2018 November AANnews

VOLUME 32 · ISSUE 11 · NOVEMBER 2018

Read the latest update on all CMS changes at AAN.com/view/SpeakOutNow

2019 ANNUAL MEETING­— WHY SHOULD YOU ATTEND? Registration Opens November 8 The AAN Annual Meetings just keep getting more innovative, offering unique and creative experiences throughout the week served up in exciting and inspirational formats to fuel your mind, body, and spirit.

The 2019 meeting in Philadelphia will be no exception, and registration opens November 8!

Whether you’re a clinician, researcher, resident, student, or other neurology professional—and no matter what your subspecialty area of interest—the 71st AAN Annual Meeting’s fully flexible and customizable format will allow you to get the most out of your time. Registering and booking your hotel by early Match will ensure the biggest possible savings and the hotel room of your choice.

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Learn How to Improve Your Relations with Payers Your relationship with your private payers is one of the most important in your career, so make sure you're doing everything you can to create the best relationship you can. This webinar will arm you with the tools and techniques necessary to create a satisfactory and advantageous relationship with private payers for the benefit of your practice and your patients.

Retain Access to the Best Neurology Resources in 2019— Renew Today!

Jones

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Axon Registry Simplifies Reporting Measures for MIPS

It’s time to renew your AAN membership for 2019! By visiting AAN.com/dues and renewing today, you’ll retain access to the world’s best neurology resources and education throughout the new year to help you grow and thrive professionally and personally.

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10 We’ve Got Your Back:

Regulatory Advocacy, Payer Relations, and the AAN

12 AAN Advocacy Continues to Push Neuro Research Funding Higher

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In Multiple Sclerosis–

THE ART OF BRAIN PRESERVATION Adding Grey to the Palette Completes the Picture

GREY MATTERS, TOO

Learn more about Multiple Sclerosis at MSBrainPreservation.com/art © 2018 Celgene Corporation All rights reserved. 03/18 USII-CELG180067

AANnews · November 2018

CONTENTS

News Briefs AAN Publishes Evidence in Focus: Nusinersen Use in SMA · · · · · · · · · · · · · · · 11

Cover 2019 Annual Meeting­— Why Should You Attend?

AAN Advocacy Continues to Push Neuro Research Funding Higher · · · · · · · · · · 12

Learn How to Improve Your Relations with Payers Retain Access to the Best Neurology Resources in 2019—Renew Today!

Capitol Hill Report · · · · · · · · 13

President’s Column AAN Task Force Tackles High Neurology Drug Pricing · · · · · 4 Through Their Eyes Recollections of Past AAN Presidents · · · · · · · · · 6 Tools & Resources Axon Registry Simplifies Reporting Measures for MIPS · · · · · · · · · · · · · · ·8 Podcast Central · · · · · · · · · ·8 Quality Measures for Epilepsy and Neurotology Published · · · · · · · · · · · · · ·9 Register for FREE December 4 Webinar: E/M and QPP Changes for 2019 · · · · · · · · · ·9

Conferences & Community AAN Study Shows Gender and Age Differences in Burnout Among Neurologists · · · · · · 16 Improving Work-life Balance Helps Diversity Leadership Program Participant Achieve Key Goal · · · · · · · · · · · · · 17 Volunteers Needed as 2019 Brain Health Fair Shifts to New Annual Meeting Day · · · · · · · · · · · 23 Education & Research December 3 Is RITE Registration Deadline · · · · · · 24 Dates & Deadlines · · · · · · · · · 31 Careers · · · · · · · · · · · · · · · 32

Policy & Guidelines We’ve Got Your Back: Regulatory Advocacy, Payer Relations, and the AAN · · · · · 10

The Vision of the AAN is to be indispensable to our members.

The Mission of the AAN is to promote the highest quality patient-centered neurologic care and enhance member career satisfaction.

Contact Information

For advertising rates, contact:

American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415

Eileen R. Henry Wolters Kluwer Health | Medical Research Lippincott, Williams & Wilkins

Phone: (800) 879-1960 (toll free) (612) 928-6000 (international) Email:

memberservices@aan.com

Website: AAN.com

Phone: (732) 778-2261 Email: Eileen.Henry@wolterskluwer.com

Comment on Guideline Protocol by November 19 The AAN requests public review and comments on a draft guideline protocol on Women with Epilepsy at AAN.com/practice-guidelines/home/ public-comments. The guideline in development that this protocol describes will address several topics for women with epilepsy who are pregnant or may become pregnant.

Academic Medicine Research The AAN recently published two studies on academic training in Neurology ®. For the article “A Dozen Years of Evolution of Neurology Clerkships in the United States: Looking Up,” the AAN Consortium of Neurology Clerkship Directors sent a survey to all neurology clerkship directors and compared the results to surveys from 2005 and 2012. Changes include shifting of the neurology clerkship to earlier in the medical school curriculum and an increase in clerkship director salary support. For the second article, the AAN surveyed adult neurology program directors and compared the results to a similar survey in 2007. The study, “2017 Program Director Survey: Feedback from Your Adult Neurology Residency Leadership,” found that deficiencies exist in compensation for program directors’ teaching and administrative time and for academic promotion for female program directors. The results will serve as a benchmark for comparison across programs and as a basis to advocate for further improvements and support for neurology residency training. 

AAN Executive Director: Catherine M. Rydell, CAE Editor-in-Chief: John D. Hixson, MD Managing Editor: Angela Babb, CAE Editor: Tim Streeter Writers: Ryan Knoke and Sarah Parsons Designers: Siu Lee Email: aannews@aan.com

AANnews is published monthly by the American Academy of Neurology for its 34,000 members worldwide. Access this magazine and other AAN publications online at AAN.com/go/elibrary.

The American Academy of Neurology ’ s registered trademarks and service marks are registered in the United States and various other countries around the world.

“American Brain Foundation” is a registered service mark of the American Brain Foundation and is registered in the United States.

President’s Column

AAN Task Force Tackles High Neurology Drug Pricing

Sacco

Increasingly over the past few years, skyrocketing drug prices have been cited by both medical providers and patients as a significant detriment to proper and effective care, particularly for neurologic diseases.

These ever-rising prices threaten the ability of the AAN to fulfill our mission to promote the highest quality patient-centered neurologic care.

The impact on patients and providers is significant. Patients’ share of costs has increased, and now nearly one in four Americans taking prescription drugs reports difficulty affording them. This often leads to prescription abandonment and compliance difficulty, including rationing drugs and mitigating their effectiveness. The effect is even higher for those taking specialty drugs, including many we provide to our patients.

In September, the AAN’s Neurology Drug Pricing Task Force, chaired by Nicholas E. Johnson, MD, FAAN, presented its final report to the Academy’s Board of Directors. The task force was charged with studying the environment of drugs for neurologic disease and proposing ways for the AAN to proactively address the challenges associated with ultra-high drug costs, including implications at the governmental, institutional, physician, and patient levels. It also was asked to evaluate other professionaland patient-advocacy organization positions and opportunities for collaborations with other organizations.

The task force held two in-person meetings and nine conference calls, as well as multiple small group calls and discussions. More than a dozen external groups were consulted, including: ALS Association American College of Rheumatology American Society of Clinical Oncology Children’s Hospital Association

Cure SMA Michael J. Fox Foundation for Parkinson’s Research National Multiple Sclerosis Society Patients for Affordable Drugs Before I get into the task force’s recommendations, I’d like to share some of its findings on the scope of this serious problem for patients, providers, institutions, and payers.

Impact on Patients and Public The US already spends the most per capita on health care among all industrialized nations. The high cost of prescription drugs contributes to that spending. Medicare’s share of national prescription drug spending rose from 2 percent in 2004 to 29 percent in 2014. Medicare accounts for a growing share of the nation’s prescription drug spending: 29 percent in 2015 compared to 18 percent in 2006, the first year of the Part D benefit.

This has serious implications for all of us—patients, providers, and taxpayers. Prescription drugs play an important role in medical care for 59 million seniors and people with disabilities, and account for $1 out of every $6 in Medicare spending.

The majority of Medicare prescription drug spending is for drugs covered under the Part D prescription drug benefit, administered by private stand-alone drug plans and Medicare Advantage drug plans. Medicare Part B also covers drugs that are administered to patients in physician offices and other outpatient settings.

Many specialty drugs cost more in the US than in other developed countries. For example, in Switzerland the average price of a month’s prescription of the MS drug Copaxone is $1,357, while in the US it is triple that, or $3,903. The Swiss pay $881 for a month’s supply of Humira for rheumatoid arthritis, while Americans pay $2,246 for the same drug. There is little evidence to show high costs are necessary to offset innovation or development expenses.

Taxpayers Pay Twice

Prescription Drug Increases Price growth since 2000 80%

Prescription drugs +69%

60

Hospital care +60%

40 Physician and clinical services +23%

20 0 2000

2005

2010

2015

Source: Centers for Medicare & Medicaid Services

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AANnews • November 2018

Research supported by the National Institutes of Health—via taxpayers—has been part of every one of the 210 drugs approved by the FDA between 2010 and 2016, and 84 of these drugs were first-in-class. More than 90 percent of this funding was basic research related to biological targets for drug action. More recently, pharma has relied on others for the basic research supporting the development of new drugs including that funded by NIH. Industry focuses its research and development on applied research, which complements the findings of the basic research

discoveries that were federally funded. When these drugs come to market, therefore, the US government and taxpayers pay again to buy these same therapies.

Unfortunately, the drug development and delivery model in the US is highly complex, and lack of transparency hinders policy solutions. Financial ties between industry and the health care system—and between industry and our political system— further complicate solutions to address cost. Clearly, current trends are unsustainable.

Impact on Physicians/Institutions High cost drugs create high institutional risk, as the cost of drugs prescribed is attributed to the prescriber. Under the new MACRA and Merit-based Incentive Payment System (MIPS), physicians will be graded based on the cost of drugs they prescribe. In 2018, the category of Cost is 10 percent of the total score, but by 2021, 30 percent of the score will be based on cost of drugs. Fortunately, the adjustment—whether negative or beneficial—will not be applied to Part B drug costs. Likewise, high drug prices are unfavorable for risk-bearing alternative payment models (APMs). Furthermore, the increased prior authorization demands and other hurdles for high cost drugs contribute to burnout and take up significant support staff time.

Renewed Interest in Rare ‘Orphan’ Diseases The approximately 7,000 rare or “orphan” diseases—those with a prevalence of less than 200,000 people—collectively impact 30 million Americans. Genetic origins account for 80 percent of these rare diseases, and 50 percent affect children.

Unfortunately, rare diseases are common in neurology.

Before the Orphan Drug Act was passed in 1983, only 10 drugs had been approved to treat rare diseases. Since passage, 591 orphan drugs were approved as of January 2017.

Supporters of the law say that the high number of approved orphan drugs is a sign of the law’s success. While critics agree that the law has boosted orphan drug development, they argue that many drugs with orphan designation would have been profitable enough to develop without the added incentives. Spending on orphan drugs for rare disease treatment has constituted a small but growing share of overall pharmaceutical spending. In 2013, this spending accounted for 8.9 percent of all drug spending. Orphan drugs may be separately promoted by drug makers for off label uses to treat non-orphan diseases.

Neurology Drug Pricing Task Force Recommendations Clearly, the problems caused by high drug prices will not go away on their own. These complicated problems will demand some hard choices by all parties involved.

discussed what the AAN should consider doing in five key areas and ranked its recommendations for the board’s consideration.

Member Guidance/Patient Education Provide rapid guidance to members on new therapies Provide member guidance on the ethical implications and considerations related to high drug costs Develop resources to help members discuss drug value with patients Public and Private Payer Advocacy Proactively engage with payers to advocate for policies aimed at controlling drug prices Regulatory Advocacy Comment on proposed drug pricing or delivery reforms at the federal and state levels to make sure the neurology perspective is represented Legislative Advocacy Continue to advocate for actions that may bring cost down Collaborate with other advocacy groups, including patient and caregiver support organizations, to publicize concerns around drug prices Industry Relations and Conflicts of Interest Expand the AAN’s disclosure requirements for volunteer leaders Review the AAN’s Principles Governing Academy Relationships with External Sources of Support Better anticipate future cost challenges On behalf of our Board, we sincerely appreciate all of the outstanding work done by Dr. Johnson and this task force.

The Board unanimously accepted the report and we now are working with staff to determine our priorities and next steps.

We will keep you informed as we make progress on this critical issue. These recommendations will be instrumental in guiding us to chart a future for the AAN to take a leadership role in addressing high drug process and more effectively carry out our mission. 

Ralph L. Sacco, MD, MS, FAHA, FAAN President, AAN rsacco@aan.com @DrSaccoNeuro on Twitter

We have roles to play in turning this crisis around, individually as physicians and collectively as the AAN. The task force

AANnews • November 2018 5

Through Their Eyes

Recollections of Past AAN Presidents Robert C. “Burch” Griggs, MD, FAAN AAN President 2009−2011 AANnews® celebrates the history of the Academy during its 70th anniversary with a series of interviews of past presidents.

The following excerpt is from a 2017 interview with Robert C. “Burch” Griggs, MD, FAAN (RG), conducted by AANnews editor Tim Streeter (TS). Prior to becoming president, Griggs served 10 years as editor of Neurology ®.

TS: Did you have any ambitions to become Academy president? How did that come about?

RG: I knew the people who’d been president before me, and I was just impressed at their impact. It looked like they were having fun: Bud Rowland, Nelson Richards, Mel Greer, Sandy Olson, and Ken Viste. He was a wonderful person. I still remember Ken Viste. I think it was he who called me and told me I was chosen as editor. Ken was a wonderful person. I just loved him. I was impressed. Ted Munsat, Stan Fahn, and Steve Ringel were all really close friends. I admired the people who had done it, and I thought the Academy was an exceedingly well-run organization and became even better run in more recent years. But it was big, and it did so much for education in terms of the science. I always thought it was, without any question, the best meeting for the practicing neurologist, as well as for the clinically focused academic neurologist. I was happy to serve. I didn’t say, “That’s what I want to be when I grow up.” I actually had thrown my hat out in the ring while I was just starting as journal editor. Somebody asked me, “Do you want to be president?” I said, “Oh, that might be fun.” I was glad I wasn’t chosen, because I ended up having so much fun being editor, but when I was asked to do it, I was overjoyed to throw my hat in the ring later as well.

