2019 October AANnews

VOLUME 33 · ISSUE 10 · October 2019

MERINO SELECTED AS NEW NEUROLOGY EDITOR-IN-CHIEF Will Succeed Gross in April 2020 The Neurology® journal recently announced José G. Merino, MD, MPhil, FAHA, FAAN, will become its new editor-in-chief. Merino will succeed Robert A. Gross, MD, PhD, FAAN, who will complete his 10-year term in April 2020.

“It is my great honor to lead Neurology into the next decade as the premier journal for clinical neurologists,” said Merino, who becomes the seventh editor-in-chief since the “green journal” first published in 1951. “My goal is for Neurology to remain at the forefront in disseminating cutting-edge, peer-reviewed information to the neurology community worldwide, and ultimately leading to improved care for the one in six people worldwide who are affected by neurologic disease.”

Merino received his medical degree from Universidad Anáhuac, Mexico, and a Master of Philosophy degree from the University of Cambridge in England. He completed his residency at the Albert Einstein College of Medicine and a fellowship at the University of Western Ontario. He has taught fellows, residents, and medical students and participated in clinical research programs at the Section of Stroke Diagnosis and Therapeutics of NINDS, Johns Hopkins Medicine, and the University of Maryland. He was named US research editor of The BMJ in 2012 and will step down from that position at the end of September to start the transition into his new role with Neurology.

Neurology, the flagship journal of the AAN, is the world’s most widely read and highly cited peer-reviewed clinical neurology journal and receives over 5,000 manuscript submissions annually. Published 48 times per year, the medical journal's purpose is to advance the field of neurology by presenting new basic and clinical research with emphasis on knowledge that will influence the way neurology is practiced. In addition to Neurology, there are also three subspecialty journals the editor-in-chief oversees.  José G. Merino, MD, MPhil, FAHA, FAAN

2020 Education Program Features Valuable CME in Diverse Learning Formats

AAN Championing Neurologists, Patients in Drug Pricing Regulations

The 72nd Annual Meeting is the place to get the very best continuing medical education in nearly every neurology topic and specialty imaginable, presented

One of the AAN's most important advocacy issues is the rising cost of prescription drugs. While Congress continues to debate ways to reduce prices, the Trump administration has been quite active over the past two years. The AAN is deeply involved in the congressional discussion around drug

Continued on page 14

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April 25 – May 1 • Toronto, Canada

Meet Your New Board Member: Brad C. Klein, MD, MBA, FAAN

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Axon Registry Quality Measures Spotlight: Quality of Life

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21 Diversity Leadership

Applications Due October 10

In Multiple

Sclerosis —

GREY MATTERS, TOO

Learn more about Multiple Sclerosis at MSBrainPreservation.com/art © 2019 Celgene Corporation All rights reserved. 04/19 US-CLG-19-0572

AANnews · October 2019

CONTENTS

News Briefs

Cover

Conferences & Community

Merino Selected as New Neurology Editor-in-Chief

Annual Meeting Abstract and Awards Deadlines this Month · · · · · · · · · · · · · · · 15

2020 Education Program Features Valuable CME in Diverse Learning Formats

Diversity Leadership Applications Due October 11 · · · · 21

AAN Championing Neurologists, Patients in Drug Pricing Regulations

President’s Column Supporting the Role and Stature of the General Neurologist · · · · · · 4

Meet Your New Board Member

Brad C. Klein, MD, MBA, FAAN · · · · 5

Tools & Resources Axon Registry Quality Measures Spotlight: Quality of Life · · · · · · · · 6 Use MCI Quality Measures to Benchmark and Improve Elder Care · · · · · · · · · · · · · · · · 6 Actor Dash Mihok Says Tourette Syndrome Has Helped Shape His Career · · · · · ·

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AAN Publications Recognized with Awards · · · · · · · · · · · · · · · 8 Get Answers You Need from practice@aan.com · · · · · · · ·9 Advocacy Skills Used to Fight Opioids, Apply Novel Technology to Treat Alzheimer’s · · · · · · · · · 10

Could Your Organization Benefit from the 2020 Exhibit Hall? · · · · · · · · · · · · · · 21 Congratulations New Fellows of the American Academy of Neurology! · · · · · · · 22

Education & Research October Continuum Eyes Neuro-ophthalmology · · · · · · · · 23 UCNS Accreditation Application Deadline Is December 1 · · · · · · · 24 UCNS Revises Common Program Requirements for Subspecialty Fellowships · · · · · · 24 Research Opportunities Open for Underrepresented Minority or Disabled Physician-scientists · · · · · · · · · · 25 Second Edition NeuroLearn Patient Safety Course Now Available · · · · · · · · · · · · · 26

Careers · · · · · · · · · · · · · · · 35

Neuroscience Is…™ Cool As students head back to the classroom, the AAN is developing resources to help teachers foster the young minds that make up the neurology pipeline. Coolkits filled with lesson plans and other classroom resources are available for K-12 educators. If you know a teacher who could benefit from this resource, direct him or her to AAN.com/view/CoolKitsRequest to request a Coolkit.

Neurology off the Hill Over the August congressional recess, nearly 40 AAN members met with their members of Congress and staff in their local district offices as a part of Neurology off the Hill.

Advocates discussed drug pricing challenges in neurology; research funding including the NIH, BRAIN Initiative, and Patient-Centered Outcomes Research Institute reauthorization; and the Safe Step Act, a bill to establish commonsense exceptions to step therapy requirements. See pictures from the meetings on Twitter by following #AANadvocacy. 

Dates & Deadlines · · · · · · · · 36

Policy & Guidelines Apply by November 4 for 2020 Neurology on the Hill · · · · · · · · Capitol Hill Report · · · · · · · · · ·

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TThe 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

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American Academy of Neurology 201 Chicago Avenue Minneapolis, MN 55415

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

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President’s Column

Supporting the Role and Stature of the General Neurologist In this age of specialization, generalists in their professions often feel they don’t get the respect they deserve. College students in the liberal arts will often get an eye roll where more marketable majors (think STEM—Science, Technology, Engineering, Mathematics) get education and career tips. Yet employers are increasingly appreciating the well-roundedness and agility these generalists can bring to a job. Just like utility players in baseball, who can successfully play several positions even if they are not the star home run batter or base stealer.

residency training programs may also undermine interest in general neurology. Overall, there is a sense that general neurologists are not accorded the same respect and esteem that fellowship-trained subspecialty neurologists receive. There also seems to be a misperception from neurologists-in-training that their employment opportunities will be limited Stevens by the absence of subspecialty training. Currently, I believe we have a poor understanding of what are the needs of the academic centers and the communities for general neurologic expertise, both in the inpatient and outpatient settings.

In our profession, the general neurologist is akin to the utility player, each day seeing a host of patients with different diagnostic and treatment needs, whether in a small practice or large hospital. But we appear to be losing general neurologists at a precarious rate.

The AAN’s 2019 Insights Report states that 4,364 of our US neurologists (or 33 percent) say that general neurology is their primary subspecialty. Including members who report one or more subspecialties, general neurology climbs to 4,945 members (37 percent). The median age for those reporting general neurology is 56 years old, putting these neurologists in the top third age range of our colleagues.

This compares to just five years ago, when 46 percent of respondents to our survey said their subspecialty was general neurology. Granted, it’s possible that more general neurologists participated in the 2014 survey than in 2019, but we believe the decline is real—and very worrisome. Moreover, the median age was 52 years old, suggesting that our general neurologists are quickly “aging out” and moving toward retirement.

While the changes and uncertainties in today’s health care environment affect us all, the needs of our general neurologists are different from other subspecialists. Many of those serving in small rural communities are finding it hard to attract new general neurologists, and as solo practitioners retire their patients’ access to care is threatened. Patients are often referred to subspecialists in epilepsy or Alzheimer’s, for instance, but this can be problematic in rural areas where a specialist may be several hundred miles away. In cities, small practices staffed by general neurologists can’t compete with large hospitals offering higher pay and more attractive benefits.

As these small practice doctors move on or retire and the ranks thin, these practices are susceptible to acquisition by large health systems.

General neurologists also are key players in academic centers, handling significant caseloads and often teaching duties as well. But there are fears that our medical schools and neurology residency programs are not recognizing the need for more general neurologists as they encourage their graduating residents to take on fellowships and develop subspecialty skills. A lack of exposure to community neurology during

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AANnews • October 2019

These are some of the concerns that have been expressed by members of the General Neurology Section and its chair, William A. Tosches, MD, FAAN; participants in their SynapseSM online community; and by some of our board members. They have proposed ideas that could help mitigate these problems, and suggested ways the AAN can support them. Based on these needs and the critical importance of general neurologists in our specialty, I’m pleased to report that I have created a new presidential task force known as the General Neurology Task Force to dive into this, spell out these issues, and make suitable recommendations for the Board of Directors to consider acting upon.

There is something of a bright spot here: In a 2017 Resident Survey, respondents indicated that 24 percent of residents are interested in pursuing general neurology, compared with 20 percent for epilepsy and 19 percent for movement disorders.

We will see what shapes these decisions and hopefully develop strategies that will encourage that 24 percent to grow.

There are other novel ways to approach this problem. One member on Synapse spoke of how he was close to burnout after three years in academic neurology and left to reinvent himself as a general neurologist in a smaller community. His passion for neurology was reengaged and his work-life balance improved greatly.

All our subspecialties deserve respect and the chance to do their best for our patients. I admire the creativity and commitment of our members and willingness to tackle such thorny issues head-on, whether individually or as a group. I look forward to sharing with you the efforts and recommendations of the General Neurology Task Force. 

James C. Stevens, MD, FAAN President, AAN jstevens@aan.com @JimStevensMD on Twitter

Meet Your New Board Member

Brad C. Klein, MD, MBA, FAAN Brad C. Klein, MD, MBA, FAAN, is a full-time practicing neurologist with additional certifications in headache medicine and electromyography in his private practice at Abington Neurological Associates, Ltd., in Willow Grove, PA.

How did you first get involved as a volunteer on committees/ subcommittees and what moved you to participate?

During my premed years, I saw decision-making power of physicians shifting to other stakeholders such as commercial payers and the government. Decisions seemed to be less focused on doing what was right for patients and more on driving cost-efficiencies. Therefore, my best option was to understand how the system works, learn the business language, and then influence decisions so that stakeholders could better appreciate why quality in care was critical. I was lucky enough to be accepted to one of the several schools at the time that offered a program combining both MD and MBA degrees. I then used this education to advocate locally through my state medical society. In my third year of residency, I saw an AAN advertisement for the Palatucci Advocacy Leadership Forum. My residency director allowed me the opportunity to apply and participate, and it opened my eyes to not only understand federal advocacy, but also realize the amazing work done and resources available at the AAN. While I took on a few national advocacy efforts thereafter, my “extracurriculars” were mostly at the state level, including building the state neurological society, growing my practice, and spending time with my family. However, in 2013, neurologist reimbursements for EMG work and botulinum toxin for migraine were significantly reduced. At that moment, I felt compelled to understand what happened and how I could assist to prevent similar events from happening in the future. As a result, I sent an email to the Academy asking to learn more about the AAN’s efforts in advocacy and medical economics and soon thereafter David Evans, then chair of the Practice Management and Technology Subcommittee, called me asking if I wanted to join his subcommittee. From there, the AAN supported me to understand the processes involved in how our work is evaluated by payers like CMS, how we get paid, and most importantly, where we can improve the system.

Why did you wish to be on the Board of Directors?

It is a true honor to serve on this board with such amazing and esteemed colleagues. I never expected this kind of opportunity.

Forgive any cliché, but I think the concept of “stronger together” is an important concept, not only for the success of our organization, but the success of our field. Our collective voice across the country, if not the world, is clearly the most powerful voice in the field of neurology. Additionally, because we have economies

of scale, we can do some really cool things and offer some spectacular resources for our members. However, what we do is only feasible because of the expansive support of our members.

As a board member, I look forward to making sure our members continue to see the AAN as indispensable and as the “go to” organization for their neurology needs, including cutting-edge science, research, clinical guidelines, and practice management.

I also want us to remain at the forefront of health care delivery, changing the direction of the tide where possible, and helping ensure our members have what they need to continue caring for patients the best way possible.

What experiences and viewpoints do you bring to this role?

Ever since I completed my business degree, I have seen care delivery a little differently. My education helped open my eyes to the opportunities we have in medicine to really make the system better. However, real change rarely happens overnight and generally requires communication and understanding, shared goals, and an appreciation for the value of change to make it happen. I firmly believe that many opportunities exist for neurologists to control their own destiny, care for their patients, and not burn out, but this requires work by all of us.

From your experiences as an AAN leader, what is one of the more common misperceptions members may have about the Academy, and how would you respond to that?

I think one of the challenges about the Academy is members’ understanding of the depth of work done on their behalf. The Academy’s successes are comprised solely of hundreds of volunteer members and Academy staff. Because the Academy works to support the needs of over 36,000 members, it can be difficult for members to know all that is going on at the Academy and where their dollar is spent. If a member is unsure about the Academy’s efforts on a particular topic, or if the member needs resources for a particular concern, the member should always feel welcome to reach out.

In your view, how does the AAN benefit the field of neurology most?

The Academy is not defined by any one institution, a preference towards academic or private practice, nor any one subspecialty.

It is an organization that represents the values within neurology that we share. It allows us the opportunity to communicate, collaborate, and produce work together that can help us all.  AANnews AANnews • October 2019 5

Tools & Resources

Axon Registry Quality Measures Spotlight: Quality of Life Why is measuring quality of life (QoL) important?

Neurologic disorders often take a toll on a patient’s well-being. An important part of quality care is to assess quality of life to identify areas of concern and appropriate interventions. Quality of life assessments can help give a clinician a more holistic view of a patient instead of solely focusing on disease activity. Patients and care partners are aware of the long-term negative outcomes of many neurologic conditions and have identified quality of life as one meaningful area of focus during treatment. They have noted that with other members of the treatment team, results can be reviewed to prompt broader discussions on lifestyle changes (like diet and exercise), medication adjustments, possible surgical options, or next phase of life decisions.

Why does Axon Registry have several QoL measures?

The Axon Registry® currently has four quality of life measures. Each of these measures has a different purpose and patient population.

Two of these measures are broad assessments for the majority of patients with neurologic conditions, whereas two are disease specific.

Below are the QoL measures in the Axon Registry. More information about these measures can be found on AAN.com.

Axon 40: Quality of Life Assessment The purpose of this measure is to assess quality of life with PROMIS-29 and provide appropriate follow up annually for those patients 18 years and older. This measure focuses on the treatment team process of collecting data and responding appropriately to any identified concerns.

Axon 54: Global Health-10 The purpose of this measure is to review whether the quality of life score for a patient aged 18 and older has been maintained or improved over time using PROMIS Global Health-10. This measure directly assesses quality of life outcomes for patients across neurology.

