compared to alprazolam C-IV (1.5 mg and 3 mg), and oral ketamine C-III (100 mg) in recreational polydrug users. Supra-therapeutic doses of FYCOMPA 24 and 36 mg produced responses for “Euphoria” that were similar to ketamine 100 mg and alprazolam 3 mg. For “High,” FYCOMPA 24 mg and 36 mg produced responses comparable to ketamine 100 mg and significantly higher than both doses of alprazolam on a visual analog scale (VAS). “Drug Liking”, “Overall Drug Liking”, and “Take Drug Again” for FYCOMPA were each statistically lower than ketamine 100 mg. In addition, for “Bad Drug Effects”, FYCOMPA 24 mg and 36 mg produced responses significantly higher than ketamine 100 mg. For “Sedation,” FYCOMPA 24 and 36 mg produced responses similar to alprazolam 3 mg and higher than ketamine 100 mg. Additionally, on VAS measures related to dissociative phenomena such as “Floating”, “Spaced Out” and “Detached,” FYCOMPA at supra-therapeutic doses produced responses similar to ketamine 100 mg and greater than both doses of alprazolam tested.

Of note, due to somnolence a number of subjects had missing data around Tmax of FYCOMPA. The above described data might represent an underestimate of FYCOMPA’s effects. The duration of effects of higher doses of FYCOMPA on the majority of measures was much greater than alprazolam 3 mg and ketamine 100 mg. In this study, the incidence of euphoria following FYCOMPA administration 8 mg, 24 mg and 36 mg was 37%, 46%, 46%, respectively, which was higher than alprazolam 3 mg (13%) but lower than ketamine 100 mg (89%).

Dependence Physical dependence is characterized by withdrawal symptoms after abrupt discontinuation or a significant dose reduction of a drug. The potential for FYCOMPA to produce withdrawal symptoms has not been adequately evaluated.

OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Acute Overdose in Humans There is limited clinical experience with FYCOMPA overdose. The highest reported overdose (approximately 264 mg) was intentional.

This patient experienced serious adverse reactions of altered mental status, agitation, and aggressive behavior and recovered without sequelae. In general, the adverse reactions associated with overdoses were similar to the reactions at therapeutic doses with dizziness reported most frequently. There were no reported sequelae.

Treatment or Management of Overdose There is no available specific antidote to the overdose reactions of FYCOMPA. In the event of overdose, standard medical practice for the management of any overdose should be used. An adequate airway, oxygenation, and ventilation should be ensured; monitoring of cardiac rhythm and vital sign measurement is recommended. A certified poison control center should be contacted for updated information on the management of overdose with FYCOMPA. Due to its long half-life, the reactions caused by FYCOMPA could be prolonged.

PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Medication Guide). Inform patients of the availability of a Medication Guide, and instruct them to read the Medication Guide prior to taking FYCOMPA. Instruct patients to take FYCOMPA only as prescribed. Serious Psychiatric and Behavioral Reactions Counsel patients, families and caregivers of patients of the need to monitor for the emergence of anger, aggression, hostility, unusual changes in mood, personality, or behavior, and other behavioral symptoms. Advise them to report any such symptoms immediately to their health care providers. Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including FYCOMPA, may increase the risk of suicidal thinking and behavior and advise them of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers and families to report behaviors of concern immediately to healthcare providers. Neurologic Effects: Dizziness, Gait Disturbance, Somnolence, and Fatigue Counsel patients that FYCOMPA may cause dizziness, gait disturbance, somnolence, and fatigue. Advise patients taking FYCOMPA not to drive, operate complex machinery, or engage in other hazardous activities until they have become accustomed to any such effects associated with FYCOMPA. Falls Counsel patients that FYCOMPA may cause falls and injuries. Withdrawal of Antiepileptic Drugs Counsel patients that abrupt discontinuation of FYCOMPA may increase seizure frequency. Contraceptives Counsel patients that FYCOMPA may decrease efficacy of contraceptives containing levonorgestrel. Alcohol and Other CNS Depressants Counsel patients that FYCOMPA may enhance the impairment effects of alcohol. These effects may also be seen if FYCOMPA is taken with other CNS depressants. Missed Doses Counsel patients that if they miss a dose, they should resume dosing the following day at their prescribed daily dose. Instruct patients to contact their physician if more than one day of dosing is missed. Controlled Substance Counsel patients that FYCOMPA is a controlled substance that can be misused and abused. Pregnancy Registry To provide information regarding the effects of in utero exposure to FYCOMPA, recommend pregnant patients treated with FYCOMPA to enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org.

FYCOMPA® is a registered trademark owned by Eisai R&D Management Co., Ltd. Manufactured and Marketed by Eisai Inc., Woodcliff Lake, NJ 07677 ©2014 Eisai Inc. FYCOXXXX

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A new study unveils a strong association between Epstein-Barr virus (EBV) genomic variants and multiple sclerosis, reinforcing the idea that EBV contributes to the development of multiple

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male, with a mean age of 46 years.

Longitudinal trends analysis revealed that rather than talking to patients about the causes and the potential sources of relief from headache pain, clinicians often referred patients to specialists and ordered advanced imaging. Both of these approaches are considered to be of little value in the treatment of routine headaches, the researchers maintained.

“I was particularly alarmed about the overall trend of more imaging tests, medications, and referrals alongside less counseling,” Dr Mafi said. “These findings seem to reflect a larger trend in the US healthcare system, beyond just headache: over-hurried doctors seem to be spending less time connecting with their patients and more time ordering tests and treatments.”

Specifically, the researchers evaluated guideline-discordant indicators, including the use of computed tomography/magnetic resonance imaging (CT/ MRI), the use of opioids/barbiturates, and referrals to other physicians, as well as guideline-concordant indicators, such as counseling on lifestyle modifications and the use of preventive medications (eg, verapamil, topiramate, amitriptyline, or propranolol). In addition, findings were stratified based on migraine versus nonmigraine headache, acute versus chronic symptoms, and whether the clinicians self-identified as the primary care physician.

The use of CT/MRI increased from 6.7% of visits in 1999-2000 to 13.9% in 2009-2010 (unadjusted P <.001), and referrals to other physicians increased from 6.9% to 13.2% (P = .005). In contrast, counseling by clinicians declined from 23.5% to 18.5% (P = .041).

Although the use of opioids and barbiturates remained unchanged at 18%, the use of preventive medications increased from 8.5% to 15.9% (P = .001). Adjusted trends were similar, as were the results after stratifying by migraine versus nonmigraine and acute versus chronic presentation. Furthermore, primary care clinicians were 46% less likely than other physicians to order CT/MRI. “Contrary to numerous guidelines, clinicians are increasingly ordering advanced imaging and referring to other physicians, and less frequently offering lifestyle counseling to their patients.

The management of headache represents an important opportunity to improve the value of US healthcare,” the authors concluded.

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Injury, Poisoning and Procedural Complications Contusion Falls Head injury Limb injury Skin laceration Investigations Weight gain Metabolism & Nutrition disorders Hyponatremia Musculoskeletal and Connective Tissue disorders Arthralgia Back pain Musculoskeletal pain Myalgia Pain in extremity Peripheral edema Nervous system disorders Asthenia Ataxia Balance disorder Coordination abnormal Dizziness Dysarthria Fatigue Gait disturbance Headache Hypersomnia Hypoaesthesia Memory impairment Paraesthesia Somnolence Psychiatric disorders Aggression Anger Anxiety Confusional state Euphoric mood Irritability Mood altered Respiratory, Thoracic and Mediastinal Disorders Cough Oropharyngeal pain

from Beth Israel Medical Center, Boston, concluded (Mafi JN, et al. J Gen Intern Med. 2015;30:548-555).

John N. Mafi, MD, and colleagues identified 9362 visits for headache from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. Patients were excluded from this analysis if they had a neurologic deficit, cancer, or trauma. Nearly 75% of patients were fe-

I

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www.ValueBasedNeurology.com

9

Stroke

Stroke Center Reduces Door-to-Needle Times... are improved with faster door-to-needle times,” said Judd M. Jensen, MD, Swedish Medical Center, Englewood, CO. “I think it’s well-established that whatever we do to our stroke patients, we have to do it fast.”

With a team of 8 neurologists who specialize in the treatment of patients with stroke, Dr Jensen’s Joint Commission–certified Comprehensive Stroke Center in metropolitan Denver annually treats more than 1000 patients who have been diagnosed with stroke.

Despite the center’s impressive doorto-needle times with respect to the national average, once these times were examined for efficiency, Dr Jensen observed an all too linear process that was almost painstakingly sequential.

Patients were moved from room to room, visiting with nurses, emergency department physicians, and, finally, a neurologist, who would wait for confirmation from the computed tomography (CT) scanner before contacting a pharmacist, who would then begin the process of mixing tissue plasminogen activator (tPA).

“There seemed to be a lot of wasted time,” Dr Jensen acknowledged. “So, with the advice, consent, and enthusiasm of our emergency room physicians, we reevaluated our process and took several steps to improve our stroke alert process.”

First Initiative: Increasing Emergency Medical Service Prehospital Alert Rate

“We made a concerted effort to get our EMS [Emergency Medical Service] providers to notify us as soon as they were en route to our hospital,” Dr Jensen explained, which allowed the hospital’s stroke team to receive advanced notice of an incoming patient.

“There is plenty of substantiation in the literature that patients’ outcomes are improved with faster door-to-needle times.”

—Judd M. Jensen, MD

Creating a launchpad in the back of the emergency department specifically designated for the treatment of patients suspected of having a stroke was the next step, which was crucial to allow for procedures to occur simultaneously upon the patient’s arrival.

“A bunch of people descend on the patient,” said Dr Jensen. “Someone registers the patient; the neurologist is there getting history; NIHSS [National Institutes of Health Stroke Scale] is performed; a stroke coordinator is there. A

lot of things happen all at once. EMS hopefully gives us a good history about last normal.”

If the patient is suspected of having ischemic stroke, the pharmacist is instructed from the launchpad to mix tPA before the patient is transferred to the CT scanner. A CT scan of the brain is then performed and interpreted by the neurologist. If tPA is indicated, it is given intravenously in the CT room.

Door-to-Needle Time: 30-Minute Average

Dr Jensen and colleagues evaluated the protocol in a study of 262 patients diagnosed with acute ischemic stroke whose mean initial NIHSS was 12.

Starting in 2013 at 39 minutes, the median door-to-needle time fell to 31 minutes after only 1 year (P<.001). There were significant changes in treatment time windows, too.

“Almost 50% of patients are getting tPA within less than 30 minutes, and nearly all of them receive tPA in less than 60 minutes,” reported Dr Jensen.

“We had a number of patients under 15 minutes, with 11 minutes being the fastest time.”

Faster door-to-needle times also led to a marked improvement in outcomes, Dr Jensen observed. Overall, 46% of patients had “excellent” discharge modified Rankin Scale values at the end of the study, marking a significant improve-

Continued from cover

ment. Drawing conclusions from the center’s success, Dr Jensen stressed that the multidisciplinary team effort needed to sustain such coordinated precision.

“Everyone has to be on board and enthusiastic,” he said. “Radiology has to clear the deck on the CT scanner when a stroke alert is coming in. Pharmacy has to be ready to mix tPA at a moment’s notice…and, very important, ED [emergency department] physicians and nurses have to be invested in this.”

As is often the case with teamwork, sacrifice is required.

“This is a disruption of their workflow,” he said. “It changes the way they do things. In particular, the ED physicians have to be comfortable with the fact that you are giving tPA to their patient in a CT scanner, because, at that point, the patient is registered as an ED patient. [The ED physicians] are the ones responsible for the patient, and yet you are giving a potentially lethal drug to their patient somewhere else.”

Finally, given the extraordinary value of time in the treatment of patients diagnosed with stroke, where a reduction of minutes can be tantamount to millions of neurons saved, Dr Jensen’s takeaway was a simple but powerful reminder of the importance of streamlining.

“It’s really about the elimination of unnecessary steps,” he concluded, “and thinking of doing things simultaneously instead of sequentially.” n

Are Active Interventions for Caregivers of Stroke Patients Cost-Effective?

By Rosemary Frei, MSc

S

everal studies have examined the costs associated with actively educating and supporting family caregivers of people who have had a stroke, yet provide only limited evidence that such interventions are cost-effective. That’s the bottom line of a new systematic review published in Clinical Rehabilitation (Heslin M, et al. Clin Rehabil. March 10, 2015. [Epub ahead of print]).

A team from the United Kingdom searched the English-language literature and found 10 relevant studies that had sufficient data to be included in their review. The 10 relevant studies had disparate designs, sites of patients recruited, interventions, and forms of analyses, and had predominantly white participants. Only 3 of these studies connected outcomes with cost data

within a “formal” economic evaluation framework; 1 had a full economic analysis (Kalra L, et al. BMJ. 2004;328:1099; Patel A, et al. BMJ. 2004;328:1102;

with similar or better outcomes than nonintervention conditions. However, 2 of these studies used the same intervention—caregiver training—and the

“It is difficult to draw firm conclusions on costeffectiveness for informing clinical practice due to the variation in the types of interventions and comparators examined in different studies.”

—Margaret Heslin, PhD, and colleagues

Pierce LL, et al. Disabil Rehabil. 2009; 31:1676-1684).

All 3 studies with economic evaluation showed that caregiver interventions are less costly and are associated

same data set (Kalra L, et al. BMJ. 2004;328:1099; Patel A, et al. BMJ. 2004;328:1102).

The paucity of full economic analyses led the team to conclude that well-de-

signed, randomized, controlled trials are needed that focus solely on interventions for stroke-patient caregivers.