On Neurology on the Hill and the need for advocacy: RG: I did go to Neurology on the Hill. I went there twice…. Congress has not paid attention to the economic issues in terms of health care, as far as I’m concerned. I spent a lot of time in England, and I myself see that the way medical care is delivered in Europe is much better. The outcomes are better, the doctors are happier, the patients are happier. I have felt that the way American medicine has developed and persisted as an outlier should be changed. I think there are lots of people in neurology who don’t necessarily agree with me, so I didn’t feel that it was my job to espouse a specific particular. I felt it was extremely important to be involved, to be supporting members

of Congress. That’s the way Congress runs. If you’re not in their office telling them about what you want, then they need to hear from us. I’ve always felt that it’s important for us to be in Washington and to talk to Congress. One of the things I did when I was on Neurology on the Hill was that I went to [New York Senator] Hillary Clinton’s office. We were a little disappointed Hillary wasn’t there, but we talked to a staffer who was a PhD neuroscientist, and that resulted in getting them to champion a bill that got the VA to develop epilepsy programs within the VA. Then I felt I could see firsthand that talking to a senator’s staff person got the ball rolling in terms of doing something that was of immense benefit to patients with epilepsy, and the veterans.

I do think that it’s important for us to be involved with our Congress people and educate them about what needs to be done. I felt strongly that it’s important for us to advocate for neurological research.

That is something the Academy has really stepped up to and had an important impact on. I established a group where we were meeting with all the institutes that deal with neurology disease in Washington, not just NINDS, and I found NINDS loved this and they continue meeting here with NINDS, making sure that they have input to what we’re doing, and we know what’s going on with the research enterprise is important as well.

TS: When you were president, the Academy took a neutral stand on Obamacare when there was the debate in Congress. Was there a particular reason for that?

Griggs at the 1992 Annual Meeting.

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AANnews • November 2018

RG: I think that the Academy has done a good job of steering a middle course, because there are lots of people, lots of conservative neurologists and lots of ultra-liberal neurologists, and I think the Academy has been wise not to pick a party and support it. I think that’s probably the right thing to do…. Doctors have always been divided in their opinions about what you do. I think you can’t take a strong alignment with a party, because we serve our members, and I can argue with anyone that it’s not right not to have good medical care for everyone, but I’m not going to argue that everybody ought to be a Democrat or Republican….

TS: One of the things that you mentioned in your final president’s column that you were very proud of was reducing the amount of time that was spent on resolving complaints and disciplinary actions. Why was that meaningful?

RG: When I became president, it would take up to a year and a half, two years, or even longer to deal with a grievance from a member. A member was sued, somebody gave a testimony during his trial that was obviously flawed, and there are a handful of neurologists—I don’t like to refer to them as bad apples, but I think they get put in a position where they’re trying to help a plaintiff or trying to help a lawyer, and get money for the patient, and they sometimes testify inaccurately. It was very important to solve these problems quickly. And so, working with the Academy legal staff, [General Counsel] Murray Sagsveen and more

recently, [Deputy General Counsel] John Hutchins, we said, “Look. We have to solve this quickly. You don’t want to have a neurologist worrying about being sued, if there wasn’t really a case for a grievance, and the people who are aggrieved need to have an answer themselves pretty quickly.” So, we ended up publishing our experience about how a grievance should be dealt with, and I thought that instead of tightening up this problem, make sure it worked for both people who were upset about being sued, and for the people who were. It’s not wrong for neurologists to testify [in] malpractice issues. We have to. It’s our responsibility. But it needs to be done, and make sure it comes to a quick conclusion.

Visit AAN.com/view/AANhistory to read the complete transcript of Griggs’ interview and learn about his experiences with Neurology and preceding journal Editors-in-Chief Russell N. DeJong, MD, FAAN; Lewis P. “Bud” Rowland, MD, FAAN; and Robert R. Daroff, MD, FAAN.  Griggs at the 2017 Annual Meeting.

(Left to right) Incoming Neurology Editor-in-Chief John H. Noseworthy, MD, FAAN (2007–2009), with predecessors Robert C. Griggs, MD, FAAN (1997–2006), Robert R. Daroff, MD, FAAN (1987–1996), and Lewis P. “Bud” Rowland, MD, FAAN (1977–1986), in 2006.

AANnews • November 2018 7

Tools & Resources

Finding a way to submit measures relevant to your practice helps alleviate the need to document information that is irrelevant to the patient visit. The Axon Registry is designated as a Qualified Clinical Data Registry (QCDR), meaning it can add neurology-specific measures that are not a part of the QPP program. In addition to 18 neurology-specific QPP measures, there are 17 measures in Axon that are not eligible for submission through any other method. They include Parkinson’s, neuro-ophthalmology, headache, multiple sclerosis, falls, epilepsy, distal symmetric polyneuropathy, and child neurology measures. All of which may be incredibly important for your patients but have not been approved for submission via claims, EMR, or manual entry.

Many other MIPS submission methods will charge anywhere from $300 to $900 per provider to send data to CMS. The Axon Registry extracts data directly from your EMR system and assesses all your documentation to calculate performance rates. You are then given a user-friendly dashboard to review in real time throughout the year. All of this is provided as a free member benefit for US-based providers with an up-to-date membership.

Early next year is the time to make a switch to a different MIPS submission method. If the Axon Registry sounds right for your practice, contact registry@aan.com or enroll directly on our website at AAN.com/view/Axon. 

credits awarded…

E M an d 0C g win gro

As the Merit-based Incentive Payment System (MIPS) under the Quality Payment Program (QPP) is completing its second reporting year, it’s important for your practice to assess your data submission method. There are multiple methods of submission and each can get you different overall point values.

Each year, it’s important to assess the method that is best for your practice. The AAN has invested heavily in your success in this program and has established the Axon Registry ®, free to US neurologist AAN members. The registry provides a free submission method that works well for practices with serverbased EHR systems and those EHRs that have agreed to send data directly to a registry on a practice’s behalf. The Axon Registry can help your practice efficiently participate in the MIPS program.

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Axon Registry Simplifies Reporting Measures for MIPS

PODCAST CENTRAL Your Guide to New and Recent AAN Podcasts

Neurology Podcasts

Visit Neurology.org/podcast to listen to Neurology ® podcasts and earn 0.5 AMA PRA Category 1 CME Credits™ by answering the multiple-choice questions in the online podcast quiz. Interviews based on articles from Neurology ® Clinical Practice, Neurology ® Genetics, and Neurology ® Neuroimmunology & Neuroinflammation are excluded from the CME program.

Available by November 1

Neurology: Use of Newer Disease-modifying Therapies in Pediatric Multiple Sclerosis in the US Stacey Lynn Clardy, MD, PhD, and Kristen M. Krysko, MD Neurology: Gray Matter Differences in Patients with Functional Movement Disorders David A. Lapides, MD, and Carine W. Maurer, MD, PhD Neurology: Nusinersen in Spinal Muscular Atrophy Type 1 Patients Older than 7 Months: A Cohort Study John R. Mytinger, MD, and Laurent Servais, MD, PhD Neurology: Early Predictors of Mortality in Parkinsonism and Parkinson’s Disease: A Population-based Study Jeffrey B. Ratliff, MD, and David C. Bäckström, MD Neurology: Clinical Practice: Devastating Neurological Injuries in the Syrian War Jason L. Crowell, MD, and Maher Saqqur, MD Neurology: Clinical Practice: Presentation and Management of Community Onset vs. Hospital Onset First Seizures Katherine Zarroli, MD, and Emma Foster, MBBS Neurology: Clinical Practice: "Is there a neurologist on this flight?" An Update Jason L. Crowell, MD, and Joseph I. Sirven, MD, FAAN

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AANnews • November 2018

Quality Measures for Epilepsy and Neurotology Published The AAN has published updated epilepsy quality measures and new measures on neurotology. Several of the new measures will be added to the AAN’s Axon Registry® this year and existing Axon measures updated in the coming year.

the measures a little less daunting and usable for doctors. The quality of life outcome measure has been implemented in the Axon Registry, and updates for existing epilepsy measures in the registry are planned for 2019.”

Roberts An executive summary of the work of a new, two-year epilepsy standing work group was published in Neurology ® on October 3, 2018. The six measures included in the update address quality of life, intractable epilepsy, counseling for women with epilepsy, depression and anxiety, and seizure frequency. The work group is tasked with developing quality improvement and implementation tools to help physicians and neurology providers use the measures in practice. Several of these tools are now available at AAN.com/view/EpilepsyMeasures.

“We have created a calculator to score the quality of life measure and developed a summary of changes for the counseling for women with epilepsy measure,” said Marianna Spanaki, MD, PhD, MBA. “Also, we are collaborating with other AAN experts to update the existing pre-visit epilepsy questionnaire. The work group hopes these resources make

The new neurotology measures were published in Neurology ® on August 31, 2018. They were created with the American Academy of Otolaryngology-Head and Neck Surgery Foundation.

J. Kirk Roberts, MD, FAAN, noted, “These measures will give general neurologists and neurotologists the resources they need to track and improve care for patients with vertigo, including those with Ménière's disease, vestibular hypofunction, and vestibular migraine.” The five measures will help doctors and providers set benchmarks for quality of life, use of vestibular rehabilitation, performance of the Dix-Hallpike maneuver and canalith repositioning procedures, and standard management of benign paroxysmal positional vertigo. Two of the measures will be implemented in the Axon Registry next year.”

Spanaki

For more information on quality measures, contact Amy Bennett at abennett@aan.com. To learn how to join the Axon Registry, contact registry@aan.com. 

Learn How to Improve Your Relations with Payers continued from cover Webinar: Improving Payer Relations November 20, 2018 12:00 p.m.–1:00 p.m. ET Deadline to Register: November 19 Faculty: Elaine C. Jones, MD, FAAN You can purchase this single webinar for $99 or subscribe to the complete series of 2018 webinars for only $189—that’s less than $19 per webinar! All webinars are now available in the new AAN Online Learning Center and feature:

Improving Payer Relations

Register for FREE December 4 Webinar: E/M and QPP Changes for 2019 A free webinar—E/M and QPP Changes for 2019—will be offered on December 4 at 12:00 p.m.

ET. Faculty Sarah M. Benish, MD, FAAN, and Bruce H. Cohen, MD, FAAN, will help attendees: Understand payment changes in the Medicare Physician Fee Schedule effective January 1, 2019

Convenient one-hour live webinar sessions from 12:00 p.m.–1:00 p.m. ET

Review final MACRA reporting requirements for 2018

On-demand access to webinar recording and presentation slides if you miss the live event

Learn how to implement new procedure codes (CPT) effective January 1, 2019

1 AMA PRA Category 1 Credit™ per webinar for physicians, or certificate of completion for non-physicians

Identify opportunities and challenges for neurology practices based on final regulations

Visit AAN.com/view/pmw18 to learn more and register or contact Jessica Nickrand at jnickrand@aan.com. 

Register by December 3 at AAN.com/view/pmw18. 

AANnews • November 2018 9

Policy & Guidelines

We’ve Got Your Back: Regulatory Advocacy, Payer Relations, and the AAN The AAN supports neurologists in seeking fair reimbursement and coverage. When we succeed, you should be able to treat your patients and get reimbursed for your time and effort without the process feeling overly burdensome or unfair. While our goal is to make these systems feel seamless, behind the scenes the AAN is working to keep these processes running smoothly through proactive regulatory advocacy and building payer relationships.

Regulatory Advocacy

Regulatory advocacy involves agencies within the US Department of Health and Human Services (HHS). This includes the Centers for Medicare & Medicaid Services (CMS), the Food and Drug Administration (FDA), the Centers for Disease Control and Prevention, and more. CMS is a major focus of the AAN’s Medical Economics and Management Committee, which guides our regulatory advocacy efforts. The agency sets Medicare reimbursement rates each year and other policies related to the government insurance program. CMS is especially important because private payers often model their own policies upon what Medicare has implemented. The FDA is also important as it helps regulate the medications and devices that neurologists and their patients use every day.

The AAN engages in proactive regulatory advocacy. This means advocating in front of federal agencies before they make rules that impact neurologists and their patients. The Academy routinely meets with regulators, such as HHS leadership in Washington, DC, and CMS staff in the agency’s Baltimore, MD, headquarters. Through the first half of 2019, the AAN met with regulators 10 times to discuss priorities such as reducing regulatory hassles and improving cognitive reimbursement.

The AAN’s proactive regulatory advocacy recently delivered value to members when our advocacy resulted in HHS reducing penalties related to performance in Medicare quality programs. The AAN estimates that the associated regulatory changes saved neurologists up to $13 million in potential penalties.

discussions with the Academy, the payer rescinded the policy.

By proactively building these relationships and establishing ourselves as reliable experts who are willing to work collaboratively, the AAN can be effectively reactive and advocate for our members when issues arise.

Teamwork

Our advocacy efforts do not happen in a vacuum. The AAN’s regulatory efforts in Washington, DC, often involve teamwork with legislative colleagues who lobby members of Congress on behalf of the AAN. For example, during the period of July through September, AAN regulatory staff met five times with HHS staff and leadership, including the deputy secretary of HHS, to discuss the recent proposal changing the structure of evaluation and management (E/M) codes. Parallel to our regulatory efforts that produced a 39-page comment letter on the subject, AAN legislative staff pushed our message through Congress by lobbying individual offices on the subject. This resulted in two bipartisan letters signed by 24 senators and 90 representatives that were submitted to CMS in opposition to the proposed E/M proposal. We also collaborate on coverage issues, making sure to coordinate comment letters to Medicare administrative contractors with comment letters to commercial payers.

Additionally, the AAN submits formal comment letters in response to HHS regulations. This usually involves digesting thousands of pages published by the agency and responding to questions posed in a proposed regulation. Generally, the AAN, along with the entire public, is given 60 days to reply to HHS proposals. The agency must review these responses and then submit an updated, final regulation.

Commercial Payer Relations

The AAN also supports its members when it comes to commercial payers. The AAN’s Payment Policy Subcommittee exists to build relationships with these payers so that we can quickly and effectively advocate for our members when they encounter an issue. For example, this year one of the largest payers in the country proposed changes to its intraoperative neurophysiological monitoring policy that would have limited both access and reimbursement. The AAN contacted the payer’s medical directors it has worked with over the years and arranged a meeting with the Payment Policy Subcommittee and one of our member experts. After

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AANnews • November 2018

Resources

We also support our members on an individual level through education and resources. For example, the AAN offers a Practice Management Webinar on November 20 on “Improving Payer Relations.” Members can email practice@aan.com with specific coding and reimbursement questions. In addition to providing guidance, we can put you in touch with local resources such as state neurosocieties that may be able to support your needs. 

AAN Publishes Evidence in Focus: Nusinersen Use in SMA The AAN published Evidence in Focus: Nusinersen Use in Spinal Muscular Atrophy online in Neurology® on October 12, 2018. This publication was endorsed by the Child Neurology Society and the American Academy of Pediatrics.

Spinal muscular atrophy (SMA) is an inherited disease of the anterior horn cells that causes progressive muscle weakness

and disability. Before nusinersen, there were no treatments that ameliorated the course of the disease.