Axon 41: Quality of Life Outcome for Patients with Epilepsy The purpose of this measure is to review whether the quality of life score for an epilepsy patient aged 18 and older has been maintained or improved over time using QOLIE-10-P. Axon 15: Quality of Life Assessment for Patients with Primary Headache Disorders The purpose of this measure is to assess the headache patient’s quality of life with a health-related quality of life tool to determine if the score has been maintained or improved over time. Some QoL tools with a score that are reviewed for this measure include: MIDAS, HIT-6, MSQ, NDI, and McGill Questionnaire.

Visit AAN.com/view/Axon to learn how the Axon Registry—a free benefit to AAN US-based members—can help you enhance the quality of care you provide your patients and reduce the burden of maintaining certification. 

Use MCI Quality Measures to Benchmark and Improve Elder Care The AAN published a new quality measurement set on mild cognitive impairment (MCI) in the September 18 online issue of Neurology ® and it will appear in the October 15 print issue. This measurement set may be of interest to any physician or treatment team that cares for patients 65 years and older. The measurement set will help physicians and treatment teams determine how frequently they are providing optimal care and can help establish benchmark performance for improvement in future years.

The measurement set includes: Annual Cognitive Health Assessment for patients 65 years and older Cognitive and functional assessment for patients with MCI MCI diagnosis disclosed and counseled on treatment options Assessment and treatment of factors contributing to MCI

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AANnews • October 2019

Avoidance of anticholinergic medications for patients with MCI Education provided to care partners of patients with MCI View the published executive summary at Neurology.org and the full measure set and tools on AAN.com. For more information, contact Amy Bennett at abennett@aan.com or call (612) 928-6072. 

Tools & Resources

AAN Championing Neurologists, Patients in Drug Pricing Regulations continued from cover

prices. But the AAN has been especially active in the regulatory space. The AAN has submitted several regulatory comment letters to the administration on the drug prices and expects to write more in the future.

A significant way the Trump administration indicated that drug pricing would be one of its top priorities was by issuing a request for information (RFI) related to the “American Patients First” drug pricing blueprint. The blueprint was a comprehensive outline of the administration’s positions on drug pricing and the RFI offered stakeholders the opportunity to weigh in on the various proposals put forth by the administration in the blueprint. In July 2018, the AAN submitted comments outlining how high drug prices uniquely impact neurologic care and offered recommendations related to several of the policies the Trump administration laid out in the blueprint. AAN feedback included opposition to indication-based payments, moving drugs from Medicare Part D to Part B and an inflation cap on reimbursement rates, support for site neutral payments, advocacy for the expansion of patient financial health tools, and support for reforming the existing rebate system.

Following the release of the drug pricing blueprint, the administration has been extremely active in issuing proposed regulations that would address high drug prices along a number of fronts.

As part of the 2019 Physician Fee Schedule proposed rule, the Centers for Medicare & Medicaid Services (CMS) proposed a change that would reimburse newly released Part B drugs (for which there are no available sales data) according to 106 percent of the drug’s wholesale acquisition cost (WAC). The AAN opposed this cut to reimbursement, noting that physicians are not responsible for setting high drug prices and that the cuts to reimbursement could harm patient access to drugs due to the high overhead costs associated with administering Part B drugs.

Despite the AAN’s opposition to this proposal, this proposal was finalized and was implemented on January 1, 2019.

In the fall of 2018, the administration released an advanced notice of proposed rulemaking related to the potential creation of a federal drug pricing and payment model that would base reimbursement for Part B drugs on an index of international prices. The AAN is concerned with the scope of this untested proposal and recommended that the administration scale back the scope of the proposal and first pilot-test it to ensure that the model results in lowered drug prices without significant detrimental impacts on patients and providers. CMS has not yet moved forward with any next steps related to this model and the AAN will plan to submit comments if and when a proposal is released.

Additionally, in the fall of 2018, the administration issued a proposed regulation that would require the disclosure of WAC prices in direct-to-consumer television advertising. The AAN supported this disclosure and it was finalized for implementation in July 2019. Prior to implementation, however, this rule was struck down by a federal court judge in response to a lawsuit from several pharmaceutical manufacturers. The AAN anticipates further litigation in relation to this proposed rule.

As 2018 was ending, CMS issued a proposed rule that would substantially change the “six protected classes” and expand step therapy within Medicare Advantage. The AAN achieved a significant win in the finalized regulation. Consistent with the AAN’s advocacy in response to the initial proposed rule, CMS scaled back a proposal related to step therapy and prior authorization and will not allow step therapy and prior authorization to be applied to patients on existing therapies within the six protected classes.

In January of 2019, the administration issued a proposal that would significantly reform the existing drug rebate system to ensure that negotiated discounts are passed through to patients through lowered out-of-pocket costs. The AAN supported this proposal noting the extremely high out-of-pocket costs that many neurology patients pay for their medications. In the comments, the AAN also opposed linking lowered spending on prescription drugs to utilization management tools like step therapy and prior authorization. Ultimately, this proposal was withdrawn by the administration, but it may move forward in some fashion through Congress.

Drug pricing remains a top AAN advocacy priority. AAN staff work every day with members of Congress and their staff to explain the impact rising drug prices have on neurologists and their patients. While we wait for congressional action in this space, the AAN has not slowed its advocacy work and has been working with regulators at the Department of Health and Human Services to refine policies that will impact drug pricing in the United States. 

AANnews • October 2019 7

Tools & Resources

Actor Dash Mihok Says Tourette Syndrome Has Helped Shape His Career The October/November issue of Brain & Life® features actor Dash Mihok (Bunchy on Showtime’s Ray Donovan), who describes how a childhood diagnosis of Tourette syndrome helped shape his career. The recent AAN guideline on the condition is also reviewed.

Another feature catches up with Mayte Garcia, a singer, dancer, and author who was married to musician Prince in the mid-1990s. For the first time since her diagnosis of multiple sclerosis (MS) in 2010, she details how she is managing the disease and how she deals with the invisible symptoms of fatigue and depression.

The article also looks at the prevalence of MS among Hispanics (Garcia is of Puerto Rican descent) and how that affects diagnosis.

Brain changes related to stroke, epilepsy, and Parkinson’s disease that increase the risk of depression are covered, with provides tips for managing depression.

Brain & Life magazine is free for AAN members in the United States to distribute to patients, who also can subscribe for free. If you would like to adjust the number of copies you receive for your patients or update your clinic address, email BeGreen@WasteFreeMail.com. All members have online access to the magazine articles and additional resources at BrainandLife.org. Please share the website with your patients! 

O C TO B E R /N OV E M B E R 2 0 1 9

Depression Tips for People with Parkinson’s, Epilepsy, and Stroke Finances How to Save on Prescription Costs Hereditary Ataxia New Research May Lead to a Cure

I hope my story helps reduce the stigma around Tourette’s.”

—AC TO R DA S H M I H O K

AAN Publications Recognized with Awards Brain and Life® and Neurology Today ® were granted Awards of Excellence in the 2019 APEX editorial awards competition, which had more than 1,200 entries. Brain and Life won in the Feature Writing category for its June/July 2018 cover feature on actor Courtney Vance, “Supporting Role” (http://bit.ly/30BUkjV).

Neurology Today won in the News Writing category for its March 22, 2018, article, “The Mystery Behind Neurological Symptoms Among US Diplomats in Cuba: Lots of Questions, Few Answers” (http://bit.ly/2NxqIjT).

Actor Courtney Vance, featured in Brain and Life®.

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AANnews • October 2019

Tools & Resources

Get Answers You Need from practice @aan.com The practice@aan.com email inbox is an efficient way to reach staff and member expertise on practice related topics such as payers, MIPS/MACRA, coding and practice management. Staff experts respond within one business day and can seek the assistance of the Practice Support Network, a group of 20 practicing neurologists and graduates of AAN’s Practice Leadership Program, for real-world expertise. Below are some recent common questions from our inbox.

PRACTICE MANAGEMENT Q: I am looking to develop a template for new and follow-up epilepsy patients. Is there a list of recommended questions/information that should be included?

A: T he AAN has developed patient questionnaires for follow-up

patients. Each questionnaire incorporates AAN guidelines and quality measures for the disease state and has been vetted by clinical experts. We encourage physicians to use the questionnaires as a guide when developing EHR templates, making edits as necessary to fit your practice.

Additionally, the questionnaires can be sent to patients via the patient portal in advance of their appointment; answers can be reviewed and documented in the EHR template by physicians or other clinical staff to streamline the office visit.

Currently, the AAN has questionnaires for patients with epilepsy, multiple sclerosis, sleep, and headache diagnoses. Find the questionnaires and other helpful hints on using the questionnaires in your practice at AAN.com/view/EHRtemplates.

CODING Q: How should I determine if a patient is new or established when he or she sees multiple subspecialists in my neurology group?

A: It is best to refer to the E/M Services Guidelines of the

CPT® Professional Codebook, which defines the use of new and established patient visits based on whether a patient has been seen by a provider of the exact same subspecialty who belongs to the same group practice within the previous three years. For the purposes of defining the subspecialties of neurology, the AAN looks to accreditation

and certification programs from the American Board of Psychiatry and Neurology (ABPN), the Accreditation Council for Graduate Medical Education (ACGME), the United Council for Neurologic Subspecialties (UCNS), and the Health Care Provider Taxonomy Code Set. However, not all payers look to the same accrediting body to identify subspecialties.

Ultimately, it is important to confer with your payers when filing a claim for a patient you are billing as a new patient but has been seen by a provider of a different neurology subspecialty within your practice.

MIPS Q: How do I make sure my practice avoids the MIPS penalty this year?

A: For 2019, clinicians who are required to report to the

Merit-based Incentive Payment System (MIPS) must meet the performance threshold of at least 30 points to avoid a negative seven-percent payment adjustment to their 2021 Medicare Part B payments. By performing and attesting to 40 points worth of Improvement Activities, practices will receive 15 points toward their total MIPS score, which is half of the points required to avoid the negative adjustment.

From there, successfully reporting Quality and Promoting Interoperability measures that equal at least 15 points will help practices surpass the 30-point threshold and ensure they receive at least a neutral payment adjustment in MIPS. The AAN offers up-to-date resources for the current and upcoming MIPS performance years to ensure successful participation for neurologists and neurology APPs. For questions specific to your practice’s participation in MIPS, contact practice@aan.com and staff can help direct you to the AAN and Quality Payment Program resources that address your question. 

AANnews • October 2019 9

Policy & Guidelines

Advocacy Skills Used to Fight Opioids, Apply Novel Technology to Treat Alzheimer’s From educating primary care physicians on the dangers of opioids to collaborating on novel clinical trials to improve delivery of medications to the brain, Umer Najib, MD, has put his AAN advocacy training to good use.

Najib is an assistant professor and program director for the Headache Medicine Fellowship Program at J.W. Ruby Memorial Hospital, WVU Rockefeller Neuroscience Institute, at West Virginia University (WVU). He got his first taste of AAN advocacy as a participant in the 2015 Neurology on the Hill event. There, he recognized the inherent powers of education and persuasion.

Najib returned to PALF as an advisor in 2018 and as a member of the faculty in 2019, sharing his insights and experiences with new classes of enthusiastic advocacy students. He also continued to hone and use his advocacy skills, this time focused on his institution.

As WVU developed its comprehensive Rockefeller Neuroscience Institute (RNI), Najib successfully advocated Najib for the inclusion of a comprehensive Transcranial Magnetic Stimulation (TMS) program. When Dr. Ali Rezai took charge of the RNI and shared his vision to create a Center of Excellence in neuromodulation, Najib’s PALF skills helped him in showcasing his previous experience with TMS and “Neurology on the Hill showed me how to effectively advocate the highlighting how a world-class TMS program would fit in the issues we are passionate about,” he said. “It opened the doors grand plan. “This was only made possible with complete support to a whole new world of organized action planning and effective and far-reaching vision of Dr. Rezai. The TMS program has three execution. It showed me firsthand the work AAN does advanced labs with different systems, all integrated with EMG, EEG, to safeguard the interests of patients and neurologists.” neuro-navigation based on MRI, virtual reality, and motion sensor Najib’s clinical focus is on headache disorders including migraine, technology. These are currently being used for research but waiting and he’s long been concerned about the over-prescription approval to have clinical use,” he said. “These are custom-built labs of opioids in pain treatment. “While the American Headache and I worked with architects and technology industry to design the Society recommends against the use of opioids in the treatment layout and integrate the different systems. TMS is often used for of headache disorders, opioid analgesics are routinely used the treatment of depression, but there’s off label use for addiction, as first line agents in the primary care setting.” Najib sought seizures, human performance enhancement, and chronic pain.” to reduce inappropriate use of opioids by developing education Najib was named director of this new TMS program, and he is resources about the treatment of headache disorders that he training people to do TMS. provided to primary care providers in West Virginia. He applied At the same time, Najib’s research has extended to Alzheimer’s and was accepted as a participant in the 2017 Palatucci Advocacy disease. He is working on a study called “Application of Transcranial Leadership Forum (PALF), where he furthered his knowledge of Magnetic Stimulation Coupled with Virtual Reality for Slowing the effective strategies employed in a sound action plan. Najib’s Rate of Cognitive Decline in Patients with Alzheimer's Disease.” efforts went a long way in helping curtail the high number of He also is the only neurologist on the 35-member team who opioid prescriptions in his state. successfully performed a phase II trial using focused ultrasound “I am fortunate to have a supportive mentor in the form of my to treat a patient with early stage Alzheimer’s. “The WVU team department chair, David B. Watson, MD, FAAN. He connected tested the innovative treatment in collaboration with INSIGHTEC, me with various primary care stakeholders in West Virginia, an Israeli medical technology company. In 2018, INSIGHTEC was which resulted in multiple invited presentations approved by the US Food and Drug Administration to begin a phase at conferences throughout the state.”

II clinical trial of the procedure and selected the WVU Rockefeller Education material was also Neuroscience Institute as the first site in the United States for that posted online in the form of a trial.” The stimulation opened a patient’s blood-brain barrier for webinar on a primary care 36 hours, a seismic breakthrough that brings hope in administering health network in the state. medications directly to the brain for Alzheimer’s, brain tumor, All these efforts helped in chronic pain, and a host of other brain disorders. disseminating information The course of Najib’s professional life clearly has been bolstered about appropriate treatment by making the most of his AAN membership. of headache disorders.

“I would strongly encourage other AAN members to get involved in advocacy and take advantage of the resources offered by AAN for advocacy training. In addition to becoming a stronger advocate for my patients and for neurology, AAN advocacy training has helped me in becoming a much more effective communicator.” 

10

AANnews • October 2019

Policy & Guidelines

Apply by November 4 for 2020 Neurology on the Hill It is crucial that members of Congress have the facts when it comes to neurologic care. Neurology on the Hill, to be held next February 24 and 25 in Washington, DC, is your chance to meet with your senators and representative to share your experiences and insights face-to-face and educate them about the

critical role of neurologists in health care and the need for legislation to improve neurologic patient care.

Washington, DC, member volunteers and Academy staff will prep you on the critical issues and AAN advocacy priorities.

Applications are open October 1 to November 4. You don't need a public policy background to join us! After you arrive at the Omni Shoreham Hotel in

Learn more and apply by November 4 at AAN.com/view/NOH. 