“It is difficult to draw firm conclusions on cost-effectiveness for informing clinical practice due to the variation in the types of interventions and comparators examined in different studies,” wrote lead author Margaret Heslin, PhD, Research Associate, Centre for the Economics of Mental and Physical Health, King’s College London, and her coauthors. “Similarly, a number of methodological limitations undermine the conclusions that can be drawn where evidence of relevance to the issue of intervention cost-effectiveness is reported.”

A 2008 review by the Cochrane Collaboration had examined the effectiveness of giving relevant information Continued on page 11

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Stroke

Mobile Stroke Units Gaining Traction in the United States

By Rosemary Frei, MSc

A

recent test-run of a mobile stroke unit (MSU) in Houston, TX, has shown preliminary success in the treatment of patients diagnosed with ischemic stroke. During an 8-week pilot of the MSU, the first of its kind in the United States, 8 of 13 patients who were diagnosed with stroke and treated with recombinant tissuetype plasminogen activator (rtPA) received the life-saving drug within 80 minutes of symptom onset. The rest received the drug between 81 and 270 minutes after onset (Rajan S, et al.

JAMA Neurol. 2015;72:229-234; Parker SA, et al. Stroke. 2015;46:1384-1391).

Several of the team members who piloted the MSU are now conducting a randomized trial that will include an evaluation of the costs of implementing and maintaining the unit, as well as of the healthcare costs associated with the unit compared with those for standard emergency medical services (EMS).

Meanwhile, officials at University of Colorado Health are reported to be preparing another of these vehicles for use later this year, and Cleveland Clinic is reported to be operating one as well.

“I am gratified to see how smoothly the MSU operation can work once it is up and running, and how fast and efficiently we can treat patients. I am optimistic that this strategy can be applied in any community in the United States to speed stroke treatment,” James Grotta, MD, Director of the Mobile Stroke Unit Consortium, told Value-Based Care in Neurology. “I am curious to know exactly how much better recovery patients will make with such earlier treatment, and [am] realistic that whatever improved outcomes occur must be balanced against the costs.”

Dr Grotta, who is the principal in-

vestigator of the project and also Director of Stroke Research, Clinical Innovation and Research Institute, Memorial Hermann–Texas Medical Center, has been working on the project for more than 2 years, dedicating 80% of his time to it since February 2014. He helped to secure funding for the project and oversee the purchase and equipping of the vehicle (including a CereTom computed tomography scanner and advanced life support supplies) as well as communication with Houston’s EMS department and training, staffing, and scheduling.

mography scan and laboratory testing.

Of the remaining 24 patients who met criteria for enrollment, 11 were not treated for various reasons: an intracerebral hemorrhage lowered their blood pressure acutely (4 patients); they experienced seizures (3 patients); their symptoms improved and obviated the need for rtPA (2 patients); a subhematoma developed (1 patient); or the time of symptom onset was undermined (1 patient). Among the remaining 13 patients who were administered rtPA, 4 (31%) were given the drug within 60 minutes of symptom onset, another 4

“I am gratified to see how smoothly the MSU operation can work once it is up and running, and how fast and efficiently we can treat patients. I am optimistic that this strategy can be applied in any community in the United States to speed stroke treatment.”

—James Grotta, MD

The MSU began operation on May 14, 2014, and underwent an 8-week pilot to test all aspects of the system.

During that 2-month period, the MSU team was dispatched 130 times. In 106 cases, the team either did not go to the destination or assessed the patients and determined they did not qualify for the study; that is, they did not have symptom onset within the previous 4.5 hours and did not meet published criteria for rtPA treatment pending computed to-

(31%) at 61 to 80 minutes from onset, and 5 (38%) at 81 to 270 minutes from symptom onset. The team also successfully attempted remote telemedicine assessment of the patients.

The total cost of equipment and supplies was $633,300 for the first year of the MSU and is projected to be $79,000 annually after that. This excludes the cost of rtPA, which Dr Grotta and his colleagues documented in their paper as being $7816 per 100-mg vial. The team

Are Active Interventions for Caregivers... to stroke patients and their caregivers.

The reviewers found just 1 published economic study, however, and therefore could not draw conclusions about the cost-effectiveness of such interventions. Dr Heslin and 3 of her colleagues conducted the systematic review to try to fill in that gap. The 10 studies they included focused on interventions either for caregivers exclusively or for both caregivers and patients. The interventions ranged from basic information-giving to active education, training, and skill-building.

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The 1 study that provided a full economic analysis—including the calculation of cost per quality-adjusted life-year (QALY)—was a 1-year, randomized trial conducted in the United Kingdom that compared caregiver training to conventional care in a stroke-rehabilitation unit (Patel A, et al. BMJ. 2004;328:1102). The economic outcomes data were collected by participant self-report. The patients whose caregivers were in the intervention arm had significantly fewer inpatient days, and less physiotherapy and occupational therapy than

I

➤ A test run of a mobile stroke unit demonstrated early success in treating patients diagnosed with ischemic stroke • During the 2-month test run, 13 patients were administered recombinant tissue-type plasminogen activator • Overall, 8 patients received the drug within 80 minutes of symptom onset and 5 received it at 80 to 270 minutes from onset

is conducting the Benefits of Stroke Treatment Delivered Using a Mobile Stroke Unit Compared to Standard Management by Emergency Medical Services (BEST-MSU) study, and began enrolling patients in August 2014.

“Formal cost analysis would have to balance these costs [for the first year] plus costs for staffing and maintenance against any reduction in the total hospital and long-term care costs to the healthcare system for each patient with an ischemic stroke treated on the MSU, estimated to average approximately $140,000 per patient in 1999 US dollars, undoubtedly much higher today,” wrote Dr Grotta and his colleagues in a paper published in JAMA Neurology (Rajan S, et al. JAMA Neurol. 2015; 72:229-234).

They also posit that the vascular neurologist who currently rides with other staff on the MSU should be replaced by a remote vascular neurologist to reduce costs. n

Continued from page 10

those in the control group. Furthermore, the total healthcare and social-care costs for patients whose caregivers were in the intervention arm were significantly lower. The cost for QALY was similar in the 2 groups.

Investigators did not calculate the incremental cost-effective ratio because “the carer training was clearly the more desirable option, with both lower costs and better outcomes,” noted Dr Heslin and her coauthors.

Of the 2 other studies that included some economic analyses, one was the

MAY 2015

at a glance

same study referenced in the 2008 Cochrane review (Kalra L, et al. BMJ. 2004;328:1099). It was conducted in the United Kingdom and involved the same intervention as the aforementioned study with full economic analysis. The third study was conducted in the United States and compared an intervention known as Caring Web to a nonweb intervention (Patel A, et al. BMJ. 2004;328:1102). Both found the intervention was associated with lower costs and better or equal patient outcomes compared with control conditions. n

www.ValueBasedNeurology.com

11

Epilepsy

Nonpsychoactive Cannabidiol Helps Children with Severe Epilepsy

By Chase Doyle Washington, DC—Patients with treatment-resistant epilepsy may benefit from a treatment regimen that includes cannabidiol (Epidiolex), a compound in medical marijuana that does not contain psychoactive properties. According to results of a multicenter study presented at the 2015 annual meeting of the American Academy of Neurology, more than half of all patients who received cannabidiol experienced a 50% reduction in seizures.

“Cannabidiol showed reductions in seizure frequency across multiple drug-resistant epilepsy syndromes and seizure types and was generally well-tolerated in this open-label cohort,” said Matthew Wong, MD, Assistant Professor of Neurology at Wake Forest School of Medicine, Winston-Salem, NC. According to the Centers for Disease Control and Prevention, approximately 5.1 million individuals in the United States have been diagnosed with epilepsy. About one-third of these patients experience seizures that cannot be controlled by medication. Severe forms of epilepsy, such as Lennox-Gastaut syn-

drome and Dravet syndrome, are marked by frequent, treatment-resistant seizures.

Cannabidiol is the most abundant nonpsychoactive component of Cannabis sativa and has shown anticonvulsant activity in preclinical models of epilepsy, independent of activity at known endogenous cannabinoid receptors, Dr Wong said. Anecdotal reports suggest that cannabidiol may be effective in treating children with treatment-resistant epilepsies, in particular Dravet syndrome, but the compound has rarely been studied in formal clinical trials.

The new study included 213 patients aged 2 to 26 years (median age, 11 years), and was conducted at 11 US centers that were granted FDA-approved open-label expanded access. To qualify for this study, patients had to have an early-onset, treatment-resistant epileptic condition, such as LennoxGastaut or Dravet syndrome.

Patients first entered into a 4-week, baseline phase where caregivers tracked countable motor seizures as well as other seizure types. After 4 weeks, patients

received a 99% pure, oil-based extract of cannabidiol, which was titrated until intolerance to a maximum daily dose of 25 mg/kg.

“All patients were prescribed cannabidiol in a liquid daily dose that was gradually increased up to a potential maximum of 25 mg/kg for 12 weeks,” explained Dr Wong. “Seizures were recorded as convulsive (countable) or nonconvulsive. Atonic seizures were also specifically recorded.”

Study Results

Of the 137 patients who received at least 12 weeks of treatment, the number of seizures was reduced by a median of 54% during the 12-week period in all patients; the number of seizures in patients with Dravet syndrome decreased by 63%. A 50% responder analysis demonstrated that 51% of patients who completed the study had at least a 50% decrease in seizures. Dr Wong noted that at 3 months, 9% of all patients were seizure-free; 16% of patients with Dravet syndrome were seizure-free. In addition, there was a 66.7% decrease in

the number of atonic seizures.

Surveillance laboratory tests were performed to identify problems with liver and kidney function, as well as anti­ epileptic drug levels. The most common adverse events that occurred in more than 10% of patients who received cannabidiol included somnolence (21%), diarrhea (17%), fatigue (17%), and decreased appetite (16%). Serious adverse events occurred in 52 patients; 22 patients experienced serious adverse events that were possibly related to cannabidiol use, the most common of which included status epilepticus (N = 10) and diarrhea (N = 3). Overall, 10 (5%) patients discontinued the use of cannabidiol as a result of adverse events.

Future research with cannabidiol will include randomized, placebo-controlled clinical trials, Dr Wong said.

“Treatment with cannabidiol is associated with a meaningful reduction in seizure frequency in patients with severe treatment-resistant epilepsy,” Dr Wong said. “The tolerability also seemed good, with very few withdrawals due to adverse events.” n

In the Literature Epstein-Barr Virus Genetic Variants Associated... Continued from page 9

sclerosis (Mechelli R, et al. Neurology.

2015;84:1362-1368).

“Despite converging evidence supporting an etiologic role for EBV in MS [multiple sclerosis], we still do not know through which mechanisms the virus may contribute to disease development,” said Rosella Mechelli, PhD, Centre for Experimental Neurological Therapies, Sapienza University, Rome, Italy.

The researchers analyzed the Epstein-Barr nuclear antigen (EBNA) 2 gene, which contains the most variable region of the viral genome, in patients with multiple sclerosis. EBNA2 is considered the best candidate for this kind of study, because it is the most polymorphic among all EBV genes, interacts with host proteins, and may have functional consequences.

The frequency of the EBNA2 gene in 53 patients with multiple sclerosis was compared with that of 38 matched healthy individuals to verify whether virus genetic variants are involved in the disease. The researchers used a seminested polymerase chain reaction

12

approach, Sanger sequencing, and, in a subgroup of controls, high-throughput sequencing by Illumina MiSeq. Patients underwent gadolinium-enhanced magnetic resonance imaging (MRI) and human leukocyte antigen (HLA) typing. The study controlled for HLA haplotype and clinical and MRI features.

The number of new variants was higher than expected. Multiple sclerosis status correlated with an excess of the EBNA2 1.2 allele (odds ratio [OR], 5.13; P = .016) and an underrepresentation of the 1.3B allele (OR, 0.23; P = .0006).

Furthermore, patients with multiple sclerosis were also more likely than healthy individuals to harbor newly identified 1.2 allele-related variants, particularly at amino acid position 245.

“By investigating a region of ENBA2 that previous studies in MS cohorts did not investigate, we have detected MS-associated EBV genetic variations that are stronger than those previously reported and seem to be independent of the donors’ HLA haplotype,” the researchers wrote, concluding that a “complex interplay between both host and viral genetic variants may contribute to disease development.”

VALUE-BASED CARE IN NEUROLOGY

I MAY 2015

Brain’s “Lightning Bolts” Indicate Learning

Lightning bolt images in the dendrites of brain cells may reveal how the brain sorts, stores, and interprets information during learning, according to researchers at New York University (NYU) Langone Medical Center (Cichon J, Gan WB. Nature. 2015;520: 180-185).

Lead author Joseph Cichon, MS, a neuroscience doctoral candidate at NYU Langone Medical Center, and his colleagues captured images of the underlying biologic activity within brain cells and dendrites of mice. Neuronal activity in dendritic nerve branches was tracked as the mice learned motor tasks, such as how to run forward and backward on a treadmill. These newly learned motor tasks appeared to induce completely separate lightning bolt patterns in the dendrites, which were the visual manifestation of calcium ion spikes. These spikes triggered chainlike reactions that were tied to the strengthening or weakening of connections between neurons––the hallmarks of learning new information.

The study also identified a unique

type of brain cell that controlled the location of these spikes. When these cells were turned off, the lightning bolt patterns were disrupted. As a result, the animals appeared to lose the information they had just learned.

Senior researcher Wen-Biao Gan, PhD, said in a press release, “We believe our study provides important insights into how the brain deals with vast amounts of information continuously as the brain learns new tasks….