Now, there is high-level evidence from clinical trials of a solid benefit of nusinersen treatment for infants and children with SMA types 1 and 2.

Benefits ranged from improved motor function to improved potential for living

without a ventilator. More benefits were seen with early treatment and in the most severe forms of SMA, and few side effects were reported.

A patient summary, patient Q&A, and slide presentation set are available on AAN.com. For more information, contact Scott Wessels at (612) 928-6056. 

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Policy & Guidelines

AAN Advocacy Continues to Push Neuro Research Funding Higher After years of flat or declining funding, Congress has prioritized medical research at the National Institutes of Health during the last three budget cycles, thanks, in part, to intense lobbying by the AAN and its members. The federal FY2018 omnibus spending bill included more than $2 billion in increased spending on brain research.

In September, Congress passed the FY2019 Labor-EducationHHS budget, and again AAN advocacy helped pave the way for significant research increases, including: $39.1 billion for the National Institutes of Health (NIH), a $2 billion increase $2.22 billion for NINDS, a $71.77 million increase $2.34 billion for Alzheimer’s disease research, a $425 million increase $429 million for the BRAIN Initiative, a $29 million increase Opioids: $500 million in dedicated funding for research related to opioid addiction, development of opioid alternatives, pain management, and addiction treatment. Funding is provided equally to NINDS and the National Institute on Drug Abuse.

The committee notes that this is in addition to the $774 million NIH is expected to spend in base funding for opioid misuse and addiction treatment as well as pain research.

$7.9 billion for the Centers for Disease Control and Prevention, which, after removing a one-time funding allocation completed in FY2018, is comparable to last year’s budget, and includes $5 million for National Neurological Conditions Surveillance System

Education and Personal Experiences Help Create Congressional Allies

involvement in supporting NIH funding and getting the 21st Century Cures Act passed. We then had a nice roundtable discussion regarding how the NIH might be better focused on translational research to find neurological cures, among other topics. I also advocated for him to help us in our fight against the new CMS coding change proposals, which would be devastating for neurology. He was very receptive and is a great advocate for us; his brother has Parkinson’s and his mother has advanced Alzheimer’s, so he has been personally touched by these issues.”

Establishing Trust Can Make a Difference David Q. Beversdorf, MD, FAAN, conducts brain research at the University of Missouri. He has participated in the AAN’s Neurology on the Hill and the Palatucci Advocacy Leadership Forum, and contributes to the Academy’s BrainPAC political action committee to help educate members of Congress. He’s also been involved in other advocacy activities, such as the Rally for Medical Research, the Society for Neuroscience Hill Day, and the Society for Neuroscience Government and Public Affairs Committee. He shared his tactics to promote increased research funding with one of his state’s senators in a recent Capitol Hill Report.

“Over the years, you can build relationships with the teams supporting your elected officials. You can also serve as a resource for them for related issues. Additionally, you will serve as a trusted source for them when a new issue comes up. This

These increases are not solely the result of pressure from AAN leadership and staff. Concerned members like Clifton L. Gooch, MD, FAAN, are stepping forward to educate lawmakers, helping to distill dry budget appropriations and complex science into highly personal terms for his district congressman, Rep. Gus Bilirakis (R-FL).

“I was pleased to host Congressman Bilirakis here at the University of South Florida,” said Gooch, “and gave him a presentation which outlined the coming epidemic in neurological diseases (using my burden of disease article in the February 15, 2017, Annals of Neurology). I then proceeded to make the case for greater funding for neurological research and advocacy, while thanking him for his pivotal

From left: Stephen B. Liggett, MD, USF associate vice president for research; Rep. Gus Bilirakis; Clifton L. Gooch, MD, FAAN, chair of USF neurology; Glenn Currier, MD, MPH, chair of USF psychiatry.

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AANnews • November 2018

has been helpful when issues have arisen that affect us as clinicians, such as the recently proposed E/M changes, where I am able to have a strong voice due to building a relationship.”

Beversdorf continued, “It is also important to recognize the positions held by your elected officials. Sen. Roy Blunt from Missouri is chair of the committee responsible for allocating the budget for NIH. He has been a staunch supporter for biomedical research. He is to a great extent responsible for the recent increases in NIH funding. I make a point to reach out to his team, and they have come to know me in this role.

This leads to the final point: SAY THANK YOU! Sometimes the decisions made by our representatives come with some heat from some of their varied constituents. They need to know, in no uncertain terms, how much their efforts are appreciated when they support us in our needs! Thanks to these very representatives, federal funding in research has taken a significant positive turn in the last few years. Educating them about its importance is up to us, as well as communicating our appreciation for their support. I believe that the combined efforts of the research community in this regard has contributed to this outcome.”

Federal Funding Pivotal to BRAIN Initiative Research At the University of Alabama-Birmingham, AAN member Harrison C. Walker III, MD, is the principal investigator for a grant from the BRAIN Initiative, which the Academy has championed since it was launched by the Obama administration in 2013. Walker’s five-year, $7.3 million grant, which began in November 2016, focuses on directional vs. circular deep brain stimulation (DBS) to help treat Parkinson’s disease. He also receives funding from the Michael J. Fox Foundation to understand and treat dystonia related to Parkinson’s with DBS. “Foundation funding is great for feasibility testing. The AAN and other foundations provide critical support that lay the groundwork for larger studies,” said Walker, who is one of several people at UAB working on the BRAIN Initiativesupported research. “The BRAIN Initiative is unique in that it focuses on advancing neuromodulation technologies in patients, both for established and emerging indications. This programmatic focus has opened doors for human studies that were less accessible under traditional funding mechanisms.

This research is critical to translate advances from all levels of neuroscience into clinical practice.”

To Walker, a donor to the AAN’s BrainPAC political action committee, “Advocacy is the biggest benefit of the AAN.” And it is a benefit that can, and will, help millions of lives beyond the AAN’s membership. 

Capitol Hill Report Capitol Hill Report presents regular updates on legislative and regulatory actions and how the Academy ensures that the voice of neurology is heard on Capitol Hill. It is emailed to US members twice monthly and is posted at AAN.com/view/HillReport. Below are some recent highlights..

Big Wins for AAN Advocacy in Final FY2019 Appropriations and Opioids Legislation President Trump signed the FY2019 appropriations bill containing full-year funding for the Departments of Defense, Education, Labor, and Health and Human Services, and stopgap funding to extend other federal agencies at current spending levels until December 7. The final legislation includes HUGE wins for neurology, including: $2 billion increase for the NIH; $29 million increase for the BRAIN Initiative; $425 million increase in Alzheimer’s research; and$5 million to establish the National Neurological Conditions Surveillance System.

Congress passed a comprehensive opioids legislative package, the SUPPORT for Patients and Communities Act. The final legislation includes the following AAN-supported provisions: The ACE Research Act gives the National Institutes of Health more flexibility in funding research on pain and opioid addiction The Standardizing ePA for Safe Prescribing Act standardizes electronic prior authorization in Medicare Part D and Medicare Advantage The Fighting the Opioid Epidemic with Sunshine Act of 2018 expands Open Payments to include nurse practitioners and physician assistants

AAN Responds to Proposed ACO Redesign The AAN submitted comments in response to a proposed rule from CMS to restructure the Medicare Shared Savings Program. The AAN’s comments primarily addressed its opposition to the proposed redesign of the available Accountable Care Organization (ACO) tracks, which would limit availability of one-sided risk models. The comments also discussed the need for additional opportunities for neurologists who want to participate in value-based arrangements. 

AANnews • November 2018 13

Conferences & Community

2019 Annual Meeting­— Why Should You Attend?

Why Should You Attend?

Science

A high-quality, innovative science experience like no other: Six cutting-edge Plenary Sessions Poster sessions—both in-person and interactive digital— featuring the latest research Partnerships with other associations featuring encore presentations of top abstracts Enhanced awards recognition to celebrate scientific achievements by AAN members

Education Customizable, experiential, and inspirational learning opportunities for professional and personal knowledge and growth:

continued from cover

New Opportunities!

See what’s new in Philadelphia: Innovative Inspirational Talks Four talks throughout the week will explore where neuroscience intersects with global themes. Explore subjects like how neuroscience is at the forefront of the Flint, MI, water crisis or what happens when neuroscience and philosophy collide.

Immersive Learning Immerse yourself in the brain’s inner workings with a guided audio-visual tour through a larger-than-life brain.

Specialty tracks to help you get the most out of your time

Experience Science in a Grand Way Research, navigating careers, awards, presentations, and more. Find out what the buzz is about in this new space.

Experiential learning areas for creative, innovative, and interactive learning

Friday Grand Finale Programming Stick around for an enhanced Friday experience, including

“Continuing the Conversation” and “What Do I Do Now?” opportunities after select courses

Networking

Unparalleled networking opportunities within your community of more than 14,000 neurology professionals from around the globe.

LeadershipTraining: 18 Leadership Ad—Half Page Horizontal> AN Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

Neurology Year in Review Plenary Session Science Innovation Lunch Neurology Update Programs and Scientific Sessions Education Blitz Programs Closing Party Celebrating May Day

Learn more and secure your hotel and the best savings by visiting AAN.com/view/AM19 today! 

Cultivating Leaders. Building Neurology’s Future.

From personal development opportunities to transformational career pathways, the AAN is here to guide your leadership growth. Apply for one of 10 unique opportunities covering the full spectrum of career stages.

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AAN.com/view/lead

AANnews • November 2018

BECAUSE OF YOU 2017 BY THE NUMBERS...

21

W O R LD ’S FIR ST N EU R O SC IENCE

CRO WD F U NDING

Projects Posted

PL ATFO R M L A U NC H ED

26 Active early career research projects

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Your help today will do more tomorrow.

The next research project could be the one…

New scholarships for cognitive aging and age-related memory loss

Support our research efforts by making a gift at

AmericanBrainFoundation.org

AANnews • November 2018 15

Conferences & Community

AAN Study Shows Gender and Age Differences in Burnout Among Neurologists A new study by the AAN found that 65 percent of female neurologists experienced at least one symptom of burnout compared Busis LaFaver to 58 percent of male neurologists, but overall burnout rates were similar when adjusted for age.

The results are published in the October 10, 2018, online issue of Neurology ® and in print on November 13, 2018. The study also found that various aspects of burnout were influenced by gender and age.

Higher burnout risk among women was associated with a greater number of weekends doing hospital rounds.

Women indicated they experienced the workplace in a different manner than men, with comments reflecting pay inequity, higher expectations for non-paid work, and less administrative support.

The qualitative and quantitative analysis is the fourth and final study based on responses from neurologists to the 2016 AAN survey that examined burnout, career satisfaction, and well-being among neurologists in the United States.

The study also examined age as a factor for burnout and found for both genders that emotional exhaustion, quality of life, and physical fatigue initially increased with age and then decreased as neurologists got older.

“Although overall burnout rates were the same for women and men when adjusted for age, the characteristics and experience of the workplace and burnout differed,” said Kathrin LaFaver, MD, FAAN, lead author and member of the AAN Gender Disparities Task Force. “The difficulties that come with a successful neurology practice may be intensified in female neurologists, who, on average, spend more time with their patients than male neurologists. Women in our study also practiced more often in lower earning subspecialties, which may contribute to lower feelings of accomplishment or recognition.”

For the study, authors evaluated survey responses from 580 female neurologists and 1,091 male neurologists.

Female respondents were about seven years younger, were 7 percent more likely to work in academic positions, 13 percent more likely to be employed at a hospital, and had eight fewer years in practice.

For both women and men, lower burnout risk was associated with greater autonomy, more meaning in work, and having effective support staff. Higher burnout risk was associated with more hours worked, more nights on call, higher outpatient volume, and a higher percentage of time in clinical practice.

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AANnews • November 2018

Other findings include the following: 10 percent lower work-life balance was reported by women than men 6 percent fewer women were satisfied with their job than men 10 percent fewer women than men indicated they would choose to be a physician again

“Solutions to prevent burnout and promote career satisfaction and well-being should focus on systemic and cultural changes and also include initiatives at the individual level,” said Neil A. Busis, MD, FAAN, senior author and member of the AAN Wellness Task Force and co-chair of the study group researching the issue. “The differences we have identified for gender and age, and the insights the AAN has gained through all four studies, will guide the AAN as it develops strategies to prevent and mitigate burnout and promote professional fulfillment for all neurologists.”

To learn more about tips, tools, and strategies to help mitigate burnout and to read the study, visit AAN.com/LiveWell. 

Improving Work-life Balance Helps Diversity Leadership Program Participant Achieve Key Goal As a Native American neurologist working in rural Arizona, Michael Stitzer, MD, had a goal he wanted to attain to broaden his impact on his community. But he also knew that job burnout—which affects neurologists at the highest rate within the medical field—could be a threat to reaching this goal.

Stitzer is the sole neurologist at the multi-specialty Winslow Indian Health Care Center in rural Arizona, working primarily with family practice and urgent care providers, “two other groups also at high risk of burnout,” he said.

AAN. “This was a great experience and gave me knowledge and tools I continue to use today,” said Stitzer. He has shared what he’s learned about burnout and balance at the forum with others at his clinic. A portion of his HeadTalks presentations on rural neurology at the 2017 and 2018 AAN Annual Meetings also addressed this important topic.

Then Stitzer applied for and was accepted into the AAN’s Diversity Leadership Program, and things began to fall into place for him.

“Helping my wife as she leads our local chapter of Healthy Kids Running Series, making time to get to some of my daughter’s after-school dance classes, and enjoying the wonders my preschool-age son sees in the everyday world have all been as rewarding as anything I’ve done professionally in the last few years,” he added.

“Part of the assessments we went over and the readings we discussed in the program were about working on personal goals,” said Stitzer. “For me, a chief one was maintaining worklife balance as my leadership roles grow. I’ve got an amazing, supportive wife and two wonderful young children, and making sure I’m being efficient in working toward my professional goals and also putting my personal goals on equal footing has been an effective way in keeping that balance.”

According to Stitzer, the program taught him a new framework for mapping out both the tactics and strategy needed for a goal well in advance, making sure to periodically block out time to revise the tactics, as needed, and periodically assessing short- and long-term goals in both professional and personal life to ensure they are in balance. “I’ve been sure to take the time every four to six months to apply the framework from the Diversity Leadership Program, and I feel that helps ensure I’m maximizing my time and energy in a smart way,” he said.

Stitzer’s improved understanding in how to strike work-life balance was key in his ability to effectively expand his role within his institution—a goal he’s had since joining in 2012. He was recently appointed to the Indian Health Service’s National Council of Chief Clinical Consultants and credits the training and mentoring he received from the Diversity Leadership Program with helping him achieve the initial goal of role creation right up to appointment. “I’ve taken those same skills to start building the plan to improve care for patients with neurologic diseases across the institution over the next several years,” he explained, “and one of the first steps will be restarting a multi-specialty conference next year, geared towards primary providers within Indian Health Services, where I’ll give several courses on common neurologic diseases and the current standards of care.”