#AANAdvocacy

NEUROLOGY COMPENSATION AND PRODUCTIVITY SURVEY DATA AVAILABLE! Compare. Act. Improve.

AAN.com/view/NCPSurvey

Policy & Guidelines

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.

AAN Continues to Fight for Long-term EEG Monitoring Services Member Perspective by Marianna Spanaki-Varelas, MD, PhD, MBA; AAN RVS Update Committee (RUC) Advisor The AAN’s participation in the AMA’s Relative Value Scale Update Committee (RUC) meetings was the first step in fighting for appropriate reimbursement for the critical services we as neurologists provide. The ultimate payment rates are determined by CMS, and as we have seen in the Proposed Rule for 2020, the agency did not fully accept the recommendations of the RUC for the long-term EEG codes. Of the 10 new professional services codes that are effective in January of 2020, CMS only accepted the RUC recommendations for six of the codes. Those not accepted by CMS are the four new codes reported when the physician has access to data throughout the recording period, generates a daily report, and are typically performed in the inpatient setting.

The AAN quickly responded and along with the other organizations that participated in the RUC survey―the American Clinical Neurophysiology Society (ACNS) and the National Association of Epilepsy Centers (NAEC)―set up a meeting with CMS leadership to voice our concerns. On September 3, I had the opportunity to participate in a face -to-face meeting with CMS representatives and explain based on my own clinical experience and in my own words the complexity and intensity of the long-term EEG monitoring services. We explained that beyond the detrimental financial impact the proposed reductions would have on the field of neurology, the care of sensitive patient populations would be greatly affected.

I believe that it was very helpful to speak not only about the time spent by a physician to interpret the studies, but the typical patient population evaluated with these services.

Although many patients can undergo long-term EEG monitoring at home, this meeting focused on the patients who require care in the inpatient setting, since CMS proposed

From left, Ellen Riker, Executive Director, NAEC; Nathan Fountain, MD, President, NAEC; Marianna Spanaki-Varelas, MD, PhD, MBA; Luana Ciccarelli, Senior Manager, Reimbursement & Coding, AAN; Erika Miller, CRD Associates, Consultant to ACNS.

further reducing the value of these services. These patients are typically either in: Epilepsy Monitoring Units (EMU) where seizures are provoked by tapering anti-seizure medication in patients with intractable epilepsy in order to localize the seizure focus and determine surgical candidacy.

Intensive care units (ICU) to assess if they have seizures with subtle or no clinical manifestations. EEG data interpretation is often provided more than once per day in order to assist the treating clinician with management and effective treatment.

In addition to our efforts directly with CMS, the AAN will continue to make this issue a priority and pursue all means possible to minimize the negative impact anticipated in 2020. Thus far, the AAN has sent out a grassroots action alert to contact Congress in opposition to the proposed EEG coding changes. If you have not yet done so I would encourage to contact your member of Congress via the AAN Advocacy Action Center. We also, along with NAEC and the Epilepsy Foundation of America, met with staff from the offices of Sen. Margaret C. Hassan (D-NH) and House Majority Leader Steny Hoyer (D-MD) to discuss having Congress express concerns to CMS about the proposed reimbursement reductions to the new long-term EEG monitoring code set.

You can visit the Medicare page of the AAN website to read about the final CMS recommendations when they are released in November of this year. 

AANnews • October 2019 13

Conferences & Community

2020 Education Program Features Valuable CME in Diverse Learning Formats continued from cover in a wide array of learning formats to fuel your mind, body, and sprit. And there’s no better city in which to experience this kind of educational diversity than Toronto, whose motto aptly declares “Diversity Our Strength.”

Whether you’re a clinician, researcher, resident, student, or other neurology professional—and no matter what your subspecialty area of interest—the 2020 Education Program is your go-to for the valuable CME and knowledge you need.

Back by Popular Demand—Friday Grand Finale Program While you’ll find fresh and creative education content all week long through more than 240 expert-led courses and experiential learning areas covering the full spectrum of neurology, you’ll want to make sure and stay until the end of the week to take in the enhanced Friday experience. The streamlined schedule for the day will offer even more opportunity for networking and community with your network of peers. Here’s a quick look at the Friday highlights: 7:00 a.m.–9:00 a.m.

Course programming Get the latest on a variety of topics from experts in the field, including the Friday Education Blitz on normal pressure hydrocephalus from 8:00 a.m.–9:00 a.m. delivering updates in an energetic one-hour format.

9:15 a.m.–11:30 a.m.

Neurology Year in Review Plenary Session Speakers will focus on the latest research that has happened in the last year within a specific subspecialty topic.

11:30 a.m.–1:00 p.m.

Science Innovation Lunch Head to the poster hall to view some of the best scientific posters and presentations from the week focusing on neuroinflammation.

1:00 p.m.–3:00 p.m.

Courses and Scientific Sessions Four major scientific sessions will focus on headache, stroke, epilepsy, and neuro-oncology and four programs will highlight new information on hyperkinetic movement disorders, Lewy body dementias, neuromyelitis optica spectrum disorders, and therapy of neuromuscular disease.

3:30 p.m.–4:30 p.m.

Encore Update Programs Look for encore presentations of four popular update programs presented earlier in the week.

4:30 p.m.–5:30 p.m.

NeuroZone Gear up for the Closing Party with this unconventional, interactive activity. Audience participation is encouraged!

5:30 p.m.

Closing Party Celebrate the end of a great meeting!

In addition, look for these other exciting education opportunities throughout your week in Toronto: Expanded Continuing the Conversation Talks This popular education program enhancement will return with the director and faculty relocating to a reception setting to engage in small group conversations with interested audience members.

Coding Sessions Look for four sessions offering opportunities to network with other physicians on the latest coding issues.

Career-focused Tracks These audience-based programming tracks offers focused programming geared specifically toward a variety of neurology professionals.

14

AANnews • October 2019

Academic Medicine: Provides a variety of offerings for academic neurologists across career roles and stages.

Business of Neurology: Perfect for individuals interested in starting a new practice or learning the fundamentals of neurology business.

Career Essentials: Offering help with early career and development or to those looking to launch into private practice or academics.

Foundations of Clinical Neurology for APPs: Created for advanced practice providers who are new to neurology.

Futures in Neurological Research: This track offers both formal coursework and learning sessions to round out research-interested trainees’ Annual Meeting experience.

Neurohospitalist: Created specifically for neurohospitalists whose primary focus is inpatient care.

Spanish-language: Courses, ELAs, and scientific updates taught in Spanish.

Visit AAN.com/view/AM20 to learn more and register. 

April 25 – May 1 • Toronto, Canada

Conferences & Community

Annual Meeting Abstract and Awards Deadlines this Month Abstract Submissions: October 21 Your breakthrough research could be seen by neurologists, neuroscientists, and researchers from all over the world if your abstract is selected for presentation at the 2020 AAN Annual Meeting in Toronto. Submit yours by no later than 11:59 p.m. CT on October 21 at AAN.com/view/20Abstracts.

For more information, contact Erin Jackson at ejackson@aan.com or (612) 928-6112.

Award Applications: October 23 Prestigious AAN scientific awards will be presented during the 2020 Annual Meeting to honor the best research and achievements by neurologists and neuroscientists around the globe and at all career stages. In addition to recognition, the awards also offer prizes and other compensation, such as complimentary travel expenses and registration for the Annual Meeting. Visit AAN.com/view/20Awards to apply—or nominate a deserving colleague—by October 23.  CESC: 20AM_Abstract Ad—Half Page Horizontal> AN

April 25 – May 1 • Toronto, Canada

Placed in AANnews 8.25 x 5.25 +0.125 bleed, 4C

Show Us Your Best Science Submit your abstract by October 21, 2019

AAN.com/view/20Abstracts

April 25 – May 1 • Toronto, Canada

FOR THE TREATMENT OF RELAPSING FORMS OF MS

START STRONG. STAY STRONG.

In the 2-year DEFINE and CONFIRM pivotal trials, Tecfidera® (dimethyl fumarate) demonstrated a 53% and 44% relative reduction in annualized relapse rate (ARR) vs placebo, respectively (0.172 vs 0.364; P<0.0001), (0.224 vs 0.401; P<0.0001)1

INDICATION

Tecfidera® (dimethyl fumarate) is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

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

©2019 Biogen. All rights reserved. 09/19 TEC-US-3189 v4

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.

THE #1 PRESCRIBED oral RMS therapy in the US since September 2013 Based on number of prescriptions from IMS NPATM Weekly Data (September 27, 2013 - March 29, 2019).

>385,000

people have been treated with TECFIDERA worldwide2

This includes clinical trial use and patients prescribed TECFIDERA

>710,000

global patient-years of experience2

This includes clinical trial use and patients prescribed TECFIDERA

>11 Years

of combined clinical trial and real-world experience1,2

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. 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.

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%).

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

Please see following pages for Brief Summary of full Prescribing Information.

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.

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.

Study Designs1 DEFINE: A 2-year, randomized, double-blind, placebo-controlled study in 1234 patients with RRMS. Secondary endpoint: ARR. CONFIRM: A 2-year, multicenter, randomized, double-blind, placebo-controlled study in 1417 patients with RRMS. Primary endpoint: ARR. DEFINE=Determination of the Efficacy and Safety of Oral Fumarate in Relapsing-Remitting MS3; CONFIRM=Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis4; RRMS=relapsing-remitting multiple sclerosis.

References: 1. TECFIDERA Prescribing Information, Biogen, Cambridge, MA. 2. Data on file, Biogen. 3. Gold R, et al. N Engl J Med. 2012;367(24):2362.

4. Fox RJ, et al. N Engl J Med. 2012;367(12):1087-1097.

To get started, simply fill out a Start Form at

www.tecfiderahcp.com

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

Brief Summary of Full Prescribing Information relapsing-remitting disease, and active secondary progressive TECFIDERA is indicated for the treatment of patients with relapsing 2 DOSAGE AND ADMINISTRATION disease, in adults.

1forms INDICATIONS AND USAGE of multiple sclerosis.

2.1 Dosing Information TECFIDERA is indicated for the treatment of patients with relapsing 2 DOSAGE AND ADMINISTRATION The starting dosesclerosis. for TECFIDERA is 120 mg twice a day orally. After 7 forms of multiple 2.1 Dosing Information days, the dose should be increased to the maintenance dose of 240 mg 2The DOSAGE twice a dayAND orally.

Temporary doseisreductions to 120 mgorally. twiceAfter a day starting doseADMINISTRATION for TECFIDERA 120 mg twice a day 7 may be forbe individuals do maintenance not tolerate the maintenance 2.1 Dosing Information days, theconsidered dose should increasedwho to the dose of 240 mg dose.

4 weeks, the recommended dose of 120 240 twice aWithin day dose orally. dose to mgorally. twiceAfter a day The starting forTemporary TECFIDERA is reductions 120 mg twice a day 7 should be Discontinuation of should be may be forbe individuals domaintenance notTECFIDERA tolerate the maintenance days, theconsidered doseresumed. should increasedwho to the dose of 240 mg considered for patients unable to tolerate return to the maintenance dose.aWithin 4 weeks, the recommended dosetoof120 240mg mgtwice twice aa day day twice day orally.

Temporary dose reductions dose. flushing may reduced by the administration of should be incidence resumed.

Discontinuation TECFIDERA should be may beThe considered forofindividuals who be do of not tolerate maintenance TECFIDERA food.

Alternatively, administration ofmaintenance non-enteric considered patients to tolerate return to the dose.

Within for 4 with weeks, theunable recommended dose of 240 mg twice a day coatedThe aspirin (up to aofdose of 325may mg)be 30ofreduced minutes prior to TECFIDERA dose. flushing by administration of should be incidence resumed.

Discontinuation TECFIDERA should be dosing mayfor reduce the unable incidence or severity of flushing [see Clinical TECFIDERA with food.

Alternatively, administration non-enteric considered patients to tolerate return to theofmaintenance Pharmacology (12.3)]. coated aspirin (up to aofdose of 325 mg)be30reduced minutesby prior to TECFIDERA dose.

The incidence flushing may administration of dosing may reduce the or whole severity of flushing [see Clinical TECFIDERA should beincidence swallowed and intact.

TECFIDERA with food.

Alternatively, administration of TECFIDERA non-enteric Pharmacology (12.3)]. shouldaspirin not be (up crushed or chewed and 30 theminutes capsuleprior contents should not coated to a dose of 325 mg) to TECFIDERA be sprinkled onshould food.the TECFIDERA canseverity be taken or without food. dosing may reduce or of with flushing [see Clinical TECFIDERA beincidence swallowed whole and intact.

TECFIDERA Pharmacology (12.3)]. should not Tests be crushed or Initiation chewed and the capsule contents should not 2.2 Blood Prior to of Therapy be sprinkled on food. TECFIDERA canwhole be taken or without food.

TECFIDERA should be swallowed andwith intact.

TECFIDERA Obtain a complete blood cell count (CBC) including lymphocyte count should not be crushed or and capsule contents(5.3)]. should not 2.2 Blood Tests tochewed Initiation of the Therapy before initiation ofPrior therapy [see Warnings and Precautions be sprinkled on food. TECFIDERA can be taken with or without food.

Obtain complete blood cell count (CBC) lymphocyte Obtain aserum aminotransferase, alkalineincluding phosphatase, and count total 2.2 Blood Testsprior Prior Initiation of Therapy before initiation of therapy [see Warnings and Precautions (5.3)]. and bilirubin levels to to treatment with TECFIDERA [see Warnings Obtain a serum complete blood cell count (CBC) including lymphocyte Precautions (5.4)].

Obtain aminotransferase, alkaline phosphatase, andcount total before initiation of therapy [see Warnings and Precautions (5.3)]. and bilirubin levels prior to treatment with TECFIDERA [see Warnings 3 DOSAGE FORMS AND STRENGTHS Precautions (5.4)].

Obtain serum phosphatase, and total TECFIDERA is aminotransferase, available as hard alkaline gelatin delayed-release capsules bilirubin levels treatment with TECFIDERA [see Warnings and 3 DOSAGE FORMS AND STRENGTHS containing 120 prior mg orto240 mg of dimethyl fumarate. The 120 mg capsules Precautions (5.4)]. have a green cap and whiteas body, withdelayed-release “BG-12 120 mg”capsules in black TECFIDERA is available hardprinted gelatin ink on the 120 body.

240mg mgofcapsules a green andcapsules a green 3containing DOSAGE FORMS STRENGTHS mgThe orAND 240 dimethyl have fumarate.

The cap 120 mg body, aprinted “BG-12 240 mg” black with inkdelayed-release on the body. have greenwith capavailable and white printed “BG-12 120 mg”capsules in black TECFIDERA is asbody, hardin gelatin ink on the120 body.

240mg mgofcapsules have a green cap mg andcapsules a green containing mgThe or 240 dimethyl fumarate.

The 120 4 CONTRAINDICATIONS body,aprinted “BG-12 240 mg” printed in blackwith ink on the body. mg” in black have green with cap and white body, “BG-12 TECFIDERA is contraindicated in patients with known120 hypersensitivity ink on the body.