We have long wondered how the brain can store new information continuously throughout life without disrupting previously acquired memories.

We now know that the generation of calcium spikes in separate branches of nerve cells is critical for the brain to encode and store large quantities of information without interfering with each other.”

These discoveries could have impor­ tant implications for explaining the underlying neural circuit problems in disorders such as autism and schizophrenia. The investigators’ next steps will be to determine if the calcium ion spikes are malfunctioning in animal models of brain disorders. n

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t: None f: None in severity to affect daily tasks, Alzheimer’s disease affects an estimated 5.2 million individuals in the United States.

The approved therapy combines 2 medications that are frequently prescribed together—approximately 70% of patients who have been prescribed memantine hydrochloride (Namenda XR) extended-release capsules are also

taking an acetylcholinesterase inhibitor such as donepezil hydrochloride (Aricept). The approved drug represents the first fixed-dose combination of extended-release memantine hydrochloride and donepezil hydrochloride.

The capsule can be swallowed once daily or opened to allow the contents to be sprinkled on food for patients who Continued on page 14

AUBAGIO® (teriflunomide) tablets, for oral use

Rx Only

Brief Summary of Prescribing Information WARNING: HEPATOTOXICITY and RISK OF TERATOGENICITY Hepatotoxicity Severe liver injury including fatal liver failure has been reported in patients treated with leflunomide, which is indicated for rheumatoid arthritis. A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Concomitant use of AUBAGIO with other potentially hepatotoxic drugs may increase the risk of severe liver injury. Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)]. If drug induced liver injury is suspected, discontinue AUBAGIO and start an accelerated elimination procedure with cholestyramine or charcoal [see Warnings and Precautions (5.3)].

AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)]. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Risk of Teratogenicity Based on animal data, AUBAGIO may cause major birth defects if used during pregnancy. Pregnancy must be excluded before starting AUBAGIO. AUBAGIO is contraindicated in pregnant women or women of childbearing potential who are not using reliable contraception. Pregnancy must be avoided during AUBAGIO treatment or prior to the completion of an accelerated elimination procedure after AUBAGIO treatment [see Contraindications (4.2), Warnings and Precautions (5.2), and Use in Specific Populations (8.1)].

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1 INDICATIONS AND USAGE AUBAGIO® is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

2 DOSAGE AND ADMINISTRATION The recommended dose of AUBAGIO is 7 mg or 14 mg orally once daily. AUBAGIO can be taken with or without food.

Monitoring to assess safety • Obtain transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO [see Warnings and Precautions (5.1)].

• Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms of infection [see Warnings and Precautions (5.4)].

• Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or blood test for mycobacterium tuberculosis infection [see Warnings and Precautions (5.4)].

• Check blood pressure before start of AUBAGIO treatment and periodically thereafter [see Warnings and Precautions (5.7)].

4 CONTRAINDICATIONS 4.1. Severe Hepatic Impairment Patients with severe hepatic impairment [see Warnings and Precautions (5.1)].

4.2 Patients Who are Pregnant or Women of Childbearing Potential Not Using Reliable Contraception AUBAGIO may cause fetal harm when administered to a pregnant woman.

In animal studies, teriflunomide has been shown to be selectively teratogenic and embryolethal in multiple species when administered during pregnancy at doses less than those used clinically. Nonclinical studies indicate further that the intended pharmacologic action of the drug is involved in the mechanism of developmental toxicity [see Use in Specific Populations (8.1)].

AUBAGIO is contraindicated in women who are pregnant or women of child bearing potential not using reliable contraception. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, the drug should be immediately discontinued and an accelerated elimination procedure should be initiated [see Warnings and Precautions (5.3)]. Under these conditions, the patient should be referred to an obstetrician/gynecologist, preferably experienced in reproductive toxicity, for further evaluation and counseling [see Warnings and Precautions and Use in Specific Populations (5.2, 8.1)].

4.3. Current treatment with leflunomide Co-administration of teriflunomide with leflunomide is contraindicated.

5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Severe liver injury including fatal liver failure and dysfunction has been reported in some patients treated with leflunomide, which is indicated for rheumatoid arthritis.

A similar risk would be expected for teriflunomide because recommended doses of teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide. Patients with pre-existing liver disease may be at increased risk of developing elevated serum transaminases when taking AUBAGIO. Patients with

pre-existing acute or chronic liver disease, or those with serum alanine aminotransferase (ALT) greater than two times the upper limit of normal (ULN) before initiating treatment, should not normally be treated with AUBAGIO. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1)].

In placebo-controlled trials, ALT greater than three times the ULN occurred in 61/1045 (5.8%) and 62/1002 (6.2%) of patients receiving AUBAGIO 7 mg and 14 mg, respectively, and 38/997 (3.8%) of patients receiving placebo, during the treatment period. These elevations occurred mostly within the first year of treatment.

Half of the cases returned to normal without drug discontinuation. In clinical trials, if ALT elevation was greater than three times the ULN on two consecutive tests, AUBAGIO was discontinued and patients underwent an accelerated elimination procedure [see Warnings and Precautions (5.3)]. Of the patients who underwent discontinuation and accelerated elimination in controlled trials, half returned to normal or near normal values within 2 months.

One patient in the controlled trials developed ALT 32 times the ULN and jaundice 5 months after initiation of AUBAGIO 14 mg treatment. The patient was hospitalized for 5 weeks and recovered after plasmapheresis and cholestyramine accelerated elimination procedure. AUBAGIO-induced liver injury in this patient could not be ruled out.

Obtain serum transaminase and bilirubin levels within 6 months before initiation of AUBAGIO therapy. Monitor ALT levels at least monthly for six months after starting AUBAGIO. Consider additional monitoring when AUBAGIO is given with other potentially hepatotoxic drugs. Consider discontinuing AUBAGIO if serum transaminase increase (greater than three times the ULN) is confirmed. Monitor serum transaminase and bilirubin on AUBAGIO therapy, particularly in patients who develop symptoms suggestive of hepatic dysfunction, such as unexplained nausea, vomiting, abdominal pain, fatigue, anorexia, or jaundice and/or dark urine. If liver injury is suspected to be AUBAGIO-induced, discontinue AUBAGIO and start an accelerated elimination procedure [see Warnings and Precautions (5.3)] and monitor liver tests weekly until normalized. If AUBAGIO-induced liver injury is unlikely because some other probable cause has been found, resumption of AUBAGIO therapy may be considered.

5.2 Use in Women of Childbearing Potential There are no adequate and well-controlled studies evaluating AUBAGIO in pregnant women. However, based on animal studies, teriflunomide may increase the risk of teratogenic effects or fetal death when administered to a pregnant woman [see Contraindications (4.2)].

Women of childbearing potential must not be started on AUBAGIO until pregnancy is excluded and it has been confirmed that they are using reliable contraception.

Before starting treatment with AUBAGIO, patients must be fully counseled on the potential for serious risk to the fetus. The patient must be advised that if there is any delay in onset of menses or any other reason to suspect pregnancy, they must notify the physician immediately for pregnancy testing and, if positive, the physician and patient must discuss the risk to the fetus. It is possible that rapidly lowering the plasma concentration of teriflunomide by instituting an accelerated elimination procedure may decrease the risk to the fetus from AUBAGIO [see Warnings and Precautions (5.3)].

Upon discontinuing AUBAGIO, it is recommended that all women of childbearing potential undergo an accelerated elimination procedure. Women receiving AUBAGIO treatment who wish to become pregnant must discontinue AUBAGIO and undergo an accelerated elimination procedure, which includes verification of teriflunomide plasma concentrations less than 0.02 mg/L (0.02 mcg/mL). Human plasma concentrations of teriflunomide less than 0.02 mg/L (0.02 mcg/mL) are expected to have minimal risk [see Contraindications (4.2), Warnings and Precautions (5.3) and Use in Specific Populations (8.1)].

5.3 Procedure for Accelerated Elimination of Teriflunomide Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, it takes on average 8 months to reach plasma concentrations less than 0.02 mg/L, although because of individual variations in drug clearance it may take as long as 2 years. An accelerated elimination procedure could be used at any time after discontinuation of AUBAGIO. Elimination can be accelerated by either of the following procedures: • Administration of cholestyramine 8 g every 8 hours for 11 days. If cholestyramine 8 g three times a day is not well tolerated, cholestyramine 4 g three times a day can be used.

• Administration of 50 g oral activated charcoal powder every 12 hours for 11 days.

If either elimination procedure is poorly tolerated, treatment days do not need to be consecutive unless there is a need to lower teriflunomide plasma concentration rapidly.

At the end of 11 days, both regimens successfully accelerated teriflunomide elimination, leading to more than 98% decrease in teriflunomide plasma concentrations.

Use of the accelerated elimination procedure may potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment.

5.4 Bone Marrow Effects/Immunosuppression Potential/Infections White Blood Cell (WBC) count decrease A mean decrease in white blood cell (WBC) count of approximately 15% (mainly neutrophils and lymphocytes) and in platelet count of approximately 10% was observed in placebo-controlled trials with 7 mg and 14 mg of AUBAGIO compared to baseline. The decrease in mean WBC count occurred during the first 6 weeks and WBC count remained low during treatment. In placebo-controlled studies, neutrophil count < 1.5×109/L was observed in 12% and 16% of patients receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 7% of patients receiving placebo; lymphocyte count <0.8×109/L was observed in 10% and 12% of patients

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Namzaric, a Single-Capsule Creative:cal Director at ATP Clinical Research in TER-BPLR-SA-OCT14 Combination... Continued from page 13AE: Costa Mesa, CA, and volunteer faculty Diana Cohen have difficulty swallowing.

“When determining therapies for my patients in the moderate to severe stages of Alzheimer’s disease, I consider the therapy’s effectiveness, safety profile, and ease of administration,” said Gustavo Alva, MD, Neuropsychiatrist and Medi-

member at the University of California, Irvine. “The FDA’s approval of Namzaric offers a new therapeutic option that provides patients a fixed-dose combination of two treatments often prescribed together, in one capsule.”

The capsule will be available in 2

VALUE-BASED CARE IN NEUROLOGY

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dosage Brief strengths, with 10 mg of doneSummary pezil hydrochloride combined with 14 bleed = 8.5” X 11.125” mg or 28 mg of memantine hydrochlotrim = 7.75” X 10.75” ride extended release; both medicasafety = 7” X 10” tions in the combination therapy have B:8.5” in the treatment demonstrated efficacy T:7.75” of patients with moderate to severe S:7” Data have also Alzheimer’s disease. demonstrated that this combination

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receiving AUBAGIO 7 mg and 14 mg, respectively, compared with 6% of patients receiving placebo. No cases of serious pancytopenia were reported in premarketing clinical trials of AUBAGIO but rare cases of pancytopenia, agranulocytosis, and thrombocytopenia have been reported in the postmarketing setting with leflunomide.

A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3) in the full prescribing information]. Obtain a complete blood cell count (CBC) within 6 months before the initiation of treatment with AUBAGIO. Further monitoring should be based on signs and symptoms suggestive of bone marrow suppression.

Risk of Infection / Tuberculosis Screening Patients with active acute or chronic infections should not start treatment until the infection(s) is resolved. If a patient develops a serious infection consider suspending treatment with AUBAGIO and using an accelerated elimination procedure. Reassess the benefits and risks prior to resumption of therapy. Instruct patients receiving AUBAGIO to report symptoms of infections to a physician.

AUBAGIO is not recommended for patients with severe immunodeficiency, bone marrow disease, or severe, uncontrolled infections. Medications like AUBAGIO that have immunosuppression potential may cause patients to be more susceptible to infections, including opportunistic infections.

In placebo-controlled studies of AUBAGIO, no overall increase in the risk of serious infections was observed with AUBAGIO 7 mg (2.2%) or 14 mg (2.7%) compared to placebo (2.2%). However, one fatal case of klebsiella pneumonia sepsis occurred in a patient taking AUBAGIO 14 mg for 1.7 years. Fatal infections have been reported in the post-marketing setting in patients receiving leflunomide, especially Pneumocystis jiroveci pneumonia and aspergillosis. Most of the reports were confounded by concomitant immunosuppressant therapy and/or comorbid illness which, in addition to rheumatoid disease, may predispose patients to infection. In clinical studies with AUBAGIO, cytomegalovirus hepatitis reactivation has been observed.

In clinical studies with AUBAGIO, cases of tuberculosis have been observed. Prior to initiating AUBAGIO, screen patients for latent tuberculosis infection with a tuberculin skin test or with a blood test for mycobacterium tuberculosis infection.

AUBAGIO has not been studied in patients with a positive tuberculosis screen, and the safety of AUBAGIO in individuals with latent tuberculosis infection is unknown.

For patients testing positive in tuberculosis screening, treat by standard medical practice prior to therapy with AUBAGIO. Vaccination No clinical data are available on the efficacy and safety of live vaccinations in patients taking AUBAGIO. Vaccination with live vaccines is not recommended. The long half-life of AUBAGIO should be considered when contemplating administration of a live vaccine after stopping AUBAGIO. Malignancy The risk of malignancy, particularly lymphoproliferative disorders, is increased with the use of some immunosuppressive medications. There is a potential for immunosuppression with AUBAGIO. No apparent increase in the incidence of malignancies and lymphoproliferative disorders was reported in the AUBAGIO clinical trials, but larger and longer-term studies would be needed to determine whether there is an increased risk of malignancy or lymphoproliferative disorders with AUBAGIO. 5.5 Peripheral Neuropathy In placebo-controlled studies, peripheral neuropathy, including both polyneuropathy and mononeuropathy (e.g., carpal tunnel syndrome), occurred more frequently in patients taking AUBAGIO than in patients taking placebo. The incidence of peripheral neuropathy confirmed by nerve conduction studies was 1.4% (13 patients) and 1.9% (17 patients) of patients receiving 7 mg and 14 mg of AUBAGIO, respectively, compared with 0.4% receiving placebo (4 patients). Treatment was discontinued in 0.7% (8 patients) with confirmed peripheral neuropathy (3 patients receiving AUBAGIO 7 mg and 5 patients receiving AUBAGIO 14 mg). Five of them recovered following treatment discontinuation. Not all cases of peripheral neuropathy resolved with continued treatment. Peripheral neuropathy also occurred in patients receiving leflunomide.