Stitzer

Since graduating from the Diversity Leadership Program, Stitzer has also increased his work on diversity issues within the AAN by participating in the AAN’s Health Care Disparities Task Force and on the Diversity Leadership Subcommittee.

Perhaps more than any specific skill, Stitzer is quick to point out the most important thing he took away from the Diversity Leadership Program was the invaluable connections to his mentor, coach, peers, and others in the AAN. “I work in a rural area and am the sole neurologist in my multi-specialty practice, so the interactions and collaborations started in 2016 and since have been invaluable. These connections remain active through formal and informal gatherings at the past two AAN Annual Meetings, and via the Academy’s Synapse community for Leadership Alumni. And I’ve reached out to both my tribe in California and the Indian Health Center’s Indians Into Medicine Program grant recipient at the University of Arizona about mentoring any students interested in neuroscience, neurology, or the medical field in general.”

The AAN wants to help members like Stitzer—and like you— achieve their fullest potential and have the greatest possible positive impact on their patients and communities. Learn more about the AAN’s multiple leadership training opportunities at AAN.com/conferences-community/leadership-programs. 

In addition, Stitzer’s interest in the topic of work-life balance led to his participation in the ABPN’s Physician Burnout Crucial Issues Forum, a role in which he represented the

AANnews • November 2018 17

BECAUSE RELAPSING MS AFFECTS MORE THAN HER. . .

NEWLY DIAGNOSED PATIENTS DESERVE THE #1 PRESCRIBED ORAL RMS THERAPY 1,2*†

Indication

Tecfidera® (dimethyl fumarate) is indicated for adults with relapsing forms of multiple sclerosis.

Important Safety Information

TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or any of the excipients of TECFIDERA. TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Patients experiencing signs and symptoms of anaphylaxis and angioedema (which have included difficulty breathing, urticaria, and swelling of the throat and tongue) should discontinue TECFIDERA and seek immediate medical care.

Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received TECFIDERA in a clinical trial. PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x109/L. The symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. At the first sign or symptom suggestive of PML, withhold

TECFIDERA and perform an appropriate diagnostic evaluation. MRI findings may be apparent before clinical signs or symptoms.

TECFIDERA may decrease lymphocyte counts; in clinical trials there was a mean decrease of ~30% in lymphocyte counts during the first year which then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but not to baseline.

Six percent of TECFIDERA patients and <1% of placebo patients had lymphocyte counts <0.5x109/L. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or ≤0.5x109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years). In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x109/L for at least six months. In these patients, the majority of lymphocyte counts remained <0.5x109/L with continued therapy. A complete blood count including lymphocyte count should be obtained before initiating treatment, 6 months after starting, every 6 to 12 months thereafter and as clinically indicated. Consider treatment interruption if lymphocyte counts <0.5x109/L persist for more than six months and follow lymphocyte counts until lymphopenia is resolved. Consider withholding treatment in patients with serious infections until resolved. Decisions about whether or not to restart TECFIDERA should be based on clinical circumstances.

Clinically significant cases of liver injury have been reported in

49

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IN THE DEFINE‡ CLINICAL TRIAL, PATIENTS WERE:

%

LESS LIKELY TO EXPERIENCE

A RELAPSE3§ TECFIDERA: 27% (n=410) Placebo: 46% (n=408) [P<0.0001] Based on proportion of patients relapsed (PPR)||

%

LESS LIKELY TO EXPERIENCE

DISABILITY PROGRESSION3¶

TECFIDERA: 16% (n=410) Placebo: 27% (n=408) [P=0.0050]

84% OF PATIENTS IN THE DEFINE TRIAL WERE FREE OF DISABILITY PROGRESSION VS 73% OF PLACEBO PATIENTS3

IN A SEPARATE ANALYSIS, THE NEWLY DIAGNOSED PATIENTS FROM THE PIVOTAL TRIALS WERE:

71

%

LESS LIKELY TO EXPERIENCE

DISABILITY PROGRESSION1

TECFIDERA: 0.073 (n=221) Placebo: 0.233 (n=223) [P<0.0001]

STUDY DESIGN: This post hoc analysis of integrated data from DEFINE and CONFIRM# was conducted to examine the efficacy and safety of TECFIDERA in 678 newly diagnosed patients (59% of patients in DEFINE and 71% in CONFIRM were treatment-naive4,5). The newly diagnosed population included patients who had been diagnosed with RRMS within 1 year prior to study entry and were naive to MS disease-modifying therapy. The analysis included clinical and neuroradiological efficacy endpoints as well as basic safety data, or adverse events. This study was not designed in advance to analyze the endpoints presented in the subgroup of newly diagnosed patients.1 Most common adverse events reported in patients receiving TECFIDERA compared with placebo included flushing, nasopharyngitis, headache, diarrhea, nausea, upper abdominal pain, and abdominal pain.3

Important Safety Information (cont’d)

patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death. However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.

Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials.

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels before initiating TECFIDERA and during treatment, as clinically indicated. Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected.

TECFIDERA may cause flushing (e.g. warmth, redness, itching, and/or burning sensation). 40% of patients taking TECFIDERA reported flushing, which was mostly mild to moderate in severity.

Three percent of patients discontinued TECFIDERA for flushing and <1% had serious flushing events that led to hospitalization.

Taking TECFIDERA with food may reduce flushing. Alternatively, administration of non-enteric coated aspirin prior to dosing may reduce the incidence or severity of flushing.

TECFIDERA may cause gastrointestinal (GI) events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). Four percent of TECFIDERA patients and <1% of placebo patients discontinued due to GI events. The incidence of serious GI events was 1%. The most common adverse reactions associated with TECFIDERA

versus placebo are flushing (40% vs 6%) and GI events: abdominal pain (18% vs 10%), diarrhea (14% vs 11%), nausea (12% vs 9%).

A transient increase in mean eosinophil counts was seen during the first two months.

TECFIDERA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Encourage patients who become pregnant while taking TECFIDERA to enroll in the TECFIDERA pregnancy registry by calling 1-866-810-1462 or visiting www.TECFIDERApregnancyregistry.com.

For additional Important Safety Information, please see adjacent Brief Summary of full Prescribing Information. *TECFIDERA is approved for adult patients only. † Based on prescriptions. ‡ Determination of Efficacy and Safety of Oral Fumarate in RelapsingRemitting MS.4 § Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted for at least 24 hours and were accompanied by new objective neurologic findings.4 || PPR is the percentage of patients who had one or more relapses over the course of the trial.4 ¶ Disability progression is defined as at least a 1-point increase from baseline EDSS of ≥1.0, OR at least a 1.5-point increase for patients with baseline EDSS of 0 sustained for 12 weeks.3 # Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis.5 References: 1. Gold R, Giovannoni G, Phillips JT, et al. Mult Scler.

2015;21(1):57-66. 2. IMS data September 27, 2013-December 8, 2017.

3. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 4. Gold R, Kappos L, Arnold DL, et al. N Engl J Med. 2012;367:10981107. Erratum in: N Engl J Med. 2012;367:2362. 5. Fox RJ, Miller DH, Phillips JT, et al. N Engl J Med. 2012;367:1087-1097. Erratum in: N Engl J Med. 2012;367:1673. © 2018 Biogen. All rights reserved. 02/18 TEC-US-2505

Tecfidera® (dimethyl fumarate) delayed-release capsules, for oral use Brief Summary of Full Prescribing Information 1 INDICATIONS AND USAGE TECFIDERA is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing Information The starting dose for TECFIDERA is 120 mg twice a day orally. After 7 days, the dose should be increased to the maintenance dose of 240 mg twice a day orally. Temporary dose reductions to 120 mg twice a day may be considered for individuals who do not tolerate the maintenance dose. Within 4 weeks, the recommended dose of 240 mg twice a day should be resumed. Discontinuation of TECFIDERA should be considered for patients unable to tolerate return to the maintenance dose. The incidence of flushing may be reduced by administration of TECFIDERA with food. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Clinical Pharmacology (12.3)].

TECFIDERA should be swallowed whole and intact. TECFIDERA should not be crushed or chewed and the capsule contents should not be sprinkled on food. TECFIDERA can be taken with or without food.

2.2 Blood Tests Prior to Initiation of Therapy Obtain a complete blood cell count (CBC) including lymphocyte count before initiation of therapy [see Warnings and Precautions (5.3)].

Obtain serum aminotransferase, alkaline phosphatase, and total bilirubin levels prior to treatment with TECFIDERA [see Warnings and Precautions (5.4)].

3 DOSAGE FORMS AND STRENGTHS TECFIDERA is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The 120 mg capsules have a green cap and white body, printed with “BG-12 120 mg” in black ink on the body. The 240 mg capsules have a green cap and a green body, printed with “BG-12 240 mg” in black ink on the body.

4 CONTRAINDICATIONS TECFIDERA is contraindicated in patients with known hypersensitivity to dimethyl fumarate or to any of the excipients of TECFIDERA. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Anaphylaxis and Angioedema TECFIDERA can cause anaphylaxis and angioedema after the first dose or at any time during treatment. Signs and symptoms have included difficulty breathing, urticaria, and swelling of the throat and tongue.

Patients should be instructed to discontinue TECFIDERA and seek immediate medical care should they experience signs and symptoms of anaphylaxis or angioedema.

5.2 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) has occurred in patients with MS treated with TECFIDERA. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability. A fatal case of PML occurred in a patient who received TECFIDERA for 4 years while enrolled in a clinical trial. During the clinical trial, the patient experienced prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years) while taking TECFIDERA [see Warnings and Precautions (5.3)].

The patient had no other identified systemic medical conditions resulting in compromised immune system function and had not previously been treated with natalizumab, which has a known association with PML. The patient was also not taking any immunosuppressive or immunomodulatory medications concomitantly.

PML has also occurred in the postmarketing setting in the presence of lymphopenia (<0.8x109/L) persisting for more than 6 months. While the role of lymphopenia in these cases is uncertain, the majority of cases occurred in patients with lymphocyte counts <0.5x109/L. At the first sign or symptom suggestive of PML, withhold TECFIDERA and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported in patients treated with

other MS medications associated with PML. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Lower PML-related mortality and morbidity have been reported following discontinuation of another MS medication associated with PML in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of MS treatment or due to differences in disease in these patients.

5.3 Lymphopenia TECFIDERA may decrease lymphocyte counts. In the MS placebo controlled trials, mean lymphocyte counts decreased by approximately 30% during the first year of treatment with TECFIDERA and then remained stable. Four weeks after stopping TECFIDERA, mean lymphocyte counts increased but did not return to baseline. Six percent (6%) of TECFIDERA patients and <1% of placebo patients experienced lymphocyte counts <0.5x109/L (lower limit of normal 0.91x109/L). The incidence of infections (60% vs 58%) and serious infections (2% vs 2%) was similar in patients treated with TECFIDERA or placebo, respectively.

There was no increased incidence of serious infections observed in patients with lymphocyte counts <0.8x109/L or ≤0.5x109/L in controlled trials, although one patient in an extension study developed PML in the setting of prolonged lymphopenia (lymphocyte counts predominantly <0.5x109/L for 3.5 years) [see Warnings and Precautions (5.2)]. In controlled and uncontrolled clinical trials, 2% of patients experienced lymphocyte counts <0.5x109/L for at least six months, and in this group the majority of lymphocyte counts remained <0.5x109/L with continued therapy. TECFIDERA has not been studied in patients with pre-existing low lymphocyte counts.

Obtain a CBC, including lymphocyte count, before initiating treatment with TECFIDERA, 6 months after starting treatment, and then every 6 to 12 months thereafter, and as clinically indicated. Consider interruption of TECFIDERA in patients with lymphocyte counts less than 0.5x109/L persisting for more than six months. Given the potential for delayed recovery of lymphocyte counts, continue to obtain lymphocyte counts until their recovery if TECFIDERA is discontinued or interrupted due to lymphopenia. Consider withholding treatment from patients with serious infections until resolution. Decisions about whether or not to restart TECFIDERA should be individualized based on clinical circumstances.

5.4 Liver Injury Clinically significant cases of liver injury have been reported in patients treated with TECFIDERA in the postmarketing setting. The onset has ranged from a few days to several months after initiation of treatment with TECFIDERA. Signs and symptoms of liver injury, including elevation of serum aminotransferases to greater than 5-fold the upper limit of normal and elevation of total bilirubin to greater than 2-fold the upper limit of normal have been observed. These abnormalities resolved upon treatment discontinuation. Some cases required hospitalization. None of the reported cases resulted in liver failure, liver transplant, or death.

However, the combination of new serum aminotransferase elevations with increased levels of bilirubin caused by drug-induced hepatocellular injury is an important predictor of serious liver injury that may lead to acute liver failure, liver transplant, or death in some patients.

Elevations of hepatic transaminases (most no greater than 3 times the upper limit of normal) were observed during controlled trials [see Adverse Reactions (6.1)].

Obtain serum aminotransferase, alkaline phosphatase (ALP), and total bilirubin levels prior to treatment with TECFIDERA and during treatment, as clinically indicated. Discontinue TECFIDERA if clinically significant liver injury induced by TECFIDERA is suspected.

5.5 Flushing TECFIDERA may cause flushing (e.g., warmth, redness, itching, and/or burning sensation). In clinical trials, 40% of TECFIDERA treated patients experienced flushing. Flushing symptoms generally began soon after initiating TECFIDERA and usually improved or resolved over time. In the majority of patients who experienced flushing, it was mild or moderate in severity. Three percent (3%) of patients discontinued TECFIDERA for flushing and <1% had serious flushing symptoms that were not lifethreatening but led to hospitalization. Administration of TECFIDERA with food may reduce the incidence of flushing. Alternatively, administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to TECFIDERA dosing may reduce the incidence or severity of flushing [see Dosing and Administration (2.1) and Clinical Pharmacology (12.3)].

6 ADVERSE REACTIONS The following important adverse reactions are described elsewhere in labeling: Anaphylaxis and Angioedema (5.1), Progressive multifocal leukoencephalopathy (5.2), Lymphopenia (5.3), Liver Injury (5.4), Flushing (5.5) [see Warnings and Precautions].

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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.

The most common adverse reactions (incidence ≥10% and ≥2% more than placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.

Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness, 1529 patients received TECFIDERA with an overall exposure of 2244 person-years [see Clinical Studies (14)].

The adverse reactions presented in the table below are based on safety information from 769 patients treated with TECFIDERA 240 mg twice a day and 771 placebo-treated patients.