The 240 have a green cap and a green 4 CONTRAINDICATIONS to dimethyl fumarate or mg to capsules any of the excipients of TECFIDERA. body, printed with “BG-12 240 mg” in black ink on the body.

Reactions have included anaphylaxis and angioedema [see Warnings TECFIDERA is contraindicated in patients with known hypersensitivity and Precautions (5.1)]. or to any of the excipients of TECFIDERA. 4to CONTRAINDICATIONS dimethyl fumarate Reactions have included anaphylaxis and with angioedema [see Warnings TECFIDERA is AND contraindicated in patients known hypersensitivity 5 WARNINGS PRECAUTIONS and Precautions (5.1)].or to any of the excipients of TECFIDERA. to fumarate 5.1dimethyl Anaphylaxis and Angioedema Reactions haveAND included anaphylaxis and angioedema [see Warnings 5 WARNINGS PRECAUTIONS TECFIDERA can(5.1)]. cause anaphylaxis and angioedema after the first dose and Precautions 5.1 Anaphylaxis and Angioedema or at any time during treatment. Signs and symptoms have included 5TECFIDERA WARNINGS AND PRECAUTIONS difficulty breathing, urticaria, and swelling of the throat andfirst tongue. can cause anaphylaxis and angioedema after the dose Patients be instructed to Signs discontinue TECFIDERA seek 5.1 Anaphylaxis and Angioedema or at anyshould time during treatment. and symptoms haveand included immediatebreathing, medical care shouldand theyswelling experience signs and the symptoms of difficulty urticaria, of the throat andfirst tongue.

TECFIDERA can cause anaphylaxis and angioedema after dose anaphylaxis or angioedema.

Patients be instructed discontinue TECFIDERA seek or at any should time during treatment.toSigns and symptoms have and included immediate medical care should they experience signs and and symptoms of difficulty breathing, urticaria, and swelling of the throat tongue.

5.2 Progressive Multifocal Leukoencephalopathy anaphylaxis or angioedema.

Patients should be instructed to discontinue TECFIDERA and seek Progressive multifocal leukoencephalopathy (PML) has occurred in immediate medical care should they experiencePML signsisand of 5.2 Progressive Leukoencephalopathy patients with MSMultifocal treated with TECFIDERA. an symptoms opportunistic anaphylaxis or angioedema. viral infection of the brain caused by the JC virus (JCV) typically Progressive multifocal leukoencephalopathy (PML) has that occurred in onlyProgressive occurs patients whowith are immunocompromised, andopportunistic that usually 5.2 Multifocal Leukoencephalopathy patients within MS treated TECFIDERA. PML is an leadsinfection to death severe disability.

A the fatalJC case of (JCV) PML inina viral oforthe brain caused by virus that typically Progressive multifocal leukoencephalopathy (PML) hasoccurred occurred patient who received TECFIDERA for 4 years enrolled in a only occurs patients who areTECFIDERA. immunocompromised, and that usually patients withinMS treated with PML while is an opportunistic clinical During the clinical trial,byA the patient experienced prolonged leadsinfection totrial. death severe disability. fatal of(JCV) PML occurred in a viral ofor the brain caused the JCcase virus that typically 9 lymphopenia (lymphocyte counts predominantly <0.5x10 /L usually for in3.5 patient whoin received TECFIDERA for 4 years while a only occurs patients who are immunocompromised, andenrolled that years)towhile taking TECFIDERA [see Warnings and Precautions (5.3)]. clinical trial.

During the clinical trial, patient prolonged leads death or severe disability.

Athe fatal caseexperienced of PML occurred in a 9 The patient had no TECFIDERA othercounts identified medical conditions lymphopenia (lymphocyte predominantly <0.5x10 /L forin3.5 patient who received for systemic 4 years while enrolled a resulting inDuring compromised system function andprolonged had not years) while taking TECFIDERA [see and Precautions (5.3)]. clinical trial. the clinicalimmune trial, theWarnings patient experienced previously been treated with counts natalizumab, which has <0.5x10 a known9association The patient had no other identified systemic medical conditions lymphopenia (lymphocyte predominantly /L for 3.5 with PML. The patient was also not taking any and immunosuppressive or resulting in compromised immune system function and had not years) while taking TECFIDERA [see Warnings Precautions (5.3)]. immunomodulatory medications concomitantly. previously been treated with natalizumab, which hasmedical a known association The patient had no other identified systemic conditions with The patient was also not taking any immunosuppressive or resulting compromised immune system function and had not PMLPML. has in also occurred in the postmarketing setting in the presence of immunomodulatory medications concomitantly.

9with natalizumab, previously been treated whichthan has a6 known association lymphopenia (<0.8x10 /L) persisting for more months.

While the with The occurred patientinwas also not taking anysetting immunosuppressive or role ofhas lymphopenia these cases is uncertain, theinmajority of cases PMLPML. also in the postmarketing the presence of immunomodulatory medications concomitantly.

9 lymphocyte occurred in patients with counts /L. lymphopenia (<0.8x10 /L) persisting for more<0.5x10 than 6 9months.

While the role of lymphopenia in in these cases is uncertain, theinmajority of cases PML has also occurred thesuggestive postmarketing setting the TECFIDERA presence of At the first sign or symptom of PML, withhold 9 9 occurred in patients with counts <0.5x10 /L. lymphopenia (<0.8x10 /L)lymphocyte persisting for more than 6 months.

While the and perform an appropriate diagnostic evaluation.

Typical symptoms role of lymphopenia in are these cases progress is uncertain, majority of cases associated with or PML diverse, overthe days toTECFIDERA weeks, and At the first sign symptom suggestive of PML, withhold 9 occurred in patients with lymphocyte counts <0.5x10 /L. include progressive weakness on one side of the body or clumsiness of and perform an appropriate diagnostic evaluation.

Typical symptoms limbs, disturbance of are vision, and changes in thinking, associated withorPML diverse, progress over days tomemory, weeks, and At the first sign symptom suggestive of PML, withhold TECFIDERA orientation leading toweakness confusion and personality include progressive on one side of thechanges. body or clumsiness of and perform an appropriate diagnostic evaluation.

Typical symptoms limbs, disturbance vision, and changes in thinking, and associated with PML are diverse, progress days tomemory, weeks,Cases and MRI findings may beofapparent before clinical over signs or symptoms. orientation leading to confusion and personality include weakness onefindings side of the body or clumsiness of of PML,progressive diagnosed based onon MRI andchanges. the detection of JCV limbs, disturbance ofapparent vision,fluid and in thinking, memory, and DNAfindings in the may cerebrospinal inchanges the absence ofsymptoms. clinical signs or MRI be before clinical signs or Cases orientation leading confusion and personality changes. symptoms specifictotobased PML, on have been reported inthe patients treated with of PML, diagnosed MRI findings and detection of JCV DNAfindings in the may cerebrospinal in clinical the absence clinical signs or MRI be apparentfluid before signs orofsymptoms.

Cases symptoms specific to PML,on have been reported patients treated with of PML, diagnosed based MRI findings and inthe 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

anddiverse, perform progress an appropriate diagnostic evaluation. sy ofTypical non-ent associated with PML are over days to weeks, and associated withside PML diverse, progress over to we to TECFID include progressive weakness on one of are the body or clumsiness of days progressive on one side ofand the body orDosin clum [see limbs, disturbance of include vision, and changesweakness in thinking, memory, limbs, disturbance of vision, and changes in thinking, mem orientation leading to confusion and personality changes.

6 ADVERS orientation leadingPML. to confusion and personality changes. otherfindings MS medications associated Many of these patients MRI may be apparent beforewith clinical signs or symptoms.

Cases The follow subsequently became symptomatic with monitoring MRI findings bePML. apparent clinical signs orinsymptom of PML, diagnosed based on MRI may findings and Therefore, the before detection of JCV labeling with MRI for signs thatofmay be consistent with PML befindings useful, PML, diagnosed based on MRI and detection other medications associated Many of these patients DNA inMSthe cerebrospinal fluid in with the PML. absence ofmay clinical signs or theleukoence any suspicious findings should lead to further investigation to allow for DNA in the cerebrospinal fluid in the absence of clinical(5 subsequently became symptomatic with PML. Therefore, monitoring symptoms specific to PML, have been reported in patients treated with Flushing an early of PML, ifbe present.

PML-related mortality andin patients trea symptoms specific to PML, have reported with MRI for signs that may consistent with PML may be useful, other MSdiagnosis medications associated withLower PML. Many of been these patients morbidity havebecame been reported discontinuation of another any suspicious findings shouldfollowing lead to further to allowMS for subsequently symptomatic with PML.investigation Therefore, monitoring medication with be in patients with PML who were initially an early of PML, ifPML present.

Lower PML-related and with MRI diagnosis for associated signs that may consistent with PML may bemortality useful, and asymptomatic to patients PML who hadofcharacteristic morbidity havecompared been reported following discontinuation another any suspicious findings should lead towith further investigation to allow MS for clinical and symptoms at diagnosis.

It is notPML known whether these medication associated withifPML in patients with who were initially an earlysigns diagnosis of PML, present.

Lower PML-related mortality and differences arecompared duereported to early detection and discontinuation of MS MS asymptomatic to patients with PML who hadofcharacteristic morbidity have been following discontinuation another treatment or due differences inindisease patients. clinical signs and to symptoms at diagnosis. isthese notPML known these medication associated with PML patientsItinwith whowhether were initially differences are due to to early detection and who discontinuation of MS asymptomatic compared patients with PML had characteristic 5.3 Lymphopenia treatment or and due symptoms to differences in diseaseItinisthese patients. clinical signs at diagnosis. not known whether these TECFIDERA may decrease lymphocyte counts. In the MS placebo differences are due early detection discontinuation of MS 5.3 Lymphopenia controlled trials, meantolymphocyte counts and decreased by approximately treatment or due to differences intreatment disease inwith these patients. and then 30% during the year oflymphocyte TECFIDERA TECFIDERA mayfirst decrease counts.

In the MS placebo remained stable.

Fourlymphocyte weeks after stopping TECFIDERA, mean 5.3 Lymphopenia controlled trials, mean counts decreased by approximately lymphocyte increased but did not return to baseline.

Six percent 30% duringcounts the first year oflymphocyte treatment with TECFIDERA and then TECFIDERA may decrease counts.

In the MS placebo (6%) of TECFIDERA patients and after <1% of placebo TECFIDERA, patients experienced remained stable.

Four weeks stopping mean controlled trials, mean lymphocyte counts decreased by approximately 9 9 lymphocyte counts <0.5x10 (lower limit of normal 0.91x10 /L).

The increased did not return to baseline.

Six percent 30% during counts the first year of/Lbut treatment with TECFIDERA and then incidence of infections (60% vsand 58%) and (2% vs 2%) (6%) of TECFIDERA patients <1% of serious placeboinfections patients experienced remained stable.

Four weeks after stopping TECFIDERA, mean 9 with TECFIDERA or placebo, respectively. was similar counts incounts patients treated lymphocyte <0.5x10 /L of normal 0.91x10 The lymphocyte increased but(lower did notlimit return to baseline.

Six9/L). percent Thereof was increased incidence observed in incidence of no infections (60% vs 58%) and seriousinfections infections (2% vs 2%) (6%) TECFIDERA patients and <1%of ofserious placebo patients experienced 9 9 9 with<0.8x10 9 patients within lymphocyte counts ≤0.5x10 /L in controlled was similar patients treated TECFIDERA or placebo, respectively. lymphocyte counts <0.5x10 /L (lower limit/Lofornormal 0.91x10 /L). The trials, patient invsan extension study infections developed(2% PML the There although was no one increased of serious observed in incidence of infections (60%incidence 58%) and serious infections vsin2%) 9 9 predominantly setting ofwith prolonged lymphopenia (lymphocyte counts patients lymphocyte counts <0.8x10 /L or or ≤0.5x10 /L respectively. in controlled was similar in patients treated with TECFIDERA placebo, 9 <0.5x10 /L no for increased 3.5 patient years)incidence [see Warnings and infections Precautions (5.2)].

In trials, although one in an extension study developedobserved PML in the There was of serious in 9 predominantly controlled and uncontrolled clinical trials,9/L2% of counts patients experienced setting of prolonged lymphopenia (lymphocyte patients with lymphocyte counts <0.8x10 or ≤0.5x10 /L in controlled 9 lymphocyte counts <0.5x10 /Lanforextension at least six months, and inPML this group <0.5x10 /L for 3.5 patient years) in9[see Warnings and Precautions (5.2)].

In trials, although one study developed in the 9 the majority of lymphocyte counts /L predominantly with continued controlled and uncontrolled clinicalremained trials, 2%<0.5x10 ofcounts patients experienced setting of prolonged lymphopenia (lymphocyte 9 9 TECFIDERA therapy. has not inmonths, patients withinpre-existing lymphocyte counts /L been forWarnings at studied least six and this group <0.5x10 /L for 3.5 <0.5x10 years) [see and Precautions (5.2)].

In 9 low counts. the lymphocyte majority of uncontrolled lymphocyte counts /L with continued controlled and clinical remained trials, 2%<0.5x10 of patients experienced 9 therapy. has not been studied inmonths, patients with Obtain a TECFIDERA CBC, including lymphocyte before initiating treatment with lymphocyte counts <0.5x10 /L for at count, least six and inpre-existing this group low lymphocyte counts.

TECFIDERA, months after starting treatment, and 9then every 6 to 12 the majority of 6lymphocyte counts remained <0.5x10 /L with continued monthsaTECFIDERA thereafter, and asnot clinically indicated.

Consider of therapy. has been studied in patients withinterruption pre-existing Obtain CBC, including lymphocyte count, before initiating treatment with 9 TECFIDERA patientsafter withstarting lymphocyte counts 0.5x10 /L low lymphocytein TECFIDERA, 6counts. months treatment, andless thenthan every 6 to 12 persisting for including moreand than months.

Given the potential for delayed months thereafter, assix clinically indicated.

Consider interruption of Obtain a CBC, lymphocyte count, before initiating treatment with 9 recovery of lymphocyte counts, continue to obtain lymphocyte counts TECFIDERA patients withstarting lymphocyte counts less 0.5x10 /L TECFIDERA, 6inmonths after treatment, and thenthan every 6 tountil 12 their recovery if TECFIDERA is discontinued orpotential interrupted due of to persisting for more than months.

Given the for delayed months thereafter, and as six clinically indicated.

Consider interruption 9 lymphopenia. withholding treatment from patients serious recovery of lymphocyte continue to obtain lymphocyte counts until TECFIDERA inConsider patientscounts, with lymphocyte counts less thanwith 0.5x10 /L infections untilmore about or not restart their recovery ifresolution.

TECFIDERA is discontinued interrupted due to persisting for than sixDecisions months.

Given whether the or potential for todelayed TECFIDERA should be individualized based on clinical circumstances. lymphopenia.

Considercounts, withholding treatment from patients with serious recovery of lymphocyte continue to obtain lymphocyte counts until infections until ifresolution.

Decisions about whether or not todue restart their recovery TECFIDERA is discontinued or interrupted to 5.4 Liver Injury TECFIDERA should be withholding individualized based on clinical circumstances. lymphopenia.