Age older than 60 years, concomitant neurotoxic medications, and diabetes may increase the risk for peripheral neuropathy. If a patient taking AUBAGIO develops symptoms consistent with peripheral neuropathy, such as bilateral numbness or tingling of hands or feet, consider discontinuing AUBAGIO therapy and performing an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.6 Skin Reactions Rare cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients with rheumatoid arthritis receiving leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3) in the full prescribing information]. If a patient taking AUBAGIO develops any of these conditions, stop AUBAGIO therapy and perform an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.7 Increased Blood Pressure In placebo-controlled studies, the mean change from baseline to the end of study in systolic blood pressure was +2.3 mmHg and +2.7 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.6 mmHg for placebo. The change from baseline in diastolic blood pressure was +1.4 mmHg and +1.9 mmHg for AUBAGIO 7 mg and 14 mg, respectively, and -0.3 mmHg for placebo. Hypertension was an adverse reaction in 3.1% and 4.3% of patients treated with 7 mg or 14 mg of AUBAGIO compared with 1.8% for placebo. Check blood pressure before start of AUBAGIO treatment and periodically thereafter. Elevated blood pressure should be appropriately managed during treatment with AUBAGIO. 5.8 Respiratory Effects Interstitial lung disease and worsening of pre-existing interstitial lung disease have been reported during treatment with leflunomide. A similar risk would be expected for AUBAGIO [see Clinical Pharmacology (12.3) in the full prescribing information].

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therapy t:leads to greater improvements None f: None in cognition and global function compared with an acetylcholinesterase inhibitor alone.

The efficacy and safety of coadministering acetylcholinesterase inhibitors such as donepezil hydrochloride with memantine hydrochloride extendedrelease were demonstrated in a random-

AUBAGIO® (teriflunomide) tablets, for oral use Interstitial lung disease may be fatal. Interstitial lung disease may occur acutely at any time during therapy and has a variable clinical presentation. New onset or worsening pulmonary symptoms, such as cough and dyspnea, with or without associated fever, may be a reason for discontinuation of the therapy and for further investigation as appropriate. If discontinuation of the drug is necessary, consider initiation of an accelerated elimination procedure [see Warnings and Precautions (5.3)].

5.9 Concomitant Use with Immunosuppressive or Immunomodulating Therapies Co-administration with antineoplastic, or immunosuppressive therapies used for treatment of multiple sclerosis has not been evaluated. Safety studies in which AUBAGIO was concomitantly administered with other immune modulating therapies for up to one year (interferon beta, glatiramer acetate) did not reveal any specific safety concerns. The long term safety of these combinations in the treatment of multiple sclerosis has not been established.

In any situation in which the decision is made to switch from AUBAGIO to another agent with a known potential for hematologic suppression, it would be prudent to monitor for hematologic toxicity, because there will be overlap of systemic exposure to both compounds. Use of an accelerated elimination procedure may decrease this risk, but may also potentially result in return of disease activity if the patient had been responding to AUBAGIO treatment [see Warnings and Precautions (5.3)].

6 ADVERSE REACTIONS The following serious adverse reactions are described elsewhere in the prescribing information: • Hepatotoxicity [see Contraindications (4.1) and Warnings and Precautions (5.1)] • Bone Marrow Effects/Immunosuppression Potential/Infections [see Warnings and Precautions (5.4)] • Peripheral Neuropathy [see Warnings and Precautions (5.5)] • Skin Reactions [see Warnings and Precautions (5.6)] • Increased Blood Pressure [see Warnings and Precautions (5.7)] • Respiratory Effects [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

A total of 2047 patients receiving AUBAGIO (7 mg or 14 mg once daily) constituted the safety population in the pooled analysis of placebo controlled studies in patients with relapsing forms of multiple sclerosis; of these, 71% were female. The average age was 37 years.

Table 1 lists adverse reactions in placebo-controlled trials with rates that were at least 2% for AUBAGIO patients and also at least 2% above the rate in placebo patients. The most common were headache, an increase in ALT, diarrhea, alopecia, and nausea. The adverse reaction most commonly associated with discontinuation was an increase in ALT (3.3%, 2.6%, and 2.3% of all patients in the AUBAGIO 7 mg, AUBAGIO 14 mg, and placebo treatment arms, respectively).

Table 1. Adverse Reactions in Pooled Placebo-Controlled Studies in Patients with Relapsing Forms of Multiple Sclerosis AUBAGIO AUBAGIO 7 mg 14 mg Placebo Adverse Reaction (N=1045) (N=1002) (N=997) Headache 18% 16% 15% Increase in Alanine aminotransferase 13% 15% 9% Diarrhea 13% 14% 8% Alopecia 10% 13% 5% Nausea 8% 11% 7% Paresthesia 8% 9% 7% Arthralgia 8% 6% 5% Neutropenia 4% 6% 2% Hypertension 3% 4% 2% Cardiovascular deaths Four cardiovascular deaths, including three sudden deaths, and one myocardial infarction in a patient with a history of hyperlipidemia and hypertension were reported among approximately 2600 patients exposed to AUBAGIO in the premarketing database. These cardiovascular deaths occurred during uncontrolled extension studies, one to nine years after initiation of treatment. A relationship between AUBAGIO and cardiovascular death has not been established.

Acute Renal Failure In placebo-controlled studies, creatinine values increased more than 100% over baseline in 8/1045 (0.8%) patients in the 7 mg AUBAGIO group and 6/1002 (0.6%) patients in the 14 mg AUBAGIO group versus 4/997 (0.4%) patients in the placebo group. These elevations were transient. Some elevations were accompanied by hyperkalemia. AUBAGIO may cause acute uric acid nephropathy with transient acute renal failure because AUBAGIO increases renal uric acid clearance.

Hypophosphatemia In clinical trials, 18% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels of at least 0.6 mmol/L, compared to 7% of placebo-treated

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ized,Dianadouble-blind, placebo-controlled Cohen clinical trial involving 677 patients with moderate to severe Alzheimer’s disease who were taking a stable dose of acetylcholinesterase inhibitors. In this clinical trial, patients were randomized to receive 28 mg of memantine hydrochloride extended-release or placebo, with 68% of patients taking donepezil

at baseline and throughout the study. bleed = 8.5” X 11.125” There was a significant improvement trim = 7.75” X 10.75” in cognition and global function with safety = 7” X 10” memantine hydrochloride extendedrelease capsules B:8.5” coadministered with T:7.75”inhibitors versus acetylcholinesterase acetylcholinesterase S:7” inhibitors alone.

Frequently observed adverse events in patients taking the combination thera-

Dyloject Gets FDA Approval for Pain Management

The FDA approved diclofenac sodium (Dyloject; Hospira) injection, a proprietary nonsteroidal anti-inflammatory drug (NSAID) analgesic, for the treat-

AUBAGIO® (teriflunomide) tablets, for oral use AUBAGIO and undergo an accelerated elimination procedure to decrease the plasma concentration of teriflunomide to less than 0.02 mg/L (0.02 mcg/mL) [see Warnings and Precautions (5.3)].

Pregnancy Registry Although AUBAGIO is contraindicated in pregnancy, a pregnancy registry has been established to monitor fetal outcomes of pregnant women exposed to AUBAGIO. Physicians are encouraged to enroll pregnant women in the AUBAGIO pregnancy registry, or pregnant women may enroll themselves, by calling 1-800-745-4447, option 2.

8.3 Nursing Mothers Teriflunomide was detected in rat milk following a single oral dose of teriflunomide.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from AUBAGIO a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of AUBAGIO did not include patients over 65 years old.

8.6 Hepatic Impairment No dosage adjustment is necessary for patients with mild and moderate hepatic impairment. The pharmacokinetics of teriflunomide in severe hepatic impairment have not been evaluated. AUBAGIO is contraindicated in patients with severe hepatic impairment [see Contraindications (4.1) Warnings and Precautions (5.1), and Clinical Pharmacology (12.3) in the full prescribing information].

8.7 Renal Impairment No dosage adjustment is necessary for patients with mild, moderate, and severe renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

10 OVERDOSAGE There is no experience regarding teriflunomide overdose or intoxication in humans.

Teriflunomide 70 mg daily up to 14 days was well tolerated by healthy subjects.

In the event of clinically significant overdose or toxicity, cholestyramine or activated charcoal is recommended to accelerate elimination [see Warnings and Precautions (5.3)].

Genzyme Corporation 500 Kendall Street Cambridge, MA 02142 A SANOFI COMPANY October 2014a TER-BPLR-SA-OCT14

ment of adult patients with mild to moderate pain, and moderate to severe pain alone or in combination with opioid analgesics. Diclofenac sodium injection is administered via a small-volume intravenous bolus for 15 seconds.

The FDA approval of diclofenac sodium injection for pain management was based on 2 double-blind, placebocontrolled, multidose clinical trials of adults with postoperative pain. In both trials, intravenous morphine was permitted as rescue medication for pain management. In 1 clinical trial, 245 patients who had undergone abdominal or pelvic surgery received diclofenac sodium, a positive NSAID control, or placebo every 6 hours after surgery for up to 5 days. Overall, there was a greater reduction in pain intensity in patients who received diclofenac sodium injection compared with patients who received placebo. In addition, approximately 63% of patients who received diclofenac sodium took rescue medication within the first 48 hours, compared with 92% of patients who received the placebo.

In the second clinical trial, 277 patients with postoperative pain who underwent orthopedic surgery received diclofenac sodium, a positive NSAID control, or placebo every 6 hours after surgery for up to 5 days. Approximately 74% of patients who received diclofenac sodium took rescue medication within the first 48 hours, compared with 92% of patients who received the placebo, and there was a greater reduction in pain intensity in patients who received diclofenac sodium injection versus patients who received placebo.

“In today’s healthcare environment, pain management and patient satisfaction are important to hospitals. As a result, various medical organizations are now recommending a multimodal approach to pain control in an effort to minimize the use of opioids,” said Sumant Ramachandra, MD, PhD, Senior Vice President and Chief Scientific Officer, Hospira. “As a leading supplier of hospital pain management medication, Hospira’s Dyloject will be a complementary addition to our existing portfolio of acute-care drugs, providing clinicians an additional nonopioid option that can be administered quickly and conveniently to treat pain.”

The most common adverse events reported with diclofenac sodium injection include nausea, constipation, headache, infusion-site pain, dizziness, flatulence, vomiting, and insomnia.

Diclofenac sodium injection includes a boxed warning stating that the use of this medication is associated with serious cardiovascular events (ie, myocardial infarction or stroke) and gastrointestinal events (ie, bleeding, ulceration, and perforation of the stomach or intestines). (December 30, 2014) n

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py included headache, diarrhea, and dizziness. (December 24, 2014)

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patients; 4% of AUBAGIO-treated patients had hypophosphatemia with serum phosphorus levels at least 0.3 mmol/L but less than 0.6 mmol/L, compared to 0.8% of placebo-treated patients. No patient in any treatment group had a serum phosphorus below 0.3 mmol/L. 7 DRUG INTERACTIONS Effect of AUBAGIO on CYP2C8 substrates Teriflunomide is an inhibitor of CYP2C8 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP2C8 (e.g., paclitaxel, pioglitazone, repaglinide, rosiglitazone) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP2C8 as required [see Clinical Pharmacology (12.3) in the full prescribing information].

Effect of AUBAGIO on warfarin Coadministration of AUBAGIO with warfarin requires close monitoring of the international normalized ratio (INR) because AUBAGIO may decrease peak INR by approximately 25%.

Effect of AUBAGIO on oral contraceptives AUBAGIO may increase the systemic exposures of ethinylestradiol and levonorgestrel. Consideration should be given to the type or dose of contraceptives used in combination with AUBAGIO [see Clinical Pharmacology (12.3) in the full prescribing information].

Effect of AUBAGIO on CYP1A2 substrates Teriflunomide may be a weak inducer of CYP1A2 in vivo. In patients taking AUBAGIO, exposure of drugs metabolized by CYP1A2 (e.g., alosetron, duloxetine, theophylline, tizanidine) may be reduced. Monitor these patients and adjust the dose of the concomitant drug(s) metabolized by CYP1A2 as required [see Clinical Pharmacology (12.3) in the full prescribing information].

Effect of AUBAGIO on organic anion transporter 3 (OAT3) substrates Teriflunomide inhibits the activity of OAT3 in vivo. In patients taking AUBAGIO, exposure of drugs which are OAT3 substrates (e.g., cefaclor, cimetidine, ciprofloxacin, penicillin G, ketoprofen, furosemide, methotrexate, zidovudine) may be increased. Monitor these patients and adjust the dose of the concomitant drug(s) which are OAT3 substrates as required [see Clinical Pharmacology (12.3) in the full prescribing information].