Table 1: Adverse Reactions in Study 1 and 2 reported for TECFIDERA 240 mg BID at ≥2% higher incidence than placebo

Flushing Abdominal pain Diarrhea Nausea Vomiting Pruritus Rash Albumin urine present Erythema Dyspepsia Aspartate aminotransferase increased Lymphopenia

TECFIDERA N=769 %

Placebo N=771 %

40 18 14 12 9 8 8 6 5 5 4 2

6 10 11 9 5 4 3 4 1 3 2 <1

Gastrointestinal TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). The incidence of GI events was higher early in the course of treatment (primarily in month 1) and usually decreased over time in patients treated with TECFIDERA compared with placebo. Four percent (4%) of patients treated with TECFIDERA and less than 1% of placebo patients discontinued due to gastrointestinal events. The incidence of serious GI events was 1% in patients treated with TECFIDERA. Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA was seen primarily during the first six months of treatment, and most patients with elevations had levels <3 times the upper limit of normal (ULN) during controlled trials.

Elevations of alanine aminotransferase and aspartate aminotransferase to ≥3 times the ULN occurred in a small number of patients treated with both TECFIDERA and placebo and were balanced between groups. There were no elevations in transaminases ≥3 times the ULN with concomitant elevations in total bilirubin >2 times the ULN. Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with TECFIDERA or placebo.

Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 months of therapy.

Adverse Reactions in Placebo-Controlled and Uncontrolled Studies In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have received TECFIDERA and been followed for periods up to 4 years with an overall exposure of 4603 person-years. Approximately 1162 patients have received more than 2 years of treatment with TECFIDERA. The adverse reaction profile of TECFIDERA in the uncontrolled clinical studies was consistent with the experience in the placebo-controlled clinical trials.

6.2 Post Marketing Experience The following adverse reaction has been identified during post approval use of TECFIDERA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Liver function abnormalities (elevations in transaminases ≥3 times ULN with concomitant elevations in total bilirubin >2 times ULN) have been reported following TECFIDERA administration in post marketing experience [See Warnings and Precautions (5.4)].

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to TECFIDERA during pregnancy.

Encourage patients to enroll by calling 1-866-810-1462 or visiting www.tecfiderapregnancyregistry.com.

Risk Summary There are no adequate data on the developmental risk associated with the use of TECFIDERA in pregnant women. In animals, adverse effects on offspring survival, growth, sexual maturation, and neurobehavioral function were observed when dimethyl fumarate (DMF) was administered during pregnancy and lactation at clinically relevant doses. [see data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

Data Animal Data In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout organogenesis, embryofetal toxicity (reduced fetal body weight and delayed ossification) were observed at the highest dose tested. This dose also produced evidence of maternal toxicity (reduced body weight). Plasma exposure (AUC) for monomethyl fumarate (MMF), the major circulating metabolite, at the no-effect dose is approximately three times that in humans at the recommended human dose (RHD) of 480 mg/day. In rabbits administered DMF orally (25, 75, and 150 mg/kg/day) throughout organogenesis, embryolethality and decreased maternal body weight were observed at the highest dose tested. The plasma AUC for MMF at the no-effect dose is approximately 5 times that in humans at the RHD. Oral administration of DMF (25, 100, and 250 mg/kg/day) to rats throughout organogenesis and lactation resulted in increased lethality, persistent reductions in body weight, delayed sexual maturation (male and female pups), and reduced testicular weight at the highest dose tested. Neurobehavioral impairment was observed at all doses. A no-effect dose for developmental toxicity was not identified. The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD. 8.2 Lactation Risk Summary There are no data on the presence of DMF or MMF in human milk.

The effects on the breastfed infant and on milk production are unknown.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for TECFIDERA and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.

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

8.5 Geriatric Use Clinical studies of TECFIDERA did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

10 OVERDOSE Cases of overdose with TECFIDERA have been reported. The symptoms described in these cases were consistent with the known adverse event profile of TECFIDERA. There are no known therapeutic interventions to enhance elimination of TECFIDERA nor is there a known antidote. In the event of overdose, initiate symptomatic supportive treatment as clinically indicated.

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Dosage Inform patients that they will be provided two strengths of TECFIDERA when starting treatment: 120 mg capsules for the 7 day starter dose and 240 mg capsules for the maintenance dose, both to be taken twice daily. Inform patients to swallow TECFIDERA capsules whole and intact. Inform patients to not crush, chew, or sprinkle capsule contents on food. Inform patients that TECFIDERA can be taken with or without food [see Dosage and Administration (2.1)].

Anaphylaxis and Angioedema Advise patients to discontinue TECFIDERA and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.1)].

Progressive Multifocal Leukoencephalopathy Inform patients that progressive multifocal leukoencephalopathy (PML) has occurred in patients who received TECFIDERA. Inform the patient that PML is characterized by a progression of deficits and usually leads to death or severe disability over weeks or months.

Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Inform the patient that typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes [see Warnings and Precautions (5.2)].

Lymphocyte Counts Inform patients that TECFIDERA may decrease lymphocyte counts.

A blood test should be obtained before they start therapy. Blood tests are also recommended after 6 months of treatment, every 6 to 12 months thereafter, and as clinically indicated [see Warnings and Precautions (5.3), Adverse Reactions (6.1)].

Liver Injury Inform patients that TECFIDERA may cause liver injury. Instruct patients treated with TECFIDERA to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice. A blood test should be obtained before patients start therapy and during treatment, as clinically indicated [see Warnings and Precautions (5.4)].

Flushing and Gastrointestinal (GI) Reactions Flushing and GI reactions (abdominal pain, diarrhea, and nausea) are the most common reactions, especially at the initiation of therapy, and may decrease over time. Advise patients to contact their healthcare provider if they experience persistent and/or severe flushing or GI reactions. Advise patients experiencing flushing that taking TECFIDERA with food or taking a non-enteric coated aspirin prior to taking TECFIDERA may help [see Adverse Reactions (6.1)].

Pregnancy and Pregnancy Registry Instruct patients that if they are pregnant or plan to become pregnant while taking TECFIDERA they should inform their physician.

Encourage patients to enroll in the TECFIDERA Pregnancy Registry if they become pregnant while taking TECFIDERA. [see Use in Specific Populations (8.1)].

41347-09 Manufactured by: Biogen Cambridge, MA 02142 TECFIDERA is a trademark of Biogen. Š 2013-2017 Biogen 2/18

Conferences & Community

Volunteers Needed as 2019 Brain Health Fair Shifts to New Annual Meeting Day For the past several years, the AAN’s popular Brain Health Fair has been offered to the local communities the day prior to the Annual Meeting’s start. But for 2019, this event will be offered during the meeting, on Thursday, May 9, from 10:00 a.m. to 4:00 p.m. at the Pennsylvania Convention Center in Philadelphia.

The AAN seeks physician, resident, and medical student volunteers throughout the day to explain the wonders of the human brain and the myriad diseases that can affect it, as well as the many professional opportunities in neurology that young women and men could begin to consider.

Philadelphia

At the 2018 Brain Health Fair in Los Angeles—which attracted more than 2,500 people—the Academy piloted a successful daylong student scholarship program for more than 80 local high school students interested in neuroscience career paths, and this program will be brought back for 2019. The fair will continue to offer interactive, handson learning for attendees as well as up-to-date information for patients and caregivers on the latest treatments for major neurologic diseases.

If you are interested in participating in the Philadelphia Brain Health Fair, contact Martha Boyle at mboyle@aan.com for more information on volunteer opportunities. 

Retain Access to the Best Neurology Resources in 2019— Renew Today! continued from cover Your Academy is your single source for essential education, science, and support, including: Unique education opportunities to earn CME or MOC credits Up-to-date information on breakthrough scientific research Valuable clinical practice guidelines The latest news relevant to the profession Representation of your interests at the federal/state levels Special pricing on AAN products, services, or meetings Exclusive access to AAN.com member-only resources Renew today at AAN.com/dues and find the full list of exclusive member benefits at AAN.com/view/benefits. For more information, contact AAN Member Services at memberservices@aan.com, (800) 879-1960, or (612) 928-6000 (international).

Please note: All AAN Junior memberships are now on the academic year cycle, running July 1 to June 30. 

AANnews • November 2018 23

Education & Research

December 3 Is RITE Registration Deadline December 3 is the deadline to register for the 2019 RITE® (Residency In-service Training Examination), which will be given on February 13 through 17. RITE registration, RITE payment, and 2019 AAN membership dues must be paid in full by this date. The fee for AAN Junior members is $210. The deadline to cancel is December 20 and includes a $50 cancellation fee.

For the first time, the 2019 exam will move to computer-based administration. To administer the exam, programs will need to secure a proctored exam site at their home institution that is equipped with computer and internet access. Programs will need to work with their institution’s IT staff to ensure systems are ready well in advance of exam administration.

Learn more and apply at AAN.com/tools-and-resources/residents-fellows/ residency-in-service-training-examination-rite. For questions regarding AAN membership applications and dues payments, contact AAN Member Services at (800) 879-1960. 

18 Advocacy Awareness Ad, AANnews, Half Page Horizontal GE: High Resolution PDF to be placed in AANnews S: Trim Size 8.25"x5.25", Full Bleed +0.125", 4C

Read Capitol Hill Report We’re fighting to make sure the future of your patients and profession isn’t decided without your input. Read Capitol Hill Report to learn what we’re doing and how you can help.

Stay informed at AAN.com/view/HillReport.

Join the conversation using #AANAdvocacy.

24

AANnews • November 2018

DECEMBER

3

What is the Axon Registry ? ®

This free AAN US member benefit is a clinical quality improvement registry exclusively for neurology.

How will it impact your practice?

• • • • • •

Get real-time data feedback for quality improvement and assessment Meet MOC Part IV clinical module activity and eight credits of Part II self-assessment Benchmark against national performance rates Use neurology specialty and subspecialty measures Use for government reporting requirements such as MIPS Illustrate quality care for contract negotiations with payers

Learn more at AAN.com/view/Axon.

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NOW AVAILABLE: AN EQUAL GENERIC SUBSTITUTE WITH BRAND-QUALITY SUPPORT1 WHAT IS VIGADRONE™ VIGADRONE™ is vigabatrin powder for oral solution, that is mixed with water prior to administration, giving you another option for treatment of:

• Infantile Spasms (IS)—monotherapy in infants 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss.

• Refractory Complex Partial Seizures—adjunctive therapy in patients ≥10 years of age who have responded inadequately to several alternative treatments; VIGADRONE™ is not indicated as a first line agent.

WARNING: PERMANENT VISION LOSS See full Prescribing Information for complete Boxed Warning.

• VIGADRONE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGADRONE may also decrease visual acuity.

• Risk increases with increasing dose and cumulative exposure, but there is no dose or exposure to VIGADRONE known to be free of risk of vision loss.

• Risk of new and worsening vision loss continues as long as VIGADRONE is used, and possibly after discontinuing VIGADRONE. • Baseline and periodic vision assessment is recommended for patients on VIGADRONE. However, this assessment cannot always prevent vision damage.

• The onset of vision loss from VIGADRONE is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

• Because of the risk of permanent vision loss, VIGADRONE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program. Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

SUPPORT SERVICES FROM ACCESS PATHWAYS® The Access Pathways® Program for VIGADRONE™ strives to overcome obstacles of prescribing vigabatrin by providing a dedicated, experienced team that surrounds physicians, patients and caregivers with support. To learn more, visit VIGADRONE.com or contact Access Pathways® at 1-866-923-1954, Monday - Friday 8am to 9pm EST.

VIGABATRIN REMS PROGRAM The U.S. Food and Drug Administration (FDA) has approved a single shared system Risk Evaluation and Mitigation Strategy (REMS) for all vigabatrin products called the Vigabatrin REMS Program. It is required by the FDA to ensure informed risk-benefit decisions before initiating treatment and to ensure appropriate use of vigabatrin while patients are treated.

Visit the Vigabatrin REMS website (vigabatrinREMS.com) for instructions and the FDA-mandated REMS forms.

IMPORTANT SAFETY INFORMATION WARNINGS & PRECAUTIONS

• Permanent Vision Loss. VIGADRONE can cause permanent vision

•

• •

loss. The risk of vision loss increases with increasing the dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss. Patient response should be periodically assessed. Patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision, which can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

Monitoring of Vision. Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is recommended. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving VIGADRONE, vision assessment is recommended at baseline, at least every 3 months while on therapy, and about 3 to 6 months after the discontinuation of therapy. Once detected, vision loss due to VIGADRONE is not reversible. It is expected that even with frequent monitoring, some VIGADRONE patients will develop severe vision loss.

Magnetic Resonance Imaging (MRI) Abnormalities in Infants.

Abnormal MRI signal changes have been reported in some infants with Infantile Spasms receiving VIGADRONE. These changes generally resolved with discontinuation of treatment.

Suicidal Behavior and Ideation. Antiepileptic drugs, including VIGADRONE, increase the risk of suicidal thoughts and behavior.

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. 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 and report behaviors of concern immediately to healthcare providers.

• Neurotoxicity. Based on animal data, VIGADRONE may cause • • • • • •

neurotoxicity. Intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range.

Anemia. VIGADRONE may cause anemia.

Somnolence and Fatigue. VIGADRONE causes somnolence and fatigue. Advise patients not to drive or operate machinery until they have gained sufficient experience on VIGADRONE. Peripheral Neuropathy. VIGADRONE causes symptoms of peripheral neuropathy in adults.

Weight Gain. VIGADRONE causes weight gain in adult and pediatric patients.

Edema. VIGADRONE causes edema in adults.

Withdrawal of AEDs. As with all AEDs, VIGADRONE should be withdrawn gradually.

USE IN SPECIFIC POPULATIONS

• Pregnancy: Based on animal data, VIGADRONE may cause fetal harm.

• Nursing Mothers: VIGADRONE is excreted in human milk.

DRUG INTERACTIONS VIGADRONE may decrease phenytoin plasma levels: dosage adjustment may be needed.

ADVERSE REACTIONS Refractory Complex Partial Seizures Most common adverse reactions in controlled studies include (incidence ≥5% over placebo): Adults: in addition to permanent vision loss, fatigue, somnolence, nystagmus, tremor, blurred vision, memory impairment, weight gain, arthralgia, abnormal coordination, and confusional state.

Pediatric patients (10 to 16 years of age): weight gain, upper respiratory tract infection, tremor, fatigue, aggression, and diplopia.

Infantile Spasms (incidence >5% and greater than on placebo) Somnolence, bronchitis, ear infection, and acute otitis media.

• • •

The most serious adverse reactions are listed above in the WARNINGS AND PRECAUTIONS section.

Refer to the DOSAGE AND ADMINISTRATION section of the full Prescribing Information for recommended dosing guidelines for VIGADRONE, including specific populations.