Consider treatment with serious Clinically significant cases of liver injury havefrom beenpatients reported in patients infections until resolution. in Decisions about whether or The not onset to restart 5.4 Liver Injury treated with TECFIDERA the postmarketing setting. has TECFIDERA should be individualized based on clinical circumstances. ranged from a few days to several months after initiation of Clinically significant cases of liver injury have been reported intreatment patients with TECFIDERA. Signs and of liver injury, including elevation 5.4 Liver Injury treated with TECFIDERA in symptoms the postmarketing setting.

The onset has of serum aminotransferases to greater thanafter 5-fold the upper limit of ranged from a few cases days toofseveral months initiation ofintreatment Clinically significant liver injury have been reported patients normal and TECFIDERA elevation of and total bilirubin to than 2-fold the upper with TECFIDERA. Signs symptoms of greater liver injury, including elevation treated with in the postmarketing setting.

The onset has limitserum of normal beentoobserved.

These abnormalities upon of aminotransferases to greater than 5-fold the resolved upper limit of ranged from a have few days several months after initiation of treatment treatment Some casesto hospitalization.

None normal anddiscontinuation. elevation total bilirubin greater than 2-fold the upper with TECFIDERA. Signsofand symptoms ofrequired liver injury, including elevation of serum the cases resulted liver failure, liver transplant, orlimit death. limit ofreported normal have been observed.

These abnormalities resolved upon of aminotransferases toingreater than 5-fold the upper of However, combination of bilirubin newcases serum aminotransferase elevations treatment discontinuation.

Some hospitalization.

None normal andthe elevation of total to required greater than 2-fold the upper with increased levels of bilirubin caused by drug-induced hepatocellular of the reportedhave cases resulted in liver failure, liver transplant, or death. limit of normal been observed.

These abnormalities resolved upon injury is an important predictor ofcases serious liver injury that may lead to However, the combination of new serum aminotransferase elevations treatment discontinuation.

Some required hospitalization.

None acute liver failure, liverof transplant, or death sometransplant, patients. with levels bilirubin by in drug-induced hepatocellular of theincreased reported cases resulted incaused liver failure, liver or death. injury is an important of serum serious livernoinjury thatthan may to However, theof combination of new aminotransferase elevations Elevations hepatic predictor transaminases (most greater 3lead times acute liver failure, orobserved death in some patients. with levels of transplant, bilirubin caused by drug-induced hepatocellular the increased upper limit ofliver normal) were during controlled trials injury is an important liverno injury that than may 3 lead to [see Adverse (6.1)].of serious Elevations of Reactions hepaticpredictor transaminases (most greater times acute liver failure, liver transplant, or observed death in some patients. the upper limit of normal) were during controlled trials Obtain serum aminotransferase, alkaline phosphatase (ALP), and total [see Adverse Reactions (6.1)]. with TECFIDERA Elevations of hepatic transaminases (most no greater thantreatment, 3 times bilirubin levels prior to treatment and during the upper limit of normal) werealkaline observed during controlled as clinically indicated.

Discontinue TECFIDERA if clinically Obtain serum aminotransferase, phosphatase (ALP),significant andtrials total [see Adverse Reactions (6.1)]. withisTECFIDERA liver injury induced TECFIDERA suspected. and during treatment, bilirubin levels prior by to treatment as Discontinue TECFIDERA if clinically Obtain serumindicated. aminotransferase, alkaline phosphatase (ALP),significant and total 5.5 clinically Flushing liver injury induced bytreatment TECFIDERA is suspected. and during treatment, bilirubin levels priorcause to with TECFIDERA TECFIDERA may flushing (e.g., warmth, redness, itching, and/or as clinically indicated.

Discontinue TECFIDERA if clinically significant 5.5 Flushing burning sensation).

In clinical trials, 40% of TECFIDERA treated patients liver injury induced

by TECFIDERA is suspected. experienced flushing.

Flushing symptoms generally began soonand/or after TECFIDERA may cause flushing (e.g., warmth, redness, itching, initiating TECFIDERA and usually or resolved over time.

In the 5.5 Flushing burning sensation).

In clinical trials,improved 40% of TECFIDERA treated patients majority of patients whoFlushing experienced it redness, was mild or moderate in experienced flushing. generally began soon after TECFIDERA may cause flushingsymptoms (e.g.,flushing, warmth, itching, and/or severity.sensation).

Three percent (3%) of patients for initiating TECFIDERA and usually improved or resolved TECFIDERA over time.

In the burning In clinical trials, 40% ofdiscontinued TECFIDERA treated patients flushing of and <1% had serious symptoms flushing symptoms that were notafter lifemajority patients who experienced flushing, it was mild or moderate in experienced flushing.

Flushing generally began soon threatening but led to hospitalization.

Administration of TECFIDERA severity.

Three percent of patients discontinued TECFIDERA for initiating TECFIDERA and(3%) usually improved or resolved over time. In with the food may reduce incidence flushing.

Alternatively, flushing <1%the had serious of flushing symptoms thatoradministration were not lifemajority ofand patients who experienced flushing, it was mild moderate in of non-enteric aspirin (uppatients to aAdministration dose of 325 mg) 30 minutes prior threatening butcoated led to hospitalization. of TECFIDERA with severity.

Three percent (3%) of discontinued TECFIDERA for to TECFIDERA dosing may reduce the incidence or severity of flushing food may reduce of flushing.

Alternatively, administration flushing and <1% the hadincidence serious flushing symptoms that were not life[see Dosingbut and Administration and Clinical (12.3)]. of non-enteric coated aspirin (up(2.1) to aAdministration dose of 325Pharmacology mg) 30 minutes prior threatening led to hospitalization. of TECFIDERA with to TECFIDERA dosing may reduce the incidence or severity of flushing food may reduce the incidence of flushing.

Alternatively, administration 6 ADVERSE REACTIONS [see Dosing and Administration Pharmacology (12.3)]. of non-enteric aspirin (up(2.1) to reactions a and doseClinical of 325 30 minutes prior The followingcoated important adverse are mg) described elsewhere to TECFIDERA dosing may the incidence or severity ofmultifocal flushing 6 ADVERSE REACTIONS in labeling: Anaphylaxis andreduce Angioedema (5.1), Progressive [see Dosing and AdministrationLymphopenia (2.1) and Clinical Pharmacology (12.3)]. leukoencephalopathy (5.3), Liver Injury (5.4), The following important(5.2), adverse reactions are described elsewhere Flushing (5.5) [see Warnings and Precautions].

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

food may theofincidence administration ymptoms teric coated aspirin (up reduce to a dose 325 mg) of 30flushing. minutes Alternatively, prior non-enteric coated aspirin to a dose of 325 mg) 30 minutes prior eeks, and DERA dosing of may reduce the incidence or (up severity of flushing to TECFIDERA dosing may reduce the incidence msiness of ng and Administration (2.1) and Clinical Pharmacology (12.3)]. or severity of flushing [see Dosing and Administration (2.1) and Clinical Pharmacology (12.3)]. mory, and SE REACTIONS 6 ADVERSE REACTIONS wing important adverse reactions are described elsewhere ms.

Cases The important reactions are described elsewhere g: Anaphylaxis andfollowing Angioedema (5.1), adverse Progressive multifocal n of JCV labeling: Anaphylaxis(5.3), and Angioedema ephalopathy in(5.2), Lymphopenia Liver Injury (5.1), (5.4), Progressive multifocal signs or leukoencephalopathy 5.5) [see Warnings and Precautions].(5.2), Lymphopenia (5.3), Liver Injury (5.4), ated with Flushing (5.5) [see Warnings and Precautions].

6.1 Clinical Trials Experience 6.1 Clinical Trialstrials Experience Because clinical are conducted under widely varying conditions, adverse ratesare observed in clinical a drug conditions, cannot be Because reaction clinical trials conducted under trials widelyofvarying directly to rates in the clinical trialstrials of another drugcannot and may adversecompared reaction rates observed in clinical of a drug be not reflect the ratestoobserved in clinical directly compared rates in the clinicalpractice. trials of another drug and may not reflect the rates adverse observedreactions in clinical(incidence practice. ≥10% and ≥2% more The most common than placebo) for TECFIDERA were flushing, abdominal pain,≥2% diarrhea, The most common adverse reactions (incidence ≥10% and more and thannausea. placebo) for TECFIDERA were flushing, abdominal pain, diarrhea, and nausea.

Adverse Reactions in Placebo-Controlled Trials Adverse Reactions in Placebo-Controlled Trials In the two well-controlled studies demonstrating effectiveness, 1529 patients TECFIDERA an overall effectiveness, exposure of 1529 2244 In the tworeceived well-controlled studieswith demonstrating person-years [see Clinical Studies (14)]. 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 769 patients treated 240 mg twice The adversefrom reactions presented in thewith tableTECFIDERA below are based on safety a day and 771 placebo-treated patients.with TECFIDERA 240 mg twice information from 769 patients treated a day and 771 placebo-treated Table 1: Adverse Reactions inpatients.

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

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

TECFIDERA N=769 TECFIDERA % N=769 % 40 40 18 18 14 14 12 12 9 9 8 8 8 6 6 5 5 5 4 4 2 2

Placebo N=771 Placebo % N=771 % 6 6 10 10 11 11 9 9 5 5 4 4 3 3 4 4 1 1 3 3 2 2 <1 <1

Gastrointestinal Gastrointestinal TECFIDERA caused GI events (e.g., nausea, vomiting, diarrhea, abdominal pain, and dyspepsia). incidence of GIvomiting, events was higher TECFIDERA caused GI eventsThe (e.g., nausea, diarrhea, early in thepain, course of treatmentThe (primarily in ofmonth 1) and abdominal and dyspepsia). incidence GI events wasusually higher decreased timeofin treatment patients treated withinTECFIDERA compared early in theover course (primarily month 1) and usually with placebo.

Four percent (4%) of patients with TECFIDERA decreased over time in patients treated withtreated TECFIDERA compared and than 1% of placebo due with to gastrointestinal with less placebo.

Four percent patients (4%) of discontinued patients treated TECFIDERA events. of serious GI discontinued events was 1% treated and lessThe thanincidence 1% of placebo patients dueintopatients gastrointestinal with TECFIDERA. events.

The incidence of serious GI events was 1% in patients treated with TECFIDERA. Hepatic Transaminases Hepatic Transaminases An increased incidence of elevations of hepatic transaminases in patients treated with TECFIDERA wasof seen primarily during the An increased incidence of elevations hepatic transaminases in first six months treatment, and most with elevations patients treated ofwith TECFIDERA waspatients seen primarily during had the levels times the limit of normal during first six<3months of upper treatment, and most (ULN) patients withcontrolled elevationstrials. had Elevations of alanine aminotransferase and aspartate levels <3 times the upper limit of normal (ULN) duringaminotransferase controlled trials. to ≥3 timesofthe ULNaminotransferase occurred in a small number ofaminotransferase patients treated Elevations alanine and aspartate with and placebo andnumber were balanced to ≥3both timesTECFIDERA the ULN occurred in a small of patientsbetween treated groups.

There were no elevations in transaminases ≥3 times between the ULN with both TECFIDERA and placebo and were balanced with concomitant in total bilirubin >2 ≥3 times groups.

There wereelevations no elevations in transaminases timesthe theULN. ULN Discontinuations to elevated transaminases werethe <1%ULN. and with concomitantdue elevations inhepatic total bilirubin >2 times were similar in patients treated with TECFIDERA or placebo.

Discontinuations due to elevated hepatic transaminases were <1% and were similar in patients treated with TECFIDERA or placebo.

Eosinophilia Eosinophilia A transient increase in mean eosinophil counts was seen during the first 2 therapy.in mean eosinophil counts was seen during the first A months transientofincrease 2 monthsReactions of therapy.in Placebo-Controlled and Uncontrolled Studies Adverse Adverse Reactions in Placebo-Controlled and Uncontrolled Studies In placebo-controlled and uncontrolled clinical studies, a total of 2513 patients have receivedand TECFIDERA andclinical been followed up to In placebo-controlled uncontrolled studies,for a periods total of 2513 4 years with overallTECFIDERA exposure of and 4603been person-years. patients havean received followed forApproximately periods up to 1162 patients received more thanperson-years.

2 years of treatment with 4 years with anhave overall exposure of 4603 Approximately TECFIDERA. profile of TECFIDERA the 1162 patients The haveadverse receivedreaction more than 2 years of treatmentin with uncontrolled studies was consistent experience inin the TECFIDERA.clinical The adverse reaction profilewith of the TECFIDERA placebo-controlled trials. uncontrolled clinicalclinical studies was consistent with the experience in the placebo-controlled trials.

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

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

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

There is ainpregnancy exposuretoregistry that monitors pregnancy Encourage enroll bytocalling 1-866-810-1462 or visiting outcomes inpatients womentoexposed TECFIDERA during pregnancy. www.tecfiderapregnancyregistry.com.

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

Risk Summary Risk Summary There are no adequate data on the developmental risk associated with the useare of TECFIDERA pregnant In animals, adverse effects There no adequate in data on the women. developmental risk associated with on survival, growth, sexual maturation, and neurobehavioral the offspring use of TECFIDERA in pregnant women.

In animals, adverse effects function were observed fumarate (DMF) was on offspring survival, growth,when sexualdimethyl maturation, and neurobehavioral administered during pregnancy and lactation function were observed when dimethylat clinically fumaraterelevant (DMF)doses. was [see data]. during pregnancy and lactation at clinically relevant doses. administered [see In thedata].

U.S. general population, the estimated background risk of major birth and miscarriage recognized pregnancies is In thedefects U.S. general population, in theclinically estimated background risk of major 2-4% and 15-20%, respectively. background risk pregnancies of major birth birth defects and miscarriage in The clinically recognized is defects and15-20%, miscarriage for the indicated population risk is unknown.

2-4% and respectively.

The background of major birth defects and miscarriage for the indicated population is unknown.

Data Data Data Animal In rats administered DMF orally (25, 100, 250 mg/kg/day) throughout Animal Data organogenesis, embryofetal toxicity fetal body weight and In rats administered DMF orally (25, (reduced 100, 250 mg/kg/day) throughout delayed ossification) were observed at the highest organogenesis, embryofetal toxicity (reduced fetal dose body tested. weight This and dose also produced were evidence of maternal toxicitydose (reduced delayed ossification) observed at the highest tested. body This weight).

Plasma exposure (AUC) of for maternal monomethyl fumarate (MMF), the dose also produced evidence toxicity (reduced body major circulating metabolite, at the no-effect dose is approximately weight).

Plasma exposure (AUC) for monomethyl fumarate (MMF), the three that inmetabolite, humans at at thethe recommended human dose (RHD) major times circulating no-effect dose is approximately of 480times mg/day.

DMF orally (25, 75, and 150 three that In in rabbits humansadministered at the recommended human dose (RHD) mg/kg/day) organogenesis, embryolethality of 480 mg/day.throughout In rabbits administered DMF orally (25, 75, and and 150 decreased body weight were observed at the highest dose mg/kg/day)maternal throughout organogenesis, embryolethality and tested.