Effect of AUBAGIO on BCRP and organic anion transporting polypeptide B1 and B3 (OATP1B1/1B3) substrates Teriflunomide inhibits the activity of BCRP and OATP1B1/1B3 in vivo. For a patient taking AUBAGIO, the dose of rosuvastatin should not exceed 10 mg once daily. For other substrates of BCRP (e.g., mitoxantrone) and drugs in the OATP family (e.g., methotrexate, rifampin), especially HMG-Co reductase inhibitors (e.g., atorvastatin, nateglinide, pravastatin, repaglinide, and simvastatin), consider reducing the dose of these drugs and monitor patients closely for signs and symptoms of increased exposures to the drugs while patients are taking AUBAGIO [see Clinical Pharmacology (12.3) in the full prescribing information].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Contraindications (4.2) and Warnings and Precautions (5.2)] When teriflunomide (oral doses of 1, 3, or 10 mg/kg/day) was administered to pregnant rats throughout the period of organogenesis, high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death were observed at doses not associated with maternal toxicity.

Adverse effects on embryofetal development were observed following dosing at various stages throughout organogenesis. Maternal plasma exposure at the noeffect level (1.0 mg/kg/day) for embryofetal developmental toxicity in rats was less than that in humans at the maximum recommended human dose (MRHD, 14 mg /day).

Administration of teriflunomide (oral doses of 1, 3.5, or 12 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in high incidences of fetal malformation (primarily craniofacial, and axial and appendicular skeletal defects) and embryofetal death at doses associated with minimal maternal toxicity. Maternal plasma exposure at the no-effect dose (1.0 mg/kg/day) for embryofetal developmental toxicity in rabbits was less than that in humans at the MRHD. In studies in which teriflunomide (oral doses of 0.05, 0.1, 0.3, 0.6, or 1.0 mg/kg/day) was administered to rats during gestation and lactation, decreased growth, eye and skin abnormalities, and high incidences of malformation (limb defects) and postnatal death were observed in the offspring at doses not associated with maternal toxicity.

Maternal plasma exposure at the no-effect dose for pre- and postnatal developmental toxicity in rats (0.10 mg/kg/day) was less than that in humans at the MRHD. In animal reproduction studies of leflunomide, embryolethality and teratogenic effects were observed in pregnant rat and rabbit at or below clinically relevant plasma teriflunomide exposures (AUC). In published reproduction studies in pregnant mice, leflunomide was embryolethal and increased the incidence of malformations (craniofacial, axial skeletal, heart and great vessel). Supplementation with exogenous uridine reduced the teratogenic effects in pregnant mice, suggesting that the mode of action (inhibition of mitochondrial enzyme dihydroorotate dehydrogenase) is the same for therapeutic efficacy and developmental toxicity. At recommended doses in humans, teriflunomide and leflunomide result in a similar range of plasma concentrations of teriflunomide.

Use in Males AUBAGIO is detected in human semen. Animal studies to specifically evaluate the risk of male-mediated fetal toxicity have not been conducted. To minimize any possible risk, men not wishing to father a child and their female partners should use reliable contraception. Men wishing to father a child should discontinue use of

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Health Economics

Preventing Disease Relapse in Patients with Multiple Sclerosis May Reduce Associated Costs

By Chase Doyle Washington, DC—In the year following a relapse, patients with multiple sclerosis remained less productive and their health deteriorated further compared with patients with multiple sclerosis whose disease had not relapsed, according to analyses presented at the 2015 annual meeting of the American Academy of Neurology.

“The work productivity of MS [multiple sclerosis] patients declined following a relapse,” reported the lead author of the study, Stefan Vormfelde, MD, PhD, Medical Advisor at Novartis Pharma GmbH in Nürnberg, Germany.

“One may bear this in mind when monitoring the disease status in relapsing-remitting MS patients. Escalating therapy early, however, may reduce such costs.”

Relapsing-remitting multiple sclerosis can be a devastating disease, with a significant impact on a patient’s health-related quality of life, Dr Vormfelde explained.

“The frequency of exacerbations and the natural progression of disability and neurologic compromise that occurs during the disease course results in considerable accumulation of medical costs and economic burden,” he said.

“Such problems have led to an ongoing discussion as to whether medical, patient, and healthcare costs caused by relapses warrant early escalation of pharma­co­therapy.”

The PEARL Study

The Prospective Pharmacoeconomic Cohort Evaluation (PEARL) trial is a 2-year, multicenter, noninterventional study involving 1705 patients with relapsing-remitting multiple sclerosis.

PEARL has focused on real-world aspects of healthcare for patients with

“Better relapse prevention by early escalation of therapy may reduce indirect costs related to reduced productivity and employment.”

—Stefan Vormfelde, MD, PhD

multiple sclerosis, describing the consequences of a multiple sclerosis relapse from an economic perspective by collecting resource utilization data from 163 neurology practices in Germany. To be included in the study, patients with relapsing-remitting multiple sclerosis were required to have been treated with interferon beta (N = 1214) or with glatiramer acetate (N = 491) for at least 30 days.

In the first year of study, 411 patients had relapsed disease at least once; these patients constituted the active group.

The remaining 1294 patients who did

not experience relapsed disease were the inactive group.

Patterns of Decline

Disability, as measured by the Expanded Disability Status Scale (EDSS), was worse in patients in the active group at baseline and deteriorated further for the duration of the study from a score of 2.5 to 3.0 on the EDSS. EDSS scores for patients in the inactive group deteriorated from a 2.2 to 2.4.

The mean annual relapse rate was 1.4 and 0.1 relapses annually during the 2-year period, in the active versus the inactive group, respectively.

As measured by the Clinical Global Impression improvement scale, health worsening peaked in active patients in the first study year and then remained elevated. Patients in the active group switched drug therapies more often than those in the inactive group (30% vs 12%, respectively) and rated their treatment to be less satisfactory than did patients in the inactive group.

Economic Implications

Having established a pattern of declining health status in the active group, Dr Vormfelde next examined the economic repercussions of disease relapse.

Data regarding employment status and work productivity; sick leave and absence from work; and hospitalization

and rehabilitation were presented in a separate analysis, which continued the depiction of impaired quality of life for patients in the active group.

“Employment declined in the active group from 58% to 53%,” reported Dr Vormfelde, “while it was stable for inactive patients (61%).”

Patients in the active group who were able to maintain employment still noted a significant impairment of their work productivity, tending to be absent from work more often than their inactive counterparts. Multiple sclerosis–related sick leave was frequent among those in the active group; the rate of sick leave in the inactive group, however, was reduced over time. Patients in the active group indicated that they felt continuously impaired, whereas patients in the inactive group recovered over time. Finally, patients in the active group tended to be hospitalized more frequently than were patients in the inactive group.

According to Dr Vormfelde, these discrepancies of health and economic productivity between patients with relapsing and nonrelapsing disease highlight the importance of avoiding relapse in the first place.

“Better relapse prevention by early escalation of therapy may reduce indirect costs related to reduced productivity and employment,” concluded Dr Vormfelde. n

Inpatient Care Coordination Could Impact Clinical Outcomes, Duration of Hospital Stays

By Chase Doyle Washington, DC—Clinical and in-hospital process variables are associated with hospital length of stay (LOS) in acute ischemic stroke patients, according to data presented at the 2015 annual meeting of the American Academy of Neurology. Specifically, results from the study demonstrate that coordination of inpatient care processes, combined with the assessment and treatment of comorbidities, could impact hospital LOS as well as long-term clinical outcomes.

“For mild ischemic stroke patients, time to therapy evaluations and likelihood of return to the emergency department were associated with length of stay, whereas the majority of clinical factors—including mRS [modified Rankin Scale], NIHSS [National Insti-

tutes of Health Stroke Scale] score, and infarct location—were not,” reported Sun Kim, MD, Assistant Professor of Medicine, Stanford University Medical Center, CA. “However, a greater percentage of those with more prolonged hospital LOS received intravenous (IV) tPA [tissue plasminogen activator], which likely impacted LOS.” The initial hospitalization of patients diagnosed with ischemic stroke significantly affects long-term outcomes and represents the majority of healthcare costs within the first year, Dr Kim explained. Poststroke care includes post-IV tPA monitoring, initiation of pharmacotherapies for stroke risk factor modification, correction of hemodynamic abnormalities, and obtainment of necessary

“These results suggest that coordination of inpatient care processes, in addition to assessing and treating comorbidities, could impact hospital LOS and, perhaps, long-term outcome such as recurrence of stroke or TIA.” —Sun Kim, MD

neuroimaging and other studies to help clarify the cause of ischemic stroke.

Services such as physical, occupa-

tional, and speech–language therapies are necessary to identify and treat physical barriers that are modifiable to avoid complications such as falls and aspiration, Dr Kim said.

“Optimization of the delivery of comprehensive poststroke care has a positive clinical and financial impact, including potentially reducing poststroke complications,” observed Dr Kim. “We hypothesize that hospital LOS is correlated with clinical characteristics, in-hospital care processes, and longterm clinical outcomes.”

Study Details

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Health Economics

Inpatient Costs for MS-Related Disease Relapse Higher for Males Than for Females

By Chase Doyle Washington, DC—The costs for inpatient care are significantly affected by the age and sex of patients with multiple sclerosis (MS) who experience disease relapse, according to data presented at the 2015 annual meeting of the American Academy of Neurology. The costs are greater for males than for females for all-cause hospitalizations, and these costs increase by age in both sexes.

“All-cause inpatient costs were higher for males than females, with costs increasing by age for both; however, cost for females increased at a greater rate with age.”

—Chris M. Kozma, PhD

“Among newly diagnosed patients with MS in a national database, inpatient rehabilitation stays had the highest cost compared with other diagnosis categories,” reported Chris M. Kozma, PhD, an independent research consultant and Adjunct Professor at the College of Pharmacy, University of South Carolina, Columbia. “And the cost of inpatient stays for all-cause and symptom-related diagnoses showed a significant age-by-sex effect.”

Relapses of MS can have a significant effect on patients’ quality of life and the management of costs related to treatment, according to Dr Kozma. Although recent literature has identified a

disparity in MS incidence, relapse rates, and disease characteristics based on the sex of the patient, the influence of age and sex on the cost and duration of inpatient encounters has not been well-studied.

“Essentially, using the IMS LifeLink dataset, we went in and identified those individuals who had an initial MS diagnosis,” said Amy Phillips of EMD Serono, who presented the findings, referring to the IMS LifeLink Health Plan Database. “We then looked at various ICD-9 [International Classification of Diseases, Ninth Revision] codes that might be indicative of a hospital-based relapse, stratifying by those different codes, whether it was an MS-specific code, other demyelinating disease, rehabilitation, or symptom-related visits. Finally, we examined the costs associated with those hospitalizations by that coding while looking at the effect of age and sex on those costs.”

A summation of costs per inpatient stay factored in the costs related to management services (provider costs related to the direct evaluation or management of a patient), surgical services, facility services, and ancillary services (cost of incidental services for the direct care of patients with MS). Researchers then evaluated the effects of age and sex on the average cost from the payer’s perspective and length of stay (LOS) per patient using a general linear model with robust variance estimation.

“We performed a cost model and a length-of-stay model, looking at the probability for effects on age and sex and age-by-sex interactions and identifying which of these had significant ef-

fects based on coding types within the hospitalization,” said Ms Phillips.

The study included 57,236 patients with MS, of whom 75% were female.

The mean age was approximately 46 years.

“Our analysis identifies the differences associated with age and sex on hospitalization costs, but we’d like to know what may have caused or driven those differences.”

—Amy Phillips

Effects of Inpatient Care on Cost

The average cost of inpatient stay was greatest for patients receiving rehabilitation services; treatment of symptom-related conditions led to the lowest costs. The models for all-cause and symptom-related costs of inpatient care,

Inpatient Care Coordination Could Impact... on a cohort of 95 patients admitted between September 2012 and September 2013 with a diagnosis of acute ischemic stroke and hospital LOS <3 days. Patients were grouped into 3 categories: patients with an LOS ≤1 day (group 1); patients with an LOS of >1 but ≤2 days (group 2); and patients with an LOS of >2 but ≤3 days (group 3).

“Clinical and demographic characteristics such as age, gender, premorbid mRS score, and vascular risk factors were recorded,” noted Dr Kim. “In-hospital variables such as time to obtain neurological consultation, time to initial CT [computed tomography] scan, time to

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initial MRI [magnetic resonance imaging], and time to various therapy services were also recorded and compared across groups. Return emergency department visits within 1 year of initial encounter were recorded for each group and differentiated by vascular versus other cause of return encounter.”

When comparing patients in group 1 versus groups 2 and 3, patients in group 1 had a significantly higher rate of history of stroke (35% vs 18%; P = .04).

There was no significant difference in the presence of other vascular risk factors, premorbid mRS, or initial NIHSS score. Patients in group 1 also received

Continued from page 16

significantly less IV tPA when compared with patients in groups 2 and 3.

There were no significant differences seen between groups in time to patients receiving an initial neurologic consultation or neuroimaging studies.

Key Opportunity for Improvement

The study’s most notable finding was that inpatient therapy evaluations took place later in patients with LOS >1 day (P <.01), suggesting opportunities for improvement for this process. Early discharge was also associated with improved clinical outcomes. Patients discharged within 1 day were less likely to

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controlling for age and sex, showed a significant age-by-sex interaction (P = .0007 and P = .0199, respectively), according to Dr Kozma.

“The age-by-sex interaction means that the cost of all-cause and symptom-related inpatient stays are different for males and females depending on how old they are,” noted Dr Kozma.

“All-cause inpatient costs were higher for males than females, with costs increasing by age for both; however, cost for females increased at a greater rate with age.”

Because LOS accounts for a substantial portion of costs associated with MS relapse, researchers also sought to describe the impact of age and sex on LOS for all-cause and MS-related in­ patient stays.