Please see following pages for Brief Summary of Prescribing Information, including Boxed Warning. Please refer to the full Prescribing Information, including Boxed Warning for vision loss for VIGADRONE, WARNINGS AND PRECAUTIONS and Medication Guide. You can also visit www.VIGADRONE.com, www.upsher-smith.com or call 1-888-650-3789.

You are encouraged to report suspected adverse reactions to Upsher-Smith Laboratories, LLC at 1-855-899-9180 or to the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

1. VIGADRONE™ is a fully substitutable, AA-rated generic version of Sabril®, (vigabatrin) Powder for Oral Solution. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. https://www.accessdata.fda.gov/scripts/cder/ ob/results_product.cfm?Appl_Type=A&Appl_No=210196. Accessed 7/2018.

VIGADRONE and Access Pathways are trademarks of Upsher-Smith Laboratories, LLC. All other marks are property of their respective owners. © 2018 Upsher-Smith Laboratories, LLC, 6701 Evenstad Drive, Maple Grove, MN 55369 113037.02

VIGADRONE™ (vigabatrin) for Oral Solution Brief Summary of Prescribing Information WARNING: PERMANENT VISION LOSS VIGADRONE can cause permanent bilateral concentric visual field constriction, including tunnel vision that can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity [see Warnings and Precautions in full PI].

• The onset of vision loss from VIGADRONE is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

• Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

• The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.

• Vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), at least every 3 months during therapy, and about 3 to 6 months after the discontinuation of therapy.

• Once detected, vision loss due to VIGADRONE is not reversible. It is expected that, even with frequent monitoring, some patients will develop severe vision loss.

• Consider drug discontinuation, balancing benefit and risk, if vision loss is documented.

• Risk of new or worsening vision loss continues as long as VIGADRONE is used. It is possible that vision loss can worsen despite discontinuation of VIGADRONE. • Because of the risk of vision loss, VIGADRONE should be withdrawn from patients with refractory complex partial seizures who fail to show substantial clinical benefit within 3 months of initiation and within 2 to 4 weeks of initiation for patients with infantile spasms, or sooner if treatment failure becomes obvious. Patient response to and continued need for VIGADRONE should be periodically reassessed.

• VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks.

• VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.

• Use the lowest dosage and shortest exposure to VIGADRONE consistent with clinical objectives [see Dosage and Administration in full PI].

Because of the risk of permanent vision loss, VIGADRONE is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the Vigabatrin REMS Program [see Warnings and Precautions in full PI]. Further information is available at www.vigabatrinREMS.com or call 1-866-244-8175.

•

INDICATIONS AND USAGE Refractory Complex Partial Seizures (CPS) VIGADRONE is indicated as adjunctive therapy for adults and pediatric patients 10 years of age and older with refractory complex partial seizures who have inadequately responded to several alternative treatments and for whom the potential benefits outweigh the risk of vision loss [see Warnings and Precautions in full PI]. VIGADRONE is not indicated as a first line agent for complex partial seizures.

Infantile Spasms (IS) VIGADRONE is indicated as monotherapy for pediatric patients with infantile spasms 1 month to 2 years of age for whom the potential benefits outweigh the potential risk of vision loss [see Warnings and Precautions in full PI].

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Permanent Vision Loss VIGADRONE can cause permanent vision loss. Because of this risk and because, when it is effective, VIGADRONE provides an observable symptomatic benefit; patient response and continued need for treatment should be periodically assessed.

Based upon adult studies, 30 percent or more of patients can be affected with bilateral concentric visual field constriction ranging in severity from mild to severe. Severe cases may be characterized by tunnel vision to within 10 degrees of visual fixation, which can result in disability. In some cases, VIGADRONE also can damage the central retina and may decrease visual acuity. Symptoms of vision loss from VIGADRONE are unlikely to be recognized by patients or caregivers before vision loss is severe. Vision loss of milder severity, while often unrecognized by the patient or caregiver, can still adversely affect function.

Because assessing vision may be difficult in infants and children, the frequency and extent of vision loss is poorly characterized in these patients. For this reason, the understanding of the risk is primarily based on the adult experience. The possibility that vision loss from VIGADRONE may be more common, more severe, or have more severe functional consequences in infants and children than in adults cannot be excluded.

The onset of vision loss from VIGADRONE is unpredictable, and can occur within weeks of starting treatment or sooner, or at any time after starting treatment, even after months or years.

The risk of vision loss increases with increasing dose and cumulative exposure, but there is no dose or exposure known to be free of risk of vision loss.

In patients with refractory complex partial seizures, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 3 months of initiating treatment. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 3 months, treatment should be discontinued at that time.

In patients with infantile spasms, VIGADRONE should be withdrawn if a substantial clinical benefit is not observed within 2 to 4 weeks. If, in the clinical judgment of the prescriber, evidence of treatment failure becomes obvious earlier than 2 to 4 weeks, treatment should be discontinued at that time.

VIGADRONE should not be used in patients with, or at high risk of, other types of irreversible vision loss unless the benefits of treatment clearly outweigh the risks. The interaction of other types of irreversible vision damage with vision damage from VIGADRONE has not been well-characterized, but is likely adverse.

VIGADRONE should not be used with other drugs associated with serious adverse ophthalmic effects such as retinopathy or glaucoma unless the benefits clearly outweigh the risks.

Monitoring of Vision Monitoring of vision by an ophthalmic professional with expertise in visual field interpretation and the ability to perform dilated indirect ophthalmoscopy of the retina is recommended [see Warnings and Precautions in full PI]. Because vision testing in infants is difficult, vision loss may not be detected until it is severe. For patients receiving VIGADRONE, vision assessment is recommended at baseline (no later than 4 weeks after starting VIGADRONE), at least every 3 months while on therapy, and about 3 to 6 months after the discontinuation of therapy. The diagnostic approach should be individualized for the patient and clinical situation.

In adults and cooperative pediatric patients, perimetry is recommended, preferably by automated threshold visual field testing. Additional testing may also include electrophysiology (e.g., electroretinography [ERG]), retinal imaging (e.g., optical coherence tomography [OCT]), and/or other methods appropriate for the patient. In patients who cannot be tested, treatment may continue according to clinical judgment, with appropriate patient counseling. Because of variability, results from ophthalmic monitoring must be interpreted with caution, and repeat assessment is recommended if results are abnormal or uninterpretable. Repeat assessment in the first few weeks of treatment is recommended to establish if, and to what degree, reproducible results can be obtained, and to guide selection of appropriate ongoing monitoring for the patient.

The onset and progression of vision loss from VIGADRONE is unpredictable, and it may occur or worsen precipitously between assessments. Once detected, vision loss due to VIGADRONE is not reversible. It is expected that even with frequent monitoring, some VIGADRONE patients will develop severe vision loss. Consider drug discontinuation, balancing benefit and risk, if vision loss is documented. It is possible that vision loss can worsen despite discontinuation of VIGADRONE. Magnetic Resonance Imaging (MRI) Abnormalities in Infants Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated with vigabatrin for infantile spasms. In a retrospective epidemiologic study in infants with IS (N=205), the prevalence of these changes was 22% in vigabatrin treated patients versus 4% in patients treated with other therapies.

In the study above, in post marketing experience, and in published literature reports, these changes generally resolved with discontinuation of treatment. In a few patients, the lesion resolved despite continued use. It has been reported that some infants exhibited coincident motor abnormalities, but no causal relationship has been established and the potential for long-term clinical sequelae has not been adequately studied.

Neurotoxicity (brain histopathology and neurobehavioral abnormalities) was observed in rats exposed to vigabatrin during late gestation and the neonatal and juvenile periods of development, and brain histopathological changes were observed in dogs exposed to vigabatrin during the juvenile period of development. The relationship between these findings and the abnormal MRI findings in infants treated with vigabatrin for infantile spasms is unknown [see Warnings and Precautions and Use in Specific Populations in full PI].

The specific pattern of signal changes observed in IS patients was not observed in older pediatric and adult patients treated with vigabatrin for refractory CPS. In a blinded review of MRI images obtained in prospective clinical trials in patients with refractory CPS 3 years and older (N=656), no difference was observed in anatomic distribution or prevalence of MRI signal changes between vigabatrin treated and placebo treated patients.

For adults treated with VIGADRONE, routine MRI surveillance is unnecessary as there is no evidence that vigabatrin causes MRI changes in this population.

Neurotoxicity Vacuolation, characterized by fluid accumulation and separation of the outer layers of myelin, has been observed in brain white matter tracts in adult and juvenile rats and adult mice, dogs, and possibly monkeys following administration of vigabatrin. This lesion, referred to as intramyelinic edema (IME), was seen in animals at doses within the human therapeutic range. A no-effect dose was not established in rodents or dogs. In the rat and dog, vacuolation was reversible following discontinuation of vigabatrin treatment, but, in the rat, pathologic changes consisting of swollen or degenerating axons, mineralization, and gliosis were seen in brain areas in which vacuolation had been previously observed. Vacuolation in adult animals was correlated with alterations in MRI and changes in visual and somatosensory evoked potentials (EP).

Administration of vigabatrin to rats during the neonatal and juvenile periods of development produced vacuolar changes in the brain gray matter (including the thalamus, midbrain, deep cerebellar nuclei, substantia nigra, hippocampus, and forebrain) which are considered distinct from the IME observed in vigabatrin-treated adult animals. Decreased myelination and evidence of oligodendrocyte injury were additional findings in the brains of vigabatrin-treated rats. An increase in apoptosis was seen in some brain regions following vigabatrin exposure during the early postnatal period. Long-term neurobehavioral abnormalities (convulsions, neuromotor impairment, learning deficits) were also observed following vigabatrin treatment of young rats.

Administration of vigabatrin to juvenile dogs produced vacuolar changes in the brain gray matter (including the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog.

These effects in young animals occurred at doses lower than those producing neurotoxicity in adult animals and were associated with plasma vigabatrin levels substantially lower than those achieved clinically in infants and children.

In a published study, vigabatrin (200, 400 mg/kg/day) induced apoptotic neurodegeneration in the brain of young rats when administered by intraperitoneal injection on postnatal days 5 to 7.

Administration of vigabatrin to female rats during pregnancy and lactation at doses below those used clinically resulted in hippocampal vacuolation and convulsions in the mature offspring.

Abnormal MRI signal changes characterized by increased T2 signal and restricted diffusion in a symmetric pattern involving the thalamus, basal ganglia, brain stem, and cerebellum have been observed in some infants treated for IS with vigabatrin. Studies of the effects of vigabatrin on MRI and EP in adult epilepsy patients have demonstrated no clear-cut abnormalities.

Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including VIGADRONE, 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 rate of suicidal behavior or ideation among 27,863 AED treated patients was 0.43%, compared to 0.24% among 16,029 placebo treated 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 to 100 years) in the clinical trials analyzed [see full PI for absolute and relative risk by indication for all evaluated AEDs]. Table 4 shows absolute and relative risk by indication for all evaluated AEDs. 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 VIGADRONE 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.

Withdrawal of Antiepileptic Drugs (AEDs) As with all AEDs, VIGADRONE should be withdrawn gradually. However, if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered. Patients and caregivers should be told not to suddenly discontinue VIGADRONE therapy.

In controlled clinical studies in adults with complex partial seizures, vigabatrin was tapered by decreasing the daily dose 1000 mg/day on a weekly basis until discontinued.

In a controlled study in pediatric patients with complex partial seizures, vigabatrin was tapered by decreasing the daily dose by one third every week for three weeks.

In a controlled clinical study in patients with infantile spasms, vigabatrin was tapered by decreasing the daily dose at a rate of 25 to 50 mg/kg every 3 to 4 days.

Anemia In North American controlled trials in adults, 6% of patients (16/280) receiving vigabatrin and 2% of patients (3/188) receiving placebo had adverse events of anemia and/or met criteria for potentially clinically important hematology changes involving hemoglobin, hematocrit, and/or RBC indices. Across U.S. controlled trials, there were mean decreases in hemoglobin of about 3% and 0% in vigabatrin and placebo treated patients, respectively, and a mean decrease in hematocrit of about 1% in vigabatrin treated patients compared to a mean gain of about 1% in patients treated with placebo.

In controlled and open label epilepsy trials in adults and pediatric patients, 3 vigabatrin patients (0.06%, 3/4,855) discontinued for anemia and 2 vigabatrin patients experienced unexplained declines in hemoglobin to below 8 g/dL and/or hematocrit below 24%.

Somnolence and Fatigue VIGADRONE causes somnolence and fatigue. Patients should be advised not to drive a car or operate other complex machinery until they are familiar with the effects of VIGADRONE on their ability to perform such activities.

Pooled data from two vigabatrin controlled trials in adults demonstrated that 24% (54/222) of vigabatrin patients experienced somnolence compared to 10% (14/135) of placebo patients. In those same studies, 28% of vigabatrin patients experienced fatigue compared to 15% (20/135) of placebo patients. Almost 1% of vigabatrin patients discontinued from clinical trials for somnolence and almost 1% discontinued for fatigue.

Pooled data from three vigabatrin controlled trials in pediatric patients demonstrated that 6% (10/165) of vigabatrin patients experienced somnolence compared to 5% (5/104) of placebo patients. In those same studies, 10% (17/165) of vigabatrin patients experienced fatigue compared to 7% (7/104) of placebo patients. No vigabatrin patients discontinued from clinical trials due to somnolence or fatigue.

Peripheral Neuropathy Vigabatrin causes symptoms of peripheral neuropathy in adults. Pediatric clinical trials were not designed to assess symptoms of peripheral neuropathy, but observed incidence of symptoms based on pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo. In a pool of North American controlled and uncontrolled epilepsy studies, 4.2% (19/457) of vigabatrin patients developed signs and/or symptoms of peripheral neuropathy. In the subset of North American placebo-controlled epilepsy trials, 1.4% (4/280) of vigabatrin treated patients and no (0/188) placebo patients developed signs and/or symptoms of peripheral neuropathy. Initial manifestations of peripheral neuropathy in these trials included, in some combination, symptoms of numbness or tingling in the toes or feet, signs of reduced distal lower limb vibration or position sensation, or progressive loss of reflexes, starting at the ankles. Clinical studies in the development program were not designed to investigate peripheral neuropathy systematically and did not include nerve conduction studies, quantitative sensory testing, or skin or nerve biopsy. There is insufficient evidence to determine if development of these signs and symptoms was related to duration of vigabatrin treatment, cumulative dose, or if the findings of peripheral neuropathy were completely reversible upon discontinuation of vigabatrin.

Weight Gain VIGADRONE causes weight gain in adult and pediatric patients.

Data pooled from randomized controlled trials in adults found that 17% (77/443) of vigabatrin patients versus 8% (22/275) of placebo patients gained ≥7% of baseline body weight. In these same trials, the mean weight change among vigabatrin patients was 3.5 kg compared to 1.6 kg for placebo patients.