The plasmabody AUC for were MMFobserved at the at no-effect dose is decreased maternal weight the highest dose approximately 5 times that RHD.no-effect dose is tested. The plasma AUCin humans for MMFat the at the approximately 5 times in (25, humans the 250 RHD.mg/kg/day) to rats Oral administration of that DMF 100,atand throughout organogenesis lactation resulted in increased Oral administration of DMF and (25, 100, and 250 mg/kg/day) to rats lethality, reductions body weight, sexual throughoutpersistent organogenesis and inlactation resulteddelayed in increased maturation (male andreductions female pups), at lethality, persistent in and bodyreduced weight,testicular delayedweight sexual the highest (male dose tested.

Neurobehavioral impairment was observed maturation and female pups), and reduced testicular weight at at doses.

A no-effect dose for developmental toxicity was not theall highest dose tested. Neurobehavioral impairment was observed identified.

TheAlowest dosedose tested associated with plasma at all doses. no-effect forwas developmental toxicity wasAUC not for MMF lower than that in humans at the RHD. identified.

The lowest dose tested was associated with plasma AUC for MMF lower than that in humans at the RHD. 8.2 Lactation

8.2 Lactation Risk Summary Risk Summary There are no data on the presence of DMF or MMF in human milk.

The theonbreastfed infant milk production are Thereeffects are noon data the presence of and DMFon or MMF in human milk. unknown.

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

The developmental and health benefits of breastfeeding should be considered along with thehealth mother’s clinical for TECFIDERA The developmental and benefits ofneed breastfeeding shouldand be any potential adverse on theclinical breastfed infant from the drug or considered along with effects the mother’s need for TECFIDERA and from the underlying maternal condition. any potential adverse effects on the breastfed infant from the drug or fromPediatric the underlying 8.4 Use maternal condition.

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

Safety and effectiveness in pediatric patients have not been established.

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

10 OVERDOSE 10 OVERDOSE Cases of overdose with TECFIDERA have been reported. The symptoms these cases werehave consistent the known Cases of described overdose in with TECFIDERA been with reported.

The adverse event profile in of these TECFIDERA. symptoms described cases were consistent with the known adverse profiletherapeutic of TECFIDERA. There areevent no known interventions to enhance elimination of TECFIDERA northerapeutic is there ainterventions known antidote.

In theelimination event of There are no known to enhance overdose, initiatenor symptomatic treatment as event clinically of TECFIDERA is there a supportive known antidote.

In the of indicated. overdose, initiate symptomatic supportive treatment as clinically indicated.

17 PATIENT COUNSELING INFORMATION 17 PATIENT COUNSELING Advise the patient to read theINFORMATION FDA-approved patient labeling (Patient Information) Advise the patient to read the FDA-approved patient labeling (Patient Information) Dosage Dosagepatients that they will be provided two strengths of TECFIDERA Inform when 120 capsules the 7 day starter dose Informstarting patientstreatment: that they will bemg provided twofor strengths of TECFIDERA and mg capsules for120 themg maintenance to be taken when240 starting treatment: capsules fordose, the 7both day starter dose twice daily. patients to swallow TECFIDERA capsules and 240 mgInform capsules for the maintenance dose, both to be whole taken and not crush, chew, or sprinkle twiceintact. daily. Inform patients to swallow TECFIDERA capsulescapsule whole contents on Inform food. Inform patients TECFIDERA be taken with and intact. patients to notthat crush, chew, or can sprinkle capsule or withouton food [see Dosage and Administration (2.1)]. contents food.

Inform patients that TECFIDERA can be taken with or without food [see Dosage and Administration (2.1)].

Inform pat when star and 240 m twice daily and intac contents o or without

eliably drug

times have keting

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)].

10 41347-09

Manufactured by: Biogen Cambridge, MA 02142 TECFIDERA is a trademark of Biogen.

9 Biogen Š 2013-2017 7/19 2/18

Books for Navigating Life with Brain Disease Available from all major booksellers or order online at

BrainLifeMag.org/Books

Conferences & Community

Diversity Leadership Applications Due October 11 The American Academy of Neurology knows “This program gave me the tools to enhance my ability to create that diversity and inclusion are essential to the future success of both the field of positive change in every aspect of my career.” neurology and our own organization. To this —Roy H. Hamilton, MD, MS, FAAN, 2017 Diversity Leadership Program Participant end, we are committed to building leadership reflective of our diverse member and patient demographics and currently are accepting An AAN Board-assigned group project and presentation applications through October 11 for the next class to the AAN Board of Directors of the Diversity Leadership Program.

If you—or someone you know—are looking to make a big This powerful program is designed specifically to help a difference in life by helping to ensure a brighter, more select group of individuals from qualifying diverse and inclusive future, then consider applying or nominating for the underrepresented ethnic backgrounds hone essential skills 2020 class. Qualifications and applications can be found at needed to influence positive change in every aspect of their AAN.com/view/20DLP.  lives, and to help build a powerful legacy of diversity and inclusion in the neurology community.

Previous participants have praised this life-enriching program, citing its positive impact on self-confidence, relationship building and camaraderie, burnout reduction, presentation and management skills, AAN engagement, and more through: Personalized coaching and leadership development training by an executive consultant Individual mentoring by a neurology leader, including a visit to the mentor’s institution/practice Personal and professional development

Could Your Organization Benefit from the 2020 Exhibit Hall?

The 2020 Annual Meeting Exhibit Hall will provide a not-to-be-missed, four-day opportunity from April 26 through 29 for your organization—or one you might work with—to showcase products, information, and services of particular interest to the neurology community.

Please help us spread the word to your or other organizations that may be less familiar with the AAN Annual Meeting to let them know how the Exhibit Hall provides a unique home for attendees to come together with hospital networks, industry partners, tech start-ups,

non-profits, and more to share information and ideas, as well as a platform for both new and established businesses to enhance brand awareness and increase lead generation.

Visit AAN.com/view/AM20 to learn more and be sure to apply for exhibit space when applications open in November. 

AANnews • October 2019 21

Conferences & Community

Congratulations New Fellows of the American Academy of Neurology!

The AAN congratulates the following members who were named prestigious Fellows of the American Academy of Neurology (FAAN) between May and August, 2019.

Malaz Almsaddi, MD, FAAN Arayamparambil Anilkumar, MD, FAAN Steven Arbogast, DO, FAAN Brandon Barton, MD, FAAN Evanthia Bernitsas, MD, FAAN Andrew S. Blum, MD, PhD, FAAN Bradley F. Boeve, MD, FAAN Marcelo Calderaro, MD, FAAN I-Hweii Amy Chen, MD, PhD, FAAN Nisha Chhabria, MD, FAAN Claudia A. Chiriboga, MD, FAAN Joseph Y. Chu, MD, FRCPC, FACP, FAAN Daniel O. Claassen, MD, FAAN Lisa D. Cohen, MD, FAAN Francis X. Conidi, DO, MS, FAAN Jody Corey-Bloom, MD, PhD, FAAN Shawna M. Cutting, MD, FAAN Nabila Dahodwala, MD, FAAN Charungthai Dejthevaporn, MD, FAAN Amanda L. Deligtisch, MD, FAAN Bart M. Demaerschalk, MD, MSc, FRCPC, FAAN Al-Noor Dhanani, MD, FAAN Asif Doja, MD, FAAN Bakri Elsheikh, MD, FAAN Glen R. Finney, MD, FAAN Paul G. Fisher, MD, FAAN Mehari Gebreyohanns, MD, FAAN Ajmal M. Gilani, MD, FAAN Robert L. Glanzman, MD, FAAN Riadh Gouider, MD, FAAN Richard M. Green, MD, FAAN Raji Paul Grewal, MD, FAAN Wolfgang Grisold, MD, FAAM Jayanti K. Gurumukhani, MD, DM, FAAN Chad Hales, MD, PhD, FAAN Rashmi B. Halker, MD, FAAN Neal S. Hermanowicz, MD, FAAN James F. Hora, MD, PhD, FAAN Koto Ishida, MD, FAAN Paul H. Janda, DO, JD, FAAN Laura Jawidzik, MD, FAAN Aki Kawasaki, MD, PhD, FAAN

22

AANnews • October 2019

Interested in Elevating Your Membership Status to FAAN? Visit AAN.com/view/FAANReq to see if you’re eligible for the FAAN designation—or encourage a qualifying colleague to apply.

Applying for FAAN status is free; acknowledges exemplary work and achievements in the neurosciences, the clinical practice of neurology, or academic/administrative neurology; helps set you apart both within the Academy and throughout your professional career; and offers eligibility to serve on the AAN Board of Directors.

Yasushi Kisanuki, MD, FAAN Lily Wong-Kisiel, MD, FAAN Prakash Kotagal, MD, MBBS , FAAN Jessica B. Kraker, MD, FAAN Nagesh Krish, MD, FAAN Lisa M. Leschek-Gelman, MD, FAAN Tobias Loddenkemper, MD, FAAN Soe Soe Mar, MD, FAAN Warren P. Mason, MD , FAAN Maryann Mays, MD, FAAN Til Menge, MD, FAAN Teshamae Monteith, MD, FAAN Sarah Anne Morrow, MD, MSC, FRCPC, FAAN Tarun Nagpal, MD, FAAN Seema Nagpal, MD, FAAN Yazmin Odia, MD, FAAN Olukayode Onasanya, MD, FAAN Richard W. Orrell, MD, FAAN Benjamin Joseph Osborne, MD, FAAN Denis A. Ostrovskiy, MD, FAAN Carlos Otero, MD, FAAN Dipak Pandya, MD, FAAN Prasad N. Policherla, MD, FAAN James J. Reese, Jr., MD, MPH, FAAN Gregory Sahagian, MD, FAAN Johnny Salameh, MD, FAAN Richard Salazar, MD, FAAN

Jack D. Schim, MD, FAAN Jonathan K. Smith, MD, FAAN B. Joy Snider, MD, PhD, FAAN Ariane Soldatos, MD, FAAN Andrew Solomon, MD, FAAN Douglas S. Stuart, MD, FAAN Paul A. Sykes, MD, PhD, FAAN Edwin Tasch, MD, FAAN Sanjeev V. Thomas, MD, FAAN Meenakshsundaram Umaiorubahan, MD, FAAN Barry K. Vaught, MD, FAAN Lidia Maria Veras Rocha Moura, MD, FAAN Michael Vertino, MD, FAAN H. Christian Von Budingen, MD, FAAN Felipe Von Glehn Silva, MD, MSc, FAAN Jayne H. Ward, DO, FAAN William D. Watson, MD, FAAN Ray L. Watts, MD, FAAN David Weidman, MD, FAAN Korwyn Williams, MD, PhD, FAAN Vernon B. Williams, MD, FAAN Eric Tai-Lee Wong, MD, FAAN Nassim Zecavati, MD, FAAN Jay-Jiguang Zhu, MD, PhD, FAAN 

Education & Research

October Continuum Eyes Neuro-ophthalmology 19 Continuum Full Page Ad—Full Page> Placed in AANne AANnews, NJ, ws, 8.25 x 10.875 +0.125 Neurology Journal, or Neurology NCP Clinical Practice bleed, 4C

The new Continuum: Lifelong Learning in Neurology looks at neuroophthalmology, and Guest Editor Marc Dinkin, MD, points to a wealth of insights that will help in the diagnosis and treatment of associated disorders. ®

“After reading this issue, neurologists’ differential for optic nerve disease will expand far beyond optic neuritis, optic nerve compression, and ischemic optic neuropathy, and they will have a better sense of how to distinguish one type of neuropathy from another so that patients can be managed properly and promptly.”

Experience wha t you’ve been m issing!

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Topics in this issue include the pupil, toxic-metabolic and hereditary optic neuropathies, idiopathic intracranial hypertension, chiasmal and postchiasmal disease, higher cortical visual disorders, approach to diplopia, nystagmus and saccadic intrusions, paraneoplastic syndromes in neuro-ophthalmology, infectious optic neuropathies, and imaging in neuro-ophthalmology.

ContinPub.co

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The issue also includes a postreading self-assessment and test with the opportunity to earn up to 20 AMA PRA Category 1™ toward SA-CME. AAN members pay only $349 per year for a subscription to Continuum® and Continuum® Audio. Subscribe now by contacting Wolters Kluwer at (800) 361-0633 or (301) 223-2300 (international) or visit Shop.LWW.com/ continuum. AAN Junior members who are transitioning to neurologist memberships can receive a 50-percent discount on the already low member rate for the Continuum and Continuum Audio subscription. 

Subscription now Continuum® Aud includes io—AAN memb ers get both produc ts for only $34 9!

Neuro-ophthalmo logy October 2019, VOL . 25, NO.5

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3/18/19 7:53 AM

Shine a light on your achievements Apply for a prestigious Fellow of the American Academy of Neurology (FAAN) designation.

AAN.com/view/FAAN

Education & Research

UCNS Accreditation Application Deadline Is December 1 Applications are now being accepted until December 1, 2019, from fellowship programs seeking accreditation in UCNS-recognized neurologic subspecialty areas including Headache Medicine, Clinical Neuromuscular Pathology, Neuro-oncology, Behavioral Neurology & Neuropsychiatry, Neurocritical Care, Neuroimaging, Autonomic Disorders, and Geriatric Neurology. New applications received by the December 1 deadline will be reviewed for approval in the spring of 2020. The UCNS is the certifying and accrediting body for emerging neurologic subspecialties in the United States and Canada. Programs achieving UCNS accreditation have proven they meet the educational standards set by the respective subspecialties and the UCNS. Learn more at UCNS.org. 

DECEMBER

1

UCNS Revises Common Program Requirements for Subspecialty Fellowships The United Council for Neurologic Subspecialties (UCNS) has completed a review and revision of the common program requirements, which are the core standards required in all UCNS-accredited training programs. The review and revisions were done by the UCNS Accreditation Council, comprised of representatives of the American Academy of Neurology,

American Neurological Association, Association of University Professors in Neurology, Child Neurology Society, and Professors of Child Neurology.

The common program requirements are reviewed every five years to assure they represent the most recent standards in neurologic subspecialty fellowship training. Revised requirements will be effective June 1, 2020. UCNS will work with each UCNS-recognized subspecialty to integrate the revised requirements into its subspecialty-specific requirements followed by a comment period by each respective subspecialty before revisions are recommended for approval by the UCNS Board of Directors. There are currently 201 UCNSaccredited fellowship training programs. Learn more at UCNS.org. 

Education & Research

Research Opportunities Open for Underrepresented Minority or Disabled Physician-scientists There is a serious and significant underrepresentation of certain populations in the biomedical, clinical, behavioral, and social sciences in the United States. Are you—or do you know someone who is—an underrepresented minority or person with a disability in a post-residency fellowship or junior faculty position looking for research and education opportunities?

The AAN and the Medical University of South Carolina are offering TRANSCENDS (Training in Research for Academic Neurologists to Sustain Careers and Enhance the Numbers of Diverse Scholars), a special program funded by a grant from the National Institutes of Health designed to increase opportunities to conduct high-quality neurologic research and develop a successful academic career.