“For all-cause stays,” said Ms Phillips, “males had a greater LOS at all ages compared with females, showing a similar trend as the cost analysis….The cost of inpatient stays and LOS for MSrelated diagnoses was significantly associated with an age effect.”

Although this study investigated the effects of age and sex on costs associated with relapsed disease, Ms Phillips acknowledged several variables not factored into the analysis that may affect costs related to patient hospitalizations (eg, comorbidities, disease severity, and current treatment). Despite these findings, questions still remain for researchers.

“Our analysis identifies the differences associated with age and sex on hospitalization costs,” concluded Ms Phillips, “but we’d like to know what may have caused or driven those differences.” n

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return to the emergency department within 1 year of an event than patients discharged after a longer LOS. Although there was no significant difference in return emergency department visits for cardiac disease within 1 year, there was less recurrent stroke or transient ischemic attack (TIA) in group 1 (0% vs 12%; P <.01).

“These results,” concluded Dr Kim, “suggest that coordination of inpatient care processes, in addition to assessing and treating comorbidities, could impact hospital LOS and, perhaps, longterm outcome such as recurrence of stroke or TIA.” n

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Parkinson’s Disease

Differences in Disease Burden Examined

By Chase Doyle Washington, DC—Those looking for equality based on race and sex won’t find it in the treatment of Parkinson’s disease. According to a study presented at the 2015 annual meeting of the American Academy of Neurology, women and minorities with Parkinson’s disease receive specialist care less often than do white men, a trend that is especially troubling given another of the study’s findings—treatment by a neurologist is associated with improved clinical outcomes.

“Overall, women were much less likely to be referred to a neurologist or access a neurologist compared to men,” said Allison W. Willis, MD, Department of Neurology, Washington University School of Medicine, St. Louis, MO, who presented the study results.

“We also found that African Americans, Hispanic Americans, and Asian Americans, when compared to white men, were much less likely to see a neurologist within the first 48 months after diagnosis.”

Neurologic disorders are common, and neurologic complaints account for up to 15% of primary care office visits, Dr Willis explained. Growing evidence, however, suggests that primary care physicians may lack sufficient training in the diagnosis and management of complicated neurodegenerative diseases such as Parkinson’s disease.

Retrospective Analysis

Researchers conducted a retrospective cohort analysis of Medicare beneficiaries newly diagnosed with Parkinson’s disease from 2002. The majority of patients were white (91%); the remaining patients were black (6%), Hispanic (2%), or Asian (1%).

Of the 138,728 cases identified, half of patients (50%) received care from a neurologist over a 48-month observation period. Before determining whether this impacted patient outcomes, Dr Willis and colleagues examined patterns of referral for disparities in utilization of specialty care.

After adjusting for individual demographic characteristics—comorbidity index, socioeconomic status, and even the number of neurologists who were practicing and seeing Medicare patients in their area—Dr Willis and colleagues concluded that race and sex were significant predictors of neurologist treatment: women (odds ratio [OR], 0.78; 95% confidence interval [CI], 0.760.80) and nonwhites (OR, 0.83; 95% CI, 0.79-0.87) were less likely to be treated by a neurologist.

Disparities Impact Outcomes

Patients who had been treated by a neurologist were less likely to be placed in a skilled nursing facility (OR, 0.79; 95% CI, 0.77-0.82) and had a lower risk

of hip fracture (OR, 0.86; 95% CI, 0.800.92). Neurologist-treated patients also had a lower adjusted likelihood of death (hazard ratio, 0.78; 95% CI, 0.77-0.79).

“Even when considering dementia as a marker of advanced Parkinson’s disease,” said Dr Willis, “we found that seeing a neurologist was associated with greater survival than seeing a primary care physician exclusively for your Parkinson’s disease.”

Researchers also examined the impact of neurologist care on hospitalizations by dividing hospitalizations into Parkinson’s disease–related and non– Parkinson’s disease–related categories.

“What we saw,” Dr Willis reported, “was that people who were seeing a neurologist regularly had a lower risk of Parkinson’s-related hospitalizations but no difference in risk of general medical hospitalizations (eg, angina, diabetes, gastrointestinal obstruction, or heart failure).”

Among 660,000 Medicare beneficiaries, only 1% of patients received deep brain stimulation surgery, “one of the greatest proven surgical therapies for Parkinson’s disease that’s uniformly covered by Medicare.” African Americans and Asian Americans were less likely to receive deep brain stimulation, as were women.

“However,” Dr Willis noted, “if you were a white man whose doctor mostly cared for African American, Asian

American, or Hispanic Americans, you were also less likely to receive deep brain stimulation.”

Finally, researchers examined the underuse of necessary care for patients with Parkinson’s disease, hypothesizing that patients who saw specialists may have better outcomes because their primary care physician is able to focus on primary care.

“By underuse of necessary care,” Dr Willis explained, “I mean, if you have diabetes and Parkinson’s disease, are you getting your blood glucose checked every 6 months as is mandated? If you are a woman who has breast cancer, are you getting surveillance mammograms?”

According to Dr Willis, patients with Parkinson’s disease had the lowest achievement of basic care for general medical conditions, but seeing a neurologist doubled their likelihood of meeting those primary care goals. Dr Willis’ next step involves case confirmation of understudied groups, examining the geographic variations in progression of Parkinson’s disease to increase the clinical effectiveness of care.

“Demonstrating that neurologist treatment improves outcomes of patients with Parkinson’s disease could influence evidence-based practice metrics and highlight the need for health policy measures that support neurology practice and neurologic education,” Dr Willis concluded. n

Clinical Trials in Neurology

Is the Science of Stem Cells Ready?

Washington, DC––At the 2015 annual meeting of the American Academy of Neurology, experts engaged in a series of debates that touched on current and controversial issues in the field of neuroscience. During a debate on the role of stem-cell science in neurologic diseases, Clive Svendsen, PhD, Director of the Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, argued that based on recent advances in technology, including induced pluripotent stem cells (iPSCs), the science of stem cells is ready for clinical trials in neurologic disease.

Conversely, C. Warren Olanow, MD, FRCPC, Henry P. and Georgette Goldschmidt Professor and Chairman Emeritus, Department of Neurology, Professor of Neuroscience, Mount Sinai School of Medicine, New York, insisted that more supportive evidence is needed in this

field before stem cells are introduced into neurologic clinical trials.

Turning Lead into Gold

The recent Nobel Prize–winning discovery that adult skin cells can be taken from patients and reprogrammed into a pluripotent state almost identical to embryonic stem cells sent shockwaves through the scientific world, and Dr Svendsen was unequivocal with regard to iPSCs’ transformative potential.

“This is a very important technology,” he said. “We can make these stem cells from patients with Parkinson’s disease or ALS [amyotrophic lateral sclerosis] or other neurologic disorders and learn about the disease mechanisms…

It’s like turning lead into gold.”

Based on Dr Svendsen’s assertion, iPSC science may eventually provide an ethically acceptable, potentially autolo-

gous source of neural cells for transplantation in patients with neurologic diseases. However, the scientific challenges facing transplantation into patients with Parkinson’s disease are substantial.

“If you put the cells back where they died, they can’t reconnect,” said Dr Svendsen. “Parkinson’s is more than just the loss of dopamine neurons. We have to face the challenge of other parts of the nervous system regenerating. But, if we can attack the dopamine system, it will be very beneficial for Parkinson’s disease.” He further added, “Embryonic stem cells can make neurons, but it’s very hard work to get these cells to integrate.”

Despite these challenges, Dr Svendsen believes that the science of creating dopamine neurons from stem cells is ready to move to the clinic again. Gene editing to regulate dopamine release,

suicide gene insertion, and improved control over the numbers and the quality of cells are just a few of the new strategies highlighted by Dr Svendsen.

“Oligodendrocytes may be even more practical,” he suggested, “and remyelinating clinical trials for MS [multiple sclerosis] are currently being developed using stem-cell technology. Oligodendrocytes could also be used for spinal cord injury.”

Dr Svendsen also discussed astrocytes, which may be dysfunctional in many neurologic diseases. Stem cells can generate new astrocytes following transplantation, Dr Svendsen said, which could be used to deliver drugs that prevent cell death and enhance plasticity.

“Replacing sick astrocytes with healthy astrocytes that secrete GDNF [glial cell-derived neurotrophic factor] in ALS may limit the progression of motor neuron degeneration,” he hyContinued on page 19

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Personalized Medicine in Neurology

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Should Whole-Exome Sequencing Be Integrated into Neurologic Care?

By Chase Doyle Washington, DC––In a series of debates at the 2015 annual meeting of the American Academy of Neurology, expert physicians addressed current and controversial issues in neuroscience. In the following debate, Christine Klein, MD, Institute of Neurogenetics, University of Lübeck, Germany, advocated the merits of whole-exome sequencing, whereas Claes Wahlestedt, MD, PhD, Leonard M. Miller Professor and Associate Dean, University of Miami, FL, argued that there are limited examples of actionable findings to support whole-exome sequencing testing.

Whole-Exome Sequencing for Diagnosis of Rare Diseases

In framing her stance, Dr Klein proposed that neurologists are uniquely positioned to capture the value of whole-exome sequencing.

“Inherited conditions are, by definition, rare,” began Dr Klein, “but there are thousands in neurology. In the United States alone, about 1 in 10 people suffer from a rare disease.”

In a process known as reverse phenotyping, whole-exome sequencing reveals the entire spectrum of mutations present in the exome, which can then be correlated with the phenotypic features of each individual patient.

“This means that the genetic finding brings you back to the clinical and informs it,” Dr Klein explained, “and, indeed, diagnoses have even been revised based on genetic findings.”

Citing the recent “Rare Diseases” report by the European Commission, Dr Klein shared that 30% of patients with rare diseases were initially misdiagnosed, enduring an average of 5 to 30 years of diagnostic delay. Whole-exome sequencing is effective and accurate; a

recently published study demonstrated that the use of whole-exome sequencing more than tripled the rate of clarification of patients with unknown ataxias compared with next-generation sequencing panels.

“All of this has a great impact on our patients in terms of an earlier and cor-

rologists, Dr Klein emphasized the role of the latter: “It should be neurologists taking the lead for our patients, expanding horizons of diagnosis and disease pathogenesis,” she said.

Whole exome-sequencing may also help to reduce healthcare costs for payers.

“Sequencing costs have been plum-

“[Whole-exome sequencing] is minimally invasive; it’s relatively inexpensive; and, this is a very unique feature: it will become even more informative over time as clinical and genetic databases and our knowledge improve.”

—Christine Klein, MD

“Technology is a wonderful thing, but [whole-exome sequencing] is still in the realm of research. Genetics, to this day and age, rarely guides treatment. We are not quite at the level of precision medicine where we want to be.”

—Claes Wahlestedt, MD, PhD rect diagnosis,” Dr Klein observed.

Although Dr Klein acknowledged that whole-exome sequencing is by far the most expensive test when compared with single-gene tests and targeted gene panels, she noted that the price of whole-exome sequencing can be misleading. “It is only the most expensive at first,” she clarified. “Single-gene tests and even gene panel tests are often ordered more than once for an individual patient, raising the costs considerably.”

Encouraging conversations between geneticists, genetic counselors, molecular biologists, informaticians, and neu-

meting over the past few years, and it’s important to note that [whole-exome sequencing] is a once-in-a-lifetime diagnostic test. It’s minimally invasive; it’s relatively inexpensive; and, this is a very unique feature: it will become even more informative over time as clinical and genetic databases and our knowledge improve,” Dr Klein concluded.

Sequencing Not Ready for Clinical Use in Neurology

Dr Wahlestedt argued that wholeexome sequencing is still largely in the realm of research, an expertise more

suited for medical geneticists than for neurologists. “[Whole-exome sequencing] plays a valuable role in research, including neurodegenerative disease gene discovery, and can be done in any research project,” Dr Wahlestedt explained. Its valuable potential for discovery notwithstanding, Dr Wahlestedt remained unconvinced of its present clinical utility.

“There are still no first-line tests in neurology or any other field for that matter,” he said. “Higher suspicion of genetic condition––including autism disorders and epilepsy––is what usually goes along with a positive result.”

In addition to the limitations of whole-exome sequencing attributed to the complexity of the genome, Dr Wahlestedt also noted several ethical considerations, including whether patients should have access to their sequencing results and whether this information should be shared with insurance companies. Whole-exome sequencing’s main limitation, Dr Wahlestedt said, is the reality that exome findings are rarely actionable.

“Even in cancer, we have hundreds of drug treatments already available and should be guided by genomics, but that’s not necessarily the case….The vast majority of tumors still don’t correlate with exact targets,” he said, explaining that despite the availability of targeted treatments, 60% of surveyed US oncologists do not base their treatment decision on patients’ genetic mutation subtype. “Technology is a wonderful thing, but [whole-exome sequencing] is still in the realm of research. Genetics, to this day and age, rarely guides treatment. We are not quite at the level of precision medicine where we want to be.” n

Is the Science of Stem Cells Ready?

Continued from page 18

pothesized. “Overall, the science is clearly ready.”

Not Ready for Prime Time

Dr Olanow countered Dr Svendsen’s position with a compelling statistic— the failure of every single double-blind clinical trial to date involving cell transplantation.

“We failed in our trial despite the fact that fetal nigral cells demonstrated robust survival with hundreds of thousands of implanted neurons and exten-

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sive striatal innervation,” said Dr Olanow. “This contrasts with stem cells, which do not show the same level of survival or the same level of striatal innervation.”