Data pooled from randomized controlled trials in pediatric patients with refractory complex partial seizures found that 47% (77/163) of vigabatrin patients versus 19% (19/102) of placebo patients gained ≥7% of baseline body weight.

In all epilepsy trials, 0.6% (31/4,855) of vigabatrin patients discontinued for weight gain. The long term effects of vigabatrin related weight gain are not known. Weight gain was not related to the occurrence of edema.

Edema VIGADRONE causes edema in adults. Pediatric clinical trials were not designed to assess edema, but observed incidence of edema based pooled data from controlled pediatric studies appeared similar for pediatric patients on vigabatrin and placebo.

Pooled data from controlled trials demonstrated increased risk among vigabatrin patients compared to placebo patients for peripheral edema (vigabatrin 2%, placebo 1%), and edema (vigabatrin 1%, placebo 0%). In these studies, one vigabatrin and no placebo patients discontinued for an edema related AE. In adults, there was no apparent association between edema and cardiovascular adverse events such as hypertension or congestive heart failure.

Edema was not associated with laboratory changes suggestive of deterioration in renal or hepatic function.

ADVERSE REACTIONS The following serious and otherwise important adverse reactions are described elsewhere in labeling: Permanent Vision Loss [see BOXED WARNING and Warnings and Precautions]; Magnetic Resonance Imaging (MRI) Abnormalities in Infants [see Warnings and Precautions]; Neurotoxicity [see Warnings and Precautions]; Suicidal Behavior and Ideation [see Warnings and Precautions]; Withdrawal of Antiepileptic Drugs (AEDs) [see Warnings and Precautions]; Anemia [see Warnings and Precautions]; Somnolence and Fatigue [see Warnings and Precautions]; Peripheral Neuropathy [see Warnings and Precautions]; Weight Gain [see Warnings and Precautions]; Edema [see Warnings and Precautions].

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 practice.

In U.S. and primary non-U.S. clinical studies of 4,079 vigabatrin-treated patients, the most common (≥5%) adverse reactions associated with the use of vigabatrin in combination with other AEDs were headache, somnolence, fatigue, dizziness, convulsion, nasopharyngitis, weight gain, upper respiratory tract infection, visual field defect, depression, tremor, nystagmus, nausea, diarrhea, memory impairment, insomnia, irritability, abnormal coordination, blurred vision, diplopia, vomiting, influenza, pyrexia, and rash.

The adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were convulsion and depression.

In patients with infantile spasms, the adverse reactions most commonly associated with vigabatrin treatment discontinuation in ≥1% of patients were infections, status epilepticus, developmental coordination disorder, dystonia, hypotonia, hypertonia, weight gain, and insomnia.

Refractory Complex Partial Seizures Adults Table 5 lists the adverse reactions that occurred in ≥2% and more than one patient per vigabatrin treated group and that occurred more frequently than in placebo patients from 2 U.S. add-on clinical studies of refractory CPS in adults.

Adverse Reactions in Pooled, Add-On Trials in Adults with Refractory Complex Partial Seizures. Adverse reactions are listed by body system with the percentage (%) of incidence of vigabatrin 3,000 mg/day (N=134) and 6,000 mg/day (N=43) followed by placebo (N=135): Ear Disorders: Tinnitus (2, 0, 1), Vertigo (2, 5, 1); Eye Disorders: Blurred vision (13, 16, 5), Diplopia (7, 16, 3), Asthenopia (2, 2, 0), Eye pain (0, 5, 0); Gastrointestinal Disorders: Diarrhea (10, 16, 7), Nausea (10, 2, 8), Vomiting (7, 9, 6), Constipation (8, 5, 3), Upper abdominal pain (5, 5, 1), Dyspepsia (4, 5, 3), Stomach discomfort (4, 2, 1), Abdominal pain (3, 2, 1), Toothache (2, 5, 2), Abdominal distension (2, 0, 1); General Disorders: Fatigue (23, 40, 16), Gait disturbance (6, 12, 7), Asthenia (5, 7, 1), Edema peripheral (5, 7, 1), Fever (4, 7, 3), Chest pain (1, 5, 1), Thirst (2, 0, 0), Malaise (0, 5, 0); Infections: Nasopharyngitis (14, 9, 10), Upper respiratory tract infection (7, 9, 6), Influenza (5, 7, 4), Urinary tract infection (4, 5, 0), Bronchitis (0, 5, 1); Injury: Contusion (3, 5, 2), Joint sprain (1, 2, 1), Muscle strain (1, 2, 1), Wound secretion (0, 2, 0); Metabolism and Nutrition Disorders: Increased appetite (1, 5, 1), Weight gain (6, 14, 3); Musculoskeletal Disorders: Arthralgia (10, 5, 3), Back pain (4, 7, 2), Pain in extremity (6, 2, 4), Myalgia (3, 5, 1), Muscle twitching (1, 9, 1), Muscle spasms (3, 0, 1); Nervous System Disorders: Headache (33, 26, 31), Somnolence (22, 26, 13), Dizziness (24, 26, 17), Nystagmus (13, 19, 9), Tremor (15, 16, 8), Memory impairment (7, 16, 3), Abnormal coordination (7, 16, 2), Disturbance in attention (9, 0, 1), Sensory disturbance (4, 7, 2), Hyporeflexia (4, 5, 1), Paraesthesia (7, 2, 1), Lethargy (4, 7, 2), Hyperreflexia (4, 2, 3), Hypoaesthesia (4, 5, 1), Sedation (4, 0, 0), Status epilepticus (2, 5, 0), Dysarthria (2, 2, 1), Postictal state (2, 0, 1), Sensory loss (0, 5, 0); Psychiatric Disorders: Irritability (7, 23, 7), Depression (6, 14, 3), Confusional state (4, 14, 1), Anxiety (4, 0, 3), Depressed mood (5, 0, 1), Abnormal thinking (3, 7, 0), Abnormal behavior (3, 5, 1), Expressive language disorder (1, 7, 1), Nervousness (2, 5, 2), Abnormal dreams (1, 5, 1); Reproductive System: Dysmenorrhea (9, 5, 3), Erectile dysfunction (0, 5, 0); Respiratory and Thoracic Disorders: Pharyngolaryngeal pain (7, 14, 5), Cough (2, 14, 7), Pulmonary congestion (0, 5, 1), Sinus headache (6, 2, 1); Skin and Subcutaneous Tissue Disorders: Rash (4, 5, 4).

Pediatrics 10 to 16 years of age Table 6 lists adverse reactions from controlled clinical studies of pediatric patients receiving vigabatrin or placebo as add-on therapy for refractory complex partial seizures. Adverse reactions that are listed occurred in at least 2% of vigabatrin-treated patients and more frequently than placebo. The median vigabatrin dose was 49.4 mg/kg (range of 8.0 to 105.9 mg/kg).

Adverse Reactions in Pooled, Add-On Trials in Pediatric Patients 10 to 16 Years of Age with Refractory Complex Partial Seizures. Adverse reactions are listed by body system with the percentage (%) incidence of vigabatrin (N=109) followed by placebo (N=46): Eye Disorders: Diplopia (5, 0), Blurred vision (3, 0); Gastrointestinal Disorders: Diarrhea (6, 2), Upper abdominal pain (3, 0), Constipation (3, 2); General Disorders: Fatigue (9, 4); Infections and Infestations: Upper respiratory tract infection (10, 4), Influenza (6, 2), Otitis media (6, 2); Investigations: Weight gain (17, 2); Nervous System Disorders: Somnolence (6, 2), Tremor (6, 0), Nystagmus (5, 2), Psychomotor hyperactivity (4, 2); Psychiatric Disorders: Abnormal behavior (6, 2), Aggression (5, 0), Disorientation (4, 0); Reproduction and Breast Disorders: Dysmenorrhea (3, 0); Skin and Subcutaneous Tissue Disorders: Acne (3, 0).

Infantile Spasms In a randomized, placebo-controlled IS study with a 5 day double-blind treatment phase (n=40), the adverse reactions that occurred in >5% of patients receiving vigabatrin and that occurred more frequently than in placebo patients were somnolence (vigabatrin 45%, placebo 30%), bronchitis (vigabatrin 30%, placebo 15%), ear infection (vigabatrin 10%, placebo 5%), and acute otitis media (vigabatrin 10%, placebo 0%).

In a dose response study of low-dose (18 to 36 mg/kg/day) versus high-dose (100 to 148 mg/kg/day) vigabatrin, no clear correlation between dose and incidence of adverse reactions was observed. The adverse reactions (≥5% in either dose group) are summarized in Table 7.

Adverse Reactions in a Placebo-Controlled Trial in Patients with Infantile Spasms. Adverse reactions are listed by body system with the percentage (%) incidence of low-dose vigabatrin (N=114) followed by high-dose vigabatrin (N=108): Eye Disorders (other than field or acuity changes): Strabismus (5, 5), Conjunctivitis (5, 2); Gastrointestinal Disorders: Vomiting (14, 20), Constipation (14, 12), Diarrhea (13, 12); General Disorders: Fever (29, 19); Infections: Upper respiratory tract infection (51, 46), Otitis media (44, 30), Viral infection (20, 19), Pneumonia (13, 11), Candidiasis (8, 3), Ear infection (7, 14), Gastroenteritis viral (6, 5), Sinusitis (5, 9), Urinary tract infection (5, 6), Influenza (5, 3), Croup infectious (5, 1); Metabolism & Nutrition Disorders: Decreased appetite (9, 7); Nervous System Disorders: Sedation (19, 17), Somnolence (17, 19), Status epilepticus (6, 4), Lethargy (5, 7), Convulsion (4, 7), Hypotonia (4, 6); Psychiatric Disorders: Irritability (16, 23), Insomnia (10, 12); Respiratory Disorders: Nasal congestion (13, 4), Cough (3, 8); Skin and Subcutaneous Tissue Disorders: Rash (8, 11).

Post Marketing Experience The following adverse reactions have been reported during post approval use of vigabatrin worldwide. All adverse reactions that are not listed above as adverse reactions reported in clinical trials, that are not relatively common in the population and are not too vague to be useful are listed in this section. These reactions are reported voluntarily from a population of uncertain size; therefore, it is not possible to estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions are categorized by system organ class.

Birth Defects: Congenital cardiac defects, congenital external ear anomaly, congenital hemangioma, congenital hydronephrosis, congenital male genital malformation, congenital oral malformation, congenital vesicoureteric reflux, dentofacial anomaly, dysmorphism, fetal anticonvulsant syndrome, hamartomas, hip dysplasia, limb malformation, limb reduction defect, low set ears, renal aplasia, retinitis pigmentosa, supernumerary nipple, talipes. Ear Disorders: Deafness. Endocrine Disorders: Delayed puberty. Gastrointestinal Disorders: Gastrointestinal hemorrhage, esophagitis. General Disorders: Developmental delay, facial edema, malignant hyperthermia, multi-organ failure. Hepatobiliary Disorders: Cholestasis.

Nervous System Disorders: Dystonia, encephalopathy, hypertonia, hypotonia, muscle spasticity, myoclonus, optic neuritis, dyskinesia. Psychiatric Disorders: Acute psychosis, apathy, delirium, hypomania, neonatal agitation, psychotic disorder. Respiratory Disorders: Laryngeal edema, pulmonary embolism, respiratory failure, stridor. Skin and Subcutaneous Tissue Disorders: Angioedema, maculo-papular rash, pruritus, Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN).

DRUG INTERACTIONS Antiepileptic Drugs Phenytoin Although phenytoin dose adjustments are not routinely required, dose adjustment of phenytoin should be considered if clinically indicated, since VIGADRONE may cause a moderate reduction in total phenytoin plasma levels [see Clinical Pharmacology in full PI].

Clonazepam VIGADRONE may moderately increase the Cmax of clonazepam resulting in an increase of clonazepam-associated adverse reactions [see Clinical Pharmacology in full PI].

Other AEDs There are no clinically significant pharmacokinetic interactions between vigabatrin and either phenobarbital or sodium valproate. Based on population pharmacokinetics, carbamazepine, clorazepate, primidone, and sodium valproate appear to have no effect on plasma concentrations of vigabatrin [see Clinical Pharmacology in full PI].

Oral Contraceptives VIGADRONE is unlikely to affect the efficacy of steroid oral contraceptives [see Clinical Pharmacology in full PI].

Drug-Laboratory Test Interactions VIGADRONE decreases alanine transaminase (ALT) and aspartate transaminase (AST) plasma activity in up to 90% of patients. In some patients, these enzymes become undetectable. The suppression of ALT and AST activity by VIGADRONE may preclude the use of these markers, especially ALT, to detect early hepatic injury.

VIGADRONE may increase the amount of amino acids in the urine, possibly leading to a false positive test for certain rare genetic metabolic diseases (e.g., alpha aminoadipic aciduria).

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C. Vigabatrin produced developmental toxicity, including teratogenic and neurohistopathological effects, when administered to pregnant animals at clinically relevant doses. In addition, developmental neurotoxicity was observed in rats treated with vigabatrin during a period of postnatal development corresponding to the third trimester of human pregnancy. There are no adequate and well-controlled studies in pregnant women. VIGADRONE should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus [see Use in Specific Populations in full PI].

Pregnancy Registry To provide information regarding the effects of in utero exposure to VIGADRONE, physicians are advised to recommend that pregnant patients taking VIGADRONE 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 Vigabatrin is excreted in human milk. Because of the potential for serious adverse reactions from vigabatrin in nursing infants, 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 [see Warnings and Precautions in full PI].

Pediatric Use The safety and effectiveness of VIGADRONE as adjunctive treatment of refractory complex partial seizures in pediatric patients aged 10 to 16 years of age have been established [see Clinical Studies in full PI]. The dosing recommendation in this population varies according to age group and is weight based [see Dosage and Administration in full PI]. Adverse reactions in this pediatric population are similar to those observed in the adult population [see Adverse Reactions in full PI].

The safety and effectiveness of VIGADRONE have not been established in pediatric patients under 10 years of age with refractory complex partial seizures.

The safety and effectiveness of VIGADRONE as monotherapy for pediatric patients with infantile spasms (1 month to 2 years of age) have been established [see Dosage and Administration and Clinical Studies in full PI].

Duration of therapy for infantile spasms was evaluated in a post hoc analysis of a Canadian Pediatric Epilepsy Network (CPEN) study of developmental outcomes in infantile spasms patients. This analysis suggests that a total duration of 6 months of vigabatrin therapy is adequate for the treatment of infantile spasms. However, prescribers must use their clinical judgment as to the most appropriate duration of use [see Clinical Studies in full PI].

Abnormal MRI signal changes were observed in infants [see Warnings and Precautions in full PI].