Up to six people will be selected to participate in 2020 to receive: A Master of Science degree in clinical research through the Medical University of South Carolina by completing a primarily online two-year course curriculum (38 credit hours) Mentoring and support in the development of your current research portfolio Support in the creation of a real or mock K application AAN member benefits Opportunities at the AAN Annual Meeting to present research and network with leadership Eligibility is limited to US citizens/permanent US residents who are disabled and/or belong to an underrepresented minority in neurology including Black/African American, Hispanic, Latino, Native American, Pacific Islander, Native Alaskan, or Hawaiian, and are in any of the following career stages: fellows in a formal neurology subspecialty training program, neurology faculty three years or less from first academic appointment (academic appointment must be in the US), or neurologist five years or less from completion of residency (residency training must have been completed in the US)

NEUROLOGY’S MOST PRESTIGIOUS AWARDS AAN Awards recognize the very best, from scientific research to advocacy.

Apply or nominate by October 23, 2019

AAN.com/view/20Awards

The application deadline is 11:59 p.m. ET, October 15, 2019, and applications are available at AAN.com/research-andawards/transcends-scholar-program-application. If you have questions, please contact transcends.aan@gmail.com. 

April 25 – May 1 • Toronto, Canada

Education & Research

Second Edition NeuroLearn Patient Safety Course Now Available A second edition of the popular NeuroLearn course in Patient Safety is now available at AAN.com/view/PatientSafetyNL. The convenient online course is designed to help you meet the ABPN’s Patient Safety component requirement of Continuing Certification (CC), offers up to 4.0 Self-assessment CME credits, and can help you identify potential patient safety risks and apply strategies to mitigate risk and improve patient safety. Topics include: Increasing Patient Safety Awareness and Practice Among Clinicians and Staff Methods for Measuring Performance and Clinical Outcomes The Role of Health Information Technology in Patient Safety Reducing Medication Errors Advancing Patient Safety Through Systems Thinking and Design Establishing a Patient Safety Culture Safety Enhancing Technology Quality Improvement Communication Patient Education and Engagement Access is free to AAN members, but limited to one course at a time. Medical students, business administrators, and advanced practice providers at the lower dues rate are not eligible for free access.

To learn more about the ABPN’s Patient Safety component requirement, visit ABPN.com/maintain-certification/moc-activityrequirements/patient-safety-activity. 

26

AANnews • October 2019

New 12th Edition of NeuroSAE Also Available Discover your strengths and weaknesses in clinical neurology, compare your performance to other neurologists, and learn about resources for improvement so you can provide optimal patient care with the latest edition of the AAN’s convenient online self-assessment program. NeuroSAE® 12th Edition is now available and is a $149 value that’s free with your AAN membership! Free access is limited to one exam at a time, with the exception of NeuroSAE Medical Student and Annual Meeting editions. Visit AAN.com/view/SAE12 to access today. 

WHO IS YOUR HERO IN THE FIGHT AGAINST BRAIN DISEASE?

Honor your heroes with a tribute gift to the American Brain Foundation and make a difference in the search for a cure.

AmericanBrainFoundation.org/MyHero

IN PATIENTS WITH RELAPSING FORMS OF MULTIPLE SCLEROSIS (RMS)

START WITH THE POWER AND EXPERIENCE OF TYSABRI

IN THE FIGHT AGAINST RMS In the 2-year AFFIRM pivotal trial:

83% placebo (primary endpoint: percentage with sustained increase in disability was 17% vs 29%; p<0.001) of patients taking TYSABRI had no sustained physical disability progression for 12 weeks vs 71% with

1,2

INDICATION TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. See Important Safety Information regarding the risk of PML with TYSABRI. IMPORTANT SAFETY INFORMATION WARNING: Progressive Multifocal Leukoencephalopathy (PML) TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI. Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation including a gadoliniumenhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.

Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH Prescribing Program.  Infection by the JC Virus (JCV) is required for the development of PML.  There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs.  Postmarketing data suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value).  MRI findings may be apparent before clinical signs or symptoms suggestive of PML. 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.

Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis.

Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

T R U S T I N T H E E X P E R I E N C E O F T Y S A B R I ® (n at a l iz u m a b) Choose the power of an established therapy

NEARLY

ALWAYS

APPROXIMATELY

200,000

COMMITTED TO SAFETY

NEW PATIENTS

for relapsing MS with the established therapy of TYSABRI, and counting3,a

The TOUCH® Prescribing Program helps you support patients throughout their treatment on TYSABRI

in the US who start TYSABRI have received no previous DMT4,b

PATIENTS TREATED

1 IN 5

OVER A DECADE OF REAL-WORLD EXPERIENCE VISIT TimeForTYSABRI.com OR TALK TO YOUR BIOGEN REPRESENTATIVE TO LEARN MORE DMT=disease-modifying therapy; a190,800 patients as of August 20183; bAs of July 2017. 4

IMPORTANT SAFETY INFORMATION WARNING: Progressive Multifocal Leukoencephalopathy (PML) (cont’d)  PML has been reported after discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for approximately 6 months after discontinuation of TYSABRI.  Adverse events that may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in TYSABRI-treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation.  JCV infection of granule cell neurons in the cerebellum, i.e., JCV granule cell neuronopathy (GCN), with symptoms similar to PML, has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML and can cause cerebellar dysfunction. Diagnosis and management of JCV GCN should follow guidance provided for PML.  Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI-treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient’s condition after TYSABRI removal (and, in some cases, after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI-treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange.

Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

Contraindications  TYSABRI is contraindicated in patients who have or have had PML.  TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI. TYSABRI TOUCH Prescribing Program  Because of the risk of PML, TYSABRI is available only through a restricted distribution program under a REMS called the TOUCH® Prescribing Program.  Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber Enrollment Form.

Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis  TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses.  Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI.  The duration of treatment with TYSABRI prior to onset ranged from a few months to several years.  Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Important Safety Information continues on the following pages. Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

IMPORTANT SAFETY INFORMATION (cont’d) Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis (cont’d)  Patients being administered TYSABRI are at a higher risk of acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of one or both eyes.  Following clinical diagnosis of ARN, consider discontinuation of TYSABRI. Hepatotoxicity  Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with TYSABRI in the postmarketing setting.  Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses.  TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

Hypersensitivity/Antibody Formation  Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%.  Reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain.  If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI.  Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared with patients who did not develop antibodies to TYSABRI in both MS and CD studies.  Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment.

Immunosuppression/Infections  The immune system effects of TYSABRI may increase the risk for infections.  In Study MS1, certain types of infections—including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections—occurred more often in TYSABRI-treated patients than in placebotreated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1.  In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids.  In a long-term safety study of patients, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients.  Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of TYSABRI alone.  In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients.  In Study MS1, the incidence of serious infections was approximately 3% in TYSABRI-treated patients and in placebo-treated patients.

Most patients did not interrupt treatment with TYSABRI during infections.

Laboratory Test Abnormalities  In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient.

Adverse Reactions  The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%).  The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%).  Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please see accompanying brief summary of full Prescribing Information, including Boxed Warning.

STUDY DESCRIPTION: The AFFIRM (NAtalizumab Safety and EFFIcacy in Relapsing-Remitting MS) study was a pivotal 2-year, double-blind, randomized, controlled trial with 942 relapsing MS patients who received either TYSABRI therapy (300 mg by intravenous infusion [n=627]) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions).1,2 References: 1. TYSABRI Prescribing Information, Cambridge, MA: Biogen Inc. 2. Polman CH, O’Connor PW, Havrdova E, et al; for the AFFIRM investigators. A randomized, placebocontrolled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 3. Data on file as of August 2018, Biogen Inc. 4. Data on file as of July 2017, Biogen Inc.

© 2019 Biogen. All rights reserved. 02/19 TYS-US-2311

TYSABRI (natalizumab) injection, for intravenous use

Table 1:

Estimated United States Incidence of PML Stratified by Risk Factor

Brief Summary of Full Prescribing Information

WARNING: PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY TYSABRI increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI [see Warnings and Precautions (5.1)].

• Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing shouldbe withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadoliniumenhancedmagnetic enhanced magnetic resonance resonance imaging imaging (MRI) (MRI) scan scan ofof the the brain brain and, and, when when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended [see Contraindications (4), Warnings and Precautions (5.1)].

• Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH® Prescribing Program [see Warnings and Precautions (5.2)].

1.

INDICATIONS AND USAGE

1.1. Multiple Sclerosis (MS) TYSABRI is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. See important information regarding the risk of PML with TYSABRI [see Warnings and Precautions (5.1)].

2.

DOSAGE AND ADMINISTRATION

2.1. Multiple Sclerosis (MS) Only prescribers registered in the MS TOUCH® Prescribing Program may prescribe TYSABRI for multiple sclerosis [see Warnings and Precautions (5.2)]. The recommended dose of TYSABRI for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks.

2.3. Dilution Instructions 1. Use aseptic technique when preparing TYSABRI solution for intravenous infusion. Each vial is intended for single use only. Discard any unused portion.

2. TYSABRI is a colorless, clear to slightly opalescent solution. Inspect the TYSABRI vial for particulate material and discoloration prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used.

3. To prepare the diluted solution, withdraw 15 mL of TYSABRI from the vial using a sterile needle and syringe. Inject TYSABRI into 100 mL of 0.9% Sodium Chloride Injection, USP. No other intravenous diluents may be used to prepare the TYSABRI diluted solution.

4. Gently invert the TYSABRI diluted solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration.

5. The final dosage diluted solution has a concentration of 2.6 mg/mL. 6. Following dilution, infuse TYSABRI solution immediately, or refrigerate the diluted solution at 2°C to 8°C, and use within 8 hours. If stored at 2°C to 8°C, allow the diluted solution to warm to room temperature prior to infusion. DO NOT FREEZE. 2.4. Administration Instructions • Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one hour (infusion rate approximately 5 mg per minute). Do not administer TYSABRI as an intravenous push or bolus injection. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP. • Observe patients during the infusion and for one hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction [see Warnings and Precautions (5.5)].

• Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with TYSABRI. 3.

DOSAGE FORMS AND STRENGTHS Injection: 300 mg/15 mL (20 mg/mL) colorless and clear to slightly opalescent solution in a single-dose vial for dilution prior to infusion.

4.

CONTRAINDICATIONS

• TYSABRI is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [see Warnings and Precautions (5.1)].

• TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI. Observed reactions range from urticaria to anaphylaxis [see Warnings and Precautions (5.5)].

5.

WARNINGS AND PRECAUTIONS

5.1. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), 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, has occurred in patients who have received TYSABRI. Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been identified: • Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 6 years of TYSABRI treatment.

• Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil).

• The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI.

Anti-JCV Antibody Positive Anti-JCV Antibody Negative

TYSABRI Exposure†

No Prior Immunosuppressant Use

1-24 months

<1/1,000

1/1,000

<1/1,000

25-48 months

3/1,000

12/1,000

49-72 months

6/1,000

13/1,000

Prior Immunosuppressant Use

Notes: The risk estimates are based on postmarketing data in the United States from approximately 69,000 TYSABRI exposed patients. †Data beyond 6 years of treatment are limited.

The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA)that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with an analytical false negative rate of 3%.

Retrospective analyses of postmarketing data from various sources, including observational studies and spontaneous reports obtained worldwide, suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value).

Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with TYSABRI. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients’ serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. After plasma exchange, wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results.

Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom suggestive of PML. 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. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold TYSABRI dosing immediately and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML. 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. 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. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation 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 TYSABRI or due to differences in disease in these patients.

There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs. PML has been reported following discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of TYSABRI. Because of the risk of PML, TYSABRI is available only under a restricted distribution program, the TOUCH® Prescribing Program.

In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYSABRI. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML. For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold TYSABRI dosing, and repeat the evaluations.

There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in TYSABRI treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation.

JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy [JCV GCN]) has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly to PML. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient’s condition after TYSABRI removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing

treatment with TYSABRI for reasons unrelated to PML. In TYSABRI treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

5.2. TYSABRI TOUCH® Prescribing Program TYSABRI is available only through a restricted program under a REMS called the TOUCH® Prescribing Program because of the risk of PML [see Warnings and Precautions (5.1)].

For prescribers and patients, the TOUCH® Prescribing Program has two components: MS TOUCH® (for patients with multiple sclerosis) and CD TOUCH® (for patients with Crohn’s disease).

Selected requirements of the TOUCH® Prescribing Program include the following: • Prescribers must be certified and comply with the following: – Review the TOUCH® Prescribing Program prescriber educational materials, including the full prescribing information.

– Educate patients on the benefits and risks of treatment with TYSABRI, ensure that patients receive the Medication Guide, and encourage them to ask questions.

– Review, complete, and sign the Patient-Prescriber Enrollment Form.

– Evaluate patients three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing TYSABRI. – Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months.

– Submit to Biogen the “TYSABRI Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter.

– Complete an “Initial Discontinuation Questionnaire” when TYSABRI is discontinued, and a “6-Month Discontinuation Questionnaire” following discontinuation of TYSABRI. – Report cases of PML, hospitalizations due to opportunistic infections, and deaths to Biogen at 1-800-456-2255 as soon as possible.

• Patients must be enrolled in the TOUCH® Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI, and complete and sign the Patient-Prescriber Enrollment Form.

• Pharmacies and infusion centers must be specially certified to dispense or infuse TYSABRI. 5.3. Herpes Infections Herpes Encephalitis and Meningitis TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with TYSABRI prior to onset ranged from a few months to several years. Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Acute Retinal Necrosis Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g., varicella zoster, herpes simplex virus). A higher risk of ARN has been observed in patients being administered TYSABRI. Patients presenting with eye symptoms, including decreased visual acuity, redness, or eye pain, should be referred for retinal screening for ARN. Some ARN cases occurred in patients with central nervous system (CNS) herpes infections (e.g., herpes meningitis or encephalitis).

Serious cases of ARN led to blindness of one or both eyes in some patients. Following clinical diagnosis of ARN, consider discontinuation of TYSABRI. The treatment reported in ARN cases included anti-viral therapy and, in some cases, surgery.

5.4. Hepatotoxicity Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with TYSABRI in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients.

TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

5.5. Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis), which occurred at an incidence of <1%. These reactions usually occur within two hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to TYSABRI. If a hypersensitivity reaction occurs, discontinue administration of TYSABRI, and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI. Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared to patients who did not develop antibodies to TYSABRI in both MS and CD studies. Therefore, the possibility of antibodies to TYSABRI should be considered in patients who have hypersensitivity reactions [see Adverse Reactions (6.2)].

Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be transient and may disappear with continued dosing. It is recommended that testing be repeated three months after an initial positive result to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of TYSABRI in a patient with persistent antibodies.

Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to TYSABRI experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to TYSABRI naïve patients [see Adverse Reactions (6.2)].

5.6. Immunosuppression/Infections The immune system effects of TYSABRI may increase the risk for infections. In Study MS1 [see Clinical Studies (14.1)], certain types of infections, including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections, occurred more often in TYSABRI-treated patients than in placebo-treated patients [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1.

In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids.

In a long-term safety study of patients treated with TYSABRI for multiple sclerosis, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients.