Transplanted fetal nigral cells also showed robust motor benefits in animal models, Dr Olanow emphasized, but still failed in a double-blind clinical trial in patients with Parkinson’s disease.

“Why would we believe stem cells would do better when they have less reinnervation, less cell survival, and less

clinical benefit?” Dr Olanow asked Dr Svendsen. The science is not only unlikely to succeed but also comes with debilitating risk, Dr Olanow said. Dopamine transplant studies were associated with the development of unanticipated graft-induced dyskinesia in as many as 50% of patients.

“This dyskinesia can be severe and requires deep brain stimulation, a source of tremendous disability for the patient,” Dr Olanow explained. “Why would stem cells obviate this risk?”

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Finally, Dr Olanow argued that even if stem-cell transplantation were to succeed, its advantage over currently available and future therapies that treat and even prevent motor complications would be negligible.

“I’m an experimental therapist. My argument is not that we shouldn’t keep going, but that we need to think about it before we do. More science is needed before we are ready to step forward into the clinic, given what we know now,” concluded Dr Olanow.—CD n

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Drug Update

Lemtrada (Alemtuzumab) a New Treatment Option Approved by the FDA for the Treatment of Relapsing Forms of Multiple Sclerosis

By Loretta Fala, Medical Writer

M

ultiple sclerosis (MS), a chronic, inflammatory disease of the central nervous system, disrupts the communication between the brain, spinal cord, and other areas of the body.1 Aside from being potentially debilitating, MS can result in irreversible nerve deterioration.1 The incidence and prevalence of MS are not consistently tracked in the United States, it is estimated that 400,000 Americans are currently affected by the disease.2 The most common symptoms associated with MS are fatigue, numbness, spasticity, vision problems, and bowel and bladder problems.1,3 The symptoms of MS can vary widely from one person to another, depending on which nerves are affected and the extent of nerve damage.1 The 4 types of this condition are relapsing-remitting MS (RRMS), secondary-progressive MS, primary-progressive MS, and progressive-relapsing MS. RRMS is the most common type, accounting for 85% of initial diagnoses of MS, whereas the progressive type of the disease accounts for 10% to 15% of cases.3 RRMS is characterized by temporary periods of relapses or exacerbations of neurologic functioning, followed by periods of disease remission, in which partial or complete recovery occurs.4 MS, particularly if untreated or in the advanced phase, is associated with multiple symptoms that can impose a substantial burden on the patient’s mobility, daily activities, cognitive function, physical well-being, and overall quality of life.

Patients with MS are also at risk for depression, osteoporosis, pressure sores, and other complications.5 Furthermore, MS has a profound impact on caregivers, as well as on the healthcare system.

A systematic review of MS-related healthcare cost studies published between 2007 and 2012 showed that the total all-cause direct and indirect costs for MS ranged from $8528 to $54,244 per patient annually.6 The direct costs accounted for an average of 77% of the total healthcare costs, and the indirect costs accounted for approximately 23% of the total costs.6 In fact, the direct allcause healthcare costs for MS ranked second to congestive heart failure when compared with other chronic conditions. This review did not take into account some of the recent, more costly Copyright © 2015 American Health & Drug Benefits.

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treatments, or the costs associated with increasing disability, early retirement, or diminished quality of life associated with MS.6 It is crucial to diagnose and treat MS early to hinder permanent neurologic damage.7 A number of effective strategies are available to help slow the progression of the disease, manage symptoms, and improve physical and neurologic functioning. Most notable of the strategies include the disease-modifying therapies, which have been shown to reduce disease activity and disease progression in many patients with relapsing forms of MS.1 Until recently, these disease-modifying therapies included the beta interferons, glatiramer acetate (Copaxone), natalizumab (Tysabri), and the 3 oral therapies fingolimod (Gilenya), teriflunomide (Aubagio), and dimethyl fumarate (Tecfidera).1 Other treatments include corticosteroids to reduce inflammation during a relapse, and dalfampridine to improve walking in patients with MS. Alemtuzumab: A Novel Option for Patients with Relapsing Multiple Sclerosis

On November 14, 2014, the US Food and Drug Administration (FDA) approved alemtuzumab (Lemtrada; Genzyme), a CD52-directed cytolytic monoclonal antibody, for the treatment of relapsing forms of MS.8 Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for the treatment of MS.8,9 Alemtuzumab (Campath; Genzyme) was initially approved by the FDA in 2001 under its accelerated approval process for previously treated patients with B-cell chronic lymphocytic leukemia (CLL).10 In September 2007, alemtuz­ umab received an FDA approval and an expanded indication as a single agent for the treatment of B-cell CLL.10 The FDA approved alemtuzumab for MS with the condition of the drug being available only through a restricted distribution program, as part of its Risk Evaluation and Mitigation Strategy (REMS) program.11 The alemtuzu­ mab REMS program is intended to inform prescribers, pharmacies, healthcare facilities, and patients about the potential risks associated with alemtuzumab

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and the recommended monitoring at period intervals for 48 months after the last dose.11 According to Edward Fox, MD, PhD, Director of the Multiple Sclerosis Center of Central Texas, “The unmet need in MS remains high. It is a great day for people living with relapsing forms of MS in the United States, who will now have access to this new meaningful treatment.”8

“The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States. We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option.”

—Timothy Coetzee, PhD

Timothy Coetzee, PhD, Chief Advocacy, Services and Research Officer at the National MS Society, commented, “The FDA approval of Lemtrada is a significant milestone for people living with relapsing MS in the United States.

We are pleased that the voices of the MS community have been recognized and that people with relapsing MS will now have access to a new, needed treatment option.”8 Dosing

Alemtuzumab is administered via intravenous infusion over 4 hours for 2 treatment courses—the first course is 12 mg daily on 5 consecutive days, and the second course is 12 mg daily on 3 consecutive days 12 months after the first treatment course.9 Premedication with corticosteroids is given before the infusion of alemtuzu­ mab for the first 3 days of each treatment course. The administration of antiviral agents for herpetic prophylaxis should be started on the first day of alemtuzumab dosing, and should be continued for a minimum of 2 months after the completion of alemtuzumab

dosing or until the CD4+ lymphocyte count is more than 200 cells/mL, whichever occurs later. Alemtuzumab must be diluted before its administration.9 Alemtuzumab is available as a 12-mg/ 1.2-mL (10-mg/mL) injection in a singleuse vial.9 Mechanism of Action

Alemtuzumab is a recombinant humanized immunoglobulin G1 kappa monoclonal antibody directed against the cell surface glycoprotein CD52. Although the precise mechanism by which alemtuzumab exerts its therapeutic effects in MS is unknown, it is presumed to involve the binding to CD52, a cell surface antigen present on T and B lymphocytes, and on natural killer cells, monocytes, and macrophages. After cell surface binding to T and B lymphocytes, alemtuzumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.9

Clinical Studies

The efficacy of alemtuzumab 12 mg was demonstrated in 2 phase 3 studies (CARE-MS I and CARE-MS II) in patients with RRMS.12,13 In these studies, alemtuzumab was administered by intravenous infusion once daily for 5 days, followed 1 year later by intravenous infusion once daily for 3 days.9 Both studies included patients who had at least 2 relapses during the 2 years before trial entry and at least 1 relapse during the year before trial entry. Neurologic examinations were conducted every 12 weeks and at the time of the suspected relapse. Magnetic resonance imaging (MRI) evaluations were performed annually. For both studies, the clinical outcome measures were the annualized relapse rate over 2 years and the time to confirmed disability progression. The MRI outcome measure was the change in T2 lesion volume.9

CARE-MS I Study The CARE-MS I study was a 2-year randomized, controlled, open-label, rater-blinded trial that compared alem­ t­uzumab 12 mg with interferon beta-1a 44 mcg (administered subcutaneously 3 times weekly) in previously untreated patients with RRMS (mean age, 33 years; mean disease duration, 2 years; mean Expanded Disability Status Scale [EDSS] score, 2).9,12 Patients receiving alemtuzumab de­ VOL. 2

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Drug Update monstrated a significantly lower annualized relapse rate (a 55% relative reduction) than patients receiving interferon beta-1a (Table 1).

No significant difference was seen between the treatment groups for the time to confirmed disability progression and the primary MRI end point (change in T2 lesion volume). At year 2, 78% of the patients receiving alemtuzumab remained relapse-free compared with 59% of the patients receiving interferon beta-1a.9,12

The use of alemtuzumab is contraindicated in patients infected with HIV.9

tions, such as immune thrombocytopenia and antiglomerular basement membrane disease, as well as serious and life-threatening infusion reactions and an increased risk for malignancies.9 Autoimmunity. Alemtuzumab can result in the formation of autoantibodies and can increase the risk for serious autoimmune-mediated conditions. Complete blood counts should be monitored with differential, serum creatinine levels, and urinalysis with urine cell counts at periodic intervals for 48 months after the last dose of alemtuzumab.9 Immune thrombocytopenia occurred in 2% of patients receiving alemtuzu­ mab in clinical studies in MS. Complete blood counts with differential should be obtained before the initiation of treatment with alemtuzumab and at monthly intervals thereafter until 48 months after the last infusion.9 Infusion reactions. Alemtuzumab causes cytokine release syndrome, resulting in infusion reactions, some of which may be serious and life-threatening. The drug must be administered in a setting that can appropriately manage anaphylaxis or serious infusion reactions. Patients should be monitored for 2 hours after each infusion and be advised that serious infusion reactions can also occur after the 2-hour monitoring period.9 Malignancies. Alemtuzumab may cause an increased risk for malignancies, including thyroid cancer, melanoma, and lymphoproliferative disorders.

Baseline and annual skin examinations should be performed.9 Thyroid disorders. Thyroid function tests should be obtained before treatment and every 3 months until 48 months after the last infusion of alemtuzumab.9 Other autoimmune cytopenias.

Complete blood counts should be monitored monthly until 48 months after the last infusion of alemtuzumab.9 Infections. In patients with active infections, delaying the initiation of alemtuzumab should be considered until the infection is fully controlled. Live viral vaccines should not be administered after a course of alemtuzumab.9 Other warnings. Glomerular nephropathies and pneumonitis have been associated with the use of alemtuz­ umab. If alemtuzumab is considered for the treatment of MS in a patient who has previously received alemtuzumab (Campath) for B-cell CLL, increased vigilance should be exercised in watching for any additive and long-lasting effects on the immune system.9

Warnings and Precautions

Use in Specific Populations

CARE-MS II Study The CARE-MS II study was a 2-year randomized, controlled, open-label, rater-blinded trial that compared alemtuz­ umab 12 mg with interferon beta-1a 44 mcg (administered subcutaneously 3 times weekly) in patients with RRMS that relapsed despite first-line disease-modifying therapy (mean age, 35 years; mean disease duration, 4.5 years; mean EDSS score, 2.7).9,13 In the alemtuzumab group, the annualized disease relapse rate was significantly lower (a 49% relative reduction) than in patients who received interferon beta-1a (Table 2). Moreover, the time to onset of 6-month confirmed disability progression at 2 years was significantly delayed in the alemtuzumab group (a 42% relative risk reduction) compared with the interferon beta-1a group. No significant difference was found between the treatment groups in change in T2 lesion volume.9,13 At year 2, 65% of patients in the alemtuzumab group were relapse-free versus 47% of patients in the interferon beta-1a group.9,13 Safety

The most common adverse reactions (incidence ≥10% and greater than interferon beta-1a) with alemtuzumab were rash (53%), headache (52%), pyrexia (29%), nasopharyngitis (25%), nausea (21%), urinary tract infection (19%), fatigue (18%), insomnia (16%), upper respiratory tract infection (16%), herpes viral infection (16%), urticaria (16%), pruritus (14%), thyroid gland disorders (13%), fungal infection (13%), arthralgia (12%), pain in extremity (12%), back pain (12%), diarrhea (12%), sinusitis (11%), oropharyngeal pain (11%), paresthesia (10%), dizziness (10%), abdominal pain (10%), flushing (10%), and vomiting (10%).9

Contraindications

Boxed warning. Alemtuzumab was approved with a boxed warning stating that alemtuzumab may cause serious, sometimes fatal, autoimmune condi-

Pregnancy. There are no adequate and well-controlled studies in pregnant women. Alemtuzumab should be used during pregnancy only if the potential

Table 1 CARE-MS I Study: Alemtuzumab versus Interferon Beta-1a as First-Line Treatment in Patients with Relapsing-Remitting Multiple Sclerosis Alemtuzumab Interferon beta-1a 12 mg 44 mcg Outcome (N = 376), % (N = 187), % P value Clinical outcomes Annualized relapse rate

0.18

0.39

<.001

11

0.22

Relative reduction

55

Patients with disability progression at year 2a

8

Relative risk reduction

30

Patients remaining relapse-free at year 2

78

59

<.001

–9.3

–6.5

.31

MRI outcomes Change in T2 lesion volume from baseline

Confirmed disability progression was defined as a ≥1-point increase above baseline EDSS (1.5 increase for patients with baseline EDSS of 0) sustained for 6 months.

EDSS indicates Expanded Disability Status Scale; MRI, magnetic resonance imaging.

Sources: Lemtrada (alemtuzumab) injection prescribing information; November 2014; Cohen JA, et al; for the CARE-MS I investigators. Lancet. 2012;380:1819-1828.

a

Table 2 CARE-MS II Study: Alemtuzumab versus Interferon Beta-1a After DiseaseModifying Therapy in Patients with Relapsing-Remitting Multiple Sclerosis Alemtuzumab Interferon beta-1a 12 mg 44 mcg Outcome (N = 426), % (N = 202), % P value Clinical outcomes Annualized relapse rate

0.26

0.52

<.001

21

.0084

Relative reduction

49

Patients with disability progression at year 2a

13

Relative risk reduction

42

Patients remaining relapse-free at year 2

65

47

<.001

–1.3

–1.2

.14

MRI outcomes Change in T2 lesion volume from baseline

Confirmed disability progression was defined as a ≥1-point increase above baseline EDSS (1.5 increase for patients with baseline EDSS of 0) sustained for 6 months.