Oral administration of vigabatrin (5, 15, or 50 mg/kg) to young rats during the neonatal and juvenile periods of development (postnatal days 4 to 65) produced neurobehavioral (convulsions, neuromotor impairment, learning deficits) and neurohistopathological (brain gray matter vacuolation, decreased myelination, and retinal dysplasia) abnormalities. The no-effect dose for developmental neurotoxicity in juvenile rats (the lowest dose tested) was associated with plasma vigabatrin exposures (AUC) substantially less than those measured in pediatric patients at recommended doses. In dogs, oral administration of vigabatrin (30 or 100 mg/kg) during selected periods of juvenile development (postnatal days 22 to 112) produced neurohistopathological abnormalities (brain gray matter vacuolation). Neurobehavioral effects of vigabatrin were not assessed in the juvenile dog. A no-effect dose for neurohistopathology was not established in juvenile dogs; the lowest effect dose (30 mg/kg) was associated with plasma vigabatrin exposures lower than those measured in pediatric patients at recommended doses [see Warnings and Precautions in full PI].

Geriatric Use Clinical studies of vigabatrin did not include sufficient numbers of patients aged 65 and over to determine whether they responded differently from younger patients.

Vigabatrin is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Oral administration of a single dose of 1.5 g of vigabatrin to elderly (≥65 years) patients with reduced creatinine clearance (<50 mL/min) was associated with moderate to severe sedation and confusion in 4 of 5 patients, lasting up to 5 days. The renal clearance of vigabatrin was 36% lower in healthy elderly subjects (≥65 years) than in young healthy males. Adjustment of dose or frequency of administration should be considered. Such patients may respond to a lower maintenance dose [see Dosage and Administration and Clinical Pharmacology in full PI].

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

Renal Impairment Dose adjustment, including initiating treatment with a lower dose, is necessary in pediatric patients 10 years of age and older and adults with mild (creatinine clearance >50 to 80 mL/min), moderate (creatinine clearance >30 to 50 mL/min) and severe (creatinine clearance >10 to 30 mL/min) renal impairment [see Dosage and Administration and Clinical Pharmacology in full PI].

DRUG ABUSE AND DEPENDENCE Controlled Substance Vigabatrin is not a controlled substance.

Abuse Vigabatrin did not produce adverse events or overt behaviors associated with abuse when administered to humans or animals. It is not possible to predict the extent to which a CNS active drug will be misused, diverted, and/or abused once marketed. Consequently, physicians should carefully evaluate patients for history of drug abuse and follow such patients closely, observing them for signs of misuse or abuse of vigabatrin (e.g., incrementation of dose, drugseeking behavior).

Dependence Following chronic administration of vigabatrin to animals, there were no apparent withdrawal signs upon drug discontinuation. However, as with all AEDs, vigabatrin should be withdrawn gradually to minimize increased seizure frequency [see Warnings and Precautions in full PI].

OVERDOSAGE Signs, Symptoms, and Laboratory Findings of Overdosage Confirmed and/or suspected vigabatrin overdoses have been reported during clinical trials and in post marketing surveillance. No vigabatrin overdoses resulted in death. When reported, the vigabatrin dose ingested ranged from 3 g to 90 g, but most were between 7.5 g and 30 g.

Nearly half the cases involved multiple drug ingestions including carbamazepine, barbiturates, benzodiazepines, lamotrigine, valproic acid, acetaminophen, and/or chlorpheniramine.

Coma, unconsciousness, and/or drowsiness were described in the majority of cases of vigabatrin overdose. Other less commonly reported symptoms included vertigo, psychosis, apnea or respiratory depression, bradycardia, agitation, irritability, confusion, headache, hypotension, abnormal behavior, increased seizure activity, status epilepticus, and speech disorder. These symptoms resolved with supportive care.

Management of Overdosage There is no specific antidote for VIGADRONE overdose. Standard measures to remove unabsorbed drug should be used, including elimination by emesis or gastric lavage. Supportive measures should be employed, including monitoring of vital signs and observation of the clinical status of the patient.

In an in vitro study, activated charcoal did not significantly adsorb vigabatrin.

The effectiveness of hemodialysis in the treatment of VIGADRONE overdose is unknown. In isolated case reports in renal failure patients receiving therapeutic doses of vigabatrin, hemodialysis reduced vigabatrin plasma concentrations by 40% to 60%.

Manufactured for UPSHER-SMITH LABORATORIES, LLC Maple Grove, MN 55369 Made in Germany Revised 0518 113119.01

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NOVEMBER 2

Application Deadline: Neurology on the Hill AAN.com/view/NOH

NOVEMBER 20

Webinar: Improving Payer Relationships (Register by November 19) AAN.com/view/pmw18

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DECEMBER 3

Registration Deadline: RITE (Residency In-service Training Examination) AAN.com/tools-and-resources/residentsfellows/residency-in-service-trainingexamination-rite ®

DECEMBER 4

Webinar: E/M and QPP Changes for 2019 (Register by December 3) AAN.com/view/pmw18

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JANUARY 3

Early Application Deadline: UCNS Neuro-oncology Certification Examination Save $500 by applying UCNS.org/go/subspecialty/neuro-oncology/ certification

AAN.com/careers

Visit the AAN’s Neurology Career Center to view hundreds of additional jobs and sign up for customized, confidential notifications when positions of interest are added.

Neurologist -Outpatient. Central Vermont Medical Center (CVMC), a partner in The University of Vermont Health Network is recruiting for a Neurologist to join our practice. Located in the heart of the Green Mountain state, CVMC has a reputation for clinical excellence with a staff deeply rooted in our community.

We have attracted and retained a very talented staff due to our focus on lifestyle and professional growth. Our Neurology practice specializes in epilepsy/seizure disorders, stroke, chronic headaches/ migraines, multiple sclerosis, Parkinson’s and Alzheimer disease, as well as movement and neuromuscular disorders. Candidates interested in reading EEG’s and/or conducting/interpreting EMG’s welcomed. Ideal candidate will have an interest in teaching 3-year medical students. We are looking for a physician who wants to work in an area where you can have a long, sustainable career and enjoy the special lifestyle that comes with living in Vermont.

The financial package includes a market based, competitive salary plus quality and productivity bonuses. Full benefit package includes moving expenses and assistance with student loans.

Job Requirements: BC/BE Neurologist. To apply for this job, contact Sarah Child at: sarah.child@cvmc.org. Phone: (802) 225-1739. Apply URL: http://cvmc.org West Virginia Neurology Opening. Practice Neurology in an Academic Medical Center affiliated with Medical school. Primarily Outpatient Neurology opportunity in new medical building.

Opportunity to join growing Neurology department of 8 Neurologists.

Faculty members including General, Pediatric, Neuromuscular, Movement, Epilepsy and Vascular. Accredited Neurophysiology Center on site. Multidisciplinary team includes Radiologists, Pharmacists, Nursing, Dietitians, Physical, Occupational and

Speech Therapists. New Neurology Residency Program. Excellent starting salary, full benefits and sign-on bonus. H1b candidates and 2019 J1 candidates accepted. Educational stipend available.

An outdoor enthusiast’s haven. Enjoy the scenic shores of a historic river. Take in the four-season views while mountain hiking. Enjoy a sunset cruise under the stars. The region’s best skiing at your doorstep. Year-round family fun. A down-to-earth place to live combined with amazing cultural sensations. NCAA Division One Intercollegiate Sports Teams. Excellent Public and Private Schools. Short Distance to 4 Major Metro Areas. Grand prize winner America’s Best Communities Competition! Mention code: 171116 – N. Job Requirements: MD or DO Medical Degree.

Eligible to be state licensed in the United States. United States Residency and/or Fellowship training. To apply for this job, contact Rob Rector at rrectorweb@phg.com. Phone: (404) 591-4218.

Fax: (404) 591-4269.

including sign on, productivity option and relocation. Berkshire Medical Center, BHS’s 302-bed community teaching hospital and Trauma Center, is a major teaching affiliate of the University of Massachusetts Medical School. With the latest technology and a system-wide electronic health record, BHS is the region’s leading provider of comprehensive healthcare services. Interested candidates are invited to contact: Shelly Sweet, Physician Recruitment Specialist: msweet@bhs1.org. Phone: (413) 4472768 or apply online at: www.berkshirehealthsystems.org

Neurology Opportunity in the Beautiful Berkshires: Western Massachusetts. We understand the importance of balancing work with a healthy personal lifestyle. Berkshires, a 4-season resort community. Endless cultural opportunities, world renowned music, art, theater, and museums. Year-round recreational activities from skiing to kayaking. Excellent public and private schools make this an ideal family location, just 2½ hours from both Boston and New York City. Berkshire Health Systems Opportunity. Full and Part Time opportunities. Subspecialty or General Neurology interests welcome. 1 in 7call arrangement gives you the ‘perfect’ position to balance both your professional interests and personal. Flexible balance of inpatient/outpatient coverage. Competitive compensation and benefits package,

d copy for the January 2019 print edition of A AANnews must be submitted by December 1, 2018.

The same deadline applies to changes/cancellations.

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he American Academy of Neurology reserves the T right to decline, withdraw, or edit advertisements at its discretion. Every care is taken to avoid mistakes, but the responsibility for clerical or printer errors does not exceed the cost of the ad.

BRIEF SUMMARY OF PRESCRIBING INFORMATION

Please see package insert for full Prescribing Information INDICATIONS AND USAGE AIMOVIG is indicated for the preventive treatment of migraine in adults.

CONTRAINDICATIONS None.

ADVERSE REACTIONS 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.

The safety of AIMOVIG has been evaluated in 2,537 patients with migraine who received at least one dose of AIMOVIG, representing 2,310 patient-years of exposure. Of these, 2,057 patients were exposed to 70 mg or 140 mg once monthly for at least 6 months, 1,198 patients were exposed for at least 12 months, and 287 patients were exposed for at least 18 months.

In placebo-controlled clinical studies (Studies 1, 2, and 3) of 2,184 patients, 787 patients received at least one dose of AIMOVIG 70 mg once monthly, 507 patients received at least one dose of AIMOVIG 140 mg once monthly, and 890 patients received placebo during 3 months or 6 months of double-blind treatment. Approximately 84% were female, 91% were white, and the mean age was 42 years at study entry.

The most common adverse reactions (incidence ≥ 3% and more often than placebo) in the migraine studies were injection site reactions and constipation.

Table 1 summarizes the adverse reactions that occurred during the first 3 months in the migraine studies (Studies 1, 2, and 3).

Adverse Reactions Occurring with an Incidence of at Least 2% for Either Dose of AIMOVIG and at Least 2% Greater than Placebo During the First 3 Months in Studies 1, 2, and 3 AIMOVIG 70 mg Once Monthly N = 787 %

AIMOVIG 140 mg Once Monthly N = 507 %

N = 890 %

Injection site reactionsa

6

5

3

Constipation

1

3

1

<1

2

<1

Adverse Reaction

Cramps, muscle spasms

Placebo

Injection site reactions include multiple adverse reactions related terms, such as injection site pain and injection site erythema. a

In Studies 1, 2, and 3, 1.3% of patients treated with AIMOVIG discontinued double blind treatment because of adverse events. The most frequent injection site reactions were injection site pain, injection site erythema, and injection site pruritus.

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation, including neutralizing antibodies, is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to erenumab-aooe in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

The immunogenicity of AIMOVIG has been evaluated using an immunoassay for the detection of binding anti-erenumab-aooe antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

In controlled studies with AIMOVIG, the incidence of anti-erenumab-aooe antibody development was 6.2% (48/778) in patients receiving AIMOVIG 70 mg once monthly (2 of whom had in vitro neutralizing activity) and 2.6% (13/504) in patients receiving AIMOVIG 140 mg once monthly (none of whom had in vitro neutralizing activity). The neutralizing anti-erenumab-aooe antibody positive rate may be underestimated because of limitations of the assay. Although these data do not demonstrate an impact of anti-erenumabaooe antibody development on the efficacy or safety of AIMOVIG in these patients, the available data are too limited to make definitive conclusions.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of AIMOVIG in pregnant women. No adverse effects on offspring were observed when pregnant monkeys were administered erenumab-aooe throughout gestation (see Data). Serum erenumab-aooe exposures in pregnant monkeys were greater than those in humans at clinical doses.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% - 4% and 15% - 20%, respectively. The estimated rate of major birth defects (2.2% - 2.9%) and miscarriage (17%) among deliveries to women with migraine are similar to rates reported in women without migraine.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data have suggested that women with migraine may be at increased risk of preeclampsia during pregnancy.

Data Animal Data In a study in which female monkeys were administered erenumab-aooe (0 or 50 mg/kg) twice weekly by subcutaneous injection throughout pregnancy (gestation day 20 - 22 to parturition), no adverse effects on offspring were observed. Serum erenumab-aooe exposures (AUC) in pregnant monkeys were approximately 20 times that in humans at a dose of 140 mg once monthly.

Lactation Risk Summary There are no data on the presence of erenumab-aooe in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AIMOVIG and any potential adverse effects on the breastfed infant from AIMOVIG or from the underlying maternal condition.

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

Geriatric Use Clinical studies of AIMOVIG did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

AIMOVIG™ (erenumab-aooe) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, CA 91320-1799 USA U.S. License No. 1080 Marketed by: Amgen Inc. (Thousand Oaks, CA 91320), and Novartis Pharmaceuticals Corporation (East Hanover, NJ 07936) Patent: http://pat.amgen.com/aimovig/ © 2018 Amgen Inc. All rights reserved. v1 05/2018

enough already. it’s time to help prevent migraine.

Aimovig™ is the first and only FDA-approved therapy specifically designed to help prevent migraine by targeting and blocking the calcitonin gene-related peptide receptor (CGRP-R).1 • Aimovig™ reduced monthly migraine days.1 • The most common adverse reactions in clinical studies (≥ 3% of Aimovig™-treated patients and more often than placebo) were injection site reactions and constipation.1 • In 3- and 6-month clinical studies, up to 95% of patients stayed on Aimovig™.1 – Less than 2% of patients receiving Aimovig™ discontinued due to adverse events.

• Patients will have access to Aimovig Ally™— a range of personalized product support services designed to help them start and stay on therapy as prescribed.

Give patients less days marked by migraine with Aimovig™.

Learn more about Aimovig™ and how to get your Hypothetical patient.

next patient started at AimovigHCP.com/GetStarted

Indication Aimovig™ is indicated for the preventive treatment of migraine in adults.

Important Safety Information • The most common adverse reactions in clinical studies (≥ 3% of Aimovig™-treated patients and more often than placebo) were injection site reactions and constipation.

Please see a brief summary of the Prescribing Information on the adjacent page.

Reference: 1. Aimovig™ (erenumab-aooe) prescribing information, Amgen.

© 2018 Amgen Inc. All rights reserved. USA-334-80644