In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of TYSABRI-treated patients; some of these patients were receiving concurrent immunosuppressants [see Warnings and Precautions (5.1), Adverse Reactions (6.1)].

In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and TYSABRI-treated patients who received steroids.

Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of TYSABRI alone [see Warnings and Precautions (5.1), Adverse Reactions (6.1)]. The safety and efficacy of TYSABRI in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with TYSABRI. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving TYSABRI [see Warnings and Precautions (5.1)].

5.7. Laboratory Test Abnormalities In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose.

Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient.

5.8. Immunizations No data are available on the effects of vaccination in patients receiving TYSABRI. No data are available on the secondary transmission of infection by live vaccines in patients receiving TYSABRI. 6.

ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: • Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions (5.1)] • Herpes Infections [see Warnings and Precautions (5.3)] • Hepatotoxicity [see Warnings and Precautions (5.4)] • Hypersensitivity/Antibody Formation [see Warnings and Precautions (5.5)] • Immunosuppression/Infections [see Warnings and Precautions (5.6)] 6.1. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn’s disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract infections and nausea.

The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of TYSABRI) in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn’s disease (4.2%) and acute hypersensitivity reactions (1.5%) [see Warnings and Precautions (5.5)].

A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI, with a median duration of exposure of 28 months. A total of 1563 patients received TYSABRI in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment.

Multiple Sclerosis Clinical Studies The most common serious adverse reactions in Study MS1 [see Clinical Studies (14.1)] with TYSABRI were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity reactions (1.1% versus 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% versus 0.3%). In Study MS2, serious adverse reactions of appendicitis were also more common in patients who received TYSABRI (0.8% versus 0.2% in placebo).

Table 2 enumerates adverse reactions and selected laboratory abnormalities that occurred in Study MS1 at an incidence of at least 1 percentage point higher in TYSABRI-treated patients than was observed in placebo-treated patients.

Table 2:

Table 3:

Adverse Reactions in Study MS1 (Monotherapy Study) Adverse Reactions (Preferred Term)

TYSABRI n=627 %

Placebo n=312 %

General Headache Fatigue Arthralgia Chest discomfort Other hypersensitivity reactions** Acute hypersensitivity reactions** Seasonal allergy Rigors Weight increased Weight decreased

38 27 19 5 5 4 3 3 2 2

33 21 14 3 2 <1 2 <1 <1 <1

Infection Urinary tract infection Lower respiratory tract infection Gastroenteritis Vaginitis* Tooth infections Herpes Tonsillitis

21 17 11 10 9 8 7

17 16 9 6 7 7 5

Psychiatric Depression

19

16

Musculoskeletal/Connective Tissue Disorders Pain in extremity Muscle cramp Joint swelling

16 5 2

14 3 1

Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test

11 10 5

10 9 4

Skin Rash Dermatitis Pruritus Night sweats

12 7 4 1

9 4 2 0

Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst

5 3 2 2

4 <1 1 <1

Neurologic Disorders Vertigo Somnolence

6 2

5 <1

Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence

9 4

7 3

Injury Limb injury NOS Skin laceration Thermal burn

3 2 1

2 <1 <1

* Percentage based on female patients only. ** Acute versus other hypersensitivity reactions are defined as occurring within 2 hours post-infusion versus more than 2 hours.

In Study MS2, peripheral edema was more common in patients who received TYSABRI (5% versus 1% in placebo).

Infections Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received TYSABRI in clinical trials [see Warnings and Precautions (5.1)]. Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These two patients had received TYSABRI in addition to interferon beta-1a [see Warnings and Precautions (5.1)]. The third case occurred after eight doses in one of the 1043 patients with Crohnâ&#x20AC;&#x2122;s disease who were evaluated for PML. In the postmarketing setting, additional cases of PML have been reported in TYSABRI-treated multiple sclerosis and Crohnâ&#x20AC;&#x2122;s disease patients who were not receiving concomitant immunomodulatory therapy.

In Studies MS1 and MS2 [see Clinical Studies (14.1)], the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections. In Study MS1, the incidence of serious infection was approximately 3% in TYSABRI-treated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In Studies CD1 and CD2 [see Clinical Studies (14.2)], the rate of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and 1.4 per patient-year in placebo-treated patients. In Study CD3, the incidence of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt TYSABRI therapy during infections, and recovery occurred with appropriate treatment. Concurrent use of TYSABRI in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall

Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse Reactions*

TYSABRI n=983 %

Placebo n=431 %

General Headache Fatigue Arthralgia Influenza-like illness Acute hypersensitivity reactions Tremor

32 10 8 5 2 1

23 8 6 4 <1 <1

Infection Upper respiratory tract infection Vaginal infections** Viral infection Urinary tract infection

22 4 3 3

16 2 2 1

6 3

4 <1

17 5 4 3 2

15 3 2 2 <1

Skin Rash Dry skin

6 1

4 0

Menstrual Disorder Dysmenorrhea**

2

<1

Respiratory Pharyngolaryngeal pain Cough Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis

* Occurred at an incidence of at least 1% higher in TYSABRI-treated patients than placebo-treated patients. ** Percentage based on female patients only.

Table 4:

Adverse Reactions in Study CD3 (Maintenance Study)

Adverse Reactions*

TYSABRI n=214 %

Placebo n=214 %

General Headache Influenza-like illness Peripheral edema Toothache

37 11 6 4

31 6 3 <1

Infection Influenza Sinusitis Vaginal infections** Viral infection

12 8 8 7

5 4 <1 3

Respiratory Cough

7

5

Gastrointestinal Lower abdominal pain

4

2

12

8

6

3

Musculoskeletal and Connective Tissue Back pain Menstrual Disorder Dysmenorrhea**

* Occurred at an incidence of at least 2% higher in TYSABRI-treated patients than placebo-treated patients. ** Percentage based on female patients only. infections compared to TYSABRI alone; however, the concomitant use of such agents could lead to an increased risk of serious infections.

In Studies CD1 and CD2, the incidence of serious infection was approximately 2.1% in both TYSABRItreated patients and placebo-treated patients. In Study CD3, the incidence of serious infection was approximately 3.3% in TYSABRI-treated patients and approximately 2.8% in placebo-treated patients.

In clinical studies for CD, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of TYSABRI-treated patients; some of these patients were receiving concurrent immunosuppressants [see Warnings and Precautions (5.6)]. Two serious non-bacterial meningitides occurred in TYSABRI-treated patients compared to none in placebo-treated patients.

Infusion-related Reactions An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of TYSABRI-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with TYSABRI compared to 7% of placebo-treated patients. Reactions more common in the TYSABRI-treated MS patients compared to the placebo-treated MS patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving TYSABRI. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients [see Warnings and Precautions (5.5)]. All patients recovered with treatment and/or discontinuation of the infusion.

Infusion-related reactions that were more common in CD patients receiving TYSABRI than those receiving placebo included headache, nausea, urticaria, pruritus, and flushing. Serious infusion reactions occurred in Studies CD1, CD2, and CD3 at an incidence of <1% in TYSABRI-treated patients.

MS and CD patients who became persistently positive for antibodies to TYSABRI were more likely to have an infusion-related reaction than those who were antibody-negative.

6.2. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation 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 natalizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

Patients in Study MS1 [see Clinical Studies (14.1)] were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab.

Approximately 9% of patients receiving TYSABRI developed detectable antibodies at least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks.

Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels.

In Study MS1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 15 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibodypositivity resulted in a substantial decrease in the effectiveness of TYSABRI. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI-treated patients and patients who received placebo. A similar phenomenon was also observed in Study MS2.

Infusion-related reactions that were most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia.

Additional adverse reactions more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.

Patients in CD studies [see Clinical Studies (14.2)] were first tested for antibodies at Week 12, and in a substantial proportion of patients, this was the only test performed given the 12-week duration of placebocontrolled studies. Approximately 10% of patients were found to have anti-natalizumab antibodies on at least one occasion. Five percent (5%) of patients had positive antibodies on more than one occasion.

Persistent antibodies resulted in reduced efficacy and an increase in infusion-related reactions with symptoms that include urticaria, pruritus, nausea, flushing, and dyspnea.

The long-term immunogenicity of TYSABRI and the effects of low to moderate levels of antibody to natalizumab are unknown [see Warnings and Precautions (5.5), Adverse Reactions (6.1)].

6.3. Postmarketing Experience The following adverse reactions have been identified during post approval use of TYSABRI. 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.

Blood disorders: hemolytic anemia 8.

USE IN SPECIFIC POPULATIONS

8.1.

Pregnancy

Risk Summary There are no adequate data on the developmental risk associated with the use of TYSABRI in pregnant women. In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals [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 developmental toxicity studies conducted in guinea pigs and monkeys, at natalizumab doses up to 30 mg/kg (7 times the recommended human dose based on body weight [mg/kg]), transplacental transfer and in utero exposure of the embryo/fetus was demonstrated in both species.

In a study in which pregnant guinea pigs were administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days throughout organogenesis (gestation days [GD] 4-30), no effects on embryofetal development were observed.

When pregnant monkeys were administered natalizumab (0, 3, 10, or 30 mg/kg) by IV infusion on alternative days throughout organogenesis (GDs 20-70), serum levels in fetuses at delivery were approximately 35% of maternal serum natalizumab levels. There were no effects on embryofetal development; however, natalizumabrelated immunological and hematologic changes were observed in the fetuses at the two highest doses. These changes included decreases in lymphocytes (CD3+ and CD20+), changes in lymphocyte subpopulation percentages, mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis.

In a study in which monkeys were exposed to natalizumab during pregnancy (IV infusion of 30 mg/kg) on alternate days from GD20 to GD70 or GD20 to term, abortions were increased approximately 2-fold compared to controls. In offspring born to mothers administered natalizumab on alternate days from GD20 until delivery, hematologic effects (decreased lymphocyte and platelet counts) were also observed.

These effects were reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and during lactation had a normal immune response to challenge with a T-cell dependent antigen.

In a study in which pregnant guinea pigs were exposed to natalizumab (30 mg/kg IV) on alternate dates during GDs 30-64, a reduction in pup survival was observed.

8.2.

Lactation

Risk Summary Natalizumab has been detected in human milk. There are no data on the effects of this exposure on the breastfed infant or the effects of the drug on milk production.

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

8.4. Pediatric Use Safety and effectiveness in pediatric patients with multiple sclerosis or Crohn’s disease below the age of 18 years have not been established. TYSABRI is not indicated for use in pediatric patients.

8.5. Geriatric Use Clinical studies of TYSABRI did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

General Counseling Information Counsel patients to understand the risks and benefits of TYSABRI before an initial prescription is written.

The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber’s direction. INSTRUCT PATIENTS USING TYSABRI TO: • Read the Medication Guide before starting TYSABRI and before each TYSABRI infusion.

• Promptly report any new or continuously worsening symptoms that persist over several days to their prescriber [see Warnings and Precautions (5.1)].

• Inform all of their physicians that they are receiving TYSABRI. • Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing TYSABRI. Progressive Multifocal Leukoencephalopathy Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received TYSABRI. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct 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. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months.

Instruct patients to continue to look for new signs and symptoms suggestive of PML for approximately 6 months following discontinuation of TYSABRI [see Warnings and Precautions (5.1)].

TYSABRI TOUCH® Prescribing Program Advise the patient that TYSABRI is only available through a restricted program called the TOUCH® Prescribing Program. Inform the patient of the following requirements: Patients must read the Medication Guide and sign the Patient Prescriber Enrollment Form. Advise patients that TYSABRI is available only from certified pharmacies and infusion centers participating in the program [see Warnings and Precautions (5.2)].

Herpes Infections Inform patients that TYSABRI increases the risk of developing encephalitis, and meningitis, which could be fatal, and acute retinal necrosis, which could lead to blindness, caused by the family of herpes viruses (e.g., herpes simplex and varicella zoster viruses). Instruct patients to immediately report any possible symptoms of encephalitis and meningitis (such as fever, headache, and confusion) or acute retinal necrosis (such as decreased visual acuity, eye redness, or eye pain) [see Warnings and Precautions (5.3)].

Hepatotoxicity Inform patients that TYSABRI may cause liver injury. Instruct patients treated with TYSABRI to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of TYSABRI [see Warnings and Precautions (5.5)].

Immunosuppression/Infections Inform patients that TYSABRI may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection [see Warnings and Precautions (5.6)].

Full Prescribing Information is available at TYSABRIhcp.com.

TYSABRI (natalizumab) Manufactured by: Biogen Inc. Cambridge, MA 02142 USA US License No. 1697 1-800-456-2255 © 2015-2018 Biogen Inc. All rights reserved.

09/2018 U.S. Patent Numbers: 5,840,299; 6,602,503

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Assistant/Associate Professor of Neurology at CUMC The Department of Neurology at Columbia University is seeking a full-time neurologist at the assistant/associate level for the Eleanor and Lou Gehrig ALS Center in our Neuromuscular Medicine Division. This position will support the clinical work in the Center and the Division, and expand its basic, translational and/or clinical research activities. The candidate will have clinical expertise in ALS care, and with neuromuscular disease patients generally.

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Assistant Professor of Neurology at CUMC The Department of Neurology at Columbia University Irving Medical Center seeks a full-time neurologist specialized in the area of clinical neuroimmunology/multiple sclerosis.

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Cognitive/Behavioral Neurologist Inova Neuroscience and Spine Institute is part of the Inova Health System and a regional leader in the diagnosis, treatment and research of complex neurological conditions involving the brain, spine and nervous system. From its hub at Inova Fairfax Hospital, the Institute also encompasses specialized programs at Inova Alexandria Hospital, Inova Fair Oaks Hospital, Inova Loudoun Hospital and Inova Mount Vernon Hospital. With a network of five hospitals and more than 14,000 neuroscience patients treated annually, Inova Neuroscience and Spine Institute is the largest program of its kind in Northern Virginia and one of the most comprehensive within the mid-Atlantic region.

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practice also offers in-office testing for a wide range of neurological and sleep disorders. Inova is a not-for-profit healthcare system based in Northern Virginia that serves more than 2 million people each year from throughout the Washington, DC, metro area and beyond. Inova is a comprehensive network of hospitals, outpatient services and facilities, primary and specialty care practices, and health and wellness initiatives. Full time position with compensation package that includes medical, dental, vision and life insurance, paid time off, CME reimbursement, as well as defined contribution retirement plans. Contact: allison.spindle@inova.org Assistant or Associate Professor, Department of Neurology, New York University School of Medicine The Department of Neurology at NYU Langone Health, a world-class, patient-centered integrated academic medical center, has an exciting opportunity to join our team as an Assistant or Associate Professor on the tenure-eligible or non-tenure academic track at the NYU Multiple Sclerosis Comprehensive Care Center. The successful candidate will join a vibrant team of neurologists, psychiatrists, neuropsychologists, nurse practitioners, and nurses specializing in multiple sclerosis, neuromyelitis optica spectrum disorder, and other immune-mediated central nervous system disorders. The Center conducts studies supported by National Institutes of Health and other federal funding agencies, National Multiple Sclerosis Society, private foundations and participates in many clinical trials and investigator-initiated research supported by industry.

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