EDSS indicates Expanded Disability Status Scale; MRI, magnetic resonance imaging.

Sources: Lemtrada (alemtuzumab) injection prescribing information; November 2014; Cohen JA, et al; for the CARE-MS I investigators. Lancet. 2012;380:1819-1828.

a

benefit justifies the potential risk to the fetus.9 Nursing mothers. It is not known whether alemtuzumab is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions from alemtuzumab in nursing infants, a decision should be made whether to discontinue nursing or to discontinue alemtuzumab, taking into account the importance of the drug to the mother.9 Pediatric use. The safety and effectiveness of alemtuzumab in patients aged <17 years have not been established.9 Geriatric use. Clinical studies of alemtuzumab did not include sufficient numbers of patients aged ≥65 years to determine whether they respond different from younger patients.9

Conclusion

The FDA’s approval of alemtuzumab marks the availability of another treatment option for patients with relapsing forms of MS. The efficacy of alemtuz­ umab was demonstrated in a clinical development program that included nearly 1500 patients with more than 6400 patient-years of safety follow-up.8 In clinical studies, alemtuzumab significantly reduced the annualized relapse rates over a 2-year period as firstline treatment and in previously treated patients with relapsing forms of MS compared with interferon beta-1a therapy. Because of its safety profile, the use of alemtuzumab should generally be reserved for patients who have had an inadequate response to 2 or more drugs indicated for the treatment of MS.9 n Continued on page 22

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Chronic Pain

Should Neurologists Prescribe Opioids for the Management... Continued from cover Director of the Comprehensive Pain Center, Albany Medical Center, Albany, NY, advocated the benefits of prescription opioids for the treatment of patients with chronic pain, whereas Gary M. Franklin, MD, MPH, Research Professor, Departments of Occupational and Environmental Health Sciences, Neurology, and Health Services, University of Washington, Seattle, criticized the medical oversight that has led to a public health epidemic of opioid abuse.

“All prescribers play an active role in reducing the risks associated with opioids,” said Dr Argoff. “When considering a chronic pain treatment plan, a

frequently misused or abused pharmaceuticals; overdose deaths from prescription painkillers increased fourfold between 1999 and 2010. According to

Meaningful Relief of Chronic Pain

According to the 2011 Institute of Medicine report, “Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research,” chronic pain affects approximately 100 million US adults. A neurologist’s goal for the management of chronic pain, Dr Argoff said, should be to define the most appropriate treatment regimen for each patient—that is, multimodal therapeutic strategies for pain and associated disability—which could include opioids.

“Most neurologists currently treat patients who, as a part and in the course of their neurological disorders, experience severe chronic pain,” said Dr Argoff, who listed more than 20 neurologic diseases defined by this condition. “Pain management is an essential part of a neurologist’s training.”

While citing abundant evidence for the use of opioid analgesics for chronic neuropathic pain, Dr Argoff also stressed the importance of using the lowest necessary dose for safety reasons.

“Not only should neurologists prescribe opioids for chronic pain, we must be well-prepared to prescribe opioids when appropriate for the best benefits to our patients while reducing the risks to the fullest extent possible.”

—Charles E. Argoff, MD

neurologist should complete an appropriate risk assessment prior to prescribing, and they should monitor the patient regularly on an ongoing basis.”

Opioid analgesics are among the most

Lemtrada (Alemtuzumab) a New Treatment Option...

Continued from page 21

References

1. Mayo Clinic staff. Diseases and conditions: multiple sclerosis. July 10, 2014. www.mayoclinic.org/diseasesconditions/multiple-sclerosis/basics/definition/CON20026689. Accessed April 23, 2015.

2. National Multiple Sclerosis Society. MS prevalence: estimating the prevalence of MS. www.nationalmssoci ety.org/About-the-Society/MS-Prevalence. Accessed April 24, 2015.

3. National Multiple Sclerosis Society. Relapsing-remitting MS (RRMS). www.nationalmssociety.org/aboutmultiple-sclerosis/relapsing-ms/relapsing-remittingms-rrms/index.aspx. Accessed April 23, 2015.

4. National Multiple Sclerosis Society. Managing relapses. www.nationalmssociety.org/Treating-MS/Man aging-Relapses. Accessed April 24, 2015.

5. National Multiple Sclerosis Society. Living with advanced MS. www.nationalmssociety.org/about-multi ple-sclerosis/living-with-advanced-ms/index.aspx. Accessed April 23, 2014.

6. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647.

7. National Multiple Sclerosis Society. Adherence. www.nationalmssociety.org/Treating-MS/Medications/ Adherence. Accessed April 24, 2014.

8. Drugs.com. FDA approves Lemtrada: FDA approves

22

Lemtrada (alemtuzumab) for relapsing forms of multiple sclerosis. Press release. November 2014. www.drugs. com/newdrugs/fda-approves-lemtrada-alemtuzumab-re lapsing-forms-multiple-sclerosis-4110.html. Accessed April 22, 2015.

9. Lemtrada (alemtuzumab) injection [prescribing information]. Cambridge, MA: Genzyme Corporation; November 2014.

10. US Food and Drug Administration. Drugs@FDA: FDA approved drug products: Campath. Label and approval history. www.accessdata.fda.gov/scripts/cder/ drugsatfda/index.cfm?fuseaction=Search.Label_Ap provalHistory#labelinfo. Accessed April 22, 2015.

11. Genzyme. Lemtrada REMS (Risk Evaluation and Mitigation Strategy) program. www.lemtradarems.com/.

Accessed April 23, 2015.

12. Cohen JA, Coles AJ, Arnold DL, et al; for the CARE-MS I investigators. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012;380:1819-1828.

13. Coles AJ, Twyman CL, Arnold DL, et al; for the CARE-MS II investigators. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet.

2012;380:1829-1839.

VALUE-BASED CARE IN NEUROLOGY

I MAY 2015

“I believe that we need to find ways to offer doctors, patients, and communities alternatives as part of the multimodal system of helping these patients with nonpharmacologic therapy for chronic pain.”

—Gary M. Franklin, MD, MPH

Dr Argoff, however, these numbers are on the decline, which is the direct result of improved guidelines in opioid prescribing practices.

“Many policy changes, such as the implementation of state prescription drug monitoring programs and screening for risk factors for misuse and abuse, have succeeded in making opioid therapy safer; misrepresenting opioid efficacy and erecting barriers to meaningful relief of chronic pain for your patients have not,” said Dr Argoff.

Dr Argoff also noted that neurologists routinely prescribe treatments that have serious risks associated with their use.

“The question of whether a neurologist should prescribe opioids is a false dichotomy,” Dr Argoff concluded. “Not only should neurologists prescribe opioids for chronic pain, we must be well-prepared to prescribe opioids when appropriate for the best benefits to our patients while reducing the risks to the fullest extent possible.”

“Worst Man-Made Epidemic in Modern History”

Dr Franklin defended his position with respect to opioid analgesics.

“Because of the teachings that occurred in the late 1990s, we are now experiencing the worst man-made epidemic in modern medical history,” he

at a glance ➤ Chronic pain affects approximately 100 million adults in the United States ➤ Overdose deaths from prescription painkillers increased fourfold from 1999 to 2010 ➤ Regional efforts to improve opioid dosing guidelines led to a 27% decline in opioidrelated deaths

began, before reciting the statistics attributed to opioid use: more than 140,000 deaths, hundreds of thousands of overdose admissions, millions of individuals addicted and/or dependent on opioids.

“We were taught originally that addiction was less than 1%,” said Dr Franklin. “But opioid use disorder is estimated in 29% of people on chronic opioids.” According to Dr Franklin, origins of the opioid use epidemic began with a lobbying effort largely funded by drug companies that changed more than 20 state laws.

“By the late 1990s, at least 20 states passed new laws, regulations, or policies moving from near prohibition of opioids to use without dosing guidance,” Dr Franklin explained.

Even after discounting the severe risks, which include mortality, overdose, dependence and addiction, and lifelong disability, Dr Franklin saw little benefit to opioid therapy––only diminishing effectiveness.

“You’re putting patients at risk,” said Dr Franklin, citing a study that demonstrated only modest pain improvement and functional improvement that was nonexistent with opioid use. “You might be improving their pain a little bit (30%), but you’re not improving their ability to do more every day.”

Efforts to improve opioid dosing guidelines in Dr Franklin’s home state of Washington have resulted in a 27% decline in overdose-related deaths, dramatically reducing the incidence rate of ongoing opioid use in the workers’ compensation system. “Opioids in our system are not only initiating but perpetuating disability among injured workers who are coming into the system with a low-back sprain,” said Dr Franklin. “I believe that we need to find ways to offer doctors, patients, and communities alternatives as part of the multimodal system of helping these patients with nonpharmacologic therapy for chronic pain.” n

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FOR PAYERS, PURCHASERS, POLICYMAKERS, AND OTHER HEALTHCARE STAKEHOLDERS

CALL FOR PAPERS American Health & Drug Benefits® offers an open forum for all healthcare participants to exchange ideas and present their

data, innovations, and initiatives to facilitate patient-centered healthcare and benefit design models that meet the needs of all stakeholders—Distributors, Employers, Manufacturers, Patients, Payers, Providers, Purchasers, Regulators, and Researchers.

Readers are invited to submit articles that aim at improving the quality of patient care and patient well-being while reducing or controlling costs, enhancing the health of communities and patient populations, as well as other topics relevant to benefit design with specific implications to policymakers, payers, and employers.

Areas of High Interest: • Adherence Concerns

• Health Information Exchange

• Pharmacogenomics

• Benefit Design

• Health Plan Initiatives

• Policy Issues

• Case Studies

• Innovations in Healthcare

• Prevention Initiatives

• Comorbidities and Cost Issues

• Literature Reviews

• Real-World Evidence

• Comparative Effectiveness Research

• Managed Care

• Reimbursement Strategies

• Decision-Making Tools

• Medicare/Medicaid

• Social Media in Healthcare

• Ethics in Medicine

• Patient Outcomes/Advocacy

• Survey Results

• Health Economics Research

• Pharmacoeconomics

• Value-Based Healthcare

Clinical Topics of High Interest: AGING—With the aging of the US population, there is a growing need for early implementation of outcomes-based preventive and therapeutic strategies for older people.

CANCER CARE—The growing focus on high-cost biologic agents dictates an enhanced study of these therapeutic options, including reimbursement policies and cost management.

ALLERGIES—Allergies, such as allergic or seasonal rhinitis, affect millions of Americans daily, resulting in a significant economic burden and human cost. Under­treatment and lack of adherence are common obstacles to patient management.

CARDIOVASCULAR DISEASE—Outcomes-based research on appropriate therapies, cost comparisons, emerging prevention strategies, and best practices will enhance readers’ decision-making.

ARTHRITIS—Musculoskeletal conditions are on the increase, yet many patients are undiagnosed and untreated.

Comparing new and emerging therapies is a key target for improving patient outcomes and reducing costs.

DIABETES, OBESITY—The growing epidemics of these twin metabolic conditions mandate a thorough examination of best therapies, adherence issues, access, and prevention strategies.

GASTROINTESTINAL CONDITIONS—Recognizing GI conditions, such as hepatitis C, Crohn’s disease, and inflammatory bowel disorder, remains a challenge.

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BUSINES

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In Actes result ela Con rdiocipa sponsored ha al-w metopro utilizatio , iluMD orAcat caPrin h d pruty pregnancy Con ll to sctor Gabricipa Dire and of re guez also tively; P = .020). lLy ar t nefan, ioid e employer- rcially inion,is A Ca ye r urce Dep Opaus s was as hig yer,er MsutDie e:60 ysis isoo nsive rdar ic blec ec ilizat Pyenson is Prin tiv he ” mbec sig s nfoare olLaw lthC < ance plan Dear Ricdhak, stPe ;iaDr plo Hea resp tively; P This anal tihyperte care reso rspagh, NY erfit Mr ed’ Bay an ng-T majority of comme forms of “em ye urce ne /d Inc; , Lo Yor 0 : er term ly ec th Be ic g so an earc N ts New on al ≥6 di old er the ol re sp on Res ns ed , Bay estien er he re use ion Am s cover the sts. n,faInc, re SIO eration rcti ntand akeh tcom syst in Pla MS;ble to oth agctor paies Millima is hstea isrise D, RP thca lated CLU Dire at program l ts Liu,lica en ics St Ou ical co , Phon dica tiplth hu app heal ial inEco nagisncMe ns rsiste tien Trudssell hea CON cond-g er CV-re d med resultsSizare amegon nberg en penom ensiDr pa Pr ion, geny, card Health as tePoptoulat te Vohy iond- Co Drg Lyn w se s, but the PhD; y ippa pertNJ; ox ongnd icals rtens m; H ojceec Wh prce ceut the tly lo CV-rela sured livePS; Xin Gao, fined prOp rma0/ icals F. 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MENTAL DISORDERS—Depression, bipolar disorder, and schizophrenia exert a huge financial and human burden on individuals, employers, and payers. Topics of interest include comparative-effectiveness analyses, adherence, best practices, and reimbursement.

NEUROLOGIC DISORDERS—The central nervous system is associated with many complicated medical disorders and an enormous economic burden.

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